Schwarz, Christopher G.

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 Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Background Studies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown. Objective The main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity. Methods We assessed whether plasma p-tau 181 and Aβ 42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD. Results Plasma Aβ 42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ 42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ 42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity. Conclusion Plasma Aβ 42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.

Abstract Increased innate immune activity promotes neurodegeneration and contributes to progression in multiple sclerosis. This prospective case-control study aims to investigate thalamic microglia density on 18kDa translocator protein PET in patients with multiple sclerosis using a third-generation radioligand, 11C-ER176, and investigate the associations of 11C-ER176 PET uptake with imaging and clinical measures of progression in multiple sclerosis. Patients with multiple sclerosis (n = 50) and controls (n = 55) were prospectively enrolled and they underwent 11C-ER176 PET and MRI including diffusion MRI with neurite orientation dispersion and density imaging. Disease characteristics, expanded disability status scale and multiple sclerosis functional composite scores were obtained in patients with multiple sclerosis. Age at imaging (mean ± standard deviation: patients = 49.6 ± 12.9 years, controls = 48.2 ± 15.4 years, P = 0.63) and sex (female ratio; patients = 72%, controls = 65%, P = 0.47) were not different between the groups. Thalamus 11C-ER176 PET uptake was highest in patients with progressive multiple sclerosis (1.272 ± 0.072 standardized uptake value ratio), followed by patients with relapsing multiple sclerosis (1.209 ± 0.074 standardized uptake value ratio) and lowest in controls (1.162 ± 0.067 standardized uptake value ratio, P < 0.001). Patients with thalamic lesions had higher thalamus 11C-ER176 PET uptake than those without thalamic lesions in both relapsing multiple sclerosis and progressive multiple sclerosis (P < 0.001). In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with lower thalamic volume (r = −0.45, P = 0.001), higher mean diffusivity (r = 0.56, P < 0.001), lower neurite density index (r = −0.43, P = 0.002), lower orientation dispersion index (r = −0.40, P = 0.005) and higher free water fraction (r = 0.42, P = 0.003) in the thalamus. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake also correlated with higher mean diffusivity (r = 0.47, P < 0.001) and lower neurite density index (r = −0.36, P = 0.012) in the corpus callosum. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with worse expanded disability status scale scores (r = 0.33, P = 0.02), paced auditory serial addition test scores (r = −0.43, P = 0.003) and multiple sclerosis functional composite z-scores (r = −0.46, P = 0.001). Microglia density in the thalamus is highest in patients with progressive multiple sclerosis and is associated with imaging biomarkers of neurodegeneration and clinical disease severity. As a signature imaging biomarker of progression in multiple sclerosis, effectively reflecting the global disease burden, 11C-ER176 PET may aid development and efficacy evaluation of therapeutics targeting microglia.

AbstractINTRODUCTIONAlzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%–50% of patients. Studies have assessed hypometabolism in CBS according to β‐amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD‐tau (T) and A with hypometabolism is incomplete.METHODSThirty‐three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound‐B PET and were classified as A± and T±. FDG‐PET uptake was extracted for 12 regions‐of‐interest in dominant (most affected) and non‐dominant hemispheres and compared across A/T groups.RESULTSA+T+ patients had greater hypometabolism in temporo‐parieto‐occipital cortices than A+T‐ and A‐T‐ groups, with no differences observed between the A+T‐ and A‐T‐ groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups.DISCUSSIONAmyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo‐parieto‐occipital cortices in CBS, with AD‐like patterns of hypometabolism observed only in A+T+ patients.Highlights Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo‐parieto‐occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto‐occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.

Abstract INTRODUCTION Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A−) individuals. METHODS We included 290 A−, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A− to A+ and with rate of amyloid PET change. RESULTS Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p‐tau217), and Amyloid Probability Score 2 were associated with 1.29 ( P = 0.09), 1.38 ( P < 0.001), and 1.20 ( P = 0.05) increases, respectively, in the hazard of progression from A− to A+ and 0.27 ( P = 0.16), 0.50 ( P = 0.007), and 0.28 ( P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change. DISCUSSION Plasma %p‐tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial. Highlights Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive. The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2. Age and apolipoprotein E ε4 carriership were also important predictors. These markers may be useful for enrichment of a primary prevention trial.

Abstract INTRODUCTION We investigated the association between alpha‐synuclein (α‐syn) pathology and brain glucose metabolism across the cognitive spectrum of Alzheimer's disease (AD) co‐pathologies. METHODS Fluorodeoxyglucose positron emission tomography (FDG‐PET) data from 829 Alzheimer's Disease Neuroimaging Initiative participants (648 cognitively impaired [CI], 181 unimpaired [CU]) were compared between α‐syn seed amplification assay (SAA) positive and negative groups. Interactions with cerebrospinal fluid (CSF) AD biomarkers were examined. RESULTS SAA+ was associated with widespread hypometabolism among CI individuals, particularly in posterior cortical regions, independent of CSF amyloid and tau levels in the occipital lobes. Regional hypometabolism mediated the effect of α‐syn SAA on disease severity in CI individuals, independent of CSF amyloid and tau levels. There were no influences of SAA on FDG‐PET in CU individuals. DISCUSSION This study supports a model in which α‐syn aggregation influences metabolic dysfunction, which then influences clinical disease severity, independent of AD. SAA+ could help optimize participant selection and outcome measures for clinical trials in AD. Highlights α‐synuclein seed amplification positivity (SAA+) was associated with hypometabolism in cognitively impaired individuals. Hypometabolism mediated the influence of α‐synuclein on disease severity. Occipital hypometabolism in SAA+ was independent of cerebrospinal fluid levels of Alzheimer's disease pathology. These findings can optimize future clinical trials targeting α‐synuclein pathology.

Background: Spinal cord (SC) atrophy is a key imaging biomarker of progressive multiple sclerosis (MS). Progressive MS is more common in men and postmenopausal women. Objective: Investigate the impact of sex and menopause on SC measurements in persons with MS (pwMS). Methods: In pwMS and age- and sex-matched controls, upper cervical SC area from brain MRI (UCC brain ) was obtained. Impact of sex and menopause on UCC brain (adjusted for total intracranial volume) and its association with progression and disability, including MS functional composite (MSFC), were investigated. Results: UCC brain was smaller in pwMS ( n = 118, 51.4 ± 5.3 mm 2 ) than controls ( n = 118, 54.2 ± 4.4 mm 2 , p < 0.001) and inversely correlated with older age in pwMS ( r = −0.24, p = 0.010) but not in controls ( r = −0.025, p = 0.786). In 173 pwMS (413 brain MRIs), UCC brain was smaller in men (49.5 ± 5.9 mm 2 ) than women (51.6 ± 5.5 mm 2 , p = 0.001), postmenopausal women (49.4 ± 5.6 mm 2 ) than premenopausal women (52.9 ± 4.1 mm 2 , p < 0.001), and progressive (47.5 ± 5.6 mm 2 ) than relapsing MS (52.1 ± 5.2 mm 2 , p < 0.001). UCC brain also correlated with disease duration ( r = −0.39, p < 0.001), 9-hole peg test ( r = −0.26, p = 0.005), and severe ambulatory disability (Expanded Disability Status Scale ⩾6) ( r = −0.27, p < 0.001). Conclusion: UCC brain , a biomarker of progressive MS, is inversely associated with age, disease duration, male sex, and menopause, highlighting the potential impact of sex and hormones on neurodegeneration in MS.

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.