Common Pathogenic Mechanisms between Down Syndrome and Alzheimer's Disease: Steps toward Therapy

Book Series: Recent Advances in Alzheimer Research

Volume 1

by

Ahmad Salehi, Michael Rafii, Cristy Phillips

DOI: 10.2174/97816810813801150101
eISBN: 978-1-68108-138-0, 2015
ISBN: 978-1-68108-139-7
ISSN: 2452-2554 (Print)
ISSN: 2452-2562 (Online)



Recommend this eBook to your Library

Indexed in: EBSCO.

Down syndrome is a chromosomal disorder affecting more than 5.8 million individuals worldwide. Down syndrome can be viewed as a comple...[view complete introduction]

Table of Contents

Preface

- Pp. i-iv (4)

Cristy Phillips, Ahmad Salehi and Michael Rafii

Download Free

Acknowledgements

- Pp. v

Cristy Phillips, Ahmad Salehi and Michael Rafii

Download Free

List of Contributors

- Pp. vi-vii (2)

Cristy Phillips, Ahmad Salehi and Michael Rafii

Download Free

The Management and Treatment of Down Syndrome and Alzheimer’s Disease: Political and Ethical Issues

- Pp. 3-19 (17)

Betsy Pohlman

View Abstract Purchase Chapter

Clinical Aspects of Down Syndrome with Alzheimer’s Disease Symptomatology

- Pp. 20-41 (22)

George Capone and Meghan O`Neill

View Abstract Purchase Chapter

Diagnosing Alzheimer’s Dementia in People with Down Syndrome

- Pp. 42-68 (27)

Shoumitro Deb

View Abstract Purchase Chapter

Managing Problem Behaviors in People with Down Syndrome and Alzheimer`s Disease

- Pp. 69-89 (21)

Shoumitro Deb

View Abstract Purchase Chapter

Sleep Abnormalities in Down Syndrome and Alzheimer’s Disease: Cognitive Consequences and New Therapeutic Strategies

- Pp. 90-115 (26)

Damien Colas

View Abstract Purchase Chapter

Role of Seizures in the Pathophysiology of Down Syndrome and Alzheimer’s Disease

- Pp. 116-125 (10)

Sheffali Gulati, Biswaroop Chakrabarty and Rachana Dubey

View Abstract Purchase Chapter

In Vivo Brain Imaging in Down Syndrome: Functional and Structural Similarities with Alzheimer’s Disease

- Pp. 126-150 (25)

Elizabeth Head, David Powell, Brian T. Gold, Ai-Ling Ling, Donna M. Wilcock and Frederick A. Schmitt

View Abstract Purchase Chapter

Neuropathological Phenotype in Alzheimer’s Disease and Down Syndrome: Chemical Nature and Anatomical Localization

- Pp. 151-172 (22)

Laura J. Pulford, Sarah Müller, Frances K. Wiseman and Amy M. Pooler

View Abstract Purchase Chapter

The Role of Inflammatory Processes in the Pathophysiology of Down Syndrome and Alzheimer’s Disease

- Pp. 173-188 (16)

Donna M. Wilcock and Elizabeth Head

View Abstract Purchase Chapter

Mouse Models of Down Syndrome and Alzheimer’s Disease: Similarities and Differences

- Pp. 189-248 (60)

Noemí Rueda and Carmen Martínez-Cué

View Abstract Purchase Chapter

Role of APP in the Pathophysiology of Down Syndrome and Alzheimer’s Disease

- Pp. 249-272 (24)

Kumar Sambamurti, Miguel A. Pappolla, Debomoy K. Lahiri, Nigel H. Greig, Panneerselvam Chinnakannu, Ann-Charlotte Granholm and Vasudevaraju Padmaraju

View Abstract Purchase Chapter

Evolution of Monoaminergic System Degeneration in Down Syndrome and Alzheimer’s Disease

- Pp. 273-291 (19)

Cristy Phillips, Atoossa Fahimi, Fatemeh S. Mojabi and Ahmad Salehi

View Abstract Purchase Chapter

Overview of Recent Clinical Trials for Cognitive Dysfunction in Alzheimer’s Disease and Down Syndrome

- Pp. 292-300 (9)

Michael S. Rafii

View Abstract Purchase Chapter

Concluding Remarks

- Pp. 301-302 (2)

Ahmad Salehi, Michael Rafii and Cristy Phillips

Download Free

Subject Index

- Pp. 303-308 (6)

Cristy Phillips, Ahmad Salehi and Michael Rafii

Download Free

Preface

It has been long been known that aging individuals with Down syndrome (DS) develop Alzheimer’s disease (AD)-related pathology [1] and have an increased risk of dementia [2]. As the most common form of live-born aneuploidy [3], DS affects 6 million people worldwide. The condition is associated with varying degrees of cognitive, behavioral, and psychological disturbances. Fortunately, significant advances in social and medical care have dramatically extended the life span of affected individuals in recent years. Whereas the average life expectancy was approximately 9 years of age in 1929 [4], it was approximately 60 years of age in 2000. Yet accompanying this increase is an ever-expanding proportion of people affected by early-onset AD, creating an imperative to disentangle the shared pathogenic mechanisms that underlie cognitive decline in both disorders. Emboldened by this challenge, a number of scientists from across the world have increasingly made effective and efficient progress towards understanding the genetic, neuropathological, and clinical correlates associated with cognitive decline in DS and AD. Indeed, a review of PubMed reveals that more than 100,000 articles have been published on topics related to AD (using term “Alzheimer’s disease” or “Alzheimer disease”) and 18,000 articles have been published on DS (“Down syndrome” or “Down’s syndrome”) since 1985. Comparatively, there were only 1900 papers that examined topics related to both DS and AD (approximately < 2% of the total). Notwithstanding, few resources have attempted to comprehensively summarize the tremendous progress that has been made in this field in recent years. To fill this void, we have assembled a team of world-renowned scientists in order to gather a compendium on the topic of shared pathogenic mechanisms in DS and AD.

Accordingly, in Chapter 1, Dr. Elizabeth Pohlman chronicles a history of changing societal attitudes towards persons with DS and AD and, in so doing, acknowledges responses that have ranged from deprivation and abuse, tolerance and protection, understanding and acceptance, to one that increasingly approximates full social and medical inclusion. Dr. Pohlman highlights current challenges that face contemporary society, particularly those deriving from the promise of cognitive enhancing therapies. Through a frank and honest discussion of this topic, she challenges us to consider the full gamut of ethical and political issues related to science and medical care for persons with DS and AD. In Chapter 2, Drs. Capone and O’Neil provide professionals with a framework for the general evaluation and management of medical care for persons with DS. Due attention is given to clinical conditions that are frequently observed in this population (e.g., mental health and sensory issues, seizure and sleep disorders, orthopedic abnormalities, feeding and swallowing difficulties, and cardiac impairments) and how these conditions present throughout the lifespan. Accordingly, this section fosters an awareness of how optimal medical management can be used to improve overall health and quality of life for affected individuals.

In Chapter 3, Dr. Shoumitro Deb describes the best practice for making an early and accurate diagnosis of dementia in aging persons with DS and long-standing cognitive impairment. Throughout the text, he carefully articulates characteristic similarities and differences in the phenotypic expression of dementia in adults with DS and AD. Moreover, he details how neuropsychological tests and informant-rated scales can be used to gather longitudinal information to detect subtle changes in status in aging adults with DS and, in turn, to optimize dementia care and intervention.

In Chapter 4, Dr. Shoumitro Deb provides a foundation to better understand the origin of problem behaviors frequently exhibited by persons with dementia. Moreover, he describes key supports that can be utilized to promote the wellbeing of affected individuals, including pharmacologic and nonpharmacologic interventions. Finally, he underscores the importance of a multidisciplinary approach to care to better meet the diverse service needs of adults with dementia and cognitive disability who reside in the community.

In Chapter 5, Dr. Damien Colas provides compelling evidence that sleep abnormalities contribute to cognitive dysfunction in both DS and AD. Initially he begins with an overview of sleep neurobiology, the mechanisms that regulate the sleep-wake cycle, and the central functions of sleep. Following this, he describes sleep abnormalities common to DS and AD and explains how sleep-based cognitive interventions may one day be utilized to mitigate cognitive dysfunction in both populations.

In Chapter 6, Dr. Gulati and colleagues provide compelling evidence that gene dosage abnormalities contribute to seizure disorder and cognitive dysfunction in DS and AD. Indeed, it has been shown that patients with AD exhibit an increased risk of focal and generalized seizures whereas older persons with DS exhibit an increased rate of late onset myoclonic epilepsy. Accordingly, data presented in this chapter clearly establishes an imperative for the earlier detection and management of seizure disorder to promote more positive outcomes in both the DS and AD population.

In Chapter 7, Dr. Head and colleagues demonstrate how in vivo neuroimaging technology is currently being used to study changes in cognition, function, and brain structure in aging adults with DS. Threaded throughout the text is a frank appraisal of the strengths and weaknesses of the various approaches along with a discussion of future opportunities, including widespread deployment of these technologies for earlier diagnosis and intervention. Clearly articulated in this chapter is the promise that technology holds for elucidating the neurobiological mechanisms that underlie dementia and for evaluating candidate therapeutics.

In Chapter 8, Dr. Pooler and colleagues carefully detail the neuropathological features of the DS brain. Documented in this chapter are characteristic lesions that occur (abnormal amyloid accumulation, tau deposition, synaptic loss, and brain atrophy) with disease progression. Following this is a description of regionally specific neuronal vulnerability commonly seen in DS and AD. Specifically noted are intraneuronal accumulations of Aβ in the DS brain (occurring as early 4 years) in a pattern that is similar to that seen in familial AD. The chapter concludes with a summary of the effects of a number of triplicated and non-triplicated genes on DS/AD pathogenesis.

In Chapter 9, Drs. Wilcock and Head discuss the relevance of inflammatory processes in the pathophysiology of AD and DS. In doing so, they successfully link the role of these processes to the accumulation of Aβ in the brain before discussing how immunotherapies may be utilized to lower brain amyloid levels and modify disease progression. By extrapolating findings from studies of AD, they offer evidence that a host of triplicated gene(s) on HSA21 may contribute to inflammatory processes and dementia in mouse models of DS.

In Chapter 10, Dr. Carmen Martínez-Cué and colleagues explore various transgenic and trisomic mouse models developed to recapitulate AD and DS phenotypes, respectively. This section demonstrates how, despite a number of inherent limitations, the various models have been strategically exploited to uncover the relationship between overexpression of genes and the cellular and molecular mechanisms implicated in AD and DS. Furthermore, a discussion on the vital role that these models play in the development and testing of pharmacotherapeutics is presented.

In Chapter 11, Dr. Kumar Sambamurti and colleagues presents evidence that the amyloid precursor protein gene (APP) plays a vital role in the pathogenesis of both DS and AD. APP is among the ~ 700 HSA21 genes typically triplicated in DS. Yet, it has been shown that adults with DS without triplication of APP do not show AD-related pathology, suggesting that APP contributes of ADpathology in DS. Further supporting this notion is evidence from mouse models of DS and AD that demonstrate that APP is both necessary and sufficient for neurodegeneration. Based upon this rationale, this section ends with a summary of therapeutic strategies that target APP in AD and DS.

In Chapter 12, we (C. Phillips and A. Salehi) review a bevy of neuropathological and biochemical studies implicating monoaminergic dysfunction and cognitive impairment in DS and AD. Indeed, convergent evidence now clearly demonstrates that neurotransmitter imbalances contribute to the cognitive and behavioral abnormalities commonly seen in both disorders. Fortunately, a number of clinical and preclinical studies suggest that treatments that mitigate neurotransmitter imbalances can be used to mitigate cognitive dysfunction, establishing a warrant for future clinical trials in this area.

The ultimate desired outcome for all preclinical research is the translation of findings into well-designed and executed clinical trials. Recognizing this, Dr. Rafii critically reviews in Chapter 13 ongoing clinical trials for cognitive dysfunction in DS. Of particular note is his prediction that continued advances in the field will enable the deployment of active and/ or passive anti-beta-amyloid immunotherapy and Betasite APP cleaving enzyme 1 (BACE) inhibitors in clinical trials for DS in the near future, therapeutic strategies that could impose strong disease modifying effects and mitigate cognitive decline.

Given the evidence presented here, it becomes clear that DS represents a naturally occurring population of individuals at increased risk for AD and, in turn, one that is well positioned to benefit from early evaluation, monitoring, and therapeutic targeting of cognitive dysfunction. Moreover, knowledge that shared pathogenic mechanisms underlie cognitive decline in both disorders suggests that robust crosstalk among researchers from the DS and AD research communities may rapidly accelerate the pace of scientific discovery. In keeping with this notion, it is our sincere hope that this compendium can be leveraged to facilitate a dialogue among researchers, ignite further scientific discovery, and improve patient care.

Cristy Phillips
DDepartment of Physical Therapy
Arkansas State University
Jonesboro, Arkansas
USA

Ahmad Salehi
Department of Psychiatry and Behavioral Sciences
Stanford University School of Medicine and VA Palo Alto Health Care System (WRIISC)
Palo Alto, California
USA

Michael Rafii
Department of Neurosciences
University of California, San Diego
San Diego, California
USA

REFERENCES

  • [1]  Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM. Alzheimer’s disease in Down’s syndrome:clinicopathologic studies. Neurology 1985; 35(7): 957-61.
  • [2]  Holland AJ, Hon J, Huppert FA, Stevens F, Watson P. Population-based study of the prevalence and presentation of dementia in adults with Down’s syndrome. Br J Psychiatry 1998; 172: 493-8.
  • [3]  Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001; 2(4): 280-91.
  • [4]  Bittles AH, Glasson EJ. Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Dev Med Child Neurol 2004; 46(4): 282-6.
  • [5]  Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD, Bitt s AH. The changing survival profile of people with Down’s syndrome: implications for genetic counselling. Clin Genet 2002; 62(5): 390-3.
  • [6]  Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet 2002; 359(9311): 1019-25.

List of Contributors

Editor(s):
Ahmad Salehi
Department of Psychiatry and Behavioral Sciences
Stanford University School of Medicine and VA Palo Alto Health Care System (WRIISC)
Palo Alto, California
USA


Michael Rafii
Department of Neurosciences
University of California, San Diego
San Diego, California
USA


Cristy Phillips
Department of Physical Therapy
Arkansas State University
Jonesboro, Arkansas
USA




Contributor(s):
Ahmad Salehi
Department of Psychiatry & Behavioral Sciences
Stanford University School of Medicine, VA Palo Alto Health Care System (WRIISC)
Palo Alto
California
USA


Ai-Ling Ling
Sanders-Brown Center on Aging
University of Kentucky
Lexington
Kentucky
USA
/
Department of Pharmacology & Nutritional Sciences
University of Kentucky
Lexington
Kentucky
USA


Amy M. Pooler
Basic and Clinical Neuroscience
King’s College London
London
UK


Ann-Charlotte Granholm
Department of Neurosciences
Medical University of South Carolina
South Carolina
USA


Atoossa Fahimi
VA Palo Alto Health Care System (WRIISC)
Palo Alto, California
USA


Betsy Pohlman
Oakland, California
USA


Biswaroop Chakrabarty
Child Neurology Division, Department of Pediatrics
All India Institute of Medical Sciences,
New Delhi
India


Brian T. Gold
Sanders-Brown Center on Aging
University of Kentucky
Lexington
Kentucky
USA
/
Department of Pharmacology & Nutritional Sciences
University of Kentucky
Lexington
Kentucky
USA


Carmen Martínez-Cué
Department of Physiology and Pharmacology
University of Cantabria
Santander
Spain


Cristy Phillips
Department of Physical Therapy
Arkansas State University
Arkansas
USA


Damien Colas
Department of Biology,
Stanford University
371 Serra Mall, Stanford
California
USA


David Powell
Magnetic Resonance Imaging and Spectroscopy Center
University of Kentucky
Lexington
Kentucky
USA
/
Department of Anatomy and Neurobiology
University of Kentucky
Lexington
Kentucky
USA


Debomoy K. Lahiri
Department of Psychiatry
Indiana University School of Medicine
Indiana
USA


Donna M. Wilcock
Sanders-Brown Center on Aging
University of Kentucky
Lexington
Kentucky
USA
/
Department of Physiology and Department of Neurology
University of Kentucky
Lexington
Kentucky
USA


Elizabeth Head
Sanders-Brown Center on Aging
University of Kentucky
Lexington
Kentucky
USA
/
Department of Pharmacology & Nutritional Sciences
University of Kentucky
Lexington
Kentucky
USA


Fatemah Mojabi
VA Palo Alto Health Care System (WRIISC)
Palo Alto, California
USA


Frances K. Wiseman
Institute of Neurology
University College London
London
UK


Frederick A. Schmitt
Sanders-Brown Center on Aging
University of Kentucky
Lexington
Kentucky
USA
/
Department of Physiology and Department of Neurology
University of Kentucky
Lexington
Kentucky
USA


George T. Capone
Department of Pediatrics, Johns Hopkins University
School of Medicine, Neurodevelopmental Medicine, Kennedy Krieger Institute
Maryland
USA


Kumar Sambamurti
Department of Neurosciences
Medical University of South Carolina
South Carolina
USA


Laura J. Pulford
Institute of Neurology
University College London
London
UK


Meghan O’Neill
Johns Hopkins University SOM, Neurodevelopmental Medicine
Kennedy Krieger Institute
Maryland
USA


Michael S. Rafii
Down Syndrome Research and Treatment Center, UC San Diego Health System
La Jolla, California
USA


Miguel A. Pappolla
Department of Neurology
University of Texas
Medical Branch
Texas
USA


H. Greig Nigel
Drug Design & Development Section
National Institute on Aging
Maryland
USA


Noemí Rueda
Department of Physiology and Pharmacology
University of Cantabria
Santander
Spain


Panneerselvam Chinnakannu
Department of Neurosciences
Medical University of South Carolina
South Carolina
USA


Rachana Dubey
Child Neurology Division, Department of Pediatrics
All India Institute of Medical Sciences
New Delhi
India


Sarah Müller
Basic and Clinical Neuroscience
King’s College London
London
UK


Sheffali Gulati
Child Neurology Division, Department of Pediatrics
All India Institute of Medical Sciences
New Delhi
India


Shoumitro Deb
Department of Medicine, Division of Brain Sciences
Imperial College London
London
UK


Vasudevaraju Padmaraju
Department of Neurosciences
Medical University of South Carolina
South Carolina
USA




Advertisement



Webmaster Contact: info@benthamscience.org Copyright © 2017 Bentham Science