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Jochems, Angela C. C., Susana Muñoz Maniega, Una Clancy, Daniela Jaime Garcia, Carmen Arteaga, Will Hewins, Rachel Penman, et al. "Associations of Peak-Width Skeletonized Mean Diffusivity and Post-Stroke Cognition." Life 12, no. 9 (August 31, 2022): 1362. http://dx.doi.org/10.3390/life12091362.
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Post-stroke cognitive impairment is common and can have major impact on life after stroke. Peak-width of Skeletonized Mean Diffusivity (PSMD) is a diffusion imaging marker of white matter microstructure and is also associated with cognition. Here, we examined associations between PSMD and post-stroke global cognition in an ongoing study of mild ischemic stroke patients. We studied cross-sectional associations between PSMD and cognition at both 3-months (N = 229) and 1-year (N = 173) post-stroke, adjusted for premorbid IQ, sex, age, stroke severity and disability, as well as the association between baseline PSMD and 1-year cognition. At baseline, (mean age = 65.9 years (SD = 11.1); 34% female), lower Montreal Cognitive Assessment (MoCA) scores were associated with older age, lower premorbid IQ and higher stroke severity, but not with PSMD (βstandardized = −0.116, 95% CI −0.241, 0.009; p = 0.069). At 1-year, premorbid IQ, older age, higher stroke severity and higher PSMD (βstandardized = −0.301, 95% CI −0.434, −0.168; p < 0.001) were associated with lower MoCA. Higher baseline PSMD was associated with lower 1-year MoCA (βstandardized = −0.182, 95% CI −0.308, −0.056; p = 0.005). PSMD becomes more associated with global cognition at 1-year post-stroke, possibly once acute effects have settled. Additionally, PSMD in the subacute phase after a mild stroke could help predict long-term cognitive impairment.
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Vinciguerra, C., A. Giorgio, J. Zhang, I. Di Donato, M. L. Stromillo, R. Tappa Brocci, A. Federico, M. T. Dotti, and N. De Stefano. "Peak width of skeletonized mean diffusivity (PSMD) as marker of widespread white matter tissue damage in multiple sclerosis." Multiple Sclerosis and Related Disorders 27 (January 2019): 294–97. http://dx.doi.org/10.1016/j.msard.2018.11.011.
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Mayer, Carola, Felix L. Nägele, Marvin Petersen, Maximilian Schell, Ghazal Aarabi, Thomas Beikler, Katrin Borof, et al. "Association between Coffee Consumption and Brain MRI Parameters in the Hamburg City Health Study." Nutrients 15, no. 3 (January 28, 2023): 674. http://dx.doi.org/10.3390/nu15030674.
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Despite associations of regular coffee consumption with fewer neurodegenerative disorders, its association with microstructural brain alterations is unclear. To address this, we examined the association of coffee consumption with brain MRI parameters representing vascular brain damage, neurodegeneration, and microstructural integrity in 2316 participants in the population-based Hamburg City Health Study. Cortical thickness and white matter hyperintensity (WMH) load were measured on FLAIR and T1-weighted images. Microstructural white matter integrity was quantified as peak width of skeletonized mean diffusivity (PSMD) on diffusion-weighted MRI. Daily coffee consumption was assessed in five groups (<1 cup, 1–2 cups, 3–4 cups, 5–6 cups, >6 cups). In multiple linear regressions, we examined the association between brain MRI parameters and coffee consumption (reference group <1 cup). After adjustment for covariates, 3–4 cups of daily coffee were associated with lower PSMD (p = 0.028) and higher cortical thickness (p = 0.015) compared to <1 cup. Moreover, 1–2 cups per day was also associated with lower PSMD (p = 0.022). Associations with WMH load or other groups of coffee consumption were not significant (p > 0.05). The findings indicate that regular coffee consumption is positively associated with microstructural white matter integrity and cortical thickness. Further research is necessary to determine longitudinal effects of coffee on brain microstructure.
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Raposo, N., M. C. Zanon Zotin, D. Schoemaker, L. Xiong, P. Fotiadis, A. Charidimou, M. Pasi, et al. "Peak Width of Skeletonized Mean Diffusivity as Neuroimaging Biomarker in Cerebral Amyloid Angiopathy." American Journal of Neuroradiology 42, no. 5 (March 4, 2021): 875–81. http://dx.doi.org/10.3174/ajnr.a7042.
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Kang, Sujin, Dong Ah Lee, Jun Won Lee, Ho-Joon Lee, and Kang Min Park. "White matter changes in patients with narcolepsy type 2: Peak width of skeletonized mean diffusivity study." Sleep Medicine 129 (May 2025): 14–19. https://doi.org/10.1016/j.sleep.2025.02.020.
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Jarholm, Jonas, Sandra Tecelão, Lene Pålhaugen, Atle Bjørnerud, Bjørn Eivind Kirsebom, Tormod Fladby, and Per Selnes. "Peak width of skeletonized mean diffusivity as a biomarker of small vessel disease in predementia Alzheimer's disease." Cerebral Circulation - Cognition and Behavior 6 (2024): 100303. http://dx.doi.org/10.1016/j.cccb.2024.100303.
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Park, Kang Min, Keun Tae Kim, Dong Ah Lee, and Yong Won Cho. "Small vessel disease in patients with restless legs syndrome evidenced by elevated peak width of skeletonized mean diffusivity." Journal of the Neurological Sciences 467 (December 2024): 123310. http://dx.doi.org/10.1016/j.jns.2024.123310.
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Lam, Bonnie Yin Ka, Kam Tat Leung, Brian Yiu, Lei Zhao, J. Matthijs Biesbroek, Lisa Au, Yumi Tang, et al. "Peak width of skeletonized mean diffusivity and its association with age‐related cognitive alterations and vascular risk factors." Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring 11, no. 1 (December 2019): 721–29. http://dx.doi.org/10.1016/j.dadm.2019.09.003.
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Xu, Man, Kangkang Xue, Xueqin Song, Yong Zhang, Jingliang Cheng, and Junying Cheng. "Peak width of skeletonized mean diffusivity as a neuroimaging biomarker in first-episode schizophrenia." Frontiers in Neuroscience 18 (September 23, 2024). http://dx.doi.org/10.3389/fnins.2024.1427947.
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Background and objectivePeak 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.MethodsA 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.ResultsCompared to HCs, patients exhibited significantly increased PSMD values (t = 2.467, p = 0.015), decreased global efficiency (Z = −2.188, p = 0.029), and increased normalized characteristic path length (lambda) (t = 2.270, p = 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 (p > 0.05). After adjusting for relevant variables, both PSMD and lambda values exhibited a significant negative correlation with reasoning and problem-solving scores (PSMD: r = −0.409, p = 0.038; lambda: r = −0.520, p = 0.006). No statistically significant correlations were observed between each PANSS score and the aforementioned metrics in the patient group (p > 0.05). Multivariate linear regression analysis revealed that increased PSMD (β = −0.426, t = −2.260, p = 0.034) and increased lambda (β = −0.490, t = −2.994, p = 0.007) were independently associated with decreased reasoning and problem-solving scores respectively (Radj2 = 0.295, F = 2.951, p = 0.029). But these significant correlations did not withstand FDR correction (p_FDR > 0.05).ConclusionPSMD 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.
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Jarholm, Jonas Alexander, Sandra Tecelao, Lene Pålhaugen, Bjørn‐Eivind Kirsebom, Atle Bjornerud, Tormod Fladby, and Per Selnes. "The role of Peak width Skeletonized Mean Diffusivity in AD disease progression." Alzheimer's & Dementia 20, S8 (December 2024). https://doi.org/10.1002/alz.095692.
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AbstractBackgroundCerebral small vessel disease (CSVD) is common in Alzheimer’s disease (AD), but it is unclear how CSVD affects cognition and disease progression. Peak width of Skeletonized Mean Diffusivity (PSMD) is a Magnetic Resonance Imaging (MRI) marker of global white matter integrity, believed to reflect both total vascular burden and the cognitive impact of CSVD. We examined the relationship between PSMD and memory, processing speed and executive function, and to assess the predictive value of PSMD on clinical progression.Method265 cases and controls between 40‐80 years old were recruited from the Norwegian multi‐center study DDI (Dementia Disease Initiation), with 2‐5 follow ups (0.7‐8 years). Subjects were according to the Clinical Dementia Rating (CDR), with 0 as cognitively unimpaired (CU) if, 0,5 as mild cognitive impairment (MCI) if CDR, and ≥ 1 as dementia. Amyloid status was determined from Amyloid‐PET or from amyloid‐β42/40. PSMD was obtained from 6 MRI scanners and harmonized for scanner effects in R using ComBat, with age, sex, staging and amyloid status at baseline as covariates.The relationship between PSMD and cognitive scores was assessed using a general linear model, with age, sex, education and an PSMD‐amyloid interaction variable as covariates. Subjects were classified into the following groups: A‐ low PSMD, A+ low PSMD, A‐ low PSMD, A+ high PSMD high, where PSMD high or low signifies above or below the group median. Survival analysis was performed in 195 subjects, using the “survival” package from R, with progression from CU to MCI/dementia or from MCI to dementia as the events of interest. Hazard ratios were assessed with the Cox proportional‐hazards model with age and A status/PSMD at baseline and sex as covariates.ResultThere was a significant relationship (p<0.01) between PSMD and TMT A and B, but not with CERAD recall. PSMD low A+ subjects had 5.5 times higher risk of cognitive decline (p<0.01) than PSMD low A‐, while PSMD high A+ had 14.3 times higher risk.ConclusionWe found that high PSMD load increases the risk of AD disease progression, but is not significantly associated with delayed recall, the core cognitive biomarker of AD.
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Horn, Mitchell J., Elif Gokcal, J. Alex Becker, Alvin S. Das, Kristin Schwab, Maria Clara Zanon Zotin, Joshua N. Goldstein, et al. "Peak width of skeletonized mean diffusivity and cognitive performance in cerebral amyloid angiopathy." Frontiers in Neuroscience 17 (April 3, 2023). http://dx.doi.org/10.3389/fnins.2023.1141007.
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BackgroundCerebral 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.MethodsEighty-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.ResultsThe 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) (p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10–4 mm2/s] compared to HCs [(3.28 ± 0.51) × 10–4 mm2/s] (p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs (ß = 0.45, 95% CI 0.13–0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed (p < 0.001), executive functioning (p = 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.DiscussionPeak 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.
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Luckey, Alison M., Saptaparni Ghosh, Chen‐Pin Wang, Alexa Beiser, Rebecca Bernal, Zhiguang Li, Djass Mbangdadji, et al. "Biological validation of peak‐width of skeletonized mean diffusivity as a VCID biomarker: The MarkVCID Consortium." Alzheimer's & Dementia, November 21, 2024. http://dx.doi.org/10.1002/alz.14345.
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AbstractBACKGROUNDPeak‐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.METHODSWe 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.RESULTSHigher 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.DISCUSSIONOur 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.
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Horn, Mitchell J., Elif Gokcal, J. A. Becker, Alvin S. Das, Kristin Schwab, Alessandro Biffi, Joshua Goldstein, et al. "Abstract 9: Peak Width of Skeletonized Mean Diffusivity and Cognition in Cerebral Amyloid Angiopathy." Stroke 52, Suppl_1 (March 2021). http://dx.doi.org/10.1161/str.52.suppl_1.9.
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Background: We hypothesized that Peak Width of Skeletonized Mean Diffusivity (PSMD), an automated marker of cerebral microangiopathy representing microstructural disruption of white matter (WM), would be increased in patients with cerebral amyloid angiopathy (CAA) compared to healthy controls (HCs) and increased PSMD would be associated with lower processing speed scores (PSSs) in patients with CAA. Methods: Seventy-two nondemented probable CAA patients and 23 HCs prospectively underwent high-resolution brain MRIs and cognitive tests. PSMD scores were quantified from a probabilistic skeleton of the WM tracts as previously validated (http://www.psmd-marker.com). In subjects with intracerebral hemorrhage (ICH, n=27), ICH regions were masked and removed from the PSMD pipeline. The analyses were repeated in the non-ICH hemisphere. Raw scores of Trail Making Test-B and Symbol Substitution Test were transformed into standardized z -scores and averaged to obtain PSSs. Results: The mean age (p=0.366) and sex (p=0.811) were similar between CAA patients and HCs. PSMD was higher in the CAA group [(3.95±0.9) х 10 –4 mm 2 /s] compared to HCs [(3.32±0.6) х 10 –4 mm 2 /s] (p=0.003). This association remained significant in a linear regression model corrected for age and sex (β=0.700, 95%CI 0.3-1, p=0.001). Within the CAA cohort, higher PSMD was associated with higher WM hyperintensity volume in a multiple regression model adjusted for all relevant variables (β=0.890, 95%CI 0.7-1, p<0.001). In a regression model corrected for age, sex, years of education and presence of ICH, a lower PSS was independently associated with increased PSMD (β=-0.405, 95%CI {-0.6}-{-0.2}, p<0.001). These results did not change when the non-ICH hemisphere was used for PSMD processing. Conclusion: PSMD is increased in CAA and is associated with worse PSSs supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA.
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Zanon Zotin, Maria Clara, Dorothee Schoemaker, Valentina Perosa, Martin Bretzner, Lukas Sveikata, Susanne Van Veluw, Andreas Charidimou, et al. "Abstract P59: Peak Width of Skeletonized Mean Diffusivity Outperforms Other Diffusion Tensor Imaging Metrics as Biomarker for Cognition in Memory-Clinic Subjects With Cerebral Amyloid Angiopathy." Stroke 52, Suppl_1 (March 2021). http://dx.doi.org/10.1161/str.52.suppl_1.p59.
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Introduction: Peak width of skeletonized mean diffusivity (PSMD) is a novel fully automated diffusion tensor imaging (DTI) marker that has been consistently associated with cognition in cerebral small vessel disease (SVD) cohorts, including cerebral amyloid angiopathy (CAA). We hypothesized that PSMD would be more strongly associated with cognitive performance compared to other conventional DTI metrics in our CAA sample. Methods: We recruited non-demented subjects with probable-CAA from a single-center memory-clinic cohort. We analyzed structural MRIs to compute a validated CAA burden score (0-6 points scale, based on the following MRI features: lobar microbleeds, superficial siderosis, perivascular spaces in centrum semiovale, and white matter hyperintensities). PSMD was obtained using a freely available script ( www.psmd-marker.com ). We used the same skeleton-mask to compute: mean of skeletonized mean diffusivity (mean MD) and mean of skeletonized fractional anisotropy (mean FA). We used linear regression analyses to explore relationships with CAA burden score and cognitive composite scores (processing speed, executive function, memory, and language - z-scores adjusted for age, sex and education level). Results: We included 43 subjects (mean age 74.4 ± 5.9 years; 48.8% female; PSMD median [IQR]: 4.05 [3.58 - 4.80] x 10 -4 mm 2 /s). In linear regression models adjusting for age, DTI metrics were significantly associated with CAA burden score (mean FA: β = -0.563, Adj. R 2 : 0.27; p < 0.001; mean MD: β = 0.581; Adj. R 2 : 0.32; p < 0.001; PSMD: β = 0.364, Adj. R 2 : 0.12; p = 0.018). PSMD was significantly associated with cognitive performance, specifically in the domains of executive function ( β = -0.568; Adj. R 2 : 0.25; p < 0.001) and processing speed ( β = -0.447; Adj. R 2 : 0.19; p = 0.004). Other DTI metrics were not significantly associated with cognitive scores. Conclusion: In this CAA sample, all DTI metrics were associated with CAA burden scores, however, only PSMD was significantly associated with cognition, in domains that are commonly affected in vascular cognitive impairment. Our results warrant confirmation in larger samples, but support PSMD as biomarker for cognition in CAA, outperforming other conventional DTI metrics.
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Lee, Dong Ah, Ho‐Joon Lee, and Kang Min Park. "Brain MRI Detection of an Abnormal Peak Width of Skeletonized Mean Diffusivity in REM Sleep Behavior Disorder." Journal of Neuroimaging 35, no. 1 (January 2025). https://doi.org/10.1111/jon.70009.
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ABSTRACTBackground and PurposePeak width of skeletonized mean diffusivity (PSMD) is a novel marker of white matter damage, which may be related to small vessel disease. This study aimed to investigate the presence of white matter damage in patients with isolated rapid eye movement sleep behavior disorder (RBD) using PSMD.MethodsWe enrolled patients with newly diagnosed isolated RBD confirmed by polysomnography and age‐ and sex‐matched healthy controls. Diffusion tensor imaging (DTI) was conducted using a 3‐Tesla MRI scanner. We measured the PSMD based on DTI in several steps, including preprocessing, skeletonization, application of a custom mask, and histogram analysis, using the Functional Magnetic Resonance Imaging of the Brain Software Library program. We compared the incidence of PSMD between patients with RBD and healthy controls and performed a correlation analysis between PSMD and clinical factors in patients with RBD.ResultsThirty patients with isolated RBD and 41 healthy controls were enrolled. The PSMD was significantly higher in patients with RBD than that in the healthy controls (3.078 vs. 2.746 × 10−4 mm2/s, p = 0.001). In addition, PSMD positively correlated with age in patients with RBD (r = 0.477, p = 0.007). However, PSMD was not associated with other clinical or polysomnographic factors.ConclusionPatients with isolated RBD had a higher PSMD than healthy controls, indicating the evidence of white matter damage in patients with RBD. This finding highlights the potential of PSMD as a marker for detecting white matter damage, which may be related to small vessel diseases, in patients with sleep disorders.
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Zanon Zotin, Maria Clara, Dorothee Schoemaker, Nicolas Raposo, Valentina Perosa, Martin Bretzner, Lukas Sveikata, Qi Li, et al. "Peak width of skeletonized mean diffusivity in cerebral amyloid angiopathy: Spatial signature, cognitive, and neuroimaging associations." Frontiers in Neuroscience 16 (November 11, 2022). http://dx.doi.org/10.3389/fnins.2022.1051038.
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BackgroundPeak width of skeletonized mean diffusivity (PSMD) is a promising diffusion tensor imaging (DTI) marker that shows consistent and strong cognitive associations in the context of different cerebral small vessel diseases (cSVD).PurposeInvestigate whether PSMD (1) is higher in patients with Cerebral Amyloid Angiopathy (CAA) than those with arteriolosclerosis; (2) can capture the anteroposterior distribution of CAA-related abnormalities; (3) shows similar neuroimaging and cognitive associations in comparison to other classical DTI markers, such as average mean diffusivity (MD) and fractional anisotropy (FA).Materials and methodsWe analyzed cross-sectional neuroimaging and neuropsychological data from 90 non-demented memory-clinic subjects from a single center. Based on MRI findings, we classified them into probable-CAA (those that fulfilled the modified Boston criteria), subjects with MRI markers of cSVD not attributable to CAA (presumed arteriolosclerosis; cSVD), and subjects without evidence of cSVD on MRI (non-cSVD). We compared total and lobe-specific (frontal and occipital) DTI metrics values across the groups. We used linear regression models to investigate how PSMD, MD, and FA correlate with conventional neuroimaging markers of cSVD and cognitive scores in CAA.ResultsPSMD was comparable in probable-CAA (median 4.06 × 10–4 mm2/s) and cSVD (4.07 × 10–4 mm2/s) patients, but higher than in non-cSVD (3.30 × 10–4 mm2/s; p < 0.001) subjects. Occipital-frontal PSMD gradients were higher in probable-CAA patients, and we observed a significant interaction between diagnosis and region on PSMD values [F(2, 87) = 3.887, p = 0.024]. PSMD was mainly associated with white matter hyperintensity volume, whereas MD and FA were also associated with other markers, especially with the burden of perivascular spaces. PSMD correlated with worse executive function (β = −0.581, p < 0.001) and processing speed (β = −0.463, p = 0.003), explaining more variance than other MRI markers. MD and FA were not associated with performance in any cognitive domain.ConclusionPSMD is a promising biomarker of cognitive impairment in CAA that outperforms other conventional and DTI-based neuroimaging markers. Although global PSMD is similarly increased in different forms of cSVD, PSMD’s spatial variations could potentially provide insights into the predominant type of underlying microvascular pathology.
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Hu, Qili, Xiaowen Zhou, Zhenxu Xiao, Qianhua Zhao, Ding Ding, and Jun Zhang. "White matter injury, plasma Alzheimer's disease, and neurodegenerative biomarkers on cognitive decline in community‐dwelling older adults: A 10‐year longitudinal study." Alzheimer's & Dementia 21, no. 2 (February 2025). https://doi.org/10.1002/alz.14594.
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AbstractINTRODUCTIONThis 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.METHODSWe 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.RESULTSParticipants 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).DISCUSSIONCombining 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.
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Lee, Dong Ah, Ho‐Joon Lee, Sung Eun Kim, and Kang Min Park. "Peak width of skeletonized mean diffusivity as a marker of small vessel disease in patients with temporal lobe epilepsy with hippocampal sclerosis." Epilepsia, December 5, 2024. https://doi.org/10.1111/epi.18205.
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AbstractObjectiveWhite matter abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) are well known. Peak width of skeletonized mean diffusivity (PSMD) is a novel marker for quantifying white matter integrity that may reflect small vessel disease. In this study, we aimed to quantify the extent of white matter damage in patients with TLE and HS by using PSMD.MethodsWe enrolled 52 patients with TLE with HS and 54 age‐ and sex‐matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3‐T magnetic resonance imaging scanner. We measured PSMD using DTI findings and compared PSMD between patients with TLE with HS and healthy controls. We also evaluated the correlation between PSMD and clinical factors in patients with TLE and HS.ResultsPSMD differed significantly between healthy controls and patients with TLE and HS, and it was higher in the patients (2.375 × 10−4 mm2/s vs. 2.108 × 10−4 mm2/s, p < .001). Furthermore, PSMD in the ipsilateral hemisphere of the HS was higher than in the contralateral hemisphere of the HS (2.472 × 10−4 mm2/s vs. 2.258 × 10−4 mm2/s, p = .040). PSMD was positively correlated with age (r = .512, p < .001) and age at seizure onset (r = .423, p = .002) in patients with TLE and HS.SignificancePatients with TLE and HS had higher PSMD values than healthy controls, and PSMD was positively correlated with age. These findings provide evidence of white matter damage probably due to small vessel disease in patients with TLE and HS and support the feasibility of PSMD as a promising imaging marker for epileptic disorders.
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Deary, Ian J., Stuart J. Ritchie, Susana Muñoz Maniega, Simon R. Cox, Maria C. Valdés Hernández, Michelle Luciano, John M. Starr, Joanna M. Wardlaw, and Mark E. Bastin. "Brain Peak Width of Skeletonized Mean Diffusivity (PSMD) and Cognitive Function in Later Life." Frontiers in Psychiatry 10 (July 26, 2019). http://dx.doi.org/10.3389/fpsyt.2019.00524.
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Li, Yuanhao, Hongquan Zhu, Yufei Liu, Yujie Ding, Shihui Li, Li Li, Jiaxuan Zhang, Jingjing Jiang, Nanxi Shen, and Wenzhen Zhu. "Assessment the Impact of IDH Mutation Status on MRI Assessments of White Matter Integrity in Glioma Patients: Insights From Peak Width of Skeletonized Mean Diffusivity and Free Water Metrics." Journal of Magnetic Resonance Imaging, August 20, 2024. http://dx.doi.org/10.1002/jmri.29561.
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BackgroundGliomas are highly invasive brain tumors that evade accurate geographic assessment by conventional MRI due to microscopic invasion along white matter (WM) tracts. Advanced diffusion MRI techniques are needed to assess occult WM involvement.PurposeTo evaluate peak width of skeletonized mean diffusivity (PSMD) and peak width of skeletonized free water (PSFW), and axonal water fraction (AWF) for assessing glioma‐induced alterations in normal‐appearing WM and their relationship with isocitrate dehydrogenase 1 (IDH1) mutation.Study TypeRetrospective.PopulationOne hundred five glioma patients (46 ± 13 years), 53 healthy controls (HCs) (46 ± 9 years).Field Strength/Sequence3.0 T, T1WI, T1‐CE, T2WI, T2FLAIR, and DKI.AssessmentPSMD and PSFW were compared between lesion and contralateral sides in glioma patients and between patients and HCs. The associations between these metrics and clinical variables, including IDH1 mutation, was assessed. Corpus callosum (CC) injury, quantified by the AWF, was evaluated for its mediated effect of IDH1 mutation on contralesional PSMD and PSFW.Statistical TestsPaired‐t tests, ANCOVA, univariate and multivariate linear regression, and mediation analysis with significance set at P < 0.05.ResultsContralateral PSMD and PSFW were significantly higher in left‐sided gliomas (PSMD: 0.206 ± 0.027 vs. 0.193 ± 0.023; PSFW: 0.119 ± 0.019 vs. 0.106 ± 0.020) than in HCs, with similar increases in right‐sided gliomas (PSMD: 0.219 ± 0.036 vs. 0.195 ± 0.023; PSFW: 0.129 ± 0.031 vs. 0.109 ± 0.020). IDH1 wild‐type gliomas were associated with higher contralateral PSMD and PSFW (β = −0.302 and −0.412). AWF of CC mediated the impact of IDH1 mutations on contralesional PSMD and PSFW (mediated proportion: 42.7% and 53.7%).Data ConclusionPSMD and PSFW are effective biomarkers for assessing WM integrity in gliomas, significantly associated with IDH1 mutation status. AWF of CC mediates the relationship between IDH1 mutation and contralesional PSMD and PSFW.Evidence Level4Technical EfficacyStage 2
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Wang, Dan, Zheng Sun, and Yuehua Li. "Horizontal analysis and longitudinal cohort study of chronic renal failure correlates and cerebral small vessel disease relationship using peak width of skeletonized mean diffusivity." Frontiers in Neurology 15 (September 6, 2024). http://dx.doi.org/10.3389/fneur.2024.1461258.
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Background and purposePeak width of skeletonized mean diffusivity (PSMD) is an MRI-based biomarker that may reflect white matter lesions (WML). PSMD is based on skeletonization of MR DTI data and histogram analysis. Both chronic renal failure (CRF) and WML may be affected by multisystemic small-vessel disorder. We aimed to explore the relationship between PSMD and estimated glomerular filtration rate (eGFR).MethodsFifty followed-up CRF patients matched for age, sex, hypertension and smoking status were enrolled and classified into a progressive group (n = 16) and stable group (n = 34) based on eGFR levels. Longitudinal and horizontal differences of PSMD were compared between the progressive and stable groups at the initial and follow-up time points. Pearson’s correlation was used for correlation of eGFR with PSMD and WML (per Fazekas scale score). ROC was used to measure the sensitivity of PSMD and WML score to changes of eGFR.ResultsAt the follow-up time point, PSMD of the progressive group was significantly higher than at the initial time point (p < 0.001), and PSMD of the progressive group was significantly higher than stable group (p < 0.001). PSMD and eGFR were significantly correlated. AUC curves explored that ΔPSMD (PSMD changes at the follow-up and initial time points) and follow-up PSMD was better for the classification of progressive and stable groups.ConclusionPSMD has significant correlation with eGFR, PSMD can reveal a close relationship between WML and CRF.
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Vinciguerra, C., A. Giorgio, J. Zhang, V. Nardone, R. Tappa Brocci, L. Pastò, C. Niccolai, et al. "Peak width of skeletonized mean diffusivity (PSMD) and cognitive functions in relapsing-remitting multiple sclerosis." Brain Imaging and Behavior, October 8, 2020. http://dx.doi.org/10.1007/s11682-020-00394-4.
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Etherton, Mark R., Markus D. Schirmer, Maria Clara Zanon Zotin, Pamela M. Rist, Gregoire Boulouis, Arne Lauer, Ona Wu, and Natalia S. Rost. "Global white matter structural integrity mediates the effect of age on ischemic stroke outcomes." International Journal of Stroke, November 3, 2021, 174749302110559. http://dx.doi.org/10.1177/17474930211055906.
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Background The relationship of global white matter microstructural integrity and ischemic stroke outcomes is not well understood. Aims To investigate the relationship of global white matter microstructural integrity with clinical variables and functional outcomes after acute ischemic stroke. Methods A retrospective analysis of neuroimaging data from 300 acute ischemic stroke patients with magnetic resonance imaging brain obtained within 48 hours of stroke onset and long-term functional outcomes (modified Rankin, mRS) was performed. Peak width of skeletonized mean diffusivity (PSMD), as a measure of global white matter microstructural injury, was calculated in the hemisphere contralateral to the acute infarct. Multivariable linear and logistic regression analyses were performed to identify variables associated with PSMD and excellent functional outcome (mRS < 2) at 90 days, respectively. Mediation analysis was then pursued to characterize how PSMD mediates the effect of age on acute ischemic stroke functional outcomes. Results White matter hyperintensity volume, age, pre-stroke disability, and normal-appearing white matter mean diffusivity were independently associated with increased PSMD. In logistic regression analysis, increased infarct volume and PSMD were independent predictors of excellent functional outcome. Additionally, the effect of age on functional outcomes was indirectly mediated by PSMD ( P < 0.001). Conclusions As a marker of global white matter microstructural injury, increased PSMD mediates the effect of increased age to contribute to poor acute ischemic stroke functional outcomes. PSMD could serve as a putative radiographic marker of brain age for stroke outcomes prognostication.
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Oberlin, Lauren E., Matteo Respino, Lindsay Victoria, Lila Abreu, Matthew J. Hoptman, George S. Alexopoulos, and Faith M. Gunning. "Late-life depression accentuates cognitive weaknesses in older adults with small vessel disease." Neuropsychopharmacology, February 9, 2021. http://dx.doi.org/10.1038/s41386-021-00973-z.
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AbstractNeuroimaging features of small vessel disease (SVD) are highly prevalent in older adulthood and associated with significant variability in clinical symptoms, yet the factors predicting these symptom disparities are poorly understood. We employed a novel metric of SVD, peak width of skeletonized mean diffusivity (PSMD), to elucidate the relationship of late-life depression (LLD) to the cognitive presentation of vascular pathology. A total of 109 older adults without a diagnosis of a neurocognitive disorder were enrolled in the study; 44 with major depressive disorder and 65 age-matched controls. Subjects completed neuropsychological testing and magnetic resonance imaging including FLAIR and diffusion tensor imaging sequences, from which white matter hyperintensity volume and diffusion metrics (fractional anisotropy, mean diffusivity, PSMD) were quantified. In hierarchical models, the relationship between vascular burden and cognitive performance varied as a function of diagnostic status, such that the negative association between PSMD and processing speed was significantly stronger in participants with LLD compared to controls. Greater PSMD also predicted poorer performance on delayed memory and executive function tasks specifically among those with LLD, while there were no associations between PSMD and task performance among controls. PSMD outperformed conventional SVD and diffusion markers in predicting cognitive performance and dysexecutive behaviors in participants with LLD. These data suggest that LLD may confer a vulnerability to the cognitive manifestations of white matter abnormalities in older adulthood. PSMD, a novel biomarker of diffuse microstructural changes in SVD, may be a more sensitive marker of subtle cognitive deficits stemming from vascular pathology in LLD.
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Kern, Kyle C., Clinton B. Wright, and Richard Leigh. "Abstract P56: Diffusion Tensor Imaging at the Time of Stroke is Associated With Cognitive Performance 4 Months Later." Stroke 52, Suppl_1 (March 2021). http://dx.doi.org/10.1161/str.52.suppl_1.p56.
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Introduction: Cognitive impairment after stroke is associated with stroke severity and baseline brain health. We hypothesized that acute diffusion tensor imaging (DTI) metrics would identify patients at risk for post-stroke cognitive impairment. Methods: Patients were enrolled prospectively in an observational study that involves serial MRI and cognitive testing in patients with recent stroke and moderate white matter disease on MRI but without dementia. DTI was performed at the time of stroke; cognitive testing with the MOCA and the Telephone Interview for Cognitive Status (TICS) were performed 3 months later. DTI was used to calculate Peak Skeletonized Mean Diffusivity (PSMD), a measure of global white matter microstructural integrity previously validated in cerebral small vessel disease. Fractional anisotropy maps were skeletonized (figure panel A) and a histogram of the corresponding MD values was used to calculate the peak width in the non-stroke hemisphere (panel B). Linear regression was used to test whether acute PSMD in the non-stroke hemisphere, acute stroke volume, or baseline NIHSS predicted cognitive performance 3 months later. Results: Fourteen patients followed-up at a median of 123 days. Patients had a median age of 73 years, mean baseline NIHSS of 1.2 (IQR 0-1.75), mean infarct volume of 4cc (range 0-16cc), mean MOCA of 25 (range 19-30), mean TICS of 33 (range 23-41), and 50% were women. Using multivariable linear regression, only acute PSMD predicted follow-up MOCA (std beta= -0.64, adj R 2 = 0.37, p= 0.013) while compared to baseline NIHSS, PSMD showed a stronger association with follow-up TICS score (std beta= -0.57 vs -0.44, p= 0.017; model adj R 2 = 0.476, p= 0.011)(Panel C). Conclusions: In this cohort of patients with small strokes we found that acute contralateral PSMD provided a measure of brain health that appears to predict cognitive performance at 3 months better than stroke size or severity. These are preliminary findings from an ongoing study.
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Lee, Wei‐Ju, Fan Huang, Shi‐Ming Wang, Hung‐Chieh Chen, Yi‐Ming Chen, Hsu‐Wen Huang, and Chih‐Mao Huang. "Peak width of skeletonized mean diffusivity might be a better neuroimage marker for cognitive functions in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)." Alzheimer's & Dementia 20, S2 (December 2024). https://doi.org/10.1002/alz.088185.
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AbstractBackgroundCerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a monogenic subcortical ischemic vascular dementia (SIVD) caused NOTCH3 gene mutations. Many different neuroimaging methods have been used to investigate the association between neuroimaging changes and clinical symptoms. We investigated the correlation between peak width of skeletonized mean diffusivity (PSMD) values and cognitive functions in preclinical CADASIL patients without a history of stroke or dementia, comparing them to white matter hyperintensities (WMH) volumes.MethodThis study recruited NOTCH3 R544C mutation carriers (n=63) without a history of stroke or dementia and age‐ and sex‐matched non‐carriers (n=35) in Taichung Veteran General Hospital. Brain MRI including T1, Fluid‐Attenuated Inversion Recovery (FLAIR), and diffusion tensor imaging (DTI) data were acquired on 1.5T MRI and neuropsychological assessments were used to evaluate the cognition functions for all participants. The domain‐specific composite Z‐scores were calculated to represent memory, executive function, processing speed, and visuospatial function. We examined the relationships between domain‐specific cognitive functions and both PSMD values and WMH volumes.ResultIn this study, the data from 65 participants carrying NOTCH3 R544C mutation and 35 non‐carriers were analyzed. Mutation carriers have more severe WMH (p < 0.001) and longer PSMD values (p = 0.011) compared to non‐carriers. After adjusting for age, sex, and years of education using partial correlation, the PSMD values are associated with processing speed (r = ‐0.252, p = 0.048) and visuospatial functions (r = ‐0.275, p = 0.03). The correlations between WMH volume and the cognitive functions were not statistically significant.ConclusionIn summary, the PSMD value might be a better imaging biomarker for the cognitive functions in preclinical CADASIL patients and represent the early subcortical cerebrovascular damage compared to WMH volumes.
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Rasing, Ingeborg, Naomi Vlegels, Manon R. Schipper, Sabine Voigt, Emma A. Koemans, Kanishk Kaushik, Rosemarie van Dort, et al. "Microstructural white matter damage on MRI is associated with disease severity in Dutch-type cerebral amyloid angiopathy." Journal of Cerebral Blood Flow & Metabolism, June 17, 2024. http://dx.doi.org/10.1177/0271678x241261771.
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Peak width of skeletonized mean diffusivity (PSMD) is an emerging diffusion-MRI based marker to study subtle early alterations to white matter microstructure. We assessed PSMD over the clinical continuum in Dutch-type hereditary CAA (D-CAA) and its association with other CAA-related MRI-markers and cognitive symptoms. We included (pre)symptomatic D-CAA mutation-carriers and calculated PSMD from diffusion-MRI data. Associations between PSMD-levels, cognitive performance and CAA-related MRI-markers were assessed with linear regression models. We included 59 participants (25/34 presymptomatic/symptomatic; mean age 39/58 y). PSMD-levels increased with disease severity and were higher in symptomatic D-CAA mutation-carriers (median [range] 4.90 [2.77–9.50]mm2/s × 10−4) compared with presymptomatic mutation-carriers (2.62 [1.96–3.43]mm2/s × 10−4) p = <0.001. PSMD was positively correlated with age, CAA-SVD burden on MRI (adj.B [confidence interval] = 0.42 [0.16–0.67], p = 0.002), with number of cerebral microbleeds (adj.B = 0.30 [0.08–0.53], p = 0.009), and with both deep (adj.B = 0.46 [0.22–0.69], p = <0.001) and periventricular (adj.B = 0.38 [0.13–0.62], p = 0.004) white matter hyperintensities. Increasing PSMD was associated with decreasing Trail Making Test (TMT)-A performance (B = −0.42 [−0.69–0.14], p = 0.04. In D-CAA mutation-carriers microstructural white matter damage is associated with disease phase, CAA burden on MRI and cognitive impairment as reflected by a decrease in information processing speed. PSMD, as a global measure of alterations to the white matter microstructure, may be a useful tool to monitor disease progression in CAA.
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Beaudet, Grégory, Ami Tsuchida, Laurent Petit, Christophe Tzourio, Svenja Caspers, Jan Schreiber, Zdenka Pausova, et al. "Age-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study." Frontiers in Psychiatry 11 (May 4, 2020). http://dx.doi.org/10.3389/fpsyt.2020.00342.
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Schipper, Manon R., Naomi Vlegels, Thijs W. van Harten, Ingeborg Rasing, Emma A. Koemans, Sabine Voigt, Alberto de Luca, et al. "Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy." Journal of Cerebral Blood Flow & Metabolism, September 14, 2023. http://dx.doi.org/10.1177/0271678x231200425.
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Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.
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Xiao, Yawen, Yifei Gui, Jiankun Dai, Heng Zhao, Zhongliang Rao, Dan Luo, Xinru Deng, and Xinlan Xiao. "Mediation of White Matter Alterations in the Association Between Ventricular Dilation and Cognitive Decline in Hydrocephalus Patients: An MRI Study." Journal of Magnetic Resonance Imaging, May 20, 2024. http://dx.doi.org/10.1002/jmri.29452.
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BackgroundCognitive impairment is commonly observed in hydrocephalus patients. Ventricular enlargement compresses brain parenchyma, especially the white matter (WM).PurposeTo investigate whether the relationship between ventricular dilation and cognitive decline in hydrocephalus patients is mediated by WM alterations.Study TypeRetrospective.Population51 communicating hydrocephalus patients (median age, 54 years), 50 obstructive hydrocephalus patients (median age, 49 years), and 53 control subjects (median age, 50 years).Field Strength/SequenceDiffusion tensors imaging, 3D T1 BRAVO, 3D FIESTA, CUBE T2, and FLAIR sequences at 3T.AssessmentDTI parameters (skeletonized fractional anisotropy (FA), skeletonized mean diffusivity (MD), and peak width of skeletonized mean diffusivity p(PSMD)) were extracted using FSL software. Global, periventricular, and deep white matter hyperintensity (WMH) volumes, degree of ventricular enlargement (Evans index), and other conventional imaging markers (number of lacunes and perivascular spaces, intracranial and brain volume) were extracted using united imaging intelligence. Cognitive tests included Montreal cognitive assessment (MoCA), clock drawing test (CDT), and vocabulary fluency test (VFT).Statistical TestsMultivariable linear regression analysis, mediation analyses, and dominance analysis. P‐value <0.05 was considered significant.ResultsThe degree of ventricular dilation, DTI parameters, and cognitive function scores were interrelated. The skeletonized FA values (β = −0.0917, 95% confidence interval (CI): −0.205, −0.024) and normalized global WMH volume (β = −0.0635, 95% CI: −0.13, −0.0005) together mediated 37.2% of the association between Evans index and MoCA. A comparable causal pathway was found for periventricular WMHs but not for deep WMHs. Dominance analysis indicated skeletonized FA values had a greater impact on cognition than WMH volume. The skeletonized FA values also mediated the association between Evans index and CDT (β = −0.0897, 95% CI: −0.165, −0.026) and VFT (β = −0.1589, 95% CI: −0.27, −0.083).ConclusionWM alterations were causal mediators between ventricular dilation and cognitive decline in hydrocephalus patients.Evidence Level3.Technical EfficacyStage 3.
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Schmitzer, Lena, Stephan Kaczmarz, Jens Göttler, Gabriel Hoffmann, Michael Kallmayer, Hans-Henning Eckstein, Dennis Martin Hedderich, et al. "Macro- and microvascular contributions to cerebral structural alterations in patients with asymptomatic carotid artery stenosis." Journal of Cerebral Blood Flow & Metabolism, March 20, 2024. http://dx.doi.org/10.1177/0271678x241238935.
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Atherosclerosis can underly internal carotid artery stenosis (ICAS), a major risk factor for ischemic stroke, as well as small vessel disease (SVD). This study aimed to investigate hemodynamics and structural alterations associated with SVD in ICAS patients. 28 patients with unilateral asymptomatic ICAS and 30 age-matched controls underwent structural (T1-/T2-weighted and diffusion tensor imaging [DTI]) and hemodynamic (pseudo-continuous arterial spin labeling and dynamic susceptibility contrast) magnetic resonance imaging. SVD-related alterations were assessed using free water (FW), FW-corrected DTI, and peak-width of skeletonized mean diffusivity (PSMD). Furthermore, cortical thickness, cerebral blood flow (CBF), and capillary transit time heterogeneity (CTH) were analyzed. Ipsilateral to the stenosis, cortical thickness was significantly decreased in the posterior dorsal cingulate cortex (p = 0.024) and temporal pole (p = 0.028). ICAS patients exhibited elevated PSMD (p = 0.005), FW (p < 0.001), and contralateral alterations in FW-corrected DTI metrics. We found significantly lateralized CBF (p = 0.011) and a tendency for lateralized CTH (p = 0.067) in the white matter (WM) related to ICAS. Elevated PSMD and FW may indicate a link between SVD and WM changes. Contralateral alterations were seen in FW-corrected DTI, whereas hemodynamic and cortical changes were mainly ipsilateral, suggesting SVD might influence global brain changes concurrent with ICAS-related hemodynamic alterations.
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Liu, Xiaodan, Giuseppe Barisano, Pauline Maillard, Caprihan Arvind, Steven Cen, Xingfeng Shao, Kay Jann, et al. "Validation of diffusivity along the perivascular space as a biomarker for vascular cognitive impairment and dementia." Alzheimer's & Dementia 20, S2 (December 2024). https://doi.org/10.1002/alz.084965.
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AbstractBackgroundTo validate the index of diffusivity along the perivascular space (ALPS index) as a biomarker for vascular cognitive impairment and dementia (VCID).MethodThe participants and MRI data used in this study were acquired as part of the MarkVCID consortium, which consisted of seven sites. A total of 578 participants (72.5±7.2 years old, 232 Male) who received baseline and follow‐up cognitive evaluations (Montreal Cognitive Assessment (MoCA), Principal Component Analysis derived General Cognitive Function (GCF_PCA), and composite score of Executive Function (EFC)) and MRI examinations were included in this study. The diffusion tensor imaging (DTI) data were processed by using an in‐house automatic processing pipeline with FMRIB Software Library 6.0.6. The mean free water (mFW) and peak width of skeletonized mean diffusivity (PSMD) were computed in the white matter (WM). The ALPS index was defined as the average of bilateral ALPS indices which were calculated by the ratio of mean of x‐axis diffusivity in the projection fibers (Dxxproj) and x‐axis diffusivity in the association fibers (Dxxassoc) to the mean of y‐axis diffusivity in the projection fibers (Dyyproj) and z‐axis diffusivity in the association fibers (Dzzassoc). The WM hyperintensity volumes (WMHV) were calculated on FLAIR images and normalized by intracranial volume (ICV). Univariate correlation (Pearson or Spearman) was used to examine the associations between imaging markers (ALPS index, mFW, PSMD, and WMHV). Linear regression models were used to evaluate the associations of baseline ALPS index with baseline and longitudinal changes of cognitive outcomes, regressing out three types of covariates: 1) age, sex, and education, 2) added vascular risk factors (VRFs), including diabetes, hypertension and smoking, 3) further added mFW, PSMD and WMHV. SAS 9.4 software was used for all statistical analyses, and P<0.05 was regarded as statistical significance.ResultThe baseline ALPS index was significantly correlated with existing biomarkers of cerebral small vessel disease (cSVD)‐related VCID, i.e., mFW and WMHV (P<0.01) (Figure 1), and baseline cognitive performances, i.e., MoCA total score, GCF_PCA score, and EFC score (P<0.05) after adjusting for the demographics, VRFs, and existing biomarkers (Figure 2).Conclusionthe ALPS index is an independent contributor to the cognitive decline in cSVD.
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Etherton, Mark R., Ona Wu, and Natalia Rost. "Abstract WMP18: Global White Matter Microstructural Injury Predicts Poor Outcomes After Ischemic Stroke." Stroke 51, Suppl_1 (February 2020). http://dx.doi.org/10.1161/str.51.suppl_1.wmp18.
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Background: Early outcome prediction after acute ischemic stroke (AIS) is critical to guide care and rehabilitation strategies. Pre-existing chronic structural injury to cerebral white matter (WM), including ischemic WM hyperintensity (WMH) and microstructural changes within the normal-appearing WM (NAWM), is known to impede post-stroke recovery. Quantitative assessment of total pre-existing WM injury may therefore improve prognostication of functional stroke outcomes. Peak width of skeletonized mean diffusivity (PSMD) is an automated marker of cerebral small vessel disease and global WM injury. In a cohort of AIS patients, we measured PSMD in the hemisphere contralateral to the acute infarct and characterized its association with 90-day functional outcomes. Methods: Brain MRI with diffusion tensor imaging sequences was acquired within 48 hours of AIS admission. WMH volume (WMHv) was measured in a semi-automated manner. NAWM masks were constructed by subtracting the WMH and chronic infarct masks from a probabilistic WM atlas. NAWM mean diffusivity (MD) was then measured in the NAWM mask. PSMD was extracted by skeletonizing the WM tracts in the MD image using the Fractional Anisotropy image and the FSL Tract-Based Spatial Statistics pipeline with a mask for the contralesional hemisphere. Excellent outcome was defined as a modified Rankin scale score < 2 at 3-6 months post-stroke. Logistic regression analysis was performed to evaluate predictors of excellent outcome. Results: In 292 AIS patients, increasing PSMD and NAWM MD, but not WMHv, were associated with decreased likelihood of excellent outcome in univariable analysis. Increasing age, admission NIHSS score, DWI volume, and female sex were also negatively associated with excellent outcome. In backward stepwise logistic regression, including all significant variables from the univariable step, increasing age (β = -0.03; P = 0.01), NIHSS (β = -0.1; P = 0.0005), DWI volume (β = -0.02; P = 0.0004), PSMD (β = -0.08; P = 0.03), and female sex (β = -0.7; P = 0.01) were associated with decreased likelihood of excellent outcome. Conclusion: In AIS patients, automated determination of contralesional PSMD, as a marker of chronic, global white matter injury, is an independent predictor of functional outcomes.
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Horn, Mitch J., Elif Gokcal, John Becker, Alvin S. Das, Isabelle Levine, Zora DiPucchio, Maria Clara Zanon Zotin, et al. "Abstract WMP78: Microstructural Alterations And Vascular Dysfunction In Cerebral Amyloid Angiopathy." Stroke 53, Suppl_1 (February 2022). http://dx.doi.org/10.1161/str.53.suppl_1.wmp78.
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Background: Cerebral amyloid angiopathy (CAA) causes impaired vascular reactivity to physiologic stimuli that mediates CAA-related white matter hyperintensities (WMH) but its relationship to microstructural changes has not yet been tested. We hypothesized that the degree of vascular dysfunction would be associated with alterations in white matter microstructure in patients with CAA. Methods: Fifty-five non-demented probable CAA patients underwent high-resolution structural MRI including Diffusion-Weighted Imaging (DWI) and functional MRI (fMRI). WMH volume was quantified and expressed as percent of total intracranial volume (pWMH). Vascular reactivity was measured as the amplitude of the blood-oxygenation-level-dependent response (BOLD_Amp) to a visual stimulus. Peak Width of Skeletonized Mean Diffusivity (PSMD) was calculated from DWI and used as a marker of microstructural integrity. Results: Patients had a mean age of 69.3±7.4 years and 36 (65%) had intracerebral hemorrhage (ICH). The mean PSMD was [(3.92±0.8) х 10–4 mm2/s] and the mean BOLD_Amp was 1.15±0.2%. Neither PSMD nor BOLD_Amp differed between patients with ICH and those without (p>0.2 for all comparisons). PSMD significantly correlated with older age (r=0.335, p=0.012), with higher pWMH (r=0.792, p<0.001) and with lower BOLD_Amp (r= –0.5, p<0.001). PSMD showed a trend to increase more in patients with hypertension (HT) than without ([(4.09±0.8) х 10–4 mm2/s] vs. ([(3.74±0.8) х 10–4 mm2/s], p=0.097). BOLD_Amp also correlated with pWMH (r= –0.409, p=0.002). In a linear regression analysis, decrease in BOLD_Amp was independently associated with increased PSMD corrected for age, sex, HTN, ICH and pWMH (β= –0.91, 95%CI (–1.77)-(–0.05), p=0.037). pWMH was also associated with PSMD in this model (β=1.22, 95%CI 0.89-1.54, p<0.001). Conclusion: This study supports the view that vascular dysfunction in CAA is closely linked with CAA-related global ischemic injury including MRI-visible white matter injury as well as microstructural tissue disruption.
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Yang, Sheng, and A/Prof Alastair John Webb. "Abstract 99: Age and White Matter Injury due to Cerebral Small Vessel Disease are Synergistically Associated with Impaired Neurovascular Coupling." Stroke 56, Suppl_1 (February 2025). https://doi.org/10.1161/str.56.suppl_1.99.
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Background: Neurovascular coupling (NVC) depends on cerebral endothelial function, and was impaired in cerebral small vessel disease (CSVD), but previous studies have been small whilst the relationship between NVC and white matter microstructural changes in CSVD remains unclear. This study investigated the association between NVC and both macro- and microstructural white matter changes in the large UK Biobank population. Methods: UK Biobank data were used to determine associations between demographics, medical history and structural MRI measures (white matter hyperintensities, WMH; peak width of skeletonized mean diffusivity, PSMD) with NVC. NVC was quantified as the z-score of the fMRI blood-oxygen-level-dependent (BOLD) response to a visual stimulus. WMH volume was calculated from T2-weighted images, normalized to total intracranial volume (ICV), and log-transformed due to skewness. PSMD was derived from diffusion-weighted data. All continuous variables were scaled. Results: Among 37,914 participants (mean age: 64.1±7.7 years; 52% female; 1.35% with a history of ischemic stroke), mean PSMD, WMH volume, and NVC were 2.25±0.40x10 –4 mm 2 /s, 0.93±0.01% ICV, and 2.55±1.35, respectively. NVC significantly decreased with age (β=-0.07, p<0.001), hypertension (β=-0.12, p<0.001), diabetes (β=-0.13, p<0.001), and stroke history (β=-0.20, p<0.001). General linear models demonstrated a significant decrease in NVC associated with higher PSMD (β=-0.03, p<0.001) and WMH (β=-0.04, p<0.001) after controlling for age, sex, hypertension, diabetes, and stroke. Additionally, there was a significant interaction such that the negative impact of PSMD and WMH on NVC was exacerbated by older age (PSMD: age β= -0.04, p<0.01; WMH: age β=-0.03, p<0.05). Conclusion: This study highlights a strong association between impaired NVC and markers of CSVD, including both macrostructural (WMH) and microstructural (PSMD) white matter abnormalities, in a large population. The synergistic exacerbation of these effects by age underscores the potentially critical role of cerebrovascular dysfunction in the development of CSVD.
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Durrani, Romella, Meng Wang, Emily Cox, Elisabeth Irving, Feryal Saad, Cheryl R. McCreary, Andrew E. Beaudin, et al. "Mediators of Cognitive Impairment in Cerebral Amyloid Angiopathy." International Journal of Stroke, April 26, 2022, 174749302210993. http://dx.doi.org/10.1177/17474930221099352.
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Background Cerebral amyloid angiopathy (CAA) is associated with cognitive decline. CAA has diverse impacts on brain structure and function; however, the brain lesions that mediate the association of CAA with cognition are not understood well. Aims To determine the degree to which CAA neuroimaging biomarkers mediate the association of CAA with cognitive dysfunction. Methods We analyzed cross-sectional data of patients with probable CAA and controls without cognitive impairment from the Functional Assessment of Vascular Reactivity study. Neuropsychological tests were grouped into domains of memory, executive function, and processing speed. Candidate CAA neuroimaging biomarkers were pre-specified based on prior literature, consisting of white matter hyperintensity volume, peak width of skeletonized mean diffusivity (PSMD) on diffusion tensor MRI, cerebrovascular reactivity (CVR), cortical thickness, and cortical thickness in a meta-region of interest typically affected by Alzheimer’s disease (AD). Cognitive scores and neuroimaging markers were standardized and reported in relation to values in controls. Mediation analysis was used to estimate the total effect of CAA on cognition and the proportion of the total effect that was mediated by neuroimaging biomarkers, controlling for age, sex, and education. Results There were 131 participants (67 CAA and 64 control). Mean age was 72.1 ± 7.7 years, and 54.2% were women. As expected, compared to controls CAA was associated with lower cognition. In mediation analyses, CAA had direct unmediated effects of 48%, 46%, and 52% on all three cognitive domains. The association of CAA with memory was mediated by CVR and PSMD, accounting for 18% and 36% of the total effect of CAA. The association of CAA with executive function was mediated by PSMD and mean cortical thickness in the AD meta-ROI, accounting for 33% and 31% of the total effect of CAA. The association of CAA with processing speed was mediated by CVR and PSMD, accounting for 8% and 34% of the total effect of CAA. Among CAA participants, the presence of cortical superficial siderosis was associated with lower processing speed. Conclusions Altered white matter diffusivity (i.e., PSMD), CVR, and atrophy, taken together, account for about half the effect of CAA on cognition. Data access statement Anonymized data will be shared by request from a qualified investigator.
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Luckey, Alison M., Alexa S. Beiser, Jayandra J. Himali, Carlos A. Gaona, Joy Zeynoun, Luis A. Mendez Rodriguez, Mohamad Habes, et al. "Joint Contribution of NfL and PSMD for Improved Risk Stratification of VCID." Alzheimer's & Dementia 20, S2 (December 2024). https://doi.org/10.1002/alz.090747.
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AbstractBackgroundAdvancing therapeutic and prevention strategies for vascular contributions to cognitive impairment and dementia (VCID) warrants identifying novel biomarkers. However, due to the high heterogeneity underlying dementia pathology, a single marker may not fully risk‐stratify for VCID. A blood‐based biomarker of neuroaxonal injury, neurofilament light chain (NfL), and a neuroimaging‐based biomarker of white matter microstructural damage on diffusion weighted imaging, peak width of skeletonized mean diffusivity (PSMD), have been related to worse general cognition and proposed as robust biomarkers for cerebral small vessel disease (cSVD). We investigated the joint contribution of NfL and PSMD for improved specificity/sensitivity to identify persons at risk for VCID.MethodDementia‐free participants from the Framingham Offspring Study with cognitive, neuroimaging, and NfL data were included (N=969). NfL was measured in plasma, and PSMD was derived from MRI diffusion weighted imaging. Executive function and general cognitive function were assessed from a neuropsychological battery. NfL and PSMD were dichotomized by the top quartile and combined to indicate a high cSVD burden. The high NfL‐PSMD risk category was related to cognitive function using linear regression adjusting for age, age‐squared, sex, education, renal function (eGFR), and total intracranial volume. Additional analyses incorporating amyloid PET uptake in 64 participants were performed to discern Alzheimer’s disease pathology from VCID.ResultHigher NfL‐PSMD was significantly associated with worse executive (Beta±SE, ‐0.06±0.02, p=0.002) and general cognitive function (‐0.15±0.07, p=0.02). Additionally, amyloid PET over‐predicted NfL levels in those with PSMD below the median (observed<predicted, Mean(SD), ‐0.06(0.31)) and under‐predicted NfL in those with PSMD above the median (observed>predicted, 0.06 (0.33)). Although results were not significant (p=0.15) due to the limited sample, they suggest that amyloid pathology does not explain cSVD burden measured with NfL and PSMD.ConclusionOur findings suggest combining NfL and PSMD can better risk‐stratify those with VCID and poorer cognitive function. This NfL‐PSMD multi‐biomarker has potential to discriminate vascular dysfunction from Alzheimer’s pathology, improving identification of persons better suited for VCID clinical trials. Utilizing a multi‐biomarker approach may improve accuracy for risk stratification of persons bearing covert cerebral vascular injury. Further studies are underway to confirm these findings in larger, diverse samples.
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Rimmele, David Leander, Elina L. Petersen, Sarah Affolderbach, Marvin Petersen, Bastian Cheng, Carola Mayer, Felix Leonard Nägele, et al. "Differences in impact of current and former shift work on cardiovascular risk factors, carotid atherosclerosis and white matter integrity." Sleep Advances, July 31, 2024. http://dx.doi.org/10.1093/sleepadvances/zpae056.
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Abstract Study Objectives The association of shift work and disrupted circadian rhythm with markers of large artery atherosclerosis and cerebral small vessel disease is uncertain. We aimed to study the separate association of current and former shift work (SW) with these markers. Methods We included participants from the population-based Hamburg City Health Study. SW was defined by monthly working hours between 6 p.m. and 7 a.m. containing night shifts for at least 12 months. Cross-sectional data were obtained from structured questionnaires, laboratory analyses, physical examinations, brain MRI, and carotid ultrasound. We performed multivariable regression analysis with carotid intima media thickness (CIMT), and peak-width skeletonized mean diffusivity (PSMD) as dependent variables. Results 344 current, 238 former and 7’162 never-shift workers were included. The median age was 60 years for both current and former shift workers, and total duration of SW was comparable for the two groups. Current shift workers were less frequently female (27.3% vs 44.5%; p<0.001), had more frequent hyperlipidemia (31.5% vs 22.3%; p=0.024), and diabetes (16.2% vs 3.2%; p<0.001). After adjustment for age and sex, reduced quality of sleep (β=1.61,p=0.001) and low education (β=2.63,p<0.001) were associated with current but not former SW. Adjusted for age and sex, current SW was associated with higher CIMT (β=0.02,p=0.001) and PSMD (β= 9.06e-06,p=0.006), whereas former SW was not. Adjusted for risk factors, current SW remained associated with PSMD (β=9.91e-06,p=0.006) but not with CIMT. Conclusions Current SW was associated with CIMT and with PSMD, with the latter association remaining after adjustment for risk factors. Former SW showed no associations with CIMT or PSMD. This may indicate that current shift work is linked with increased neurovascular risk through disrupted circadian rhythms.
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Luckey, Alison M., Saptaparni Ghosh, Rebecca Bernal, Haykel Snoussi, Angel G. Velarde, Hector Trevino, Monica Goss, et al. "PSMD, a novel biomarker of small vessel disease, and its association with cognitive function — A comprehensive clinical validation study." Alzheimer's & Dementia 19, S16 (December 2023). http://dx.doi.org/10.1002/alz.077894.
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AbstractBackgroundA recent instrumental validation analysis positioned peak‐width of skeletonized mean diffusivity (PSMD) as a biomarker for vascular contributions to cognitive impairment and dementia (VCID) with excellent reliability, repeatability, and reproducibility. As the next step of biomarker development, the current study aimed to (1) perform a clinical validation of PSMD and cognitive function in MarkVCID and three independent replication samples, and (2) assess whether PSMD explains cognitive function above and beyond white matter hyperintensities (WMH).MethodThe clinical validation of PSMD included n = 395 participants from the multi‐site MarkVCID consortium, n = 6172 from population‐based CHARGE cohorts, n = 287 from RUSH, and n = 435 from the UC Davis ADRC cohort spanning diverse ages and racial/ethnic backgrounds. PSMD was derived from DTI using an automated algorithm and further log‐transformed to normalize its distribution. A composite measure of general cognitive function was calculated from neuropsychological tests assessing at least three different cognitive domains. Linear regression models were run to determine the association between PSMD and cognitive function, adjusting for age, sex, and education. A secondary model was adjusted for vascular risk factors: hypertension, diabetes, and smoking. Lastly, both models included WMH volume to evaluate PSMD beyond WMH.ResultHigher PSMD values were associated with lower general cognitive function in the MarkVCID (Beta (95% CI), ‐0.82 (‐1.03, ‐0.61), p<0.001) in primary models, and remained unchanged after additional adjustment for vascular risk factors in secondary model (‐0.87 (‐1.09, ‐0.65), p<0.001). These findings were replicated across the CHARGE, RUSH, and UC Davis ADRC cohorts (Table 1). We further observed that PSMD explained an additional 0.2% of the variance in cognitive function beyond WMH in the youngest cohort (48.1 ±8.9 years), whereas the variance explained rose to 2.51% for the oldest cohort (76.4 ±5.2 years).ConclusionThis comprehensive clinical validation study suggests that PSMD is related to general cognition across diverse samples, potentially explaining more variation in cognitive function than a classic cerebrovascular marker such as WMH. Together, our instrumental and clinical validation studies support using PSMD as a robust biomarker with potential for risk stratification and disease monitoring in multi‐site clinical trials of VCID. Additional longitudinal validation studies are underway.
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Gokcal, Elif, J. Alex Becker, Mitchell J. Horn, Alvin S. Das, Avia Abramovitz Fouks, Kristin Schwab, Alessandro Biffi, et al. "Abstract 162: Molecular And Microstructural Alterations In Cerebral Amyloid Angiopathy-related Hemorrhagic Manifestations." Stroke 54, Suppl_1 (February 2023). http://dx.doi.org/10.1161/str.54.suppl_1.162.
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Background and Purpose: We aimed to compare the amyloid load and degree of microstructural injury among Cerebral Amyloid Angiopathy (CAA) patients with either higher lobar cerebral microbleed (CMB) counts or higher cortical superficial siderosis (cSS) extent against CAA patients with lower hemorrhagic load. Methods: The study included 38 cognitively healthy probable CAA patients with lobar intracerebral hemorrhage (ICH) and 38 age, sex-matched healthy controls (HC) who underwent advanced MRI, and Pittsburgh Compound B (PiB) PET scans. Patients were categorized into CMB-Dominant (CMB-D) and cSS-Dominant (cSS-D) based on the number and extent of CMB and cSS using previously identified cutoffs (Figure). The mean global cortical amyloid load was calculated from PiB-PET scans and represented by PiB-DVR. Within the CAA cohort, the Peak Width of Skeletonized Mean Diffusivity (PSMD) was calculated from diffusion MRIs and used as a marker of microstructural integrity. Results: Patients with CAA had significantly higher PiB-DVR than HCs (1.40±0.24 vs. 1.19±0.22, p<0.001). Both CMB-D and cSS-D CAA patients had significantly higher amyloid and increased (worse) PSMD compared to CAA patients with a non-dominant low hemorrhagic load (Figure). These results did not change in separate regression models corrected for age and sex. PiB-DVR significantly correlated with increased PSMD (r=0.346, p=0.033). Conclusions: Our findings support the view that vascular amyloid load drives higher CMB counts, more extensive cSS, and microstructural injury in patients with CAA. Furthermore, the correlations among these markers suggest that these MRI-based categorizations (CMB-D and cSS-D patients) can be used for disease staging and further research.
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Charisis, Sokratis, Meghan I. Short, Rebecca Bernal, Tiffany F. Kautz, Hector A. Treviño, Julia Mathews, Angel Gabriel Velarde Dediós, et al. "Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age." Alzheimer's & Dementia, August 12, 2024. http://dx.doi.org/10.1002/alz.13879.
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AbstractINTRODUCTIONWe 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.METHODSWe 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.RESULTSHigher 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).DISCUSSIONHigher 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.
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Luckey, Alison M., Alexa S. Beiser, Jayandra J. Himali, Carlos A. Gaona, Joy Zeynoun, Luis A. Mendez Rodriguez, Mohamad Habes, et al. "Joint Contribution of NfL and PSMD for Improved Risk Stratification of VCID." Alzheimer's & Dementia 20, S9 (December 2024). https://doi.org/10.1002/alz.093907.
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AbstractBackgroundAdvancing therapeutic and prevention strategies for vascular contributions to cognitive impairment and dementia (VCID) warrants identifying novel biomarkers. However, due to the high heterogeneity underlying dementia pathology, a single marker may not fully risk‐stratify for VCID. A blood‐based biomarker of neuroaxonal injury, neurofilament light chain (NfL), and a neuroimaging‐based biomarker of white matter microstructural damage on diffusion weighted imaging, peak width of skeletonized mean diffusivity (PSMD), have been related to worse general cognition and proposed as robust biomarkers for cerebral small vessel disease (cSVD). We investigated the joint contribution of NfL and PSMD for improved specificity/sensitivity to identify persons at risk for VCID.MethodDementia‐free participants from the Framingham Offspring Study with cognitive, neuroimaging, and NfL data were included (N = 969). NfL was measured in plasma, and PSMD was derived from MRI diffusion weighted imaging. Executive function and general cognitive function were assessed from a neuropsychological battery. NfL and PSMD were dichotomized by the top quartile and combined to indicate a high cSVD burden. The high NfL‐PSMD risk category was related to cognitive function using linear regression adjusting for age, age‐squared, sex, education, renal function (eGFR), and total intracranial volume. Additional analyses incorporating amyloid PET uptake in 64 participants were performed to discern Alzheimer’s disease pathology from VCID.ResultHigher NfL‐PSMD was significantly associated with worse executive (Beta±SE, ‐0.06±0.02, p = 0.002) and general cognitive function (‐0.15±0.07, p = 0.02). Additionally, amyloid PET over‐predicted NfL levels in those with PSMD below the median (observedpredicted, 0.06 (0.33)). Although results were not significant (p = 0.15) due to the limited sample, they suggest that amyloid pathology does not explain cSVD burden measured with NfL and PSMD.ConclusionOur findings suggest combining NfL and PSMD can better risk‐stratify those with VCID and poorer cognitive function. This NfL‐PSMD multi‐biomarker has potential to discriminate vascular dysfunction from Alzheimer’s pathology, improving identification of persons better suited for VCID clinical trials. Utilizing a multi‐biomarker approach may improve accuracy for risk stratification of persons bearing covert cerebral vascular injury. Further studies are underway to confirm these findings in larger, diverse samples.
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Fongang, Bernard, Claudia Satizabal, Tiffany F. Kautz, Yannick N. Wadop, Jazmyn A. S. Muhammad, Erin Vasquez, Julia Mathews, et al. "Cerebral small vessel disease burden is associated with decreased abundance of gut Barnesiella intestinihominis bacterium in the Framingham Heart Study." Scientific Reports 13, no. 1 (August 21, 2023). http://dx.doi.org/10.1038/s41598-023-40872-5.
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AbstractA bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimer's disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance of Pseudobutyrivibrio and Ruminococcus genera was associated with lower WMH and PSMD (p values < 0.001), as well as better executive function (p values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacterium Barnesiella intestinihominis was strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses using PICRUSt implicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and β-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.
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Schulz, Maximilian, Carola Mayer, Eckhard Schlemm, Benedikt M. Frey, Caroline Malherbe, Marvin Petersen, Jürgen Gallinat, et al. "Association of Age and Structural Brain Changes With Functional Connectivity and Executive Function in a Middle-Aged to Older Population-Based Cohort." Frontiers in Aging Neuroscience 14 (February 25, 2022). http://dx.doi.org/10.3389/fnagi.2022.782738.
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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 (MRI) (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 predefined 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.
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Pålhaugen, Lene, Bjørn‐Eivind Kirsebom, Sandra Tecelao, Jonas Alexander Jarholm, Berglind Gisladottir, Erik Christensen, Line Amundsen, et al. "CSF AβX‐34 ‐ a new biomarker for amyloid‐related small vessel pathology in early Alzheimer’s Disease." Alzheimer's & Dementia 19, S14 (December 2023). http://dx.doi.org/10.1002/alz.079964.
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AbstractBackgroundBrain small vessel disease (SVD) increases Alzheimer’s disease (AD) risk. Impaired amyloid β (Aβ) clearance is linked to amyloid plaque formation and cerebral amyloid angiopathy (CAA). Aβ1‐40 is deposited in vessel walls, and Aβ with a C‐terminal 34' cut‐point is produced by perivascular cells. Evidence for SVD‐AD interactions in early AD is elusive, but incipient CAA putatively increases susceptibility for amyloid‐related imaging abnormalities (ARIA) in AD patients.Here we compare the SVD MRI marker “peak width of skeletonized mean diffusivity” (PSMD) to cerebrospinal fluid (CSF) Aβ species and the neurodegeneration marker Neurofilament light chain (Nfl), assessing links between SVD and AD pathologies and Aβ species as potential markers for incipient CAA.MethodCross‐sectional data from the Dementia Disease Initiation (DDI) cohort were available, comprising (n = 112) cognitively normal (CN) and (n = 115) cases with mild cognitive impairment (MCI) (n = 227). CSF markers for AD A/T/N‐staging identified 134 cases with negative markers (A‐/T‐/N‐), 21 with amyloid positive markers (A+/T‐/N‐) and 72 with amyloid and tau‐positive markers (A+/T or N+) (see table 1 for sample descriptives). Multiple linear regression models were used with PSMD by lobe as the dependent variable, and NfL, Aβ1‐40 (MesoScale), Aβx‐34 (Bioventix, Pre Diagnostic) (separately) and interactions with A/T/N group as independent variables. Variables were log‐transformed and standardized.ResultHigher Nfl was related to higher PSMD independently of the Aβ species in all lobes. Although Nfl correlated with Aβ1‐40 (figure 1), no multicollinearity was observed in the model. In A+, lower Aβ markers were related to higher PSMD in all lobes, but particularly for the temporal lobe (figure 2). Aβx‐34 showed more robust relationships with PSMD in both A+ groups particularly in the temporal lobes (A+/T‐/N‐ b = .62, p = <.001, A+/T or N+ b = .52, p<.001) than Aβ1‐40. (A+/T‐/N‐ b = .66, p = <.01, A+/T or N+ b = .33, p<.001). Neither t‐ nor p‐tau measures were associated with PSMD (not shown).ConclusionNfl independently related to PSMD, possibly reflecting amyloid‐independent neurodegeneration. CSF Aβx‐34 was in particular tightly linked to increased temporal lobe PSMD even in A+/T‐/N‐, pointing to early AD‐related SVD. This supports further evaluation of Aβx‐34 as a marker for CAA and susceptibility marker for ARIA.
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Pruzin, Jeremy J., Kyle C. Kern, David M. Reboussin, William C. Cushman, Aditi Gupta, Clinton B. Wright, Jeff D. Williamson, Pierre N. Tariot, Ilya M. Nasrallah, and Nicholas M. Pajewski. "Potential Relative Effect of Intensive Systolic Blood Pressure Control on Preventing White Matter Damage Across Age Groups." Alzheimer's & Dementia 20, S2 (December 2024). https://doi.org/10.1002/alz.093113.
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AbstractBackgroundIn the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic blood pressure (SBP) lowering slowed progression of white matter injury (WMI) on MRI. We hypothesized that intensive lowering would be equally as effective and may confer greater benefits for brain health at younger ages compared to older ages. We tested whether the relative effects of intensive lowering on WMI differed by age using 2 MRI measures: white matter hyperintensity volume (WMHv) and peak‐width skeletonized mean diffusivity (PSMD) in SPRINT.MethodParticipants were age ≥50 with cardiovascular risk and randomized to intensive (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). We calculated WMHv and PSMD in a subgroup of participants who had a baseline and follow‐up MRI. WMHv were inverse‐hyperbolic sine‐transformed, and the ratio of follow‐up to baseline used to quantify progression. PSMD progression was quantified as a difference. Using mixed‐effects linear models, we estimated the effects of age on relative progression in MRI markers between groups. Age effects were investigated as categorical (<65, 65‐75, or ≥75 years) or continuous.ResultFor participants in the intensive group (n=251 with follow‐up), mean SBP was 122 mmHg versus 135 mmHg in the standard group (n=201) over a median 3.9‐year MRI interval. The largest treatment effect on WMHv progression was found in the <65 age group (i.e. greatest relative reduction with intensive treatment): ‐0.19, 95%CI [‐0.27, ‐0.11]), followed by the 65‐75 age group (‐0.11, [‐0.21, ‐0.01]), and least in the >75 age group (‐0.06, [‐0.20, ‐0.08]) (Figure 1). Intensive treatment resulted in a 73%, 52%, and 20% reduction in WMHv progression respectively, although this was not statistically significant (p=0.21). Analyses of PSMD progression produced similar results (Figure 2). When using age as a continuous measure, the beneficial effect of intensive treatment waned with increasing age (Figure 3) without reaching statistical significance (p=0.19).ConclusionIntensive SBP lowering was equally as effective and may have a greater relative effect on reducing WMI when implemented at younger ages compared to older ages. Large prospective interventional studies that include younger individuals are needed to determine the effects of SBP on white matter integrity across the lifespan.
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Pruzin, Jeremy J., Kyle C. Kern, David M. Reboussin, William C. Cushman, Aditi Gupta, Clinton B. Wright, Jeff D. Williamson, Pierre N. Tariot, Ilya M. Nasrallah, and Nicholas M. Pajewski. "Potential Relative Effect of Intensive Systolic Blood Pressure Control on Preventing White Matter Damage Across Age Groups." Alzheimer's & Dementia 20, S9 (December 2024). https://doi.org/10.1002/alz.094121.
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AbstractBackgroundIn the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic blood pressure (SBP) lowering slowed progression of white matter injury (WMI) on MRI. We hypothesized that intensive lowering would be equally as effective and may confer greater benefits for brain health at younger ages compared to older ages. We tested whether the relative effects of intensive lowering on WMI differed by age using 2 MRI measures: white matter hyperintensity volume (WMHv) and peak‐width skeletonized mean diffusivity (PSMD) in SPRINT.MethodParticipants were age =50 with cardiovascular risk and randomized to intensive (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). We calculated WMHv and PSMD in a subgroup of participants who had a baseline and follow‐up MRI. WMHv were inverse‐hyperbolic sine‐transformed, and the ratio of follow‐up to baseline used to quantify progression. PSMD progression was quantified as a difference. Using mixed‐effects linear models, we estimated the effects of age on relative progression in MRI markers between groups. Age effects were investigated as categorical (<65, 65‐75, or =75 years) or continuous.ResultFor participants in the intensive group (n=251 with follow‐up), mean SBP was 122 mmHg versus 135 mmHg in the standard group (n=201) over a median 3.9‐year MRI interval. The largest treatment effect on WMHv progression was found in the <65 age group (i.e. greatest relative reduction with intensive treatment): ‐0.19, 95%CI [‐0.27, ‐0.11]), followed by the 65‐75 age group (‐0.11, [‐0.21, ‐0.01]), and least in the >75 age group (‐0.06, [‐0.20, ‐0.08]) (Figure 1). Intensive treatment resulted in a 73%, 52%, and 20% reduction in WMHv progression respectively, although this was not statistically significant (p=0.21). Analyses of PSMD progression produced similar results (Figure 2). When using age as a continuous measure, the beneficial effect of intensive treatment waned with increasing age (Figure 3) without reaching statistical significance (p=0.19).ConclusionIntensive SBP lowering was equally as effective and may have a greater relative effect on reducing WMI when implemented at younger ages compared to older ages. Large prospective interventional studies that include younger individuals are needed to determine the effects of SBP on white matter integrity across the lifespan.
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Bauer, Christopher E., Valentinos Zachariou, Colleen Pappas, Pauline Maillard, Arvind Caprihan, Claudia L. Satizabal, and Brian T. Gold. "Healthy Dietary Intake Diminishes the Effect of Vascular Pathology on Cognitive Performance in Older Adults." Alzheimer's & Dementia 20, S2 (December 2024). https://doi.org/10.1002/alz.091804.
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AbstractBackgroundCognitive reserve (CR) in the context of Alzheimer’s’ disease has been widely studied, yet less is known about how CR protects against vascular brain pathologies. Here, we explored whether dietary factors might attenuate the association between magnetic resonance imaging (MRI)‐derived vascular biomarkers and cognition.MethodSeventy‐one older adults (ages 60‐85) were scanned using a 3‐Tesla MRI Siemens Magnetom Prisma at the University of Kentucky. Data from a 3D T1‐weighted sequence, a 3D fluid‐attenuated inversion recovery sequence, and a 126‐direction diffusion MRI sequence were acquired. The vascular biomarkers used [White Matter Hyperintensity Volume (WMHV), Free Water (FW), and Peak Width of Skeletonized Mean Diffusivity (PSMD)] were developed and validated through the MarkVCID consortium (https://markvcid.partners.org). WMHV was computed using a 4‐tissue segmentation model, mean FW in all white matter was calculated using a two‐compartment model, and PSMD was calculated as the difference between the 95th and 5th percentiles in white matter MD values. Grey matter volume (GMV; non‐vascular biomarker) and intracranial volume (ICV) were estimated using FreeSurfer. The “Newly Developed Antioxidant Nutrient Questionnaire” was used to quantify dietary‐intake for the preceding month. Nutrients were grouped into nutrition factors based on previous literature and factor analysis (Factor 1= representing fruits and vegetables; Factor 2= representing nuts, healthy oils, and fish; Factor 3= representing green tea). All participants completed the Montreal Cognitive Assessment (MoCA). Multivariate linear regression models tested whether dietary factors, vascular biomarkers, and/or their interaction (i.e. moderation) were associated with MoCA scores. All models controlled for age, sex, ICV, and education.ResultThere were no significant main effects of WMHV, FW, PSMD, or GMV on MoCA scores. However, Factor 2 (but not other factors) positively moderated all 3 vascular biomarkers [WMHV (β=0.309, p=0.009); FW (β=0.324, p=0.007); PSMD (β=0.354, p=0.008)] such that a negative association between vascular markers and MoCA scores was only present in those with low but not high Factor 2 intake (Figure 1). Factor 2 did not moderate the association between non‐vascular biomarkers (i.e. GMV) and MoCA scores.ConclusionOur results suggest that consuming more nuts, healthy oils, and fish may help protect against vascular contributions to cognitive impairment.
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Kern, Kyle C., Clinton B. Wright, and Richard Leigh. "Abstract P64: Longitudinal Brain Structural Changes After Stroke." Stroke 52, Suppl_1 (March 2021). http://dx.doi.org/10.1161/str.52.suppl_1.p64.
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Background: Stroke causes focal and diffuse structural brain changes that may contribute to subsequent cognitive decline and dementia. We hypothesize that MRI structural measures can detect continued cerebral degeneration over the first year after stroke. We identify predictors for progression of brain atrophy, leukoaraiosis and diffusion tensor imaging (DTI) metrics. Methods: Patients with ischemic stroke were enrolled prospectively in an observational study that included serial brain MRI. Patients underwent MRI FLAIR and DTI at the time of acute stroke and were followed for at least 9 months with multiple MRIs between 30 days and 15 months post-stroke. We used FLAIR to measure brain atrophy as the percent brain parenchymal fraction (BPF) of the total intracranial volume (TICV) and white matter hyperintensity volume (WMHV) as a percentage of TICV. DTI was used to calculate Peak Skeletonized Mean Diffusivity (PSMD), a global measure of white matter integrity previously validated in cerebral small vessel disease. Longitudinal changes in BPF, WMHV or PSMD were measured from 30 days post-stroke onward using linear regression models that included age, stroke volume, baseline BPF and WMHV as predictors. Results: Twenty-six patients had a median of 4 follow-ups over 9-15 months. Median age was 74 years (range 51-84) and 38% were women. Mean stroke volume was 4.5cc (0 - 30cc). Mean BPF was 78% (72 - 86%) and mean baseline WMHV was 1.1% (0.1 - 3.9%). BPF was associated with age and declined by 0.7% per year (t(111) = 2.7, p = 0.007). Progression was associated with baseline BPF (t(111) = -3.4, p < 0.001). WMHV in the non-stroke hemisphere was associated with age and increased by 0.10% per year (t(87) = -5.8, p < 0.001). Accumulation was associated with age (t(87) = 5.8, p < 0.001). PSMD was associated with baseline WMHV and had a relative increase of 1.9% per year in the non-stroke hemisphere and 4.5% in the stroke hemisphere (t(174) = -2.1, p = 0.03). Progression was associated with age (t(174) = 2.3, p = 0.03) and stroke volume (t(174) = 2.4, p = 0.02). Conclusions: During the months after ischemic stroke, BPF, WMHV and PSMD can detect persistent structural changes that may reflect later phases of stroke injury or ongoing contributions of aging, silent ischemia, or neurodegeneration.
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Raghavan, Sheelakumari, Robert I. Reid, Scott A. Przybelski, Michael G. Kamykowski, Timothy G. Lesnick, Jonathan Graff‐Radford, Val J. Lowe, et al. "Comparing regional and global diffusion MRI markers as biomarkers of VCID." Alzheimer's & Dementia 20, S9 (December 2024). https://doi.org/10.1002/alz.093870.
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AbstractBackgroundQuantifying white matter using diffusion MRI (dMRI) has been proposed for measuring early microstructural tissue changes due to cerebral small vessel disease and aid in quantifying vascular contributions to cognitive impairment and dementia (VCID). Our goal was to compare the usefulness of longitudinal white matter changes in the commonly available diffusion MRI measures for VCID prevention trials.MethodWe included 718 participants over 50 years of age (mean age: 71.1(9.6) years) from the Mayo Clinic Study of Aging, a population‐based sample, with at least two dMRI scans and structural imaging. We computed the commonly available single‐shell dMRI measures (fractional anisotropy, mean diffusivity, and two MarkVCID measures ‐ free water and peak‐width skeletonized mean diffusivity [PSMD]) at each time point. We tested for voxel‐wise associations between dMRI markers and vascular risk measured by cardiovascular metabolic condition (CMC) and observed a region‐specific dependance across all dMRI measures. Using both global and regional dMRI measures, we (i) examined the longitudinal association of dMRI measures with cognition and (ii) computed sample size estimates for a hypothetical clinical trial. We also included white matter hyperintensities (WMH) and our previously proposed composite vascular white matter score (combination of WMH and fractional anisotropy of the genu) as a comparison.ResultVascular risk was associated with all single shell dMRI measures in the genu of the corpus callosum, which we included as a regional dMRI marker for comparison (Figure 1). All dMRI markers correlated with cognitive performance longitudinally (Table 1) and had comparable sample size estimates required for hypothetical VCID clinical trials (Figure 2). Further, global free water and the composite vascular white matter score had the smallest sample size estimates.ConclusionAll commonly used dMRI markers had significant frontal lobe changes due to vascular risk. Both global and regional corpus callosum dMRI markers were sensitive to longitudinal cognitive decline, suggesting their utility in measuring the slowing down of VCID. The composite vascular white matter score, global free water, and WMH show promise as VCID biomarkers. Further work is needed to validate these markers on multiple populations.