Jack, Clifford R

AbstractIntroductionThe Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020.MethodsWe identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion.ResultsDisease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity.DiscussionADNI has had a profound impact in improving clinical trials for AD.

AbstractIntroductionBlood‐based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers.MethodsPlasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) were measured on the Quanterix Simoa HD‐1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years. All other data were collected during in‐person MCSA visits or abstracted from the medical record.ResultsAmong cognitively unimpaired (CU) participants, all plasma markers correlated with age. Linear regression models revealed multiple relationships. For example, higher Charlson Comorbidity Index and chronic kidney disease were associated with higher levels of all biomarkers. Some relationships differed between mild cognitive impairment and dementia participants.DiscussionMultiple variables affect plasma biomarkers of amyloid pathology and neurodegeneration among CU in the general population. Incorporating this information is critical for accurate interpretation of the biomarker levels and for the development of reference ranges.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross‐sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03–1.83) after adjusting for demographic and cardiovascular risk factors. In race‐stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15–3.50), compared with White participants (OR, 1.29; 95% CI, 0.89–1.89). However, the race interaction was not statistically significant ( P interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.

AbstractBackgroundDysphagia is a common symptom of progressive supranuclear palsy often leading to aspiration pneumonia and death.ObjectiveThe aim of this study was to examine how impairments of the oral and pharyngeal phases of the swallow and airway incursion during liquid swallows relate to gray and white matter integrity.MethodsThirty‐eight participants with progressive supranuclear palsy underwent videofluorographic swallowing assessment and structural and diffusion tensor head magnetic resonance imaging. Penalized linear regression models assessed relationships between swallowing metrics and regional gray matter volumes and white matter fractional anisotropy and mean diffusivity.ResultsOral phase impairments were associated with reduced superior parietal volumes and abnormal diffusivity in parietal and sensorimotor white matter, posterior limb of the internal capsule, and superior longitudinal fasciculus. Pharyngeal phase impairments were associated with disruption to medial frontal lobe, corticospinal tract, and cerebral peduncle. No regions were predictive of airway incursion.ConclusionsDifferential patterns of neuroanatomical impairment corresponded to oral and pharyngeal phase swallowing impairments. © 2021 International Parkinson and Movement Disorder Society

Abstract Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.

AbstractIntroductionThe prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p‐tau217) and p‐tau181 is not understood.MethodsAnalyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p‐tau181 were measured with Elecsys immunoassays. CSF p‐tau181 and p‐tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain‐specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging.ResultsCSF p‐tau217 was superior to p‐tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p‐tau181 and p‐tau217 were associated with risk of MCI among amyloid‐positive individuals. Differences between CSF p‐tau measures predicting cortical thickness were subtle.DiscussionThere are subtle differences for CSF p‐tau217 and p‐tau181 as prognostic AD markers.

Abstract Introduction We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers. Methods Cut points for Elecsys amyloid beta 42 (Aβ42), total tau (t‐tau), hyperphosphorylated tau (p‐tau), and t‐tau/Aβ42 and p‐tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants. Results The t‐tau/Aβ42 and p‐tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)‐based cut points were 0.26 (0.24–0.27) for t‐tau/Aβ42 and 0.023 (0.020–0.025) for p‐tau/Aβ42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA). Conclusion CSF t‐tau/Aβ42 and p‐tau/Aβ42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen.

Abstract Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer’s disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer’s disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer’s disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = −0.39, P = 0.04) and amyloid-PET uptake (r = −0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer’s disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer’s disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer’s disease co-pathology in patients with DLB is associated with more Alzheimer’s disease-like changes in functional connectivity. Furthermore, we found an association between the brain’s functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer’s disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.