Background
Subcortical vascular dementia (SVaD) is the most common type of vascular dementia in the memory clinic setting. Unlike other types of vascular dementia showing a stepwise deterioration and fluctuating course, patients with SVaD have insidious onset and gradual progression of disease, similarly to neurodegenerative dementia [
1]. SVaD is characterized by extensive cerebral small vessel disease (CSVD), such as white matter hyperintensities (WMH) and lacunes, on magnetic resonance imaging (MRI) [
2]. Previous studies showed that about 30% of patients with SVaD had increased uptake of amyloid-β (Aβ) measured by carbon-11-labeled Pittsburgh compound B ([
11C]PiB) positron emission tomography (PET) [
3]. Aβ-negative patients with SVaD and those with its prodromal stage, subcortical vascular mild cognitive impairment (svMCI), showed cortical thinning prominently in the frontal and perisylvian regions, although CSVD was located predominantly in the subcortical regions [
4]. In fact, cortical thinning might be considered as an important biomarker in patients with SVaD and patients with svMCI because it has been reported that CSVD was independently associated with cortical thinning, regardless of increased uptake of Aβ [
5].
In previous studies, the protective effects of education reducing the risk of dementia have been shown in neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD) [
6‐
9]. Neuroimaging studies showed higher levels of education to be correlated with more severe neurodegeneration as measured by cortical atrophy, hypometabolism, or hypoperfusion in patients with AD dementia [
10,
11], mild cognitive impairment (MCI) [
12], preclinical AD [
13], or FTD [
14] when controlled for cognitive performance. Results from these studies have been explained by the theory of cognitive reserve [
15]. Cognitive reserve refers to the ability to make efficient and flexible use of the brain for task performance, and it is estimated using education, IQ, and leisure activities [
16]. In the cognitive reserve concept, individuals with higher education can cope with a larger extent of neurodegeneration before showing a level of cognitive impairment similar to that of someone with a lower level of education. Higher network efficiency and capacity (neural reserve) or compensatory functional brain differences (neural compensation) may account for such a higher reserve ability [
16,
17]. Thus, according to the cognitive reserve hypothesis, protective life factors such as education mitigate the impact of brain pathology in cognition.
Beyond AD, cognitive reserve theory has not been well studied in vascular dementia. Previous studies reported that lower education levels predicted an increased risk of developing of poststroke cognitive impairment [
18,
19]. In support of the hypothesis that education is related to reserve capacity in vascular dementia, it was previously shown that patients with higher education had a higher cognitive status than those with lower education despite similar degrees of subcortical hyperintensities [
20]. However, these studies did not assess the influence of education on possible comorbidities such as AD pathology or on the level of brain integrity, including gray matter atrophy.
Previous studies by our group [
10,
21,
22] suggested there were differences in the relationships between levels of education and cortical thickness among levels of cognition. That is, healthy control subjects showed a positive correlation between level of education and cortical thickness, whereas patients with dementia showed a negative correlation between level of education and cortical thickness. Another study by our group [
23] suggested that there might be an inflection point in MCI stage. That is, the protective effects of education against cognitive decline remain in early-stage amnestic MCI and disappear in late-stage amnestic MCI. It would therefore be reasonable to expect that the correlation of education with cortical thinning might be more prominent in dementia stage rather than in MCI stage.
In the present study, we examined the correlation of education with cortical thickness and CSVD markers in patients with PiB(-) svMCI and patients with PiB(-) SVaD. We divided these patients into svMCI and SVaD groups because the cortical thinning patterns and the severity of cortical thinning and CSVD markers are different between these two groups [
4]. The correlation of education might be distinct according to different vulnerable areas. On the basis of the cognitive reserve hypothesis, we predicted that both patients with SVaD and patients with svMCI would show a negative correlation between education and cortical thickness or a positive correlation between education and CSVD MRI markers when controlling for cognitive status in each group. In addition, we supposed that the correlation of education would be maximized in the SVaD group.
Discussion
In the present study, we investigated the correlation of education with cortical thinning and CSVD in patients with svMCI and patients with SVaD. Our main findings were as follows. First, in the SVaD group, higher education was correlated with more severe cortical thinning, whereas in the svMCI group, there was no correlation of education with cortical thickness. Second, the correlation between education and cortical thinning in patients with SVaD had regional specificity for the bilateral dorsolateral frontal, left medial frontal, and parahippocampal areas. In contrast, we did not find any correlation between education and CSVD, including WMH and lacunes, in patients with svMCI and patients with SVaD. Taken together, our findings suggested that education gives an ability to endure cortical thinning in patients with SVaD, which might be explained by the cognitive reserve hypothesis.
Our major finding was that a higher level of education was correlated with more severe cortical thinning in patients with SVaD. Our findings are consistent with a previous study based on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is a genetic variant of pure vascular cognitive impairment with severe CSVD. That study demonstrated that education had a protective effect on cognitive performance in patients with vascular pathology [
39]. However, there was no correlation between education and cortical thickness in patients with svMCI in our study. The results are also consistent with studies in patients with AD dementia, showing higher education levels to be associated with more cortical thinning [
10], whereas these effects were not prominent in MCI stage [
40,
41]. In terms of MCI, not subcortical vascular type, there are several studies with inconsistent results regarding cognitive reserve. Cognitive reserve proxies, including education, are not associated with cortical atrophy [
40,
41] or functional activity [
12], but cognitive reserve has a negative association with brain volumes [
12]. Researchers in one study reported that higher cognitive reserve, including education, is related to more severe hypometabolism in MCI [
42].
Although the correlation of education with gray matter thinning in AD but not in MCI seems perplexing, the results may be reconciled when considering the dynamic evolution of reserve effects during the course of AD. We previously observed in a longitudinal study that better-educated participants with early-stage MCI had a slower decline in cognition, whereas better-educated participants with late-stage MCI had faster rates of cognitive decline than less well-educated participants with MCI [
23]. Better-educated participants with late-stage MCI were more likely to convert to AD dementia within the next 1.4 years [
23]. Consistent with those results, previous longitudinal studies showed higher education to be associated with steeper cognitive decline shortly before conversion to AD [
43,
44]. These results suggest that individuals with higher education may dynamically exhaust the reserve capacity until a threshold where an even steeper cognitive decline follows owing to the relatively high degree of accumulated pathology. Thus, better-educated individuals should have accrued, especially at the dementia level, much more neurodegeneration than individuals with lower education levels, whereas at the MCI level, the accrued neurodegeneration will be more subtle. Although reserve effects in prodromal AD have been demonstrated across different studies [
45,
46], the neurodegeneration in svMCI may be more subtle, and thus any reserve effects may be more difficult to detect.
Unexpectedly, we did not find any correlation between the level of education and CSVD MRI markers in patients with svMCI and patients with SVaD, suggesting that high education level had no role in buffering against vascular pathology. In a previous study, higher cognitive reserve (e.g., education) was associated with more severe WMH [
47]. In healthy elderly people, higher cognitive reserve protects against the cognitive deterioration related to WMH [
47‐
49]. One study in which researchers investigated patients with CADASIL showed that education significantly influenced cognitive function in patients with mild to moderate brain pathology, including lacunes, whereas there was no effect of education on cognition in patients with severe pathology [
39]. We supposed that cognitive reserve mitigates the impact of cortical thinning but not CSVD in patients with already substantial vascular pathology such as our participants. In svMCI and SVaD, CSVD burden may exceed a threshold beyond which the attenuating effect of education on cognitive function may disappear.
Our final finding was that the association between education and cortical thinning in SVaD had regional specificity for the frontal region, which is partially different from the distribution of the association in AD. There have been no studies investigating the specific brain regions related to education in patients with SVaD. Considering that patients with PiB(-) SVaD had cortical thinning prominently in the frontal and perisylvian regions, our findings suggested that the regions related to education in PiB(−) SVaD seemed to overlap with prominently involved regions in PiB(−) SVaD. In fact, a previous study based on patients with AD showed that higher education levels were found to correlate with cortical thinning prominently in the temporoparietal association region where patients with AD had characteristic cortical thinning [
10]. Our findings therefore suggest that the correlation of education with cortical thickness occurs in the vulnerable regions where each type of dementia showed cortical thinning [
4]. The compensatory mechanism related to specific areas has not been extensively established. Further investigation is needed. However, our findings suggested that the cognitive hypothesis might be applicable to patients with PiB(-) SVaD.
The strengths of our study are that we investigated the correlation of education with cortical thickness in patients with vascular pathologies without AD pathologies using multimodal imaging analyses. However, there are some limitations of the current study. First, we did not obtain more information on sociodemographic variables, such as occupation and leisure activities, other than the duration of education to confirm cognitive reserve. Second, we did not consider the effects of other pathologies, including other AD pathologies (soluble Aβ and neurofibrillary tangles), microinfarcts, or possible combined degenerative dementia (dementia with Lewy bodies and FTD) pathologies, which are also associated with cortical thinning. Third, the education level (mean 8.7 years) of our participants was lower than that of other cohorts (mean 15–17 years), such as the Alzheimer’s Disease Neuroimaging Initiative [
41,
50]. Elderly Koreans had less opportunities for educational attainment owing to the Korean War and an increased dropout rate owing to financial reasons following the war. Finally, our study population included a large proportion of patients with significant vascular burden, which may limit the generalizability of our data to other populations.