Wayne Silverman

The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome

The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer’s disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS.

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.

Alzheimer's Disease in Adults with Down Syndrome.

Abstract Down syndrome is associated with increased mortality rates due to congenital cardiac defects and leukemia early in life, and with Alzheimers disease and a tendency toward premature aging later in life. Alzheimers disease was once considered an inexorable result of growing old with Down syndrome, but recent data indicate that risk does not reach 100%. Although some individuals exhibit signs and symptoms of Alzheimers disease in their 40s, other individuals have reached the age of 70 without developing dementia. This chapter presents a wealth of data from a longstanding longitudinal study with the overall objective of understanding and recounting the mechanisms responsible for these substantial individual differences.

Vision Deficits in Adults with Down Syndrome

BACKGROUNDnIn 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.nnnMATERIALS AND METHODSnParticipants 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.nnnRESULTSnAdults 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 Alzheimers disease.nnnCONCLUSIONSnOur findings suggest that a common mechanism may be responsible for the pattern of deficits observed, possibly the presence of Alzheimers 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.

Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior.

Copy number variants (CNVs) were detected and analyzed in 14 probands with autism and intellectual disability with self-injurious behavior (SIB) resulting in tissue damage. For each proband we obtained a clinical history and detailed behavioral descriptions. Genetic anomalies were observed in all probands, and likely clinical significance could be established in four cases. This included two cases having novel, de novo copy number variants and two cases having variants likely to have functional significance. These cases included segmental trisomy 14, segmental monosomy 21, and variants predicted to disrupt the function of ZEB2 (encoding a transcription factor) and HTR2C (encoding a serotonin receptor). Our results identify variants in regions previously implicated in intellectual disability and suggest candidate genes that could contribute to the etiology of SIB.