Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD). Methods: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing. Results: In AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles. Conclusion: We report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.
IMPORTANCE Neuronal and axonal destruction are hallmarks of neurodegenerativa diseases, but it is difficult to estimate the extent and progress of the damage in the disease process. OBJECTIVE To Investigate cerebrospinal fluid (CSF) levels of neurofllament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine Its association with longitudinal cognitive decline. DESIGN, SETTING, AND PARTICIPANTS In this case-control study, we Investigated NFL levels In CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016. EXPOSURES Concentrations of NFL in CSF. MAIN OUTCOMES AND MEASURES Levels of CSF NFL and correlations with cognition scores. RESULTS A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398–777] pg/mL), participants with MCI (831 [526–1075] pg/mL), and those with Alzheimer disease (951 [758–1261] pg/mL), indicating that NFL levels increase with Increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, −0.19; P < .001) in the full cohort (n = 822) and annual score decline in the full cohort (ρ, 0.36, P < .001), participants with AD (ρ, 0.25; P < .001), and participants with FTD (ρ, 0.46; P = .003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207–7453] pg/mL) and frontotemporal dementia (2094 [230–7744] pg/mL). In Individuals with parkinsonian disorders, NFL concentrations were highest In those with progressive supranuclear palsy (median [range], 1578 [1287–3104] pg/mL) and corticobasal degeneration (1281 [828–2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau Increased accuracy of discrimination of diseases. CONCLUSIONS AND RELEVANCE Levels of CSF NFL are associated with cognitive Impairments In patients with Alzheimer disease and frontotemporal dem...
Previous studies of Aβ plasma as a biomarker for Alzheimer’s disease (AD) obtained conflicting results. We here included 715 subjects with baseline Aβ1–40 and Aβ1–42 plasma measurement (50% with 4 serial annual measurements): 205 cognitively normal controls (CN), 348 patients mild cognitive impairment (MCI) and 162 with AD. We assessed the factors that modified their concentrations and correlated these values with PIB PET, MRI and tau and Aβ1–42 measures in cerebrospinal fluid (CSF). Association between Aβ and diagnosis (baseline and prospective) was assessed. A number of health conditions were associated with altered concentrations of plasma Aβ. The effect of age differed according to AD stage. Plasma Aβ1–42 showed mild correlation with other biomarkers of Aβ pathology and were associated with infarctions in MRI. Longitudinal measurements of Aβ1–40 and Aβ1–42 plasma levels showed modest value as a prognostic factor for clinical progression. Our longitudinal study of complementary measures of Aβ pathology (PIB, CSF and plasma Aβ) and other biomarkers in a cohort with an extensive neuropsychological battery is significant because it shows that plasma Aβ measurements have limited value for disease classification and modest value as prognostic factors over the 3-year follow-up. However, with longer follow-up, within subject plasma Aβ measurements could be used as a simple and minimally invasive screen to identify those at increased risk for AD. Our study emphasizes the need for a better understanding of the biology and dynamics of plasma Aβ as well as the need for longer term studies to determine the clinical utility of measuring plasma Aβ.
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