Higher was associated with lower general cognition (Beta -0.8, P < 0.001).
PSMD, a marker derived from neuroimaging, reflects cerebral small vessel disease.
The relationship between PSMD and cognitive function was observed in a sample of 396 participants and replicated in three additional cohorts.
The findings indicate that PSMD may provide insights into cognitive impairment independent of other factors like age and education.
PSMD accounted for cognitive status beyond the influence of .
Simplified
BACKGROUND: (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD.
METHODS: We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID-1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimer's Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders.
RESULTS: Higher PSMD was associated with lower general cognition in MarkVCID-1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], -0.8 [-1.2, -0.4], P < 0.001). These findings were replicated in independent samples. Furthermore, PSMD explained cognitive status above and beyond .
DISCUSSION: Our biological validation work supports the pursuit of larger clinical validation studies evaluating PSMD as a susceptibility/risk biomarker of small vessel disease contributing to cognitive impairment and dementia.
HIGHLIGHTS: Peak-width of skeletonized mean diffusivity (PSMD) is a novel small vessel disease neuroimaging biomarker. A prior instrumental validation study demonstrated that PSMD is a robust biomarker. This biological validation study shows that high PSMD relates to worse cognition. PSMD explains cognitive function above and beyond white matter hyperintensities. Future clinical validation will assess PSMD as a vascular contribution to cognitive impairment and dementia biomarker in clinical trials.
Key numbers
-0.8
Decrease in Cognitive Function
Beta coefficient from MarkVCID-1 cohort analysis.
396
Participants in MarkVCID-1
Total number of participants analyzed in the study.
1.8%
Variance Explained by
Percentage of variance in cognitive function explained by in MarkVCID-1.
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Dr. Luckey, Dr. Ghosh, Ms. Bernal, Dr. Chen‐Pin Wang, Dr. Fadaee, Dr. Snoussi, Mr. Velarde Dediós, Mr. Trevino, Dr. Goss, Ms. Hillmer, Dr. Lu, Dr. Gold, Dr. Bauer, Dr. Stables, Dr. Danny J.J. Wang, Dr. Beiser, Dr. Fornage, Dr. Mosley, Dr. Launer, Dr. Guðnason, Dr. Rosenberg, Mr. Baljeet Singh, Herpreet Singh, Ms. Schwab, Dr. Helmer, Dr. Himali, Dr. Caprihan, Dr. Maillard, and Dr. Satizabal have no conflicts of interest to report. Dr. Arfanakis is on the advisory board for an External Advisory Committee, NIH‐funded clinical research study titled “Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY Network (DISCOVERY).” Dr. Staffaroni is a consultant to Alector, Lilly/Prevail, Passage Bio, and Takeda. He receives licensing fees as the developer of digital cognitive tests not used in this study. Dr. Kramer has received royalties from Pearson, Inc. Dr. Greenberg is a consultant for Roche (payment to Dr. Greenberg), Washington University/IQVIA (payment to Dr. Greenberg), Bayer (payment to Dr. Greenberg), and Biogen (payment to Dr. Greenberg), and receives royalties or licenses from Up‐To‐Date (payment to Dr. Greenberg). Dr. Habes is a consultant for Biogen on ARIA. Dr. Seshadri is a consultant for Biogen. Dr. DeCarli is a consultant to Novartis on a safety trial for heart failure. Author disclosures are available in the supporting information.
