Structural MRI discriminates individuals with Mild Cognitive Impairment from age-matched controls: A combined neuropsychological and voxel based morphometry study

Background: Several previous studies have reported that amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer\u27s disease (AD), is associated with greater atrophy in the medial temporal lobe (MTL) and posterior cingulate gyrus (PCG). Method: In the present study, we examined the cross-sectional accuracy (i.e., the sensitivity and specificity) of voxel-based morphometry (VBM) in discriminating individuals with MCI (n = 15) from healthy age-matched controls (n = 15). In addition, we also sought to determine whether baseline GM volume predicted aMCI patients that converted to AD from those that did not approximately 2 years after the baseline visit. Results: MCI patients were found to display significantly less GM volume in several hypothesized regions including the MTL and PCG relative to the age-matched controls (p \u3c 0.01). Logistic regression analysis and receiver operating characteristic (ROC) curves for GM volume in the anterior MTL and PCG revealed high discriminative accuracy of 87%. By contrast, baseline GM volume in anterior MTL and PCG did not appear to be sensitive to changes in clinical status at the follow-up visit. Conclusion: These results suggest that VBM might be useful at characterizing GM volume reductions associated with the diagnosis of aMCI. © 2006 The Alzheimer\u27s Association

Item-level story recall predictors of amyloid-beta in late middle-aged adults at increased risk for Alzheimer’s disease

Background: Story recall (SR) tests have shown sensitivity to rate of cognitive decline in individuals with Alzheimer’s disease (AD) biomarkers. Although SR tasks are typically scored by obtaining a sum of items recalled, item-level analyses may provide additional sensitivity to change and AD processes. Here we examined the difficulty and discrimination indices of each item from the Logical Memory (LM) SR task, and determined if these metrics differed by recall conditions, story version (A vs. B), lexical categories, serial position, and amyloid status. Methods: n=1141 participants from the Wisconsin Registry for Alzheimer’s Prevention longitudinal study who had item-level data were included in these analyses, as well as a subset of n=338 who also had amyloid PET imaging. LM data were categorized into 4 lexical categories (proper names, verbs, numbers, and ‘other’), and by serial position (primacy, middle, and recency). We calculated difficulty and discriminability/memorability by item, category, and serial position and ran separate repeated measures ANOVAs for each recall condition, lexical category, and serial position. For the subset with amyloid imaging, we used a two-sample t-test to examine whether amyloid positive (A+) and amyloid negative (A-) groups differed in difficulty or discrimination for the same summary metrics. In review Results: In the larger sample, items were more difficult (less memorable) in the delayed recall condition across both story A and story B. Item discrimination was higher at delayed than immediate recall, and proper names had better discrimination than any of the other lexical categories or serial position groups. In the subsample with amyloid PET imaging, proper names were more difficult for A+ than A-; items in the verb and ‘other’ lexical categories and all serial positions from delayed recall were more discriminate for the A+ group compared to the A- group. Conclusion: This study provides empirical evidence that both LM stories are effective at discriminating ability levels and amyloid status, and that individual items vary in difficulty and discrimination by amyloid status, while total scores do not. These results can be informative for the future development of sensitive tasks or composite scores for early detection of cognitive decline

Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals

BACKGROUND: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. OBJECTIVE: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. METHODS: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. RESULTS: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. CONCLUSION: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms

Associations Between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer\u27s Disease

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer\u27s disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer\u27s Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD

Positive Affect Predicts Cerebral Glucose Metabolism in Late Middle-aged Adults.

Positive affect is associated with a number of health benefits; however, few studies have examined the relationship between positive affect and cerebral glucose metabolism, a key energy source for neuronal function and a possible index of brain health. We sought to determine if positive affect was associated with cerebral glucose metabolism in late middle-aged adults (n = 133). Participants completed the positive affect subscale of the Center for Epidemiological Studies Depression Scale at two time points over a two-year period and underwent 18F-fluorodeoxyglucose-positron emission tomography scanning. After controlling for age, sex, perceived health status, depressive symptoms, anti-depressant use, family history of Alzheimer’s disease, APOE ε4 status and interval between visits, positive affect was associated with greater cerebral glucose metabolism across para-/limbic, frontal, temporal and parietal regions. Our findings provide evidence that positive affect in late midlife is associated with greater brain health in regions involved in affective processing and also known to be susceptible to early neuropathological processes. The current findings may have implications for interventions aimed at increasing positive affect to attenuate early neuropathological changes in at-risk individuals

Temporal Order of Alzheimer\u27s Disease-Related Cognitive Marker Changes in BLSA and WRAP Longitudinal Studies

Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimer\u27s disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental state using data spanning normal cognition, mild cognitive impairment (MCI), and AD from 1661 participants with a total of 7839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging and 1542 participants with a total of 4467 visits (age at last visit 59.9 SD 7.3) in the Wisconsin Registry for Alzheimer\u27s Prevention. This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog‑PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes

The Effect of Rare Variants in TREM2 and PLD3 on Longitudinal Cognitive Function in the Wisconsin Registry for Alzheimer\u27s Prevention

Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer\u27s disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer\u27s Prevention, a longitudinal study of initially asymptomatic adults, aged 36–73 years at baseline, enriched for a parental history of AD. A comprehensive cognitive test battery was performed at up to 5 visits. A factor analysis resulted in 6 cognitive factors that were standardized into z scores (∼N [0, 1]); the mean of these z scores was also calculated. In linear mixed models adjusted for age, gender, practice effects, and self-reported race/ethnicity, PLD3 V232M carriers had significantly lower mean z scores (p = 0.02) and lower z scores for story recall (p = 0.04), visual learning and memory (p = 0.049), and speed and flexibility (p = 0.02) than noncarriers. TREM2 R47H carriers had marginally lower z scores for speed and flexibility (p = 0.06). In conclusion, a functional variant in PLD3 was associated with significantly lower cognitive function in individuals carrying the variant than in noncarriers