Reichard, R. Ross

Abstract Background Cognitive resilience is the discrepancy in individuals with intermediate to high Alzheimer's disease neuropathologic change (ADNC) and normal cognition. Currently, the role of microglial activation in cognitive resilience is understudied. Method In the MCSA brain bank, high‐cognitively unimpaired (high‐CU) participants were defined as those performing in the upper quartile of their respective age groups based upon antemortem global cognition z‐scores, computed from memory, language, executive function, and visuospatial domain z‐scores. From the high‐CU group ( N = 118, global z‐scores from 1.55 to 1.78), cognitively resilient (CR) individuals were identified as those with intermediate to high ADNC upon neuropathologic evaluation. First, regression models were fit to evaluate global cognition as a function of age, sex, amyloid PET, and microglial‐specific genes of interest, including MS4A gene cluster SNPs. Second, a subset of CR participants was analyzed for postmortem ARM expression in the dorsolateral prefrontal cortex. Single immunohistochemistry was performed on formalin‐fixed, paraffin‐embedded sections using antibodies against beta‐amyloid (6F3D) and CD163 (10D6). Digital image analysis was performed on scanned sections (40x, Leica Aperio GT 450), and ARM (CD163%area) and beta‐amyloid (%area) measurements were obtained using QuPath. Cognitively impaired (CI) control group was matched on age, sex, ADNC level, and APOE4 status. Spearman correlations were performed between postmortem ARM and antemortem MRI, PET, plasma, and global cognition metrics. Result A third (39/118) of high‐CU cases showed intermediate/high ADNC (CR group). Furthermore, 28% of CR individuals harbored an MS4A6A SNP, which showed a protective effect on cognition via amyloid‐PET ( p = 0.043, Figure 1). Moreover, CR individuals harbored significantly higher ARM:amyloid than the CI group ( p <0.001, Figure 2) and fewer neuritic plaques ( p = 0.03, Figure 3). Antemortem white matter hyperintensities and global cognition were significantly correlated to ARM expression (r=0.556 [p=0.042] and r=0.648 [p=0.02], respectively). Conclusion Microglial specific MS4A6A SNP, which modulates microglial activation, was seen in a third of CR individuals. Postmortem analyses in CR individuals revealed increased ARM:amyloid, which was also associated with higher antemortem cognitive performance. These findings underscore the role of microglial activation in cognitive resilience. Future work is needed to investigate microglial protective mechanisms and links between vascular disease and microglial activation.

Abstract Background Neuropathologic evaluation is essential for diagnosing and treating dementia, but definitive diagnoses is only available after post‐mortem brain autopsy. Positron emission tomography (PET) offers a potential in vivo proxy for predicting neuropathology. This study proposes a semi‐supervised learning (SSL) model using a single FDG‐PET image to predict underlying neuropathology. Method The SSL model leverages a self‐organized graph structure based on a patient similarity network (PSN) created from 1,495 FDG‐PET images across the aging and neurodegenerative spectrum. Each patient is represented by a node, with edges indicating image similarity derived from principal component analysis features and cosine similarity weights. The PSN structure connects 20 nearest neighbors. Neuropathologic labels were available for 204 autopsied patients. The Poisson Learning Method was employed to propagate labels from these annotated nodes to unlabeled nodes, guided by the PSN structure. FDG‐PET images were collected from clinical and research participants at the Mayo Clinic and processed using an MRI‐free pipeline. Neuropathologic labels were assigned based on widely accepted diagnostic criteria. Leave‐one‐out cross‐validation (LOOCV) was used to assess model performance. Results The confusion matrix demonstrated high accuracy in predicting Alzheimer's disease, frontotemporal lobar degeneration with tau inclusions, and Lewy body disease pathology. A Sankey diagram and label distribution analysis revealed strong correlations between clinical and predicted neuropathologic labels. Conclusion This study highlights the potential of a graph‐based SSL pipeline to predict neuropathological changes using FDG‐PET imaging data, despite limited pathology labels. The findings underscore the value of SSL in bridging the gap between abundant neuroimaging data and scarce neuropathologic labels, contributing to improved dementia diagnosis and understanding.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Objective Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α‐synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically‐defined series of LBD cases. Methods We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High‐resolution whole‐genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes. Results Our analysis identified 1 significant ( P < 3.43 × 10 −5 ) and 4 suggestive ( P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA‐mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA‐DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus ( P = 3.30 × 10 −5 ), with weaker and suggestive associations observed in the middle frontal ( P = 1.80 × 10 −4 ) and inferior parietal gyrus ( P = 6.33 × 10 −4 ). Additionally, although only suggestive, HLA‐DRB1*11:01 correlated with a lower Thal amyloid phase ( P = 1.56 x 10 −4 ), and HLA‐B*15:01 correlated with an increased risk of diffuse LBD ( P = 7.58 x 10 −4 ). Interpretation This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune‐related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501

Abstract Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical–pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease‐modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. Highlights We celebrate 40 years of NIA‐funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease‐modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

Context.— After-death care can be complicated and time-consuming for clinical staff, and frustrating for bereaved families. Delays and errors can have damaging legal and reputational consequences for hospitals. Offices of Decedent Affairs (ODAs) have been proposed as a solution, and their potential benefits have been described in several single institution reports. The literature lacks a contemporary and comprehensive review of existing ODAs and their approaches. Objective.— To describe the process of establishing a new ODA and to provide a snapshot of the spectrum of structure, function, and impact of existing ODAs in the United States. Design.— A survey was administered to 11 established ODAs spread across the continental United States. Programs were identified through the College of American Pathologists Autopsy Committee and a Medical Autopsy Listserv. Results.— Eleven ODAs returned the survey, representing more than 190 cumulative years of experience in decedent care in the hospital setting (median, 10 years). There was a wide range in staffing (both staff size and background) as well as scope of services offered. The median ratio of hospital deaths to full-time equivalent (FTE) staffing was 360 deaths per FTE. Respondents reported that ODAs unburden clinical providers and facilitate decedent management. Some respondents reported a quicker turnover of hospital beds and shorter intervals between pronouncement of death and autopsy. ODAs increased autopsy rates when the autopsy services were part of the ODA. Conclusions.— This survey provides practical information for hospitals considering establishing a new ODA and useful benchmarks for existing ODA programs.

Context.— Decedent Affairs Offices and Programs can serve as an avenue to assist medical centers in facilitating efficient and comprehensive decedent management, despite a paucity of literature on their roles, establishment, and efficacy. Objective.— To characterize the motivations and rationales for establishing Decedent Affairs Offices. Design.— A survey was administered to 11 established Decedent Affairs Offices/Programs, identified through the College of American Pathologists Autopsy Committee and a Medical Autopsy Listserv. The questions comprehensively cover establishment, operations, and outcomes data available by institution. Results.— Survey respondents reported the rationale for starting their programs and the benefits such offices can have. Conclusions.— Decedent Affairs Offices and Programs provide a useful option to medical centers to navigate the increasingly complex task of comprehensive decedent management. The present survey helps to delineate the similarities and differences between these programs at 11 institutions, to aid nascent programs in their establishment and growth over time.