The many faces of globular glial tauopathy: A clinical and imaging study.

BACKGROUND: Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non-globular glial 4-repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). METHODS: For this case-control study the Mayo Clinic brain banks were queried for all cases with an autopsy-confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR-parkinsonism index, midbrain volume, and white matter hyperintensities.18 F-Fluorodeoxyglucose-, 11 C Pittsburg compound-, and 18 F-flortaucipir-positron emission tomography scans were reviewed. RESULTS: Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55-87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson-plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR-parkinsonism index, and larger midbrain volumes. CONCLUSIONS: Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Association of Initial ß-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment.

Importance: Tau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum. Objective: To investigate the association of ß-amyloid (Aß) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between Aß and tau accumulation and inform clinical trial design. Design, Setting, and Participants: This cohort study included individuals aged 65 to 85 years who were CU and had participated in the Mayo Clinic Study of Aging, with serial cognitive assessments, serial magnetic resonance imaging, 11C-Pittsburgh compound B (Aß) PET scans, and 18F-flortaucipir PET scans, collected from May 2015 to March 2020. Persons were excluded if they lacked follow-up PET scans. A similarly evaluated CU group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were also studied. These data were collected from September 2015 to March 2020. Exposures: Participants were stratified by index Aß levels on PET into low Aß (≤8 centiloid [CL]), subthreshold Aß (9-21 CL), suprathreshold Aß (22-67 CL), and high Aß (≥68 CL). Main Outcomes and Measures: Changes over a mean of 2.7 (range, 1.1-4.1) years in flortaucipir PET in entorhinal, inferior temporal, and lateral parietal regions of interest and an AD meta-region of interest (ROI). Results: A total of 167 people were included (mean age, 74 [range, 65-85] years; 75 women [44.9%]); 101 individuals were excluded lacking follow-up, and 114 individuals from the ADNI were also studied (mean [SD] age, 74.14 [5.29] years; 64 women [56.1%]). In the Mayo Clinic Study of Aging, longitudinal flortaucipir accumulation rates in the high Aß group were greater than the suprathreshold, subthreshold, and low Aß groups in the entorhinal ROI (suprathreshold, 0.025 [95% CI, 0.013-0.037] standardized uptake value ratio [SUVR] units; subthreshold, 0.026 [95% CI, 0.014-0.037] SUVR units; low Aß, 0.034 [95% CI, 0.02-0.049] SUVR units), inferior temporal ROI (suprathreshold, 0.025 [95% CI, 0.014-0.035] SUVR units; subthreshold, 0.027 [95% CI, 0.017-0.037] SUVR units; low Aß, 0.035 [95% CI, 0.022-0.047] SUVR units), and the AD meta-ROI (suprathreshold, 0.023 [95% CI, 0.013-0.032] SUVR units; subthreshold, 0.025 [95% CI, 0.016-0.034] SUVR units; low Aß, 0.032 [95% CI, 0.021-0.043] SUVR units) (all P < .001). Flortaucipir accumulation rates in the subthreshold and suprathreshold Aß groups in temporal regions were nonsignificantly elevated compared with the low Aß group. In the ADNI cohort, the variance was larger than in the Mayo Clinic Study of Aging but point estimates for annualized flortaucipir accumulation in the inferior temporal ROI were very similar. An estimated 216 participants who were CU per group with PET Aß of 68 CL or more would be needed to detect a 25% annualized reduction in flortaucipir accumulation rate in the AD meta-ROI with 80% power. Conclusions and Relevance: Substantial flortaucipir accumulation in temporal regions is greatest in persons aged 65 to 85 years who were CU and had high initial Aß PET levels, compared with those with lower Aß levels. Recruiting persons who were CU and exhibiting Aß of 68 CL or more on an index Aß PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure.

Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes.

OBJECTIVE: To characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome. METHODS: Seventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [18F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [18F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine ß-amyloid positivity. RESULTS: The bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was ß-amyloid-positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter. CONCLUSION: Patterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.

Entorhinal cortex tau, amyloid-ß, cortical thickness and memory performance in non-demented subjects.

As more biomarkers for Alzheimer's disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with 11C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, 18F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-ß levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.