[Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighed magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population

The aim of this investigation was to determine whether circulating inflammatory biomarkers c-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to structural brain measures assessed by magnetic resonance imaging (MRI). High-resolution structural MRI was collected on 680 non-demented elderly (mean age 80.1 years) participants of a community-based, multiethnic cohort. Approximately three quarters of these participants also had peripheral inflammatory biomarkers (CRP, IL6, and ACT) measured using ELISA. Structural measures including brain volumes and cortical thickness (with both global and regional measures) were derived from MRI scans, and repeated MRI measures were obtained after 4.5 years. Mean fractional anisotropy was used as the indicator of white matter integrity assessed with diffusion tensor imaging. We examined the association of inflammatory biomarkers with brain volume, cortical thickness, and white matter integrity using regression models adjusted for age, gender, ethnicity, education, APOE genotype, and intracranial volume. A doubling in CRP (b = −2.48, p = 0.002) was associated with a smaller total gray matter volume, equivalent to approximately 1.5 years of aging. A doubling in IL6 was associated with smaller total brain volume (b = −14.96, p < 0.0001), equivalent to approximately 9 years of aging. Higher IL6 was also associated with smaller gray matter (b = −6.52, p = 0.002) and white matter volumes (b = −7.47, p = 0.004). The volumes of most cortical regions including frontal, occipital, parietal, temporal, as well as subcortical regions including pallidum and thalamus were associated with IL6. In a model additionally adjusted for depression, vascular factors, BMI, and smoking status, the association between IL6 and brain volumes remained, and a doubling in ACT was marginally associated with 0.054 (p = 0.001) millimeter thinner mean cortical thickness, equivalent to that of approximately 2.7 years of aging. None of the biomarkers was associated with mean fractional anisotropy or longitudinal change of brain volumes and thickness. Among older adults, increased circulating inflammatory biomarkers were associated with smaller brain volume and cortical thickness but not the white matter tract integrity. Our preliminary findings suggest that peripheral inflammatory processes may be involved in the brain atrophy in the elderly. © 2017 Elsevier Inc

Alcohol intake and brain structure in a multiethnic elderly cohort

Background & aims: Evidence suggests that consuming light-to-moderate amounts of alcohol reduces the risk of dementia and is associated better cognitive function and less cardiovascular disease, relative to those consuming no or heavy alcohol. There are only minimal data on the association between alcohol and brain magnetic resonance imaging (MRI) markers. This study aimed to examine the association between alcohol and brain structure measured with MRI. Methods: In this cross-sectional study, high-resolution structural MRI was collected on 589 multi-ethnic community residents of New York aged ≥65 with available alcohol intake assessments via a food frequency questionnaire. Total brain volume (TBV), white matter hyperintensity volume (WMHV), and presence of infarcts were derived from MRI scans with established methods. We examined the association of alcohol intake with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors. Results: Compared to non-drinking, light-to-moderate total alcohol (b=0.007, p=0.04) or wine (b=0.008, p=0.05) intake, but not beer or liquor intake, was associated with larger TBV. Further analysis showed a dose-response association between alcohol (p-trend=0.03) or wine (p-trend=0.006)and TBV. Overall, alcohol intake was not associated with WMHV or brain infarcts. Conclusions: Our study suggests that among older adults in the community, light-to-moderate alcohol intake, in particular wine, is associated with larger TBV. These findings suggest that light to moderate alcohol consumption is potentially beneficial for brain aging, but replication is needed. © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism

Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults With Cerebral Small Vessel Disease

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD. Methods: Older adults (ages 55–90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes. Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [β = 1.0 × 105, 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [β = 0.001, 95% CI (0.000, 0.001), p = 0.048]. Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD. © Copyright © 2021 Kapoor, Gaubert, Marshall, Meier, Yew, Ho, Blanken, Dutt, Sible, Li, Jang, Brickman, Rodgers and Nation.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]