Kinetic evaluation and assessment of longitudinal changes in reference region and extracerebral [18F]MK-6240 PET uptake.

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study.

OBJECTIVE: Women have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults. METHODS: 328 CN participants from the Framingham Study (mean age = 57 years (±10 years), 161 women, of whom, 104 were post-menopausal) underwent tau and ß-amyloid (Aß)-PET neuroimaging. We examined global Aß-PET, and tau-PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aß and APOEε4 genotype. RESULTS: Women exhibited higher tau-PET signal (p < 0.002), and global Aß-PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age-matched men, post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions (p < 0.0001). By contrast, no differences in tau-PET signal existed between pre-menopausal women and men. Aß-PET was not associated with menopausal status or age. Neither Aß-PET nor APOEε4 status moderated sex or menopause associations with tau-PET. INTERPRETATION: Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aß and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aß burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways. ANN NEUROL 2022;92:11-22.

Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease.

OBJECTIVE: To compare how structural MRI, Fluorodeoxyglucose (FDG), and Flortaucipir (FTP) PET signal predict cognitive decline in high-amyloid versus low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. METHODS: In this prospective cohort study, we analyzed data from clinically-normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and PiB-PET acquired within a year, and prospective cognitive evaluations over a mean three-year follow-up. We focused analyses on pre-defined regions-of-interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed using the Preclinical Alzheimer's Cognitive Composite (PACC5). We evaluated the association between biomarkers and cognitive decline using linear-mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. RESULTS: Data from 131 participants [52 females, 73.98±8.29 years old] were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high-PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high-PiB. DISCUSSION: In preclinical Alzheimer's disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with preclinical Alzheimer's disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.

Association of Midlife Depressive Symptoms with Regional Amyloid-ß and Tau in the Framingham Heart Study.

BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-ß (Aß) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aß and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aß and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (ß= 0.446, SE = 0.155, p = 0.006) and amygdala (ß= 0.350, SE = 0.133, p = 0.012). CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline.

OBJECTIVE: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. METHODS: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aß-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. RESULTS: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). ß-amyloid (Aß)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aß + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04). INTERPRETATION: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aß were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.