Graff‐Radford, Jonathan

AbstractINTRODUCTIONAlzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%–50% of patients. Studies have assessed hypometabolism in CBS according to β‐amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD‐tau (T) and A with hypometabolism is incomplete.METHODSThirty‐three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound‐B PET and were classified as A± and T±. FDG‐PET uptake was extracted for 12 regions‐of‐interest in dominant (most affected) and non‐dominant hemispheres and compared across A/T groups.RESULTSA+T+ patients had greater hypometabolism in temporo‐parieto‐occipital cortices than A+T‐ and A‐T‐ groups, with no differences observed between the A+T‐ and A‐T‐ groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups.DISCUSSIONAmyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo‐parieto‐occipital cortices in CBS, with AD‐like patterns of hypometabolism observed only in A+T+ patients.Highlights Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo‐parieto‐occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto‐occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.

Abstract Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra. Associations between variants and outcomes were assessed using regression models appropriate for the nature of the given neuropathological outcome and that were adjusted for age at death, sex and top principal components of genetic data. In the discovery series, APOE rs429358 (i.e. APOE ε4) was associated with a greater severity of each of Braak NFT stage [odds ratio (OR) = 3.07, P = 2.34 × 10−32], Thal amyloid phase (OR = 3.57, P = 3.28 × 10−29) and LBD subtype (OR = 1.78, P = 9.85 × 10−9), with similar findings observed in the independent replication series (Braak NFT stage, OR = 2.30, P = 2.70 × 10−11; Thal amyloid phase, OR = 3.17, P = 6.39 × 10−18; LBD subtype, OR = 2.68, P = 3.85 × 10−10). In the subgroup of cases with lower levels of Alzheimer's disease pathology (Braak NFT stage ≤ III and Thal amyloid phase ≤2), there was a strong association between APOE rs429358 and LBD subtype even when adjusting for Braak stage and Thal phase in the discovery series (n = 218, OR = 2.47, P = 0.007) and the replication series (n = 141, OR = 3.60, P = 0.006). Although additional genome-wide significant associations were identified in the discovery series between LINC01581/MCTP2 rs547411734 and lower middle frontal LB counts, between TLE3 rs3743309 and lower cingulate LB counts, and between GRIN2A/ATF7IP2 rs1097915 and lower parahippocampal LB counts, these findings were not observed in the replication series. Our results indicate that the APOE ε4 allele is the most prominent genetic determinant of severity of neuropathology in LBD. These findings represent a key step forward in our understanding of genetic drivers of neuropathological features in LBD. Future studies utilizing meta-analytical approaches will be important to more precisely assess other associations that were not quite genome-wide significant in the discovery series.

Abstract INTRODUCTION Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A−) individuals. METHODS We included 290 A−, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A− to A+ and with rate of amyloid PET change. RESULTS Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p‐tau217), and Amyloid Probability Score 2 were associated with 1.29 ( P = 0.09), 1.38 ( P < 0.001), and 1.20 ( P = 0.05) increases, respectively, in the hazard of progression from A− to A+ and 0.27 ( P = 0.16), 0.50 ( P = 0.007), and 0.28 ( P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change. DISCUSSION Plasma %p‐tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial. Highlights Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive. The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2. Age and apolipoprotein E ε4 carriership were also important predictors. These markers may be useful for enrichment of a primary prevention trial.

Background: Cerebral microbleeds (CMBs) are associated with incident dementia, but the impact of specific CMB patterns is unclear. CMBs in lobar regions suggest cerebral amyloid angiopathy (CAA), which is sometimes accompanied by superficial siderosis (SS), while subcortical CMBs indicate hypertensive origins. This study investigates the association between CMB patterns and dementia risk in the community-based longitudinal Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: All ARIC-NCS participants with a 3T research MRI at visit 5 (2011-13; aged 67-90) without intracerebral hemorrhage or dementia were included. CMB and SS presence and location were coded from T2* GRE sequences. Individuals were classified into one of four patterns: no CMBs, only subcortical, mixed (lobar and/or SS + subcortical), and only lobar and/or SS. Incident dementia diagnoses were defined by cognitive testing (in-person and telephone), informant interviews, and hospital discharge codes or death certificates. Cox proportional-hazards models assessed the association between the presence, patterns, and frequency of CMBs (0,1,2,3+), presence of SS, and incident dementia from visit 5 through 2020. Model covariates included demographics, vascular risk factors, and imaging markers of small vessel disease. Results: Among 1609 participants, 364 had CMBs (Table 1). Participants with CMBs tended to be older and female compared to those without CMBs. Compared to individuals with no CMBs, presence of any CMBs was associated with an increased risk of dementia (Table 2). Compared to individuals without CMBs, individuals with only lobar CMBs and/or SS had an increased risk of incident dementia, as did individuals with mixed CMBs, but individuals with subcortical-only did not. Participants with ≥3 CMBs of any variant had an increased risk of incident dementia vs no CMBs. Although SS was infrequent, its presence (vs no SS) was associated with an elevated risk of dementia. Conclusion: CMBs, particularly in a mixed or lobar and/or SS-only pattern, are linked to an increased risk of incident dementia. The number of recurrent CMBs and any SS also showed an increased dementia risk. These data support that dementia risk is high in individuals with a CAA-type CMB pattern, but also emphasize that a mixed pattern, not typical of CAA alone, is associated with a high risk of dementia. Further studies should evaluate mechanisms by which these different patterns contribute to dementia.