Cerebrovascular disease emerges with age and Alzheimer's disease in adults with Down syndrome.

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. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

A pathway linking pulse pressure to dementia in adults with Down syndrome.

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. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

Small vessel cerebrovascular disease is associated with cognition in prospective Alzheimer's clinical trial participants.

BACKGROUND: Secondary prevention clinical trials for Alzheimer's disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a secondary prevention trial. METHODS: Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. RESULTS: Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. CONCLUSION: These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model.

INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aß) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aß, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aß, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.

Psychotic symptoms are associated with elevated tau PET signal in the amygdala independent of Alzheimer's disease clinical severity and amyloid burden.

Background: Psychosis in Alzheimer's disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau PET burden across older individuals with and without psychotic symptoms. Methods: [18F]AV1451 tau PET binding was compared between 26 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 26 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed on a region-of-interest and voxel level, corrected for amyloid PET burden. Results: Tau was greater in individuals with psychotic symptoms in the amygdala in region-of-interest analyses, and in amygdala, thalamus, putamen, right hippocampus, right entorhinal cortex, and right frontal cortex in voxel-based analyses. When considering different onset and type of psychotic symptoms, tau binding was greatest in those with concurrent delusions. Conclusion: Elevated tau in limbic regions may be relevant for psychotic symptoms in aging and AD.

Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome.

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. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aß42/Aß40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main Outcomes and Measures: We examined the bivariate relationships of WMH, Aß42/Aß40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and Relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.

Pathways linking pulse pressure to dementia in adults with Down syndrome.

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. Participants with DS from the Biomarkers of Alzheimer's Disease in Adults with Down Syndrome study (ADDS; n=195, age=50.6±7.2 years, 44% women, 18% diagnosed with dementia) were included. Higher pulse pressure was associated with greater global, parietal, and occipital WMH volume. Pulse pressure was not related to enlarged PVS, microbleeds, infarcts, entorhinal cortical thickness, or dementia diagnosis. However, in a serial mediation model, we found that pulse pressure was indirectly related to dementia diagnosis through parieto-occipital WMH and, subsequently through entorhinal cortical thickness. Higher pulse pressure may be a risk factor for dementia in people with DS by promoting cerebrovascular disease, which in turn affects neurodegeneration. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET.

Background: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Longitudinal decline in semantic versus letter fluency, but not their ratio, marks incident Alzheimer's disease in Latinx Spanish-speaking older individuals.

OBJECTIVE: To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer's disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores. METHOD: Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., 'semantic index'), between individuals who developed Alzheimer's disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance. RESULTS: Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer's disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer's disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index. CONCLUSION: A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer's disease from controls. Using the semantic index was not a superior marker of incident Alzheimer's disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer's disease in Latinx Spanish speakers, a historically understudied population.

Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults.

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults.

Importance: Neuroimaging studies have documented racial and ethnic disparities in brain health in old age. It remains unclear whether these disparities are apparent in midlife. Objective: To assess racial and ethnic disparities in magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration in midlife and late life. Design, Setting, and Participants: Data from 2 community-based cohort studies, Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Offspring Study of Racial and Ethnic Disparities in Alzheimer Disease (Offspring), were used. Enrollment took place from March 2011 and June 2017, in WHICAP and Offspring, respectively, to January 2021. Of the 822 Offspring and 1254 WHICAP participants approached for MRI scanning, 285 and 176 refused participation in MRI scanning, 36 and 76 were excluded for contraindications/ineligibility, and 4 and 32 were excluded for missing key variables, respectively. Main Outcomes and Measures: Cortical thickness in Alzheimer disease-related regions, white matter hyperintensity (WMH) volume. Results: The final sample included 1467 participants. Offspring participants (497 [33.9%]) had a mean (SD) age of 55 (10.7) years, had a mean (SD) of 13 (3.5) years of education, and included 117 Black individuals (23.5%), 348 Latinx individuals (70%), 32 White individuals (6.4%), and 324 women (65.2%). WHICAP participants (970 [66.1%]) had a mean (SD) age of 75 (6.5) years, had a mean (SD) of 12 (4.7) years of education, and included 338 Black individuals (34.8%), 389 Latinx individuals (40.1%), 243 White individuals (25.1%), and 589 women (65.2%). Racial and ethnic disparities in cerebrovascular disease were observed in both midlife (Black-White: B = 0.357; 95% CI, 0.708-0.007; P = .046) and late life (Black-Latinx: B = 0.149, 95% CI, 0.068-0.231; P < .001; Black-White: B = 0.166; 95% CI, 0.254-0.077; P < .001), while disparities in cortical thickness were evident in late life only (Black-Latinx: B = -0.037; 95% CI, -0.055 to -0.019; P < .001; Black-White: B = -0.064; 95% CI -0.044 to -0.084; P < .001). Overall, Black-White disparities were larger than Latinx-White disparities for cortical thickness and WMH volume. Brain aging, or the association of age with MRI measures, was greater in late life compared with midlife for Latinx (cortical thickness: B = 0.006; 95% CI, 0.004-0.008; P < .001; WMH volume: B = -0.010; 95% CI, -0.018 to -0.001; P = .03) and White (cortical thickness: B = 0.005; 95% CI, 0.002-0.008; P = .001; WMH volume: B = -0.021; 95% CI -0.043 to 0.002; P = .07) participants but not Black participants (cortical thickness: B = 0.001; 95% CI, -0.002 to 0.004; P =.64; WMH volume: B = 0.003; 95% CI, -0.010 to 0.017; P = .61), who evidenced a similarly strong association between age and MRI measures in midlife and late life. Conclusions and Relevance: In this study, racial and ethnic disparities in small vessel cerebrovascular disease were apparent in midlife. In Latinx and White adults, brain aging was more pronounced in late life than midlife, whereas Black adults showed accelerated pattern of brain aging beginning in midlife.

Obstructive sleep apnea, cerebrovascular disease, and amyloid in older adults with Down syndrome across the Alzheimer's continuum.

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer's disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer's Disease in Down Syndrome (ADDS) study were included given available research MRI (n = 116; 50 ± 8 years; 42% women) and amyloid PET scans (n = 71; 50 ± 7 years; 39% women) at the time of analysis. Participants were characterized as cognitively stable (CS; 64%), with mild cognitive impairment-DS (MCI-DS; 23%), with possible AD dementia (5%), or with definite AD dementia (8%). OSA was determined via medical records and interviews. Models tested the effect of OSA on MRI-derived cerebrovascular biomarkers and PET-derived amyloid burden, and the moderating effect of OSA and AD diagnosis on biomarkers. OSA was reported in 39% of participants, which did not differ by clinical AD diagnostic group. OSA was not associated with cerebrovascular biomarkers but was associated with greater cortical amyloid burden. White matter hyperintensity (WMH) volume (primarily in the parietal lobe), enlarged perivascular spaces, and cortical and striatal amyloid burden were greater across clinical AD diagnostic groups (CS

Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample.

We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69-96 years; 62% women; 31%/49%/20% Non-Hispanic White/Non-Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non-Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non-Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group. Importantly, treatment strategies exist to minimize vascular contributions to cognitive decline.

Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Automatic quantification of white matter hyperintensities on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging.

White matter hyperintensities (WMH) are areas of increased signal visualized on T2-weighted fluid attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) sequences. They are typically attributed to small vessel cerebrovascular disease in the context of aging. Among older adults, WMH are associated with risk of cognitive decline and dementia, stroke, and various other health outcomes. There has been increasing interest in incorporating quantitative WMH measurement as outcomes in clinical trials, observational research, and clinical settings. Here, we present a novel, fully automated, unsupervised detection algorithm for WMH segmentation and quantification. The algorithm uses a robust preprocessing pipeline, including brain extraction and a sample-specific mask that incorporates spatial information for automatic false positive reduction, and a half Gaussian mixture model (HGMM). The method was evaluated in 24 participants with varying degrees of WMH (4.9-78.6 cm3) from a community-based study of aging and dementia with dice coefficient, sensitivity, specificity, correlation, and bias relative to the ground truth manual segmentation approach performed by two expert raters. Results were compared with those derived from commonly used available WMH segmentation packages, including SPM lesion probability algorithm (LPA), SPM lesion growing algorithm (LGA), and Brain Intensity AbNormality Classification Algorithm (BIANCA). The HGMM algorithm derived WMH values that had a dice score of 0.87, sensitivity of 0.89, and specificity of 0.99 compared to ground truth. White matter hyperintensity volumes derived with HGMM were strongly correlated with ground truth values (r = 0.97, p = 3.9e-16), with no observable bias (-1.1 [-2.6, 0.44], p-value = 0.16). Our novel algorithm uniquely uses a robust preprocessing pipeline and a half-Gaussian mixture model to segment WMH with high agreement with ground truth for large scale studies of brain aging.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

White matter microstructure associations to amyloid burden in adults with Down syndrome.

INTRODUCTION: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS. METHODS: In this study of 96 adults with DS, the relation of white matter microstructure using diffusion tensor imaging (DTI) and amyloid plaque burden using [11C]PiB PET were examined. The amyloid load (AßL) derived from [11C]PiB was used as a global measure of amyloid burden. AßL and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age. RESULTS: TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed. DISCUSSION: These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations.

Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults.

Importance: Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. Objective: To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. Design, Setting, and Participants: This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Exposures: Total and regional WMH volumes. Main Outcomes and Measures: The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. Results: In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized ß = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: ß = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: ß = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: ß = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: ß = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: ß = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: ß = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004). Conclusions and Relevance: In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.

Cortical thickness in the right inferior frontal gyrus mediates age-related performance differences on an item-method directed forgetting task.

Evidence suggests that older adults have difficulty relative to younger adults in forgetting irrelevant information. Here we sought to understand the physical basis of this deficit by investigating the relationship between cortical thickness and intentional forgetting, using an item-method directed forgetting task. We tested younger (n = 44) and older (n = 54) adults' memories for words that they were instructed to either remember or to forget, and then extracted cortical thickness values from brain regions previously shown, using functional neuroimaging, to be associated with memory suppression, including the right inferior frontal gyrus, the right postcentral gyrus and the left superior/middle frontal gyrus. Results from a parallel mediation model indicated that variations in cortical thickness in the right inferior frontal gyrus, but not the right postcentral gyrus or left superior/middle frontal gyrus, partially explained age-related differences in directed forgetting: older adults with thinner cortices in this area showed worse forgetting ability. This is the first study to explore how neuromorphological differences affect the ability to intentionally suppress items in memory. The results suggest that age-related differences in directed forgetting may be partly driven by cortical thickness in a brain structure known to be functionally involved in directed forgetting, and inhibitory control more broadly, supporting a contribution of deficient inhibition to this phenomenon.