Jack, Clifford R

Abstract Disruption of the default mode network is a hallmark of Alzheimer’s disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and 1-year longitudinal changes in default mode network sub-systems in the visual and language variants of Alzheimer’s disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer’s disease participants diagnosed with posterior cortical atrophy (n = 33) or logopenic progressive aphasia (n = 28) underwent structural MRI, resting-state functional MRI and [18F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer’s disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer’s disease participants, 26 amnestic Alzheimer’s disease participants and 40 cognitively unimpaired individuals had one follow-up functional MRI ∼1–2 years after the baseline scan. Default mode network connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral and anterior dorsal sub-systems derived from independent component analysis. A global measure of default mode network connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer’s disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer’s disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer’s disease participants had lower connectivity than the older ones, particularly in the ventral default mode network. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral default mode network connectivity in atypical Alzheimer’s disease. Connectivity in the ventral default mode network declined over time in atypical Alzheimer’s disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal default mode network connectivity, lower posterior and ventral default mode network connectivity and decline in ventral default mode network connectivity over time in atypical Alzheimer’s disease. Visuospatial symptoms were associated with default mode network connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer’s disease variants, and discriminated Alzheimer’s disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity and with disruption more pronounced in younger participants. The ventral default mode network declined over time in atypical Alzheimer’s disease, suggesting a shift in default mode network connectivity likely related to tau pathology.

AbstractINTRODUCTIONThe implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A‐.METHODSWe evaluated 98 participants from the Mayo Clinic who were T+ and A‐. Participants were matched 2:1 to A‐ and T‐ cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups.RESULTSThe A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini‐Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale‐Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A‐T+ and CI A‐T+.DISCUSSIONA‐T+ participants show an association with lower cognitive performance.

Abstract Objective To determine the association between brain MRI abnormalities and incident epilepsy in older adults. Methods Men and women (ages 45–64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late‐onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status. Results Among 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25–75 percentile 5.8–6.9) of follow‐up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0–4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2–7.3). Interpretation This study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE.

AbstractBackgroundWhite matter (WM) plays an important role in cognitive function and undergoes substantial changes due to aging and increase in AD and AD related dementia (AD/ADRD) pathologies. While recent work proposed measurement of global WM changes from diffusion MRI as biomarkers for Cerebrovascular disease (CVD) such as PSMD and free water, there needs to be a better understanding of WM changes due to AD/ADRD pathologies. The goal of our recent work was to understand white matter changes with CVD and AD – common pathologies in AD/ADRD ‐ utilizing data from Mayo Clinic Study of Aging and Mayo ADRC.MethodUsing diffusion MRI (dMRI) in 718 participants from Mayo Clinic Study of Aging (mean age = 71.1 years, 56% male), we investigated relationships between commonly used dMRI measures and vascular risk as well as global amyloid PET. In a subset of 233 participants who were amyloid‐PET positive and also competed Tau‐PET (flortaucipir) from Mayo Clinic Study of Aging and Mayo ADRC, we investigated associations between regional flortaucipir SUVRs in Braak stages and regional WM changes.ResultsWe found greater frontal lobe WM damage with increasing vascular risk across all dMRI measures. We previously validated the strong relationship between the genu of the corpus callosum (anterior interhemispheric connections) dMRI measurements made on antemortem scans and cerebrovascular pathology observed on postmortem tissue (Nguyen et. al. Acta Neuropathologica 2022) supporting the utility of genu of the corpus callosum dMRI measures as a potential CVD biomarker. Also, we found greater posterior WM damage with increasing amyloid burden. Among the 233 amyloid positive participants, we found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages with greater extent of posterior WM damage. Further, dMRI measurements of the WM damage provided complementary information about disease staging and progression of AD in addition to flortaucipir SUVR measurements.ConclusionsAnterior WM measurements may be more specific to CVD and posterior WM changes are seen with increasing AD pathological burden. Our results suggest that WM changes observed with CVD and typical AD may be different and have clinical utility for differential diagnosis and disease staging.

Background: Lower (worse) left atrial (LA) function is associated with higher dementia risk. It is unclear whether lower LA function is associated with vascular brain injury on brain MRI, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities (ARIC) study, we assessed the cross-sectional association between LA function measures and brain MRI markers of vascular brain injury (cerebral microbleeds, brain infarcts). Hypothesis: Participants with lower LA function will be more likely to have presence of > 1 cerebral microbleed or brain infarct. Methods: ARIC participants who had both an echocardiogram and brain MRI at visit 5 (2011-13) were included. We excluded those with prevalent dementia, stroke, or atrial fibrillation. LA function measures were obtained from 2D-echocardiograms and assessed in quartiles (highest quartile was the reference). Brain MRI measures were assessed as the presence or absence of > 1 cerebral microbleed or brain infarct. Logistic regression was used. Results: Of the 1502 participants (mean [SD] age 76 [5], 60% female, 27% Black) in this analysis, 345 (23%) and 351 (23%) had > 1 cerebral microbleed or brain infarct present. Compared to the highest quartile, lower LA reservoir and conduit strain quartiles were associated with higher odds of cerebral microbleeds. LA contractile strain was not associated with cerebral microbleeds. Compared to the highest quartile, the lowest LA conduit strain quartile, but not reservoir strain, was associated with higher odds of brain infarcts. LA contractile strain was inversely associated with brain infarcts. Conclusion: In this community-based cohort, lower LA function was cross-sectionally associated with cerebral microbleeds and brain infarcts. The inverse relationship with LA contractile strain may be due to contractile function compensating for a decrease in early diastolic filling. Prospective studies are needed to confirm these findings.

Abstract Transactive response DNA-binding protein 43 (TDP-43) pathology is categorized as type A-E in frontotemporal lobar degeneration and as type α-β in Alzheimer disease (AD) based on inclusion type. We screened amygdala slides of 131 cases with varying ages at death, clinical/neuroimaging findings, and AD neuropathologic changes for TDP-43 pathology using anti-phospho-TDP-43 antibodies. Seven cases (5%) only showed atypical TDP-43 inclusions that could not be typed. Immunohistochemistry and immunofluorescence assessed the atypical star-shaped TDP-43 pathology including its distribution, species, cellular localization, and colocalization with tau. All 7 had died at an extremely old age (median: 100 years [IQR: 94–101]) from nonneurological causes and none had dementia (4 cognitively unimpaired, 3 with amnestic mild cognitive impairment). Neuroimaging showed mild medial temporal involvement. Pathologically, the star-shaped TDP-43-positive inclusions were found in medial (subpial) amygdala and, occasionally, in basolateral regions. Hippocampus only showed TDP-43-positive neurites in the fimbria and subiculum while the frontal lobe was free of TDP-43 inclusions. The star-shaped inclusions were better detected with antibodies against N-terminal than C-terminal TDP-43. Double-labeling studies confirmed deposition of TDP-43 within astrocytes and colocalization with tau. We have identified a novel TDP-43 pathology with star-shaped morphology associated with superaging, with a homogeneous clinicopathologic picture, possibly representing a novel, true aging-related TDP-43 pathology.

Abstract INTRODUCTION The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co‐evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p‐tau217, p‐tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS Individual timing of plasma p‐tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p‐tau, and tau PET temporal meta‐regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION Plasma p‐tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p‐tau and Aβ PET was the strongest. Highlights Plasma p‐tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p‐tau was associated with Aβ PET and GFAP progression. P‐tau181 and p‐tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p‐tau and Aβ PET.

AbstractINTRODUCTIONCost‐effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non‐imaging indicators of VCID using magnetic resonance imaging (MRI)‐measured white matter (WM) damage and hypothesized that these indicators differ based on age.METHODSIn 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid‐attenuated inversion recovery (FLAIR)‐MRI, we examined associations between baseline non‐imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles.RESULTSVRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata.DISCUSSIONNon‐imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID.Highlights Non‐imaging indicators of VCID can aid in prediction of MRI‐measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non‐imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non‐imaging VCID indicators proposed in the future.

AbstractCarriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐σ and FLAIR‐σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐μ decreased and T1‐σ and FLAIR‐σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

Abstract INTRODUCTION Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early‐onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS We analyzed MRI scans to define the sporadic EOAD‐signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early‐onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS The EOAD‐signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD‐signature atrophy was associated with the severity of cognitive impairment. DISCUSSION The EOAD‐signature atrophy is a reliable and clinically valid biomarker of AD‐related neurodegeneration that could be used in clinical trials for EOAD. Highlights We developed an early‐onset Alzheimer's disease (EOAD)–signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD‐signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.