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BACKGROUND Peak‐width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD. METHODS We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID‐1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimer's Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders. RESULTS Higher PSMD was associated with lower general cognition in MarkVCID‐1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], −0.8 [−1.2, −0.4], P < 0.001). These findings were replicated in independent samples. Furthermore, PSMD explained cognitive status above and beyond white matter hyperintensities. DISCUSSION Our biological validation work supports the pursuit of larger clinical validation studies evaluating PSMD as a susceptibility/risk biomarker of small vessel disease contributing to cognitive impairment and dementia. Highlights Peak‐width of skeletonized mean diffusivity (PSMD) is a novel small vessel disease neuroimaging biomarker. A prior instrumental validation study demonstrated that PSMD is a robust biomarker. This biological validation study shows that high PSMD relates to worse cognition. PSMD explains cognitive function above and beyond white matter hyperintensities. Future clinical validation will assess PSMD as a vascular contribution to cognitive impairment and dementia biomarker in clinical trials.

INTRODUCTION We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle‐aged adults. METHODS We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB‐R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme‐linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS Higher sOB‐R was associated with lower fractional anisotropy (FA, β = −0.114 ± 0.02, p < 0.001), and higher free water (FW, β = 0.091 ± 0.022, p < 0.001) and peak‐width skeletonized mean diffusivity (PSMD, β = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (β = 0.115 ± 0.027, p < 0.001) and lower FW (β = ‐0.096 ± 0.029, p = 0.001) and PSMD (β = ‐0.085 ± 0.028, p = 0.002). DISCUSSION Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle‐aged adults, supporting the putative neuroprotective role of leptin in late‐life dementia risk. Highlights Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Perivascular diffusion holds great potential for the non-invasive assessment of the glymphatic system (GS). However, Gaussian model-based diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is limited by microstructural alterations. This study aimed to compare cross-sectional and longitudinal trajectories of diffusion kurtosis imaging ALPS (DKI-ALPS) and DTI-ALPS and investigate their association with white matter (WM) microstructural integrity, free water (FW), Aβ burden, and cognitive impairment (CI). This study included 128 healthy controls (HCs) and 83 individuals with cognitive impairment (CI) who underwent multi-shell diffusion-weighted magnetic resonance imaging (dMRI). Four dMRI indices were quantified: DTI-ALPS and DKI-ALPS to assess the GS function; peak width of skeletonized mean diffusivity (PSMD) to evaluate the WM microstructural integrity; and FW-WM to quantify the extracellular fluid accumulation in WM. Cohen's was reported as the measure of effect size, with generalized linear models (GLMs) adjusting for confounding factors. Functional principal component analysis (FPCA) was used to determine the trajectories of dMRI indices. CIs exhibited significantly lower DTI-ALPS (1.28 vs. 1.37;  = 0.007; Cohen's  = 0.383) and DKI-ALPS (1.37 vs. 1.63,  < 0.001; Cohen's  = 0.770) than HCs. GLMs confirmed significant group differences in DKI-ALPS indices. DTI-ALPS was positively correlated with DKI-ALPS (  = 0.551;  < 0.001), with stronger associations in HCs than in those with CIs (  = 0.628 vs. 0.370; all  < 0.05). Both DTI-ALPS and DKI-ALPS were negatively correlated with PSMD (  -0.327 and -0.251; all  < 0.05) and FW-WM (  = -0.317 and -0.393; all  < 0.05). The FPCA revealed distinct trajectories of DTI-ALPS, DKI-ALPS, PSMD, and FW-WM between HCs and CIs, and Cohen's of the first FPC score was 0.685, 0.977, 0.573, and 1.004, respectively (all  < 0.001). Compared with baseline dMRI measurements, the trajectory patterns exhibited stronger correlations with Aβ burden (DTI-ALPS, 0.277 vs. -0.217; DKI-ALPS, 0.552 vs. -0.468; PSMD, 0.278 vs. 0.201; FW-WM, 0.313 vs. 0.113) and cognitive performance. Our study indicated that DKI-ALPS provides an accurate assessment of GS function compared with DTI-ALPS. Longitudinal trajectories, particularly the trajectory of DKI-ALPS, demonstrate stronger associations with Aβ burden and cognitive decline.

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.

Aging is accompanied by structural brain changes that are thought to underlie cognitive decline and dementia. Yet little is known regarding the association between increasing age, structural brain damage, and alterations of functional brain connectivity. The aim of this study was to evaluate whether cortical thickness and white matter damage as markers of age-related structural brain changes are associated with alterations in functional connectivity in non-demented healthy middle-aged to older adults. Therefore, we reconstructed functional connectomes from resting state functional magnetic resonance imaging (rsfMRI) data of 976 subjects from the Hamburg City Health Study, a prospective population-based study including participants aged 45-74 years from the metropolitan region Hamburg, Germany. We performed multiple linear regressions to examine the association of age, cortical thickness, and white matter damage quantified by the peak-width of skeletonized mean diffusivity (PSMD) from diffusion tensor imaging on whole-brain network connectivity and four pre-defined resting state networks (default mode, dorsal, salience and control network). In a second step, we extracted subnetworks with age-related decreased functional connectivity from these networks and conducted a mediation analysis to test whether the effect of age on these networks is mediated by decreased cortical thickness or PSMD. We observed an independent association of higher age with decreased functional connectivity, while there was no significant association of functional connectivity with cortical thickness or PSMD. Mediation analysis identified cortical thickness as a partial mediator between age and default subnetwork connectivity, and functional connectivity within the default subnetwork as a partial mediator between age and executive cognitive function. These results indicate that, on a global scale, functional connectivity is not determined by structural damage in healthy middle-aged to older adults. There is a weak association of higher age with decreased functional connectivity which, for specific subnetworks, appears to be mediated by cortical thickness.

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.

    Purpose Peak width of skeletonized mean diffusivity (PSMD) is a robust and fully automated imaging marker employed to detect microstructural damage in white matter. This study aimed to evaluate whether PSMD reflects the severity of white matter damage and tracks disease progression in patients with spinocerebellar ataxia type 2 (SCA2). Methods Nine patients with SCA2 and sixteen age- and gender-matched healthy controls were enrolled. Clinical and imaging data were collected at baseline and after 3.5 years. Each participant underwent MRI scans twice to obtain diffusion tensor imaging data, from which PSMD were automatically calculated. Differences in PSMD between SCA2 patients and healthy controls were analyzed using a linear mixed model. Additionally, Spearman's rank correlations were employed to assess associations between PSMD values and clinical variables. Results Patients with SCA2 exhibited higher PSMD values at baseline and follow-up compared to HCs, indicating more severe white matter damage. Longitudinal data revealed a continual increase in PSMD values in SCA2 patients over time. The mixed-effects model confirmed significant differences in PSMD values between the two groups, as well as an interaction effect suggesting different progression rates. These findings suggest that SCA2 associates with progressive deterioration of white matter. No significant correlations were observed between PSMD values and clinical variables in this study. Conclusion This study underscores the potential of PSMD as a neuroimaging biomarker for detecting microstructural white matter damage and monitoring disease progression in patients with SCA2.

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.