By investigating the aging hippocampal formation in a large clinically-characterized cohort, our results clarify how type 2 diabetes and brain infarcts, two common diseases of late-life, interact with the hippocampal formation. Moreover, taken together with previous studies, our results suggest mechanisms underlying cognitive aging and point to therapeutic strategies.
The results highlight the importance of evaluating the hippocampal formation in a manner compatible with its anatomical and molecular complexity. As indicated by the multivariate results, both diabetes and infarcts were associated with global hippocampal dysfunction; it was only by examining the univariate results subregion-by-subregion that differences between the diseases were observed. Showing that each disease is differentially linked to separate subregions immediately suggests distinct mechanisms of pathogenesis. Moreover, by pinpointing the individual subregions linked to each disease specific hypotheses could be generated and tested.
In the case of diabetes, our primary human findings suggested that the dentate gyrus is differentially vulnerable to blood glucose levels. Illustrating the utility of cross-species CBV mapping, we were then able to test this hypothesis, first in aging rhesus monkeys in whom there is greater experimental control, and then, more definitively, in a mouse model of hyperglycemia. Although each study had it own limitations, as a composite the human, monkey, and rodent findings establish that blood glucose differentially targets the dentate gyrus.
In the case of vascular disease, our results suggested that infarcts outside of the hippocampal formation are differentially linked to dysfunction in the CA1 subfield and the subiculum. Guided by previous studies7, 22
, we postulated that the link between CA1 dysfunction and infarcts might reflect transient hippocampal hypoperfusion. Non-human primates do not naturally develop infarcts, and experimentally causing an infarct selectively in the hippocampal vascular territory is difficult. Therefore, unable to test this hypothesis in animal models we returned to the human dataset. By showing that CA1 dysfunction was differentially observed only in subjects with infarcts in the hippocampal vascular territory, this proposed mechanism was provisionally confirmed. More direct confirmation will be provided by generating hippocampal CBV maps during the acute phases of stroke in different vascular territories.
In contrast to the CA1 subfield, we also found stroke-related dysfunction in the subiculum, and by showing that this effect occurs independent of vascular territory our results suggest that there are additional mechanisms that link infarcts to hippocampal dysfunction. Nevertheless, strokes in the hippocampal vascular territory are common, and the proposed mechanism for CA1 dysfunction has potential therapeutic implications. Specifically, because excitotoxicity is thought be mediate CA1 dysfunction, our results suggest that as in the case of bilateral carotid occlusion23
, glutamate blocking agents such as memantine might be beneficial in patients who suffer an acute focal stroke in the hippocampal vascular territory.
A range of previous studies have established that the entorhinal cortex is differentially vulnerable to the early stages of AD, which has been captured by hippocampal CBV imaging15
. Because diabetes and infarcts might interact with AD pathology, it is theoretically possible that hippocampal dysfunction observed in stroke and diabetes is simply a reflection of these processes accelerating underlying AD pathology. By targeting other hippocampal subregions, our results suggest that both diabetes and infarcts can cause hippocampal dysfunction independent of AD pathophysiology. At the same time, our last analysis, showing that the entorhinal cortex is differentially sensitive to insulin in a stroke-dependent manner, provides an interesting anatomical site of convergence linking AD, diabetes, and infarcts. Because this final analysis was based on a relatively low number of subjects, however, further studies are required to better understand this complex relationship.
Showing that blood glucose selectively targets the dentate gyrus is not only our most conclusive finding, but it is the one most important for ‘normal’ aging—i.e., hippocampal dysfunction that occurs in the absence of disease states, such as AD, infarcts, and diabetes. Indeed, cognitive studies have established that normal age-related hippocampal dysfunction begins quite early24
, typically during the 4th
decade of life, before the onset of age-related diseases. Furthermore, age-related hippocampal dysfunction occurs in all non-human mammals25
, who do not typically develop AD, stroke, or diabetes. Consistent with this, our cross-species findings document that the detrimental affects of glucose on the hippocampus19, 20
occurs independent of AD and infarcts, and our monkey findings in particular suggest that it occurs independent of overt diabetes.
With increasing longevity and decreasing morbidity age-related hippocampal dysfunction has emerged as a cognitive epidemic. Nevertheless, underlying causes of age-related hippocampal dysfunction have remained unknown. Importantly, converging evidence in humans26 27
, non-human primates14 28
, and rodents14, 15
have suggested that the dentate gyrus is differentially vulnerable to normal aging29
. At the same time, an independent series of cross-species studies has shown that glucose regulation worsens with advancing age30, 31
. Taken together, our findings suggest that glucose dysregulation is as at least one systemic etiology underlying age-related hippocampal dysfunction.
Beyond the obvious conclusion that preventing late-life disease would benefit the aging hippocampal formation, our findings suggest that maintaining glucose control, even in the absence of disease, should be strongly recommended to preserve cognitive health. More specifically, our findings predict that any intervention that causes a decrease in blood glucose should increase dentate gyrus function and would therefore be cognitively beneficial. In fact, separate studies examining the effects of physical exercise support this prediction. Imaging studies in humans and mice have documented that among all hippocampal subregions physical exercise causes a differential improvement in dentate gyrus function 32
. By improving glucose metabolism, physical exercise also reduces blood glucose33
. It is possible, therefore, that the cognitive enhancing effects of physical exercise are mediated by the beneficial effect of lower glucose on the dentate gyrus. Whether through physical exercise or other behavioral or pharmacological interventions, our results suggest that improving glucose metabolism is a clinically tractable approach for ameliorating the cognitive slide that occurs in all of us as we age.