The brain in the age of old: the hippocampal formation is targeted differentially by diseases of late life

Abstract

Objective: To rely on the anatomical organization of the hippocampal formation in understanding whether and how late-life diseases such as diabetes and stroke contribute to age-related cognitive decline.

Methods: Magnetic resonance imaging (MRI) was used to document brain infarcts and to generate high-resolution functional maps of the hippocampal formation in 240 community-based nondemented elders (mean age, 79.7 years) who received a comprehensive medical evaluation. Sixty participants had type 2 diabetes mellitus, whereas 74 had MRI-documented brain infarcts, and the first analysis was designed to pinpoint hippocampal subregions differentially linked to each disorder. Then, guided by the results, additional functional MRI studies in aging rhesus monkeys and mice were used to test proposed mechanisms of dysfunction.

Results: Although both diabetes and brain infarcts were associated with hippocampal dysfunction, each was linked to separate hippocampal subregions, suggesting distinct underlying mechanisms. The hippocampal subregion linked to diabetes implicated blood glucose as a pathogenic mechanism, a hypothesis confirmed by imaging aging rhesus monkeys and a mouse model of diabetes. The hippocampal subregion linked to infarcts suggested transient hypoperfusion as a pathogenic mechanism, a hypothesis provisionally confirmed by comparing anatomical patterns across subjects with infarcts in different vascular territories.

Interpretation: Taken together with previous findings, these results clarify how diseases of late life differentially target the hippocampal formation, identify elevations in blood glucose as a contributing cause of age-related memory decline, and suggest specific interventions that can preserve cognitive health.

Figure 1. Functional maps of the hippocampal formation

A. A sagital scout image was used to identify the long axis of the hippocampal formation (demarcated by the solid line). High-resolution T1-weighted images are acquired perpendicular to the hippocampal long axis (stippled line). B. The general locale of 4 hippocampal subregions are shown in a post-mortem hippocampal slice (upper left panel)-- the entorhinal cortex (EC), dentate gyrus (DG), CA1 subfield (CA1), and the subiculum (Sub). A single MRI slice (upper right panel) contains all 4 hippocampal subregions and provides sufficient anatomical information to parse the hippocampal formation. Specifically, by identifying the external morphology of the hippocampal formation (as demarcated by the white line in lower left and right panels), and its internal architecture (as demarcated by the black line in the lower left and right panels), regions-of-interest can be drawn in the entorhinal cortex (green), dentate gyrus (blue), CA1 subfield (red), and the subiculum (yellow). C. Cerebral blood volume (CBV) maps are shown for an individual control, and a subject with diabetes or infarcts. Maps are color-coded such that warmer colors indicate greater CBV.

Figure 2. Diabetes and infarcts are differentially linked to separate hippocampal subregions

A. The distribution of subjects with and without type 2 diabetes mellitus (diabetes), with and without infarcts. B. Mean cerebral blood volume (CBV) of subjects with (gray bars) and without (black bars) diabetes across the different hippocampal subregions—the entorhinal cortex (EC), dentate gyrus (DG), CA1 subfield (CA1), and the subiculum (SUB). Compared to subjects without diabetes (no diabetes), those with diabetes (diabetes) have selective reductions in entorhinal cortex and dentate gyrus CBV (as indicated by asterisks). C. Mean cerebral blood volume (CBV) of subjects with (gray bars) and without (black bars) infarcts across the different hippocampal subregions. Compared to subjects without infarcts, those with infarcts have selective reductions in CA1 and subiculum CBV (as indicated by asterisks).

Figure 3. Blood glucose selectively targets the dentate gyrus

A. Blood glucose levels are inversely correlated with dentate gyrus (DG) CBV in rhesus monkeys. B. Compared to control mice (black bars), streptazosin-treated mice (gray bars) have dominant reductions in dentate gyrus (DG) CBV.

Figure 4. Infarcts in the hippocampal vascular territory are linked to the CA1 subfield

A reduction in CA1 CBV was found selectively among subjects with infarcts in the hippocampal vascular territory (“hippo”). In contrast, a reduction in subiculum CBV was found in subjects with infarcts in the hippocampal vascular territory and infarcts in other vascular territories (“other”).

Figure 5. Blood insulin selectively targets the entorhinal cortex in a stroke-dependent manner

A. Blood insulin levels are inversely correlated with entorhinal cortex (EC) CBV in subjects with infarcts in the hippocampal vascular territory (left scatter plot) but not in subjects without infarcts (right scatter plot). B. Blood insulin levels are not correlated with dentate gyrus (DG) CBV in subjects with infarcts in the hippocampal vascular territory (left scatter plot) or in subjects without infarcts (right scatter plot).