Granholm et al., J Alzheimers Dis 2012, 2:1
http://dx.doi.org/10.4172/2161-0460.1000e108
Alzheimer’s Disease &
Parkinsonism
Editorial
Open Access
Alzheimer’s Disease and Down Syndrome: Developing a National Tissue
Repository
Ann-Charlotte Granholm1*, Cynthia T. Welsh2, Kumar Sambamurti1, David Bachman1, H. Ronald Zielke3 and Elliott J. Mufson4
Department of Neurosciences and the Center on Aging, Medical University of South Carolina, USA
Department of Pathology, Medical University of South Carolina, USA
3
Department of Pediatrics, University of Maryland, USA
4
Department of Neurology, Rush University Medical Center, Chicago, IL, USA
1
2
Keywords: Down syndrome; Alzheimer’s disease; Brain bank;
Neuropathology
With the recent Notice of Change in Funding Mechanism for
Human Tissue Banks (NOT-MH-12-020), the NIH has emphasized
the need for widespread availability of high quality human brain tissue
stored with a linked IT system and database. The well-recognized
need for the careful collection of tissues that include good controls
and a variety of disease states also highlights the limitations of animal
models in faithfully replicating the spectrum of defects in human
neurological diseases. The ultimate goal of such a repository is to
obtain a detailed understanding of the defects in the disease to be
able to target and correct them. An important question today is how
to develop appropriate medication paradigms for individuals with
Down syndrome (DS) and Down syndrome related dementia (DSD).
According to the Center for Disease Control (CDC), there are 6,000
babies born with DS every year in the US, and the incidence of DS is 1
in 691 births, an increase from the previously recorded 1 in 733 births.
Individuals with DSD do not respond as well to Alzheimer’s disease
(AD) medications, and some AD medications may be contraindicated
in DSD, due to gastric or cardiac consequences of the trisomy [1]. DS is
caused by a complete or segmental chromosome 21 trisomy, resulting
in variable intellectual ability at birth, and progressive memory loss and
neurodegeneration with age. Most research in DS neuropathology has
focused on development of the central nervous system, but age-related
changes are important, in view of the increased life span observed in
DS over the last few decades [2]. DS leads to pathological hallmarks
of Alzheimer’s disease (AD) by 40 or 50 years of age, coupled with an
increased risk of early onset dementia [2]. One of the major pathways
explored in the pathogenesis of AD is processing of the amyloid
precursor protein, APP [3]. Located on chromosome 21, APP is
triplicated in DS, and amyloid-beta deposition is frequently profound
in these individuals, even in early childhood or adolescence [4]. Thus,
while familial causes of AD are rare, and idiopathic AD is difficult to
model, DS represents a relatively homogenous population with relevant
animal models that can serve to explore biological pathways involved in
both AD and in DSD [5]. The high predictability with which individuals
with DS acquire AD neuropathology and clinical dementia makes this
population important to study.
Because individuals with DS often exhibit deficits in cardiac and
metabolic systems, cholinesterase (AChE) inhibitors prescribed to
AD patients may be contraindicated in some people with DSD [1]. In
addition, a recent multi-site study on the use of donepezil in individuals
with DS [6], revealed variable efficacy, suggestive of phenotypic
variability of DSD. On the other hand, a recent Japanese study
reported improvement in activities of daily living in DSD individuals
maintained on the AChE inhibitor donepezil [7]. Another promising
AD drug, memantine, a glutamate NMDA receptor antagonist, was
recently reported to have very modest, if any, effects on a cohort of DS
individuals with dementia [8]. The investigators concluded that there
is a striking absence of data showing cognitive improvement in DSD
J Alzheimers Dis
ISSN:2161-0460 JADP an open access journal
individuals with pharmacotherapies, and that memantine does not
hold promise for future treatment of DSD. These studies suggest that
novel or modified medications should be developed for DSD, since
individuals with this disorder appear not to respond as wellto existing
AD medications, despite strong experimental evidence in a DS mouse
model for successful treatment with memantine [5]. Consequently,
despite the value of the available animal models, some factors remain
human disease-specific, with resources required for understanding
human disease processes. Therefore, we propose the establishment of
a national Down syndrome repository for brain tissue from cognitively
characterized individuals with, and without, DSD. The availability of
brain tissue from DSD cases will lead to collaborative studies to examine
the neurobiological similarities and differences between people with
DSD and AD, to better understand the underlying pathology. These
findings will provide data as to why individuals with DS and dementia
are relatively unresponsive to AD medication, allow for the examination
of biological mechanisms for the disease process leading to dementia in
DS individuals, and to the development of novel treatment approaches
for DSD.
While there are several studies in the literature showing
neuropathological changes in the DSD versus AD brain [9,10], a concerted
effort has not been made to establish a national repository for clinically,
neuropsychologically and neuropathologically well characterized
DSD subjects including cognitive data. One year ago, a request for
information (RFI) came out from the NIH asking for information
regarding “Acquisition, Processing, Storage, and Distribution of
Human Brain and Other Tissues to Advance Understanding and
Treatment of Down Syndrome” (see NOT-HD-11-001). The request
was issued by the Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD). The Brain and Tissue
Bank for Developmental Disorders at the University of Maryland (Dr.
H. Ronald Zielke, director), has been classified as an NICHD repository
for DS brains, but cognitive information is generally not available for
these specimens. A nationally integrated collection program should
be established, to provide researchers with tissue from multiple brain
regions for both histological and molecular analysis, which can be
correlated with cognitive decline and common biomarkers for AD.
Because of the rapid increase in life expectancy in DS individuals [2],
*Corresponding author: Ann-Charlotte Granholm, Department of Neurosciences
and the Center on Aging, Medical University of South Carolina, USA, E-mail:
granholm@musc.edu
Received March 26, 2012; Accepted March 27, 2012; Published March 29, 2012
Citation: Granholm AC, Welsh CT, Sambamurti K, Bachman D, Zielke HR, et al.
(2012) Alzheimer’s Disease and Down Syndrome: Developing a National Tissue
Repository. J Alzheimers Dis 2:e108. doi:10.4172/2161-0460.1000e108
Copyright: © 2012 Granholm AC, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Volume 2 • Issue 1 • 1000e108
Citation: Granholm AC, Welsh CT, Sambamurti K, Bachman D, Zielke HR, et al. (2012) Alzheimer’s Disease and Down Syndrome: Developing a
National Tissue Repository. J Alzheimers Dis 2:e108. doi:10.4172/2161-0460.1000e108
Page 2 of 2
the time has come to initiate a national collaborative effort to develop
and coordinate a brain donation program for clinical molecular and
pathological research into the processes underlying the biology of DS.
Acknowledgement
This work was made possible by grants from the National Institutes on Aging
(AG012122-16) and NICHD (HD057564).
References
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8. Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, et al. (2012)
MEADOWS trial researchers. Memantine for dementia in adults older than
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9. Head E, Lott IT, Patterson D, Doran E, Haier RJ (2007) Possible compensatory
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Alzheimers Dis 11: 61-76.
10.Sendera TJ, Ma SY, Jaffar S, Kozlowski PB, Kordower JH, et al. (2000)
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J Alzheimers Dis
ISSN:2161-0460 JADP an open access journal
Volume 2 • Issue 1 • 1000e108