Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aβ and tau levels. While multiple previous studies identified non-Aβ, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis. Here we analyzed nine promising neurodegenerative markers in a three-centered cohort using independent assays to identify candidates most likely to complement Aβ and tau in the A/T/N framework.MethodsCSF samples from 125 subjects recruited at the three centers were exchanged such that each of the nine previously identified biomarkers can be measured at one of the three centers. Subjects were classified according to cognitive status and CSF AD biomarker profiles as having normal cognition and normal CSF (n = 31), normal cognition and CSF consistent with AD (n = 13), mild cognitive impairment and normal CSF (n = 13), mild cognitive impairment with CSF consistent with AD (n = 23), AD dementia (n = 32; CSF consistent with AD), and other non-AD dementia (n = 13; CSF not consistent with AD).ResultsThree biomarkers were identified to differ among the AD stages, including neurofilament light chain (NfL; p < 0.001), fatty acid binding protein 3 (Fabp3; p < 0.001), and interleukin (IL)-10 (p = 0.033). Increased NfL levels were most strongly associated with the dementia stage of AD, but increased Fabp3 levels were more sensitive to milder AD stages and correlated with both CSF tau markers. IL-10 levels did not correlate with tau biomarkers, but were associated with rates of longitudinal cognitive decline in mild cognitive impairment due to AD (p = 0.006). Prefreezing centrifugation did not influence measured CSF biomarker levels.ConclusionCSF proteins associated with AD clinical stages and progression can complement Aβ and tau markers to inform neurodegeneration. A validated panel inclusive of multiple biomarker features (etiology, stage, progression) can improve AD phenotyping along the A/T/N framework.

Interleukin 9 alterations linked to alzheimer disease in african americans

“…In our laboratory, we achieve average intermediate precision (over experiments performed over 9 days) of 9.4% for TNF-α, 12.9% for MDC, 14.7% for IL-7, 4.8% for IP-10, 12.0% for IL-10, 9.2% for IL-9, and 7.6% for IL-8. Freeze-thawing experiments 23 using CSF from 6 separate subjects showed significant degradation over two freeze-thaw cycles for MDC and TNF-α (p=0.021 and p=0.012 for slope in exponential decay), and we previously showed light centrifugation 21 to have minimal impact on these CSF cytokine levels.…”

“…On the other hand, Th2-related IL-4 levels were too low for detection in this cohort, and Th2/Th9-related IL-10 levels did not differ according to race or cognition in the older cohort (consistent with previously reported U-shaped curve for IL-10). 21 Thus, while AD was associated with increased Th9 activity only in African Americans, it may be associated with decreased Th1 activity only in Caucasians.…”

“…We previously prospectively determined that 2,000 rpm centrifugation did not influence cytokine levels measured here. 21 …”

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

“…Combinations of synaptic degeneration markers (e.g., neurogranin, synaptosomal-associated protein 25, and VILIP-1) with the inflammation marker YKL-40 revealed a remarkable and differential longitudinal change across the clinical spectrum of AD patients 9 . This finding suggests that specific biomarkers become more useful at particular disease stages 9,72,80 . Therefore, synaptic, axonal, and inflammation-related biomarkers are complementary to each other in terms of staging AD and predicting clinical progression, in addition to representing different aspects of AD-related brain pathology.…”

Neurofilaments: The C-Reactive Protein of Neurology

“…Given that cognitive impairment and particularly frontotemporal dementia (FTD) can be found in up to 10%-15% of patients with ALS [123], it is interesting that in this particular form of dementia, blood and CSF NF-L levels are associated with functional outcome, brain atrophy, and severity, and can be used to discern FTD from other types of dementia and healthy controls but not be used to distinguish between FTD subtypes [124][125][126]. However, the use of varied biomarker panels comprised of NF-L, total and phosphorylated tau, and Aβ 1-42 improved discrimination between AD dementia, FTD, and some other types of dementia [118,127,128] and increased sensitivity in AD stage differentiation using NF-L and fatty acid binding protein 3 [129]. A panel of biomarkers that includes proteins involved in the pathogenic mechanisms of dementia helps improve diagnosis and clinical staging of the disease.…”