Instrumental and biological validation of PSMD as a VCID biomarker

Abstract Background Peak‐width of skeletonized mean diffusivity (PSMD) is an emerging biomarker of cerebral small vessel disease (cSVD)‐related vascular contributions to cognitive impairment and dementia (VCID). Higher PSMD values reflect greater white matter microstructural damage, and prior research has related PSMD to sporadic and monogenic forms of cSVD and worse cognitive function. Therefore, we proposed PSMD as a risk stratification biomarker for VCID. This study aimed to perform a rigorous instrumental and biological validation for PSMD in the MarkVCID‐1 consortium. Method Methods to derive PSMD were packaged in a kit containing a protocol, scripts, and instructions. The instrumental validation included a pre‐specified plan to assess inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility among MarkVCID‐1 participants aged 53‐78 years across the spectrum of cSVD. We used intra‐class correlations for absolute agreement (ICC AA ) and consistency (ICC C ) to evaluate results, with ICC>0.07 as the pre‐specified goal. The biological validation was performed on 7,289 participants of diverse ages and racial/ethnic backgrounds from MarkVCID‐1 and population‐based cohorts from CHARGE, RUSH, and UCD‐ADRC. All sites derived a composite measure of general cognitive function using neuropsychological tests assessing distinct cognitive domains. Finally, we used linear regression models to assess the association between log‐PSMD and general cognition adjusting for age, age 2 , sex, and education. Result Our instrumental validation results (Figure 1) showed excellent reliability between raters from seven sites (overall ICC AA =0.945, P<0.001), agreement between test and retest measurements obtained within two weeks (ICC AA =0.986, P<0.001), and reproducibility across Philips Achieva, Siemens Prisma, and Siemens Trio scanners (ICC C = 0.954, P<0.001). In the biological validation, higher PSMD values were associated with lower general cognitive function in MarkVCID‐1 (Beta=‐0.82, P<0.001), and these findings were replicated across the CHARGE, RUSH, and UCD‐ADRC cohorts (Table 1). Conclusion Our rigorous instrumental validation study showed excellent inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility for the PSMD kit. We further observed strong associations between higher PSMD values and poorer cognitive function across diverse samples in the biological validation. Taken together, our findings support using PSMD as a robust risk stratification biomarker in multi‐site clinical trials of VCID. Additional longitudinal validation studies for PSMD are underway in MarkVCID‐2.

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Journal
Alzheimer s & Dementia
Published
2024-12-01
DOI
https://doi.org/10.1002/alz.086590
Primary Topic
Cardiovascular Disease and Adiposity
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article
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article

Instrumental and biological validation of PSMD as a VCID biomarker

Vilmundur Guðnason, Brian T. Gold, Alison M. Luckey, Sudha S. Seshadri et al.
Alzheimer s & Dementia
Cardiovascular Disease and Adiposity
article

Instrumental and biological validation of PSMD as a VCID biomarker

Vilmundur Guðnason, Brian T. Gold, Alison M. Luckey, Sudha S. Seshadri, Christopher E. Bauer, Adam M. Staffaroni, Monica Goss, Lenore J. Launer, Mohamad Habes, Hanzhang Lu, Joel H. Kramer, Lara Stables, Arvind Caprihan, Lars A. Forsberg, Laura J. Hillmer, Chen‐Pin Wang, Konstantinos Arfanakis, Djass Mbangdadji, Pauline Maillard, Gary A. Rosenberg, Kristin Schwab, Steven Mark Greenberg, Alexa S. Beiser, Danny J.J. Wang, Baljeet Singh, Charles DeCarli, Hector Trevino, Herpreet Singh, Thomas H. Mosley, Saptaparni Ghosh, Karl G. Helmer, Myriam Fornage, Zhiguang Li, Angel G. Velarde, Claudia L. Satizábal, Marilyn S. Albert, Jayandra J. Himali, Rebecca Bernal
article en

Abstract

Abstract Background Peak‐width of skeletonized mean diffusivity (PSMD) is an emerging biomarker of cerebral small vessel disease (cSVD)‐related vascular contributions to cognitive impairment and dementia (VCID). Higher PSMD values reflect greater white matter microstructural damage, and prior research has related PSMD to sporadic and monogenic forms of cSVD and worse cognitive function. Therefore, we proposed PSMD as a risk stratification biomarker for VCID. This study aimed to perform a rigorous instrumental and biological validation for PSMD in the MarkVCID‐1 consortium. Method Methods to derive PSMD were packaged in a kit containing a protocol, scripts, and instructions. The instrumental validation included a pre‐specified plan to assess inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility among MarkVCID‐1 participants aged 53‐78 years across the spectrum of cSVD. We used intra‐class correlations for absolute agreement (ICC AA ) and consistency (ICC C ) to evaluate results, with ICC>0.07 as the pre‐specified goal. The biological validation was performed on 7,289 participants of diverse ages and racial/ethnic backgrounds from MarkVCID‐1 and population‐based cohorts from CHARGE, RUSH, and UCD‐ADRC. All sites derived a composite measure of general cognitive function using neuropsychological tests assessing distinct cognitive domains. Finally, we used linear regression models to assess the association between log‐PSMD and general cognition adjusting for age, age 2 , sex, and education. Result Our instrumental validation results (Figure 1) showed excellent reliability between raters from seven sites (overall ICC AA =0.945, P<0.001), agreement between test and retest measurements obtained within two weeks (ICC AA =0.986, P<0.001), and reproducibility across Philips Achieva, Siemens Prisma, and Siemens Trio scanners (ICC C = 0.954, P<0.001). In the biological validation, higher PSMD values were associated with lower general cognitive function in MarkVCID‐1 (Beta=‐0.82, P<0.001), and these findings were replicated across the CHARGE, RUSH, and UCD‐ADRC cohorts (Table 1). Conclusion Our rigorous instrumental validation study showed excellent inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility for the PSMD kit. We further observed strong associations between higher PSMD values and poorer cognitive function across diverse samples in the biological validation. Taken together, our findings support using PSMD as a robust risk stratification biomarker in multi‐site clinical trials of VCID. Additional longitudinal validation studies for PSMD are underway in MarkVCID‐2.

Alzheimer s & DementiaVol. 20(S2)
Boston University (US), University of Southern California (US), Uppsala University (SE), Rush University Medical Center (US), Mind Research Network (US), Harvard University (US), University of Kentucky (US), Johns Hopkins University (US), The University of Texas at San Antonio Health Science Center (US), University of New Mexico (US), University of California, San Francisco (US), Johns Hopkins Medicine (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Massachusetts General Hospital (US), University Memory and Aging Center (US), Alzheimer’s Disease Neuroimaging Initiative (US), Institute for Neurodegenerative Disorders (US), Athinoula A. Martinos Center for Biomedical Imaging (US), Brown Foundation (US), National Institute on Aging (US), Icelandic Heart Association (IS), University of California, Davis (US), The University of Texas Health Science Center at Houston (US)
Quality Education
Openalex Percentile: Top 55%
Cardiovascular Disease and Adiposity
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