Classification and prediction of cognitive trajectories of cognitively unimpaired individuals.

Objectives: Efforts to prevent Alzheimer's disease (AD) would benefit from identifying cognitively unimpaired (CU) individuals who are liable to progress to cognitive impairment. Therefore, we aimed to develop a model to predict cognitive decline among CU individuals in two independent cohorts. Methods: A total of 407 CU individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 285 CU individuals from the Samsung Medical Center (SMC) were recruited in this study. We assessed cognitive outcomes by using neuropsychological composite scores in the ADNI and SMC cohorts. We performed latent growth mixture modeling and developed the predictive model. Results: Growth mixture modeling identified 13.8 and 13.0% of CU individuals in the ADNI and SMC cohorts, respectively, as the "declining group." In the ADNI cohort, multivariable logistic regression modeling showed that increased amyloid-ß (Aß) uptake (ß [SE]: 4.852 [0.862], p < 0.001), low baseline cognitive composite scores (ß [SE]: -0.274 [0.070], p < 0.001), and reduced hippocampal volume (ß [SE]: -0.952 [0.302], p = 0.002) were predictive of cognitive decline. In the SMC cohort, increased Aß uptake (ß [SE]: 2.007 [0.549], p < 0.001) and low baseline cognitive composite scores (ß [SE]: -4.464 [0.758], p < 0.001) predicted cognitive decline. Finally, predictive models of cognitive decline showed good to excellent discrimination and calibration capabilities (C-statistic = 0.85 for the ADNI model and 0.94 for the SMC model). Conclusion: Our study provides novel insights into the cognitive trajectories of CU individuals. Furthermore, the predictive model can facilitate the classification of CU individuals in future primary prevention trials.

Longitudinal amyloid cognitive composite in preclinical Alzheimer's disease.

BACKGROUND AND PURPOSE: Previous studies have developed several cognitive composites in preclinical Alzheimer disease (AD). However, more sensitive measures to track cognitive changes and therapeutic efficacy in preclinical AD are needed considering the diverse sociocultural and linguistic backgrounds. This study developed a composite score that can sensitively detect the amyloid-ß (Aß)-related cognitive trajectory of preclinical AD using Korean data. METHODS: A total of 196 cognitively normal participants who underwent amyloid positron emission tomography were followed-up with neuropsychological assessments. We developed the Longitudinal Amyloid Cognitive Composite in Preclinical AD (LACPA) using the linear mixed-effects model (LMM) and z scores. The LMM was also used to investigate the longitudinal sensitivity of the LACPA and the association between time-varying brain atrophy and the LACPA. RESULTS: Considering the group-time interaction effects of each subtest, the Seoul Verbal Learning Test-Elderly version immediate recall/delayed recall/recognition, the Korean Trail Making Test B Time, and the Korean Mini-Mental State Examination were selected as components of the LACPA. The LACPA exhibited a significant group-time interaction effect between the Aß+ and Aß- groups (t = -3.288, p = 0.001). Associations between time-varying LACPA and brain atrophy were found in the bilateral medial temporal, right lateral parietal, and right lateral frontal regions, and hippocampal volume. CONCLUSIONS: The LACPA may contribute to reduction in time and financial burden when monitoring Aß-related cognitive decline and therapeutic efficacy of the disease-modifying agents specifically targeting Aß in secondary prevention trials.

Association between APOE ε2 and Aß burden in patients with Alzheimer- and vascular-type cognitive impairment.

OBJECTIVE: To investigate the association between APOE genotype and ß-amyloid (Aß) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease-related cognitive impairment (ADCI). METHODS: This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aß positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach. RESULTS: In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aß positivity (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.79), while in the SVCI group, ε2 carriers showed a higher frequency of Aß positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aß positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aß-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aß-positive APOE ε2 carriers with SVCI and Aß-positive APOE ε4 carriers with ADCI. CONCLUSIONS: Our findings suggest that APOE ε2 is distinctly associated with Aß deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aß-positive APOE ε2 carriers with SVCI among patients with cognitive impairment.

The preclinical amyloid sensitive composite to determine subtle cognitive differences in preclinical Alzheimer's disease.

Recently, the focus of Alzheimer's disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (Aß+) and negative (Aß-) status in cognitively normal (CN) participants. A total of 423 CN participants with Aß positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the Aß+ and Aß- groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the Aß+ group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ε4 for distinguishing between Aß+ and Aß- was adequate (AUC = 0.764; 95% CI = 0.667-0.860) in the external validation set (N = 179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.

The Cortical Neuroanatomy Related to Specific Neuropsychological Deficits in Alzheimer's Continuum.

BACKGROUND AND PURPOSE: In Alzheimer's continuum (a comprehensive of preclinical Alzheimer's disease [AD], mild cognitive impairment [MCI] due to AD, and AD dementia), cognitive dysfunctions are often related to cortical atrophy in specific brain regions. The purpose of this study was to investigate the association between anatomical pattern of cortical atrophy and specific neuropsychological deficits. METHODS: A total of 249 participants with Alzheimer's continuum (125 AD dementia, 103 MCI due to AD, and 21 preclinical AD) who were confirmed to be positive for amyloid deposits were collected from the memory disorder clinic in the department of neurology at Samsung Medical Center in Korea between September 2013 and March 2018. To analyze neuropsychological test-specific neural correlates representing the relationship between cortical atrophy measured by cortical thickness and performance in specific neuropsychological tests, a linear regression analysis was performed. Two neural correlates acquired by 2 different standardized scores in neuropsychological tests were also compared. RESULTS: Cortical atrophy in several specific brain regions was associated with most neuropsychological deficits, including digit span backward, naming, drawing-copying, verbal and visual recall, semantic fluency, phonemic fluency, and response inhibition. There were a few differences between 2 neural correlates obtained by different z-scores. CONCLUSIONS: The poor performance of most neuropsychological tests is closely related to cortical thinning in specific brain areas in Alzheimer's continuum. Therefore, the brain atrophy pattern in patients with Alzheimer's continuum can be predict by an accurate analysis of neuropsychological tests in clinical practice.

Distinct Brain Regions in Physiological and Pathological Brain Aging.

BACKGROUND: Studying structural brain aging is important to understand age-related pathologies, as well as to identify the early manifestations of the Alzheimer's disease (AD) continuum. In this study, we investigated the long-term trajectory of physiological and pathological brain aging in a large number of participants ranging from the 50s to over 80 years of age. OBJECTIVE: To explore the distinct brain regions that distinguish pathological brain aging from physiological brain aging using sophisticated measurements of cortical thickness. METHODS: A total of 2,823 cognitively normal (CN) individuals and 2,675 patients with AD continuum [874 with subjective memory impairment (SMI), 954 with amnestic mild cognitive impairment (aMCI), and 847 with AD dementia] who underwent a high-resolution 3.0-tesla MRI were included in this study. To investigate pathological brain aging, we further classified patients with aMCI and AD according to the severity of cognitive impairment. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age, diagnostic groups, and cortical thickness. RESULTS: Aging extensively affected cortical thickness not only in CN individuals but also in AD continuum patients; however, the precuneus and inferior temporal regions were relatively preserved against age-related cortical thinning. Compared to CN individuals, AD continuum patients including those with SMI showed a decreased cortical thickness in the perisylvian region. However, widespread cortical thinning including the precuneus and inferior temporal regions were found from the late-stage aMCI to the moderate to severe AD. Unlike the other age groups, AD continuum patients aged over 80 years showed prominent cortical thinning in the medial temporal region with relative sparing of the precuneus. CONCLUSION: Our findings suggested that the precuneus and inferior temporal regions are the key regions in distinguishing between physiological and pathological brain aging. Attempts to differentiate age-related pathology from physiological brain aging at a very early stage would be important in terms of establishing new strategies for preventing accelerated pathological brain aging.