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Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

ABSTRACT: INTRODUCTION:Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS:CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS:The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION:Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

SUBMITTER: Schindler SE

PROVIDER: S-EPMC6511459 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

Schindler Suzanne E SE Li Yan Y Todd Kaitlin W KW Herries Elizabeth M EM Henson Rachel L RL Gray Julia D JD Wang Guoqiao G Graham Danielle L DL Shaw Leslie M LM Trojanowski John Q JQ Hassenstab Jason J JJ Benzinger Tammie L S TLS Cruchaga Carlos C Jucker Mathias M Levin Johannes J Chhatwal Jasmeer P JP Noble James M JM Ringman John M JM Graff-Radford Neill R NR Holtzman David M DM Ladenson Jack H JH Morris John C JC Bateman Randall J RJ Xiong Chengjie C Fagan Anne M AM

Alzheimer's & dementia : the journal of the Alzheimer's Association 20190304 5

<h4>Introduction</h4>Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).<h4>Methods</h4>CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations.<h4>Results</h4>The four emerging CSF biomarkers were significantly elevated in t ...[more]

PMID: 30846386

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Project description:Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.CSF neurogranin and YKL-40 were measured in a cohort of 338 individuals including cognitively healthy controls and patients with stable mild cognitive impairment (sMCI), MCI who later developed AD (MCI-AD), AD dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTD). The diagnostic accuracy of neurogranin and YKL-40 were compared with the core AD biomarkers, β-amyloid (Aβ42 and Aβ40) and tau.Neurogranin levels were increased in AD and decreased in non-AD dementia compared with healthy controls. As a result, AD patients showed considerably higher CSF levels of neurogranin than DLB/PDD, VaD and FTD patients. CSF YKL-40 levels were increased in AD compared with DLB/PDD but not with VaD or FTD. Neither CSF neurogranin nor YKL-40 levels differed significantly between sMCI patients and MCI-AD patients. Both biomarkers correlated positively with CSF Aβ40 and tau. CSF neurogranin and YKL-40 could separate AD dementia from non-AD dementias (neurogranin, area under the curve [AUC] = 0.761; YKL-40, AUC = 0.604; Aβ42/neurogranin, AUC = 0.849; Aβ42/YKL-40, AUC = 0.785), but the diagnostic accuracy was not better compared to CSF Aβ and tau (Aβ42, AUC = 0.755; tau AUC = 0.858; Aβ42/tau, AUC = 0.895; Aβ42/Aβ40, AUC = 0.881). Similar results were obtained when separating sMCI from MCI-AD cases.CSF neurogranin and YKL-40 do not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to the core CSF AD biomarkers. Nevertheless, the CSF level of neurogranin is selectively increased in AD dementia, whereas YKL-40 is increased in both AD and FTD suggesting that synaptic degeneration and glial activation may be important in these neurodegenerative conditions.

Project description:ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid-β 1 to 42 (Aβ42 ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models.ResultsWe found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1-3,297.0; p < 0.05-0.001) and a moderate-to-strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50-0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ42 at baseline and these patients with PD had lower p-tau levels (median = 10.8 pg/mL; range = 8.0-32.8) compared with 27.7% of HCs with pathologically low CSF Aβ42 (CSF p-tau median = 12.8 pg/mL; range 8.2-73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ42 (mean difference = -41.83 pg/mL; p = 0.03) and CSF p-tau (mean difference = -0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.InterpretationOur data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3-year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574-587.

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Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

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Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

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