Browsing by Subject "Vascular contributions to cognitive impairment and dementia (VCID)"

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    Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia
    (Wiley, 2025-01-09) Kautz, Tiffany F.; Mathews, Julia J.; Bernal, Rebecca; Wang, Chen-Pin; Liu, Qianqian; Gonzales, Mitzi M.; Tracy, Russell P.; Parent, Danielle; Wilcock, Donna M.; Sudduth, Tiffany L.; Wang, Danny J. J.; Sagare, Abhay P.; Rosenberg, Gary A.; Lu, Hanzhang; Kramer, Joel H.; Decarli, Charles; Jin, Lee-Way; Maillard, Pauline; Singh, Herpreet; Schwab, Kristin; Helmer, Karl; Greenberg, Steven M.; Kivisäkk, Pia; Aparicio, Hugo J.; Beiser, Alexa S.; Ghosh, Saptaparni; Fornage, Myriam; Mosley, Thomas H.; Mbangdadji, Djass; Launer, Lenore J.; Gudnason, Vilmundur; Bis, Josh; Psaty, Bruce M.; Seshadri, Sudha; Satizabal, Claudia L.; Neurology, School of Medicine
    Background: The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort. Method: Plasma NfL was measured using HD‐X and HD‐1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). Result: We found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in test‐retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD‐X and HD‐1; R2≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=‐0.23; [95% CI ‐0.41; ‐0.01), CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.17; ‐0.06]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC. Conclusion: We have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.
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    Selective sex‐based differences in the association between angiogenic and Alzheimer’s Disease biomarkers in a preliminary cohort of rrAD participants
    (Wiley, 2025-01-09) Lutshumba, Jenny; Wilcock, Donna M.; Lee, Tiffany; Zhu, David C.; Scheel, Norman; German, Dwight C.; Zhang, Rong; Trout, Amanda; Stowe, Ann M.; Neurology, School of Medicine
    Background: Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD) are the two most common forms of dementia, with overlapping risk factors including cardiovascular risk factors such as hypertension and dyslipidemia. The etiology of both VCID and AD shows sex‐based differences, as well as sex‐based differences in cardiovascular risk factors. However, how sex differences influence AD and angiogenic biomarkers in older adults who have high cardiovascular risk factors is not known. Method: AD and angiogenic biomarkers for VCID were measured from the plasma of a subgroup (n=96) of participants from the ‘risk reduction for Alzheimer’s disease’ (rrAD) two‐year clinical trial (NCT02913664; completed Jan. 2022; n=513 total participants). rrAD participants had a family history of dementia or subjective memory complaints, hypertension, and dyslipidemia. The subgroup in the study included 31 males and 65 females (aged: 71‐85). Baseline values for AD biomarkers: Total tau, pTau181, Aβ40, and Aβ42, angiogenic biomarkers: Tie‐2, VEGF‐A, VEGF‐C, VEGFR1, and VCID biomarkers: bFGF, VEGF‐D, PlGF were analyzed using Meso Scale Discovery (MSD). Nonparametric analysis evaluated the sex differences in biomarkers, linear regression evaluated the relationship between AD biomarkers and angiogenic biomarkers in both sexes. Result: We found sex‐based differences in AD biomarkers such that females had a higher expression in Total tau and Total tau/Aβ42 (p=0.0021, p=0.0003, respectively) while pTau181 was higher in males (p=0.0216). pTau181/ Aβ42 and Aβ42/40 ratios showed no sex differences, nor did baseline angiogenic biomarkers. There was, however, a selective sex difference in the association between angiogenic and AD biomarkers. In females, Total tau is associated with VEGF‐D (R2= 0.0746, p=0.0277), and Tau/Aβ42 is associated with VEGF‐A and VEGFR‐1(R2= 0.0747, p=0.0275; R2= 0.0973, p=0.0114, respectively). In males, pTau181 and pTau181/Aβ42 are associated with VEGF‐D (R2= 0.2637, p=0.0031; R2= 0.1799, p=0.0174, respectively), Aβ42/Aβ40 is associated with VEGF‐C (R2= 0.1491, p=0.0319), and Tau/Aβ42 is associated with bFGF (R2= 0.1458, p=0.0340). Conclusion: There is a selective sex‐based difference in plasma AD biomarkers and their association with angiogenic biomarkers in this preliminary cohort of older adults with high risks of developing Alzheimer’s disease and related dementias.