Background The utility of combining early markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer’s Disease (AD) remains uncertain. Methods 148 outpatients with MCI, broadly defined, were followed at 6-month intervals. Hypothesized baseline predictors for follow-up conversion to AD (entire sample: 39/148 converters) were cognitive test performance, informant report of functional impairment, apolipoprotein E genotype, olfactory identification deficit, MRI hippocampal and entorhinal cortex volumes. Results In the 3-year follow-up patient sample (33/126 converters), five of eight hypothesized predictors were selected by backward and stepwise logistic regression: FAQ (informant report of functioning), UPSIT (olfactory identification), SRT immediate recall (verbal memory), MRI hippocampal volume, MRI entorhinal cortex volume. For 10% false positives (90% specificity), this five-predictor combination showed 85.2% sensitivity, combining age and MMSE showed 39.4% sensitivity, and combining age, MMSE, and the three clinical predictors (SRT immediate recall, FAQ, and UPSIT) showed 81.3% sensitivity. Area under ROC curve was greater for the five-predictor combination (0.948) than age plus MMSE (0.821; p =.0009), and remained high in sub-samples with MMSE ≥ 27/30 and amnestic MCI. For the entire patient sample, based on dichotomizing estimated risk at 0.5, positive likelihood ratio was 16.8 (95% CI 6.4, 44.3) and negative likelihood ratio was 0.2 (95% CI 0.1, 0.4). Conclusions The five-predictor combination strongly predicted conversion to AD and was markedly superior to combining age and MMSE. Combining only clinically administered measures also led to strong predictive accuracy. If independently replicated, the findings have potential utility for early detection of AD.

Odor identification deficits occur in Alzheimer's disease (AD) and mild cognitive impairment (MCI), and predict clinical conversion from MCI to AD. In an epidemiologic study conducted in a multiethnic community elderly sample (average 80 years old), the University of Pennsylvania Smell Identification Test (UPSIT, range 0-40) was administered to 1092 non-demented subjects. Women (mean 26.6 SD 6.6) scored higher than men (mean 24.4 SD 7.4, p < .02), and ethnic differences were not significant after controlling for age and education. UPSIT scores correlated inversely with age (r=−0.24, p < .0001) and positively with Selective Reminding Test immediate recall (r=0.33), delayed recall (r=0.28), category fluency (r=0.28) and the 15-item Boston Naming Test (r=0.23), all p's < . 0001. In a sub-sample in which MRI was done, UPSIT scores showed a significant correlation with Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

Amyloid load in the brain using 11C-PIB PET and cerebral glucose metabolism using 18F-FDG PET were evaluated in patients with mild Alzheimer’s disease (AD, n=18), mild cognitive impairment (MCI, n=24) and controls (CTR, n=18). 11C-PIB binding potential (BPND) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI, and in prefrontal cortex for MCI compared to CTR. For 18F-FDG, rCMRGlu was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI-CTR differences. For the AD-CTR comparison, precuneus BPND area under the ROC curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination AUC was 0.989. 11C-PIB PET BPND clearly distinguished diagnostic groups, and combined with 18F-FDG PET rCMRGlu this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

SUMMARYObjective-To compare state and trait anxiety in mild cognitive impairment (MCI) patients and matched control subjects, and to assess the impact of these variables in predicting conversion to Alzheimer's disease.Methods-One hundred and forty-eight patients with MCI, broadly defined, were assessed and followed systematically. Baseline predictors for follow-up conversion to AD (entire sample: 39/148 converted to Alzheimer's disease (AD)) included the Spielberger State-Trait Anxiety Inventory (STAI).Results-At baseline evaluation, MCI patients had higher levels of state and trait anxiety than controls, with no differences between future AD converters (n = 39) and non-converters. In agestratified Cox proportional hazards model analyses, STAI State was not a significant predictor of conversion to AD (STAI State ≤30 vs. > 30 risk ratio, 1.68; 95% CI, 0.75, 3.77; p = 0.21), but higher Trait scores indicated a lower risk of conversion when STAI State, education, the Folstein MiniMental State Examination and HAM-D (depression score) were also included in the model (STAI Trait ≤30 vs. > 30 risk ratio, 0.36; 95% CI, 0.16, 0.82; p = 0.015).Conclusions-In contrast to two other recent studies that showed anxiety predicted cognitive decline or conversion to AD, in this clinic-based sample, state anxiety was not a significant predictor. However, higher Trait anxiety predicted a lower risk of future conversion to AD. Further research with systematic long-term follow-up in larger samples is needed to clarify the role of state and trait anxiety in predicting MCI conversion to AD.

Blockage of vasoactive intestinal peptide (VIP) receptors during early embryogenesis in the mouse has been shown to result in developmental delays in neonates, and social behavior deficits selectively in adult male offspring. Offspring of VIP deficient mothers (VIP +/-) also exhibited developmental delays, and reductions in maternal affiliation and play behavior. In the current study, comparisons among the offspring of VIP deficient mothers (VIP +/-) mated to VIP +/- males with the offspring of wild type (WT) mothers mated to VIP +/- males allowed assessment of the contributions of both maternal and offspring VIP genotype to general health measures, social behavior, fear conditioning, and spatial learning and memory in the water maze. These comparisons revealed few differences in general health among offspring of WT and VIP deficient mothers, and all offspring exhibited normal responses in fear conditioning and in the acquisition phase of spatial discrimination in the water maze. WT mothers produced offspring that were normal in all tests; the reduced VIP in their VIP +/- offspring apparently did not contribute to any defects in the measures under study. However, regardless of their own VIP genotype, all male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning. The deficits in these behaviors in the female offspring of VIP deficient mothers were less severe than in their male littermates, and the extent of their impairment was related to their own VIP genotype. This study has shown that intrauterine conditions had a greater influence on behavioral outcome than did genetic inheritance. In addition, the greater prevalence of deficits in social behavior and the resistance to change seen in reversal learning in the male offspring of VIP deficient mothers indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders such as autism.