[Show abstract][Hide abstract] ABSTRACT: Background
Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population.Methods
In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT).ResultsThe RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six-month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs(114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment.Conclusion
Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia.
Journal of Intellectual Disability Research 05/2015; 59(11). DOI:10.1111/jir.12200 · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: People with intellectual disability (ID) are living longer than ever before, raising concerns about old-age associated disorders. Dementia is among the most serious of these disorders, and theories relating cognitive reserve to risk predict that older adults with ID should be particularly vulnerable. Previous estimates of relative risk for dementia associated with ID have been inconsistent, and the present analyses examined the possible influence of variation in diagnostic criteria on findings. As expected, relaxation in the stringency of case definition for adults with ID increased relative risk, underscoring the importance of developing valid criteria for defining mild cognitive impairment, early dementia, and distinguishing between the two in adults with ID. Once available, these standards will contribute to more effective evidence-based planning.
Journal of Policy and Practice in Intellectual Disabilities 09/2013; 10(3). DOI:10.1111/jppi.12042 · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Parental characteristics were significant predictors of health, functional abilities, and behavior problems in adults with Down syndrome (n = 75) over a 22-year time span, controlling for initial levels and earlier changes in these outcomes. Lower levels of behavior problems were predicted by improvements in maternal depressive symptoms. Higher levels of functional abilities were predicted by prior measures of and improvements in maternal depressive symptoms. Better health was predicted by prior measures of maternal depressive symptoms, paternal positive psychological well-being, relationship quality between fathers and their adult children, and improvements in maternal positive psychological well-being. Dementia status was also predicted by parental characteristics. The study suggests the importance of the family context for healthy aging in adults with Down syndrome.
American Journal on Intellectual and Developmental Disabilities 07/2013; 118(4):294-309. DOI:10.1352/1944-7558-118.4.294 · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
In individuals with Down syndrome, virtually all structures of the eye have some abnormality, which likely diminishes vision. We examined basic vision functions in adults with Down syndrome.
Materials and methods:
Participants completed a battery of psychophysical tests that probed a comprehensive array of visual functions. The performance of adults with Down syndrome was compared with younger and older adults without intellectual disability.
Adults with Down syndrome had significant vision deficits, reduced sensitivity across spatial frequencies and temporal modulation rates, reduced stereopsis, impaired vernier acuity and anomalies in colour discrimination. The pattern of deficits observed was similar to those seen by researchers examining adults with Alzheimer's disease.
Our findings suggest that a common mechanism may be responsible for the pattern of deficits observed, possibly the presence of Alzheimer's disease neuropathology in the visual association cortex. We also showed that individuals with mild to moderate intellectual disability are capable of participating in studies employing state-of-the-art psychophysical procedures. This has wider implications in terms of their ability to participate in research that use similar techniques.
Journal of Applied Research in Intellectual Disabilities 06/2013; 27(3). DOI:10.1111/jar.12062 · 1.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chromosome 21 gene RCAN1, encoding a modulator of the calcineurin (CaN) phosphatase, is a candidate gene for contributing to cognitive disability in people with Down syndrome (DS; trisomy 21). To develop a physiologically relevant model for studying the biochemistry of RCAN1 and its contribution to DS, we generated bacterial artificial chromosome-transgenic (BAC-Tg) mouse lines containing the human RCAN1 gene with a C-terminal HA-FLAG epitope tag incorporated by recombineering. The BAC-Tg was expressed at levels only moderately higher than the native Rcan1 gene: approximately 1.5-fold in RCAN1 (BAC-Tg1) and twofold in RCAN1 (BAC-Tg2). Affinity purification of the RCAN1 protein complex from brains of these mice revealed a core complex of RCAN1 with CaN, glycogen synthase kinase 3-beta (Gsk3b), and calmodulin, with substoichiometric components, including LOC73419. The BAC-Tg mice are fully viable, but long-term synaptic potentiation is impaired in proportion to BAC-Tg dosage in hippocampal brain slices from these mice. RCAN1 can act as a tumor suppressor in some systems, but we found that the RCAN1 BAC-Tg did not reduce mammary cancer growth when present at a low copy number in Tp53;WAP-Cre mice. This work establishes a useful mouse model for investigating the biochemistry and dose-dependent functions of the RCAN1 protein in vivo.
[Show abstract][Hide abstract] ABSTRACT: A public-private partnership to establish biomarkers of dementia in Down's syndrome could aid the development of preventive therapies for the dementia associated with both Down's syndrome and Alzheimer's disease, based on the apparent common pathogenic role of amyloid precursor protein in the two conditions.
[Show abstract][Hide abstract] ABSTRACT: This special issue of the Current Gerontology and Geriatrics Research journal was intended to cover selected issues defining the concerns faced by adults with Down syndrome as they grow older. As can be seen from this selection of papers, substantial gaps in our knowledge of the aging process in people with DS continue to persist and are critically important to address. Further, approaches for maintaining healthy aging in individuals with DS may also inform strategies for enhancing quality of life for other adults with ID or indeed in the general population. Ongoing longitudinal studies that monitor changes in health status, cognition, function, the development of dementia, and mortality will all be critically important for informing the development of policies and interventions to promote healthy aging in DS. A key challenge to aging adults with DS is the increasing risk for developing dementia; yet our social and medical infrastructure is not as well prepared for providing care to adults with DS as they age relative to the outstanding support available to children with DS and their families. The use of FDA-approved treatments for AD in the general population has met with limited success in people with DS . Therefore, it is critically important to explore novel interventions and potential prophylactic approaches that may provide individuals with DS the best possible opportunity to age gracefully. Such interventions along with further study of aging, dementia, and Alzheimer disease in DS are likely to be of fundamental importance in understanding AD in the general population.
Current Gerontology and Geriatrics Research 07/2012; 2012(6):412536. DOI:10.1155/2012/412536
[Show abstract][Hide abstract] ABSTRACT: Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer's disease) had shorter telomeres than did those from age- and sex-matched people with DS only, quantified as significantly reduced numbers of signals of peptide nucleic acid (PNA) telomere probes in whole metaphases [Jenkins et al. (2008); Neurosci Lett 440:340-343] as well as reduced telomere probe light intensity values in interphases [Jenkins et al. (2010); Neurobiol Aging 31:765-771]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a "normalizing ratio" involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2012; 159B(5):598-604. DOI:10.1002/ajmg.b.32066 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A myriad of ophthalmic disorders is associated with the phenotype of Down syndrome including strabismus, cataracts, and refractive errors potentially resulting in significant visual impairment. Ophthalmic sequelae have been extensively studied in children and adolescents with Down syndrome but less often in older adults. In-depth review of medical records of older adults with Down syndrome indicated that ophthalmic disorders were common. Cataracts were the most frequent ophthalmic disorder reported, followed by refractive errors, strabismus, and presbyopia. Severity of intellectual disability was unrelated to the presence of ophthalmic disorders. Also, ophthalmic disorders were associated with lower vision-dependent functional and cognitive abilities, although not to the extent that was expected. The high prevalence of ophthalmic disorders highlights the need for periodic evaluations and individualized treatment plans for adults with Down syndrome, in general, but especially when concerns are identified.
Current Gerontology and Geriatrics Research 04/2012; 2012(6):974253. DOI:10.1155/2012/974253
[Show abstract][Hide abstract] ABSTRACT: We have observed evidence of increased telomere shortening in short-term T-lymphocyte cultures following freezing and thawing of the original inoculum obtained by ficoll-paque gradient centrifugation, compared to T-lymphocytes that were cultured immediately without freezing and thawing from the same blood sample from 3 female and 3 male adults. Because freezing may have similar effects on other cell types, and because telomere shortening may only manifest its effects after many years or decades, we suggest there is a pressing need for evaluation of the effects of freezing on any cells envisioned for clinical applications, including embryo implantation.
[Show abstract][Hide abstract] ABSTRACT: Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD. HSD17B1 encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol. Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31-78 years of age, were followed at 14-18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in the HSD17B1 gene region, and their association with incident AD was examined. Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 in COASY (rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1-3.1). Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.
Current Gerontology and Geriatrics Research 03/2012; 2012(2):361218. DOI:10.1155/2012/361218
[Show abstract][Hide abstract] ABSTRACT: Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). We examined the relation of polymorphisms in the gene for the estrogen receptor-beta (ESR2) to the risk of AD in women with Down syndrome.
Two hundred and forty-nine women with Down syndrome, 31-70 years of age and nondemented at baseline, were followed at 14- to 18-month intervals for 4 years. Women were genotyped for 13 single-nucleotide polymorphisms (SNPs) in the ESR2 gene, and their association with AD incidence was examined.
Among postmenopausal women, we found a 2-fold increase in the risk of AD for women carrying 1 or 2 copies of the minor allele at 3 SNPs in introns seven (rs17766755) and six (rs4365213 and rs12435857) and 1 SNP in intron eight (rs4986938) of ESR2.
These findings support a role for estrogen and its major brain receptors in modulating susceptibility to AD in women.
[Show abstract][Hide abstract] ABSTRACT: CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.
[Show abstract][Hide abstract] ABSTRACT: Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 × of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS.
Journal of Neuropathology and Experimental Neurology 01/2011; 70(1):36-50. DOI:10.1097/NEN.0b013e318202bfa1 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2'deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.