Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure

Background Lower hippocampal volume is associated with late‐life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late‐life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [APOE ε4], and diabetes). Methods and Results Data came from 765 community‐based older people (91 years old on average at death; 72% women), from 2 ongoing clinical‐pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. Conclusions Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations

Ex-vivo quantitative susceptibility mapping of human brain hemispheres.

Ex-vivo brain quantitative susceptibility mapping (QSM) allows investigation of brain characteristics at essentially the same point in time as histopathologic examination, and therefore has the potential to become an important tool for determining the role of QSM as a diagnostic and monitoring tool of age-related neuropathologies. In order to be able to translate the ex-vivo QSM findings to in-vivo, it is crucial to understand the effects of death and chemical fixation on brain magnetic susceptibility measurements collected ex-vivo. Thus, the objective of this work was twofold: a) to assess the behavior of magnetic susceptibility in both gray and white matter of human brain hemispheres as a function of time postmortem, and b) to establish the relationship between in-vivo and ex-vivo gray matter susceptibility measurements on the same hemispheres. Five brain hemispheres from community-dwelling older adults were imaged ex-vivo with QSM on a weekly basis for six weeks postmortem, and the longitudinal behavior of ex-vivo magnetic susceptibility in both gray and white matter was assessed. The relationship between in-vivo and ex-vivo gray matter susceptibility measurements was investigated using QSM data from eleven older adults imaged both antemortem and postmortem. No systematic change in ex-vivo magnetic susceptibility of gray or white matter was observed over time postmortem. Additionally, it was demonstrated that, gray matter magnetic susceptibility measured ex-vivo may be well modeled as a linear function of susceptibility measured in-vivo. In conclusion, magnetic susceptibility in gray and white matter measured ex-vivo with QSM does not systematically change in the first six weeks after death. This information is important for future cross-sectional ex-vivo QSM studies of hemispheres imaged at different postmortem intervals. Furthermore, the linear relationship between in-vivo and ex-vivo gray matter magnetic susceptibility suggests that ex-vivo QSM captures information linked to antemortem gray matter magnetic susceptibility, which is important for translation of ex-vivo QSM findings to in-vivo

Ex-vivo magnetic susceptibility as a function of in-vivo magnetic susceptibility.

<p>Plot of regional gray matter magnetic susceptibility values measured ex-vivo as a function of the corresponding susceptibility values measured in-vivo in the same hemispheres, for all hemispheres of Dataset 2. Each point in the scatter plot represents a single gray matter brain region of a single hemisphere. Ex-vivo magnetic susceptibility values shown in the plot have been corrected for the effects of lower temperature during ex-vivo imaging [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188395#pone.0188395.ref004" target="_blank">4</a>].</p

Correspondence of in-vivo and ex-vivo data within the same participants.

<p>In-vivo and ex-vivo magnetic susceptibility and gradient-echo magnitude maps for a section of the basal ganglia of three hemispheres from Dataset 2 imaged both in-vivo and ex-vivo.</p

Dataset 1 characteristics.

<p>Dataset 1 characteristics.</p

Ex-vivo magnetic susceptibility maps.

<p>Examples of axial ex-vivo magnetic susceptibility maps of human brain hemispheres from five participants.</p

Magnetic susceptibility over time postmortem for gray and white matter regions.

<p>Plots of ex-vivo magnetic susceptibility in selected gray and white matter regions as a function of time postmortem, for all hemispheres of Dataset 1. Error bars around individual data points represent the 95% confidence interval of the susceptibility values within the region at that specific time point.</p

Postmortem brain hemisphere in imaging container.

<p>Example of a participant’s brain hemisphere submerged in formaldehyde solution.</p

Voxel-wise differences in magnetic susceptibility maps of consecutive time-points.

<p>Ex-vivo magnetic susceptibility difference maps between consecutive time-points, for all hemispheres of Dataset 1. The corresponding susceptibility map and spin-echo image of the last time-point are displayed on the rightmost two columns. Note: For hemisphere D, the difference map marked with an asterisk represents the difference between the third and fifth time-points.</p

Measurements from 3T as a function of measurements from 1.5T.

<p>Plot of magnetic susceptibility in selected gray and white matter regions of the same hemisphere imaged postmortem using both in-vivo (1.5T) and ex-vivo (3T) QSM methods (Dataset 3).</p