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  [Ken Tucker] was picked in August 2011 to run the prison agency after Gov. Rick Scott forced then-Secretary Edwin Buss to resign. Tucker had been the deputy commissioner of the Florida Department of Law Enforcement.

  [Ken Tucker] was picked in August 2011 to run the prison agency after Gov. Rick Scott forced then-Secretary Edwin Buss to resign. Tucker had been the deputy commissioner of the Florida Department of Law Enforcement.

The pathogenesis of Alzheimer’s disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell–cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context. Spatial and single-nucleus analyses in human postmortem Alzheimer’s disease (AD) brain tissues at early and late stages from individuals with and without Down syndrome, as well as in AD mouse models, show sex and species-specific phenotypic changes.

Plasma biomarkers associated with Alzheimer's disease could improve prognostic assessment for people with Down syndrome in both clinical practice and research settings. We aimed to identify the plasma biomarkers that most accurately predict longitudinal changes in Alzheimer's disease-related pathology and cognitive functioning in individuals with Down syndrome. This longitudinal cohort study included data from 258 adults (aged ≥25 years) with Down syndrome who were followed up prospectively every 16 months as part of the longitudinal Alzheimer's Biomarker Consortium–Down Syndrome study (recruited from seven university sites in the USA and UK between July 13, 2016, and Jan 15, 2019). Participants had baseline and longitudinal assessments of plasma tau phosphorylated at threonine 217 (p-tau217), glial fibrillary acidic protein (GFAP), amyloid β (Aβ)42/40, neurofilament light (NfL), or total tau (t-tau). Associations of baseline plasma biomarkers and longitudinal changes in plasma biomarkers with changes in global cognitive functioning (Down Syndrome Mental Status Examination [DS-MSE] scores), Aβ-PET, and tau-PET were examined using linear regression models. Plasma biomarker-associated risk of progression to dementia was assessed using Cox regression analysis. Baseline p-tau217, as well as GFAP, NfL, or t-tau, were individually associated with longitudinal changes in DS-MSE, Aβ-PET, and tau-PET, and with progression to dementia. However, in combined models, only baseline p-tau217 remained associated with changes in DS-MSE (β –0·30 [95% CI –0·45 to –0·15], p=0·0001, n=220), tau-PET (0·42 [0·14 to 0·70], p=0·0039, n=88), and progression to dementia (hazard ratio 3·51 [95% CI 1·76–7·00], p=0·0004, n=194), whereas baseline p-tau217 (0·29 [0·14–0·45], p=0·0003) and GFAP (0·37 [0·18–0·56], p=0·0003) were associated with changes in Aβ-PET (n=106 for both). Similar associations were shown between longitudinal p-tau217 or GFAP and changes in DS-MSE (p-tau217: β –0·33 [95% CI–0·52 to –0·13], p=0·0015, n=133), tau-PET (p-tau217: 0·61 [0·40 to 0·83], p<0·0001, n=87), and Aβ-PET (p-tau217: 0·35 [0·19 to 0·50], p<0·0001; GFAP: 0·49 [0·27 to 0·70], p<0·0001, n=88). Baseline and longitudinal plasma p-tau217 were associated with subsequent decline in global cognition, progression to dementia, and increased tau burden, whereas baseline p-tau217 and GFAP were associated with Aβ accumulation. These findings suggest that plasma p-tau217 and GFAP might be valuable for prognostic assessment of Alzheimer's disease in people with Down syndrome in both clinical and research contexts. The results further support evaluation of these biomarkers for monitoring disease progression in clinical trials of Down syndrome-related Alzheimer's disease. The European Research Council and National Institute on Aging (National Institute of Health).

INTRODUCTION Cerebrovascular disease is elevated across the Alzheimer's disease (AD) continuum in adults with Down syndrome (DS), but regional change within individuals is unknown. METHODS Participants from the Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) study (n = 187) had magnetic resonance imaging (MRI) scans quantified for white matter hyperintensity (WMH) volume. Annualized WMH change was assessed across cognitive diagnostic groups defined by progression or stability between two visits (78% remained cognitively stable (CS), 6% progressed from CS to mild cognitive impairment [MCI]‐DS, 5% remained MCI‐DS, 6% progressed from MCI‐DS to AD, 4% remained AD). RESULTS Compared to those who remained CS, WMH changes, particularly in posterior regions, over time were faster in advanced diagnostic groups (i.e., MCI‐DS to AD, AD at both timepoints). Monotonic increase across progressive diagnostic groups suggest an acceleration in WMH over time. CONCLUSION Posterior WMH accelerates with AD progression in adults with DS beginning at the progression from MCI‐DS to AD. Highlights White matter hyperintensity (WMH) volume increased and decreased over time in adults with Down syndrome. WMH decreased over time in the cognitively stable group. WMH increased over time in advanced Alzheimer's disease diagnostic groups. Change in posterior WMH accelerated across progressive Alzheimer's disease groups.