Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population
Background and Purpose—White matter hyperintensity (WMH) volume and covert brain infarcts are highly prevalent in older adults and are often asymptomatic. We compared the impact of WMH volume and brain infarcts on risk of clinical stroke and dementia in older adults in the population.
Methods—Participants were 1677 individuals aged ≥65 years from the 3-City Dijon study, who were free of stroke and dementia at baseline, followed-up for ≤12 years.
Results—Both lesion types were comparably associated with an increased risk of stroke (adjusted hazard ratio, 1.72; 95% confidence interval, 1.24–2.40 for WMH volume and hazard ratio, 2.15; 95% confidence interval, 1.18–3.93 for brain infarcts), but only WMH volume was associated with an increased risk of dementia (hazard ratio, 1.41; 95% confidence interval, 1.09–1.83).
Conclusions—The differential impact of WMH and brain infarcts on clinical stroke and dementia suggests relatively different prognostic value of the 2 lesions. WMHs may represent a particularly pertinent magnetic resonance imaging intermediate marker that can be utilized in optimizing prevention strategies for both stroke and dementia in primary care and in trials.
White matter hyperintensities (WMHs) and covert brain infarcts (BIs) are often asymptomatic and are commonly observed on brain magnetic resonance imaging performed in the general population.1 They have been independently shown to substantially increase risk of stroke and dementia in the general population.2,3 However, the relative prognostic importance of these magnetic resonance imaging markers with respect to risk of stroke and dementia, and whether they result from the same pathological processes, remain unclear. WMH are mostly believed to reflect chronic hypoperfusion (other mechanisms have been suggested as well, such as impaired blood–brain barrier) and are commonly considered as less severe than BIs. To date, no studies have simultaneously examined the impact of both WMH and BI on risk of stroke and dementia in the older population.
In a large population-based sample of older adults with ≤12 years of follow-up, we investigated the relationship of WMH and BI with risk of incident stroke and dementia.
Materials and Methods
The 3-City (3C) Dijon study is a French population-based cohort study of 4931 community individuals.4 Our study sample consisted of 1677 individuals who were free of stroke and dementia followed-up for ≤12 years (see Methods section in the online-only Data Supplement).
Magnetic resonance imaging acquisition was performed with a 1.5-T Magnetom Siemens scanner using T1-weighted, T2-weighted, and proton density-weighted sequences. Automated image processing software was developed to detect and localize WMH, and measure total WMH volume (WMHV).5 These were classified according to distance to the ventricle, as periventricular (<10 mm, periventricular WMHV [PWMHV]), or deep (deep WMHV [DWMHV]). Covert BIs were defined as focal lesions ≥3 mm with the same signal characteristics as cerebrospinal fluid on all sequences. Lacunes of presumed vascular origin were defined as BIs of 3 to 15 mm, located in the basal ganglia or subcortical white matter. They were distinguished from dilated perivascular spaces using multiplanar reformatting. Lesions with a typical vascular shape following the orientation of perforating vessels were regarded as perivascular spaces.6
Incident stroke was defined as a new focal neurological deficit of sudden or rapid onset, of presumed vascular origin, that persisted for >24 hours, or leading to death. An expert panel of neurologists adjudicated diagnosis of stroke based on criteria of the World Health Organization, and dementia, based on criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (See Methods section in the online-only Data Supplement).
WMHV was examined both as a continuous variable (expressed as a proportion of WM mask volume to account for differences in WM detection mask size) and dichotomized with the top quartile of WMHV, PWMHV, and DWMHV representing extensive total WMHV, extensive DWMHV, and extensive PWMHV. Covert BI and lacunes were defined as the presence of at least one infarct/lacune versus none. Participants with at least 1 magnetic resonance imaging–defined nonlacunar BI were not included in analyses of lacunes (n=31).
We examined the association of WMHV and BI with incident stroke and incident dementia using Cox proportional-hazards regression analysis with age as the time scale, adjusted for sex, education, diabetes mellitus, hypertension, hypercholesterolemia, history of cardiovascular disease, current smoking, and APOE-ε4 genotype. In addition, we used linear mixed effects models to examine the association of WMHV and BI with longitudinal change in IST scores (Isaacs Set Test; semantic fluency), using 5 assessments over 12 years. Finally, to test whether the association of WMHV with dementia was mediated by incident stroke, we further adjusted these analyses for interim stroke events.
Mean age of participants at baseline was 72±4 years, 61% were women. Detailed characteristics of the study sample are shown in the online-only Data Supplement Table. During follow-up, 68 participants were diagnosed with stroke (10 fatal), and 124 participants were diagnosed with dementia (89 AD).
Larger WMHV, PWMHV, and DWMHV were associated with increased risk of incident stroke; BI and lacunes were also associated with increased risk of incident stroke, all independently of vascular risk factors (Table; Figure 1).
Total WMHV was associated with increased risk of dementia (Table; Figure 2); when looking at WMHV subtypes only PWMHV was associated with incident dementia (Table). These results were independent of vascular risk factors (Table) and interim stroke (for total WMHV hazard ratio, 1.38; 95% confidence interval [CI], 1.07–1.79; P=0.01). Covert BIs (or lacunes) were not associated with incident dementia (Table; Figure 2). When contrasting covert BIs according to the presence of ≥2 BI (n=47) versus none and one BI only (n=105) versus none, associations with dementia were hazard ratio, 1.65; 95% CI, 0.72 to 3.78; P=0.23 for the former and hazard ratio, 0.83; 95% CI, 0.38 to 1.79, P=0.63 for the latter. Extensive WMHV and PWMHV were associated with more rapid decline in IST scores: β=−0.10; 95% CI, −0.16 to 0.03; P=0.002 and β=−0.13; 95% CI, −0.19 to 0.06, P<0.0001, respectively; ext-DWMHV was not associated with accelerated cognitive decline (β=−0.02; 95% CI, −0.08 to 0.04; P=0.54). Covert BIs were not associated with more rapid cognitive decline (β=−0.02; 95% CI, −0.12 to 0.07; P=0.64).
In this population-based study, WMHV (in all locations) and BI equally conferred an increased risk of clinical stroke, but only WMHV, overall and in the periventricular location were associated with an increased risk of dementia. This differential association raises important points about the relative prognostic value and potentially distinct underlying mechanisms of the 2 lesion types.
Our findings about the risk of stroke are consistent with previous population-based studies, reporting a 3- to 4-fold increase in risk associated with extensive WMH burden and BI in the general population.2,7–9 The similar effect of these distinct lesion types on stroke risk, as we highlight here in the same data set, suggests WMHV and BI to be comparable independent markers of cerebrovascular burden and risk.
Similarly, the association of WMHV with increased risk of dementia is consistent with previous population-based studies.2,7,10 One previous study had also described a more prominent association of PWMHV than DWMHV with dementia.10 The exclusive association of PWMHV (not DWMHV) with accelerated decline in IST scores supports findings of a similar association with increased risk of dementia in our study and may suggest an early impact of PWMHV on cognitive decline during the preclinical phase of dementia. These observations may point to differential mechanisms underlying PWMHV and DWMHV. Periventricular WM may be more vulnerable to hypoperfusion; in individuals with WMH, reduced cerebral blood flow in normal appearing periventricular (but not deep) WM has been observed.11
However, BIs were not associated with incident dementia in our study, contrary to previous population-based studies,3,7,12 although some only showed borderline associations of BI after adjustment for vascular risk factors.12 Population characteristics, vascular profiles, and methodological differences (especially distinction of BI from dilated perivascular spaces) may partly explain these differences. We speculate that most single small covert BI may not, in isolation, predispose to greater risk of dementia, but may reflect underlying cerebrovascular pathology that may in some instances escalate over time and later contribute to dementia risk. In contrast, WMHV may be a marker of more widespread cerebrovascular pathology or may be more interactive with dementia-related neurodegenerative processes.13,14 Nonvascular mechanisms including reverse causation by Wallerian degeneration secondary to cortical atrophy, possibly induced by preexisting neurodegenerative mechanisms, may also contribute to the relationship between WMH and dementia.15
The strong association of WMH with both stroke and dementia makes it a potentially valuable surrogate end point in trials of preventive or potentially disease modifying interventions for stroke and dementia. In clinical practice, presence of extensive WMH should lead to cognitive evaluation and follow-up. To this end, there is an urgent need for recommendations on optimal management of individuals with covert cerebrovascular disease, especially WMH burden.
Drs Kaffashian, Debette, and Tzourio helped in study concept/design. Dr Kaffashian performed the statistical analysis. Drs Kaffashian, Debette, and Tzourio helped in analysis/interpretation. Drs Zhu, Mazoyer, and Tzourio processed data acquisition. Drs Debette and Tzourio helped in study supervision/coordination. Drs Kaffashian, Soumaré, Zhu, Mazoyer, Debette, and Tzourio helped in drafting/revising the article.
Sources of Funding
The 3-City Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. It is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme Cohortes et collections de données biologiques. Drs Tzourio and Debette have received investigator-initiated research funding for this project from the French National Research Agency (Agence Nationale de la Recherche), the Fondation Leducq, and the Initiative of Excellence (IdEX) of Bordeaux University.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.014695/-/DC1.
- Received July 13, 2016.
- Revision received July 13, 2016.
- Accepted August 1, 2016.
- © 2016 American Heart Association, Inc.
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