title: Neuronal Pentraxin 2 predicts medial temporal atrophy and memory decline across the Alzheimer's disease spectrum.
abstract: Chronic neuroinflammation is thought to potentiate medial temporal lobe (MTL) atrophy and memory decline in Alzheimer's disease (AD). It has become increasingly important to find novel immunological biomarkers of neuroinflammation or other processes that can track AD development and progression. Our study explored which pro- or anti-inflammatory cerebrospinal fluid (CSF) biomarkers best predicted AD neuropathology over 24months. Using Alzheimer's Disease Neuroimaging Initiative data (N=285), CSF inflammatory biomarkers from mass spectrometry and multiplex panels were screened using stepwise regression, followed up with 50%/50% model retests for validation. Neuronal Pentraxin 2 (NPTX2) and Chitinase-3-like-protein-1 (C3LP1), biomarkers of glutamatergic synaptic plasticity and microglial activation respectively, were the only consistently significant biomarkers selected. Once these biomarkers were selected, linear mixed models were used to analyze their baseline and longitudinal associations with bilateral MTL volume, memory decline, global cognition, and established AD biomarkers including CSF amyloid and tau. Higher baseline NPTX2 levels corresponded to less MTL atrophy [R2=0.287, p<0.001] and substantially less memory decline [R2=0.560, p<0.001] by month 24. Conversely, higher C3LP1 modestly predicted more MTL atrophy [R2=0.083, p<0.001], yet did not significantly track memory decline over time. In conclusion, NPTX2 is a novel pro-inflammatory cytokine that predicts AD-related outcomes better than any immunological biomarker to date, substantially accounting for brain atrophy and especially memory decline. C3LP1 as the microglial biomarker, by contrast, performed modestly and did not predict longitudinal memory decline. This research may advance the current understanding of AD etiopathogenesis, while expanding early diagnostic techniques through the use of novel pro-inflammatory biomarkers, such as NPTX2. Future studies should also see if NPTX2 causally affects MTL morphometry and memory performance.
authors.affiliation: Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, United States.
authors.forename: Ashley
authors.initials: A
authors.lastname: Swanson
authors.affiliation: Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, United States; Department of Psychology, Iowa State University, Ames, IA, United States; Aging Mind and Brain Institute, University of Iowa, Iowa City, IA, United States. Electronic address: awillett@iastate.edu.
authors.forename: A A
authors.initials: AA
authors.lastname: Willette
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000209:etiology / Q000473:pathology* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001284:Atrophy; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002097:C-Reactive Protein / Q000134:cerebrospinal fluid*; D000071451:Chitinase-3-Like Protein 1 / Q000134:cerebrospinal fluid; D004660:Encephalitis / Q000134:cerebrospinal fluid* / Q000150:complications; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000134:cerebrospinal fluid*; D009483:Neuropsychological Tests; D013702:Temporal Lobe / Q000473:pathology*; D016875:tau Proteins / Q000134:cerebrospinal fluid; D000099153:Pentraxins
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D002097:C-Reactive Protein; D000071451:Chitinase-3-Like Protein 1; D009419:Nerve Tissue Proteins; D016875:tau Proteins; D000099153:Pentraxins; C054369:MAPT protein, human
keywords: Alzheimer’s disease; Amyloid; Biomarkers; C3LP1; Immunology; Inflammation; Medial temporal lobe; Memory; NPTX2; Tau