IntroductionThe objective of this study was to assess the utility of novel verbal fluency scores for predicting conversion from mild cognitive impairment (MCI) to clinical Alzheimer's disease (AD).MethodVerbal fluency lists (animals, vegetables, F, A, and S) from 107 MCI patients and 51 cognitively normal controls were transcribed into electronic text files and automatically scored with traditional raw scores and five types of novel scores computed using methods from machine learning and natural language processing. Additional scores were derived from structural MRI scans: region of interest measures of hippocampal and ventricular volumes and gray matter scores derived from performing ICA on measures of cortical thickness. Over 4 years of follow-up, 24 MCI patients converted to AD. Using conversion as the outcome variable, ensemble classifiers were constructed by training classifiers on the individual groups of scores and then entering predictions from the primary classifiers into regularized logistic regression models. Receiver operating characteristic curves were plotted, and the area under the curve (AUC) was measured for classifiers trained with five groups of available variables.ResultsClassifiers trained with novel scores outperformed those trained with raw scores (AUC 0.872 vs 0.735; P < .05 by DeLong test). Addition of structural brain measurements did not improve performance based on novel scores alone.ConclusionThe brevity and cost profile of verbal fluency tasks recommends their use for clinical decision making. The word lists generated are a rich source of information for predicting outcomes in MCI. Further work is needed to assess the utility of verbal fluency for early AD.

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Background Brain-derived neurotrophic factor (BDNF) plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. BDNF function is adversely affected by amyloid beta in AD. BDNF levels in brain and peripheral tissues are lower in patients with AD and mild cognitive impairment (MCI) than in controls. Here we examined the association between plasma levels of BDNF and amyloid deposition in the brain measured with Pittsburgh Compound B (PiB). Method Our data set consisted of 18 AD, 56 MCI, and 3 normal control Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) subjects with available [ 11 C] PiB and peripheral blood protein data. Magnetic resonance imaging (MRI)-coregistered positron emission tomography data were smoothed with a 15 mm kernel and mapped onto three-dimensional (3D) hemispheric models using the warping deformations computed in cortical pattern matching of the associated MRI scans. We applied linear regression to examine in 3D the associations between BDNF and PiB standard uptake value ratio, while adjusting for age and sex. We used permutation statistics thresholded at P < .01 for multiple comparisons correction. Results Plasma BDNF levels showed significant negative associations with left greater than right amyloid burden in the lateral temporal, inferior parietal, inferior frontal, anterior and posterior cingulate, and orbitofrontal regions (left P corrected = .03). Conclusions As hypothesized, lower plasma levels of BDNF were significantly associated with widespread brain amyloidosis.

The hallmark of Alzheimer's disease (AD) is declarative memory loss, but deficits in semantic fluency are also observed. We assessed how semantic fluency relates to cortical atrophy to identify specific regions that play a role in the loss of access to semantic information. Whole-brain structural magnetic resonance imaging (MRI) data were analyzed from 9 Normal Control (NC)(M=76.7, SD=5.6), 40 Mild Cognitive Impairment (MCI) (M=74.4, SD=8.6), and 10 probable AD (M=72.4, SD=8.0) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). They all were administered the Category Fluency (CF) animals and vegetables tests. Poorer semantic fluency was associated with bilateral cortical atrophy of the inferior parietal lobule (Brodman areas (BA) 39 and 40) and BA 6, 8, and 9 in the frontal lobe, as well as BA 22 in the temporal lobe. More diffuse frontal associations were seen in the left hemisphere involving BA 9, 10, 32, 44, 45, and 46. Additional cortical atrophy was seen in the temporoparietal (BA 37) and the right parastriate (BA 19, 18) cortices. Associations were more diffuse for performance on vegetable fluency than animal fluency. The permutation-corrected map-wise significance for CF animals was pcorrected=0.01 for the left hemisphere, and pcorrected=0.06 for the right hemisphere. The permutation-corrected map-wise significance for CF vegetables was pcorrected=0.009 for the left hemisphere, and pcorrected=0.03 for the right hemisphere. These results demonstrate the profound effect of cortical atrophy on semantic fluency. Specifically, tapping into semantic knowledge involves the frontal lobe in addition to the language cortices of the temporoparietal region.

Objective:We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association.Methods:Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes.Results:Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A.Conclusions:Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.