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Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

ABSTRACT: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-? and Tau. Additionally, we explore whether any such association differs by sex or APOE ?4 genotype.From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n?=?45), amnestic mild cognitive impairment (n?=?44), or AD (n?=?49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-?1-42, total (t-)Tau, and phosphorylated (p-)Tau.CSF insulin levels did not differ between the diagnostic groups (p?=?0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p?0.131). Importantly, however, we observed effect modification by sex and APOE ?4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p?=?0.008) and higher p-Tau levels (0.353; p?=?0.040). Among non-carriers of the APOE ?4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p?=?0.008) and p-Tau (0.246; p?=?0.029).Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ?4 genotype when assessing the role of insulin.

SUBMITTER: Geijselaers SLC

PROVIDER: S-EPMC5734123 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

Geijselaers Stefan L C SLC Aalten Pauline P Ramakers Inez H G B IHGB De Deyn Peter Paul PP Heijboer Annemieke C AC Koek Huiberdina L HL OldeRikkert Marcel G M MGM Papma Janne M JM Reesink Fransje E FE Smits Lieke L LL Stehouwer Coen D A CDA Teunissen Charlotte E CE Verhey Frans R J FRJ van der Flier Wiesje M WM Biessels Geert Jan GJ

Journal of Alzheimer's disease : JAD 20180101 1

<h4>Background</h4>Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).<h4>Objective</h4>To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.<h4>Methods</h4>From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we ...[more]

PMID: 29154275

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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.

Dataset Information

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

Publications

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

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