Wood, Ashley C.

Abstract Background An intense search is underway for tau PET tracers with enhanced capability to visualize tau aggregates. Research indicates that [18F] AV1451 and [18F]MK 6240 exhibit comparable binding properties in terms of spatial distribution and severity of tau aggregates, as observed both in‐vivo and in‐vitro. This study focused on head‐to‐head pathological comparison of both the tracers binding specificity to tangle maturity levels (pretangles, mature tangles and ghost tangles) of tau aggregates as seen on autoradiography as compared to CP‐13 (early tangle maturity marker) and PHF‐1(middling tangle maturity marker) immunohistochemical (IHC) stains in Alzheimer's disease (AD) and non‐AD tauopathies. Method Study participants included included those with AD and non‐AD tauopathies. Analyses were performed on serial 5um formalin fixed paraffin embedded postmortem human brain sections acquired from Mayo clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. IHC sections were incubated with antibodies CP‐13 (recognizing early tangle maturity) and PHF‐1 (recognizing middling tangle maturity). Result A total of 38 participants were examined. The participants included a spectrum from normal to AD, including mild cognitive impairment (MCI) and atypical AD. Participants with N279K (4R), P301L (4R), and R406W MAPT mutations (3R+4R) were included as well. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non‐AD tauopathies. Generally, early tangle maturity tau accumulation participants had more tau demonstrated with CP‐13 than PHF‐1 and both the tracers [18F]MK 6240 and [18F]AV 1451 binding are well correlated with the PHF‐1 staining suggesting the preference for middling tangle level and minimal to early tangles. Conclusion The emergence and validation of these new tau PET tracers have opened new opportunities for the development of more accurate diagnostic and management tools for AD. In our study on post‐mortem sections, [ 18 F]MK‐6240 and [ 18 F]Flortaucipir showed similar binding profiles with preference to middling tangle maturity levels.

Abstract Neurofibrillary tangles are dynamic neuropathologic hallmarks of Alzheimer’s disease with a hypothesized lifespan morphologically-defined by three maturity levels: pretangles, mature tangles, and ghost tangles. To better understand the progression of tangle pathophysiology, we characterized tangle maturity level predilection of 15 tau antibodies recognizing a broad range of linear, phosphorylation, conformational, and truncation epitopes in the hippocampus of 24 postmortem brains. We developed the tangle maturity scoring system to semi-quantitatively evaluate each tangle maturity level. Based on proportions of tangle maturity levels, we classified antibodies as “early” (mostly pretangles and mature tangles), “middling” (mature tangles with pretangles and ghost tangles), and “advanced” (mostly ghost tangles and mature tangles) tangle maturity markers. To summarize tangle maturity predilection, we developed the tangle maturity scale to integrate individual tangle maturity scores. Correlations showed stronger relationships between tangle maturity scale and subsector thickness for more advanced tangle maturity markers in CA1 and subiculum, whereas Braak tangle stage remained consistently correlated throughout markers of the tangle lifespan. To aid in scoring hippocampi, we used machine learning to recognize tangle maturity levels, which performed comparably to a domain expert and showed similar relationships by Spearman correlation. Pattern recognition software was used to assess tangle and neuritic tau burden separately, which generally correlated with Braak stage and neuronal counts. However, tangle-derived tau burden more consistently correlated with hippocampal subsector thickness. In conclusion, we developed manual and automated scoring systems to evaluate tangle maturity levels, demonstrating early 4R, phosphorylated, and oligomeric tau accumulation preceding more advanced 3R and truncated tau. Our study provides supportive evidence of disease-relevant ordering of tau posttranslational modifications in the brain, which may have implications for theragnostic development. These findings underscore the promise of computerized quantitative analyses (i.e., pathomics) for high-throughput feature extraction from whole-slide images to enhance our understanding of microscopically observed morphologic changes.

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 < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .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 < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .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.