In this cohort of 425 community-dwelling, older persons, microinfarcts are common and associated with increased odds of dementia. The effect on dementia appears to be driven by multiple cortical infarcts. Further, both single and multiple cortical microinfarcts are associated with lower cognition, specifically perceptual speed and semantic memory, with a lesser but significant effect on episodic memory. Analyses took into account demographic and neuropathologic covariates, including common neuropathologic causes of dementia. Associations with dementia and cognition were not modified by the presence of macroscopic infarcts or differing levels of AD pathology, suggesting effects of microinfarcts were independent of these other common neuropathologies.
Few epidemiologic, clinical-pathologic studies have examined the frequency of microinfarcts and their relation with dementia or cognition.4,6,21
Several have reported frequencies of microinfarcts in the range of 20–50%.5–8
Similarly, we found that microinfarcts are common, affecting almost a third of all subjects, and present in a third of those with dementia and a quarter of those without. Previous data have suggested a relation of microinfarcts with dementia. Because microinfarcts are associated with macroscopic infarcts and pathologies causing dementia often co-exist,3,22
analyses need to take into account a variety of vascular and non-vascular pathologies. We are aware of only four community-based cohort studies in which the role of microinfarcts in dementia has been directly addressed, while taking into account other pathologies. Three of these found a relation of microinfarcts to dementia5–7
and one found a trend,8
and relations appeared to be driven by multiple and cortical pathology. Our study confirms and extends the findings from these previous published data. We found that microinfarcts, particularly multiple cortical microinfarcts, independently increased odds of dementia even after accounting for both macroscopic infarcts and level of AD pathology, as well as other demographic and pathologic covariates. In addition, we found that microinfarcts are additive to macroscopic infarcts and AD pathology and do not modify their association to dementia or cognitive function.
Little is known about microinfarcts and global cognition or specific cognitive domains. In the Honolulu Asia Aging Study including 443 autopsied men, microvascular infarcts (microinfarcts and lacunar infarcts) were associated with a lower score on a brief screening measure of global cognition (CASI), but specific cognitive domains were not studied.21
We similarly found an association between microinfarcts and global cognition. Unlike for dementia which was related to only multiple microinfarcts, both single and multiple microinfarcts were implicated when cognition was the outcome measure; this finding may be the result of increased power using a continuous outcome rather than the dichotomous outcome of dementia. Moreover, both single and multiple cortical microinfarcts were specifically associated with lower levels of perceptual speed and semantic memory. This profile is similar to that of macroscopic infarcts. Further, we found a weaker but significant association with episodic memory impairment. While this type of impairment is most commonly associated with clinical AD, other pathologies including macroscopic infarcts have also been associated with it.22
These data further highlight that impairment of episodic memory is not specific for AD pathology and suggest that differing pathologies may result in similar cognitive phenotypes.
Mechanisms by which microinfarcts relate to dementia and cognition are currently unknown. Half of persons with microinfarcts did not have macroscopic infarcts; in addition, the microinfarct effects were independent of other common pathologies. Notably, we did not find evidence that microinfarcts modified the clinical expression of macrosopic infarcts or AD pathology. A variety of plausible mechanisms linking microinfarcts to dementia and cognition may be considered. Volume of infarcts is often considered an important factor in the association of infarcts to dementia,3,6,23,24
yet microinfarcts by definition are of very small volume. One may consider that there is an unrecognized large burden of microinfarcts resulting in a large volume of tissue loss.
Alternatively, microinfarcts may represent a diffuse vascular process with deleterious tissue effects, such as diffuse hypoperfusion with hypoxia, oxidative stress, or inflammation. In addition, these processes may mediate or modify the effect of microinfarcts. Single and multiple infarcts thereby may represent proxies for small and large volumes of infarcts or mild or severe diffuse injury.
We found that cortical but not subcortical microinfarcts are related to dementia and cognitive impairment. This has also been found in previous studies.6,25
This dissociation may represent differing mechanisms for the evolution or effects of microinfarcts in the subcortical versus cortical locations. Alternatively, specific anatomical regions may need to be affected in order to have a clinical expression of dementia or cognitive impairment. Indeed, we have previously reported an association of subcortical macroscopic infarcts with cognition.26
This may be related to cohort differences, regional sampling differences, or other unrecognized factors. Further study, including specific regions within cortical and subcortical structures, with larger numbers, will be needed to tease out mechanisms underlying relations of microinfarcts to dementia and cognition.
There are limitations to this study. First, assessment for microinfarcts was performed on a relatively small number of brain regions from one hemisphere, and likely underestimated the number of microinfarcts and regional involvement. While a more comprehensive evaluation, including more regions/both hemispheres and additional staining methods,27
may provide more accurate estimates, it is important to note that our results are similar to those who performed more extensive sampling strategies, while using a comparable definition of microinfarcts.21
Also, identification of microinfarcts was based on assessment of cortical and subcortical regions, unlike in some other studies.25
Second, because of the unique demographic and life-style features of this cohort, findings may not be generalizable and will need to be replicated in a more diverse cohort.
Strengths of the study include detailed, systematic neuropathologic assessments blinded to clinical data, and availability of common neuropathologies in aging and dementia. Clinical data were available on dementia status and a detailed battery of neuropsychological tests obtained proximate-to-death, from which summary measures of five different cognitive systems were derived, minimizing sources of measurement error. Finally, this cohort comprised a large group of community-dwelling women and men with and without dementia, and the study benefits from high follow-up and autopsy-rates (both >90%), providing internal validity of findings.