Spychalla, Anthony J.

Abstract Lower cerebral perfusion is associated with adverse outcomes, but risk factors are poorly understood. This study examined associations of cumulative systolic blood pressure [SBP], diabetes, and BMI from mid- to late-life with late-life cerebral perfusion, using whole-brain MRI Arterial Spin Labeling (ASL). Cumulative exposures were defined as either average continuous SBP or BMI across visits or number of years with diabetes, hypertension, or obesity. Multiple regression, adjusted for age and gender, estimated ASL (β: 95% CI) among participants without prevalent conditions at baseline in participants with ASL data from the Atherosclerosis Risk in Communities Study (ARIC; Jackson, MS; n = 100; age=81±3 years; 65% Female; 100% Black participants; 34 years retrospective risk factor assessments (1987-2021); pulsed ASL, 8/2021-1/2024) and the Mayo Clinic Study of Aging (MCSA; Rochester, MN; n = 537; age=71±13 years; 36.3% Female, 100% White participants; 18 years retrospective risk factor assessments (2005-2023); pseudo-continuous ASL 2/2023-3/2024). A 10 mmHg higher cumulative SBP was associated with a 0.04 lower ASL (MCSA β=-0.04; -0.01, -0.07; ARIC β=-0.04; -0.09, 0.01). A 10 kg/m2 higher cumulative BMI was associated with a 0.30 lower ASL (-0.51, -0.08) in ARIC and 0.03 lower ASL (-0.16, 0.10) in MCSA participants. Every five additional years of diabetes exposure was associated with a 0.03 (-0.06, -0.01) lower ASL in ARIC and 0.11 (-0.27, 0.05) lower ASL in MCSA participants. High BP, obesity, and diabetes may contribute to poor cerebral perfusion over extended exposures from midlife. Longer risk factor assessment periods and different ASL techniques may explain differences in the cohorts.

Abstract Background White matter hyperintensity topography, particularly posterior confluent and subcortical multispot (WMH‐MS), has been implicated as surrogate imaging biomarker of cerebral amyloid angiopathy (CAA). Usefulness of WMH‐MS for prediction of future cerebral microbleeds (CMB's) has significant clinical implications for anti‐amyloid therapy risk assessment. Our primary goal was to identify the prevalence of positive WMH‐MS status and their utility for predicting the incident CMBs in a population‐based sample. Our secondary goal was to evaluate its usefulness after accounting for amyloid (surrogate for CAA) and WMH burden (surrogate of small vessel disease) which are both risk factors for CMBs. Method We identified 651 participants (mean age (SD) 69.8 (10.0) years, 55% male) from the Mayo Clinic Study of Aging, who had 3T baseline whole brain fluid‐attenuated inversion recovery (FLAIR) MRI and at least two T2*‐weighted gradient recalled echo (GRE) sequences (concomitant with or after FLAIR) which were used to ascertain CMBs. Amyloid positron emission tomography (PiB‐PET) scans were available in 87% of the sample. Visual reads on FLAIR scans were performed using a 4‐point Fazekas rating scale of periventricular and deep WMH (positivity: Fazekas ≥ 2) and a 3‐point MS severity visual scale (positivity: nWMH‐MS > 10 circular or ovoid WMH spots, Figure 1) according to established criteria. Using univariate and multivariable logistic regression, we assessed the independent association of WMH‐MS > 10 and Fazekas ≥ 2 for prediction of incident CMB's. Result The frequency of WMH‐MS pattern was greater in those who developed an incident CMB compared to those who did not develop a CMB (20.8% vs. 2.8%, p < 0.001). Older age and male sex were predictive of incident CMBs (Figure 2A). In univariate models, presence of WMH‐MS pattern but not Fazekas was associated with incident CMBs after adjusting for age and sex. The associations remained significant after additional adjustment for APOE4 , hypertension, number of baseline CMBs (Prior CMB), and amyloid effects (Figure 2B). Conclusion Visually identified WMH‐MS patterns on FLAIR‐MRI were predictive of incident CMBs in this population and may be useful markers of CAA. Future studies evaluating its utility as an additional biomarker of amyloid related imaging abnormalities in clinical trials are necessary.

AbstractBackgroundWe recently developed a novel tau‐PET summary measure THETA, capturing regional heterogeneity and identifying tau status, using ground truth visual assessments from a large single‐center cross‐sectional dataset and validated on independent cohorts [1, 2]. In this study, we aimed to evaluate the performance of THETA on longitudinal and histopathology data.MethodWe included longitudinal tau‐PET ([18F]flortaucipir) data from 696 Mayo Clinic Study of Aging (MCSA) and ADRC participants, with histopathology in n = 90. Fig. 1 shows the model that uses regional standard uptake value ratios (SUVR) and a target of binary class of tau positivity for prediction of THETA. This model was applied to predict tau status on each followup scan. Slopes of the meta‐ROIs’ tau SUVRs and THETA were evaluated by diagnostic group and as a function of baseline amyloid SUVR in discordant CU participants (where meta‐ROI and visual assessments did not match at baseline) and in incident‐THETA+ CU participants (whose THETA moved from below to above 1 over serial tau‐PET scans). We evaluated tau measurements as a function of Braak stages for neurofibrillary tangles.ResultLongitudinal plots of meta‐ROIs for diagnostic groups were very similar, but the expanded range of THETA based on visual positivity prediction clearly identified tau positive or tau‐negative scans. In discordant‐CU (n = 97) and incident‐THETA+ CU participants (n = 14 all amyloid positive at follow‐up but only 65% at baseline), the relationship between baseline amyloid and rate of tau increase was stronger for THETA than temporal meta‐ROI (Fig. 2). Separation between baseline and follow‐up was greater for THETA (t‐statistics = 90) compared to temporal meta‐ROI (t‐statistics = 20) (p<0.01) in the incident‐THETA+ CU participants. THETA showed a slightly stronger association with Braak stage than meta‐ROIs (rho = 0.87 vs. ≤0.83, p<0.05), with better separation of clinical diagnoses (Fig. 3).ConclusionTHETA remained clearly negative or positive in MCI and AD, providing consistent information on underlying etiology of impairment at both baseline and follow‐up. Although binary in its construction, THETA both provided separation of values based on tau status and its change correlated with baseline amyloid burden especially in discordant‐CU where tau deposition is not in typical meta‐ROIs. Further work is needed to confirm if THETA captures early tau changes.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P &amp;lt; .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P &amp;lt; .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P &amp;lt; .001). Hippocampal MRI volume (Spearman ρ = −0.45; P &amp;lt; .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P &amp;lt; .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Abstract Alzheimer's disease (AD) exhibits spatially heterogeneous 3R/4R tau pathology distributions across participants, making it a challenge to quantify extent of tau deposition. Utilizing Tau-PET from three independent cohorts, we trained and validated a machine learning model to identify visually positive Tau-PET scans from regional SUVR values and developed a novel summary measure, THETA, that accounts for heterogeneity in tau deposition. The model for identification of tau positivity achieved a balanced test accuracy of 95% and accuracy of ≥87% on the validation datasets. THETA captured heterogeneity of tau deposition, had better association with clinical measures, and corresponded better with visual assessments in comparison with the temporal meta-region-of-interest Tau-PET quantification methods. Our novel approach aids in identification of positive Tau-PET scans and provides a quantitative summary measure, THETA, that effectively captures the heterogeneous tau deposition seen in AD. The application of THETA for quantifying Tau-PET in AD exhibits great potential.