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.

The Role of Vascular Endothelial Growth Factor in Neurodegeneration and Cognitive Decline

“…A higher VEGF level was associated with larger baseline hippocampal volume, less hippocampal atrophy over time, and less cognitive decline over time. Interestingly, the neuroprotective effect of VEGF appeared strongest in the presence of enhanced AD biomarkers, consistent with previous reports in Aβ-42 participants, 13 suggesting that angiogenic factors may be particularly important in those individuals showing early hallmarks of the AD cascade. In further support of this theoretical pathway, the baseline effect of VEGF was also strongest in participants with MCI, and when performing stratified analyses, the majority of associations were driven by effects in the MCI group.…”

“…12 Yet the mechanisms of this effect remain elusive. Our findings add to previous literature associating VEGF with various brain aging outcomes, 13 and suggests that the observed effects may have strong implications for potential interventions. For example, VEGF plays a large role in maintaining neural perfusion homeostasis.…”

“…It is interesting that we did not observe a VEGF x Aβ-42 interaction in relation to hippocampal volume, particularly given the reported protective effect of VEGF in the hippocampus of APP transgenic mice, 6,8,9 and the previously reported effect of VEGF in Aβ-42 positive individuals. 13 Our models treated both VEGF and Aβ-42 as continuous variables rather than binary (positive vs. negative) variables and explicitly tested for an interaction, which may explain the discordant results. We confirmed a strong effect of VEGF in Aβ-42 positive participants in relation to both baseline and longitudinal hippocampal volume (results not shown), so the difference in outcomes between the studies is likely due to the statistical model applied.…”

“…A recent study evaluated over 80 CSF analytes in relation to brain aging outcomes and found that lower levels of CSF VEGF are related to smaller hippocampi, larger ventricles, and faster decline on the Mini-Mental State Examination over 12-months. 13 Interestingly, these observations were only present in amyloid positive individuals. It is not yet clear whether an interaction between VEGF and such AD biomarkers is specific to amyloid or whether similar interactions are also present with tau, another primary pathology in AD.…”

The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans

“…In an RBM study using CSF samples from the ADNI cohort, several markers were associated with neurodegeneration in Aβ amyloid-positive subjects but not in Aβ amyloid-negative subjects. Lower levels of trefoil factor 3, VEGF, and chromogranin A, and a higher level of cystatin C were significantly associated with increased rates of neurodegeneration, indicating that these candidate markers potentially provide prognostic information and insights into AD pathobiology [72]. In another analysis of the multiplex RBM study of ADNI 1 CSF samples, high CSF apolipoprotein ε (apoE) levels were shown to be associated with a slower cognitive decline and decreased brain atrophy [126].…”