Warren B. Zigman

Prevalence of Chronic Medical Conditions in Adults with Mental Retardation: Comparison with the General Population.

We interviewed caregivers and reviewed medical records of 278 adults with mental retardation with and without Down syndrome, 45 to 74 years of age. Standardized morbidity ratios were used to compare frequency of medical disorders in these adults to frequency in the general population. In adults with mental retardation, the frequency of common age-related disorders was comparable to that in the general population, but there was an increased frequency of thyroid disorders, nonischemic heart disorders, and sensory impairment. Surveillance of health status and increased access to health care for screening and treatment of age-related disorders that are more frequent in adults with mental retardation would be important to prevent the development or delay the impact of these conditions and to promote healthy aging.

Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome

We compared levels of plasma amyloid beta-peptides Abeta1-42 and Abeta1-40 in 108 demented and nondemented adults with Down syndrome (DS) and 64 adults from the general population. Abeta1-42 and Abeta1-40 levels were significantly higher in adults with DS than in controls (P=0.0001). Compared to nondemented adults with DS, Abeta1-42 levels in demented adults with DS were selectively increased by 26% (28.2 pg/ml vs. 22.4 pg/ml, P=0.004). In addition, mean plasma levels of Abeta1-42 were 22% higher in DS cases with the apolipoprotein varepsilon4 allele than in DS subjects without an varepsilon4 allele (25.9 pg/ml vs. 21.2 pg/ml, P=0.01), while mean plasma levels of Abeta1-40 did not vary by APOE genotype. These results support the hypothesis that Abeta1-42 plays an important role in the pathogenesis of dementia associated with DS, as it does in Alzheimers disease, and that variations in plasma levels may be related to disease progression.

Incidence and Prevalence of Dementia in Elderly Adults with Mental Retardation without Down Syndrome.

Rates of dementia in adults with mental retardation without Down syndrome were equivalent to or lower than would be expected compared to general population rates, whereas prevalence rates of other chronic health concerns varied as a function of condition. Given that individual differences in vulnerability to Alzheimers disease have been hypothesized to be due to variation in cognitive reserve, adults with mental retardation, who have long-standing intellectual and cognitive impairments, should be at increased risk. This suggests that factors determining intelligence may have little or no direct relationship to risk for dementia and that dementia risk for individuals with mental retardation will be comparable to that of adults without mental retardation unless predisposing risk factors for dementia are also present.

Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21.

BackgroundDown syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood.MethodsWe used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry.ResultsWe found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78MX1 protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR.ConclusionDifferent subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects.

Dementia in Adults with Mental Retardation: Assessment at a Single Point in Time.

Dementia status of 273 adults with mental retardation was rated based upon two extensive evaluations conducted 18 months apart. Overall, 184 individuals did not have dementia, 33 had possible or definite dementia, and 66 had findings suggesting uncertain or questionable status. These ratings were compared to binary classifications (dementia vs. no dementia) generated from the Dementia Questionnaire for Persons With Mental Retardation (Evenhuis, 1995) and the IBR Mental Status Examination (Wisniewski & Hill, 1985). When performance was referenced to IQs (established earlier in adulthood), quantitative criteria effectively distinguished between individuals with and without dementia based upon assessment at a single point in time. Findings suggest that procedures of this type could soon contribute to more accurate and rapid diagnoses of dementia.

Incidence and Temporal Patterns of Adaptive Behavior Change in Adults with Mental Retardation.

The age-associated incidence of significant decline in adaptive behavior and the temporal pattern of decline in specific functional skill domains were examined in 646 adults with mental retardation through 88 years of age. Cumulative incidence of significant decline for adults with Down syndrome increased from less than.04 at age 50 to.67 by age 72, whereas cumulative incidence of significant decline for adults with mental retardation without Down syndrome increased from less than.02 at age 50 to.52 at age 88. Among adults experiencing overall decline, four clusters of behaviors were identified based upon the sequence and magnitude of changes, suggesting a pattern of loss not unlike that noted in the population without mental retardation with dementia.

Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia

Telomere shortening has been recently correlated with Alzheimers disease status. Therefore, we hypothesized that a possible association might exist for adults with Down syndrome (DS). Using blind, quantitative telomere protein nucleic acid FISH analyses of metaphase and interphase preparations from 18 age-matched trisomy 21 female study participants with and without dementia, we have observed increased telomere shortening in adults with DS and dementia (p < .01). From this initial study, we conclude that telomere shortening is associated with dementia in this high-risk population and suggest that additional research may show that telomere shortening may be a biological marker of dementia status.

Change in plasma Aβ peptides and onset of dementia in adults with Down syndrome

Objective: To examine changes in levels of plasma amyloid-β (Aβ) peptides, Aβ42 and Aβ40, in relation to onset of Alzheimer disease (AD) in adults with Down syndrome (DS). Methods: Plasma Aβ42 and Aβ40 were measured at initial examination and at follow-up in a community-based cohort of 225 adults with DS who did not have dementia at baseline and were assessed for cognitive/functional abilities and health status and followed at 14- to 20-month intervals. We used Cox proportional hazards modeling to estimate the cumulative incidence of AD by Aβ peptide change group (increasing, no change, or decreasing), adjusting for covariates. Results: Sixty-one (27.1%) of the participants developed AD. At follow-up, a decrease in Aβ42 levels, a decrease in the Aβ42/Aβ40 ratio, and an increase in Aβ40 levels were related to conversion to AD. Compared with the group with increasing levels of Aβ42, the likelihood of developing AD was 5 times higher for those whose plasma Aβ42 levels decreased over follow-up (hazard ratio [HR] = 4.9, 95% confidence interval [CI] 2.1–11.4). Decreasing Aβ42/Aβ40 was also strongly related to AD risk (HR = 4.9, 95% CI 1.8–13.2), while decreasing Aβ40 was associated with lower risk (HR = 0.4, 95% CI 0.2–0.9). Conclusions: Among adults with DS, decreasing levels of plasma Aβ42, a decline in the Aβ42/Aβ40 ratio, or increasing levels of Aβ40 may be sensitive indicators of conversion to AD, possibly reflecting compartmentalization of Aβ peptides in the brain.

Aging and dementia among adults with mental retardation and Down syndrome

The life expectancy of people with mental retardation has dramatically increased over the past several decades. However, relatively little attention has been paid to the phenomenon of aging in this population, largely due to the historic fact that few of these people survived to become senior citizens. A rapidly expanding population of older adults with lifelong histories of atypical development may require unique patterns of services. Vulnerability to Alzheimers disease is among the specific concerns that will need to be addressed. Because adults with Down syndrome exhibit many indications of accelerated aging, including a substantially increased risk for Alzheimers disease, it is particularly important to understand their patterns of aging. Literature relevant to these issues is reviewed.

Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimers disease (AD) in Northern European, Hispanic, African-American and Isreali-Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of beta amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45-70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR=0.26, 95% CI: 0.08-0.86; and HR=0.40, 95% CI: 0.16-0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.