Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals

R W Paterson; J W Bartlett; K Blennow; N C Fox; Alzheimer's Disease Neuroimaging Initiative; L M Shaw; J Q Trojanowski; H Zetterberg; J M Schott

doi:10.1038/tp.2014.58

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Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals

Journal article

Open access

Peer reviewed

Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals

R W Paterson, J W Bartlett, K Blennow, N C Fox, Alzheimer's Disease Neuroimaging Initiative, L M Shaw, J Q Trojanowski, H Zetterberg and J M Schott

Translational psychiatry, Vol.4(7), pp.e419-e419

07/29/2014

DOI: 10.1038/tp.2014.58

PMCID: PMC4119225

PMID: 25072324

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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.

Cerebral Ventricles - pathology

Amyloidosis - pathology

Humans

Amyloidosis - cerebrospinal fluid

Male

Hippocampus - pathology

Statistics as Topic

tau Proteins - cerebrospinal fluid

Cognitive Dysfunction - cerebrospinal fluid

Cognitive Dysfunction - pathology

Peptides - cerebrospinal fluid

Alzheimer Disease - cerebrospinal fluid

Alzheimer Disease - pathology

Atrophy

Aged, 80 and over

Brain - pathology

Cystatin C - cerebrospinal fluid

Mental Status Schedule

Trefoil Factor-3

Apolipoprotein E4 - cerebrospinal fluid

Female

Aged

Biomarkers - cerebrospinal fluid

Details

Title: Subtitle: Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals
Creators: R W Paterson - Department of Neurodegeneration, Dementia Research Centre, UCL Institute of Neurology, London, UK
J W Bartlett - Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London
K Blennow - Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
N C Fox - Department of Neurodegeneration, Dementia Research Centre, UCL Institute of Neurology, London, UK
Alzheimer's Disease Neuroimaging Initiative
L M Shaw - 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
J Q Trojanowski - 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
H Zetterberg - 1] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
J M Schott - Department of Neurodegeneration, Dementia Research Centre, UCL Institute of Neurology, London, UK
Contributors: Laura L Boles-Ponto (Contributor) - University of Iowa, Radiology
Resource Type: Journal article
Publication Details: Translational psychiatry, Vol.4(7), pp.e419-e419
DOI: 10.1038/tp.2014.58
PMID: 25072324
PMCID: PMC4119225
NLM abbreviation: Transl Psychiatry
ISSN: 2158-3188
eISSN: 2158-3188
Publisher: United States
Grant note: UL1 TR001108 / NCATS NIH HHS U24 AG021886 / NIA NIH HHS P30 AG013846 / NIA NIH HHS P30 AG010129 / NIA NIH HHS P41 EB015922 / NIBIB NIH HHS U01 AG024904 / NIA NIH HHS K01 AG030514 / NIA NIH HHS
Language: English
Date published: 07/29/2014
Academic Unit: Radiology; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984051727002771

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