Enhancing cognitive performance prediction by white matter hyperintensity connectivity assessment
Marvin Petersen, Mirthe Coenen, Charles DeCarli, Alberto De Luca, Ewoud van der Lelij, Alzheimer’s Disease Neuroimaging Initiative, Michael Weiner, Paul Aisen, Ronald Petersen, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack, William J. Jagust, Susan Landau, Monica Rivera-Mindt, Ozioma Okonkwo, Leslie M. Shaw, Edward B. Lee, Arthur W. Toga, Laurel Beckett, Danielle Harvey, Robert C Green, Andrew J. Saykin, Kwangsik Nho, Richard J. Perrin, Duygu Tosun, Pallavi Sachdev, Robert C Green, Erin Drake, Tom Montine, Cat Conti, Michael W Weiner, Rachel L. Nosheny, Diana Truran Sacrey, Juliet Fockler, Melanie J. Miller, Catherine Conti, Winnie Kwang, Chengshi Jin, Adam Diaz, Miriam T. Ashford, Derek Flenniken, Ronald Petersen, Paul Aisen, Michael S. Rafii, Rema Raman, Gustavo Jiménez, Michael Donohue, Jennifer Salazar, Andrea Fidell, Virginia Boatwright, Justin Robison, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Taylor Clanton, Elizabeth Shaffer, Caitlin Webb, Lindsey Hergesheimer, Stephanie Smith, Sheila Ogwang, Olusegun Adegoke, Payam Mahboubi, Jeremy Pizzola, Cecily Jenkins, Laurel Beckett, Danielle Harvey, Michael Donohue, Naomi Saito, Adam Diaz, Kedir Adem Hussen, Ozioma Okonkwo, Monica Rivera-Mindt, Hannatu Amaza, Mai Seng Thao, Shaniya Parkins, Omobolanle Ayo, Matt Glittenberg, Isabella Hoang, Kaori Kubo Germano, Joe Strong, Trinity Weisensel, Fabiola Magana, Lisa Thomas, Vanessa Guzmán, Adeyinka Ajayi, Joseph Di Benedetto, Sandra Talavera, Clifford R Jack, Joel P. Felmlee, Nick C. Fox, Paul M. Thompson, Charles DeCarli, Arvin Forghanian-Arani, Bret Borowski, Calvin Reyes, Caitie Hedberg, Chad Ward, Christopher G. Schwarz
Abstract
White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.