Browsing by Author "Wang, Danny J. J."

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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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    Synergistic effects of plasma S100b levels and MRI‐based water exchange rate across the blood‐brain‐barrier on memory performance among older adults
    (Wiley, 2025-01-09) Pappas, Colleen; Zachariou, Valentinos; Bauer, Christopher E.; Sudduth, Tiffany L.; Wilcock, Donna M.; Jicha, Gregory A.; Hartz, Anika M. S.; Shao, Xingfeng; Wang, Danny J. J.; Gold, Brian T.; Neurology, School of Medicine
    Background: Non‐invasive biofluid and MRI measures of blood‐brain‐barrier (BBB) dysfunction may aid early detection of cerebral small vessel disease (cSVD). Plasma markers of astrocytic function and injury, such as S100 calcium‐binding protein B (S100b), have gained increased attention in relation to BBB integrity and cognition. Here we explored the inter‐relationships between plasma S100b levels, an MRI measure of water exchange rate across the BBB (kw), and cognitive performance among older adults. Method: The participant sample consisted of 74 older adults without dementia recruited from the University of Kentucky Sanders Brown Center on Aging. Relationships between S100b and cognition (memory, executive function) and MRI‐based BBB water exchange rate were tested. Plasma S100b levels (pg/mL) were measured using Meso Scale Discovery R‐PLEX assay at the University of Kentucky’s CCTS Biomarker Analysis Lab. Composite scores were created for memory and executive function. A diffusion‐prepared arterial spin labeling (DP‐ASL) MRI sequence was used to estimate water exchange rate across the BBB (expressed as kw). All data (S100b, cognition, MRI) were collected within 1 year of each other. Multiple linear regression models examined the impact of plasma S100b on memory, executive function, and kw. Covariates included age, gender, and education (for cognition models only). Additionally, kw was tested as moderator of the S100b‐cognition relationships using the PROCESS macro. Result: A negative relationship was observed between S100b and memory, where higher S100b levels were associated with poorer memory performance. A similar relationship was not observed with executive function. S100b was also not associated with kw. However, there was an interaction between S100b levels and kw in the parietal lobe on memory performance such that participants with both lower parietal kw and higher S100b showed the poorest memory performance. Conclusion: Our results indicate that S100b levels are negatively associated with memory performance, but not MRI‐based BBB kw. However, higher S100b levels coupled with lower MRI‐based water exchange rate further contributed to the strong negative effects observed for memory performance. This suggests that plasma S100b and BBB kw may be different proxies of BBB function and may have synergistic negative effects on cognition.