Vitality, Medicine & Engineering Journal

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1. Brain Watch Coalition of the Campaign to Prevent Alzheimer’s Disease, Rockville, Maryland, United States of America; 2. Campaign to Prevent Alzheimer’s Disease, Potomac, Maryland, United States of America; 3. International Neurodegenerative Disease Research Center, International Neurodegenerative Disorders Research Center, Prague, Czech Republic; 4. University of Las Vegas, Nevada, National Supercomputing Institute & Dedicated Research Network, Las Vegas, Nevada, United States of America

Corresponding to:  Ara S. Khachaturian, 9812 Falls Road Suite 114-155, Potomac, MD 20854-3963, Email:,,

VM&E 2023;6:17-22
Published online October 27, 2023;



The grand challenge for healthcare systems worldwide is the escalating costs of prolonged care for older people with various chronic disabling disorders. Among these protracted brain incapacitating conditions, progressive deterioration of cognitive functions, different types of dementia, and Alzheimer’s syndrome profoundly impact quality of life, economic and psycho-social, and burdens of family caregivers. This report provides an overview of the deliberations at a think-tank workshop organized by PAD2020 before the AAIC 2022 in July 2022. The participants of this forum included leading experts representing government, academia, industry, and the philanthropic sector. The overarching aim for convening this workgroup (WG) was to seek suggestions for a potential global action plan, a comprehensive public health initiative, aiming for a significant reduction in the incidence of cognitive impairment or dementia-Alzheimer syndrome. The future aim of this undertaking (specifically, the pending task of this WG) is to develop a roadmap for a coordinated large-scale effort to demonstrate the putative efficacy of reducing risks for cognitive impairment/dementia-Alzheimer syndrome via existing interventions for modifiable risks of vascular-metabolic disorders. The primary rationale for such global action plans is that a practical, broad-scale approach to this growing public health crisis problem will substantially reduce the demand and cost for prolonged personalized care of people with dementia. The proposed initiative will require a greater focus on research and investments in therapeutic strategies to delay the onset of cognitive impairment and reduce dementia-related morbidity. Such an approach would emphasize addressing modifiable risks for dementia with affordable, accessible interventions that target modifiable risks for vascular and metabolic disorders likely to result in the most tremendous success.

Keywords: Healthcare systems, chronic disorders, personal autonomy, dementia, Alzheimer’s disease, pragmatic trials, randomized group design, vascular-metabolic disorders, health equity, population public health.


Introduction and Context

Although the aspiration for a world without dementia-Alzheimer syndrome1 is the ultimate long-range goal of public health services worldwide, a more pragmatic near-term objective is the development-validation of wide-ranging interventions to delay or prevent disabilities and chronic brain disorders such as dementia.

1. In this perspective paper, dementia-Alzheimer syndrome is used as an umbrella term, a convenient proxy, for discussing a spectrum of chronic brain disorders that require prolonged, costly, and personalized care. Dementia, in various forms, is the prototype for a class of disabilities that have a profound economic impact on healthcare systems and extremely burdensome psychosocial ramifications for family caregivers. These unremitting brain conditions’ most common clinical features include a) progressive functional impairments of cognition, motor skills, and affect and b) advancing function deterioration that eventually leads to total dependence on labor-intense care to sustain life. Due to increasing lifespan, the average period of disability associated with these chronic conditions is gradually being prolonged. For example, at-risk individuals now face the prospects of nearly 30–40 years of disability related to a) total dependence on personal care, b) increasing economic burden, and c) deteriorating quality of life, especially those people who are destined to survive beyond the ninth or tenth decade of life.


The primary premise for the initial formulation of a prospective public policy to promote prevention in 1992 was that delaying the onset of disabling symptoms of dementia would substantially reduce its prevalence. This proposal for new program initiatives at the NIA/NIH asserted that even a modest delay of five years in the onset of disabling symptoms would cut by nearly 50% both the number of people with dementia and the related costs of care (1, 2).
Considering burgeoning psycho-social burdens and escalating costs of long-term care, the rationale for a wide-ranging global effort on prevention, precisely the public health initiatives for reducing risks and disabilities associated with chronic brain disorders, has become particularly compelling (3, 4). Even though the benefits of such notions as prevention or delaying the onset of cognitive impairment or reducing prevalence are widely acknowledged, these vital public health goals have remained abstract targets, needing more specific roadmap(s) to attain them.
To address the need for an actionable comprehensive plan, PAD2020 convened an international forum5 at the AAIC 2022 in July 2022 on the issue of prevention of dementia by treating vascular and metabolic disorders (5).
The participants of this think-tank style workshop were tasked to assess the challenges for the launch of a potential demonstration project(s) to test whether any of the readily available medications for a range of vascular-metabolic disorders might offer pragmatic public-health measures for reducing risks of cognitive impairment or delaying the onset of dementia.
This paper is the interim report on the outcome of the PAD2020 workshop. It is a work-in-progress towards a final perspective paper that will critically analyze the vital perquisites for a potential comprehensive, collaborative project to reduce the risks for cognitive impairment and dementia, along with recommendations for a global action plan.
The present summary of the AAIC’22 think-tank proceeding outlines the major issues, challenges, and obstacles such a large-scale undertaking must address. Most importantly, it provides a brief overview of the pending tasks for future expert panels of the PAD2020 Workgroup to consider the array of open questions or issues to be resolved in a prospective collaborative project to demonstrate the effectiveness of a program to reduce risks for dementia via interventions for vascular-metabolic disorders; specifically, repurposing readily available medications for these conditions. Here, we cover some of the significant issues considered by the PAD2020 Workgroup (WG).


Why focus on the role of vascular-metabolic factors in dementia?

Although the putative role of vascular factors (specifically, hardening of arteries) was one of the earliest conventional wisdom on the origins of senile dementia and an enduring controversy due to the lack of systematic research to substantiate this longstanding theory. Now, at long last, evidence from different types of research is converging to provide compelling mechanistic explanations for the links between early risks or upstream changes in the structure-function of cerebral microvasculature and downstream loss of synaptic connectivity, cognitive impairment, and dementia-Alzheimer syndrome.
The emerging story about functional relationships of vascular-metabolic factors and clinical manifestations of dementia-Alzheimer syndrome, for example, cognitive impairment, is persuasive due to the triangulation of findings from research that include not only human studies (for example, / clinical observations/population-based longitudinal epidemiology) but also animal research (for example, neurobiology-neurophysiology/and molecular-genetics) (6-8).
In short, converging data now provide compelling support for the proposition that disruption in neuronal energetics (specifically, metabolic variables), mediated by structural-functional changes in the brain vasculature, plays a vital role in cognitive impairment, neurodegeneration, and dementia-Alzheimer syndrome. Therefore, vascular-metabolic factors represent feasible targets for preventive intervention and a promising area for future therapy development for various forms of other chronic brain disorders in aging.
The discussion among the WG covers several lines of evidence that provide solid arguments for the vital role of vascular-metabolic factors in dementia, for example:
• Epidemiological findings increasingly suggest that various forms of vascular-metabolic disorders are among the most consistent precursors or comorbid factors that affect cognitive health, particularly for older adults. Virtually all forms of dementia have some vascular component, ranging from 61% in FTD to 82% in AD. Nearly 25% of aging populations have the hallmark AD pathology yet do not have symptoms of dementia. In older people with vascular pathology, the risk for cognitive impairment or dementia is doubled (9, 10).
• Since the 1980s, many prospective longitudinal studies have demonstrated a causal relationship between hypertension and the incidence of Alzheimer’s disease (AD) and vascular cognitive impairment (11). Hypertension-induced vascular abnormalities, which are particularly widespread in older adults, can lead to the development of atherosclerotic plaques in cerebral arteries that a) interfere with normal cerebral blood flow, b) compromise the structural-functional integrity of the cerebral microcirculation, and c) increase the risk for stroke and other life-threatening medical conditions (12). Approximately two-thirds of adults 60 years of age and older have hypertension, which currently is defined as systolic blood pressure (SBP) ≥ 140 mmHg and diastolic blood pressure (DBP) ≥ 90 mmHg)2. The prevalence of elevated blood pressure typically increases with age and currently affects approximately 1 billion individuals worldwide.

2. Note: The official definition in the US may now differ (based on SPRINT findings) from the official international cutoff, which is still 140/90—see AHA definition:


• Emerging evidence has now begun to pinpoint the mechanistic links between genetic-molecular variables that influence vascular physiology, specifically, changes in the intricate brain-perfusion system. Recent advances in isolating cerebrovascular cells and the technology of single-nucleus RNA sequencing analysis have enabled the study of how the complex vasculature of the brain deteriorates during dementia-Alzheimer syndrome (13). Sun et al. have uncovered nearly 2,700 differentially expressed (dysregulated) genes in vascular cells taken from six brain regions of 220 people with AD. In APOE ε4 carriers, the cells expressed yet different transcriptomes (14). They have identified 11 subtypes of neurovascular cells and 125 genes linked to AD risk variants. In the neurovascular cells, the ramped-up genes are involved in the immune response and suppressed in those needed to maintain blood-brain barrier integrity. Overall, this study provides further credence to the need for future studies to focus on systematic investigation of vascular contribution to cognitive impairment and dementia-Alzheimer. This study explains how upstream variables might control differential genes, associate with the expression of dementia, and stress the dynamics of cell-cell communication in the neurovascular cells. The insights gained from this study may lead to a more manageable selection of therapeutic targets in the future. Lastly, these new insights should be thoroughly investigated to investigate the causal relationship further.
• The vascular component of dementia is the only known aspect that can be treated and potentially prevented. Additionally, a vascular element increases the chances of developing dementia. Thus, it is essential to detect and prevent vascular pathology to delay, mitigate, or potentially prevent several types of dementia. For instance, nearly 80% of strokes can be prevented, and there are already potential interventions that can guide stroke prevention efforts through demonstration projects, at least as a starting point (8, 12).
• Interventions and medications for various vascular and metabolic conditions are widely available at reasonable costs (15, 16). These might be good candidates for re-purposing and may be used successfully to delay dementia. However, it will be essential to identify other drugs that may be good candidates.


Why comingle vascular and metabolic factors?

In this paper, the umbrella constructs of vascular and metabolic factors fuse into a single entity to propose a future demonstration study to determine whether available medications for a wide range of vascular-metabolic conditions disorders might reduce the risks of cognitive impairment or delay the onset of dementia. The term terms vascular factors are intended to include all circulatory system conditions that affect the efficiency of brain perfusion (for example, small vessel disease, BBB, stroke, CVD, CoV, etc.). Likewise, the term metabolic factor is meant to include various upstream variables or physiological mechanisms that affect or disrupt neurons’ need for a constant supply of energy (for example, ATP production, glucose transporter deficiencies, insulin resistance, diabetes, nutrition-diet, obesity, hypertension, and dyslipidemia, etc.).
The conceptual framework for linking these broadly defined constructs of vascular and metabolic factors into a unitary continuum is discussed in the Berlin Manifesto by Hachinski et al. (7, 8), where the authors outline the mechanistic details for the chain of physiological processes triggered by various upstream variables or pathologies that affect the efficiency of brain perfusion or produce multiple levels and duration of decrements in neuronal energy supply (for example, BBB, small vessel disease, mitochondrial dysfunction, deficiencies in glucose-transporter proteins, hypoperfusion due to mineralization vessel walls or some other micro-vessel pathology, etc.)
Although this conceptual model can accommodate several alternative upstream variables leading to loss of connectivity, for a future demonstration project, the emphasis is on variables that affect brain energetics, specifically, alternative paths that influence metabolic, a constant supply of energy (for example, glucose), which is a requirement for peak performance of a neuron and maintaining synaptic resilience.
So, the reason for combining the umbrella constructs of vascular and metabolic factors into a single entity is that even though the initial trigger for the chain of events leading to synaptic dysfunction may start as a vascular event, its effects on neuronal performance are mediated by metabolic factors, the final common path to neurodegeneration.
Although the details of the mechanical relationships among various pathologies associated with metabolic disorders/syndrome3 have not yet been fully established, insulin resistance is a core underlying cause of most metabolic and vascular disorders, including hypertension and cardiovascular disease. It is a significant risk for AD and other dementias, including vascular dementia. Insulin resistance, a causal factor in most cases of adult-onset or type 2 diabetes mellitus, may cause only mild glucose intolerance for many years before the onset of diabetes.

3. Metabolic disorders/syndrome is defined as the co-occurrence of hypertension, diabetes, obesity, and dyslipidemia ( Craft 2009, Cornier 2008, REFs). (Pathogenic connection between hypertension and type 2 diabetes: how do they mutually affect each other? | Hypertension Research (


What are the essential steps for the launch of a potential collaborative project?

The wide-ranging discussion of the PAD2020 WG provided the panoramic picture of earlier studies’ successes, failures, and limitations on the association between vascular-metabolic conditions and neurodegenerative disorders. These conversations revealed the rich available data from ongoing efforts on this topic and the diversity of perspectives on framing the problem. They also exposed the consensus in this field about the timeliness and the need for a comprehensive global effort to demonstrate–whether widely prescribed medications for various vascular-metabolic disorders may reduce the risk of cognitive impairment and dementia-Alzheimer syndrome.
Here, we outline the major unresolved issues considered by the participants of the PAD2020 WG at the AAIC’22 think-tank workshop regarding the question of ideas on how to proceed toward creating a federated consortium. The deliberation of the WH covers some of the important unresolved issues along with the list of potential tasks that a subset of WG members with appropriate expertise or interests might undertake.
So, to move on to the next phase of this project, the plan calls for assembling several (virtual) issue-specific panels (sub-groups of the current WG) to prepare brief (500-1000 word) specific, actionable recommendations regarding the next steps necessary for further planning of proposed global initiative such as a collaborative demonstration project on the efficacy for maintaining brain health via widely prescribed medications4 for various vascular-metabolic disorders.

4. The primary goal is to accelerate the process of developing preventive interventions that are safe, effective, and readily available at low cost via repurposing existing medication in contrast to traditional approaches to demonstrate the efficacy of de novo agents.


The list of future WG tasks regarding open questions that will require further elaboration by one or more of the newly reconstituted expert panels is summarized below, followed by a more detailed discussion on some of the key unresolved issues.


Summary of open questions & potential topics-tasks for further consideration

1. How do we frame this essential question/problem?
2. How can the proposed demonstration project articulate a simple and unambiguous long-range public health objective, such as reducing the risk of cognitive impairment by 20% within ten years in populations with greater incidence-vulnerability for vascular conditions?
3. A clear consensus statement of specific aims for a potential pilot/demonstration project, for example, to show feasibility or test the hypothesis that widely prescribed medications for various vascular disorders that are safe, effective, and readily available at low cost may delay the onset of cognitive impairments.
4. Need to:
• Distinguish prospective interventions aim to treat a vascular-metabolic disorder, cognitive impairment, or dementia-Alzheimer syndrome.
• Clarify the distinction between the constructs of treatment, which is applied to an existing condition after it has already started, and the notion of intervention, which may include therapy, is a broader concept intended to block or delay the onset of the condition; it also encompasses non-pharmacological approaches (for example, lifestyle, etc.) to alter the course of the condition?
• Clarify the discrepancy between the intervention’s clinical aims and the treatment medium. For example, to illustrate the need for clarification, assume the ultimate target for intervention is to delay or prevent cognitive decline and the medium is a treatment for hypertension or some other vascular-metabolic condition. In such a scenario, a particular medication may not effectively treat hypertension, yet it is a viable intervention to delay cognitive impairment (15).

5. Criteria-rationale for selection (inclusion-exclusion) of study subjects/cohorts/populations for testing (for example, population with greater incidence-vulnerability or some other well-characterized cohorts-subject).
6. The impact (specifically, the study design) of selective vulnerability in some populations (with disproportionately higher incidence and prevalence of vascular/metabolic comorbidities) on the heterogeneity and complexity of the global problem (17, 18).
7. How to take advantage of ongoing projects and get the most out of well-established resources and databases; recommendations for specific steps to link or coordinate the prospective global initiative to add value to these longstanding related projects.
8. Among the several approaches to explore the validity of the assertion that early intervention of various vascular-metabolic system-related dysfunctions will reduce the risk or delay cognitive impairment, the WG should assess the merits, limitations, and cost-effectiveness/practicality of multiple approaches to tackle the central question. For example, one option for study design might be a pragmatic clinical trial based on the model of a traditional clinical trial to demonstrate effectiveness. Another possibility is a public health approach using a risk cohort for a population-based prospective longitudinal study on the putative preventive effects of meditation. A third alternative is a data-mining epidemiological study on existing populations/databases to determine the impact of such intervention on the incidence or prevalence of cognitive impairment.
9. Specification of risk, comorbid conditions, upstream variables, etc., for consideration-inclusion.
10. What should be the precise operational definition(s) for a) independent variable(s) (for example, better definition of current for umbrella construct of vascular-metabolic factors/conditions); b) intermediate or mechanistic variables (for example, hypoperfusion due to vascular changes and energy crisis due to reduced energy supply to neurons); and c) dependent variable (for example, specification of clinically meaning outcome(s) such as cognitive functioning/impairment)?
11. What should be the index for the effectiveness of the intervention, a) clinically meaningful outcome (for example, delay in onset, slowing of progression, prevention) and b) public health success (for example, risk reduction, lowering incidence, reducing prevalence) and c) recommendations for instrument(s)-measure(s) to be used?
12. Recommendations are needed regarding the selection of biomarkers for a) early detection-identification of subjects at elevated risk in asymptomatic cohorts; b) monitoring disease progression and tracking drug-effect regarding the effectiveness of the intervention; and c) prognostic use, specifically, a validated surrogate marker that can accurately-precisely predict putative outcome that is clinically meaningful (19).
13. The WG should consider the most promising options among safe, effective, and readily available at low cost for an initial demonstration of effective interventions initially developed for various vascular-metabolic conditions (7, 8). This task should include wider-ranging interventions (beyond medication) to fit lifestyle and behavioral approaches, for example, the FINGER Study (20, 21).
14. There is a need to increase the availability and access to low-cost and effective intervention, particularly in low-middle-income countries, to widen the participation of people at elevated risk or under-served populations (17, 18, 22).
15. How do we build R&D capacity and resources for clinical studies in low-middle-income countries to widen the participation base of people at elevated risk or under-served populations?
16. There is a great need for novel approaches to overcome many of the failures and limitations of earlier studies for example, WGs should pinpoint barriers (psycho-social, resources, etc.) unique to different populations that are preventing adherence to medication/lifestyle changes to lower vascular/dementia risk and (especially on a global scale) to understand better the current sentiment in various populations towards dementia prevention to help design trials, guide policy changes – specifically, beliefs and attitudes towards the connections between dementia risk and certain lifestyle factors? For example, one such prevailing view is that dementia-Alzheimer syndrome is simply a normal part of aging).
17. Evaluate various models for the governance of a global alliance of stakeholders to sponsor such an initiative.


Ethical standards
Ara S. khachaturian is editor-in-chief of Vitality, Medicine & Engineering; he has recused himself from any editorial decision on this manuscript. Dr. Bruno Vellas was responsible for the editorial peer-review process.

PAD2020 Workgroup on: “Prevention of dementia by treating vascular & metabolic disorders”. AAIC 2022 Pre-Conference Workshop. // The think-tank format of the symposium is designed to promote critical analysis and thoughtful discussion by KOLs regarding their assessments and recommendations. // The was convened by Prevent Alzheimer’s Disease 2020 (PAD2020). The steering committee members include Vladimir Hachinski, Bill Potter, Walter Kukull, Ara Khachaturian and Zaven Khachaturian.

Developing strategic solutions to the medical, scientific, economic, and policy challenges related to cognitive impairment in an aging society is the primary mission of Prevent Alzheimer’s Disease 2020 (PAD2020), a Maryland-based non-profit organization established in (___). In recent years we have begun to mobilize (many of the) the scientific and intellectual resources of the neuroscience community with the goal of establishing a scientific consensus on recommendations for (national and global) initiatives that aim to maintain brain health and extend independent functioning among adult populations at risk for dementia. Planning, assembling and coordinating issue-specific workgroups for the purpose of arriving at actionable expert recommendations have been among our core capabilities, along with providing unique scientific forums for exploring solutions to the large global challenge of reducing dementia-related morbidity.



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1. Brain Watch Coalition of the Campaign to Prevent Alzheimer’s Disease, Rockville, Maryland, United States of America; 2. Campaign to Prevent Alzheimer’s Disease, Potomac, Maryland, United States of America; 3. International Neurodegenerative Disease Research Center, International Neurodegenerative Disorders Research Center, Prague, Czech Republic; 4. University of Las Vegas, Nevada, National Supercomputing Institute & Dedicated Research Network, Las Vegas, Nevada, United States of America

Corresponding to: Ara S. Khachaturian, 9812 Falls Road Suite 114-155, Potomac, MD 20854-3963, Email:,,

VM&E 2023;6:4-16
Published online October 27, 2023;



The overarching aim of this perspective paper is to reformulate the calcium hypothesis from the standpoint of systems theory to address the complexity of the calcium signaling system to maintain homeostasis of cytosol calcium ion concentration essential for the optimal functioning of a neuron. The intent is to recast the earlier attempt of the calcium hypothesis to formulate a unifying theory linking brain aging and the dementia-Alzheimer syndrome in terms of a systems failure model1. This re-definition of the problem of the linkages between aging and dementia will encourage the development of novel in silico models and applications of machine learning algorithms and other quantum computing modeling approaches to tackle the complexity of neuronal calcium regulation and, eventually, describe systems failures in brain aging-dementia continuum.

Keywords: Calcium hypothesis, aging, dementia, Alzheimer, systems failure model, complexity, systems theory, in silico model, modeling system, machine learning, artificial intelligence, calcium, signaling, neuron, multiscale.

1. The construct of a system defines a molecular signaling path, or single neuron, or neural circuit, or anatomical structure or an organism.


Introduction, Background and Context

Efforts to find treatments for chronic brain disorders such as the dementia-Alzheimer syndrome2 are imperative, given the growing psycho-social challenges and escalating expenses associated with caring for affected individuals on a global scale. The aim of eradicating the dementia-Alzheimer syndrome from the world is a top priority for public health systems globally. However, there is still no clear path to achieving this goal. Despite significant investments in research for over 40 years, there are only a few effective interventions available to slow down the progression of the disease or delay the onset of cognitive impairment and other disabling symptoms.

2. This paper discusses the concept of the dementia-Alzheimer syndrome, which is used as a broad term to encompass a range of chronic brain disorders that require extensive and personalized care. These disabilities can have a significant impact on healthcare systems and can be emotionally taxing for family caregivers. The common characteristics of these disorders include a decline in cognitive, motor, and emotional function, as well as a gradual loss of independence that necessitates labor-intensive care. With increasing life expectancy, these disabilities are lasting longer, with some individuals facing up to 30-40 years of dependency, economic strain, and reduced quality of life, especially those who live beyond their 9th or 10th decade of life.

One of the main challenges in developing therapies for chronic brain disorders like dementia is the complexity of the neurobiology involved. Another is the lack of a conceptual framework connecting the components and variables involved. These two factors contribute to the difficulty of discovering effective interventions.
Over the past four decades, studies on the dementia-Alzheimer syndrome have uncovered a wealth of information about the aging of the brain and the process of neurodegeneration. However, the field lacks a unifying theory3 that can connect the dots and guide the exploration, testing, and validating of new interventions. Therefore, the calcium hypothesis, which was originally proposed as a potential unifying concept, has been restructured as a set of testable postulates based on system theory. This approach may eventually lead to a comprehensive theory that links aging and neurodegenerative disorders, such as the dementia-Alzheimer syndrome.

3. A theory is the proven statement that represents the culmination one or more hypothesis that are tested under different conditions/experiments. Whereas a hypothesis is the unproven statement that suggests a possible answer for a question.

The task of formulating a comprehensive theory of aging and dementia-Alzheimer syndromic continuum is fraught with several conceptual, scientific, and methodological impediments. Among these the most relevant include the nature of the disease itself (i.e., an ambiguous and shifting definition), the lengthy time course for degenerative processes, the heterogeneity in the phenomenology of the syndrome, the complex interactions among genetic and other risk factors, the poorly understood nonlinear relationships between the neurobiological and the clinical phenotypes, and the paucity of appropriate modeling systems. This paper focuses primarily on a fictional neuron system, and does not address Alzheimer’s, dementia, or any other medical condition. The primary objective is to thoroughly understand and elucidate the complex interplays—at the conceptual level—among different variables and factors that are essential for maintaining optimal functionality of a hypothetical neuron. Once completed, this serves as the fundamental and comprehensive framework for constructing a neural network or circuit. Once finished, this effort will establish an essential framework for developing, testing and updating an all-encompassing blueprint for building a neural network or circuit.
The first attempts to formulate unifying theories on brain aging and Alzheimer’s disease (AD) began in the early 1980s as an integral part of planning and developing a U.S. national research program on brain aging and Alzheimer’s disease at the National Institute of Aging (1). The specific aim of this initial effort, “Towards a theory of brain aging,” was to consolidate existing knowledge and redirect the focus of the prospective research toward more molecular or mechanistic studies; and less emphasis on descriptive studies (2-4). Since then, the knowledge about the aging brain and the neurodegenerative process has proliferated, but unfortunately, this massive amount of information has had only a minor impact on the development of interventions and diagnostics for persons with dementia, especially AD.
Too often, the identification of a promising molecular target or the discovery of a biological marker for AD has failed to translate into an effective intervention or a robustly valid diagnostic. This problem is due partially to the lack of knowledge about the precise functional relationships between clinical features/symptoms and the neurobiological markers/mechanisms. This nonlinear relationship between molecular events and clinical symptoms remains a major challenge for neuroscience, as well as AD research.
Another major obstacle is the lack of tools for effectively managing and sharing knowledge across diverse domains. It is imperative to have a universal vocabulary and methodology to convey the intricate interconnections between molecular, biochemical, or neuronal events and the overall functioning of the brain. Currently, it is a daunting task to precisely describe clinical features, such as cognitive decline, that result from substantial changes in protein structure/function, timing, and sequence of key biological processes. Similarly, it is challenging to identify the specific role of genetic and environmental factors in symptom expression. The development of an integrated theory that links molecular data to disease behaviors and symptoms is an arduous task that is not exclusive to AD or neuroscience research.
The current state of research struggles to comprehend the behavior of complex systems through repetitive analysis of smaller, simpler constituent parts. Even with advanced research instruments, detailed information on molecular sequence-structure-function is unlikely to yield significant answers or insights on the manifestation of AD’s clinical symptoms. Despite knowing the gene for Huntington’s disease for several decades and ongoing clinical trials to maintain functioning early in the disease, this knowledge has yet to produce a curative therapy. In protein chemistry, even detailed information on amino acid sequences or secondary or tertiary protein structures cannot predict function, such as protein-protein interactions.
Prevailing translational theories of Alzheimer’s (AD) pathogenesis presently do not consider adequately the complex relationship between the clinical and biological phenotypic expressions of the resulting dementia. The initial amyloid hypothesis, for example, is based on a conceptual model for early-onset autosomal dominant (familial) AD (FAD). Generalizing this model to sporadic AD requires a major assumption: the etiology and pathogenesis of autosomal dominant illness determined by mutations in the amyloid precursor protein (APP) or the presenilin 1 or 2 (PS1/2) genes is equivalent to the conditions that lead to the late-onset, sporadic forms of AD. This may be true. However, the latter, and the much more common form of AD, is a complex, non-Mendelian genetic entity with a multitude of protective- and risk-variant patterns. The sporadic, or late-onset, AD has a complex and variable genetic signature that may account for approximately 60 to 80 percent of disease risk (6).
Therefore, any unifying theory of AD must acknowledge that disease pathogenesis will not be reduced to a single etiological factor. Rather, a theory of AD must account for: 1) specific biological signals from multiple upstream factors/processes, 2) the intricate interactions—that include timing and sequencing—among multiple signaling paths that regulate the balance between cell repair/regeneration versus cell degeneration, 3) the complexity of convergence among a vast signaling network—upstream and downstream transmissions—from multiple sources toward a final common path (i.e., this is not equivalent to a single factor).
Where to start? Although the definition of AD continues to evolve, there are several common, known neurobiological indications at the cellular level. These include persistent waning in synaptic transmission, continuing pruning of dendritic arbors, massive loss of synapses, and decrements in repair and restoration functions1. It is the loss of neurons recognized to be the clearest and most identifiable feature of AD. Therefore, a unified theory of AD is predicated on two central questions: 1) How and why do some select sets of neurons become dysfunctional? 2) Why do some neurons die?
Neurons share many characteristics with other cell types, but in addition they have some unique features that include: 1) very high metabolic rate, 2) critical need for a constant supply of oxygen and glucose to survive, 3) loss of ability to divide by mitosis and 4) capacity to repair-regenerate-recycle essential components of the cell [e.g., membrane, organelle, receptors, channels, synapses, dendrites, etc.] in lieu of cell division by mitosis.
There are different types of neural cells in specific areas of the nervous system that serve specialized functions. The variety of cell types includes anterior horn cells, basket cells, Betz cells, granule cells, medium spiny neurons, Pukinje cells, Renshaw cells and pyramidal cells. Among these the pyramidal cells are of particular interest to AD as it may be viewed as the archetype neuron for modeling a neural system. The pyramidal neurons in the cerebral cortex, hippocampus, and amygdala, with proper connections, take part in the circuitry responsible for cognitive ability. These neurons have numerous voltage-gated Na+, Ca 2+ and K+ ion-channels in the dendrites, and soma. The ability of pyramidal neurons to integrate information depends on the number and distribution of the synaptic inputs they receive. Because a single pyramidal cell receives about 30,000 excitatory inputs and approximately 1,700 inhibitory inputs, this neuron-type incorporates virtually all characteristics of self-contained “subunit” that may be used to construct rudimentary models of a more complex neural system. This opens the possibility to test the accuracy of a unified theory of AD.
There are two research avenues that have motivated the exploration of calcium ion (noted as Ca2+) signaling as a theoretical basis to explain AD. First, the disruption of Ca2+ signaling could be an early upstream event where evidence from familial AD models provides important clues1. Second, there is evidence relating calcium ion dysregulation mechanistically to the neuropathological correlates of AD—namely, the presence of senile plaques and neurofibrillary tangles.


Reformulating the Calcium Hypothesis as the Calcium Systems Theory of the Dementia-Alzheimer Syndrome (CAST-DAS)

The Calcium Systems Theory of the Dementia Alzheimer Syndrome (CAST-DAS) asserts that sustained disruption of mechanisms that normally regulate intracellular Ca2+ signaling is pivotal for triggering adverse changes in the functioning of neurons. Ca2+ disruption serves as a necessary precursor and driver not only of aging-associated decrements in neuronal performance but also the molecular mechanisms underlying neuronal degeneration associated with AD pathogenesis (3). Compromised neuronal Ca2+ handling is thought to be an outcome of the various upstream events, including metabolic, oxidative, and proteotoxic stress (3). Changes and modulations of subcellular components [e.g., ion channels, buffers, ATP-dependent ion pumps, or other regulatory mechanisms] may also regulate the homeostasis of cytosol calcium concentration [Ca2+]i (1, 5). Furthermore, the deterioration of neuronal Ca2+ handling systems likely has an important downstream impact on virtually all of the major molecular alterations underlying the pathogenesis of AD, such as dendrite pruning, synapse loss, aggregated amyloid β-peptide (Aβ), Tau, p-Tau, mitochondrial dysfunction, oxidative stress and inflammation (1, 6, 7).
The core premise of CAST-DAS suggests conceptualizing AD as an accumulation of progressive “system failures” across an array of interconnected networks within the brain. Using a “systems perspective” to characterize AD goes beyond identifying a single etiologic factor that leads to pathogenesis (3, 8). Instead, this theory promotes not only explaining the interactions among crucial pieces of the system [e.g., genetic, biological events, temporal changes that occur in sequence or in parallel] but also identifying approaches to optimize the overall performance of the “system” by examining its constitutive components. CAST-DAS provides a pathway to address the difficulties in conceptualizing and communicating non-linear relationships between the behavioral and clinical features of Alzheimer’s disease and the underlying neurobiological mechanisms of pathology.
So how does CAST-DAS help elucidate the rules and regulatory mechanisms that operate/control molecular and network systems in the brain? The theory offers a conceptual framework to help overcome the difficulties of translating phenomenological modeling of genome-scale, protein-scale and molecular scale, and multiple other scales of information that influence the performance of neural systems. Assuming the validity of the modular network organization hypothesis (9), this assumption suggests a likelihood that genomic, proteomic, and ionic processes form subsystems of insolated functions and that emergent characteristics/behaviors should self-organize to comprise progressively higher scale systems (10). Further, these emergent characteristics will form higher-level regulatory networks with fewer interactions. From a computational and experimental perspective, this modeling schema may be calibrated so that the effective set of interactions is mathematically soluble given the data available (11).
The CAST-DAS contemplates simulations of biological systems at the molecular level to provide the most intricate mechanistic details, aid in interpreting experiments and provide predictive insight into intervention development. One of the emerging techniques is the use of multiscale computational modeling that integrates detailed knowledge from: 1) neuronal systems, 2) biomolecular/biochemical relevant parameters (12, 13), 3) brain topography that spans spatial scales from regions to a single synapse, and 4) timescales spanning single action-potentials, microsecond, hours or days. This modeling approach may also be viewed as a “knowledge management tool” that may inform strategic-level thinking of what types of key or additional data are required to validate intermediate hypotheses (14) and potentially provide an in silico platform for drug discovery (15, 16). Unlike traditional computational neuroscience—with foci on electrophysiology, synaptic signaling and corresponding network activity (17)—multiscale modeling for Ca2+ must include not only neuronal function but also intracellular and extracellular molecular dynamics.
Multiscale modeling computes information from a finer/smaller scale and forwards (or “couples”) that information to a model at a coarser/larger scale and omits degrees of freedom along the transition from a lower to higher. These models aim to predict higher-order behaviors (so-called “upscaling or bottom-up approach”) within a complex system (18). The rationale for multiscale models may be traced to Newton, Hooke, Bernoulli, Einstein, Bodenstein, and others (18), whereby omitting several degrees of freedom, and enabled them to propose continuum-based constitutive equations and simple models of relevant complex systems. In addition, multiscale models provide flexibility to simulate control conditions at a higher scale-level that then may permit simulated predictions at a lower scale-level (e.g., “downscaling” or “top-down approach”). Further, reverse engineering is another aim of top-down information flow: for AD research, this affords a rational approach to the prediction and identification of novel intervention targets (e.g., multicomponent, or multifunctional pathway combinations).
There are several applications for multiscale modeling using “well-mixed” biological systems (19). The multiscale nature of stochastic simulation for well-mixed systems arises from the separation of time scales, either disparity in rate constants or population sizes (20). The disparity of time scales—slow and fast events—is the rule rather than the exception in biochemical kinetics, irrespective of deterministic or stochastic modeling, and represents perhaps one the key innovations for CAST-DAS.


Key Assertions and Assumptions

CAST-DAS describes a unified theoretical basis of neurodegenerative processes in AD. There are several key assertions that support this framework.

Assertion #1

Sustained disruptions of intracellular calcium homeostasis are a final common pathway in brain aging and neurodegenerative disease, which drive aging-related cellular dysfunction and diverse disease-related pathobiology in brain disorders, including dementia/Alzheimer’s disease (AD). 1 Calcium is stored in several locations such as the mitochondria, endoplasmic reticulum and lysosomes, as well as protein-bound calcium that may all be relevant to the role of calcium in aging and AD. The concept of dyshomeostasis includes the possibility of impaired calcium management in organelles and other cellular compartments. Therefore, calcium regulation and homeostasis may be considered beyond cytosolic free calcium. Dyshomeostasis implies a departure from normal homeostasis that may be dynamic over time and may depend on the cell type. As a normal part of brain function and aging, changes in calcium homeostasis are dynamic (1, 5-7, 21-23).

Assertion #2

Changes in local [Ca2+]i levels centrally regulate the plasticity of neuroarchitecture, synaptic transmission by modulating the equilibrium between maintenance, growth/regeneration, and regression. The direction of this equilibrium, either toward growth, synaptogenesis and synaptic plasticity, or away to synaptic and neuritic regression, is governed by intracellular calcium concentrations (1). The presumption is that neuronal dysfunction, dendritic regression, and loss of synapses observed in AD and other neurodegenerative processes reflect aberrations of inherently normal processes from optimally functioning adult brain. Shifts in the equilibrium between growth and regression are a consequence of system failures that control [Ca2+]i homeostasis. Small, yet chronic, elevations in [Ca2+]i may disrupt the equilibrium in favor of degeneration. The critical idea is that a pre-existing process is being altered or exacerbated (4, 22, 24-41).

Assertion #3

Slow progressive decrements in efficiency in one or more cellular compartments/mechanisms for regulating [Ca2+]i or maintaining homeostasis could cause damage comparable to that due to a large acute insult, such as in TBI or stroke.1 The idea that prolonged small and rapid large increases of [Ca2+]i produce equivalent damage is yet to be validated. The postulate recognizes that both small sustained and large rapid increases of [Ca2+]i can each generate pathogenic conditions that contribute to aging-related deficits and pathologies associated with neurodegeneration. Each condition may recruit different compensatory mechanisms and homeostatic responses, but the net effect is that a brain is more vulnerable to AD or some other chronic brain disorder. The ability of neurons to compensate for low-level calcium dysregulation suggests that dysregulation during early and mid-life is counteracted. This concept may explain why presenilin (PS) mutations (i.e., those with early onset familial AD) have no discernable effects on brain function in youth but have progressive detrimental effects with advancing age. Presumably, “aging” produces additional changes in calcium signaling, such as reduced calcium buffering in the cells and reduced mitochondrial capacity to handle calcium. These changes, together with PS-induced calcium dyshomeostasis, lead to a neurodegenerative phenotype in aging neurons (4, 6, 24, 40, 42-51).

Assertion # 4

The concept of a final common pathway refers to the role of calcium dyshomeostasis in individual neurons. There is a presumption that the combined total effects of alterations from multiple sites regulating [Ca2+]i homeostasis, such as ion channels and pumps, calcium-binding proteins, etc. (1). It follows that different antecedent disease factors, including oxidative stress, impaired bioenergetics, lysosome dysfunction, and reduced neurotrophic support, may initiate individual cascade streams of pathological events. However, these aggregated streams amplify calcium dyshomeostasis to produce catastrophic effects on neural function and integrity. The assertion will be an aid therapy development in terms of developing new target leads. Different initial disruptions can result in various types of calcium dyshomeostasis but converge on common outcomes, such as dysfunctional mitochondrial calcium handling (27, 34, 51-66).

Assertion #5

The decline in optimal performance of a neuron with age or neurodegeneration is not due to a single event. Instead, these deviations are due to the convergence of multiple aberrant processes occurring in combination or in sequence over an extended period (1). The concept is related to temporal summation; taken neurophysiology where signals from two or more different neurons impinging on a third neuron must coincide in time (rhythm) in order to receive a response. Progress in understanding the neural basis of AD requires broad implementation of the concept of nonlinearity as used in engineering. Two or more interacting processes are almost certain to lead to an outcome that is not obtained by simple additives of the two inputs; instead, they are most likely to combine in a nonlinear manner that makes combinatorial predictions difficult if not impossible (25, 28, 31, 67, 68).

Assertion #6

Replace the concepts of “Healthy vs. Disease” with Objective Measures of Performance (47, 69, 70). Although the concept of “time” is an important risk factor for neurodegeneration, the relationship between chronological (calendar) age and biological age is not perfectly correlated. This means within any chronological age-year the performance of individuals varies over a range, based on an individual’s functioning. Too often chronological age [rather than biological age] is used as the anchor for comparisons of behaviors between age-matched normal versus patients with disease. Not everyone at age-80 or age-90 functions at the same level. Thus, going forward to develop a biological age construct, CAST-DAS will focus on quantitative objective measures of neuron performance on a continuous scale. This means establishing values that range from optimal performance to sub-optimal.
Moving beyond the concepts of “normal”, “disease”, and “aging” and by adopting objective measures of performance/functioning of a system, this affords several analytical advantages: 1) eliminates ambiguity in defining a subjective health state, 2) establishes a standard metric for ascribing performance of the system [e.g., neuron] in various settings or conditions and 3) advances neuron performance/function as a common dependent variable or outcome measure in analyses. This should allow direct comparison of various other theories of AD and should reduce current “disease” classification bias, or the problem of “AD heterogeneity.”

Assertion #7

Define Neuron Performance from a Systems Perspective. Although various prevailing ideas on the pathogenesis of AD may start with very different assumptions, any viable theory must account for the deficits in functional connectivity of various neural networks associated with neurodegeneration dementia. The CAST-DAS focuses on the performance of a neuron and neuronal circuits as a system (71).
Progressive decline in the performance of normal neuron functions represents the most proximal event common to all neurodegenerative conditions. The CAST-DAS explicitly stresses this notion to account for the complex interactions among the array of molecular mechanisms for maintaining optimal functionality of individual neurons and neuronal networks as systems. The theory explains how early age-related upstream alterations at the molecular and cellular levels affect the performance of neurons and their ability to cope with genetic and/or environmental stressors (72).
The central idea of a systems model of performance enables a continuous scale to indicate varying performance levels (e.g. from optimal to sub-optimal to catastrophic failure, without imposing subjective demarcations between unaffected and affected states). In this way, the concept of AD (either as a disease or syndrome) may now be conceptualized in terms of progressive failures in an array of interconnected complex systems at the subcellular and neural network levels. Specifically, “performance degradation” is no longer considered the linear result of a single causal/etiological factor. Rather, “performance degradation” arises from multiple hits that leads to neuronal dysfunction and degeneration (73).
Further, the embedded-sets of nested subsystems describes a modeling framework that may support many other theories. The approach requires allowances for the complex interactions among several predisposing biologic events: especially focused on the timing that might occur in sequence and/or in parallel. CAST-DAS permits explanations of functional and temporal relationships among key components of a system (74).
The explicit challenge for this conceptual framework is to shift the focus of future research toward solving the complex interactions necessary to maintain or restore the optimal performance of the system, which could be defined by the functionality of: a biochemical signaling pathway, an organelle or sub-cellular compartment, an individual cell/neuron, a synapse, a neuronal network, a well-defined anatomic structure, or an emergent characteristic, a system with higher-level organization such as memory (70, 74-76).

Assertion #8

Ca2+ Signaling as a Final Common Path: It is the sustained decline in the performance of the neuron that sets the stage for neurodegenerative processes leading to the deterioration of performance in a neural net. There are several alternative mechanisms for dysregulation of [Ca2+]i . Thus, there are differing paths toward the decline in a neuron’s functionality – performance. Calcium is a common denominator in many signaling processes including some beneficial pathways that are crucial to normal brain function [e.g., long-term potentiation, memory mechanisms and learning] and, accordingly, its role in disease is likely to involve disruption of multiple pathways (3, 29, 68, 77-79).

Assertion #9

Emergent Behaviors and the Complex Systems: The concept of emergent behavior is often overlooked to account for the non-linear relationships between clinical features of dementia such as impairments of memory, language, and affect with the underlying neurobiological processes. CAST-DAS asserts that emergent behaviors [e.g., “cognition”] arise from complex systems [e.g., neural networks] are not the linear result of a single factors. Rather, these characteristics emerge from stochastic processes and the resulting complex interactions among signaling and metabolic pathways. Multifaceted constructs such as cognition, memory or language involve large numbers of biological phenomena temporally activated across different echelons of organization in a system. These levels are stacked within a hierarchy of increasing complexity (e.g. from least complex to most complex). Macroscopic changes of how the system functions are observed at the relatively simpler levels of complexity, yet they can also be mechanistically characterized in a bottom-up fashion to inform what might occur at higher levels. Changes in subcellular systems (i.e., signal transduction pathways) result in alterations in gene expression, protein translation and protein functionality, that mediate and propagate upwards cellular outputs. This includes structural and dynamic changes in neuronal networks at higher levels, ultimately giving rise to clinical manifestations. The concept of emergent behaviors provides a useful approach to a) examine the characteristics of the constitutive subcomponents of the neuron and neural network systems, b) explain the functional relationships among key components within a given hierarchy of a system, and c) identify approaches to optimize the functioning of the overall system, i.e., discover and test new therapeutic targets (16, 28, 70, 74, 80).


Supporting Evidence: Experimental and Observational Data

The CAST-DAS needs to be viewed in terms of systems level function—the propagation of cellular signals through multi-synaptic pathways—to address the neural correlates of cognition. It is unknown how variations in biochemical signals translate to changes in cognition. A greater appreciation for subcellular compartmentalization is very important. Dysregulated Ca2+ signaling can have effects in different sub-cellular compartments, including cytoplasm, nucleus, endoplasmic reticulum, and mitochondria. What are these effects? How do they change organelle function, gene expression, and cell physiology over time and with age? However, there are fascinating clues based on the CAST-DAS suggesting differences in Ca2+ handling systems may be pivotal determinants of selective neuronal vulnerability (57, 62, 81-84). For example, hippocampal dentate gyrus granule neurons are remarkably resistant to degeneration, whereas CA1 neurons are highly vulnerable (35, 57, 68, 85-87). This differential vulnerability is reflected in the resistance of granule neurons (and the vulnerability of CA1 neurons) to Ca2+-mediated excitotoxicity and metabolic (i.e., mitochondrial) impairment. This differential neuronal vulnerability is also associated with differences in the expression of Ca2+-binding proteins (e.g., calbindin) (53, 78, 88, 89). Such disturbances suggest that in neuronal Ca2+ handling both are “necessary for” and “sufficient to” induce degeneration of vulnerable neuronal populations in a wide array of experimental models that are relevant to AD and Parkinson’s disease (1).
Interestingly, evidence now supports early pre-symptomatic roles for dysregulated cellular [Ca2+]i homeostasis in promoting amyloidogenesis (90), cytoskeletal pathologies, mitochondrial dysfunction, synaptic transmission and plasticity dysfunction, and oxidative stress (53, 55, 58, 59, 84, 91-99). For example, gene mutations or polymorphisms that increase AD risk promote aberrant neuronal Ca2+ handling early in the disease, and may thereby be early triggers for synaptic dysfunction, neuronal degeneration and cognitive impairment. Emerging findings also suggest that exercise, intellectual challenges, social interactions, and dietary energy restriction stimulate neuroprotective-signaling pathways modulating neuronal Ca2+ handling and may thereby forestall AD. Evidence now may indicate that diabetes and/or obesity may adversely alter calcium channel function (100, 101).
There is a growing consensus about the upstream and downstream cellular Ca2+ handling mechanisms. This includes activation of innate CNS immune responses, including local inflammation and microglial activation (102). Also, associated protein aggregation likely exacerbates other age-related problems (103). In addition, there are AD pathological features that have important linkages to neuron performance including: 1) energy-generating deficits and accumulate oxidative damage (52, 104), 2) impaired lysosomal function and autophagic mechanisms leading to problems eliminating damaged molecules and organelles, repairing DNA, and maintaining protein quality (62, 95), 3) compromised ability to respond to metabolic challenges or cellular stress (54, 56). These emerging data suggest that calcium signaling alterations are related to oxidative damage (as associated with compromises in calcium and sodium regulation), adenosine triphosphate (ATP) production by mitochondria, protease activation, and other cellular processes (22, 52, 104).


Future Research Questions

The CAST-DAS asserts that early synaptic dysfunction leading to subsequent decrements in performance, or complete failure, in neural network functions are the most critical molecular mechanisms leading to cognitive decline and clinical dementia. However, several uncertainties remain that will require future experiments to validate these claims (47, 82, 105). The following is a summary of some important unanswered questions:

Question: Why are some neurons more resilient than others and what are those mechanisms that may protect against chronic [Ca2+]i dysregulation? The question is whether changes in the mechanisms for regulating [Ca2+]i dynamics and maintaining calcium homeostasis represent necessary and sufficient conditions for the decline in functionality of a neuron1. Future studies should include multiple cell types and brain regions. Thus, beyond CA1 hippocampal neurons, there is a need to understand [Ca2+]i regulation in neurons of the entorhinal cortex, prefrontal cortex, parietal lobes, default mode network, and basal forebrain cholinergic neurons (47, 68, 101).

Question: Why does selective neuronal vulnerability (SNV) matter? Selective neuronal vulnerability (SNV) is often overlooked and yet a fundamental characteristic of both aging and neurodegeneration (1). There are cells, structures, systems that are affected while other vast areas are relatively unaffected or appear normal. What factors account for these differences or the underlying mechanisms of various neurodegenerative diseases that attack different but specific parts of the brain? Until recently, the molecular and cellular mechanisms to account for SNV were not well studied. New technologies now permit investigating the fundamental mechanisms regulating SNF in clinical samples of aging and dementia.
Future investigation will be needed to examine the effects of various types of stresses on SNV. Functional genomic analyses may compare the sensitivity of cells, to an oxidative insult, within specific brain regions. GeneChip-based transcriptomics may evaluate those with unaffected brain aging and AD to assess the question of how injured/vulnerable neurons are characterized by significant decreases in the expression of genes related to mitochondrial metabolism and energy production (9, 53, 56, 57, 62, 66, 84, 106). In this way, biochemical analyses may provide critical validation of lower energy levels (in the form of ATP) between different neurons (i.e., primary CbG compared with cortical neurons). In total, these future experiments would provide a foundational basis to evaluate low energy reserves and high intrinsic stress levels as two underlying factors for SNV to oxidative stress (57, 84). In a systems-based analytical framework, this future work may lead to establishing a conceptual basis to for “coupling transition” between higher and lower order sub-systems within the overall neuronal architecture.
Detecting genomic differences—between sensitive and resistant neurons—can now be used to explore suggested molecular mechanisms of cell injury in aging and AD. In the future such whole genome expression studies, may lead to further insights into the organization of SNV complexity that could be then targets for interventions to protect vulnerable neurons (57, 83, 84). The Allen Brain Atlas may be used to explore the expression of aggregation-related genes and their localization in the Braak staging regions where AD develops early (107). The spatial transcriptomics strategy allows visualization and quantitative analysis of the transcriptome with spatial resolution in individual tissue sections. This approach enables pattern analysis proteins or messenger RNAs (mRNAs) in histological tissue sections (106).

Question: Will the Calcium System Theory be sufficiently inclusive to explain selective neuronal vulnerability (SNV)? In light of the previous question one of the lingering crucial challenges for all theories of AD is to explain the functional mechanisms for the specificity of decline in performance of the system affected; where the system could be defined either in terms of cell type, anatomical region, neural network or neurochemical system (2, 3, 8, 73). An important consideration for the theory will be whether corollaries will be required for different cell types. It is likely that in order to produce models with greater fidelity, future studies will need to identify mechanistic insights for specific cell types sufficiently so to supply cell type-specific in vivo functional data.

Question: What are the distinguishing differences between the more general decline in a neuron’s performance from those changes in functionality that underlie disease-specific system failure? Is there a way to identify specific neural systems, networks, pathways, or mechanisms that are selective for various forms of neurodegeneration and/or different forms of dementia? Although there are multiple pathways for regulating [Ca2+]i in what way do are each of these paths involved or affected by age and/or dementia/AD. Further studies should differentially examine the nature of these nonlinear interactions and pathways. Several of the identified AD susceptibility genes will be important study targets. The objective will be to determine if and how these genes may contribute to, and if so, to what extent [Ca2+]i dysregulation. For example, calcium-linked susceptibility genes such as PICALM, CLUSTERIN and APOE are of particular interest in this regard (10, 21, 88, 94, 108, 109). The role of calcium in neuro-immunology as it relates to the expression or modulation of susceptibility genes is not known. Further studies should investigate how changes in [Ca2+]i dyshomeostasis affect or modulate the immune system in AD (70, 86, 93, 98).

Question: How does how intracellular Ca2+ homeostasis change during aging and what is the clinical impact? Because emerging evidence suggests that systemic abnormalities and diseases such as such as diabetes, cardiovascular disease and obesity can increase the risk of dementia/AD, it will be important to understand how such peripheral alterations due to comorbid conditions influence cellular [Ca2+]i homeostasis in the brain (66, 110).

Question: What are the prospects of developing Ca2+-primed biomarkers to monitor neuronal performance, overall system health, and correlates of human health? The concept of Ca2+ biomarkers needs to be approached with an open mind. One useful biomarker could be a blood marker of Ca2+ dysregulation in the brain, such as might be possible by using brain-specific extracellular vesicles (exosomes) (77, 88, 90, 111). Future biomarkers should follow the performance of individual neurons as they function within neuronal networks. The important challenge will be to develop the appropriate nanotechnologies to measure and monitor the changes in Ca2+ in living animal models. There is a need to measure Ca2+ dysregulation in vivo in the clinic with human subjects. The goal will be developing ways to monitor Ca2+ homeostasis in living people, and to distinguish normal homeostasis from pathologic conditions, for example by using indirect measures of Ca2+ homeostasis or biomarkers. Links to obesity and diabetes show promise as peripheral biomarkers. There is evidence that calcium dysregulation occurs in the periphery (adipocytes, neurons) in response to diabetes (110). There is a question whether there are effects of neurodegeneration, or more specific changes associated with dementia/AD, in the peripheral nervous system that could be measured. Development of direct measures of calcium function is underway in vivo (87). One possibility is the calcium-activated K current responsible for the afterhyperpolarization. Advanced calcium imaging methods will prove valuable for studies of aging. Some other peripheral markers that are potential surrogates for neurodegeneration include retinal imaging to study retinal vasculature Ca2+ in retinal cells (1). Future research should explore if the olfactory epithelium is also accessible for similar studies as biopsies of olfactory epithelium is possible. Studies of more readily accessible cells, such as fibroblasts, may also provide clues regarding changes in calcium regulation in patients with sporadic AD (1).

Question: How does CAST-DAS address the temporal and functional relationship between [Ca2+]i dyshomeostasis and molecular mechanisms underlying other putative etiologic factors such as amyloid, tau, inflammation, mitochondrial dysfunction etc.? This is a key consideration for the CAST-DAS: [Ca2+]i dyshomeostasis is considered a final common pathway leading to the decline in a damaged neuron and eventually playing a central role in the downstream neurodegeneration process (1, 2, 5, 7, 12, 70, 71, 73, 75, 96). With multiple pathogenic effects that seem unrelated, there is a need to address how [Ca2+]i dyshomeostasis serves as a common final path—a point of convergence—for both upstream and downstream contributors to the neurodegenerative process including amyloid beta and Tau pathologies, lysosome and mitochondrial dysfunction, and impaired adaptive cellular stress responses. Future studies should determine how well the CAST-DAS could account for: a) Large variance, measured in years, in the latency of expression in the decrement of function or deviation from optimal performance or the onset of symptoms [e.g., cognitive impairment] and, b) Heterogeneity in not only the timing of onset or the trend toward the decline in performance but also the expression of biological markers associated with aging or neurodegeneration.

Question: What are the major technical challenges for CAST-DAS? The list of immediate steps required to understand the role of calcium dysregulation in neurodegeneration includes the following (1). First, developing in vivo methods to observe sub-cellular localization of calcium dynamics and identify organelle(s) exhibiting compromised neuronal calcium behavior, without altering inherent neuronal activity. Second, improving the temporal resolution to reveal key timing features that are presently unobservable. This is important because of the extremely short duration of calcium dynamics [i.e., nanoseconds]. Third, developing bioassays to allow accurate and reliable characterization of therapeutic interventions in disease models. Fourth, developing new analytical modeling techniques that allow predictions of synaptic, neuron, and neural systems functionalities based on experimental findings of calcium dynamics.



The CAST-DAS posits that a decline in the functioning of a neuron due to [Ca2+]i dyshomeostasis is the necessary and sufficient condition that affects the performance of a neural system. This deterioration underlies many impairments of human behaviors as a consequence and the expression of clinical phenotypes related to Alzheimer’s disease. Thus, CAST-DAS represents significant progress towards offering a comprehensive account for AD pathogenesis by providing explanations that are more integrative than other prevailing theories (75, 96).
Why is CAST-DAS a promising framework for developing therapies for AD and other complex chronic brain disorders? This theory has already provided the rationale for one FDA-approved medication for AD—Memantine. The conceptual framework proposed by CAST-DAS provides both an explanation for the limited or short duration of effectiveness of other current treatments and outlines the essential features for a novel drug discovery-development paradigm based on a systems approach. The primary premise of CAST-DAS is to use the complex neuronal mechanism for regulating the [Ca2+]i dyshomeostasis as a template to map functional relationships among multiple variables. CAST-DAS provides both a theoretical and experimental basis to develop targeted nanotherapies that can isolate specific brain regions or specific cell types for intervention. Future drug products may be designed on an individual patient-specific basis in response to their own unique physiological make-up to tailor precision drug targeting of novel neuroprotective strategies.


Conflicts of Interest
Ara S. Khachaturian, Ph.D. is an Officer and director of the Campaign to Prevent Alzheimer’s Disease (PAD 20/20) and; Officer, director and employee of Khachaturian and Associates; Founding executive-editor of Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association (retired), Founding executive-editor of Alzheimer’s & Dementia: Translational Research & Clinical Intervention (retired), Founding executive-editor of Alzheimer’s & Dementia: Diagnoses, Assessment & Disease Monitoring (retired); Executive Officer and Director, Brain Watch Coalition; Senior Research Fellow, University of Nevada Las Vegas, National Supercomputing Institute & Dedicated Research Network; Received payments through organizational affiliations for grants, contracts, consulting fees, honoraria, meeting support, travel support, in-kind research/professional support over the last 36 months from the Alzheimer’s Association, Acadia Pharmaceuticals, Alzheon, Biogen, Clinical Trials Alzheimer’s Disease Conference, Davos Alzheimer’s Consortium, Eisai, Eli Lilly & Company, and International Neurodegenerative Disorders Research Center, and Serdi Publishing.

Ethical standards
Ara S. Khachaturian is editor-in-chief of Vitality, Medicine & Engineering; he has recused himself from any editorial decision on this manuscript, Dr. Bruno Vellas was responsible for the editorial peer-review process.



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Ara S. Khachaturian


Corresponding to: Ara S. Khachaturian, Editor-in-Chief, Rockville, MD, USA, Tel.: 1-301-309-6730, Fax: 1-301-309-6724,

VM&E 2023;6:1-3
Published online May 24, 2023;



As the modern era of brain health care and research approaches the quarter-century mark, there is a growing recognition across many related fields in medicine, life science, engineering and public of the need for the timely exchange of new knowledge and new insights from a diverse spectrum of disciplines, perspectives, and people. Vitality, Medicine & Engineering is launched to address this gap.
Vitality, Medicine & Engineering—or VM&E— is a peer-reviewed journal that address gaps in conceptual linkages and knowledge medicine, life/physical sciences, public health, and engineering. VM&E seeks the publication of content that can be understood by diverse international academic, professional, and general audiences. VM&E will publish multi-disciplinary peer-reviewed original research manuscripts, reviews, perspectives, and meeting reports as well as consumer-oriented content including news, policy reviews, and opinions. Thematic topic will include (and not be limited to) neuroscience, geriatrics, behavior , psychological, cardio-pulmonary science, sports medicine, medical/nursing care, nutrition, electrical/mechanical engineering, computer science/informatics, industrial/financial engineering/reimbursement, design, architecture and care, aging in place/assistive technologies, promotion of care interventions to sustain independence, development of instruments/tools to assess and monitor, and global health economics and policy.


Editorial Philosophy

The proliferation of translational research and the resulting translational knowledge now presents an important publication challenge for articulating new ideas and insights. The editorial vision for Vitality, Medicine & Engineering embraces the view of a balanced consideration of both the theoretical and the experimental aspects of research, as well as the practical application of medicine, public health, and engineering. While there is no question about the importance of reporting novel data or new investigative techniques, there is now a growing imperative for authors to articulate their new insights, ideas, or hypotheses within the context of a summation of previous investigations and conceptual frameworks, placing their research in context. In addition to the commitment of upholding standards of excellence in peer review, the responsibility of the editors of Vitality, Medicine & Engineering also includes a fealty to the concerns of the people living with chronic diseases and disorders that reduce or preclude personal autonomy and independent living. It is the mission of Vitality, Medicine & Engineering to decipher these data, interpret trends, anticipate new science, help validate novel interventions and services, and ultimately advance new knowledge to accelerate improvement of global public health.


Lessening the burden of disability due to chronic diseases and disorders

Vitality, Medicine & Engineering will publish manuscripts that seek the novel development of effective, affordable, and equitable treatments and medical care services for persons with many chronic diseases and disorders that diminish quality life, reduce personal autonomy and independence. Presently, a key public health objective to combat these limitations is the identification of efficacious and effective new interventions (i.e., pharmacological, non-pharmacological, and medical and social care) particularly for under-served and under-represented populations. Going forward, this is an important editorial priority for VM&E, namely the publication of manuscripts that lessen the burden of disability due to chronic diseases and disorders and its comorbid conditions. Given the broad audience of VM&E, the publication of manuscripts on these topics will be of importance to numerous fields, research funders, health policy planners/decision-makers, and general health news consumers.
Health Equity, Health Equality, and Sustained Lifespan Individualized Care
Although there is broad consensus that public health, scientific and medical research efforts should diminish disease and enrich life, there is growing concern for and among under-represented and under-served populations. Regrettably in some instances, public health and scientific research has given us the ability to prolong life without prolonging health. This results in increasing numbers of individuals at risk for numerous chronic diseases and conditions that.
Vitality, Medicine & Engineering is uniquely positioned though the use of editorials, virtual special issues/special topic sections, work groups/task forces and the editorial board to advocate and advance new thinking on research questions, methodologies, analytical approaches that expand opportunities to improve health equity, equality and individualized option for care across the lifespan.


Integrating Clinical Research, Clinical Care, Public Health and Engineering

An editorial priority of Vitality, Medicine & Engineering will be to publish research that further elucidates the neurobiology of many neurodegenerative disease and related brain diseases/disorders as neuropathologic entities and their temporal relationship to cognitive, behavioral and functional impairments. The heterogeneous underpinnings of many neurogenerative disorders, its pathologies and its complex relationship to the cognitive/behavioral/functional impairments remains an important challenge for the medicine, life science, public health, and engineering. New knowledge and new analytical approaches are necessary to map better the multiple, non-linear, and non-sequential interactions of associated factors and temporal influences. VM&E will focus on research that validates technologies and algorithms for early pre-symptomatic detection of a many different brain disease and disorders, irrespective of pathology, in the general population and in routine health care populations.
VM&E encourages researchers from epidemiology, information science, bioinformatics and primary/family medicine to play expanded roles in both submitting and reviewing research. The Journal will support and guide efforts to expand application of modern epidemiological methods with more targeted research between various exposures, behaviors, lifestyles, social determinants of health as well as potentially precipitating disease (e.g., subclinical cardiovascular disease), and pathological features of AD. The Journal will also promote collaboration through meetings, task forces and special topic sections, the linkage of epidemiological methods together with computational systems biology approaches to study relationships between exposures, epigenetics, transcriptomics, metabolomics, proteomics, and the pathogenesis of many chronic disease and disorders. Finally, and perhaps most importantly, these efforts must be examined in diverse multi-national, multi-cultural populations that includes samples taken beyond the clinic that consider important strata such as geographical, racial, sex/gender, socio-economic, cultural/ethnic, as well as other factors.


Journal Operations

The composition of Vitality, Medicine & Engineering’s editorial board reflects the multi-disciplinary nature of research. The membership includes broad representation from experts in such areas as neurology, general medicine, psychiatry, geriatrics, psychology, genetics, molecular biology, epidemiology, sociology, biostatistics, mathematics, computational science, health services research, health economics, financial engineering, political science, and public policy. Among the Journal editors, the roles of Executive Editor, Deputy Executive Editor, Senior Associate Editor, Associate Editor, Senior Editor and Statistical Editor would be appointed. Given the increasing quality, complexity, and number of submissions as well as the increasing demand by authors for quality and rapid reviews of manuscripts, the Vitality, Medicine & Engineering editors will be given autotomy and responsibility to evaluate new submissions for publication.
Editorial board membership has also sought diversification based on geography, nationality, and gender. As an English-language journal, that has a growing international audience, Vitality, Medicine & Engineering will explore additional opportunities to recruit and retain qualified, editorial members, particularly among non-native English language speakers. Also, intellectual diversification among the editorial board members is essential to establishing the Journal’s reputation for editorial independence. A commitment to viewpoint diversity fosters promotion of new ideas and countervailing approaches, methods, and theories. To help facilitate this overall goal, Vitality, Medicine & Engineering will establish several editorial board committees including Recruitment and Nominations, Research Ethics and Conflicts, and Task Force/Special Topics Sections.
Vitality, Medicine & Engineering will seek to increase audience engagement by developing uniquely clear and concise on-demand web-content related to the care and treatment of Alzheimer’s disease in partnership with Serdi (the publisher). In addition to traditional peer-reviewed manuscripts, Vitality, Medicine & Engineering will support the production of digital weekly content, curated by the editors, covering the most important news, published research and “trends-heard-in-the-field”. Based on Vitality, Medicine & Engineering’s thematic interests, content could be produced and published using a variety written articles, video abstracts, visual abstracts, augmented reality (AR) illustrations, infographics, animations, video podcasts, and live town-hall style webinars.


Conflicts of Interest
Ara S. Khachaturian, Ph.D. is an Officer and director of the Campaign to Prevent Alzheimer’s Disease (PAD 20/20) and; Officer, director and employee of Khachaturian and Associates; Founding executive-editor of Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association (retired), Founding executive-editor of Alzheimer’s & Dementia: Translational Research & Clinical Intervention (retired), Founding executive-editor of Alzheimer’s & Dementia: Diagnoses, Assessment & Disease Monitoring (retired); Executive Officer and Director, Brain Watch Coalition; Senior Research Fellow, University of Nevada Las Vegas, National Supercomputing Institute & Dedicated Research Network; Received payments through organizational affiliations for grants, contracts, consulting fees, honoraria, meeting support, travel support, in-kind research/professional support over the last 36 months from the Alzheimer’s Association, Acadia Pharmaceuticals, Alzheon, Biogen, Clinical Trials Alzheimer’s Disease Conference, Davos Alzheimer’s Consortium, Eisai, Eli Lilly & Company, RELX Plc, High Lantern Group, International Neurodegenerative Disorders Research Center, and Serdi Publishing.




Li Hongyan1, Lu Wanting2, Li Fei1


1. General Surgery Department of Xuanwu Hospital of Capital Medical University, Beijing City 100000 PRC; 2. Department of Neurology of Xuanwu Hospital of Capital Medical University, Beijing City 100000 PRC

Corresponding to: Li Hongyan, General Surgery Department of Xuanwu Hospital of Capital Medical University, Beijing City 100000 PRC,; Phone:18600346925

Care Weekly 2021;5:1-5
Published online April 28, 2021,



Purpose: To evaluate mental health, cognitive function, and living quality of colon and rectal carcinoma patients with oxaliplatin-induced neurotoxicity. Methods: Fifty recurrence-free colorectal cancer (CRC) patients with oxaliplatin chemotherapy while 50 control patients without oxaliplatin chemotherapy were enrolled in this study. Subjective and objective aspects of oxaliplatin chemotherapy symptoms were assessed with oxaliplatin neurotoxicity classification. Psychological assessment was measured via the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Cognitive function was measured via Montreal Cognitive Assessment (MoCA). Quality of Life (QOL) was assessed using the World Health Organization’s Quality of Life (WHOQOL-BREF) shortened instrument. Results: Of the patients with oxaliplatin chemotherapy, 41 patients had depression and 42 patients had anxiety. Patients with oxaliplatin chemotherapy scored higher on average on both the SDS (64.36 ± 7.22) and SAS (67.49 ± 9.41) compared to those without oxaliplatin chemotherapy (SDS, 57.86 ± 5.27, p=0.006; SAS, 61.57 ± 10.06, p = 0.004). Patients with oxaliplatin chemotherapy, on average, scored lower on the MoCA (23.46 ± 3.17) compared to patients without oxaliplatin chemotherapy (27.49 ± 2.03, p < 0.05). In addition, patients with oxaliplatin chemotherapy scored significantly lower on measures of physical health (18.9 ± 7.8 vs. 37.8 ± 6.2, p<0.05), psychological health (19.3 ± 8.2vs. 39.8 ± 8.1, p<0.05), and social relationship (50.2 ± 10.1 vs. 70.6 ± 10.5, p<0.05) compared to patients without oxaliplatin chemotherapy. Multivariate linear regression analysis demonstrated that anxiety and cognitive impairment performance significantly predicted for global Quality of Life (QOL). Conclusions: colorectal cancer (CRC)patients with oxaliplatin chemotherapy experience mood disorders, cognitive impairment, and reduced Quality of Life (QOL). The clinical symptoms severity of oxaliplatin cemotherapy plays an important role in mood change and cognitive function. Decreased Quality of Life (QOL) was associated with anxiety and cognitive impairment.

Keywords: Chemotherapy-induced neuropathy, oxaliplatin, colon and rectum carcinoma, psychological disorders, cognitive impairment, quality of life.



Cancer is a lethal menace to human health while chemotherapy is one of the leading effective treatments (1). Colorectal cancer accounts for 10% to 15% and ranks top 2 in leading causes of death for all cancers (2). Metastatic diseases arise in about 50% of patients with colorectal cancer. Palliative chemotherapy enables patients to lengthen survival time and improve QOL. The latest methods that target critical biological pathways have provided more treatment options and a substantial improvement in survival and progression-free survival (PFS) for metastatic colorectal cancer (mCRC) patients. Oxaliplatinis, a third-generation platinum drug, is extensively used in first line treatment for CRC. However, cancer treatment can be interrupted by painful symptoms caused by undesirable side effects of various chemotherapy drugs, including oxaliplatin (3).
Platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel) are likely to cause chemotherapy-induced neuropathy, which is one of the most serious side effects. Among these side effects, chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-dependent side effect that interferes with cancer therapy regimens, significantly induces functional abilities loss, and affects QOL. Moreover, CIPN can lead to lowering of the dose and discontinuation of assumption, ultimately affecting overall survival ratio (4-6).
Sensory neuropathy symptoms include pain, allodynia, loss of sensation, paresthesia, numbness, tingling, and gait disturbance (7). CIPN normally caused by Taxanes, vinca alkaloids, platinum derivatives, bortezomib, and thalidomide, which predominantly impair afferent sensory fibers with a symmetric, distal, length-dependent “glove and stocking” distribution. Unfortunately, there are few strategies to treat this kind of neuropathy, partially due to the complexity of its pathogenesis (8). Therefore, it has great significance to develop analgesic drugs with novel mechanisms.
Patients with CRC have worse social and role dysfunction (9, 10). There have been few reports about the psychological, cognitive, QOL impairment of CRC patients following oxaliplatin chemotherapy and oxaliplatin-induced neuropathic pain. The comparative of psychological disorders and QOL between oxaliplatin chemotherapy patients and those without oxaliplatin chemotherapy is not fully understood. There is no significant evidence that chemotherapy causes psychological disorders. Therefore, we assessed the psychological functioning of CRC patients with and without oxaliplatin chemotherapy. We measured emotional wellness using the Zung Self-Rating Anxiety Scale (SAS) and Zung Self-Rating Depression Scale (SDS), cognitive function using the Montreal Cognitive Assessment (MoCA), and QOL using the World Health Organization’s Quality of Life instrument, abbreviated version (WHOQOL-BREF).



This research was approved by the Ethics Committee of The Xuan Wu Hospital. Patients included inpatients and outpatients of Xuan Wu Hospital, Capital Medical University. Written informed consent was signed from all participants.


From September 2017 – December 2019, patients who fulfilled the following criteria were enrolled into the case group: (1) History of CRC with oxaliplatin chemotherapy; (2) no recurrent tumor, brain metastasis, brain tumor, brain abscess, cerebral infarction, encephalitis, demyelinating disease or other central nervous system (CNS) diseases; and (3) no consciousness disorder and vital sign changes. A total of 50 patients matched this criteria (35 males, 15 females) and were placed into the case group. During the same time period, [add control sample number] patients with a history of CRC and no history of oxaliplatin chemotherapy were recruited and placed into the control group. Control group participants met the following additional criteria. The age, gender, educational level, and treatment modalities of the subjects were matched. The same number of patients were recruited into the control group according to the inclusion criteria, which were the same as the case group, except for criteria (2).

Materials and Procedures

The following clinical information was collected from each patient: (1) age, gender, educational background, occupation and marriage status, residence area, and medical record (date of starting chemotherapy, dosage, the target volume, whether has another CNS diseases); (2) physical exam findings; and (3) oxaliplatin toxicity scores assessed by oxaliplatin neurotoxicity classification (for patients undergoing oxaliplatin chemotherapy).

Neuropsychological test

Self-Rating Depression Scale (SDS)

The Zung SDS is a 20-item self-report rating scale that measures symptoms of depression; cognitive condition, somatic symptoms, and psychomotor and emotional changes of the subjects were assessed via the scale. Each item is scored on a Likert scale ranging from 1 to 4. Participants with a total raw score of 25-43 do not exhibit clinical depressive symptoms, 50-59 are considered to have mild to moderate depression, etc. Participants with a total raw score of 54 or higher were labeled as having depression based on this scale (Chinese version).

Self-Rating Anxiety Scale (SAS)

The Zung SAS is a 20-item scale, with some of the items keyed positively and some negatively. They are answered on a four-point scale ranging from 1 (none or a little of the time) to 4 (most or all the time). After being converted into the standardized score, a cut-off 50 was used to define anxiety according to the scale (Chinese version).

Montreal Cognitive Assessment (MoCA)

The MoCA is a widely used screening tool for detecting early signs of dementia or mild cognitive decline. The MoCA assesses different cognitive domains: attention and concentration, executive function, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The time to administer the MoCA is approximately 10 minutes. The total possible score is 30. A score of 26 or above is considered normal.


The WHOQOL-BREF is an abbreviated version of the WHOQOL-100, which measures the functional domains of an individual’s life deemed vital to a person’s quality of life. The WHOQOL-BREF is a 26-item measure that assesses an individual’s physical health (e.g., energy, mobility, sleep and rest), psychological health, social relationships, and environment (e.g., financial resources, home environment, physical safety).

Statistical analysis

SPSS for windows, version 13.0 was used for statistical analysis. Between the case group and control group, the clinical features and the SDS, SAS, MoCA, and WHOQOL-BREF scores were compared by a paired-sample t-test; the depression and anxiety scores were used for comparison by X2 test. Stepwise multiple linear regression was applied to explore predictors of psychological and cognitive disorders. Spearman’s correlation was performed to examine the relationship between oxaliplatin neurotoxicity classification and the scores of SDS, SAS, and MoCA. All tests were two-tailed, and the significance level was maintained at 5%.



In total, 100 patients were recruited from Xuanwu Hospital. Fifty patients were placed into the case group and 50 were placed into the control group. The demographic data and baseline characteristic for the two groups were similar (Table 1). mFOLFOX and Xelox were applied to the primary tumor. Nineteen of the patients suffered from chronic underlying diseases such as hypertension, diabetes, chronic bronchitis and other medical co-morbidities.

Table 1. Demographics of Case and Control Group Participants

Emotional Wellness

On measures of emotional wellness, 41 (82.0%) case group participants had depression, 42 (84.0%) had anxiety, and 38 (76.0%) had both. In the control group, 38 (76.0%) patients had depression, and 40 (80.0%) had anxiety. The differences in incidence rates of depression and anxiety between case group and control group participants were not statistically significant (SDS, 82% vs. 76%, p = 0.46; SAS, 84% vs. 80%, p = 0.62; Table 2); however, the standardized SDS score and SAS score were higher in the case group than those in the control group (64.36 ± 7.22 vs. 57.86 ± 5.27, P = 0.006; 67.49 ± 9.41 vs. 61.57 ± 10.06, P =0.004).

Table 2. Depression and Anxiety Scales


For the incidence of severe depression, the case group was 18% (nine patients) while the control group was 0% (no patient). The percentage of patients with severe depression, as defined by standardized SDS, was significantly higher in the case group compared with the control group (p= 0.018). In the case group, the number of patients with severe anxiety was 27 (54%). In the control group, the number of severe anxiety cases was 11 (22%); the percentage of patients with severe anxiety was significantly higher in the case group (p =0.005).

Cognitive function

The (mean) MoCA standardized scores from the case group and control group were (23.46 ± 3.17) and (27.49 ± 2.03), respectively. Patients without oxaliplatin chemotherapy tended to score higher than those with oxaliplatin chemotherapy (p<0.05).

Quality of Life

The raw scores are transformed into standard scores in line with the WHOOL-100 Instrument. The higher the score, the better QOL the patients felt. A comparison of QOL scores between the two groups are presented in Figure 1. Patients in the case group obtained a lower mean score (18.9 ± 7.8) on the domain of physical health of the WHOQOL-BREF compared to participants in the control group (37.8 ± 6.2, p<0.05). The mean score for psychological health of the cases was 19.3 ± 8.2, while the control score was 39.8 ± 8.1; data were considered significant in groups with P < 0.05. Additionally, regarding social relationships, the scores in the cases and the controls were 50.2 ± 10.1 and 70.6 ± 10.5 respectively; the difference was significant (p<0.05). In the environmental domain, the scores for the two groups were similar (49.6 ± 9.2 vs. 53.8 ± 9.3, p = 0.325, respectively).
To identify the determinants of QOL, the demographic data and scores of the SAS/SDS/MoCA were entered into the regression analysis. We found that the SAS score (p= 0.052) and MoCA score (p<0.005) were both the significant predictors (Table 3).

Table 3. Multiple linear regression analysis of age, gender, education, chemotherapy, SAS, SDS and MoCA to predict QOL

Figure 1. QOL in two groups. The X-axis represents the mean score per group on each of the four domains of the WHOQOL-BREF with a standard deviation of 6 represented by the vertical line

Participants in the case group obtained a lower score on the domains of physical health (p<0.05), psychological health (p<0.05), and social relationship (p<0.05). There was no statistically significant difference in mean scores on the environment domain between groups (p = 0.325). Abbreviations: QOL = quality of life



This study evaluated emotional wellness (or mental health), cognitive function, and QOL of CRC patients with oxaliplatin chemotherapy. Data were compared with no-oxaliplatin chemotherapy CRC patients. More than three fourths of patients after oxaliplatin chemotherapy had either depression or anxiety based on SDS and SAS assessment. As reported previously, psychological disorders such as depression and anxiety were apparent as early as the start of chemotherapy and might even remain throughout the entire treatment (12-14). However, it is still not clear that how psychological disorders develop, and the mechanism of how they affect patients’ QOL during chemotherapy remains unresolved.
In this research, according to the SDS and SAS scores, depression and anxiety were more severe in patients with oxaliplatin chemotherapy than those without oxaliplatin chemotherapy. Regarding the factors influencing anxiety and depression, we found that age, gender, education, and chemotherapy had no significant correlation. Patients often are acutely aware of minute changes in their body during and following chemotherapy. Patients undergoing chemotherapy and those who have recently completed chemotherapy treatment often worry about the recurrence of tumors, and will frequently meet with their medical providers (citation), all of which are indicative of anxiety (citation).
MoCA can assess patients’ attention and concentration, executive function, memory, language, visuoconstruction abilities, conceptual thinking, calculations, and orientation. Ferlay J. founds that the late effects of chemotherapy on cognitive function include three situations: transitory cognitive impairment primarily affecting attention and recent memory; mild or moderate cognitive impairment and dementia with leukoencephalopathy occurring in the late delayed period (15). In our study, the case group participants/ participants with a history of chemotherapy performed worse on a cognitive function measure than patients without chemotherapy. Chemotherapy also proved to be a predictor of cognitive dysfunction.
In our study, the most common symptoms in patients with oxaliplatin chemotherapy included impaired cognition, bulbar palsy, headache, dizziness, and syncope. These symptoms significantly decreased patients’ QOL.
Presently, a cure for neurotoxicity to the nervous system, effective treatment strategies are missing. Chemotherapy-induced neuropathy is harmful toa patient’s QOL and leads to dose reduction or even treatment cessation. The current approaches to counteract the side effects of chemotherapy are not completely effective, fail to solve long-term consequences, and can induce other side effects (16-18).
Oxaliplatin (Third-generation platinum) differs from cisplatin due to the presence of an oxalate leaving group and a DACH (diaminocyclohexane) linker. Oxaliplatin is effective in cisplatin-resistant tumors because the DNA repair system does not recognize its adducts. Thus, it is widely used in colorectal cancer (19). Neves and Vargas pointed to epidemiological data demonstrating a large scale of use of platinum (monotherapy or in combination with other drugs) in clinical oncology (20). Patients with NPC after oxaliplatin chemotherapy often have chemotherapy-induced neuropathy. It predominantly impairs afferent sensory fibers with a symmetric, distal, length-dependent “glove and stocking” distribution. Our score of QOL showed a significant difference between patients with oxaliplatin chemotherapy and patients without oxaliplatin chemotherapy in the following domains: physical and psychological health, and social relationships. Regression analysis also found that anxiety and cognitive impairment might explain the lower QOL scores.


Funding Support
This work was supported by the Beijing Municipal Administration of Hospitals’ Youth Programme (QMS20180805); Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five–year Plan (CIT&TCD201904093); Beijing Excellent Talents Training Funding Project (2018000026833ZK78); and the Xuanwu Hospital Huizhi Talent Project (XW2019091680124).

We thank LetPub ( for its linguistic assistance and scientific consultation during the preparation of this manuscript.

Conflicts of Interest
The authors have declared that no competing interests exist.

Ethical standards
This research was approved by the Ethics Committee of The Xuan Wu Hospital. All participants gave informed consents.



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Atsushi Hamuro1, Minoru Honda2, Yuya Wakaura2, Shouko Mori3, Ryuichi Tanaka4

1. Yuzuriha Hospital, Department of Psychiatry, Nagasaki City, Japan; 2. Yuzuriha Hospital, Department of Nursing, Nagasaki City, Japan; 3. Yuzuriha Hospital, Department of Nutrition, Nagasaki City, Japan; 4. Yuzuriha Hospital, Department of Dentistry, Nagasaki City, Japan

Corresponding to: Atsushi Hamuro, 413 Sanwamachi, Nagasaki City, Nagasakiken 850-0975, Japan. Tel: +81-95-878-3734; Fax: +81-95-878-3289. E-mail:

Care Weekly 2020;4:8-10
Published online December 10, 2020,


We investigated the effect of mousse meals on improvement in nutritional status. We conducted a 12-week, prospective, structured clinical trial on 11 elderly patients with psychiatric disorders. We compared the participants’ body mass index, blood protein and albumin levels, activities of daily living, and swallowing function, as well as presence of pneumonia, urinary-tract infection, and incidences of gastrointestinal symptoms due to consumption of mousse meals during the baseline and 12-week follow up. Results showed that Body Mass Index levels significantly increased, while blood protein and albumin levels, activities of daily living, and swallow function varied. One patient with pneumonia and another with urinary-tract infection could resume eating mousse meals within one week from the onset of infection. No participant suffered from gastrointestinal symptoms. The results of this study indicate that mousse meals are a viable choice for improving low nutritional status of elderly patients with psychiatric disorders.

Keywords: Mousse meal, Low nutrition, Psychiatric disorder.



In many countries, including Japan, life expectancy is growing. As a result, the elderly among the population (above 65 years) are increasing (1). Nutritional issues are important as the nutritional status among the elderly tends to be lower (2). However, nutritional issues have received little attention in geriatric psychiatry research (3).
Some of the factors that cause low nutritional status in elderly patients with psychiatric disorders include health complications (e.g., hypertension, heart disorder, and diabetes), gastrointestinal disorders (e.g., constipation, ileus, and diarrhea), malignant tumors, infections, and worsening psychiatric symptoms (4). Moreover, other studies considered inadequate meal forms as its cause (e.g., soft food, mixer food) (5). Thus, we investigated the effects of special food, i.e., mousse meals, considering the adhesion, cohesion, and hardness of food such as jelly, on the improvement of nutritional status.



Study Design

This study was 12-week, prospective, structured clinical trial.


Of the patients (N = 319) who were hospitalized at the Department of Psychiatry in Yuzuriha Hospital, we enrolled a total of 11 hospitalized patients (four females and seven males; mean age: 78.73±10.9) with psychiatric disorders (Alzheimer’s disease = 3, vascular dementia = 3, schizophrenia = 1, and mental retardation = 4) on October 2017, which serves as the point of baseline. Their psychiatric disorders were diagnosed according to the criteria of the International Classification of Diseases, Tenth Revision (ICD-10). We excluded those on general meals (N = 127), soft meals (N = 171), and mixed meals (N = 10). All the patients required assistance while eating. Moreover, we used Global Assessment of Functioning (GAF) (6) to compute for the scale-defined psychological function (ranging from 0 to 100, with lower scores indicating increased severity of psychological function) of our patients, resulting in an average score of 30.


Patients’ medications related to the treatment of their psychiatric disorders were not changed during the study period. The criteria for providing mousse meals were as follows: patients had to (1) store food in their mouth without swallowing, (2) experience loss of appetite, and (3) exhibit the presence of dysphagia, as determined by the Nutrition Dysphagia Rehabilitation Committee of Yuzuriha Hospital. Body mass index (BMI), blood protein and albumin levels, activities of daily living (ADL), and swallowing function, as well as the presence of pneumonia, urinary-tract infection, and incidences of gastrointestinal symptoms due to the consumption of the mousse meal were compared at the baseline and 12-week follow up. The mousse meals comprised a total energy of 1400 Kcal (protein = 42.1g, lipid = 35.2g, and carbohydrate = 210.7g) per day. ADL and swallowing function were evaluated using the Physical Self-Maintenance Scale (PSMS) (7), and the scale based on the Japanese Society of Dysphagia Rehabilitation (8). The scale assesses sitting in an upright posture, palsy, pronunciation, lip protrusion, tongue movement, and pharyngeal reflex, with scores for each item ranging from 0 to 3, where higher scores mean enhanced swallowing function normality.

Data Analysis

Statistical differences between all scores were determined using the Wilcoxon signed rank test. P values of <0.05 were considered to be statistically significant.



All the patients completed the study. Table 1 shows the comparison and scores at baseline and at 12 weeks for all the patients. Only BMI level was significantly associated between the baseline and at 12 weeks. The levels of blood protein and albumin, scales of ADL, and swallow function did not significantly increase. During the study, there was one patient with pneumonia and another with urinary-tract infection. No patient suffered from gastrointestinal symptoms such as stomachache, vomiting, constipation, ileus, or diarrhea.

Table 1. Mean scores for blood protein, albumin, BMI, PSMS, and swallowing scale in the 11 elderly patients with psychiatric disorders

Statistical differences between all scores were determined using the Wilcoxon signed rank test P values of <0.005(*) were considered to be statiscally significant; BMI: body mass index; PSMS: Physical Self-Maintenance Scale



Patients with psychiatric disorders and low GAF scores often react poorly (e.g., they do not open their mouths or store food in them) when receiving assistance to eat a meal (9, 10). As a result, poor nutrition is common in elderly hospitalized patients with psychiatric disorders (11). Previous studies have been conducted to determine the relationship between falls, infection, mortality, and nutritional risks (12, 13). However, to our knowledge, few studies involving elderly patients with psychiatric disorders have described the relationship between low nutritional status and special food forms, such as mousse meals. Therefore, we sought to determine which meal form is most suitable to the conditions of elderly hospitalized patients with psychiatric disorders. As blended meals, with several ingredients mixed in a mixer, do not collect in the mouth, swallowing function often worsens. Moreover, it is difficult to determine the ingredients of blended meals. On the other hand, mousse meals, which grind only one ingredient (e.g., meat, fish, vegetable) and add thicker liquids address this problem, given that they are portioned in a suitable bolus outside the mouth and their ingredients are clearly visible.
Although the BMI levels of patients showed a significant increase, they are still unsatisfactory as per the BMI defined in Japan (14).The levels of blood protein and albumin varied during the study since they may take a little longer to increase. There was no negative impact on ADL and swallowing function. Patients with pneumonia and urinary-tract infection were completely cured within one week from the onset of infection, thus, the mousse meal was resumed. The patients did not present any gastrointestinal symptoms after consuming the mousse meal.
The limitations of this study include the small number of patients and lack of reliability and validity testing. However, we were able to increase staff awareness about the food forms they could provide to hospitalized patients with psychiatric disorders. Such awareness is as important as nursing homes and care centers in the community.
The results of this study indicate that mousse meals are a viable choice for improving the low nutritional status of elderly patients with psychiatric disorders. Further studies are needed to explore the relationship between mousse meals and improvement in low nutritional status, while also considering the meal forms and observation of complications, oral care, swallowing function, and psychiatric symptoms in the future.


This study received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

The authors wish to thank Mamiko Shimada, Mayumi Yamasaki, and Junko Kamito for the help in following up with patients in the present study.

Conflicts of Interest
The authors declare no conflicts of interest.

Ethical standards
The Yuzuriha Hospital Ethics Committee approved the safeguards, protocols, and informed consent procedure of the study in according with the declaration of Helsinki. After explaining the study to the patients and caregivers, written informed consent was obtained from all the patients.



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*Suggested Citation: Fernandes-Alcantara, A. L. (2017). Vulnerable youth: Employment and job training programs (CRS Report R40929). Washington, D.C.: Congressional Research Service.

Published online November 9, 2017,



In an increasingly global economy, and with retirement underway for the Baby Boomer generation, Congress has indicated a strong interest in ensuring that today’s young people have the educational attainment and employment experience needed to become highly skilled workers, contributing taxpayers, and successful participants in civic life. Challenges in the economy and among certain youth populations, however, have heightened concern among policymakers that some young people may not be prepared to fill these roles. The employment levels for youth under age 25 have declined markedly in recent years, including in the wake of the 2007-2009 recession. Certain young people—such as high school dropouts, current and former foster youth, and other at-risk populations—face challenges in completing school and entering the workforce.
Since the 1930s, federal job training and employment programs and policies have sought to connect vulnerable youth to work and school. Generally, these young people have been defined as being at-risk because they are economically disadvantaged and have a barrier to employment.
During the Great Depression, the focus was on employing young men who were idle through public works and other projects. The employment programs from this era included an educational component to encourage youth to obtain their high school diplomas. Beginning in the 1960s, the federal government started funding programs for low-income youth that address their multiple needs through job training, educational services, and supportive services.
Currently, there are four major federal youth employment and job training programs, all of which are administered by the Department of Labor’s (DOL’s) Employment and Training Administration (ETA). Although these programs have varying eligibility requirements and are carried out under different funding arrangements, they generally have a common purpose—to provide vulnerable youth with educational and employment opportunities and access to leadership development and community service activities. The Youth Activities program offers job training and other services through what are known as local workforce development boards, whose members are appointed by the chief local elected official(s). The program was funded at $873.4 million in FY2016. The Job Corps program provides career and technical training in a number of trades at 125 residential centers throughout the country. The program received FY2016 appropriations of $1.7 billion. Another program, YouthBuild, engages youth in educational services and job training that focus on the construction trades. YouthBuild received FY2016 appropriations of $84.5 million. Separately, the Reentry Employment Opportunities program, formerly known as the Reintegration of Ex-Offenders program, includes job training and other services for juvenile and adult offenders. The youth component of the program was funded at $39.5 million in FY2016.
The four programs were authorized under the Workforce Investment Act of 1998 (WIA, P.L. 105-220) through FY2003, and Congress continued to appropriate funding for the programs in subsequent years. On July 22, 2014, President Obama signed into law the Workforce Innovation and Opportunity Act (WIOA, P.L. 113-128). WIOA amended these programs, particularly the Youth Activities program and Job Corps. Like WIA, WIOA does not explicitly authorize the Reentry Employment Opportunities program; however, Congress appropriated funding for the program in FY2016 (P.L. 114-113) under the authority of Section 169 of WIOA and the Second Chance Act. Section 169 authorizes evaluations and research. The amendments made by WIOA generally went into effect on July 1, 2015.



In an increasingly competitive economy, and with retirement underway for the Baby Boomer generation, Congress has indicated a strong interest in ensuring that today’s young people have the educational attainment and employment experience necessary to become highly skilled workers, contributing taxpayers, and successful participants in civic life. Challenges in the economy and among vulnerable youth populations, however, have heightened concern among policymakers that many young people may not be prepared to fill these roles.
The employment levels for youth under age 25 have generally declined since 2000, though attachment to the workforce has improved for this population in the wake of the recession that extended from December 2007 through June 2009 (1). Certain young people in particular— including those from low-income families, high school dropouts, foster youth, and other at-risk populations—face barriers to completing school and entering the workforce. Since the 1960s, federal job training programs and policies have sought to connect these youth to education and employment pathways. Contemporary federal employment programs with this same purpose include the Youth Activities program; Job Corps; YouthBuild; and the Reentry Employment Opportunities (REO) program, which includes a youth component. These programs provide a range of services and supports to youth. Some of the programs concentrate on specific job trades and/or serve targeted at-risk populations. The programs were previously authorized under the Workforce Investment Act (WIA) of 1998 (P.L. 105-220). On July 22, 2014, President Obama signed into law the Workforce Innovation and Opportunity Act (WIOA, P.L. 113-128). WIOA superseded WIA and made significant amendments to the youth programs (2). Changes made by WIOA generally went into effect on July 1, 2015 (3).
This report provides an overview of federal employment programs for vulnerable young people. It begins with a discussion of the current challenges in preparing all youth today for the workforce. The report then provides a chronology of job training and employment programs for at-risk youth that began in the 1930s and were expanded or modified from the 1960s through the 1990s. It goes on to discuss the four youth programs authorized under WIOA, and draws comparisons between these programs. Following this section is a detailed discussion of each of the programs.



As they leave high school, either through graduation or by dropping out, young people can pursue various options. Youth with a high school diploma may attend a two- or four-year college, enlist in the armed services, or secure part-time or full-time employment (sometimes paired with attending school). Youth without a high school diploma can do some of these same things, but their opportunities are more limited. They cannot enroll in a four-year college or, in most cases, enlist in the military. These youth will likely have difficulty supporting themselves if they do work (4).
In fact, individuals who drop out are less likely to secure employment and have lower earning power. As the level of education rises, the unemployment rate decreases and median weekly earnings increase for those who work (5).  In 2015, among workers with less than a high school degree, the unemployment rate was 8.0% and earnings averaged $493 per week. This is compared to an unemployment rate of 5.4% and $678 in weekly earnings for workers with a high school degree. Workers with a bachelor’s degree had an unemployment rate of 2.8% and median weekly earnings of $1,137. With the shift to a knowledge-based economy, many new jobs will require some college education or better. According to DOL’s Bureau of Labor Statistics (BLS), the fastest growing occupations between 2014 and 2024 will require some postsecondary education (6). The costs of dropping out extend beyond the individual’s foregone job opportunities and lower wages. According to the research literature, costs can be incurred by society overall. These costs include possible lost payroll tax revenue and increased transfers for welfare payments, imprisonment, and programs to re-enroll dropouts in school (7).
Federal youth employment and job training programs have long targeted services to young people who leave school before graduating or are in school and may be vulnerable to dropping out. The purpose of these programs, as they currently exist, is to provide job training, employment, educational services, and social services that can help youth become economically self-sufficient and achieve their career and academic goals. These contemporary programs also emphasize leadership development and community service. Note that while youth employment and job training programs are also enhanced with state workforce and other dollars, the extent to which this support is provided is unclear.


History of Federal Youth Employment and Job

Training Programs (8)

For more than 90 years, the federal government has played a role in helping young people secure employment and achieve academic success. Generally, these young people have been defined as being vulnerable in some way—either because they are economically disadvantaged and/or have a barrier to securing employment or completing their education. During the Great Depression, the focus was on employing idle young men in public works and other projects. The employment programs from this era included an educational component to encourage youth to obtain their high school diplomas. Beginning in the 1960s, the federal government started funding programs for low-income youth, such as Job Corps, that address their multiple needs, including job training, educational services, housing, and supportive services. During the 1970s and 1980s, Job Corps was expanded and the federal government funded additional programs for both in-school and out- of-school youth. Funding was also appropriated to test the efficacy of some of these programs.
The Workforce Investment Act of 1998 extended earlier programs and created new ones, with the intention of providing more seamless job training and education services for youth year-round.
The Workforce Innovation and Opportunity Act maintained these programs and changed some of their requirements. Generally, these programs are targeted to teenagers and young adults, usually to age 24, who are at risk of dropping out or have already done so.


Depression Era

Prior to the 1930s, the federal government’s involvement in youth employment was primarily limited to regulating child labor (9). The Great Depression served as a catalyst for the creation of federal programs to employ and educate young people who were out of work or at risk of dropping out of school due to financial difficulties. The Civilian Conservation Corps (CCC) began in 1933 as an employment program for unemployed males ages 18 to 25 (and veterans, Indians, and residents of territories of any age) to participate in projects planned by the Departments of the Interior and Agriculture. These projects focused on creating and improving infrastructure, transportation, and recreational services, among other categories. The young men lived in camps and were provided with an allowance, food, and medical care. The CCC also included an educational component, which taught nearly 35,000 participants to read and write and assisted a smaller number with attaining their high school and college degrees. Until the program ended in 1945, it served nearly 3 million men, of whom approximately 10% were veterans.
Other Depression era programs—the Student Aid program, Works Project program, and Guidance and Placement program—were administered by the National Youth Administration, which was created as part of the now-defunct Works Progress Administration by an executive order in 1935. The programs provided funds for part-time employment of needy high school, college, and graduate students to assist them in completing school, as well as funds for part-time employment for unemployed out-of-school youth. These young people, all of whom were ages 16 through 25, were employed in a number of broad areas, including construction, clerical work, and research.
These programs served hundreds of thousands of youth before they were discontinued in the early 1940s.


War on Poverty Programs

The 1960s marked a period of federal efforts to assist poor and disadvantaged children, adolescents, and their families through job training and other programs. In response to concerns about high unemployment, the Manpower Development and Training Act of 1962 (P.L. 87-415) and subsequent amendments to it authorized funding for employment training. Specifically, amendments to the act in 1963 (P.L. 88-214) encouraged the Department of Labor to provide assistance to youth so that they might be able to successfully enter the labor force, and expanded the share of job training funds that could be used to train youth under age 22 from 5% to 25%.
Further, federal funding was first authorized through the 1963 amendments to provide employment opportunities to youth from low-income families.
President Lyndon B. Johnson’s subsequent War on Poverty established new youth-targeted programs in job training and educational assistance under an initiative known as the Neighborhood Youth Corps (NYC). The NYC was made up of work training programs, the Work Study program, and Job Corps. The work training programs provided work experience, job training, and supportive services to low-income unemployed youth ages 16 through 21 who were in school or out of school, including dropouts. The Work Study program was modeled on the Depression-era Student Aid program and provided money to high school and college students from low-income families who needed earnings to stay in school. The program continues today for college students. Job Corps, which also continues today, was established under the Economic Opportunity Act of 1964 (P.L. 88-452) to provide educational and job training opportunities to disadvantaged youth at residential and non-residential centers. (See “Job Corps,” below, for further information.)


Expanding Youth Programs

The 1973 Comprehensive Employment and Training Act (CETA, P.L. 93-203) was the first of four laws enacted during the 1970s and 1980s that focused greater federal attention on youth employment and training. The second law, the Youth Employment and Demonstrations Project Act (YEDPA, P.L. 95-93) was enacted in 1977 and established a variety of employment, training, and demonstration programs for youth. The 1982 Job Training Partnership Act (JTPA, P.L. 97-300 repealed CETA. JTPA was subsequently repealed by WIA. Separately, the School-to-Work Opportunities Act of 1994 (STWOA, P.L. 103-239) supported the development of programs that encouraged students to pursue learning opportunities and experiences that incorporated occupational skills. Activities authorized under these acts were administered by DOL. STWOA was additionally carried out by the Department of Education (ED).


Comprehensive Employment and Training Act (CETA) and Youth Employment and Demonstrations Project Act (YEDPA)

As amended through 1978, CETA authorized a range of employment and training programs for adults and youth. Job Corps and the Summer Program for Economically Disadvantaged Youth (SPEDY) were the primary youth programs authorized under CETA. SPEDY provided funding to employers to hire low-income youth ages 14 through 21 during the summer months. Youth served as assistants in hospitals, libraries, community service organizations, and schools, among other settings.
The Youth Employment and Demonstrations Project Act (YEDPA), signed into law in 1977, amended CETA (10). YEDPA increased authorization of appropriations for Job Corps and SPEDY and authorized three additional programs targeted to “economically disadvantaged” (defined under the act) youth ages 14 through 21: Youth Employment and Training Programs (YETP), Youth Community Conservation and Improvement Projects (YCCIP), and Youth Incentive Entitlement Pilot Projects (YIEPP) (11). YEDPA was passed in response to high levels of unemployment among youth relative to adults, even during periods of economic expansion, and growing gaps in youth unemployment among whites and blacks, males and females, and in- school and out-of-school youth. The programs were carried out during the Carter Administration, from 1977 through 1981. Over this period, YEDPA served 6.1 million youth.
YETP and YCCIP were intended to meet the immediate employment needs of youth, and funding for the programs was allocated primarily on a formula basis. YETP activities include work experience, pre-employment skills, and an emphasis on the transition from school to work.
YCCIP was intended to assist unemployed, out-of-school youth obtain a high school degree, conditional on satisfactory performance in work and school. Further, it was aimed at improving coordination between the job training and educational systems as a means of addressing the dropout problem (12). Finally, YIEPP funded evaluations to test the efficacy of demonstration programs; the other two programs included funding for demonstration programs. During the YEDPA years, more than 60 major demonstrations were funded in about 300 sites, operated by DOL in cooperation with six other federal agencies and private nonprofit intermediaries.


Job Training Partnership Act (JTPA)

CETA was repealed in 1982 by the Job Training Partnership Act (13). JTPA was distinct from its predecessor because it emphasized that states and localities, rather than the federal government, had the primary responsibility for administering job training and employment programs. Funding was appropriated under JTPA through FY1999. JTPA programs focused on the training needs of “economically disadvantaged” (defined under the act) youth and adults facing significant barriers to employment. JTPA programs included the Summer Youth Employment and Training program, the Youth Training Program, and Job Corps.
The Summer Youth Employment and Training program provided employment and training activities during the summer months for low-income youth ages 14 through 21 to strengthen basic educational skills, encourage school completion, provide work exposure, and enhance citizenship skills. In the summer of 1997, an estimated 500,000 youth participated. The Youth Training Program was established by the Job Training Reform Amendments of 1992 (P.L. 102-367), which amended JTPA to address concerns that school dropouts were not being reached by the then- existing combined program for disadvantaged adults and youth, and that the program primarily served youth who were the easiest to place in jobs and required the fewest services (14).  The program was year-round and provided direct services, such as on-the-job training, tutoring and study skills training, and school-to-work transition services. It also provided training-related and supportive services, including job search assistance, drug and alcohol abuse counseling, and cash incentives based on attendance and performance in a program. Economically disadvantaged in- school and out-of-school youth ages 16 through 21 were eligible, but 50% of participants had to be out of school. Further, at least 65% of youth had to be hard to serve, meaning they were school dropouts (if out of school), pregnant or parenting, or offenders, among other qualifications. In program year 1997, an estimated 107,000 youth participated. JTPA was replaced by WIA.


School to Work Opportunity Act (STWOA)

The School to Work Opportunity Act of 1994 authorized the School-to-Work (STW) program administered jointly by DOL and the Department of Education through the National School-to- Work Office (15). The program was funded from FY1994 through FY2000. The law supported the development of programs with three main elements: work-based learning to provide participating students with work experience and on-the-job training; school-based learning, involving upgrading and integrating the occupational skills participating students learn in school and the workplace; and program coordination to aid the planning, implementation, and operation of the program. STWOA grants were competitively awarded to states, local partnerships, programs for Indian youth, and U.S. territories to implement school-to-work systems. In addition, STWOA authorized national activities, such as research and demonstrations. Some school-to-work programs that received seed money from the federal program continue to operate today.


Workforce Investment Act (WIA)

The Workforce Investment Act of 1998 replaced JTPA. WIA includes titles that authorize programs for job training and related services (Title I), adult education and literacy (Title II), employment services (Title III), and vocational rehabilitation (Title IV). Title I of WIA authorized job training programs for youth, adults, and dislocated workers (16). Funding was authorized for the program through FY2003, and Congress continued to appropriate funding for the programs in subsequent years.


Workforce Innovation and Opportunity Act (WIOA)

Congress took steps toward reauthorizing WIA from the 108th to the 113th Congresses, ultimately passing the Workforce Innovation and Opportunity Act (WIOA) on July 9, 2014. President Obama signed the bill into law (P.L. 113-128) on July 22, 2014. As of July 1, 2015, the law superseded WIA. Like WIA, WIOA includes titles that authorize programs for job training and related services (Title I), adult education and literacy (Title II), employment services (Title III), and vocational rehabilitation (Title IV). The major job training programs for youth and other workers are authorized in Title I.


Overview of Youth Programs Authorized Under Title I of WIOA

WIOA authorizes, and Congress has funded, three job training and employment services for youth:
•    Youth Workforce Investment Activities Program (hereinafter, Youth Activities Program), a formula grant program for state and local workforce development boards (WDBs) that includes employment and other services that are provided year-round;
•    Job Corps, a program that provides job training and related services primarily at residential centers maintained by contractor organizations; and
•    YouthBuild, a competitive grant program that emphasizes job training and education in the construction trades.

As mentioned, Job Corps was enacted as part of the Economic Opportunity Act of 1964 (P.L. 88- 452), and was later incorporated into CETA, JTPA, and WIA. YouthBuild was originally authorized under the Cranston-Gonzalez National Affordable Housing Act of 1992 (P.L. 102- 550). The program was administered by the Department of Housing and Urban Development (HUD) until it was transferred to DOL in 2007 under the YouthBuild Transfer Act (P.L. 109-281) and incorporated into WIA. Under WIA’s pilot and demonstration authority, DOL established the Reintegration of Ex-Offenders (ReXO) program, a program for juvenile and adult offenders that provides job training and other services. WIOA does not explicitly authorize the program, now known as the Reentry Employment Opportunities (REO) program; however, Congress appropriated funding in FY2016 (P.L. 114-113) under the authority of Section 169 of WIOA and the Second Chance Act. Section 169 authorizes evaluations and research.
DOL’s Employment and Training Administration (ETA) administers the four programs. All of the programs offer employment, job training, and educational services. For example, local workforce development areas must provide specific elements, including mentoring and follow-up, to youth who receive services under the Youth Activities program. YouthBuild program participants engage in employment and other activities primarily related to housing and other types of construction work. Job Corps is the only one of the programs that provides residential services; youth can live onsite and receive health care services, child care, and other supports. Further, the programs generally serve vulnerable youth. Participants in YouthBuild and Job Corps must be low-income and have specified barriers to employment. The same is true in the Youth Activities program, except those who are out-of-school do not have to be low-income. The youth component of the Reentry Employment Opportunities program serves youth who have become involved in the juvenile justice or criminal justice system or youth at risk of becoming involved. The programs are funded somewhat differently. DOL allocates funding for the Youth Activities program to state WDBs based on a formula, while Job Corps enters into contracts with nonprofit and for-profit organizations and into an interagency agreement with the U.S. Department of Agriculture’s Forest Service. The other programs competitively award grants to nonprofit and other organizations and local communities. Table 1 summarizes the programs’ major features.

Table 1. Features of Youth Programs As Authorized Under Both WIA and (as of July 1, 2015) WIOA

Table 1. Features of Youth Programs As Authorized Under Both WIA and (as of July 1, 2015) WIOA



The WIOA Youth program and other youth programs make up a network of job training and employment opportunities for youth. In some communities, this may be formalized while in others, coordination between the programs may be less structured. WIOA includes provisions that encourage or require the programs to coordinate with one another. The state workforce board may include representatives of organizations that have demonstrated experience and expertise in addressing the employment, training, or education needs of eligible youth, including representatives of organizations that serve out-of-school youth (17). These boards are responsible for carrying out WIOA programs at the state level and allocating funds to local WDBs.
Further, under the state workforce plan (“unified state plan”), states are required to submit a description of the state’s strategic vision and goals for preparing an educated and skilled workforce—including preparing youth and individuals with barriers to employment—and for meeting the skilled workforce needs of employers, among other requirements (18). In addition, local WDBs, which receive funds to carry out the Youth Activities program are required, as part of their local plans, to describe and assess the type and availability of youth workforce investment activities in the local area, including activities for youth with disabilities. The plan must identify successful models of such youth workforce investment activities (19). Local workforce boards may choose to establish a standing committee to provide information and assist with planning to provide services to youth (20). Further, the Youth Activities program, Job Corps, and YouthBuild are required partners at one-stop centers. One-stop centers are operated by local WDBs and include federal programs that coordinate employment and other services in a community for all youth and adults (21).



WIOA provides funding authorization from FY2015 through FY2019 for youth employment and job training programs. Funds appropriated for a program or activity carried out under Title I of the act are available for obligation on the basis of a program year (22). The program year begins on July 1 in the fiscal year for which the appropriation is made and ends June 30 of the following year. Funds for the Youth Activities program may first become available for a new program year in the preceding April. In addition, Congress has tended to specify that funds appropriated for YouthBuild and the youth component of the Reentry Employment Opportunities program are available for obligation beginning in the April preceding a given program year. Congress has generally required that obligated funds for Job Corps are made available for one program year, although funding for certain purposes can be obligated through later dates. Funds obligated for any program year for the Youth Activities may be expended by each state receiving such funds during that program year and the two succeeding program years. Local areas may expend funds received from the state during the program year and the succeeding program year (23).


Funding for FY2000-FY2016

Table 2 includes the level of funds appropriated to each of the youth job training and employment programs for FY2000 through FY2016. Appropriations for these years correspond to the same program year, and are reported as such in the table (i.e., PY2000 through PY2016). Congress appropriated a total of $2.4 billion to $2.8 billion annually for these programs in most years over this period. Table A-1 in the Appendix presents Youth program funding allocated to the states and outlying areas for PY2009 through PY2016.
Job Corps has generally received the largest appropriation each year, followed by the Youth program, YouthBuild, and the youth component of the Reintegration of Ex-Offenders (although in two years, YouthBuild received less funding than the ReXO youth component).

Table 2. Appropriations for DOL Youth Job Training and Employment Programs, PY2000-PY2016 and Under the American Recovery and Reinvestment Act (ARRA, P.L. 111-5) Dollars in thousands; the fiscal year generally corresponds to the program year for each program

Table 2. Appropriations for DOL Youth Job Training and Employment Programs, PY2000-PY2016 and Under the American Recovery and Reinvestment Act (ARRA, P.L. 111-5)
Dollars in thousands; the fiscal year generally corresponds to the program year for each program


FY2016 Funding

Following three continuing resolutions (P.L. 114-53, P.L. 114-96, and P.L. 114-100), Congress passed, and President Obama enacted, the Consolidated Appropriations Act, 2016 (P.L. 114-113) to fund the Department of Labor and other agencies. FY2016 funding for the four youth job training and employment programs totaled $2.7 billion. Funding increased from FY2015 by nearly $42 million for the Youth program and nearly $5 million for the YouthBuild program. The funding for the youth component of the Reentry Employment Opportunities program decreased by $4.5 million and for Job Corps by $3.1 million.


FY2015 Funding

Following two continuing resolutions (P.L. 113-164 and P.L. 113-202), Congress passed, and President Obama enacted, the Consolidated and Further Continuing Appropriations Act, 2015 (P.L. 113-235) to fund DOL programs through FY2015. Funding for the youth programs totaled $2.6 billion. Funding increased from FY2014 by over $11 million for the Youth program; over $7 million for the YouthBuild program; and nearly $2 million for the youth component of the Reentry Employment Opportunities program; Job Corps funding remained level.


FY2014 Funding

FY2014 (PY2014) appropriations were not enacted prior to the beginning of the fiscal year (October 1), resulting in a 16-day shutdown of the federal government. On October 16, 2013, the Senate and House agreed to a bill (H.R. 2775) to provide temporary government-wide FY2014 funding through January 15, 2014 (or until full-year funding was appropriated). This bill was signed by the President on October 17, 2013 (P.L. 113-46). A second short-term continuing resolution (P.L. 113-73) extended appropriations through January 18, 2014. On January 17, 2014, the President signed into law the Consolidated Appropriations Act, 2014 (P.L. 113-76) to fund appropriations through September 30, 2014. In total, $2.6 billion was appropriated for youth job training and employment programs.
The next section of the report provides further discussion about the youth programs authorized under Title I of WIOA.


WIOA Youth Activities Program (24)

Overview and Purpose

The Youth Activities program is one of three formula grant programs that were initially authorized by WIA, and is now authorized under WIOA as the Youth Workforce Investment Activities program. The other two WIOA programs target adults (Adult Activities) and dislocated workers (Dislocated Worker Activities), although youth ages 18 or older are eligible for services provided through the Adult Activities program. These programs provide core funding for a coordinated system of employment and training services overseen by a state workforce development board and the governor, and composed of representatives of businesses and other partners. WIOA does not include purpose areas for the Youth Activities program; however, it generally seeks to provide assistance to youth in achieving academic and employment success.

Program Structure

With assistance from the state workforce development board, the governor develops a plan (known as the unified state plan) that is submitted to DOL. The plan is to address several items related to employment and training needs, performance accountability, and employment and training activities. The plan is to be submitted every four years for the Youth Activities, Adult Activities, and Dislocated Activities programs (25).  Further, the unified state plan is to address youth primarily in two places. It must outline the state’s strategic vision and goals for preparing an educated and skilled workforce, include preparing youth with barriers to employment. It must also outline the criteria to be used by local boards in awarding contracts for youth services and describing how local WDBs will take into consideration the ability of providers to meet performance measures that are based on primary indicators of performance for the Youth Activities program (these indicators are discussed in a subsequent section).
As specified under WIOA, a local workforce area is overseen by the local workforce development board. The local board is made up of partners that collaborate to provide coordinated employment and training services in the community (26). Membership of the local board is to include representatives of businesses, local education entities, labor organizations, community-based organizations, and economic development agencies, among others (27).  The boards may include representatives of organizations that have demonstrated experience and expertise in addressing the employment, training, or education needs of eligible youth, including representatives of organizations that serve out-of-school youth (28).
Local boards are to competitively award funds to local organizations and other entities to provide employment and job training services to youth (29).  Grants or contracts awarded are to be based on criteria in the state plan, and by taking into consideration the ability of the providers to meet performance accountability measures that are based on primary indicators of performance for the Youth Activities program. Further, a local board may award funding on a sole-source basis if the board determines there is an insufficient number of eligible providers of youth workforce investment activities in the local area to participate on a competitive basis. Local boards may terminate “for cause” the eligibility of these providers (30).
The local board develops a local plan that discusses items similar to those in the state plan, except that the plan describes the local area’s one-stop delivery system. A one-stop system is intended to provide central access to employment and training services in a community. The Youth Activities program is a required partner in the one-stop system under WIOA. The WIOA regulations specify that local boards must either collocate youth program staff at one-stop centers and/or ensure one- stop centers and staff are equipped to advise youth in order to increase youth access to services and connect youth to the program that best aligns with their needs (31).  Further, one-stop systems may have specialized centers to address special needs. WIOA specifies that this may include the needs of youth.
The local board must ensure that parents and other stakeholders are involved in designing and implementing the Youth Activities program (32).  In addition, the local board may establish a standing committee to provide information and to assist with planning, operational, and other issues relating to providing services to youth, including community-based organizations with a demonstrated record of success in serving eligible youth (33).  If a local board establishes a standing youth committee, it may assign it the responsibility of selecting youth providers. The WIOA regulations discuss the potential role of a standing youth committee, including to recommend policy direction to the local board for the design and development of programs to benefit all youth; the design of a comprehensive community workforce development system to ensure a full range of services and responsibilities for all youth, including disconnected youth; and ways to leverage resources and coordinate services among schools, public programs, and community- based organizations serving youth, among other possible responsibilities (34).


Funding for the Youth Activities program is allocated from DOL to states, including Puerto Rico and Washington, DC, and the outlying areas (35). WIOA requires that not more than 0.25% is reserved for outlying areas and not more than 1.5% is reserved for youth activities in programs to serve Native American youth (36). WIOA specifies that the allotments for the outlying areas are based on a competitive grant process (37).
The remainder of the funds are allocated to states by a formula. The formula is based (1) one- third on the relative number of unemployed individuals residing in areas of substantial unemployment (an average unemployment rate of at least 6.5% for the most recent 12 months); (2) one-third on the relative “excess” number of unemployed individuals (an unemployment rate of at least 4.5%); and (3) one-third on the relative number of disadvantaged youth (individuals 16 through 21 who receive an income that, in relation to family size, does not exceed the higher of the poverty line or 70% of the lower living standard income level) (38).  WIOA specifies that states are to receive, at minimum, the higher of 90% of their relative share of the prior year’s funding or, at maximum, 130% of their relative share of the prior year’s funding (39).
Of the funds allocated to states for the Youth Activities program (as well as for the Adult and Dislocated Worker programs), not more than 15% can be reserved for statewide activities (only 5% of reserved funds may be used for administrative activities, per WIOA) (40). States must use these funds for certain specified activities, and may use the funds for other specified activities. For example, WIOA requires states to use the statewide funds to carry out monitoring and oversight activities of the Youth Activities program (and Adult and Dislocated Worker programs), which may include a review comparing the services provided to male and female youth (41).
The balance of funding that goes to states is allocated to local workforce development areas on the same basis that Youth Activities funds are allocated to states, to take into account the relative numbers of unemployed individuals and low-income youth in the area compared to other local areas of the state. In addition, the law includes provisions for minimum (90% of the average allocation for the preceding two years) and maximum (130% of the average allocation for the preceding two years) funding that goes to local areas (42).  Local areas may reserve no more than 10% of funds allotted under the program for administrative costs.


Elements of Local Programs

Job training and employment programs that are funded under WIOA and carried out by local WDBs are responsible for providing direct services to youth participants. The programs must be designed to include an objective assessment of the youth’s skills, and they must develop service strategies for these youth that are linked to employment goals (43). These service strategies must be directly linked to one or more of the indicators of performance for the program and they must identify career pathways that include both education and employment goals. Each local program for youth must also provide specific services, or elements. Table 3 shows the 14 elements required under WIOA. WIOA amended some of these elements and added some new ones. The table is organized based on whether the elements are targeted for educational achievement, employment services, linkages between educational achievement and employment services, leadership development activities, additional support for youth services, and other activities.

Table 3: Elements of Youth Programs as Specified Under WIOA

Table 3: Elements of Youth Programs as Specified Under WIOA


Local boards must provide each youth with information on the full array of applicable or appropriate services available through the local board, other eligible providers, or one-stop partners, and they must also refer youth to appropriate training and educational programs, among other activities (44). In addition, at least 20% of the funds allocated to the local area must be used to provide youth (whether they are in school or not) with paid and unpaid work experiences that have academic and occupational education as a component (45).
Although local boards have to make all program elements available to youth, each individual youth does not need to participate in all elements. Further, a local program that receives Youth Activities funding is not required to provide all program elements with WIOA funds; however, these other activities would have to be provided by a partner organization, and the other activities must be closely coordinated with the local programs. The program must have an agreement in place if it partners with another organization to ensure that a program element will be offered by that organization. In practice, this means that youth program case managers must contact and monitor the other provider to ensure the activity is of high quality and beneficial to the youth participant (46).


As shown in Table 4, WIOA specifies that youth are eligible for the Activities program if they are ages 14 through 24. In addition, local workforce development areas (and states) must use no less than 75% of funds for serving out-of-school youth. Up to 5% of the in-school youth in a local area may be eligible because they require additional assistance to complete an educational program or to secure or hold employment. A local workforce development area (or state) may adjust the share of out-of-school youth to 50% if the state determines it will be unable to use a certain share of funding to serve these youth (47). WIOA requires in-school youth generally and two groups of out-of-school youth to be low-income, and enables up to 5% of these youth to not meet the income criteria (48).  Youth ages 18 through 21 may enroll in the Youth Activities program or Adult Activities program, or may co-enroll in both programs (49).

Table 4: Youth Program Eligibility Under WIOA

Table 4: Youth Program Eligibility Under WIOA



WIOA established six primary indicators of performance for the Youth program that superseded the WIA performance measures. These six primary indicators apply to all youth, regardless of age, and went into effect at the beginning of PY2016 (50):
•    percentage of program participants who are in education or training activities, or in unsubsidized employment, during the second quarter after exit from the program;
•    percentage of program participants who are in education or training activities, or in unsubsidized employment, during the fourth quarter after exit from the program;
•    median earnings of program participants who are in unsubsidized employment during the second quarter after exit from the program;
•    percentage of program participants who obtain a recognized postsecondary credential, or a secondary school diploma or its recognized equivalent (51), during participation in or within one year after exit from the program;
•    percentage of program participants who, during a program year, are in an education or training program that leads to a recognized postsecondary credential or employment and who are achieving measurable skill gains toward such a credential or employment; and indicators of effectiveness in serving employers (52).  States are required to reach an agreement with DOL, in conjunction with the Department of Education (ED), about the levels of performance for each state. These levels of performance are to be based on specified factors, including how the levels compare with other states’ adjusted levels of performance. Further, states are to ensure the levels are adjusted using an objective statistical model established by DOL (53).

The following sections of the report discuss, in less detail, additional programs for youth that are authorized under WIOA.


Job Corps (54)

Overview and Purpose

The Job Corps program is carried out by the Office of Job Corps within DOL’s Employment and Training Administration, and consists of residential centers throughout the country. The purpose of the program is to provide disadvantaged youth with the skills needed to—obtain secondary school diplomas or recognized postsecondary credentials leading to successful careers in in- demand industry sectors or occupations or the Armed Forces; or enroll in postsecondary education, including apprenticeship programs (55).

Program Structure

Currently, 125 Job Corps centers are in operation, and there is at least one center in every state and Puerto Rico (56).  Of these 125 centers, 26 are known as Civilian Conservation Corps Centers, which are operated by the U.S. Department of Agriculture’s Forest Service, through an interagency agreement with DOL. Programs at these sites focus on conserving, developing, or managing public natural resources or public recreational areas. Most Job Corps centers are located on property that is owned or leased long-term by the federal government. Job Corps campuses include dormitories, classrooms, workshops for various trades, health centers, a cafeteria, a career services building, and administrative buildings. In addition to WIOA and its regulation, centers are to follow detailed guidelines about all aspects of the program as they are outlined in the program’s extensive policy guidance, known as the Policy and Requirements Handbook (57).
As specified under WIOA, Job Corps centers may be operated by a federal, state, or local agency; an area career and technical education school, or residential vocational school; or a private organization. Authorization for new Job Corps centers is contained in appropriations law. DOL initiates a competitive process seeking applicants that are selected based on their ability to coordinate activities in the workforce system for youth; ability to offer career and technical training opportunities that reflect local employment opportunities; relationships with the surrounding communities, employers, and other stakeholders; and (where applicable) past performance. Additionally, under WIOA, an entity applying to operate a center must submit to DOL certain information, such as how employment, education, and other opportunities offered at the center will reflect state and local employment opportunities and a description of the entity’s strong fiscal controls in place, among other information. WIOA specifies the contract may be for up to a two-year period with up to three one-year renewal periods (58).

Services for Students

While at a Job Corps center, students receive the following services:
•    education programs, including English language acquisition programs;
•    career and technical education, work experience, and work-based learning; and
•    recreational activities, physical rehabilitation and development, driver’s education, and counseling, which may include information about financial literacy.

Youth also receive personal allowances while in the program and transition allowances as they are leaving the program. WIOA specifies that these transition allowances are to be incentive- based to reflect the graduate’s completion of academic, career and technical education or training, and attainment of recognized postsecondary credentials (59).
Students tend to experience the program in four stages (60). First, students learn about the program and center through orientation sessions and other outreach efforts conducted by the center and its contractor for outreach and admissions. Second, students who decide they want to pursue the program and are selected to continue on in with career preparation activities in the first few weeks of enrolling in the program. Third, students who continue on focus on career development activities. During this period, students learn and demonstrate career technical, academic, and employability skills. Training focuses on academic subject matters and how they are applied to specific trades or occupations. Students who did not graduate from high school can pursue a high school diploma or GED. Finally, students participate in a period of career transition, in which they receive placement services that focus on transitioning them in full-time jobs that are related to their career and technical training and pay wages that allow them to be self-sufficient, or placing them in higher education or advanced training programs, including apprenticeship programs.
For one year after exiting the program, Job Corps must provide graduates with services that include transition support and workplace counseling. Some graduates may go on to participate in an advanced career training program. These students continue to remain in the program for another year while obtaining additional training and education, such as an Associate’s Degree (61).
DOL contracts with entities—known as outreach and admissions (OA) contractors (though not referred to in the law as such)—to recruit students to the program. OA contractors seek out potential applicants, conduct interviews with applicants to identify their needs and eligibility status, and identify youth who are interested and likely Job Corps participants. Similarly, DOL contracts career transition services (CTS) providers—organizations that enter into a contract or other agreement with Job Corps—to provide placement services for graduates and, to the extent possible, former students. OA and CTS providers work closely with Job Corps centers, and in some cases are operated by the same organizations.

Community Engagement

Each Job Corps center director must establish relationships with employers, applicable one-stop centers and local boards, entities carrying out relevant apprenticeship programs and youth programs, and other stakeholders (62).  Each center must establish a workforce council, made up of private sector employers who must have substantial management and other responsibilities and represent businesses with employment opportunities for youth in the program; representatives of labor organizations (where present) and representatives of employees; and Job Corps students and graduates (63). A majority of the members must be employers. The council must work with local workforce development boards and review local market information to provide recommendations about the center’s education and training offerings.


DOL enters into contracts with nonprofit and for-profit organizations to operate the centers. Contracts are competitively awarded to organizations based on ranked scores, in conjunction with other factors. The contract period is two years, with three one-year-option renewals. DOL transfers funding for Civilian Conservation Centers to the U.S. Department of Agriculture (USDA) under an interagency agreement.


Job Corps participants must be ages 16 through 24 (64), low-income, and be one or more of the following: (1) basic skills deficient; (2) a school dropout; (3) homeless, a runaway, or a foster child (including an individual who was in foster care and has aged out of foster care); (4) a parent; (5) victims of a severe form of trafficking, as defined by the Trafficking Victims Protection Act; or (6) an individual in need of additional education, vocational training, or intensive counseling and related assistance in order to participate in regular schoolwork or to secure and maintain employment. A veteran is eligible if he or she meets the eligibility criteria; however, the income requirement does not apply if the veteran’s income earned in the military (within the six-month period prior to applying for the program) exceeds the income limit (65).
Job Corps centers take additional factors into consideration when selecting participants, such as whether the program can best meet their educational and vocational needs and whether the youth can engage successfully in group situations and settings. The applicant must also pass a background check that is conducted in accordance with applicable state and local laws (66). WIOA prohibits an individual from being denied a position in the Job Corps program solely on the basis of his or her contact with the criminal justice system, except that an individual can be denied a position if he or she has been convicted of a felony consisting of murder (as described in Title 18 of the U.S. Code), child abuse, or a crime involving rape or sexual assault (67). Each Job Corps center must develop standards for student conduct and implement what is known as a zero tolerance policy for offenses related to violence and drug and alcohol use, and selected other behaviors. Students are dismissed from the program if they violate this policy.
Students are to be assigned to the center that offers the type of career and technical education and training that he or she selects (unless the parent or the guardian of an enrollee under 18 objects). Among the centers that offer such education and training, the enrollee is to be assigned to the one closest to his or her home (68). No more than 20% of participants may live off the grounds of the Job Corps center (69).
WIOA specified that no individual may be enrolled in Job Corps for more than two years, except when completing an advance training program that would require the individual to participate for more than an additional year (as permitted for such a program); (2) an individual with a disability who would reasonably be expected to graduate, if allowed to participate for up to an additional year; and (3) in the case of an individual who participates in national service (as authorized by the Civilian Conservation Corps program) who may extend enrollment to equal the period of such national service (70).


WIOA directs DOL to establish expected levels of performance for the program and individual centers that relate to each of the six primary indicators of performance for the Youth Workforce Activities program. These indicators include (1) entry into education, training, or unsubsidized employment (during both the (a) second quarter and (b) fourth quarter after exiting the program); (2) median earnings; (3) obtaining a recognized postsecondary credential or secondary school diploma or its equivalent; (4) participation in an education or training program that leads to a credential or employment; and (5) program effectiveness in serving employers (71).
WIOA further specifies performance measures for recruiters (outreach and admissions) and CTS contractors. The OA performance measures pertain to recruitment and performance of students, as well as some of the same information that is to be included in a DOL report to Congress (72). This report must include information on the performance of each center, the program overall, and the OA and CTS contractors; demographic information on enrollees; the number of graduates who entered the Armed Forces, apprenticeships, unsubsidized employment, and postsecondary education; average wage of graduates; total cost per enrollee and graduate; information regarding the state of Job Corps facilities and buildings; and information regarding the national and community service activities of students, particularly those enrolled at Civilian Conservation Centers, among other information (73).

Performance Oversight

WIOA designates centers as high-performing based on their ranking and performance under the primary indicators of performance for youth. It also enables the operator of a high-performing center to compete in any competitive selection process carried out for an award to operate such center (74).
WIOA specifies that a Job Corps center operator failing to meet expected performance levels can be placed under a performance improvement plan (PIP). PIPs are documented plans that outline deficiencies in program performance, corrective actions, and targets for improvement. The plan is to encompass certain actions taken by DOL during a one-year period, including providing technical assistance to the centers; changing the career and technical training offered at the center; changing the management staff of the center; replacing the operator of the center; reducing the capacity of the center; relocating the center; or closing the center. WIOA also enables DOL to establish additional PIPs when a Job Corps center fails to meet performance requirements. These discretionary PIPs have to include the actions described above (75).
WIOA provides that DOL may not renew the agreement with a center operator if in the most recent two preceding years for which data are available the center is ranked in the lowest 10% of centers and fails to achieve an average of 50% or higher in the expected levels of performance under each of the primary indicators of performance for eligible youth in the program (76). The law allows DOL to renew an agreement with these centers (for up to two years and if in the best interest of the program) under certain circumstances (e.g., performance is due to circumstances beyond the operator’s control, etc.), and specifies standards that all centers must meet for agreements to be renewed (e.g., satisfactory record of integrity and business ethics, etc.). DOL must inform Congress of such renewals. WIOA specifies that DOL must select another entity to operate a Civilian Conservation Center if it fails to meet the expected levels of performance relating to the primary indicators of performance or fails to improve performance after three program years (77).
Prior to the closure of any Job Corps center, DOL must ensure (1) that the proposed decision to close the center is announced in advance to the general public through publication in the Federal Register or other appropriate means; (2) that a reasonable comment period, not to exceed 30 days, is established for interested individuals to submit written comments to the Secretary; and (3) that the Member of Congress who represents the district in which a center is located is notified within a reasonable period of time in advance of any final decision to close the center.
Finally, WIOA directs DOL to provide for a third-party evaluation of the program every five years, and to submit the results to Congress. The evaluation must address the general effectiveness of the program in relation to its costs; the effectiveness of the performance measures for the program; the effectiveness of the structure and mechanisms for delivering services; the impact of the program on the community, businesses, and participants involved; the extent to which the program and activities meet the needs of various demographic groups, and other such factors that may be appropriate (78).

Financial Oversight

WIOA requires DOL to prepare and submit reports to Congress that include information about implementing financial oversight measures suggested in a 2013 DOL IG report about oversight of Job Corps funding (79), a description of any budgetary shortfalls in the period covered by the report, and an explanation for approving contract expenditures that are in excess of the amount specified under a contract. The reports are to be provided every six months for an initial three-year period, then annually for another two years. WIOA further requires DOL to submit an additional report to Congress if the program has a budget shortfall, including an explanation of how the shortfall will be addressed. The report must be submitted within 90 days after the shortfall is identified (80).


YouthBuild (81)

Overview and Purpose

In 2007, YouthBuild was transferred from the Department of Housing and Urban Development to DOL under the YouthBuild Transfer Act (P.L. 109-281). As stated in WIOA, the purpose of YouthBuild is to (1) enable disadvantaged youth to obtain the education and employment skills necessary to achieve economic self-sufficiency in occupations in demand and post-secondary education and training opportunities; (2) provide disadvantaged youth with opportunities for meaningful work and service to communities; (3) foster the development of employment and leadership skills and commitment to community development among youth in low-income communities; (4) expand the supply of permanent affordable housing for homeless individuals and low-income families by utilizing the energy of disadvantaged youth; and (5) improve the quality and energy efficiency of community and other nonprofit and public facilities, including those facilities that are used to serve homeless and low-income families (82).

Program Structure

DOL competitively awards YouthBuild funds to organizations that carry out the program in cooperation with subgrantees or contractors or through arrangements made with local education agencies and certain other entities. Entities that are eligible to apply for funding include a public or private nonprofit agency or organization, including a consortium of such agencies or organizations. Specifically, such entities may include community-based or faith-based organizations; entities that carry out activities authorized under certain other parts of WIOA, such as a local workforce development board; community action agencies; state or local housing development agencies; an Indian tribe or agencies primarily serving Indians; state or local youth service or conservation corps; or any other entity eligible to provide education or employment training under a federal program (83).
While in the program, youth participate in a range of education and workforce investment activities, as listed in Table 5. These activities include instruction, skill building, alternative education, mentoring, and training in rehabilitation or construction of housing. Notably, any housing unit that is rehabilitated or reconstructed may be available only for rental by, or sale to, homeless individuals or low-income families; or for use as transitional or permanent housing to assist homeless individuals achieve independent living. All educational programs, including programs that award academic credit, and activities supported with YouthBuild funds must be consistent with applicable state and local educational standards.
At least 40% of the time, youth must participate in certain work and skill development activities (these activities are denoted by footnote “a” in Table 5). At least an additional 50% of the time, participants must be engaged in education and related services and activities designed to meet their educational needs (these activities are denoted by footnote “b” in Table 5). If approved by the DOL Secretary, training and supports may be provided in additional in-demand industry sectors or occupations. This is consistent with a 2012 regulation for the program that enables grantees to expand their occupational skills training beyond construction skills training; however, all programs must still provide training in the construction trades (84).

Table 5: Eligible Activities Funded by YouthBuild as Specified Under WIOA

Table 5: Eligible Activities Funded by YouthBuild as Specified Under WIOA


Youth are eligible for the program if they are (1) ages 16 through 24; (2) a member of a low- income family, a youth in foster care, a youth offender, an individual with a disability, a child of incarcerated parents, or a migrant youth; and (3) a school dropout. However, up to 25% of youth in the program are not required to meet the income or dropout criteria, so long as they are basic skills deficient despite having earned a high school diploma, GED, or the equivalent; or have been referred by a high school for the purpose of obtaining a high school diploma.


Grants are competitively awarded to organizations based on ranked scores, in conjunction with other factors, such as the applicant’s potential for developing a successful YouthBuild program; the need for the program in the community; the applicant’s commitment to providing skills training, leadership development, and education to participants; regional distribution of grantees; and the applicant’s coordination of activities to be carried out with certain other stakeholders, including employers, one-stop partners, and national service and other systems; among other criteria.
DOL makes awards for three years (two years of program operations with a one-year period of follow-up). Applicants must provide cash or in-kind resources equivalent to at least 25% of the grant award amount as matching funds. Prior investments and federal resources do not count toward the match.


WIOA requires YouthBuild grantees to meet the primary indicators of performance for eligible youth described in the Youth Activities program. Specifically, these indicators pertain to entry into education, training, or unsubsidized employment (both two and four quarters after exiting the program); median earnings; obtaining a recognized postsecondary credential or secondary school diploma or its equivalent; participation in an education or training program that leads to a credential or employment; and program effectiveness in serving employers (85).


Reentry Employment Opportunities Program (86)

Overview and Purpose

Grants to provide education and employment activities for youth offenders have been funded by DOL since FY1999 (87). Under WIA, these grants were made part of the Reintegration of Ex- Offenders program. Funding for the program was authorized under both WIA and Section 112 (Responsible Reintegration of Offenders) of the Second Chance Act (P.L. 110-199), enacted on April 9, 2008. The Second Chance Act authorizes DOL to make grants to nonprofit organizations for the purpose of providing mentoring, job training and job placement services, and other comprehensive transitional services to assist eligible offenders ages 18 and older in obtaining and retaining employment. Following the enactment of WIOA, Congress has appropriated funding for the program, now known as the Reentry Employment Opportunities program, under the authority of Section 169 of WIOA and the Second Chance Act. Section 169 authorizes evaluations and research.
The youth component of the REO program (and its predecessor programs) has been comprised of related initiatives that seek to assist youth offenders and youth at risk of dropping out (or who have dropped out) with pre-release, mentoring, housing, case management, and employment services; to reduce violence within persistently dangerous schools through a combination of mentoring, educational, employment, case management, and violence prevention strategies; and to provide alternative education and related services for youth at risk of involvement with the justice system (88). Currently , the program supports education and reentry initiatives.

Program Structure

The earliest DOL initiatives for youth offenders, from FY1999 through FY2004, operated under what is known as the Youth Offender Demonstration Project (YODP) (89). The pilot funded 52 grantees to assist youth at risk of court or gang involvement, youth offenders, and gang members ages 14 to 24 in finding long-term employment.
The more contemporary grant programs for youth offenders have funded multiple projects in recent years that have a focus similar to the earlier projects under YODP. These projects have included (1) education-related grants; (2) apprenticeship and related grants under grants collectively called Categorical Grants (Youth Offender Registered Apprenticeship, Alternative Education, and Project Expansion Grants); (3) grants that focus on reentry, including Beneficiary- Choice Demonstration, High Growth Youth Offender Initiative, Planning, State/Local Implementation, and Replication Grants; and (4) grants that focus on community service, including Civic Justice Grants and Serving Young Adult Ex-Offenders through Training and Service Learning. Grantees have included local and state governments, nonprofit organizations, including faith-based organizations; school districts; and community colleges (90).
FY2016 appropriations support an education-related grant, the Pathways to Justice Careers program. Funds have been provided to five nonprofit organizations and two local governments to support youth 16 to 21 who are at risk of dropping out of high school, becoming involved in the juvenile justice system, or already have had involvement in the juvenile justice system. The program focuses on providing mentoring—by individuals in justice-related positions (e.g., police officers, fire fighters, lawyers, etc.)—and career training that uses a career pathways model for youth who are in school. A career pathway model includes a sequence of rigorous academic and career and technical education courses that result in educational and skills credentials. The program also aims to ensure that youth graduate from high school and/or pursue further training or post-secondary education.
A reentry program, Reentry Demonstration Projects for Young Adults, is also funded with FY2016 appropriations. These projects are designed to assist youth ages 18 to 24 who are reentering, with a focus on interventions such as mentoring, registered apprenticeships, family unification efforts, and other promising practices that focus on providing occupational training and credentials. DOL intends to conduct a rigorous evaluation of the seven grantees.


Each of the initiatives funded under the Reentry Employment Opportunities program (and its predecessor programs) have generally served select groups of at-risk youth. However, the projects generally serve youth ages 14 and older (or 18 or older) who have been involved with or have a high risk of involvement in gangs or the juvenile justice system or criminal justice system.


As noted, grants have been competitively awarded to entities such as community-based organizations and state and local juvenile justice agencies, based on ranked scores and other factors, depending on the project. Only schools that meet the criteria of “persistently dangerous,” as specified by the states and as permitted under the Elementary and Secondary Education Act were eligible to apply for funds under the Persistently Dangerous Schools Initiative (91). Allocations have varied for each of the projects, but, generally, grantees have received grants of $1 million to $5 million for one or more years.


DOL has three performance measures for each REO initiative: (1) attainment of a degree or industry-recognized certificate for individuals age 18 or older; (2) literacy and numeracy attainment; and (3) out-of-school participants age 18 or older who are placed in unsubsidized jobs, post-secondary education, or occupational training (92).



1.     CRS Report R42519, Youth and the Labor Force: Background and Trends, by Adrienne L. Fernandes-Alcantara
2.    Two rules accompany the WIOA law. U.S. Department of Labor (DOL), Employment and Training Administration (ETA), “Workforce Innovation and Opportunity Act; Final Rule,” 81 Federal Register 56072, August 19, 2016; and U.S. Department of Labor, Employment and Training Administration and Department of Education, “Workforce Innovation and Opportunity Act; Joint Rule for Unified and Combined State Plans, Performance Accountability, and the One-Stop System Joint Provisions; Final Rule,” 81 Federal Register 56072, August 19, 2016. See other DOL, ETA resources: “Workforce Innovation and Opportunity Act,”; Training and Employment Guidance Letter (TEGL) No. 19-14, “Vision for the Workforce System and Initial Implementation of the Workforce Innovation and Opportunity Act of 2014,” February 19, 2015; and TEGL No. 23-14, “Workforce Innovation and Opportunity Act (WIOA) Youth Program Transition.” See also, CRS Report R44252, The Workforce Innovation and Opportunity Act and the One-Stop Delivery System, by David H. Bradley.
3.    Most workforce programs operate on a program year basis, which extends from July 1 of one year through June 30 of the following year.
4.    For further information about youth prospects in the labor market, see CRS Report R42519, Youth and the Labor Force: Background and Trends, by Adrienne L. Fernandes-Alcantara; and CRS Report R40535, Disconnected Youth: A Look at 16 to 24 Year Olds Who Are Not Working or In School, by Adrienne L. Fernandes-Alcantara.
5.    DOL, BLS, “Employment projections: Earnings and Unemployment Rates by Educational Attainment,” March 15, 2015,
6.    Emily Richards and David Terkanian, “Occupational Employment Projections to 2024,” Monthly Labor Review, December 2015, pp. 9-10, 2022.pdf. (Hereinafter Emily Richards and David Terkanian, “Occupational Employment Projections to 2024.”) See also, Anthony P. Carnevale, Nicole Smith, and Jeff Strohl, Help Wanted: Projections of Jobs and Education Requirements through 2018, Georgetown University, Center on Education and the Workforce, June 2010,
7.    Northeastern University, Center for Labor Market Studies, The Consequences of Dropping Out of High School: Joblessness and Jailing of High School Dropouts and the High Cost for Taxpayers, October 1, 2009,; Paul E. Barton, One Third of a Nation: Rising Dropout Rates and Declining Opportunities, Educational Testing Services, February 2009, Media/Education_Topics/pdf/onethird.pdf; and Clive R. Belfield, Henry M. Levin, and Rachel Rosen, The Economic Value of Opportunity Youth, prepared for the Corporation for National and Community Service and the White House Council for Economic Solutions, January 2012,
8.    Unless otherwise noted, this section draws heavily on an archived report by the Congressional Research Service, Youth Employment: A Summary History of Major Federal Programs, 1933-1976. Available upon request.
9.    John H. Bremner, Tamara K. Hareven, and Robert M. Mennel, eds., Children & Youth in America, Vol. II: 1866- 1932, Parts 1-6 (Cambridge, MA: Harvard University Press, 1971), pp. 687-749.
10.    Much of this section on YEDPA was drawn from Charles L. Betsey, Robinson G. Hollister, and Mary R. Papageorgiou, eds., Youth Employment and Training Programs: The YEDPA Years, National Research Council, Washington, DC, 1985, true&_&ERICExtSearch_SearchValue_0=ED265245&ERICExtSearch_SearchType_0=no&accno=ED265245. (Hereinafter, Betsey, Hollister, and Papageorgiou, Youth Employment and Training Programs.)
11.     A fourth program, the Young Adult Conservation Corps (YACC), was operated by the Department of Agriculture and Department of the Interior, in cooperation with DOL, and targeted unemployed youth ages 16 to 23 who were not necessarily disadvantaged. This program operated year-round and was separate from a similarly named program, the Youth Conservation Corps (YCC). YCC was permanently authorized by the Youth Conservation Corps Act of 1970 (P.L. 91-378) and continues to operate.
12.     Other parts of YEDPA required close coordination with the school system. According to an assessment of the act’s implementation, the schools maintained their focus on in-school youth and provided essentially the same set of educational services as usual. The lack of influence of YEDPA on schools may be largely attributed to the schools’ resistance to allocating services according to income and the schools’ perception that their mission was exclusively to educate students. Betsey, Hollister, and Papageorgiou, Youth Employment and Training Programs, pp. 84-87.
13 .    Unless otherwise noted, this section was drawn heavily from an archived report by the Congressional Research Service, The Job Training Partnership Act: A Compendium of Programs. Available upon request.
14.     Archived report by the Congressional Research Service, Job Training Partnership Act: Legislation and Budget Issues. Available upon request.
15.     Archived report by the Congressional Research Service, The School-to-Work Opportunities Act. Available upon request.
16.    For further information about the Adult and Dislocated Worker programs, see CRS Report RL33687, The Workforce Investment Act (WIA): Program-by-Program Overview and Funding of Title I Training Programs, by David H. Bradley.
17.     Section 101(b)(1)(II) of WIOA.
18.     Section 102(b)(1)(D) of WIOA.
19.      Section 108(b)(9) of WIOA.
20.      Section 107(b)(4)(ii) of WIOA.
21.     Section 121(b)(1)(B) of WIOA. For further information, see CRS Report R44252, The Workforce Innovation and Opportunity Act and the One-Stop Delivery System, by David H. Bradley.
22.     Section 189(g)(1)(A) of WIOA. Section 173(h)(2), which pertains to authorization for YouthBuild, states that notwithstanding Section 189(g), appropriations for any fiscal year for programs and activities carried out under this section are to be available for obligation only on the basis of a fiscal year.
23.      Section 189(g)(2) of WIOA.
24.      Title I, Chapter 2 of WIOA and 20 C.F.R. 20 C.F.R. §681.
25.      Section 102 and Section 103 of WIOA.
26.      Section 121 of WIOA.
27.      Section 107(b) of WIOA.
28.      Section 107(2)(iv) of WIOA.
29.     Section 123(b) of WIOA. The regulations (20 C.F.R. §681.400) specify that local workforce development boards may choose to directly provide some or all youth workforce activities.
30.     Section 107(d)(10(B) and Section 123 of WIOA.
31.      20 C.F.R. §681.700.
32.      Section 129(c)(3)(C) of WIOA.
33.      Section 107(b)(4)(A)(ii) of WIOA.
34 .     20 C.F.R. §681.100.
35.     The outlying areas comprise the U. S. Virgin Islands, Guam, American Samoa, the Commonwealth of the Northern Mariana Islands, the Republic of the Marshall Islands, the Federated States of Micronesia, and the Republic of Palau. WIOA specifies that the Republic of Palau may not apply for funding during any period during which DOL and the Department of Education (ED) determine that a Compact of Free Association (COFA) is in effect and contains provisions for training and education assistance that prohibit the assistance provided under WIOA. COFA defines the relationship that Palau has entered into as an associated state agreement with the United States. No such determination prohibiting assistance to Palau has been made.
36      Section 127(1) of WIOA.
37.     Section 127(b)(1)(B)(ii) of WIOA. In practice, funds for outlying are based on a formula determined by the Secretary that was used under WIOA. See, for example, DOL, ETA, Training and Employment Guidance Letter (TEGL) No. 17- 5, “Workforce Innovation and Opportunity Act (WIOA) Adult, Dislocated Worker and Youth Activities Program Allotments…. ” April 5, 2016.
38.     The word “relative” means the number of individuals in a state compared to the total number in all states.
39.     WIOA provides small state minimums such that no state receives less than the total of three-tenths of 1% of $1 billion that is allocated to states, or two-thirds of 1% of the excess if the allocation exceeds $1 billion.
40.      Section 128(a) of WIOA.
41.      Section129(b) of WIOA.
42.      Section 128(b) of WIOA.
43.      Section 129(c) of WIOA.
44.      Section 129(c)(3) of WIOA.
45.     Section 129(c)(3)(4) of WIOA
46.      20 C.F.R. §681.470. 47 A local area is exempt if it is in a state that (1) receives 90% of the allotment percentage for the preceding fiscal year for the Youth Activities program (per Section 127(b)(1)(C)(iv)(I)) or Adult program (Section 132(b)(1)(B)(iv)(I)); or (2)    receives the small state minimum allotment under the Youth Activities program (per Section 127(b)(1)(C)(iv)(II)) or Adult program (per Section 132(b)(1)(B)(iv)(II). A local area that meets one of these two criteria would be able to decrease the funds used for out-of-school youth to 50% of their allotment (that is used for non-administrative costs) only if the state (1) determines that the local area will be unable to use at least 75% of the funds available due to a low number of out-of-school youth; (2) submits to the Secretary of DOL, on behalf of the local area, a request including a proposed percentage decrease (not less than 50%), and (3) a summary of the analysis about the determination. This request has to be approved by the Secretary.
48.      Section 129(a)(4) of WIOA
49.      20 C.F.R. §681.430.
50.      Section 116(A) of WIOA.
51.     Program participants who obtain a secondary school diploma or its recognized equivalent are to be included in the percentage counted if, in addition to obtaining such diploma or its recognized equivalent, they have obtained or retained employment or are in an education or training program leading to a recognized postsecondary credential within one year after exit from the program.
52.     The law specifies that DOL and the Department of Education are to jointly develop and establish one or more indicators of performance that indicate the effectiveness of the Youth program (and Adult and Dislocated Worker programs) in serving employers.
53.      Section 116(b(3)(v) of WIOA.
54.      Title I, Chapter 4, Subtitle C of WIOA and 20 C.F.R. §670.
55.      Section 141 of WIOA.
56.     DOL closed the Treasure Lake Job Corps Center in Oklahoma in 2014 and the Ouachita Civilian Conservation Center in Arkansas in 2016 due primarily to low performance. See, DOL, ETA, “Final Notice of Job Corps Center for Closure,” 79 Federal Register 61099, October 9, 2014; and DOL, ETA, “Final Notice of Job Corps Center for Closure,” 81 Federal Register 43250, July 1, 2016.
57.     DOL, ETA, Office of Job Corps, Policy and Requirements Handbook, prh.sflb. (Hereinafter, DOL, ETA, Office of Job Corps, Policy and Requirements Handbook.)
58.     Section 147(a) of WIOA.
59.      Section 150 of WIOA.
60.    DOL, ETA, Office of Job Corps, Policy and Requirements Handbook: and U.S. Government Accountability Office, Job Corps Better Targeted Career Training and Improved Preenrollment Information Could Enhance Female Residential Student Recruitment and Retention, GAO-09-470, June 2009.
61.      Section 148(c) of WIOA.
62.      Section 153 of WIOA.
63.      Section 154(c) of WIOA.
64.     No more than 20% of participants may be ages 22 through 24 on the date of enrollment. The age limit may be waived by DOL, in accordance with DOL regulations, for individuals with a disability.
65.      Section 145 of WIOA.
66.    Section 145(a) of WIOA.
67.     Section 145(b) of WIOA. 68 Section 145(d) of WIOA. 69 Section 147(b) of WIOA. 70  Section 146 of WIOA.
71.      Section 159(c)(1) of WIOA.
72 .     Section 159(c)(2) and Section 159(c)(3) of WIOA.
73.      Section 159(d) of WIOA.
74.      Section 147(b) of WIOA.
75.      Section 159(f) of WIA and WIOA.
76.    Section 147(g) of WIOA.
77.      Section 147(g)(4) of WIOA.
78.      Section 161(b) of WIOA.
79.     DOL, Office of Inspector General, The U.S. Department of Labor’s Employment and Training Administration Needs to Strengthen Controls Over Job Corps Funds.
80.      Section 161(a) of WIOA.
81.    Title I, Chapter 4, Subtitle D, Section 171 of WIOA. 82 Section 171(a) of WIOA (Section 173A(a) of WIA). 83  Section 173(b) of WIOA (Section 173A(b) of WIA).
84.     U.S. Department of Labor, Employment and Training Administration, “YouthBuild Program Final Rule,” 77 Federal Register 9112, February 15, 2012.
85.      Section 171(c) of WIOA (and Section 173(c) of WIA).
86.      Title I, Chapter 4, Subtitle D, Section 169 of WIOA.
87.     This program was known as the Youth Offender Pilot Program, and funded 14 communities that provided educational, employment, re-entry, and other services to youth.
88.     This is based on a review of initiatives funded by the Reintegration of Ex-Offenders program. DOL, ETA, Youth Services Discretionary Grants,
89.     The earliest funding for the program was authorized under Title IV of the Job Training Partnership Act. See U.S. Department of Labor, Employment and Training Administration, Notice Inviting Proposals for Youth Offender Demonstration Projects, August 28, 1998,
90.     For a list of grantees and grant funding amounts, see DOL, ETA, Youth Services Discretionary Grants,
91.     ESEA requires each state receiving funds under the act to establish and implement a statewide policy requiring that a student attending a persistently dangerous school, as determined by the state in consultation with a representative sample of local education agencies (LEAs), or a student who becomes a victim of a violent criminal offense on school grounds be allowed to attend a safe school within the LEA.
92.      CRS correspondences with DOL, ETA, December 2016.