Just Accepted by International Journal of Neuroscience
Cerebral white matter hyperintensities (WMH): an analysis of cerebrovascular risk factors in Lebanon S. Gebeily, Y. Fares, M. Cordahi, P. Khodeir, G. Labaki, F. Fazekas
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doi:10.3109/00207454.2014.884087
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Cerebral white matter hyperintensities (WMH): an analysis of cerebrovascular risk factors in Lebanon
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Gebeily S.1; Fares Y.2;Cordahi M.3; Khodeir P.4; Labaki G.5 and Fazekas F6. Key words: Cerebral white matter hyperintensities, leukoaraiosis, cerebrovasular disease, stroke, hypertension,
Souheil Gebeily: Neurology Division. Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
2
Youssef Fares: Neurosurgery Division, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
3
Manale Cordahi: Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
4
Pierre Khodeir: Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
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5 Ghattas Labaki: Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon 6
Fazekas Franz: Department of Neurology, Medical University of Graz, Graz, Austria
Correspondent’s address: Souheil Gebeily Neurology Division; The Lebanese University Hospital - Geitawi – Beirut, Lebanon. [email protected]; [email protected]
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INTRODUCTION:
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Cerebral white matter hyperintensities (WMH) are reported in various geriatric disorders, including cerebrovascular diseases, cognitive impairment and dementia; however, the pathogenesis of WMH commonly observed on magnetic resonance images (MRIs) in elderly people remains poorly understood.
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The descriptive term leukoaraiosis (LA),which is frequently applied to these neuroimaging abnormalities of the brain white matter, refers to bilateral patchy or diffuse areas of hyperintensities on T2-weighted brain MRIs. Cerebral small vessel disease (CVD) may be involved as a possible underlying mechanism and is more often than not detected within areas of WMH/LA. Thus, CVD may be related to altered blood
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Diabetes Mellitus, aging, cognitive impairment
supply to the brain white matter. This vascular alteration may lead to localized ischemic areas of necrosis and cavitation [1–2]. Although several studies have highlighted the role of aging and chronic hypertension (HTN) as risk factors for stroke, the correlation between the presence of WMH and its potential role on ischemic stroke and cognitive impairment remains under debate. The goal of this study was to determine whether the periventricular WMH (PVWMH) or the deep WMH (DWMH) would be
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significantly more correlated with potential vascular risk factors such as aging, gender, hypertension (HTN) and diabetes mellitus (DM).
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MATERIALS AND METHODS: This study was conducted by the neurology division of the faculty of medical sciences (FMS) at the
Lebanese University (LU). Ethical permission was given by Rafik Hariri University Hospital (RHUH)
inpatients aged 40 years and older who underwent a brain MRI, regardless of their underlying pathology.
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We reviewed 257 medical files from 753 patients who had a brain MRI from January 1 to December 31, 2010, and a problem-oriented medical record (POMR) on their medical files. Brain MRIs were obtained in the transverse plane using a 1.0-T unit (Magnetom Impact; Siemens, Erlangen, Germany), and a T2-
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weighted fast spin-echo sequence (4,000/96 repetition time msec/echo time msec; section thickness, 5
Definitions:
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mm; acquisition time, 1 minute 53 seconds; intersection gap, 1.5 mm) was performed.
Hypertension (HTN): A subject was considered to have HTN if their systolic blood pressure was 140
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mmHg or higher, their diastolic blood pressure was 90 mmHg or higher, if the subject was using an antihypertensive or if the subject had a self-reported history of hypertension. Diabetes Mellitus (DM): A subject was considered diabetic if he/she had persistent fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl).
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and the FMS of the LU. The study was performed at the Beirut RHUH medical department on Lebanese
Cognition: A subject who had a report of memory impairment or cognitive decline in his patient file was
considered to have a cognitive disorder; unfortunately, no cognitive assessment was available in most of the patients’ medical files. Cerebral white matter hyperintensities (WMH): WMH appear hyperintense on T2-weighted images and do not exhibit prominent hypointensity on T1-weighted images. Ischemic lesions such as lacunes and silent infarcts were excluded from the WMH definition; these ischemic lesions would appear hyperintense on T2-weighted images and hypointense on T1-weighted images,
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approaching the hypointensity of cerebrospinal fluid. Lesions described as “leukoaraiosis” were included as WMH.
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WMH and revised Fazekas classification: We analyzed the MRIs using the semiquantitative rating scale of Fazekas et al. [3]. This method separates brain WMH scores into deep WMH and periventricular lesions (PVLs). Fazekas et al. were the first to
lateral ventricle margin and DWMH as WMH that are distal to this margin. Both variables were divided
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into a 4-point scale of increasing severity: grade 0: normal; grade 1: punctuate lesions; grade 2: coalescing or mildly confluent lesions; and grade 3: confluent lesions.
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Patient categorization by age:
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The 257-person study population was classified by 10-year age intervals into 5 subgroups: subgroup A: aged from 40 to 49 years; subgroup B: aged from 50 to 59 years; subgroup C: aged from 60 to 69 years; subgroup D: aged from 70 to 79 years; and subgroup E: aged over 80 years.
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Patient categorization according to WMH:
Patient classification according to the brain MRI results: The 257 study patients were classified into 4 subgroups according to the MRI results as follows: subgroup 1: absence of WMH; subgroup 2: presence of DWMH; subgroup 3: presence of PVWMH; and subgroup 4: presence of both DWMH and PVWMH.
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rate PVWMH and DWMH separately. They defined PVWMH as WMH that are contiguous with the
We studied the possible correlation between WMH and HTN, DM, past history of stroke or transient ischemic attack TIA and coronary heart disease, which were considered to be potential independent risk
factors.
Statistics analysis methods
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All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) (version 16.0.2, 2008, IBM Inc., Armonk, NY, USA). A descriptive analysis was conducted, and categorical data were reported as frequencies and percentage counts. A 0.05 significance level was
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utilized for strength of association to guarantee a 95% confidence level. Log linear analysis was used to identity three possible correlations between various combinations of categorical variables. Cross-
RESULTS:
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Study patient demography:
Demographic details of study population are shown in [table 1].
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The mean age was 62.2 years, with a median of 62 years. There were 139 women and 118 men, with a female predominance of 54.1%. The female population was younger and had a median age of 60 years,
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whereas the median age of the male population was 73.5 years. HTN was reported in 129 patients (50.2% of total study patients population); the hypertensive population was older (mean age: 66.3 years, median 68.5 years) than was the non-hypertensive population (mean age: 55.3; median 55.5 years). There was no
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significant difference in age between the male and female hypertensive populations. The mean age among hypertensive women was 66.85 years, whereas it was 65.8 years in the male hypertensive population. HTN was more frequent among women (74 women were hypertensive, which represents 53.2 % of the women), whereas HTN was reported in only 55 males (42.6% of the men). Additionally, 33% of the study
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tabulation and the Chi squared test were used for two-way correlations.
population was diabetic. A previous history of stroke or TIA was reported in 52 patients (20.6%). Overall, 152 of the study population (59%) were smokers. Thirty-two patients (12.5%) had a past history of CHD or MI, with a mean age of 63 years. Age and WMH: There was a significant relationship between WML level and age (p < .001; CI.0.95). Moreover, as the age increased, more individuals showed a linear WML correlation that was highly significant in the age category 60 – 70 years and over and reached 94% in subgroup E, i.e., 80 years and
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over. A sub-analysis on the effect of age on PVWMH and DWMH alone showed no significance [Figs. 1 - 2]. HTN and WMH: WML were reported in 76% of the 129 hypertensive patients. PVWMH were the most
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frequently observed in 57% of the patients. Both PVWMH and DWMH were observed in 26.5% of the
patients, whereas DWMH alone was reported in only 16.3% of the patients. Hence, PVWH were reported
age and WMH: The presence of WMH was positively correlated with age and with HTN. In both
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subgroups, there was a statistically significant correlation for age and/or HTN with the presence of WMH (p value < 0.001; CI: 95%). Moreover, in the subcategory of patients aged over 60 years, WMH were observed in 86.7% of the hypertensive patients compared to 68% of the non-hypertensive patients. In the
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subcategory of patients aged over 70 years, 100% of the hypertensive patients had WMH on their brain MRIs compared to 87% of the non-hypertensive patients. Considering only the WMH subtypes, PVWH
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was statistically correlated with HTN (p=0.045; CI=0.95). DM and WMH: WMH were reported in 78.8% of the diabetic patient subgroup compared to 49.4% of the non-diabetic patients. Only 21% of the diabetic individuals did not show WMH in their brain MRIs compared with 50.6% of the non-diabetics.
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There was no significant difference with regard to WMH subtypes in either the diabetic or non-diabetic groups; however, taken together, there was a tendency favoring the PVWMH subtypes in diabetic patients over the DWMH subtypes [Table 6]. History of previous stroke or TIA and WMH: WMH were observed in almost all patients (98%).
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alone or in combination with DWMH in 81 of the 98 hypertensive patients (82.6%) [Tables 4 - 5]. HTN,
Smoking: WML were reported in 30 patients (19.7%), whereas 20 (13.8%) had no WMH found in their
brain MRIs. Past history of CHD: In this category, 65.6 % of the patients reported having WML found
in their brain MRIs. Cognitive impairment: Thirty-two patients (12.5 %) were reported to have a cognitive disorder. DISCUSSION
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Based on the literature, the prevalence of WMH on brain MRI may roughly vary from 20% to 50% among individuals aged 55 years and over. Among hypertensive individuals, the prevalence of WMH increases to 40 – 44% [4 –9]. These differences may be due to subtle variations in WMH assessment,
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relative to different study populations and, most importantly, to the different impact of risk factors, such as age and hypertension, which are influenced by the subject criteria selection. In our study population,
WMH were reported in 60% of patients. Ki Woong Kim et al. suggested a new classification for WMH in
categorized BWMH into four subgroups: juxtaventricular, periventricular, deep white, and juxtacortical
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[10].
However, for simplicity and clarity, we adapted the revised Fazekas classification into two different
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imaging patterns: PVWMH versus DWMH [3]. Fazekas et al reported that DWMH are likely to have a vascular origin. Postmortem studies have indicated that WMH observed on MRI scans are associated with
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degenerative changes in arterioles that are related to atherosclerosis, suggesting that cerebral arteriosclerosis of the penetrating vessels is the main factor in the pathogenesis of ischemic WMH. PVWMH might be linked to the disruption of the ependymal lining and myelin degradation. Hypertension
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may cause disturbances in the blood-brain barrier by activating astrocytes via destructive enzymes that pass through the damaged vessel walls, which may cause lesions in the white matter by cerebral edema.[6]
Aging is the major risk factor for WMH [5,11,12]. The results from our study are consistent with
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2008, highlighting that DWMH and PVWMH may have different mechanisms and pathogenesis. They
published data from the literature in regard to WMH and aging. Furthermore, the incidence of WMH seems to increase significantly among the Lebanese elderly population, particularly in the last three quintiles, starting from ages 60 – 70 and continuing to increase over age 80 (subgroup E), where 94 % of the individuals presented with WMH in their brain MRIs, compared with only 17.5 % and 19 % of the individuals from subgroups A and B, respectively.
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Hypertension with degenerative alterations of cerebral arterioles is considered to have a predominant role in WMH pathogenesis. Following hypoperfusion, brain lesions described as “incomplete infarctions” are reported in the literature [5-7, 11]. Goldstein et al found a correlation between WMH and office systolic,
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but not diastolic, BP [4]. Hypertension was associated with increased odds of WMH, and treated, uncontrolled hypertensive subjects have greater odds of WMH than do those with treated, controlled HTN [5]. This association between hypertension and WMH has been established in cross-sectional and
24-hour ABPM is used to assess BP. In this sense, the severity of WMH was correlated with both systolic
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and diastolic BP, measured by ABPM. Shimada et al also found a correlation between the number of lacunae and periventricular hyperintensities with 24-hour BP, but not with office BP. [13]
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Consistent with the published data from the literature, in our study, WMH were observed more frequently in hypertensive patients than in non-hypertensive (86.7% versus 68%). This difference was statistically
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significant in patients aged over 70. Interestingly, in this category, PVWH was significantly correlated with HTN, which was not the case for DWMH. Moreover, PVWMH correlated in a linear-like progression with aging, but DWMH did not (Fig.2). Kozera et al. reported a lower cerebral vasomotor
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reactivity (CVR) in middle-aged hypertensive men with WMH compared to those without WMH, underlining the potential role of functional impairment of the cerebral microvasculature [14]. Fu JH. et al. correlated the CVR impairment with the extent of WMH and the dysfunction of cerebral vascular autoregulation [15]. Bakker et al confirmed the association between decreased vasomotor reactivity and
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longitudinal studies. However, some reports have suggested that this relationship is only evident when a
WMH, which were measured using a transcranial Doppler in 73 elderly individuals, 56% of whom were hypertensive [16]. The presence of WMH can predict ischemic stroke and TIA. Van Dijk and colleagues confirmed a relationship between inflammation, the severity and progression of WMH/LA and silent brain lacunar infarcts (SBLI ) [17]. More recently, Stephanie Debette reported from a large meta-analysis including 46
longitudinal studies that WMH may predict an increased risk of ischemic stroke, dementia and death [18].
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In our study, stroke and TIA were reported in 20.1 % of the study population, and the majority of the patients had WMH in their brain MRIs (96%). Several studies have shown an association between WMH and cognitive function in both normotensive
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and hypertensive elderly populations. Swan et al showed that midlife SBP is a significant predictor of WMH and decline in cognitive function [19].
MRIs; PVWMH were also more frequently observed than were DWMH (60.4% versus 38.9%). However,
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in the multivariate analysis with age and DM, there was no significant correlation with either DWMH or PVWMH subtypes or with DM alone, whereas PVWMH were again found to be significantly correlated
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with aging in this subpopulation.
Metabolic syndrome may be associated with a higher incidence of cerebral ischemic injury and cognitive
CONCLUSION:
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impairment, thereby favoring the development of vascular dementia or dementia with stroke [20].
In this first-ever retrospective Lebanese study, WMH were reported to increase with aging in accordance
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with the data from the literature. PVWMH were found to be significantly more correlated with aging and HTN than were DWMH alone. The increase occurs with a clear shift toward patients over the age of 60 (reaching 84 % in the patient subgroup of 70 – 79 years old and 94 % in the patient subgroup over 80 years old). Interestingly, high-grade PVWMH were found to increase in a linear-like progression with age
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In our results, 78 % of the diabetic individuals included in the study reported having WMH in their brain
and correlated more significantly in hypertensive patients than did DWMH. From the multivariate analysis, we found no specific WMH profile in patients with a history of stroke or in patients with DM. A larger prospective, multicenter registry study should be initiated to further investigate the longitudinal correlation between cognitive decline, risk of stroke and WMH subtypes. REFERENCES
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[10] Ki Woong Kim, MacFall J.R, and Payne M.E. Classification of white matter lesions on magnetic resonance imaging in the elderly. Biol Psychiatry. 2008 August 15; 64(4): 273–280.Published online 2008 May 8. doi: 10.1016/j.biopsych.2008.03.024.
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[11] Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in
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[14] Kozera GM; Dubaniewicz M; Zdrojewski T; Madej-Dmochowska A; Mielczarek M; Wojczal J; Chwojnicki K; Swierblewska E; Schminke U; Wyrzykowski B; Nyka WM; Cerebral vasomotor reactivity and extent of white matter lesions in middle-aged men with arterial hypertension: a pilot.
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[18] Debette S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010; 341:c3666. [19] Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D. Association of midlife
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[20] GorelickB. P, Scuteri A, Black E.S, DeCarli C, Greenberg M.S, Ladecola C, Launer L.J, Laurent S,
Higashida T.R, Lindquist R, Nilsson M.P, RomanC.G, Sellke W.F, Seshadri S, on behalf of the American
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Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular
Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery
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and Anesthesia. Stroke 42(9):2672-2713, September 2011.
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LopezL.O, Nyenhuis D, Petersen C.R, Schneider J.A, Tzourio C, Arnett K.D, Bennett A.D, Chui C.H,
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n (%) Male
118 (45.9)
Age ( by 10-year intervals)
40-49
57 (22.1)
50-59
60 (23.3)
60-69 70-79 Yes
Diabetes Mellitus Myocardial Infarct
Yes Yes
TIA / STROKE
Yes
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Hypertension
Dyslipidemia Smoking
47 (18.2) 35 (13.6
129 (50.2) 85 (33.0)
32 (12.4)
53 (20.6)
Yes Yes
35 (13.6) 51 (19.8)
Absence of WMH
105 (40.8)
Presence of PVWMH
70 (27.2)
Presence DWMH
51 (19.8)
Presence of both PVWMH & DWMH
31 (12.0)
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MRI Classification
58 (22.5)
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Table 1: Demographic characteristics and vascular risk factors of the study population and MRI WMH subgroups
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> or = 80
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Gender
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Absence of WMH PVWMH DWMH DWMH+PVWMH
50-59 n=60 n (%) 31 (51.7) 10 (16.7) 12 (20) 7(11.7)
Age 60-69 n=58 n (%) 16 (27.6) 22 (37.9) 12 (20.7) 8 (13.8)
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Table 2: WMH subtypes by 10-year interval subgroups
≥ 80 n=35 n (%) 2 (5.7) 18 (51.4) 7 (20) 8 (22.9)
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WMH: White matter hyperdensity. DWMH: Deep WMH. PVWMH: Periventricular WMH
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Pearson Chi-Square, Asymp. Sig. (2-sided) p= 0.001 0.95CI.
70-79 n=47 n (%) 10 (21.3) 17 (36.2) 13 (27.7) 7 (14.9)
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40-49 n=57 n (%) 46 (80.7) 3(5.3) 7 (12.3) 1 (1.8)
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Age
Number of individuals Absence of WMH (n=105) PVWMH (n=70) DWMH (n=51) DWMH+PVWMH (n=31)
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Table 3: Correlation between age and WMH
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WMH: White matter hyperintensities. DWMH: Deep WMH. PVWMH: Periventricular WMH
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Pearson Chi-Square, Asymp. Sig. (2-sided) p=0.00
≥65 years old 115 (44.7%) 20 (19.0%) 49 (70.0%) 29 (56.8%) 17 (54.8%)
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no DM DM 14 21 0 2
50.0% 86.8% 27.8% 35.0% 13.6% 38.2% 14.3% 26.9%
9.5%
DWMH %
3 50.0%
5 9.4%
2 9.5%
PVWMH
0
3
6 11 9 12 10 10 4 33.3% 27.5% 40.9% 35.3% 47.6% 38.5% 26.8% 11
14
12
13
12
12
14
61.1% 15.0% 63.6% 35.3% 61.9% 46.2% 85.7% 66.7%
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6.5%
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Table 6: Correlation between Diabetes Mellitus, age and white matter hyperintensities
PVWMH: Periventricular WMH
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DM: Diabetes Mellitus, WMH: White matter hyperintensities, DWMH: Deep WMH,
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This table shows that no specific WMH subtype correlates with DM; however, in the DM population, PVWMH incidence increases with aging, as for the general study population.
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n patients No WMH
40–49 No DM DM 6 53 3 46
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Age
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Fig: 1. BWMH: Brain white matter hyperdensities
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BWMH increase with age in a linear-like progression. This BWMH correlation is mostly
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significant starting from the third quintile (60–69 years)
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Fig. 2 Impact of age on cerebral white matter hyperdensities ( WMH ) subtypes: DWMH: deep white matter hyperdensities ( DWMH 1: grade 1 punctuate DWMH; DWMH 2+3: confluent DWMH); PVWH: Periventricular white matter hyperdensities ( PVWMH 1: grade 1 punctuate PVWMH; PVWMH 2+3: confluent PVWMH)
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Among the WMH, only the confluent subtypes ( grade 2 and 3 ) increase significantly and in a
linear-like progression with age, in contrast with other WMH subtypes, whereas, the chance of having a normal brain MRI decreases with age with a linear-like progression
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Cerebral white matter hyperintensities (WMH): an analysis of cerebrovascular risk factors in Lebanon S. Gebeily, Y. Fares, M. Cordahi, P. Khodeir, G. Labaki, F. Fazekas
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doi:10.3109/00207454.2014.884087
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Cerebral white matter hyperintensities (WMH): an analysis of cerebrovascular risk factors in Lebanon
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Gebeily S.1; Fares Y.2;Cordahi M.3; Khodeir P.4; Labaki G.5 and Fazekas F6. Key words: Cerebral white matter hyperintensities, leukoaraiosis, cerebrovasular disease, stroke, hypertension,
Souheil Gebeily: Neurology Division. Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
2
Youssef Fares: Neurosurgery Division, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
3
Manale Cordahi: Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
4
Pierre Khodeir: Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
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5 Ghattas Labaki: Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon 6
Fazekas Franz: Department of Neurology, Medical University of Graz, Graz, Austria
Correspondent’s address: Souheil Gebeily Neurology Division; The Lebanese University Hospital - Geitawi – Beirut, Lebanon. [email protected]; [email protected]
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INTRODUCTION:
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Cerebral white matter hyperintensities (WMH) are reported in various geriatric disorders, including cerebrovascular diseases, cognitive impairment and dementia; however, the pathogenesis of WMH commonly observed on magnetic resonance images (MRIs) in elderly people remains poorly understood.
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The descriptive term leukoaraiosis (LA),which is frequently applied to these neuroimaging abnormalities of the brain white matter, refers to bilateral patchy or diffuse areas of hyperintensities on T2-weighted brain MRIs. Cerebral small vessel disease (CVD) may be involved as a possible underlying mechanism and is more often than not detected within areas of WMH/LA. Thus, CVD may be related to altered blood
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Diabetes Mellitus, aging, cognitive impairment
supply to the brain white matter. This vascular alteration may lead to localized ischemic areas of necrosis and cavitation [1–2]. Although several studies have highlighted the role of aging and chronic hypertension (HTN) as risk factors for stroke, the correlation between the presence of WMH and its potential role on ischemic stroke and cognitive impairment remains under debate. The goal of this study was to determine whether the periventricular WMH (PVWMH) or the deep WMH (DWMH) would be
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significantly more correlated with potential vascular risk factors such as aging, gender, hypertension (HTN) and diabetes mellitus (DM).
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MATERIALS AND METHODS: This study was conducted by the neurology division of the faculty of medical sciences (FMS) at the
Lebanese University (LU). Ethical permission was given by Rafik Hariri University Hospital (RHUH)
inpatients aged 40 years and older who underwent a brain MRI, regardless of their underlying pathology.
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We reviewed 257 medical files from 753 patients who had a brain MRI from January 1 to December 31, 2010, and a problem-oriented medical record (POMR) on their medical files. Brain MRIs were obtained in the transverse plane using a 1.0-T unit (Magnetom Impact; Siemens, Erlangen, Germany), and a T2-
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weighted fast spin-echo sequence (4,000/96 repetition time msec/echo time msec; section thickness, 5
Definitions:
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mm; acquisition time, 1 minute 53 seconds; intersection gap, 1.5 mm) was performed.
Hypertension (HTN): A subject was considered to have HTN if their systolic blood pressure was 140
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mmHg or higher, their diastolic blood pressure was 90 mmHg or higher, if the subject was using an antihypertensive or if the subject had a self-reported history of hypertension. Diabetes Mellitus (DM): A subject was considered diabetic if he/she had persistent fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl).
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and the FMS of the LU. The study was performed at the Beirut RHUH medical department on Lebanese
Cognition: A subject who had a report of memory impairment or cognitive decline in his patient file was
considered to have a cognitive disorder; unfortunately, no cognitive assessment was available in most of the patients’ medical files. Cerebral white matter hyperintensities (WMH): WMH appear hyperintense on T2-weighted images and do not exhibit prominent hypointensity on T1-weighted images. Ischemic lesions such as lacunes and silent infarcts were excluded from the WMH definition; these ischemic lesions would appear hyperintense on T2-weighted images and hypointense on T1-weighted images,
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approaching the hypointensity of cerebrospinal fluid. Lesions described as “leukoaraiosis” were included as WMH.
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WMH and revised Fazekas classification: We analyzed the MRIs using the semiquantitative rating scale of Fazekas et al. [3]. This method separates brain WMH scores into deep WMH and periventricular lesions (PVLs). Fazekas et al. were the first to
lateral ventricle margin and DWMH as WMH that are distal to this margin. Both variables were divided
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into a 4-point scale of increasing severity: grade 0: normal; grade 1: punctuate lesions; grade 2: coalescing or mildly confluent lesions; and grade 3: confluent lesions.
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Patient categorization by age:
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The 257-person study population was classified by 10-year age intervals into 5 subgroups: subgroup A: aged from 40 to 49 years; subgroup B: aged from 50 to 59 years; subgroup C: aged from 60 to 69 years; subgroup D: aged from 70 to 79 years; and subgroup E: aged over 80 years.
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Patient categorization according to WMH:
Patient classification according to the brain MRI results: The 257 study patients were classified into 4 subgroups according to the MRI results as follows: subgroup 1: absence of WMH; subgroup 2: presence of DWMH; subgroup 3: presence of PVWMH; and subgroup 4: presence of both DWMH and PVWMH.
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rate PVWMH and DWMH separately. They defined PVWMH as WMH that are contiguous with the
We studied the possible correlation between WMH and HTN, DM, past history of stroke or transient ischemic attack TIA and coronary heart disease, which were considered to be potential independent risk
factors.
Statistics analysis methods
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All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) (version 16.0.2, 2008, IBM Inc., Armonk, NY, USA). A descriptive analysis was conducted, and categorical data were reported as frequencies and percentage counts. A 0.05 significance level was
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utilized for strength of association to guarantee a 95% confidence level. Log linear analysis was used to identity three possible correlations between various combinations of categorical variables. Cross-
RESULTS:
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Study patient demography:
Demographic details of study population are shown in [table 1].
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The mean age was 62.2 years, with a median of 62 years. There were 139 women and 118 men, with a female predominance of 54.1%. The female population was younger and had a median age of 60 years,
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whereas the median age of the male population was 73.5 years. HTN was reported in 129 patients (50.2% of total study patients population); the hypertensive population was older (mean age: 66.3 years, median 68.5 years) than was the non-hypertensive population (mean age: 55.3; median 55.5 years). There was no
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significant difference in age between the male and female hypertensive populations. The mean age among hypertensive women was 66.85 years, whereas it was 65.8 years in the male hypertensive population. HTN was more frequent among women (74 women were hypertensive, which represents 53.2 % of the women), whereas HTN was reported in only 55 males (42.6% of the men). Additionally, 33% of the study
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tabulation and the Chi squared test were used for two-way correlations.
population was diabetic. A previous history of stroke or TIA was reported in 52 patients (20.6%). Overall, 152 of the study population (59%) were smokers. Thirty-two patients (12.5%) had a past history of CHD or MI, with a mean age of 63 years. Age and WMH: There was a significant relationship between WML level and age (p < .001; CI.0.95). Moreover, as the age increased, more individuals showed a linear WML correlation that was highly significant in the age category 60 – 70 years and over and reached 94% in subgroup E, i.e., 80 years and
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over. A sub-analysis on the effect of age on PVWMH and DWMH alone showed no significance [Figs. 1 - 2]. HTN and WMH: WML were reported in 76% of the 129 hypertensive patients. PVWMH were the most
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frequently observed in 57% of the patients. Both PVWMH and DWMH were observed in 26.5% of the
patients, whereas DWMH alone was reported in only 16.3% of the patients. Hence, PVWH were reported
age and WMH: The presence of WMH was positively correlated with age and with HTN. In both
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subgroups, there was a statistically significant correlation for age and/or HTN with the presence of WMH (p value < 0.001; CI: 95%). Moreover, in the subcategory of patients aged over 60 years, WMH were observed in 86.7% of the hypertensive patients compared to 68% of the non-hypertensive patients. In the
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subcategory of patients aged over 70 years, 100% of the hypertensive patients had WMH on their brain MRIs compared to 87% of the non-hypertensive patients. Considering only the WMH subtypes, PVWH
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was statistically correlated with HTN (p=0.045; CI=0.95). DM and WMH: WMH were reported in 78.8% of the diabetic patient subgroup compared to 49.4% of the non-diabetic patients. Only 21% of the diabetic individuals did not show WMH in their brain MRIs compared with 50.6% of the non-diabetics.
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There was no significant difference with regard to WMH subtypes in either the diabetic or non-diabetic groups; however, taken together, there was a tendency favoring the PVWMH subtypes in diabetic patients over the DWMH subtypes [Table 6]. History of previous stroke or TIA and WMH: WMH were observed in almost all patients (98%).
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alone or in combination with DWMH in 81 of the 98 hypertensive patients (82.6%) [Tables 4 - 5]. HTN,
Smoking: WML were reported in 30 patients (19.7%), whereas 20 (13.8%) had no WMH found in their
brain MRIs. Past history of CHD: In this category, 65.6 % of the patients reported having WML found
in their brain MRIs. Cognitive impairment: Thirty-two patients (12.5 %) were reported to have a cognitive disorder. DISCUSSION
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Based on the literature, the prevalence of WMH on brain MRI may roughly vary from 20% to 50% among individuals aged 55 years and over. Among hypertensive individuals, the prevalence of WMH increases to 40 – 44% [4 –9]. These differences may be due to subtle variations in WMH assessment,
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relative to different study populations and, most importantly, to the different impact of risk factors, such as age and hypertension, which are influenced by the subject criteria selection. In our study population,
WMH were reported in 60% of patients. Ki Woong Kim et al. suggested a new classification for WMH in
categorized BWMH into four subgroups: juxtaventricular, periventricular, deep white, and juxtacortical
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[10].
However, for simplicity and clarity, we adapted the revised Fazekas classification into two different
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imaging patterns: PVWMH versus DWMH [3]. Fazekas et al reported that DWMH are likely to have a vascular origin. Postmortem studies have indicated that WMH observed on MRI scans are associated with
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degenerative changes in arterioles that are related to atherosclerosis, suggesting that cerebral arteriosclerosis of the penetrating vessels is the main factor in the pathogenesis of ischemic WMH. PVWMH might be linked to the disruption of the ependymal lining and myelin degradation. Hypertension
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may cause disturbances in the blood-brain barrier by activating astrocytes via destructive enzymes that pass through the damaged vessel walls, which may cause lesions in the white matter by cerebral edema.[6]
Aging is the major risk factor for WMH [5,11,12]. The results from our study are consistent with
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2008, highlighting that DWMH and PVWMH may have different mechanisms and pathogenesis. They
published data from the literature in regard to WMH and aging. Furthermore, the incidence of WMH seems to increase significantly among the Lebanese elderly population, particularly in the last three quintiles, starting from ages 60 – 70 and continuing to increase over age 80 (subgroup E), where 94 % of the individuals presented with WMH in their brain MRIs, compared with only 17.5 % and 19 % of the individuals from subgroups A and B, respectively.
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Hypertension with degenerative alterations of cerebral arterioles is considered to have a predominant role in WMH pathogenesis. Following hypoperfusion, brain lesions described as “incomplete infarctions” are reported in the literature [5-7, 11]. Goldstein et al found a correlation between WMH and office systolic,
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but not diastolic, BP [4]. Hypertension was associated with increased odds of WMH, and treated, uncontrolled hypertensive subjects have greater odds of WMH than do those with treated, controlled HTN [5]. This association between hypertension and WMH has been established in cross-sectional and
24-hour ABPM is used to assess BP. In this sense, the severity of WMH was correlated with both systolic
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and diastolic BP, measured by ABPM. Shimada et al also found a correlation between the number of lacunae and periventricular hyperintensities with 24-hour BP, but not with office BP. [13]
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Consistent with the published data from the literature, in our study, WMH were observed more frequently in hypertensive patients than in non-hypertensive (86.7% versus 68%). This difference was statistically
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significant in patients aged over 70. Interestingly, in this category, PVWH was significantly correlated with HTN, which was not the case for DWMH. Moreover, PVWMH correlated in a linear-like progression with aging, but DWMH did not (Fig.2). Kozera et al. reported a lower cerebral vasomotor
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reactivity (CVR) in middle-aged hypertensive men with WMH compared to those without WMH, underlining the potential role of functional impairment of the cerebral microvasculature [14]. Fu JH. et al. correlated the CVR impairment with the extent of WMH and the dysfunction of cerebral vascular autoregulation [15]. Bakker et al confirmed the association between decreased vasomotor reactivity and
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longitudinal studies. However, some reports have suggested that this relationship is only evident when a
WMH, which were measured using a transcranial Doppler in 73 elderly individuals, 56% of whom were hypertensive [16]. The presence of WMH can predict ischemic stroke and TIA. Van Dijk and colleagues confirmed a relationship between inflammation, the severity and progression of WMH/LA and silent brain lacunar infarcts (SBLI ) [17]. More recently, Stephanie Debette reported from a large meta-analysis including 46
longitudinal studies that WMH may predict an increased risk of ischemic stroke, dementia and death [18].
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In our study, stroke and TIA were reported in 20.1 % of the study population, and the majority of the patients had WMH in their brain MRIs (96%). Several studies have shown an association between WMH and cognitive function in both normotensive
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and hypertensive elderly populations. Swan et al showed that midlife SBP is a significant predictor of WMH and decline in cognitive function [19].
MRIs; PVWMH were also more frequently observed than were DWMH (60.4% versus 38.9%). However,
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in the multivariate analysis with age and DM, there was no significant correlation with either DWMH or PVWMH subtypes or with DM alone, whereas PVWMH were again found to be significantly correlated
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with aging in this subpopulation.
Metabolic syndrome may be associated with a higher incidence of cerebral ischemic injury and cognitive
CONCLUSION:
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impairment, thereby favoring the development of vascular dementia or dementia with stroke [20].
In this first-ever retrospective Lebanese study, WMH were reported to increase with aging in accordance
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with the data from the literature. PVWMH were found to be significantly more correlated with aging and HTN than were DWMH alone. The increase occurs with a clear shift toward patients over the age of 60 (reaching 84 % in the patient subgroup of 70 – 79 years old and 94 % in the patient subgroup over 80 years old). Interestingly, high-grade PVWMH were found to increase in a linear-like progression with age
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In our results, 78 % of the diabetic individuals included in the study reported having WMH in their brain
and correlated more significantly in hypertensive patients than did DWMH. From the multivariate analysis, we found no specific WMH profile in patients with a history of stroke or in patients with DM. A larger prospective, multicenter registry study should be initiated to further investigate the longitudinal correlation between cognitive decline, risk of stroke and WMH subtypes. REFERENCES
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white matter signal hyperintensities. Neurology. 1993; 43:1683–1689. [4] Goldstein IB, Bartzokis G, Hance DB, Shapiro D. Relationship between blood pressure and
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[10] Ki Woong Kim, MacFall J.R, and Payne M.E. Classification of white matter lesions on magnetic resonance imaging in the elderly. Biol Psychiatry. 2008 August 15; 64(4): 273–280.Published online 2008 May 8. doi: 10.1016/j.biopsych.2008.03.024.
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[11] Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in
Alzheimer's dementia and normal aging. Ajr. 1987;149:351–356. [Pub Med study. Am J Hypertens. 2010;
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Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 2002; 52:335341.
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[14] Kozera GM; Dubaniewicz M; Zdrojewski T; Madej-Dmochowska A; Mielczarek M; Wojczal J; Chwojnicki K; Swierblewska E; Schminke U; Wyrzykowski B; Nyka WM; Cerebral vasomotor reactivity and extent of white matter lesions in middle-aged men with arterial hypertension: a pilot.
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[15] Fu JH; Lu CZ; Hong Z; Dong Q; Ding D; Wong KS. Relationship between cerebral vasomotor reactivity and white matter lesions in elderly subjects without large artery occlusive disease. J Neuroimaging. 2006; 16(2):120-5 (ISSN: 1051-2284).
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[18] Debette S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010; 341:c3666. [19] Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D. Association of midlife
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[20] GorelickB. P, Scuteri A, Black E.S, DeCarli C, Greenberg M.S, Ladecola C, Launer L.J, Laurent S,
Higashida T.R, Lindquist R, Nilsson M.P, RomanC.G, Sellke W.F, Seshadri S, on behalf of the American
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Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular
Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery
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and Anesthesia. Stroke 42(9):2672-2713, September 2011.
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LopezL.O, Nyenhuis D, Petersen C.R, Schneider J.A, Tzourio C, Arnett K.D, Bennett A.D, Chui C.H,
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n (%) Male
118 (45.9)
Age ( by 10-year intervals)
40-49
57 (22.1)
50-59
60 (23.3)
60-69 70-79 Yes
Diabetes Mellitus Myocardial Infarct
Yes Yes
TIA / STROKE
Yes
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Hypertension
Dyslipidemia Smoking
47 (18.2) 35 (13.6
129 (50.2) 85 (33.0)
32 (12.4)
53 (20.6)
Yes Yes
35 (13.6) 51 (19.8)
Absence of WMH
105 (40.8)
Presence of PVWMH
70 (27.2)
Presence DWMH
51 (19.8)
Presence of both PVWMH & DWMH
31 (12.0)
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MRI Classification
58 (22.5)
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Table 1: Demographic characteristics and vascular risk factors of the study population and MRI WMH subgroups
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> or = 80
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Gender
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Absence of WMH PVWMH DWMH DWMH+PVWMH
50-59 n=60 n (%) 31 (51.7) 10 (16.7) 12 (20) 7(11.7)
Age 60-69 n=58 n (%) 16 (27.6) 22 (37.9) 12 (20.7) 8 (13.8)
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Table 2: WMH subtypes by 10-year interval subgroups
≥ 80 n=35 n (%) 2 (5.7) 18 (51.4) 7 (20) 8 (22.9)
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WMH: White matter hyperdensity. DWMH: Deep WMH. PVWMH: Periventricular WMH
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Pearson Chi-Square, Asymp. Sig. (2-sided) p= 0.001 0.95CI.
70-79 n=47 n (%) 10 (21.3) 17 (36.2) 13 (27.7) 7 (14.9)
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40-49 n=57 n (%) 46 (80.7) 3(5.3) 7 (12.3) 1 (1.8)
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Age
Number of individuals Absence of WMH (n=105) PVWMH (n=70) DWMH (n=51) DWMH+PVWMH (n=31)
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Table 3: Correlation between age and WMH
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WMH: White matter hyperintensities. DWMH: Deep WMH. PVWMH: Periventricular WMH
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Pearson Chi-Square, Asymp. Sig. (2-sided) p=0.00
≥65 years old 115 (44.7%) 20 (19.0%) 49 (70.0%) 29 (56.8%) 17 (54.8%)
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no DM DM 14 21 0 2
50.0% 86.8% 27.8% 35.0% 13.6% 38.2% 14.3% 26.9%
9.5%
DWMH %
3 50.0%
5 9.4%
2 9.5%
PVWMH
0
3
6 11 9 12 10 10 4 33.3% 27.5% 40.9% 35.3% 47.6% 38.5% 26.8% 11
14
12
13
12
12
14
61.1% 15.0% 63.6% 35.3% 61.9% 46.2% 85.7% 66.7%
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6.5%
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Table 6: Correlation between Diabetes Mellitus, age and white matter hyperintensities
PVWMH: Periventricular WMH
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DM: Diabetes Mellitus, WMH: White matter hyperintensities, DWMH: Deep WMH,
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This table shows that no specific WMH subtype correlates with DM; however, in the DM population, PVWMH incidence increases with aging, as for the general study population.
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n patients No WMH
40–49 No DM DM 6 53 3 46
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Age
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Fig: 1. BWMH: Brain white matter hyperdensities
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BWMH increase with age in a linear-like progression. This BWMH correlation is mostly
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significant starting from the third quintile (60–69 years)
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Fig. 2 Impact of age on cerebral white matter hyperdensities ( WMH ) subtypes: DWMH: deep white matter hyperdensities ( DWMH 1: grade 1 punctuate DWMH; DWMH 2+3: confluent DWMH); PVWH: Periventricular white matter hyperdensities ( PVWMH 1: grade 1 punctuate PVWMH; PVWMH 2+3: confluent PVWMH)
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Among the WMH, only the confluent subtypes ( grade 2 and 3 ) increase significantly and in a
linear-like progression with age, in contrast with other WMH subtypes, whereas, the chance of having a normal brain MRI decreases with age with a linear-like progression
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