We found that brain infarcts are associated with a smaller hippocampus, and that both infarcts and hippocampal volume are independently associated with global memory functioning. Furthermore, infarcts and hippocampal volume are associated with specific aspects of memory functioning, which are overlapping but unique.
The traditional view is that vascular disease and AD are frequent causes of dementia.29
The clinical profile of vascular dementia is thought of as primarily a decline in nonmemory domains of cognition, in particular executive function and perceptual speed, and any significant memory decline is attributed to coexisting AD and AD-associated hippocampal atrophy. Although the current study did not examine individuals with dementia per se, the implication of our data is significant in that they suggest that history of brain infarcts can lead to a phenotype that is typically thought of as prodromal AD—that is, infarcts are associated with poorer memory, and smaller hippocampus, not just poorer performance in nonmemory domains. Brain infarcts, particularly subcortical ones, are associated primarily with executive dysfunction, whereas hippocampal volume is correlated with memory performance.9,30,31
Cortical infarcts, in addition to being associated with deficits in processing speed, are also associated with worse episodic memory, but these findings have been interpreted with caution.7,8
A significant gap has remained in the literature: to our knowledge, ours is the first study to examine whether memory is associated with the presence of prior infarcts independently of hippocampal atrophy.
Memory processing is dependent on communication of the hippocampus with diffuse brain networks, including association cortices, and subcortical structures such as the thalamus, the basal forebrain, and the amygdala. Infarcts causing injury to parts of this network likely cause dysfunction in some aspect of memory processing and performance. Memory deficits could also be secondary to destruction of brain parenchyma, granular cortical atrophy, or other cortical changes due to infarcts themselves or hypoperfusion,32
or a consequence of deficits in other cognitive domains. Another possibility is that the ischemia that causes infarcts can also affect the hippocampus. The CA1 subfield of the hippocampus is most susceptible to ischemia, and infarcts are related to lower blood volume in this region.16
Thus, it is also possible that infarcts and neurodegenerative disease affect the hippocampal formation in distinct and complementary ways that result in similar clinical phenotypes.33
Interestingly, the phenotype may be only grossly identical—with prominent memory deficit—but under the surface there appears to be a unique effect of infarcts and hippocampus volume on memory. Hippocampal volume was associated specifically with memory performance, whereas infarcts were associated with poorer performance in all cognitive domains. When we examined specific aspects of memory testing, we found that although overlapping to some degree, the performance profiles associated with smaller hippocampus, cortical, and subcortical infarcts are unique. Hippocampal volume is associated with performance on long-term recall, delayed recognition, and delayed free recall. This finding is consistent with classically described hippocampus-dependent functions.14
Subcortical infarcts, on the other hand, showed a significant association with performance on learning, long-term recall, and delayed recall. Although we cannot rule out that executive dysfunction9
is contributing to the learning and memory deficit observed, participants with subcortical infarcts show evidence of deficits in learning and long-term memory. Cortical infarcts were associated with performance on delayed recognition of the selective reminding test. It should be noted that infarct data were coded categorically as present or absent; quantitative volumetric analysis of cerebral infarcts may yield more precise information about the relationship between the severity of cerebrovascular disease and cognition.
In addition to the observed hippocampus independent effect on memory performance, we found that infarcts are associated with a smaller hippocampus above and beyond whole-brain atrophy, and in turn that a smaller hippocampus is associated with poorer memory performance. These findings suggest that memory deficits may occur with brain infarcts secondary to both extrahippocampal and hippocampal processes—two independent sources of memory dysfunction. The etiology of hippocampal atrophy in aging is generally thought to be neurodegeneration related to AD or sclerosis.34,35
The observed associations of infarcts and hippocampal volume with cognitive function in our study could be explained by either or a combination of these processes. Numerous studies have suggested an association or interaction between cerebrovascular disease and AD,36,37
possibly due to accelerated AD pathology, such as increased deposition of amyloid. Hippocampal sclerosis in those with brain infarcts could be secondary to transient or chronic hypoperfusion related to vascular disease, or wallerian degeneration secondary to cortical injury in brain regions communicating with the hippocampus.32,38
Our observation that hippocampal atrophy is not related to infarcts within the vascular territory supplying the hippocampus may support the latter hypothesis.
A recent study among 425 elderly subjects with neuropathologic examination found an association of cortical microinfarcts with worse semantic and episodic memory8,9
and there was no interaction of microinfarcts with AD pathology. Taken together with our results, these observations further support the notion that brain infarcts exert a negative effect on memory function independently of markers of incipient AD, including hippocampal atrophy. The observation that brain infarcts have an effect on memory and other cognitive domains independently of changes in hippocampus has significant implications with regard to a critical need for stroke prevention. In a prospectively followed community sample of elderly subjects, more than 50% of those with dementia had multiple pathologies on autopsy, whereas among those without dementia over 80% have single or no pathology.11
This observation suggests that dementia is a cumulative effect of “multiple hits” that most often include AD, Parkinson/Lewy body pathology, and brain infarcts; focusing on prevention of one of the “hits” may decrease the incidence of dementia. The majority of individuals in our study who were found to have brain infarcts on MRI had no clinical history of stroke. In this community cohort, the sensitivity of stroke self-report for a diagnosis of stroke on MRI is only 32.4%.39
Therefore, brain infarction is largely a silent injury, and aggressive clinical screening and neuroradiologic examination would be needed to identify individuals with and at risk for development of brain infarcts. Brain infarcts are a largely preventable brain injury, with clearly identified risk factors, and prevention programs. A public health push toward emphasizing stroke prevention may significantly decrease incidence of dementia.