Mekala R. Raman

Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly

Vemuri et al. show that amyloid and vascular pathologies are independent processes, and that both are major drivers of cognitive decline in the elderly. Cognitive reserve as measured by educational/occupational level and mid/late-life cognitive activity seems to offset the deleterious effects of both pathologies on cognitive trajectories.

Loss of Fornix White Matter Volume as a Predictor of Cognitive Impairment in Cognitively Normal Elderly Individuals

IMPORTANCE Magnetic resonance imaging markers of incipient cognitive decline among healthy elderly individuals have become important for both clarifying the biological underpinnings of dementia and clinically identifying healthy individuals at high risk of cognitive decline. Even though the role of hippocampal atrophy is well known in the later stages of decline, the ability of fornix-hippocampal markers to predict the earliest clinical deterioration is less clear. OBJECTIVES To examine the involvement of the hippocampus-fornix circuit in the very earliest stages of cognitive impairment and to determine whether the volumes of fornix white matter and hippocampal gray matter would be useful markers for understanding the onset of dementia and for clinical intervention. DESIGN A longitudinal cohort of cognitively normal elderly participants received clinical evaluations with T1-weighted magnetic resonance imaging and diffusivity scans during repeated visits over an average of 4 years. Regression and Cox proportional hazards models were used to analyze the relationships between fornix and hippocampal measures and their predictive power for incidence and time of conversion from normal to impaired cognition. SETTING A cohort of community-recruited elderly individuals at the Alzheimer Disease Center of the University of California, Davis. PARTICIPANTS A total of 102 cognitively normal elderly participants, with an average age of 73 years, recruited through community outreach using methods designed to enhance ethnic diversity. MAIN OUTCOMES AND MEASURES Our preliminary hypothesis was that fornix white matter volume should be a significant predictor of cognitive decline among normal elderly individuals and that fornix measures would be associated with gray matter changes in the hippocampus. RESULTS Fornix body volume and axial diffusivity were highly significant predictors (P = .02 and .005, respectively) of cognitive decline from normal cognition. Hippocampal volume was not significant as a predictor of decline but was significantly associated with fornix volume and diffusivity (P = .004). CONCLUSIONS AND RELEVANCE This could be among the first studies establishing fornix degeneration as a predictor of incipient cognitive decline among healthy elderly individuals. Predictive fornix volume reductions might be explained at least in part by clinically silent hippocampus degeneration. The importance of this finding is that white matter tract measures may become promising candidate biomarkers for identifying incipient cognitive decline in a clinical setting, possibly more so than traditional gray matter measures.

Antemortem MRI findings associated with microinfarcts at autopsy

Objective: To determine antemortem MRI findings associated with microinfarcts at autopsy. Methods: Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic–based, population–based, and community clinic–based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods. Results: The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts. Conclusions: Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets.

An investigation of cerebrovascular lesions in dementia with Lewy bodies compared to Alzheimer's disease.

Cerebrovascular lesions on MRI are common in Alzheimers disease (AD) dementia, but less is known about their frequency and impact on dementia with Lewy bodies (DLB).

Correlation of Brain Atrophy, Disability, and Spinal Cord Atrophy in a Murine Model of Multiple Sclerosis

Disability progression in multiple sclerosis (MS) remains incompletely understood. Unlike lesional measures, central nervous system atrophy has a strong correlation with disability. Theilers murine encephalomyelitis virus infection in SJL/J mice is an established model of progressive MS. We utilized in vivo MRI to quantify brain and spinal cord atrophy in this model and analyzed the temporal relationship between atrophy and disability.

Association between microinfarcts and blood pressure trajectories

Importance Cerebral microinfarcts are associated with increased risk of cognitive impairment and may have different risk factors than macroinfarcts. Subcortical microinfarcts are associated with declining blood pressure (BP) in elderly individuals. Objective To investigate BP slopes as a risk factor for microinfarcts. Design, Setting, and Participants From the population-based Mayo Clinic Study of Aging, 303 of 1158 individuals (26.2%) in this cohort study agreed to have an autopsy between November 1, 2004, and March 31, 2016. Cerebral microinfarcts were identified and classified as cortical or subcortical. Baseline and BP trajectories were compared for groups with no microinfarcts, subcortical microinfarcts, and cortical microinfarcts. A secondary logistic regression analysis was performed to assess associations of subcortical microinfarcts with midlife hypertension, as well as systolic and diastolic BP slopes. Main Outcomes and Measures The presence of cerebral microinfarcts using BP slopes. Results Of the 303 participants who underwent autopsy, 297 had antemortem BP measurements. Of these, 177 (59.6%) were men; mean (SD) age at death was 87.2 (5.3) years. The autopsied individuals and the group who died but were not autopsied were similar for all demographics except educational level with autopsied participants having a mean of 1 more year of education (1.06; 95% CI, 0.66-1.47 years; P < .01). Among 297 autopsied individuals with antemortem BP measurements, 47 (15.8%) had chronic microinfarcts; 30 (63.8%) of these participants were men. Thirty (63.8%) had cortical microinfarcts, 19 (40.4%) had subcortical microinfarcts, and 4 (8.5%) had only infratentorial microinfarcts. Participants with microinfarcts did not differ significantly on baseline systolic (mean difference, −1.48; 95% CI, −7.30 to 4.34; P = .62) and diastolic (mean difference of slope, −0.90; 95% CI, −3.93 to 2.13; P = .56) BP compared with those with no microinfarcts. However, participants with subcortical microinfarcts had a greater annual decline (negative slope) of systolic (mean difference of slope, 4.66; 95% CI, 0.13 to 9.19; P = .04) and diastolic (mean difference, 3.33; 95% CI, 0.61 to 6.06; P = .02) BP. Conclusions and Relevance Subcortical microinfarcts were associated with declining BP. Future studies should investigate whether declining BP leads to subcortical microinfarcts or whether subcortical microinfarcts are a factor leading to declining BP.

Regional T1 relaxation time constants in Ex vivo human brain: Longitudinal effects of formalin exposure

Relaxation time constants are useful as markers of tissue properties. Imaging ex vivo tissue is done for research purposes; however, T1 relaxation time constants are altered by tissue fixation in a time‐dependent manner. This study investigates regional changes in T1 relaxation time constants in ex vivo brain tissue over 6 months of fixation.

Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy

Objective: Women with a history of preeclampsia are at an increased risk of hypertension and structural brain changes. However, the combined effect of both preeclampsia and late-life hypertension on brain structural changes is not known and was investigated in this study. Methods: Participants were identified from the population-based Rochester Epidemiology Project cohort. Four groups of women were recruited and investigated in this study: first, women with a history of normotensive pregnancy who have late-life hypertension (n = 8, median age = 62), second, women with a history of normotensive pregnancy who do not have late-life hypertension (n = 32, median age = 59), third, women with a history of preeclampsia who have late-life hypertension (n = 24, median age = 60), and fourth, women with a history of preeclampsia who do not have late-life hypertension (n = 16, median age = 57). Cerebrovascular disease lesions on MRI, and total gray matter volumes were assessed. Results: Total gray matter volumes were smaller in women with a history of preeclampsia and late-life hypertension compared with the other groups. Voxel-based morphometry demonstrated that the volume changes were localized to the posterior brain regions, particularly the occipital lobe gray matter in women with a history of preeclampsia and late-life hypertension. Conclusion: Having late-life hypertension superimposed on a history of preeclampsia affects the brain structure differently than having either a history of preeclampsia alone or a history of normotensive pregnancy either with or without late-life hypertension.

Spontaneous amyloid-related imaging abnormalities in a cognitively normal adult

An 81-year-old cognitively normal man (APOE ε3/ε3) without risk factors had amyloid-related imaging abnormalities with sulcal effusions and edema (ARIA-E), siderosis, and microhemorrhages (ARIA-H) on MRI (figure 1).1 He was identified from 1,006 participants followed with 3,385 MRIs in 2010–2013 in Alzheimers Disease Neuroimaging Initiative (ADNI) 2/ADNI Grand Opportunities. Amyloid standard uptake value ratio on PET was 1.85 (positive) (figure 2). ARIA-E and associated ARIA-H can be observed in cognitively normal elderly without the APOE ε4 risk allele, who have no prior microhemorrhages, and who are not receiving amyloid-modifying treatments. Focal amyloid deposits around the region of ARIA-H suggest that cerebral amyloid angiopathy may be responsible for the occurrence of ARIA in this case.2

An MRI‐Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease

Pathologic diagnosis is the gold standard in evaluating imaging measures developed as biomarkers for pathologically defined disorders. A brain MRI atlas representing autopsy‐sampled tissue can be used to directly compare imaging and pathology findings. Our objective was to develop a brain MRI atlas representing the cortical regions that are routinely sampled at autopsy for the diagnosis of Alzheimers disease (AD).