Diaz‐Galvan, Patricia

Abstract Background Tau‐PET neuroimaging is increasingly applied to diagnose and stage, track progression, and assess response to putative disease‐modifying treatments in individuals with Alzheimer disease. However, it remains to be seen whether findings established in predominantly non‐Hispanic White (nHW) cohorts will generalize to Black and Latino participants who are underrepresented in dementia research. Method Community‐dwelling Black ( n = 83) and Latino participants ( n = 27) completed MRI (with quantification of white matter hyperintensity volumes), and amyloid‐ (PiB or florbetapir) and tau‐ (flortaucipir) PET brain imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Global and regional tau‐PET standardized uptake value ratios (normalized to the cerebellar crus) were determined in Black and Latino participants and compared with findings from an independent cohort of nHW participants ( n = 110), 1:1‐matched for age, sex, education, and global Clinical Dementia Rating®. Conditional logistic modeling compared 47 regions of interest, adjusted for false discovery rate. Relevant associations between flortaucipir retention and clinical outcomes were assessed using Spearman rank correlations. Result Eighty‐three Black (mean 72±10.8‐years‐old, 63% female, 33% cognitively impaired) and 27 Latino participants (mean 65.8‐years‐old, 56% female, 11% cognitively impaired) completed neuroimaging. Data were compared with findings in 110 matched nHW individuals. Global tau‐PET burden was similar between matched cohorts (Black and nHW participants, mean SUVR: 1.34±0.39 vs 1.36±0.37, p = 0.71; Latino and nHW participants, mean SUVR: 1.17±0.09 vs 1.20±0.11, p = 0.66). Lower flortaucipir uptake was noted in the caudate ( p = 0.005) and putamen ( p = 0.022) of Black/Latino participants (vs nHW), although differences attenuated following adjustment for white matter hyperintensity volume. Global flortaucipir retention increased with age (Black: Rho=0.31; Latino: Rho=0.46; nHW: Rho=0.27; p <0.05), amyloid Centiloids (Black: Rho=0.65; Latino: Rho=0.41; nHW: Rho=0.58; p <0.05), and cognitive impairment (i.e., Clinical Dementia Rating® Sum‐of‐Box scores, Black/Latino: Rho=0.31, p = 0.07; nHW: 0.76, p <0.001). Conclusion Tau‐PET patterns were similar across ethnoracial groups after adjusting for white matter hyperintensity volumes—a biomarker of small vessel disease. Flortaucipir retention increased with age, amyloid accumulation, and cognitive impairment across all cohorts. These findings affirm the clinical and research applications of tau PET in diverse cohorts. Acknowledgements : Flortaucipir precursor and technology was supported by Avid Radiopharmaceuticals.

Abstract Objective To compare iron deposition in the substantia nigra (SN) as measured with quantitative susceptibility mapping (QSM) on antemortem magnetic resonance imaging (MRI) between individuals with and without Lewy‐related pathology at autopsy. Methods We performed a retrospective cohort study including 54 participants who underwent autopsy and antemortem MRI with QSM. Cases were classified as Lewy body disease (LBD)‐present (n = 13) if they had Lewy‐related pathology and LBD‐absent (n = 41) if they did not have Lewy‐related pathology. QSM was calculated for the whole SN and the two subregions: pars compacta (SNc) and pars reticulata (SNr). Nonparametric Wilcoxon rank‐sum tests were used to compare SN QSM values between LBD‐present and LBD‐absent cases. Area under the receiver operating characteristic (ROC) curve (AUC) analyses tested the accuracy of SN QSM values to distinguish the two groups. Associations of QSM values in the SN and its subregions with clinical features were tested with Spearman's correlations. Results The LBD‐present group had higher QSM values in the SNc ( P = 0.008) than the LBD‐absent group with no differences in SNr. QSM values of the SNc distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC = 0.74) and correlated with the presence of parkinsonism and parkinsonism severity. Conclusions This study provides neuropathological confirmation of the utility of SNc QSM as an in vivo biomarker of Lewy‐related pathology. Imaging evidence of abnormal iron deposition in the SNc could potentially serve as a biomarker for inclusion in emerging research frameworks aimed at defining individuals with LBD based on their biological characteristics. Ultimately, this could facilitate more precise diagnoses and guide treatment strategies in LBD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Importance Although 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a well-established cross-sectional biomarker of brain metabolism in dementia with Lewy bodies (DLB), the longitudinal change in FDG-PET has not been characterized. Objective To investigate longitudinal FDG-PET in prodromal DLB and DLB, including a subsample with autopsy data, and report estimated sample sizes for a hypothetical clinical trial in DLB. Design, Setting, and Participants Longitudinal case-control study with mean (SD) follow-up of 3.8 (2.3) years. Cases were recruited consecutively between 2007 and 2022 at a referral center and among the population. Patients with probable DLB or mild cognitive impairment with Lewy bodies (MCI-LB) were included. Individuals without cognitive impairment were included from a population-based cohort balanced on age and sex for comparison. All participants completed at least 1 follow-up assessment by design. Exposure Patients with MCI-LB and DLB. Main Outcomes and Measures Rate of change in FDG-PET was assessed as standardized uptake value ratios (SUVr). Clinical progression was assessed with the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Results Thirty-five patients with probable DLB, 37 patients with MCI-LB, and 100 individuals without cognitive impairment were included. The mean (SD) age of the DLB and MCI-LB groups combined (n = 72) was 69.6 (8.2) years; 66 patients (92%) were men and 6 (8%) were women. At follow-up, 18 participants (49%) with MCI-LB had progressed to probable DLB. Patients with MCI-LB had a faster decline in FDG-SUVr, compared with that of participants without cognitive impairment, in the posterior cingulate, occipital, parietal, temporal, and lateral frontal cortices. The same regions showed greater metabolic decline in patients with DLB than in participants without cognitive impairment, with the addition of anterior-middle cingulate, insula, and medial frontal orbital cortices. Rates of change in FDG-PET in these brain regions were combined into a region of interest (ROI) labeled longitudinal FDG-PET LB meta-ROI. The rate of change in FDG-SUVr in the meta-ROI correlated with the rate of change in CDR-SB, and sample size estimates were reported for potential clinical trials in DLB. Findings were confirmed in the subsample with neuropathologic confirmation (n = 20). Conclusions and Relevance This study found that brain hypometabolism begins to evolve during the prodromal stages of DLB with changes paralleling symptomatic progression. These data may inform clinical practice and trials planning to use FDG-PET for biologic staging, monitoring disease progression, and potentially assessing treatment response.

AbstractBackgroundParkinson’s disease and dementia with Lewy bodies are characterized by abnormal iron deposition in the substantia nigra, which can be measured with quantitative susceptibility mapping (QSM) on MRI. However, neuropathologic validation of the increased QSM in the substantia nigra associated with Lewy body disease (LBD) is lacking. We compared substantia nigra QSM on antemortem MRI between patients with and without Lewy‐related pathology which was confirmed by autopsy in all cases.MethodWe studied cases with antemortem QSM who underwent autopsy from the Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging (n=54). Immunohistochemistry was performed with rabbit NACP antibody against the amino acids 98‐115 of the α‐synuclein protein to detect Lewy‐related pathology. After neuropathologic evaluation, cases were classified as LBD‐present (n=13) if they had Lewy‐related pathology and LBD‐absent (n=42) if they did not have Lewy‐related pathology. Alzheimer’s disease co‐pathology was present in 9 of the LBD‐present cohort (70%). QSM was calculated for the whole substantia nigra and the two sub‐regions: pars compacta and pars reticulata. Non‐parametric Wilcoxon rank‐sum test was used to compare substantia nigra QSM values between LBD‐present and LBD‐absent cases. Area under the curve (AUC) analyses tested the accuracy of QSM to distinguish the two groups.ResultsLBD‐present group had higher QSM values in the substantia nigra than LBD‐absent group. Furthermore, sub‐regional analyses showed that the LBD‐present group had higher QSM in the substantia nigra pars compacta (p=0.008) but not in the pars reticulata than the LBD‐absent group (Figure 1). QSM of the substantia nigra pars compacta distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC=0.74; p=0.006; Figure 2).ConclusionThis study provides neuropathologic insight into the relevance of QSM of substantia nigra pars compacta as an in‐vivo biomarker of autopsy‐confirmed LBD. These findings indicate that imaging evidence of abnormal iron deposition in the substantia nigra may serve as a biomarker of Lewy‐related pathology in patients with primary LBD (i.e., Parkinson disease, dementia with Lewy bodies) and patients with potential LBD co‐pathology (e.g., patients with Alzheimer disease).

AbstractINTRODUCTIONPatients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease.METHODSThe cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI‐LB), or DLB, with a concurrent blood draw and PET scans.RESULTSAbnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI‐LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p‐tau)‐181 and neurofilament light (NfL) were found at the DLB stage. Plasma p‐tau‐181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB.DISCUSSIONThe range of AD co‐pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p‐tau‐181 and GFAP.

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

Abstract INTRODUCTION Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS We included 436 patients from the European‐DLB consortium and the Mayo Clinic. Sex differences and sex‐by‐age interactions were assessed through visual atrophy rating scales ( n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness ( n = 165; 69 ± 9 years, 72% males). RESULTS We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex‐by‐age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.