WMH and infarcts on brain MRI were related to MCI. WMH was more strongly related to amnestic MCI than non-amnestic MCI, while infarcts were more strongly related to non-amnestic than amnestic MCI. Supporting these observations, WMH were related to a memory score, while infarcts were not, and the association between infarcts and non-amnestic cognitive scores was stronger than for WMH. WMH was related to word recognition deficits, suggesting that the association between WMH and memory was not completely explained by retrieval deficits.
CVD is the main culprit in vascular cognitive impairment,15
but CVD may be important in AD. CVD alone can result in cognitive impairment,16
but recent postmortem data suggest that CVD may interact with AD to increase the likelihood of dementia.17,18
Infarctions and WMH are 2 CVD manifestations that can be identified during life.19
Both stroke history20
and CVD on MRI21
are related to higher AD risk. MCI is increasingly used in research and clinical practice. MCI has been characterized into subtypes.2
Amnestic MCI is thought to be more specific to AD, while non-amnestic MCI seems to be related to other causes including CVD.
WMH is related to impairment in frontal-executive abilities22
and our finding of a stronger relation between WMH and amnestic MCI was unexpected. A number of studies have previously reported increased WMH in association with MCI.23,24
Few studies have explored WMH in relation with MCI subtypes. Most are small and clinic-based. Some studies found an association of WMH with amnestic MCI and AD.24,25
Others found that WMH is associated with non-amnestic MCI.26,27
One study found no relation between WMH and MCI subtypes.28
Most studies examining the association of infarcts and MCI are hospital or clinic-based and address MCI following clinical stroke.15,29–34
Cognitive impairment after a stroke is frequent,34
and is characterized by deficits in frontal-executive abilities,32
but persons with dementia after stroke also demonstrate memory problems.32
The Cardiovascular Health Study reported an association between infarcts on MRI and amnestic MCI35
in a large community-based sample.
Our findings suggest that higher WMH is more specific to amnestic than non-amnestic MCI, while infarcts are more specific to non-amnestic MCI. A traditional view is that WMH causes frontal-subcortical pathways disruption resulting in frontal-executive impairment.22
WMH in this context are interpreted as an expression of cerebral small vessel disease,36
possibly of ischemic nature,37
and are proposed as a surrogate marker of small vessel ischemia.36
Thus, our findings for WMH seem paradoxical because amnestic MCI is considered an AD precursor,2,38
while non-amnestic MCI is commonly associated with vascular disease. However, white matter disease is an important correlate of AD.39
WMH are frequent in AD39
and in cerebral amyloid angiopathy (CAA). CAA is related to higher WMH, WMH progression, and cognitive impairment.40
It is possible that some of the WMH we observed in amnestic MCI are not due to cerebral ischemia but could be part of a process accompanying AD, such as CAA or other neurodegenerative changes. Disruption of frontal subcortical pathways by WMH can result in memory deficits due to retrieval impairment, but we found that WMH were associated with recognition deficits. Finally, it is possible that WMH are entirely ischemic, not related to a degenerative pathology, and they are markers for ischemic insults that precipitate the manifestations of AD, memory impairment, and amnestic MCI. We cannot make inferences about the underlying pathology of WMH in our sample, but our results for WMH could be explained by its heterogeneity. That is, some WMH may be ischemic in nature, and some may be secondary to CAA or other degenerative processes. Thus, we believe that the nature of WMH requires further exploration, and that assuming that they are a surrogate marker of cerebral ischemia and systemic vascular burden may not be accurate.
There are alternative explanations for our findings. The apparent stronger association between WMH or infarcts with either amnestic or non-amnestic MCI could be due to chance due to sample variability and multiple comparisons, or to a lack of power to find statistical significance. Our results need to be reproduced in a larger sample.
Our study has several limitations. One is that we selected a group of elderly individuals without dementia to undergo MRI, which may have excluded persons with a higher CVD burden and cognitive impairment. Another limitation is the cross-sectional study design, which limits the inferences that can be made. Strengths of the study include the quantitative measures of WMH and infarcts, the detailed characterization of MCI, and the large community-based sample.