| 3. |
- Cicognola, C., et al.
(författare)
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Associations of CSF PDGFR & beta; With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes
- 2023
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Ingår i: NEUROLOGY. - 0028-3878. ; 101:1
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesInjured pericytes in the neurovascular unit release platelet-derived growth factor & beta; (PDGFR & beta;) into the CSF. However, it is not clear how pericyte injury contributes to Alzheimer disease (AD)-related changes and blood-brain barrier (BBB) damage. We aimed to test whether CSF PDGFR & beta; was associated with different AD-associated and age-associated pathologic changes leading to dementia.MethodsPDGFR & beta; was measured in the CSF of 771 participants with cognitively unimpaired (CU, n = 408), mild cognitive impairment (MCI, n = 175), and dementia (n = 188) from the Swedish BioFINDER-2 cohort. We then checked association with & beta;-amyloid (A & beta;)-PET and tau-PET standardized uptake value ratio, APOE & epsilon;4 genotype and MRI measurements of cortical thickness, white matter lesions (WMLs), and cerebral blood flow. We also analyzed the role of CSF PDGFR & beta; in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb), and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes).ResultsThe cohort had a mean age of 67 years (CU = 62.8, MCI = 69.9, dementia = 70.4), and 50.1% were male (CU = 46.6%, MCI = 53.7%, dementia = 54.3%). Higher CSF PDGFR & beta; concentrations were related to higher age (b = 19.1, & beta; = 0.5, 95% CI 16-22.2, p < 0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b = 3.4, & beta; = 0.5, 95% CI 2.8-3.9, p < 0.001), GFAP (b = 27.4, & beta; = 0.4, 95% CI 20.9-33.9, p < 0.001), and worse BBB integrity measured by QAlb (b = 37.4, & beta; = 0.2, 95% CI 24.9-49.9, p < 0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFR & beta; and neuroinflammatory markers (16%-33% of total effect). However, PDGFR & beta; showed no associations with APOE & epsilon;4 genotype, PET imaging of A & beta; and tau pathology, or MRI measures of brain atrophy and WMLs (p > 0.05).DiscussionIn summary, pericyte damage, reflected by CSF PDGFR & beta;, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathologic changes.
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| 4. |
- Leuzy, A., et al.
(författare)
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Robustness of CSF A beta 42/40 and A beta 42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 2994-3004
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThis study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (A beta)42/A beta 40 or A beta 42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., A beta-positron emission tomography [PET] visual read and AD neuropathology). MethodsWe studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (A beta-PET visual read as outcome). Using longitudinal variability in A beta-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. ResultsFor A beta 42/A beta 40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For A beta 42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was approximate to 90% for both A beta 42/A beta 40 and A beta 42/p-tau181 using these cutoffs. Using A beta-PET as an outcome, 8.7% of participants fell within a gray zone interval for A beta 42/A beta 40, compared to 4.5% for A beta 42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma A beta 42/40, the number of individuals within the gray zone was approximate to 1.5 to 3 times greater when using plasma A beta 42/40. DiscussionCSF A beta 42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.
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