Objective
Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, ...allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)‐based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross‐sectional relationship with age, beta‐amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.
Methods
Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI‐based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET‐based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment–DS (MCI‐DS), possible AD dementia, or definite AD dementia based on in‐depth assessments of cognition, function, and health status.
Results
There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI‐DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.
Interpretation
The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165–1177
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Introduction
Adults with Down syndrome, the largest population genetically predisposed to high risk for Alzheimer's disease (AD), are ideally suited participants for clinical trials targeting ...prevention. Critically important considerations for the design of such trials include appropriate selection of participants, outcome measures, and duration of follow‐up.
Methods
Archived data for 12 measures of performance over a 3‐year period were analyzed for 185 adults with Down syndrome 36 years of age and older with presumptive preclinical AD.
Results
Declines over 3 years were not observed prior to 46 years of age. However, declines were observed at older ages, increasing monotonically for groups aged 46‐49, 50‐55, and >55, as did incidence of prodromal AD and dementia.
Discussion
Significant decline over a 2‐ to 3‐year period for a prospective placebo group of adults with Down syndrome enrolled in clinical prevention trials can only be expected when inclusion is limited to adults older than 45 years of age.
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Introduction
Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) and vary in their age of transition from AD preclinical to prodromal or more advanced clinical stages. ...An empirically based method is needed to determine individual “estimated years from symptom onset (EYO),” the same construct used in studies of autosomal dominant AD .
Methods
Archived data from a previous study of > 600 adults with DS were examined using survival analysis methods. Age‐specific prevalence of prodromal AD or dementia, cumulative risk, and EYOs were determined.
Results
Individualized EYOs for adults with DS ranging in age from 30 to 70+ were determined, dependent upon chronological age and clinical status.
Discussion
EYOs can be a useful tool for studies focused on biomarker changes during AD progression in this and other populations at risk, studies that should contribute to improved methods for diagnosis, prediction of risk, and identification of promising treatment targets.
HIGHLIGHTS
Years from Alzheimer's disease (AD) onset (EYO) was estimated for adults with Down syndrome (DS).
EYOs were informed by AD clinical status and age, ranging from 30 to > 70 years.
Influences of biological sex and apolipoprotein E genotype on EYOs were examined.
EYOs have advantages for predicting risk of AD‐related dementia compared to age.
EYOs can be extremely informative in studies of preclinical AD progression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
The accuracy of the National Task Group‐Early Detection Screen for Dementia (NTG‐EDSD) was evaluated in a sample of 185 adults with Down syndrome (DS), emphasizing ‘mild cognitive ...impairment (MCI‐DS)’.
Method
Knowledgeable informants were interviewed with the NTG‐EDSD, and findings were compared to an independent dementia status rating based on consensus review of detailed assessments of cognition, functional abilities and health status (including physician examination).
Results
Results indicated that sections of the NTG‐EDSD were sensitive to MCI‐DS, with one or more concerns within the ‘Memory’ or ‘Language and Communication’ domains being most informative.
Conclusions
The NTG‐EDSD is a useful tool for evaluating dementia status, including MCI‐DS. However, estimates of sensitivity and specificity, even for detecting frank dementia, indicated that NTG‐EDSD findings need to be supplemented by additional sources of relevant information to achieve an acceptable level of diagnostic/screening accuracy.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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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.
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Vision Deficits in Adults with Down Syndrome Krinsky-McHale, Sharon J.; Silverman, Wayne; Gordon, James ...
Journal of applied research in intellectual disabilities,
20/May , Volume:
27, Issue:
3
Journal Article
Peer reviewed
Open access
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.
Results
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.
Conclusions
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.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
INTRODUCTION
Alzheimer's disease (AD) affecting adults with Down syndrome (DS‐AD), like late‐onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only ...tasks placing high demands on cognition are expected to be affected during the prodromal stage, with activities of daily living (ADLs) typically being spared. However, cognitive demands of ADLs could be high for adults with DS and may be affected during prodromal DS‐AD.
METHODS
Cognitively stable cases that subsequently developed prodromal DS‐AD were identified within a set of archived data from a previous longitudinal study. Measures of ADLs and multiple cognitive domains were examined over time.
RESULTS
Clear declines in ADLs accompanied cognitive declines with prodromal DS‐AD while stability in all measures was verified during preclinical DS‐AD.
DISCUSSION
Operationally defining prodromal DS‐AD is essential to disease staging in this high‐risk population and for informing treatment options and timing as new disease‐modifying drugs become available.
Highlights
Cognitive and functional stability were demonstrated prior to the onset of prodromal DS‐AD.
ADL declines accompanied cognitive declines as adults with DS transitioned to prodromal AD.
Declines in ADLs should be a defining feature of prodromal AD for adults with DS.
Better characterization of prodromal DS‐AD can improve AD diagnosis and disease staging.
Improvements in DS‐AD diagnosis and staging could also inform the timing of interventions.
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10.
Outcome Measures for Clinical Trials in Down Syndrome Esbensen, Anna J; Hooper, Stephen R; Fidler, Deborah ...
American journal on intellectual and developmental disabilities,
05/2017, Volume:
122, Issue:
3
Journal Article
Peer reviewed
Open access
Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the ...outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the National Institutes of Health (NIH) assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This article focuses on measures in the areas of cognition and behavior.
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