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.
Highlights
Alzheimer’s disease (AD) is a relentless progressive condition there is considerable variation in the rate of progression between individuals.[1]
PATIENTS AND METHODS Subjects We investigated subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multicenter publicly/privately funded
The mean ± s.d. age of this group was 74.9 ± 6.9 years, 21.6% had a clinical diagnosis of AD, 48.1% mild cognitive impairment (MCI) and 30.3% were controls
Summary
Alzheimer’s disease (AD) is a relentless progressive condition there is considerable variation in the rate of progression between individuals.[1]. Either of brain or brain substructures can be measured with a high degree of precision from serially acquired MRI and provide a robust measure of progression which correlates with cognitive decline.[7] Cerebrospinal fluid (CSF) can be used to assess neuronal, synaptic, inflammatory, and other proteins involved, or potentially involved, in AD pathogenesis.[8] To date, Aβ1-42 and tau are routinely measured as AD biomarkers,[8] with good evidence that these are markers of AD pathology and predict cognitive decline in mild cognitive impairment.[9] What is less clear is which CSF markers best reflect rates of neuronal damage or loss in AD—and may be useful predictors of progression. In this study we aimed to assess whether any analytes in a large panel of CSF biomarkers were associated with increased rates of atrophy across the Alzheimer spectrum
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