Abstract In the United States, estimates indicate there are between 250,000 and 400,000 individuals with Down syndrome (DS), and nearly all will develop Alzheimer's disease (AD) pathology starting in ...their 30s. With the current lifespan being 55 to 60 years, approximately 70% will develop dementia, and if their life expectancy continues to increase, the number of individuals developing AD will concomitantly increase. Pathogenic and mechanistic links between DS and Alzheimer's prompted the Alzheimer's Association to partner with the Linda Crnic Institute for Down Syndrome and the Global Down Syndrome Foundation at a workshop of AD and DS experts to discuss similarities and differences, challenges, and future directions for this field. The workshop articulated a set of research priorities: (1) target identification and drug development, (2) clinical and pathological staging, (3) cognitive assessment and clinical trials, and (4) partnerships and collaborations with the ultimate goal to deliver effective disease-modifying treatments.
The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21-linked early-onset Alzheimer's disease (EOAD) and dementia. The aims of this ...study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26-72 years of age were to identify the magnitude of brain region-specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26-41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43-49, 51-59, and 61-72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26-41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43-49 years of age; a 28.0% maximum neuronal loss at 51-59 years of age; and a 11.0% minimum neuronal loss at 61-72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.
Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood.
Here, we profile CpG methylation in ...DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects.
These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning.
Increase in human life expectancy has resulted in the rapid growth of the elderly population with minimal or no intellectual deterioration. The aim of this stereological study of 10 structures and 5 ...subdivisions with and without neurofibrillary degeneration in the brains of 28 individuals 25-102-years-old was to establish the pattern of age-associated neurodegeneration and neuronal loss in the brains of nondemented adults and elderly. The study revealed the absence of significant neuronal loss in 7 regions and topographically selective reduction of neuronal reserve over 77 years in 8 brain structures including the entorhinal cortex (EC) (-33.3%), the second layer of the EC (-54%), cornu Ammonis sector 1 (CA1) (-28.5%), amygdala, (-45.8%), thalamus (-40.5%), caudate nucleus (-35%), Purkinje cells (-48.3%), and neurons in the dentate nucleus (40.1%). A similar rate of neuronal loss in adults and elderly, without signs of accelerating neuronal loss in agers or super-agers, appears to indicate age-associated brain remodeling with significant reduction of neuronal reserve in 8 brain regions. Multivariate analysis demonstrates the absence of a significant association between neuronal loss and the severity of neurofibrillary degeneration and β-amyloidosis, and a similar rate of age-associated neuronal loss in structures with and without neurofibrillary degeneration.
Introduction
Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) and its associated dementia, warranting the development of strategies to improve early detection ...when prevention is possible.
Methods
Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we evaluated the psychometrics of measures in a large sample of 561 adults with DS. We tracked longitudinal stability or decline in functioning in a subsample of 269 participants over a period of 3 years, all initially without indications of clinically significant aging‐related decline.
Results
Results identified an array of objective measures that demonstrated sensitivity in distinguishing individuals with incident “mild cognitive impairment” (MCI‐DS) as well as subsequent declines occurring with incident dementia.
Discussion
Several instruments showed clear promise for use as outcome measures for future clinical trials and for informing diagnosis of individuals suspected of experiencing early signs and symptoms of a progressive dementia process.
Introduction
Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. ...Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.
Methods
We describe the development of a multi‐center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid‐based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16‐month intervals), as well as genetic modifiers of AD risk and progression.
Results
Approximately 400 individuals will be enrolled in the study (more than 370 to date). The methodological approach from the administrative, clinical, neuroimaging, omics, neuropathology, and statistical cores is provided.
Discussion
This represents the largest U.S.‐based, multi‐site, biomarker initiative of AD in DS. Findings can inform other multidisciplinary networks studying AD in the general population.
Alzheimer's disease (AD) has become one of the most pressing public health concerns facing the world, with prevalence and costs of care increasing dramatically with extended life expectancy. 1 ...Current investments in research target risk reduction and discovery of disease-modifying treatments, but efforts to date have had only marginal impact, if even that. ...individuals without DS but with micro-trisomy of APP (APPdup) also show extremely high risk for AD (e.g., Rovelet-Lecrux et al. 9). Advances in medical care is an obvious contributor, but we believe the evidence implicates improved quality of life more broadly.
Measures of general cognitive and adaptive ability in adults with Down syndrome (DS) used by previous studies vary substantially. This review summarises the different ability measures used ...previously, focusing on tests of intelligence quotient (IQ) and adaptive behaviour (AB), and where possible examines floor effects and differences between DS subpopulations. We aimed to use information regarding existing measures to provide recommendations for individual researchers and the DS research community.
Nineteen studies reporting IQ test data met inclusion for this review, with 17 different IQ tests used. Twelve of these IQ tests were used in only one study while five were used in two different studies. Eleven studies reporting AB test data met inclusion for this review, with seven different AB tests used. The only AB scales to be used by more than one study were the Vineland Adaptive Behaviour Scale (VABS; used by three studies) and the Vineland Adaptive Behavior Scale 2nd Edition (VABS-II; used by two studies). A variety of additional factors were identified which make comparison of test scores between studies problematic, including different score types provided between studies (e.g. raw scores compared to age-equivalent scores) and different participant inclusion criteria (e.g. whether individuals with cognitive decline were excluded). Floor effects were common for IQ tests (particularly for standardised test scores). Data exists to suggest that floor effects may be minimised by the use of raw test scores rather than standardised test scores. Raw scores may, therefore, be particularly useful in longitudinal studies to track change in cognitive ability over time.
Studies assessing general ability in adults with DS are likely to benefit from the use of both IQ and AB scales. The DS research community may benefit from the development of reporting standards for IQ and AB data, and from the sharing of raw study data enabling further in-depth investigation of issues highlighted by this review.
Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in ...T‐lymphocyte interphases from individuals with Down syndrome (DS) with and without “mild cognitive impairment” (MCI‐DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI‐DS in this high‐risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI‐DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18‐month intervals with clinical and telomere assessments: (1) MCI‐DS group data were collected approximately three years prior to development of MCI‐DS; (2) 18 months later; (3) when MCI‐DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI‐DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18‐months prior to recognition of MCI‐DS onset and completely non‐overlapping distributions of telomere measures were observed by the time of MCI‐DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.
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.
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