ABSTRACT
BACKGROUND: Genetic factors that influence Alzheimer's disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E, influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology. OBJECTIVE: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS. METHODS: To assess allele frequency and haplotype associations ApoE, Tau, TREM2, and HLA-DR were analyzed by SNP analysis in DS participants (nâ=â47) and controls (nâ=â50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry. RESULTS: Haplotype analysis showed that individuals with Tau H1/H1 and ApoEÉ4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus. CONCLUSION: Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aß42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoEÉ4, Tau/H1, and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia.
Subject(s)
Alzheimer Disease/metabolism , Apolipoproteins E/metabolism , Choroid Plexus/metabolism , Dementia/metabolism , Down Syndrome/metabolism , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , tau Proteins/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , PhosphorylationABSTRACT
INTRODUCTION: Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. METHODS: Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [11C]-PiB-PET, four structural magnetic resonance imagings, as well as a [18F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. RESULTS: Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. DISCUSSION: Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau.
ABSTRACT
RATIONALE: Parkinson's disease (PD) impairs working memory (WM)-the ability to maintain items in memory for short periods of time and manipulate them. There is conflicting evidence on the nature of the deficits caused by the disease, and the potential beneficial and detrimental effects of dopaminergic medication on different WM processes. OBJECTIVES: We hypothesised that PD impairs both maintenance and manipulation of items in WM and dopaminergic medications improve this in PD patients but impair it in healthy older adults. METHODS: We tested 68 PD patients ON and OFF their dopaminergic medication, 83 healthy age-matched controls, and 30 healthy older adults after placebo and levodopa administration. We used the digit span, a WM test with three components (forwards, backwards, and sequence recall) that differ in the amount of manipulation required. We analysed the maximum spans and the percentage of lists correctly recalled, which probe capacity of WM and the accuracy of the memory processes within this capacity, respectively. RESULTS: PD patients had lower WM capacity across all three digit span components, but only showed reduced percentage accuracy on the components requiring manipulation (backwards and sequence spans). Dopaminergic medication did not affect performance in PD patients. In healthy older adults, levodopa did not affect capacity, but did impair accuracy on one of the manipulation components (sequence), without affecting the other (backwards). CONCLUSIONS: This suggests that the deficit of maintenance capacity and manipulation accuracy in PD patients is not primarily a dopaminergic one and supports a potential "overdosing" of intact manipulation mechanisms in healthy older adults by levodopa.