University of Kentucky

UKnowledge
Pharmacology and Nutritional Sciences Faculty
Pharmacology and Nutritional Sciences
Publications

2012

Aging and Down Syndrome

Elizabeth Head
University of Kentucky, elizabeth.head@uky.edu

Wayne Silverman
Johns Hopkins University

David Patterson
University of Denver

Ira T. Lott
University of California, Irvine

Follow this and additional works at: http://uknowledge.uky.edu/pharmacol_facpub

Part of the Medical Nutrition Commons, Medical Pharmacology Commons, and the
Pharmacology, Toxicology and Environmental Health Commons

Repository Citation
Head, Elizabeth; Silverman, Wayne; Patterson, David; and Lott, Ira T., "Aging and Down Syndrome" (2012). Pharmacology and
Nutritional Sciences Faculty Publications. Paper 22.
http://uknowledge.uky.edu/pharmacol_facpub/22

This Editorial is brought to you for free and open access by the Pharmacology and Nutritional Sciences at UKnowledge. It has been accepted for
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Hindawi Publishing Corporation
Current Gerontology and Geriatrics Research
Volume 2012, Article ID 412536, 6 pages
doi:10.1155/2012/412536

Editorial
Aging and Down Syndrome

Elizabeth Head,1 Wayne Silverman,2 David Patterson,3 and Ira T. Lott4

1 Department of Molecular and Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky,
800 South Limestone Street, Lexington, KY 40536, USA
2 Kennedy Krieger Institute, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, MD 21205, USA
3 Eleanor Roosevelt Institute and the Department of Biological Sciences, University of Denver, 2101 E. Wesley Avenue,

Denver, CO 80208, USA

4 Department of Pediatrics and Neurology, School of Medicine, University of California-Irvine (UCI),

101 The City Dr. ZC 4482, Orange, CA 92868, USA

Correspondence should be addressed to Elizabeth Head, elizabeth.head@uky.edu

Received 15 May 2012; Accepted 15 May 2012

Copyright 2012 Elizabeth Head et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

1. Introduction of significant concern (e.g., depression, seizures). Significant

contributors to quality of life in aging individuals with DS
The initial clinical description of Down syndrome (DS) was also include gait disturbances (B. A. Smith et al.) and oph-
made by Down in 1866 [1] and identified as trisomy of thalmic disorders (e.g., S. J. Krinsky-MC. Hale et al.), both of
chromosome 21 by Lejeune et al. in 1959 [2]. DS, or tri- which increase with age.
somy 21, is one of the most common causes of intellectual
disability (ID), and recent national prevalence estimates sug- 2. Dementia and Aging in DS
gest that 14.47 per 10,000 live births are infants with DS,
leading to an average of 6037 annual DS births [3]. This A key concern to aging adults with DS is the increasing risk
represents an increase from previous prevalence rates. Cha- for developing Alzheimers disease (AD). The profile and
racteristic physical features, deficits in the immune and end- sequence of cognitive impairments in adults with DS are
ocrine systems, and delayed cognitive development [4] can similar to those seen with AD in the general population
be present in children with DS. [813]. Memory processes are aected early in the course
Improvements in medical care for children and adults of DS dementia [14]. Severe cognitive deterioration, such as
with DS have led to significant extensions in lifespan and acquired apraxia and agnosia, has been reported in 28% of
enhanced quality of life. As a consequence, up to 35 years individuals with DS at age 30 years, with a higher prevalence
of age, mortality rates are comparable in adults with DS to of these impairments in the subsequent years [8, 9]. The
individuals with ID from other causes. However, after age 35, earliest manifestations of dementia in DS may involve
mortality rates double every 6.4 years in DS, as compared changes in personality and behavior [1517]. Pragnosia or
to 9.6 years for people without DS [5], and the current- socially deficient communication may be an early sign of
ly estimated life expectancy of a 1-year-old child with frontal lobe dysfunction in DS and can represent a striking
DS is between 43 and 55 years (depending on the level change from previous well-developed social capacities [18].
of disability). Although longevity in adults with DS has Individuals with DS typically show less of a decline in
been increasing progressively, these increases have been sub- language compared to performance skills associated with
stantially lower for some minority groups [6, 7]. Further, as aging throughout adulthood as compared to individuals with
described by L. Thorpe et al., adults with DS are still dis- ID but not DS [19]. The diagnosis of dementia in DS can
advantaged compared to adults with other types of ID in be challenging against the background of pre-existing intel-
terms of mortality rate, with multiple comorbidities being lectual impairment. Standardized criteria for the diagnosis
2 Current Gerontology and Geriatrics Research

of dementia in DS include both informant-based and direct without DS who by imaging studies or autopsy examinations
measures [16, 2022]. The severity of preexisting cognitive show A deposition in the brain but are clinically normal,
impairment may also be a predictor of the rate of cognitive suggesting that similar compensatory processes may also
deterioration in DS [23]. occur [3739].
Potentially modifiable risk factors are now being iden- A novel hypothesis is also provided by A. Reed-Cossairt
tified that can lead to enhanced susceptibility to dementia et al. regarding a role for reduced clearance of A as a con-
in people with DS [24]. For example, women with DS may sequence of slower cerebrospinal fluid (CSF) turnover. In
develop dementia 1020 years earlier than women in the gen- addition, vascular dysfunction, specifically in the jugular
eral population [9, 25, 26]. One possible mechanism under- reflux, may be a significant contributor to slowed CSF turn-
lying increasing dementia risk for women with DS is sug- over and the development of dementia in adults with DS. An
gested by J. H. Lee et al. The study describes a genetic poly- additional consequence of reduced vascular function may be
morphism in the hydroxysteroid-17-dehydrogenase gene the development of white matter neuropathology that is typi-
that is responsible for converting estrone to estradiol. Poly- cally seen in AD. Many gaps in our knowledge regarding
morphisms of this gene may lead to changes in activity of this potential feature of aging in DS that could be modified
hydroxysteroid-17-dehydrogenase and modify circulating with appropriate interventions are also discussed by Reed-
levels of neuroprotective estrogen. In a cohort of women with Cossairt.
DS followed longitudinally, the onset of dementia was linked Additional neurobiological events that may impact the
to three of five single nucleotide polymorphisms (SNPs) in risk of dementia may also compromise cognition in DS. As
this gene, and women with high-risk SNPs were 2-3 times summarized by J. P. Lockrow et al., a loss of neurons in
more likely to develop AD. the locus coeruleus and basal forebrain (BFCNs) can lead to
reductions in two neurotransmitters that play a critical role
3. Neurobiology of Aging in DS in learning and memory, norepinephrine, and acetylcho-
line. Further, these authors provide additional data suggest-
Middle-aged individuals with DS develop AD pathology ing that reduced norepinephrine may also lead to increased
[25, 2729], no doubt contributing to their high risk of neuroinflammation and degeneration in the hippocampus
developing dementia [9, 30]. Still, not every individual (another area critical for memory). Reduced neurotransmit-
with DS will develop dementia. Although clinical signs of ter levels in DS may also lead to a loss of trophic support
dementia are more commonly observed when individuals for neurons in the DS brain with age. Based upon research
are over 50 years of age [9, 3133], by 40 years of age, in mouse models of DS (described in detail by G. N. Vacano
virtually all individuals with DS have neuropathological et al.), a loss of brain derived neurotrophic factor (BDNF)
changes that are consistent with AD, including senile plaques occurs in response to norepinephrine losses and leads to cog-
and neurofibrillary tangles (NFT) [13, 27, 28]. Senile plaques nitive deficits. A decrease in BDNF, in turn, has been linked
contain the beta-amyloid peptide (A) toxic to neurons and to enhanced vulnerability of neurons to oxidative stress, sug-
thought to be a causative event in the pathogenesis of AD gesting a cycle of increasing insults that may eventually lead
[34, 35]. to neurodegeneration or death.
DS involves the overexpression of the amyloid pre- Oxidative damage has been extensively studied in people
cursor protein (APP) on chromosome 21. APP is cleaved with DS, because a significant number (>10) of genes
sequentially by beta- and gamma-secretases to release A, encoding proteins relevant to oxidative damage [4042]
which forms toxic conformations and aggregates (e.g., and ROS production located on chromosome 21 [43].
senile plaques) in the AD and DS brain [34]. Indeed, the Many of these are overexpressed in DS. SOD1 has been
development of AD neuropathology in most individuals with perhaps the most studied protein with regard to ROS meta-
DS after the age of 40 years is considered to be key evidence bolism in DS. Increased levels of this endogenous antioxidant
in support of the amyloid cascade hypothesis as a cause for without parallel increases in catalase can lead to higher levels
sporadic AD. Beta-secretase has been characterized as the of hydrogen peroxide. As reviewed by M. Perluigi et al., oxi-
enzyme beta-amyloid cleaving enzyme (BACE), of which a dative damage may be a significant contributor to neurode-
homologous version, BACE2, is present on chromosome 21
generation associated with the AD neuropathology seen
[36]. However, despite increases in BACE2 mRNA in DS
in DS with advancing age. Specifically, in the aging DS
brain, protein levels appear similar in DS compared to non-
brain, the presence of age-associated A can in turn cause
DS brain. Further, BACE2 activity appears to decrease the
production of A from APP in contrast to the activity of oxidative damage, but there is also evidence that compensa-
BACE1. R. L. Webb and M. P. Murphy also describe evidence tory mechanisms may support normal neuronal function
that BACE activity overall is not increased in the aged DS until some threshold is crossed. Further, changes in mito-
brain, leading to the conclusion that APP overexpression chondrial functioning may produce damaging free radicals
may be the prime cause of A overproduction. It is also that contribute to oxidative stress, given that we see higher
fascinating to consider that despite earlier ages of onset of levels of mitochondrial DNA mutations in DS (P. E. Coskun
A deposition in the brain (30 years), people with DS are and J. Busciglio), although the combination of mitochon-
able to compensate for progressive AD neuropathology and drial dysfunction and oxidative stress may lead to adaptive
many people with DS do not show signs of cognitive decline responses in DS, perhaps prior to the development of
until their 50s or even later [24]. Similarly, there are people AD.
Current Gerontology and Geriatrics Research 3

A and oxidative damage may contribute to brain L-threo-DOPS (Droxidopa) can improve learning and mem-
inflammation, either independently or in concert. Neuroin- ory in DS mice and may be a possible target for DS clinical
flammation, however, has not been studied as extensively as trials addressing improvement of age- and AD-associated
these two other markers of neuropathology and represents cognitive dysfunction. As a parallel component to enhancing
an area of focus that may be highly relevant to aging in DS norepinephrine function, neuroinflammation appears to be
(D. M. Wilcock) [44, 45]. Given that genes involved with intimately linked to the levels of this neurotransmitter and
neuroinflammation are located on chromosome 21, the neu- increased in DS aging mice.
roinflammatory milieu in DS may be dierent from AD in Another pharmacological approach to preventing AD
the general population. For example, S100 is present in in people with DS may be to modify the production of
triplicate in DS, is expressed by astrocytes, and is released A due to overexpression of APP (R. L. Webb and M. P.
in response to inflammatory cytokines. As shown in Table Murphy). Clinical trials are currently addressing the reduc-
1 of the review by D. M. Wilcock, this is one of multiple tion of BACE activity in sporadic cases of AD (http://www
genes that could lead to enhanced neuroinflammation in .clinicaltrials.gov/), but gamma-secretase inhibitors may not
DS, although these genes may also prime the brain towards be a viable option given adverse side eects. An intriguing
an M1 inflammatory response. Inflammatory responses may report in a mouse model of DS showed that reducing BACE
lead to enhanced vulnerability of DS neurons in the presence activity in young animals reduced learning and memory
of Atangles and oxidative damageand could be a signi- deficits, suggesting that APP overexpression and production
ficant target for intervention. Neuroinflammation has not of A may not only be involved with AD development with
been fully explored as a function of age in DS and is an active age but also contribute to intellectual disability in younger
area of research in AD in the general population. individuals [52].
G. Tansley et al. provide novel evidence that circulating Reducing oxidative damage (which is a lifelong issue
levels of 24S-OH-cholesterol, thought to reflect brain levels for DS) may require a multitargeted approach that is pre-
of cholesterol, are unchanged in aging individuals with DS ventative in nature, given that supplementing demented
compared to those without DS. Further, the overall lipid adults with DS with antioxidants (or individuals with AD in
metabolism profile of plasma observed in DS is similar to the absence of DS) has shown little or no benefit to clini-
those without DS. The exception may be brassicasterol levels, cal outcomes [53]. Indeed, compensatory mechanisms at
which are reduced for older DS individuals compared to younger ages in DS may be enhanced by antioxidant supple-
those without DS. While this is a very intriguing finding and mentation (M. Perluigi and D. A. Butterfield). Focusing on
may reflect AD-associated neuropathology, this is the first mitochondrial dysfunction is also a promising approach, as
report of the eect and further confirmation is required. these organelles are the primary producers of reactive oxygen
species (P. E. Coskun and J. Busciglio). In addition, isolated
4. Pharmacological and Nonpharmacological mitochondria have a higher rate of DNA mutations, suggest-
Intervention Strategies ing a progressive exacerbation in mitochondrial function in
DS. Given this evidence for mitochondrial dysfunction in
There are only 5 FDA-approved drugs for the treatment DS, there are several possible interventions that may reduce
of AD in the general population, and these have met with age-associated declines (e.g., dietary changes and/or supple-
moderate or little success for the treatment of AD in DS [46 mentation with mitochondrial cofactors). A combinatorial
51]. This suggests that other disease-modifying approaches approach may be particularly valuable for adults with DS
are going to be critically important for future therapeutics. who may benefit from a supplement including both anti-
Prevention, however, may be the most promising approach to oxidants (e.g. vitamins E and C) and mitochondrial co-
healthy aging in DS and may include both pharmacological factors (e.g., lipoic acid, acetylcarnitine). However, it may
and nonpharmacological interventions. be critical to use these approaches as a preventative measure
Critically important to the development of novel thera- rather than as a treatment protocol for AD in DS [53]. Given
peutics or prevention strategies is the use of mouse models the interaction between A, oxidative damage and neu-
for DS where promising strategies can be first tested. There roinflammation, and the relative paucity of data regarding
are several mouse models for DS that capture developmental inflammation in the aging DS brain, unexplored potential
and aging-associated phenotypes (G. N. Vacano et al.). new targets for intervention may exist (D. M. Wilcock).
Although DS is a complex genetic disorder, careful dissection Several key issues highlighted in this special issue topics
of the role of individual or groups of genes to the DS pheno- suggest that lifestyle modification and regular health mon-
type provides an exciting approach for the development itoring may also lead to successful aging in people with
of new interventions. In combination with existing mouse DS. For example, although older adults show decreased
models for AD, promising new pharmacological or nonphar- stability and eciency in gait during walking, evidence for
macological treatments may be identified. However, it is also adaptation suggests potential for improvements with appro-
critical to note that translation of outcomes from mouse priate interventions (B. A. Smith et al.). Changes in gait
studies to human clinical trials is not necessarily direct, but should be taken into consideration, as they may lead to less
the mouse studies provide important proof of principle out- physical activity and/or functional decline.
comes that can be pursued. A substantial number of people with DS develop oph-
As one example of using this approach, J. P. Lockrow et al. thalmic disorders, aecting up to 50% of adults between
review studies suggesting that the norepinephrine precursor 50 and 59 years of age (S. J. Krinsky-MC. Hale et al.).
4 Current Gerontology and Geriatrics Research

The development of age-associated visual deficits occurs at Itkin Foundation to D. Patterson, NIH HD-65160 and AG-
younger ages in DS than that in the general population. 16573 to I. T. Lott and NIH P30 HD024061 to W. Silverman.
The presence of ophthalmic disorders is higher in DS indi-
viduals with more severe intellectual disability, leading to Elizabeth Head
additional challenges and significant functional consequen- Wayne Silverman
ces. Interestingly, in S. J. Krinsky-MC. Hales report of longi- David Patterson
tudinally followed individuals with DS, cataracts were the Ira T. Lott
most frequent problem in older adults but were not asso-
ciated with the level of ID. However, the presence of cat-
aracts does compromise functioning and readily available
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