Longitudinal resting-state functional connectivity and regional brain atrophy-based biomarkers of preclinical cognitive impairment in healthy old adults.

BACKGROUND: Intervention against age-related neurodegenerative diseases may be difficult once extensive structural and functional deteriorations have already occurred in the brain. AIM: Investigating 6-year longitudinal changes and implications of regional brain atrophy and functional connectivity in the triple-network model as biomarkers of preclinical cognitive impairment in healthy aging. METHODS: We acquired longitudinal cognitive scores and magnetic resonance imaging (MRI) data from 74 healthy old adults. Resting-state functional MRI (rs-fMRI) analysis was conducted using FSL6.0.1 to examine functional connectivity changes and regional brain morphometries were quantified using FreeSurfer5.3. Finally, we cross-validated and compared two support vector machine (SVM) regression models to predict future 6-year cognition score from the baseline regional brain atrophy and resting-state functional connectivity (rs-FC) measures. RESULTS: After a 6-year follow-up, our results (P < 0.05-corrected) indicated significant connectivity reduction within all the three brain networks, significant differences in regional brain volumes and cortical thickness. We also observed significant improvement in episodic memory and significant decline in executive functions. Finally, comparing the two models, we observed that regional brain atrophy predictors were more efficient in approximating future 6-year cognitive scores (R = 0.756, P < 0.0001) than rs-FC predictors (R = 0.6, P < 0.0001). CONCLUSION: This study used longitudinal data to keep subject variability low and to increase the validity of the results. We demonstrated significant changes in structural and functional MRI over 6 years. Our findings present a potential neuroimaging-based biomarker to detect cognitive impairment and prevent risks of neurodegenerative diseases in healthy old adults.

Effects of apolipoprotein E4 genotype on cerebro-cerebellar connectivity, brain atrophy, and cognition in patients with Alzheimer's disease.

INTRODUCTION: While several studies have substantially revealed the influence of the apolipoprotein E4 genotype (APOE4) on the vulnerability of Alzheimer's disease (AD), there are still far fewer studies investigating whether and how APOE4, in the absence of the amyloid-ß (Aß), alters regional brain atrophy, cerebro-cerebellar connectivity and cognitive performance in AD patients. METHODS: We employed MRI and neuropsychological data from 234 old adults with AD dementia, including 143 APOE4-positive (with ε2/ε4, ε3/ε4, or ε4/ε4 alleles) and 91 APOE4-negative (with ε2/ε2, ε2/ε3 or ε3/ε3), to investigate the cerebro-cerebellar connectivity in three cerebro-cerebellar brain networks: default mode network, motor network and affective-limbic network. Amyloid PET images were used to evaluate individual Aß burdens, later used as covariates. Regional volumetric and cortical thickness measures were quantified in both the cerebellum and the cerebrum using the cerebellum segmentation algorithm and Freesurfer5.3, respectively. RESULTS: Our corrected functional connectivity (FC) results showed that APOE4 carriers (APOE4+) had lower FC within the cerebro-cerebellar motor network. In addition, significant group differences in regional cortical thickness were observed in the left Crus I, the right VIIB, left superior frontal, and right middle temporal gyri. Group differences in regional brain volumes were observed in the left lobule V and right parstriangularis. Furthermore, multiple linear regression analysis indicated that APOE4+ AD patients show greater episodic memory impairment. CONCLUSION: Since amyloid-ß, age, education, and gender were included as confounds in the statistical models, our findings suggest that APOE4 independently contributes to brain atrophy, disrupted FC, and associated memory declines in AD patients.

Altered Glymphatic System in Middle-Aged cART-Treated Patients With HIV: A Diffusion Tensor Imaging Study.

Objective: The brain relies on the glymphatic system to clear metabolic wastes and maintain brain homeostasis to fulfill its functions better. Yet, the complexity of the glymphatic flow and clearance and its changes in HIV infection and its role in neurocognitive dysfunction remain poorly understood. This study aims to explore the impact of HIV and combination antiretroviral therapy (cART) on the glymphatic system and establish a potential biomarker of HIV-associated neurocognitive disorders (HAND). Methods: Here, we examined the glymphatic profiles of middle-aged virosuppressed patients with HIV (n = 27) receiving cART over 1-6 years and healthy controls (n = 28) along the perivascular space (PVS) using diffusion tensor image analysis along the perivascular space (ALPS) with guided and unguided approaches. We later combined data from these analyses to investigate MRI glymphatic correlates of cognitive impairment and other clinical tests of HIV (CD4+ T-cell counts and CD4+/CD8+ ratio). Results: We found that glymphatic function as measured by the ALPS index increased significantly in the right and left PVSs of patients with HIV having cART. On antiretroviral therapy, a changing pattern in glymphatic clearance function in patients with HIV having cART correlated with attention and working memory. Duration on cART was also associated with cognitive performances of abstract and executive function and learning and memory. Conclusion: These findings provide MRI evidence of the presence of HIV-induced changes in the glymphatic flow and clearance, which might underlie cognitive impairment among patients with HIV having cART. An increase in the glymphatic activity might reflect a compensatory mechanism to regulate microenvironment homeostasis compromised by HIV. This compensation might be necessary to maintain the proper functioning of the brain while coping with HIV pathology. These findings also shed light on the clinical importance of evaluating glymphatic function based on the ALPS index and suggest that improving the glymphatic system may serve as an alternative therapeutic strategy for HAND.