Kantarci, Kejal

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 A workgroup assembled by the Alzheimer’s Association recently described a conceptual framework for Alzheimer’s disease biological staging based on amyloid and tau PET imaging. However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer’s disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages. The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer’s Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer’s Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian mixture models to characterize Alzheimer’s disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination. A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to produce, collectively, the four Alzheimer’s disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer’s Disease Neuroimaging Initiative cohort. This study provided empirical validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer’s disease into four biological stages with distinct characteristics.

ABSTRACT Objective Autosomal dominant progranulin ( GRN ) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN ‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Methods Utilizing T1 and task‐free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole‐brain degree, and GRN ‐relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive‐compulsive disorder symptom severity, and gray matter volume. Results Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive‐compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN ‐frontotemporal dementia. Interpretation In asymptomatic carriers, the co‐occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

The study assesses the relationship between thalamic proton-MR spectroscopy (1H-MRS) metabolites and thalamic 11C-ER176 translocator-protein positron emission tomography (TSPO-PET) standardized uptake value ratios (SUVR) to advance our understanding of thalamic involvement in multiple sclerosis (MS)-associated neurodegeneration and disability. In this prospective cross-sectional study, patients with MS (pwMS) and controls underwent 3T-MRI, 1H-MRS, and 11C-ER176-PET targeting the thalamus. MRI-derived thalamic volume was normalized by intracranial volume. 1H-MRS metabolites—N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), total choline (tCho), and myo-inositol (mIns)—were normalized to total creatine (tCr). Clinical disability was evaluated using MS-specific tests of Expanded Disability Status Scale-EDSS and MS-functional composite-MSFC (including Paced Auditory Serial Addition Test-PASAT). Compared to controls (n = 30), pwMS (n = 21) exhibited smaller thalamic volume, higher thalamic 1H-MRS mIns/tCr (putative gliosis marker), and higher thalamic 11C-ER176-PET SUVR (glial density marker). In pwMS, higher thalamic mIns/tCr (r = −0.67) and tCho/tCr (r = −0.52) correlated with smaller thalamic volume. In pwMS, higher thalamic mIns/tCr correlated with higher thalamic 11C-ER176-PET SUVR (r = 0.48) and decreased cognitive function (PASAT, rho = −0.48). In controls, decreased thalamic NAA/tCr correlated with increased thalamic 11C-ER176-PET SUVR (r = −0.41). Thalamus, a core central nervous system relay, is affected early in MS disease course. Glial-mediated innate immune activation in the thalamus, evaluated by increased 1H-MRS mIns/tCr and 11C-ER176-PET SUVR, is associated with loss of thalamic volume and increased disability in pwMS. The multimodal imaging approach with 1H-MRS mIns/tCr and 11C-ER176-PET SUVR emerges as potential glial biomarkers, to better understand disease mechanisms and evaluate therapeutic interventions targeting glial activity in MS.

Abstract INTRODUCTION Primary age‐related tauopathy (PART) is defined by neurofibrillary tangles (NFTs) with absent‐minimal amyloid beta (Aβ) plaques. Currently, definitive diagnosis of PART occurs with autopsy. This study investigated whether [ 18 F]fluorodeoxyglucose positron emission tomography (FDG‐PET) could detect PART‐related metabolic changes and assessed the impact of common co‐pathologies. METHODS We performed a retrospective cross‐sectional study of 88 individuals (mean age 85.6) with autopsy‐confirmed PART (Braak I to IV; Thal phases 0 to 2) who underwent ante mortem FDG‐PET. Visual ratings and standardized uptake value ratios (SUVRs) were analyzed in medial and lateral temporal lobes, inferior temporal pole, precuneus, and posterior cingulate regions. RESULTS Medial temporal hypometabolism was observed in PART, in the presence of co‐pathologies. Argyrophilic grain disease and TAR DNA‐binding protein 43 were associated with greater hypometabolism ( p < 0.01). Lewy body disease affected parietal regions. DISCUSSION FDG‐PET reveals that PART‐related hypometabolism occurs when co‐pathologies are present, but PART alone appears to have minimal effect on medial temporal lobe hypometabolism. Highlights FDG‐PET hypometabolism worsens with Braak NFT stage. FDG‐PET detects mild lateral temporal lobe hypometabolism in PART alone. PART alone has a minimal effect on medial temporal lobe hypometabolism. Medial temporal hypometabolism is worse in PART with TDP‐43 and especially AGD. The presence of LBD contributes to parietal hypometabolism on FGD‐PET in PART.

Objective To study the reliability and validity of adverse childhood experiences (ACE) scores measured using a questionnaire versus abstraction of medical records, and to test whether the scores vary by history of bilateral oophorectomy, or by age and presence of anxiety or depressive symptoms at the time of questionnaire administration. Design The study involved a reliability component and a predictive validity component. Setting A population-based sample in Olmsted County, Minnesota, was derived from the Mayo Clinic Cohort Study of Oophorectomy and Aging-2. Participants We included 198 women who underwent premenopausal bilateral oophorectomy for a non-malignant indication between 1988 and 2007 and 174 referent women of the same age randomly sampled from the general population (total of 372 women). At a later time (median of 22.7 years later), the women were contacted and invited to self-administer the ACE questionnaire during an inperson visit. Independent of the visit, their medical records were abstracted for ACE by a physician. Interventions Questionnaire and abstraction-based ACE scores. Main outcome measures Agreement between the two ACE scores (reliability; weighted kappa statistics) and comparison of incidence of multimorbidity in women with ACE scores ≥1 vs 0 (predictive validity; survival analyses). Data were analysed in March and April 2024. Results The 372 women in the study had a median age of 65 years at the time of ACE questionnaire self-administration (IQR, 62–69). Questionnaire-based ACE scores showed moderate agreement with abstracted ACE scores (weighted kappa 0.44 (95% CI 0.34 to 0.54)). The cut-off score of ACE ≥1 showed an overall fair agreement between the two scores (kappa 0.33 (95% CI 0.24 to 0.43)). A comparison of the cumulative incidence of multimorbidity in women with an ACE score ≥1 versus women with ACE score of 0 yielded a HR of 1.13 (95% CI 1.00 to 1.27) for abstracted ACE and 1.13 (95% CI 1.01 to 1.27) for questionnaire-based ACE. The best predictive validity was for ACE measured by both methods combined (either or) with a HR of 1.29 (95% CI 1.13 to 1.46). Conclusions and relevance Questionnaire-based ACE scores have moderate agreement with medical records abstracted ACE scores. However, both sets of ACE scores are predictive of the accumulation of multimorbidity at older age and should be considered complementary.

Objectives: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain’s white matter architecture in women who initiated mHT within 3 years of menopause onset. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. Results: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. Conclusions: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

Abstract Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease‐modifying agents. Consequently, definitions of Alzheimer's disease and Parkinson's disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging‐Alzheimer's Association) and alpha‐synucleinopathy and dopaminergic degeneration (Neuronal α‐synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha‐synuclein (α‐synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. Highlights DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer's and Parkinson's definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson's under one pathobiology.

Objective: To explore potential differences in physical activity and sedentary behavior volumes and patterns among postmenopausal women with and without premenopausal bilateral oophorectomy (PBO). Methods: Women with a history of PBO (n = 50) and age-matched postmenopausal referent women (n = 50) were recruited. Participants wore accelerometers on both ankles for 7 days. Volume metrics of sedentary behavior and physical activity, such as step counts, active time, and sedentary time, as well as the sedentary behavior and habitual physical activity distribution, and accumulation patterns, were quantified from the accelerometer data and compared between groups. Results: Metrics indicating volume of sedentary behavior and physical activity were not statistically different between groups. PBO was significantly associated with higher variability in stepping bout time ( P = 0.022), indicating a potentially more complex walking pattern. In addition, PBO was significantly associated with lower variability in sedentary break time ( P = 0.012), and lower activity time Gini index ( Z = −2.428, P = 0.015). This suggests that women with PBO may have broken up their sedentary time with shorter and less variable activity bouts, and because they had relatively shorter average daily active time, they might be at a higher risk of subsequent adverse health outcomes such as low bone mineral density. Conclusions: Although there were no differences in overall activity volume, some differences in activity patterns emerged between women with PBO and referent women. The study highlights the need for longitudinal research to understand how physical activity and sedentary behavior patterns evolve in postmenopausal women with a history of PBO.