Month: October 2021

Proximity to dementia onset and multi-modal neuroimaging changes: The prevent-dementia study.

Elijah Mak, Maria-Eleni Dounavi, Audrey Low, Stephen F Carter, Elizabeth McKiernan, Guy B Williams, Simon Jones, Isabelle Carriere, Graciela Muniz-Terrera, Karen Ritchie, Craig Ritchie, Li Su, John T O’Brien.

NeuroImage. 2021.

doi:https://doi.org/10.1016/j.neuroimage.2021.117749

Summary

First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Here, we investigate “estimated years to onset of dementia” (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum. The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with brain abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. 

Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study.

Audrey Low, Li Su, James Stefaniak, Elijah Mak, Maria-Eleni Dounavi, Graciela Muniz-Terrera, Karen Ritchie, Craig W Ritchie, Hugh S Markus, John T O’Brien.

Neurobiology of Aging. 2020

doi:https://doi.org/10.1016/j.neurobiolaging.2020.10.029

Summary 

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer’s disease (AD),Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.

Higher midlife CAIDE score is associated with increased brain atrophy in a cohort of cognitively healthy middle-aged individuals

Xulin Liu, Marialena Dounavi, Karen Ritchie, Katie Wells, Craig W Ritchie, Li Su, Graciela Muniz-Terrera, John T O’Brien.

Journal of Neurology. 2021.

DOI:10.1007/s00415-020-10383-8

Summary

Structural brain changes associated with Alzheimer’s disease (AD) can occur decades before the onset of symptoms. The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score has been suggested to be associated with accelerated brain atrophy in middle-aged subjects but the regional specificity of atrophic areas remains to be elucidated. MRI imaging brain scans of 160 cognitively healthy middle-aged participants in the PREVENT-Dementia cohort, from baseline and follow-up after 2 years, were examined. Compared to subjects with CAIDE score ≤ 6 (low risk), subjects with CAIDE score > 6 (high risk) showed lower volume in the temporal, occipital, and fusiform cortex and lingual gyrus at baseline, and greater percentage of loss over 2 years in the supramarginal gyrus, angular gyrus, precuneus, lateral occipital cortex, superior parietal lobule and cingulate gyrus. This study demonstrated accelerated atrophy concentrated in several AD signature cortical regions in healthy middle-aged subjects with high CAIDE scores.

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study.

Marialena Dounavi, Audrey Low, Elizabeth McKiernan, Elijah Mak, Graciela Muniz-Terrera, Karen Ritchie, Craig W Ritchie, Li Su and John O’Brien.

Journal of Cerebral Blood Flow & Metabolism. 2021

DOI: https://journals.sagepub.com/doi/pdf/10.1177/0271678X211020863

Summary

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer’s disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged APOE4 carriers were investigated. MRI data from 158 participants (40–59 years old) in the PREVENT-Dementia study were analysed. Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. At baseline, APOE4 carriers showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEe4 noncarriers) and verbal fluency (for APOEe4 carriers) cognitive tests. These observations are consistent with neurovascular ysregulation in middle-aged APOE carriers.