This is the first multi-center study to formally assess the prevalence of moderate-to-severe WML in stroke/TIA and AD/MCI, in different age groups, and from 9 Asian cohorts. The prevalence of moderate-to-severe WML was higher in stroke/TIA (43.3%) than that in AD/MCI (38.2%), X2 (1, n = 3904) = 10.6, p = 0.001. Moderate-to-severe WML was associated with hypertension, hyperlipidemia and a lower MMSE score.
In this study we primarily reported the prevalence of moderate-to-severe WML, rather than any presence of WML. Previous studies that included any presence of WML (i.e. including those with mild WML as well) reported a much higher prevalence of WML, reaching 81.4% in the community.36 We recorded only moderate-to-severe WML because previous studies showed that only those with moderate-to-severe WML as defined by a grade 2 or above in the global rating of Fazekas or ARMCW scale were associated with increased risk of incident cognitive decline. Although mild or focal/punctate WML may still represent early or minor SVD, previous studies showed that it had no or minimal clinical relevance, while longitudinal studies revealed no progression of mild WML over time. Whereas, early confluent to confluent WML will likely progress in size and is clinically relevant.15,18,20,34 In cohorts where the prevalence of mild WML is high and that of moderate-to-severe WML is low, reporting any presence of WML may overestimate the severity of CSVD.
WML in stroke/TIA
Despite the mean age of the stroke/TIA group was the youngest (67.7 ± 12.2 years old) when compared with AD/MCI group (76.3 ± 8.7 years old) and controls (70.3 ± 6.0 years old), stroke/TIA group had a higher prevalence of moderate-to-severe WML to that of AD/MCI group as a whole and at each age group, with a prevalence of 32.2% for age ≤ 60 that increased to 64.2% for subjects older than 80 years (Fig. 1). The high prevalence of moderate-to-severe WML in stroke/TIA was most probably explained to a large extent by the fact that both stroke/TIA and WML shared a strong association with cardiovascular risk factors, in particular hypertension.37 The most alarming finding was observed in Bandung, Indonesia where the prevalence of moderate-to-severe WML is highest among all cities. In particular, hypertension (81.5%) in this group was high despite the relatively young mean age (59 years old). Note further that the Indonesian cohort provided only CT imaging and hence we might have even underestimated the prevalence of moderate-to-severe WML, as CT is less sensitive in detection of WML relative to MRI. This is indeed the first study investigating the prevalence of WML in Indonesia, which showed a very high prevalence of WML in this region, alongside a high prevalence of hypertension.
WML in AD/MCI
The prevalence of moderate-to-severe WML in AD/MCI group was lower than that in stroke/TIA across all age distributions by about 12–15%. Still, the prevalence ranged from 20% for age ≤ 60 to almost 50% for subjects older than 80 year old. The prevalence of HT and other cardiovascular risk factors were lower in AD/MCI than that in the stroke/TIA group, which might at least partially explain the lower prevalence of WML in AD/MCI than in the stroke/TIA group. Another interesting observation was seen in Manila, despite having a large proportion of patients having hypertension (63.1%) and being a current or a past smoker (30%), only 18.9% of the patients in Manila had the lowest prevalence of moderate-to-severe WML. Note that all subjects in the Manila cohort had MRI, and hence, under-reporting of WML was not likely. Whether Filipinos are less susceptible to the development of WML in association with hypertension requires further investigation.38
WML in the control group
Our previous report on the prevalence of CSVD in Asian communities did not report specifically the prevalence of moderate-to-severe WML according to different age groups.27 In the current study, the prevalence of moderate-to-severe WML rose from 28.1% at 61–70 years old to 65.2% at ≥ 81 years old. Of note, this prevalence of WML is even slightly higher than the prevalence rates of amyloid positivity reported previously among subjects with normal cognition, which vary from around 20% at 70 years old to slightly above 40% at 90 years old.39 Among the three cities with community subjects, Singapore recorded the highest prevalence of moderate-to-severe WML despite a mean age of only 69.96 years old, which could again be related to the fact that Singapore group had the highest prevalence of hypertension (80.4%) and hyperlipidemia (75.4%) relative to other cities.
Association between WML, vascular risk factors and global cognition
We found that the strength of association between hypertension and moderate-to-severe WML decreased with increasing age, which suggested that the effects of blood pressure-lowering therapy may be more effective in the younger age group. While among older patients, factors other than high blood pressure (e.g. impaired autoregulation) may have a greater contribution to WML.40 Note further that the strength of association between hypertension and WML in the AD/MCI group (p < 0.001; OR = 1.75, 95% CI = 1.39–2.21) was similar to that of in the stroke/TIA (p < 0.001; OR = 1.76, 95% CI = 1.37–2.25) or control groups (p < 0.001; OR = 1.97, 95% CI = 1.52–2.55), suggesting that moderate-to-severe WML observed in subjects with AD/MCI did have a significant vascular component.
Previous studies showed conflicting results with respect to the association between hyperlipidemia and WML.41,42 The present study with a large sample size of approximately 6000 subjects did show a small yet significant association between hyperlipidemia and moderate-to-severe WML. The strength of association was less than that for hypertension. Similar to most previous studies, we could not demonstrate an association between DM and WML. Note, however, that other studies showed that DM was related to measures of lacunes, rather than to WML.43–45
Above all, we have shown that moderate-to-severe WML was associated with worse cognitive performance in stroke/TIA, AD/MCI and controls. MMSE of those with moderate-to-severe WML was approximately 2 points lower compared to those without moderate-to-severe WML among all subjects and among each of the clinical groups.
Strengths and limitations
The strength of this study includes the large sample size, the inclusion of the AD/MCI and stroke/TIA groups that are known with a high prevalence of moderate-to-severe WML, as well as a large control group for comparison. Further, this is the first joint international effort with standardized measurement of the WML burden across multiple clinical cohorts in different Asian cities. In addition, analyses in this study were also adjusted with confounders such as age, sex, education, vascular risk factors, disease groups, and different Asian cities.
However, there are certain limitations in this study. First, we acknowledge that certain biases were introduced in the study. Similar to any multi-center study, the pooled sample may contain a more heterogeneous dataset across centers, as well as a potential source of sampling bias from non-random recruitment. However, we have set the study-specific inclusion and exclusion criteria, and used the same neuropsychological screening test (MMSE). Survival bias may be introduced as the patients enrolled into study could have been biased to the younger group who had better cognitive function, and milder chronic brain changes. This could lead to an underestimation of the true magnitude of the prevalence of WML in each city, as well as the association between WML, vascular risk factors and cognition. Hypertension was based on patient history and any use of antihypertensive medication. This can induce systematic bias into the study. However, clinicians and researchers have ensured accurate reporting and entry during the data collection period to reduce such bias.
Second, we have only used a brief screening test to measure the overall cognitive function. MMSE is not sensitive in detecting executive dysfunction or slow processing speed that are predominantly affected by CSVD. Further, the MMSE was administered in various languages and cultures specific to the local population and there may be characteristics differences in each version.46 Third, we acknowledge that Fazekas and ARWMC are two different visual rating scales for WML. Although the scales are different, a cut-off at ≥ 2 in both scales was selected as they both indicated a certain severity of WML that are progressive, and thus, malignant, 47 and lead to devastating outcomes such as global functional decline or delayed-onset dementia.20,48,49 The Hong Kong community dataset with both Fazekas and ARWMC global ratings showed that the correlation between the scales is high (p < 0.0001; r = 0.943).
Forth, WML can be associated with inflammation, cerebral amyloid angiopathy, or neurodegenerative disease secondary to Wallerian degeneration, which we were unable to differentiate in this study. Fifth, although we had included data from Bengaluru India to investigate the prevalence and vascular risk factors of WML, the small sample size prevented us from making a comparison on its prevalence of WML with other cities/ethnicities. Finally, other CSVD imaging markers such as lacunes, cerebral microbleeds, enlarged perivascular space and microinfarcts were not assessed and may have impact on the overall clinical manifestation.
Our findings that there was a high burden of CSVD/WML in stroke/TIA, AD/MCI, community controls and specific cities (e.g. Indonesian, Singaporean), and that it was associated with hypertension, hyperlipidemia and poor global cognition. These findings have huge implications in the management, research and public health strategies for preventing dementia in Asia. Strategies that can improve management of high blood pressure and lipids at both population and individual levels cannot only prevent stroke, but also potentially prevent or delay the development and progression of subclinical CSVD/WML. Recent clinical trials of large sample sizes and long durations did show positive effects of aggressive blood pressure lowering and use of statins upon reducing the progression of WML, along with possible benefits upon cognition.50–53 54 Note that any strategies targeting CSVD should also incorporate other measures relevant to dementia prevention (e.g. reduce air pollution, limit alcohol, avoid smoking, provide primary and secondary education, reduce obesity and diabetes, increase physical exercise, improve sleep) so as to achieve the maximal effect in reducing dementia burden. Note further that control in hypertension, in particular, should start in mid-life as the evolution of WML from no to severe WML may take more than a decade. Such comprehensive strategies if can be implemented aggressively and efficiently in cities with high burden of vascular risk factors and CSVD (e.g. Indonesia), the effect size in preventing dementia cases in these cities may be more pronounced. In addition to primary preventive strategies, we propose that more clinical trials should target individuals who already harbor moderate-to-severe CSVD/WML at different clinical contexts, e.g. poststroke/TIA with cognitive impairment (without dementia), MCI (prodromal AD) or even in “preclinical CSVD” dementia- and stroke-free individuals, as they are at high risk of further cognitive decline or dementia. Preferably, such trials should include Asians so that findings from these trials can be generalized to Asians as well.