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Peak width of skeletonized mean diffusivity (PSMD), a fully automated diffusion tensor imaging (DTI) biomarker of white matter (WM) microstructure damage, has been shown to be associated with cognition in various WM pathologies. However, its application in schizophrenic disease remains unexplored. This study aims to investigate PSMD along with other DTI markers in first-episode schizophrenia patients compared to healthy controls (HCs), and explore the correlations between these metrics and clinical characteristics. A total of 56 first-episode drug-naive schizophrenia patients and 64 HCs were recruited for this study. Participants underwent structural imaging and DTI, followed by comprehensive clinical assessments, including the Positive and Negative Syndrome Scale (PANSS) for patients and cognitive function tests for all participants. We calculated PSMD, peak width of skeletonized fractional anisotropy (PSFA), axial diffusivity (PSAD), radial diffusivity (PSRD) values, skeletonized average mean diffusivity (MD), average fractional anisotropy (FA), average axial diffusivity (AD), and average radial diffusivity (RD) values as well as structural network global topological parameters, and examined between-group differences in these WM metrics. Furthermore, we investigated associations between abnormal metrics and clinical characteristics. Compared to HCs, patients exhibited significantly increased PSMD values ( = 2.467, = 0.015), decreased global efficiency ( = -2.188, = 0.029), and increased normalized characteristic path length (lambda) ( = 2.270, = 0.025). No significant differences were observed between the groups in the remaining metrics, including PSFA, PSAD, PSRD, average MD, FA, AD, RD, local efficiency, normalized cluster coefficient, small-worldness, assortativity, modularity, or hierarchy ( > 0.05). After adjusting for relevant variables, both PSMD and lambda values exhibited a significant negative correlation with reasoning and problem-solving scores (PSMD: = -0.409, = 0.038; lambda: = -0.520, = 0.006). No statistically significant correlations were observed between each PANSS score and the aforementioned metrics in the patient group ( > 0.05). Multivariate linear regression analysis revealed that increased PSMD (β = -0.426, = -2.260, = 0.034) and increased lambda (β = -0.490, = -2.994, = 0.007) were independently associated with decreased reasoning and problem-solving scores respectively ( = 0.295, = 2.951, = 0.029). But these significant correlations did not withstand FDR correction ( > 0.05). PSMD can be considered as a valuable neuroimaging biomarker that complements conventional diffusion measurements for investigating abnormalities in WM microstructural integrity and cognitive functions in schizophrenia.

Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA. Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained. The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) ( = 0.581 and = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10 mm /s] compared to HCs [(3.28 ± 0.51) × 10 mm /s] ( < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs ( = 0.45, 95% CI 0.13-0.76, = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed ( < 0.001), executive functioning ( = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain. Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.

INTRODUCTION Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin‐1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre‐/postcodon 200) influences these pathologic features and dementia at different stages. METHODS Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross‐sectionally evaluated regional Pittsburgh compound B‐positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging‐based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Highlights Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre‐200 group had stronger associations between Aβ burden and disease stage. PSEN1 post‐200 group had stronger associations between SVD markers and disease stage. PSEN1 post‐200 group had worse dementia score than pre‐200 in late disease stage. Diffusion tensor imaging‐based SVD markers mediated mutation position effects on dementia in the late stage.

INTRODUCTION This study aimed to investigate the synergistic impact of white matter injury, Alzheimer's disease, and neurodegenerative pathology on long‐term cognitive decline and dementia risk in older adults. METHODS We included 262 dementia‐free participants with baseline and follow‐up interviews (2010–2021). At baseline, peak width of skeletonized mean diffusivity (PSMD) was assessed from diffusion tensor imaging. Plasma phosphorylated tau 217 (p‐tau217) and neurofilament light chain (NfL) were measured using a single‐molecule immune‐array assay. Cognitive function was evaluated using Mini‐Mental State Examination (MMSE) and domain‐specific cognitive tests. RESULTS Participants with high‐level PSMD, p‐tau217, and NfL showed the fastest decline of MMSE (β = −0.30) and the highest dementia incidence of 3.54/100 person‐years. A combination model with three markers demonstrated a good predictive value for dementia, incorporating age, sex, education, and apolipoprotein E (area under the curve = 0.93, 95% confidence interval = 0.86, 0.99). DISCUSSION Combining co‐pathology markers may identify individuals with a high risk of cognitive decline. Highlights Peak width of skeletonized mean diffusivity (PSMD) was correlated with long‐term cognitive decline, and this correlation was modified by plasma phosphorylated tau (p‐tau)217 and neurofilament light chain (NfL). Participants with high levels of PSMD, p‐tau217, and NfL showed the fastest cognitive decline and the highest risk of dementia. A combination of the three markers exhibited a good predictive value of incident dementia over a 10‐year follow‐up period.