Petersen, Ronald C.

Abstract INTRODUCTION When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid‐beta‐peptide (Aβ) related pathology are discordant, therapeutic decision‐making becomes uncertain. METHODS Using data from patients with mild cognitive impairment ( n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints. RESULTS Discordant groups for brain Aβ status (CSF+/PET− and CSF−/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF−/PET− group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures. DISCUSSION In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET− or CSF−/PET+ brain amyloid patterns did not exhibit incipient decline. Highlights Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF‐PET discrepant persons with MCI tend to have less abnormal values initially. CSF‐PET discrepant persons with MCI have a benign prognosis at 4 years.

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.