Publications by authors named "Mark Mapstone"

Introduction: Adults with Down syndrome demonstrate striatum-first amyloid accumulation with [ C]PiB PET imaging, which has not been replicated with [ F]florbetapir (FBP). Early striatal accumulation has not been temporally quantified with respect to global cortical measures.

Methods: Longitudinal PiB (n=175 participants) and FBP (n=92 participants) data from the Alzheimer Biomarkers Consortium-Down Syndrome were used to measure cortical and striatal binding.

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  • This study focused on the risk of Alzheimer's disease in adults with Down syndrome, using amyloid and tau PET imaging to track disease progression.
  • It involved a longitudinal analysis of 167 participants, assessing cognitive functioning and biomarkers over two visits between 2017 and 2022.
  • The research aimed to determine the timeline for symptomatic Alzheimer's based on "amyloid age" and its relation to cognitive decline and tau accumulation.
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  • Blood-based biomarkers are being studied to improve the detection and monitoring of Alzheimer's Disease in individuals with Down Syndrome, as current clinical diagnostics are challenging.
  • Key biomarkers like phosphorylated tau (p-tau217, p-tau181) have shown strong connections to disease progression in Down Syndrome, suggesting they could be valuable in clinical settings.
  • The research emphasizes the need for more understanding of biomarker variability, particularly regarding sex differences and the appropriate contexts for their clinical application in Alzheimer's diagnosis and treatment.
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  • - Development of Alzheimer's disease (AD) pathology occurs faster in individuals with Down's syndrome (DS) compared to others; this study focuses on comparing specific biomarkers in DS individuals and their siblings.
  • - Researchers found that plasma levels of glial fibrillary acidic protein (GFAP) and pTau-217 were elevated in individuals with DS, indicating increased astrogliosis and tau pathology, and GFAP played a mediating role in the relationship between amyloid and tau levels.
  • - The findings suggest that astrogliosis is crucial in the early stages of Alzheimer's in DS, and targeting neuroinflammation might be beneficial primarily for those with amyloid positivity.
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  • - Individuals with Down syndrome (DS) face a high risk of developing Alzheimer's disease (AD), but about 20% do not show dementia symptoms until later in life, potentially due to the presence of mosaicism, which can reduce gene expression from chromosome 21.
  • - Researchers analyzed data from two major studies (ABC-DS and a legacy study) that included neuropsychological assessments and biomarkers to determine the prevalence and impact of mosaicism, finding it in less than 10% of participants.
  • - Those with mosaicism exhibited lower levels of AD-related biomarkers and a slower decline in cognitive scores compared to individuals with full trisomy, indicating a potential protective effect against dementia, though more research is needed to fully understand these findings.
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  • By age 40, over 90% of adults with Down syndrome develop Alzheimer’s disease, with many progressing to dementia, despite having few typical vascular risk factors.
  • This study analyzed how small vessel cerebrovascular disease impacts Alzheimer's disease progression and neurodegeneration in adults with Down syndrome, using MRI and plasma biomarker data from 185 participants.
  • Results indicated a complex relationship where white matter hyperintensity (WMH) levels influenced phosphorylated tau, linked by glial fibrillary acidic protein, suggesting that cerebrovascular health affects Alzheimer’s pathology in this population.
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The cognitive deterioration of politicians is a critical emerging issue. As professions including law and medicine develop and implement cognitive assessments, their insights may inform the proper strategy within politics. The aging, lifetime-appointed judiciary raises legal and administrative questions of such assessments, while testing of older physicians experiencing cognitive decline provides real-life examples of implementation.

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The amyloid beta (Aβ) 42/40 ratio has been widely studied as a biomarker in Alzheimer's disease (AD); however, other Aβ peptides could also represent relevant biomarkers. We measured levels of Aβ38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aβ levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aβ peptides individually and the Aβ42/40 ratio, but not the Aβ42/38 ratio, were significantly correlated with brain amyloid (Aβ-PET).

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  • The study investigates the relationship between amyloid-beta (Aβ) and tau biomarkers and the onset of symptomatic Alzheimer's disease (AD) in adults with Down syndrome (DS), highlighting the concept of "amyloid age."* -
  • It analyzes data from 167 adults with DS over roughly five years, finding that cognitive decline becomes noticeable about 2.7 years after reaching Aβ+ status, with tau levels also increasing subsequently.* -
  • The findings suggest a quicker progression to cognitive impairment and dementia in individuals with DS compared to typical late-onset AD, emphasizing the relevance of amyloid age for clinical practice and research.*
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  • * Key findings include her ApoE genotype (E2/3) linked to a lower dementia risk, neuroimaging showing stable amyloid and moderate tau levels, and intermediate Alzheimer’s pathology with added Lewy body and cerebrovascular issues.
  • * The study highlights the complex relationship between Alzheimer's symptoms and brain changes in Down syndrome, suggesting the need for more research on factors that contribute to cognitive resilience in this population.
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Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis.

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Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy.

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  • The study investigates early Alzheimer's disease changes in the brains of people with Down syndrome and those with genetic variants linked to Alzheimer's, aiming to better understand disease development and improve prevention strategies.
  • Using cross-sectional data from two cohort studies, researchers analyzed tau protein spread and its relationship with amyloid accumulation in participants aged 25 and older.
  • Findings revealed significant differences in the pattern and timing of tau accumulation in the two groups, suggesting implications for early intervention and clinical trials targeting Alzheimer's pathology.
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Introduction: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials.

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Biomarkers that predict the clinical onset of Alzheimer's disease (AD) enable the identification of individuals in the early, preclinical stages of the disease. Detecting AD at this point may allow for more effective therapeutic interventions and optimized enrollment for clinical trials of novel drugs. The current biological diagnosis of AD is based on the AT(N) classification system with the measurement of brain deposition of amyloid-β (Aβ) ("A"), tau pathology ("T"), and neurodegeneration ("N").

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Introduction: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.

Methods: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).

Results: Eighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA).

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Background: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).

Methods: CRISPR-Cas9 was used to generate an Abca7 variant in mice, modeling the homologous human ABCA7 variant, and extensive characterization was performed.

Results: Abca7 microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity.

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  • Late-onset Alzheimer's disease (LOAD) has a significant genetic basis, and the Long-Life Family Study (LLFS) provides an opportunity to study genetics through families that experience delayed dementia onset.
  • A whole genome sequence analysis of 3,475 LLFS members, along with association studies involving over 14,000 participants, identified specific genetic variants, particularly within the MTUS2 gene, that are linked to LOAD and are influenced by beta amyloid levels.
  • The MTUS2 gene plays a role in the nervous system's development and function, making it a potential target for further research on the biology of LOAD, as the identified genetic variants were consistent across various studies and populations.
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Introduction: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS.

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Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors.

Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS.

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Individuals with Down syndrome (DS) are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease, entorhinal cortical atrophy, and diagnosis of dementia in adults with DS.

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Introduction: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers.

Methods: AD polygenic risk scores (PRS) were tested for association with DS-related traits.

Results: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS.

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Background: Mild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD.

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Background: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD).

Objective: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site.

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Introduction: People with Down syndrome (DS) often develop Alzheimer's disease (AD). Here, we asked whether ultrasensitive plasma immunoassays for a tau N-terminal fragment (NT1-tau) and Aβ isoforms predict cognitive impairment.

Methods: Plasma NT1-tau, Aβ , Aβ , and Aβ levels were measured in a longitudinal discovery cohort (N = 85 participants, 220 samples) and a cross-sectional validation cohort (N = 239).

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