title: Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals.
abstract: We aimed to identify cerebrospinal fluid (CSF) biomarkers associated with neurodegeneration in individuals with and without CSF evidence of Alzheimer pathology. We investigated 287 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (age=74.9±6.9; 22/48/30% with Alzheimer's disease/mild cognitive impairment/controls) with CSF multiplex analyte data and serial volumetric MRI. We calculated brain and hippocampal atrophy rates, ventricular expansion and Mini Mental State Examination decline. We used false discovery rate corrected regression analyses to assess associations between CSF variables and atrophy rates in individuals with and without amyloid pathology, adjusting in stages for tau, baseline volume, p-tau, age, sex, ApoE4 status and diagnosis. Analytes showing statistically significant independent relationships were entered into reverse stepwise analyses. Adjusting for tau, baseline volume, p-tau, age, sex and ApoE4, 4/83 analytes were significantly independently associated with brain atrophy rate, 1/83 with ventricular expansion and 2/83 with hippocampal atrophy. The strongest CSF predictor for the three atrophy measures was low trefoil factor 3 (TFF3). High cystatin C (CysC) was associated with higher whole brain atrophy and hippocampal atrophy rates. Lower levels of vascular endothelial growth factor and chromogranin A (CrA) were associated with higher whole brain atrophy. In exploratory reverse stepwise analyses, lower TFF3 was associated with higher rates of whole brain, hippocampal atrophy and ventricular expansion. Lower levels of CrA were associated with higher whole brain atrophy rate. The relationship between low TFF3 and increased hippocampal atrophy rate remained after adjustment for diagnosis. We identified a series of CSF markers that are independently associated with rate of neurodegeneration in amyloid-positive individuals. TFF3, a substrate for NOTCH processing may be an important biomarker of neurodegeneration across the Alzheimer spectrum.
authors: Department of Neurodegeneration, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors: R W
authors: RW
authors: Paterson
authors: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London.
authors: J W
authors: JW
authors: Bartlett
authors: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
authors: K
authors: K
authors: Blennow
authors: Department of Neurodegeneration, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors: N C
authors: NC
authors: Fox
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: L M
authors: LM
authors: Shaw
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: J Q
authors: JQ
authors: Trojanowski
authors: 1] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden [2] Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: H
authors: H
authors: Zetterberg
authors: Department of Neurodegeneration, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors: J M
authors: JM
authors: Schott
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology*; D000686:Amyloidosis / Q000134:cerebrospinal fluid* / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid; D001284:Atrophy; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D001921:Brain / Q000473:pathology*; D002552:Cerebral Ventricles / Q000473:pathology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000473:pathology*; D055316:Cystatin C / Q000134:cerebrospinal fluid; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D010455:Peptides / Q000134:cerebrospinal fluid*; D013223:Statistics as Topic; D000071165:Trefoil Factor-3; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D053327:Apolipoprotein E4; D015415:Biomarkers; C525030:CST3 protein, human; D055316:Cystatin C; C054369:MAPT protein, human; D010455:Peptides; C082495:TFF3 protein, human; D000071165:Trefoil Factor-3; D016875:tau Proteins