Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Age-Related White Matter Changes

Age-Related White Matter Changes SAGE-Hindawi Access to Research Journal of Aging Research Volume 2011, Article ID 617927, 13 pages doi:10.4061/2011/617927 Review Article Yun Yun Xiong and Vincent Mok Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Shatin 999077, Hong Kong Correspondence should be addressed to Vincent Mok, vctmok@cuhk.edu.hk Received 5 May 2011; Revised 28 June 2011; Accepted 28 June 2011 Academic Editor: Leonardo Pantoni Copyright © 2011 Y. Y. Xiong and V. Mok. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Age-related white matter changes (WMC) are considered manifestation of arteriolosclerotic small vessel disease and are related to age and vascular risk factors. Most recent studies have shown that WMC are associated with a host of poor outcomes, including cognitive impairment, dementia, urinary incontinence, gait disturbances, depression, and increased risk of stroke and death. Although the clinical relevance of WMC has been extensively studied, to date, only very few clinical trials have evaluated potential symptomatic or preventive treatments for WMC. In this paper, we reviewed the current understanding in the pathophysiology, epidemiology, clinical importance, chemical biomarkers, and treatments of age-related WMC. 1. Introduction Further searches on bibliographies in the main articles and relevant papers were performed. Age-related white matter changes (WMC) are prevalent findings among the elderly. WMC are considered to be 2. Prevalence and Risk Factors etiologically related to cerebral small vessel disease and are important substrates for cognitive impairment and WMC are almost endemic in community elderly with functional loss in the elderly [1]. Although extensive studies prevalence ranging from 50% to 98% [2–6]. In stroke have investigated various aspects on WMC, controversies still patients, prevalence of WMC varies from 67% to 98% [7– exist in the pathophysiology and clinical phenotypes, and 10]. In Alzheimer’s disease, WMC are also common with consensus regarding to treatments for WMC has not been prevalence ranges from 28.9% to 100% [11–13]. About 30– reached. In this paper, we aimed to provide an update review 55% of patients with Parkinson’s disease (PD) also harbor on the epidemiology, pathophysiology, neuroimaging, clini- WMC [14–16]. Age [2, 4, 6, 17–20]and hypertension cal importance, chemical biomarkers, and treatments of age- [3, 18, 20–30] are established risk factors for WMC. A related WMC. recent Manhattan study in community elderly found that The literature search was conducted using the National compared with individuals with low blood pressure (BP) Center for Biotechnology Information (NCBI) PubMed/ and low fluctuations in BP, the risk of WMC increased with Medline to identify relevant articles related to WMC that higher BP and BP fluctuations [31]. Associations of diabetes were published until June 2011. We used the following mellitus (DM), cholesterol, smoking, and homocysteine are keywords for the search: white matter, white matter changes, less consistent between studies. Although past studies had white matter lesions, leukoaraiosis, white matter hyperinten- suggested that WMC are highly heritable [32] and that sities, and small vessel disease. several polymorphisms in various candidate genes, such as The articles were included in this paper if (1) the journal apolipoprotein E (epsilon 4±), methylenetetrahydrofolate article was published in English and (2) they were related reductase (677 cytosine/thymine polymorphism (C/T)), and to epidemiology, pathophysiology, neuroimaging, genetics, angiotensinogen (Met235Thr), were found to be associated clinical phenotypes, biomarkers, and treatment of WMC. with WMC, [33–35] a recent meta-analyses failed to show 2 Journal of Aging Research convincing evidence for an association between WMC and to disruption of the ependymal lining with subependymal the candidate genetic polymorphisms [36]. widening of the extracellular space resulting from disruption of the blood brain barrier, whereas the DWMC were mainly related to incomplete ischemic arteriolosclerosis [58, 59]. 3. Progression of WMC Vascular risk factors, especially hypertension, cause lipo- Age-related WMC are not static lesions. The lesions may hyalinosis of the media and thickening of the vessel walls, progress, or even regress, over time. Several longitudinal which attributes to narrowing of the lumen of the small studies have investigated the rate and predictors for progres- perforating arteries and arterioles nourishing the deep white sion of WMC [37–47]. Perhaps the most consistent predictor matter [60]. The perforating vessels, which originate from for progression of WMC is the baseline severity of WMC [44, cortical and leptomeningeal arteries, have a relatively poor 47, 48]. Patients with punctate WMC usually have minimal anastomotic system, which makes the white matter vulnera- progression of WMC, whereas those with early confluent and ble to cerebral ischemia. Hypertension can also cause distur- confluent WMC at baseline have rapid progression of WMC bances in the blood-brain barrier and lead to WMC by cere- [44, 49]. In the Austrian Stroke Prevention Study, the median bral edema, activation of astrocytes, or destructive enzymes (interquartile range) volume increase over the 6-year period or other poisons which pass through the damaged vessel 3 3 was 0 cm in subjects with no lesions, 0.2 (0.0–1.1) cm in walls [60]. DM alters the glucose and insulin transfer across subjects with punctuate lesions, 2.7 (0.5–5.9) cm in subjects the blood-brain barrier, thus affects regional metabolism with early confluent lesions, and 9.3 (7.1–21.0) cm for indi- and microcirculation. Chronic hyperglycemia, which further viduals with confluent WMC at baseline [44]. In AD and PD alters membrane permeability and decreases regional blood patients, the baseline severity of WMC also predicted lesion flow, might lead to permanent cell damage. Therefore, progression, AD median WMC progression was 0.08%, while DM seems to be associated with progressive metabolic PD dementia was 0.07% [50]. Sachdev et al. study in 51 disturbance in the cerebrovascular bed that may affect blood healthy subjects with follow-up duration of 6 years found flow and accelerate the white matter ischemia [61, 62]. that increase in DWMC volume (43.8%) was greater than Recently, postmortem Medical Research Council Cog- that of PVWMC (29.7%) [47]. Furthermore, female may nitive Function and Ageing Study using RNA microarray have more lesion progression than male. A longitudinal and pathway analysis found that 8 major pathways in which study in 554 elders (313 men, 241 women) aged 70 to 82 multiple genes showed altered RNA transcription (immune years indicated that women had significantly higher DWMC regulation, cell cycle, apoptosis, proteolysis, ion transport, volume than men at baseline; after 3 years followup, they had cell structure, electron transport, metabolism) and WMC accumulated approximately twice as much DWMC as men, represented areas with a complex molecular phenotype [63]. whereas their progression of PVWMC was similar to men Xu et al. study revealed that 241 genes specific for WMC [51]. Other factors associated with faster decline in WMC are expression were associated with inflammation, oxidative higher age, cigarette smoking, and elevated BP [48]. stress, detoxification, and hormonal responses, included genes associated with brain repair, long-term potentiation, and axon guidance, and included genes associated with 4. Pathology and Physiology oligodendrocyte proliferation, axon repair, long-term poten- Pathologically, WMC are characterized by partial loss of tiation, and neurotransmission [64]. These neurogenetic myelin, axons, and oligodendroglial cells; mild reactive findings support the ischemia, blood-brain barrier dysfunc- tion, systemic oxidative stress, and inflammation in the astrocytic gliosis; sparsely distributed macrophages as well as stenosis resulting from hyaline fibrosis of arterioles and pathogenesis of WMC, as well as other potential processes smaller vessels [52]. Nowadays, the most accepted opinion is in the pathogenesis which warrant future research. that WMC represents incomplete ischemia mainly related to Other mechanisms hypothesized to be involved in the cerebral small vessel arteriolosclerosis [53]. pathophysiology of WMC encompassing dysfunction of Another mechanism is blood-brain barrier dysfunction. vasomotor reactivity and autoregulation [65–69], chronic Small vessel alterations could lead to damage of the blood- edema [70, 71], apoptosis [72], and endothelial dysfunction brain barrier and chronic leakage of fluid and macro- [73, 74]. Therefore, the pathophysiology of WMC is complex and molecules in the white matter [53]. Increased concentration of cerebrospinal fluid albumin and IgG values were found may be multifactorial. Further studies should address more in patients with CT-detected WMC [54, 55]. A recent MRI on how these different pathways interact with each other. study even found that blood-brain barrier permeability increased in normal-appearing white matter in patients 5. Neuroimaging Assessment with WMC and its presence in normal-appearing white matter would be consistent with it playing a causal role WMC are ill defined hypodensities on CT. On MRI, which in disease pathophysiology [56]. Moreover, a pathological is more sensitive than CT on delineating the lesions, they study showed that albumin extravasation was widespread in appear as hypointensities on T1-weighted imaging and the ageing brain and enhanced in WMC [57]. According hyperintensities on T2-weighted imaging, proton density to the location of the lesions, WMC can be divided into and fluid-attenuated inversion recovery sequences (FLAIR) periventricular WMC (PVWMC) and deep WMC (DWMC). (Figure 1). The FLAIR sequence is probably the best to Pathological studies have shown that PVWMC were related assess the severity of WMC because of clear distinction Journal of Aging Research 3 6row (a) (b) (c) (d) (e) Figure 1: WMC on CT and MRI. (a) Hypodensities on CT; (b) hypointensities on T1-weighted MRI; (c, d, e) hyperintensities on T2- weighted MRI, proton-density, and FLAIR sequences, respectively. (d) The lower arrow shows the PVWMC, and the upper one shows the DWMC. between ventricles and the PVWMC. Lesions are defined as it has been validated against volumetric measurement and PVWMC when their largest diameters are adjacent to the cognitive impairment [83]. The operationalized ARWMC ventricles, otherwise they are considered as DWMC [75]. scale further gave operational definitions on ARWMC scale The more recent diffusion tensor imaging (DTI) technique and improved interrater reliability on CT [84]. Noteworthy provides information on the integrity of white matter tracts is that visual rating scale for assessing the progression of by estimation of the diffusion trace (mean diffusivity) WMC is lacking. Both the Rotterdam progression scale [85] and the directionality-fractional anisotropy (FA). In WMC, and Schmidt progression scale [42]werecorrelatedwith mean diffusivity is elevated and FA is reduced [76], which volumetric measurements. The Rotterdam progression scale suggests impaired white matter integrity. Measures of DTI had moderate to good reliability (weighted Cohen’s = 0.63 are probably more sensitive than WMC volume in detecting (intraobserver), 0.59 (interobserver)), whereas the Schmidt cognitive changes over time [77]. progression scale was less reliable [85, 86]. Nowadays, fully automated techniques and semiauto- As to the assessment of WMC severity, various visual mated segmentation methods become increasingly available. rating scales have been proposed. The visual rating scales Different from the visual rating scales, volumetric measure- are quick and easy to perform on different quality of scans ment is more accurate and provides continuous data without [78]. However, they varied from each other, and data is not ceiling effect. However, it is more time-consuming with quantitative and has ceiling effect. In addition, discrepancies higher requirement of expertise and excellent quality of MRI, between the various scales may lead to inconsistent findings. which limits its use for research purpose. Overall, volumetric Two most popular visual rating scales are Fazekas scale [79] method is preferred over visual rating scales for longitudinal which has been validated histopathologically and Scheltens studies. scale [80] which is detail with good reliability but relatively time-consuming. To unite the visual rating for WMC, the vascular cognitive impairment harmonization standard rec- 6. Clinical Importance ommends the age-related WMC (ARWMC) scale [81] as the preferred visual rating scale [82]. This scale can be applied to 6.1. Cognitive Impairment and Decline. Large amounts of both MRI and CT with moderate to excellent reliability, and evidence shows that WMC are associated with cognitive 4 Journal of Aging Research impairment (executive function [2, 87, 88], mental pro- of Cognition and Gait study showed that the risk of cessing speed [89, 90], and global cognition [2, 91]) and incident falls was doubled in people with WMC volumes long-term cognitive decline in both community and stroke in the highest quintile of its distribution compared with patients [92]. Although some inconsistent results exist, part the lowest (adjusted relative risk 2.32, 95% confidence of the discrepancies stem from different sensitivities of rating interval: 1.28–4.14) [122]. Regardings the WMC location on scales for WMC, small sample size, and use of different gait, Tasmanian Study of Cognition and Gait study found neuropsychological tests [60]. Longitudinal studies have that bilateral frontal and periventricular WMC-affected demonstrated that WMC progression parallels cognitive voxels corresponded to major anterior projection fibers decline [92]. Baseline PVWMC volume was longitudinally (thalamic radiations, corticofugal motor tracts) and adjacent associated with reduced mental processing speed [93]and association fibers (corpus callosum, superior frontooccipital increased the risk of dementia [94, 95]. In some studies, fasciculus, short association fibers) showed the greatest when brain atrophy was added into the predicting models, covariance with poorer gait [123]. A DTI study also found influence of WMC became insignificant whereas global white matter integrity in the genu of corpus callosum and/or regional atrophy (i.e., medial temporal lobe atrophy, was an important marker of gait in the elderly [124]. cortical gray matter (cGM) and hippocampus atrophy) Another two recent DTI studies revealed that in elderly exerted greater influence upon cognitive decline [96–98]. subjects with small vessel disease, widespread disruption These studies also showed that whole brain or cGM atrophy of white matter integrity, predominantly in the normal- was related to severity of WMC. It was thus proposed appearing white matter, was involved in gait disturbances that cognitive decline in patients with WMC was mediated [125, 126]. Iseki et al. study using single-photon emission- by brain atrophy [96]. The hypothesized mechanisms of computed tomography suggested that abnormalities in the how WMC induce cortical atrophy include demyelination basal ganglia-thalamocortical loops partly explained gait of axons leading to cortical-subcortical deafferentation and disturbance in WMC [127]. Thus, accumulating evidence subsequent secondary cortical neuronal loss, [99, 100] suggests that the disruptions in motor network may account hypoperfusion, and hypometabolism [101, 102], as well as for gait disturbance in WMC. concomitant cortical microinfarct, which its detection is WMC correlate with gait disturbance in community beyond the ability of current neuroimaging techniques [102]. residents, and some of these abnormalities overlap with A recent study also showed that severe WMC were associated features of PD. In postmortem study with 700 parkinsonism with hippocampus atrophy [103]. Moreover, Smith et al. cases, 27 brains (3.9%) showed WMC and/or lacunes in study in community residents revealed that WMC progres- the basal ganglia, white matter, or brainstem, without sion might predict normal to mild cognitive impairment, significant nigral lesions [128]. Studies also found that WMC whereas global atrophy predicted mild cognitive impairment contributed to dementia in PD patients [16, 129, 130]. Albeit to dementia [104]. With the development of DTI technique, inconclusive, evidences accumulating that cognitive effects of studies indicated that microstructural integrity of both WMC tend to preferentially affect executive functions and WMC and normal-appearing white matter was associated may reflect frontal lobe WMC [129]. with cognitive function, regardless of white matter atrophy, WMC volume, and lacunar infarcts [105, 106]. 6.3. Urinary Incontinence. Studies had shown that WMC Certain factors need to be considered in the evaluation were associated with urgency urinary incontinence [131– of the relationship between WMC and cognitive impair- 135]. A community study found that among 100 residents, ment. First, the relationship between WMC and cognitive 64% of them had urinary incontinence. The presence of impairment may not be linear, and a threshold effect was WMC in right inferior frontal regions and selected WM proposed [107]. Second, cognitive impact of WMC may vary tracts predicted incontinence, incontinence severity, and with its location. PVWMC may affect cognition more than degree of bother. The study confirmed a critical role for the DWMC. Thus, studies evaluating total WMC may dilute the cingulum in bladder control and suggested potential involve- cognitive influence of region-specific WMC [108]. Third, ment of anterior corona radiata and superior frontooccipital psychometric tests in studies may not be comprehensive fasciculus [132]. A study in old women indicated that the for the assessment of executive function; hence, the impact presence of WMC in specific pathways (anterior thalamic of WMC may be underestimated [108]. Forth, silent brain radiation and superior longitudinal fasciculus) might affect infarcts and microbleeds were reported to be associated with continence control [136]. cognitiveimpairmentaswell[109–113], and brain atrophy (cGM, hippocampus and medial temporal lobe atrophy) may be a confounder between WMC and cognitive impairment, 6.4. Depression. Lines of evidence suggested that WMC these neuroimaging measures were not assessed in some are associated with late life depression [45, 137–144]. In studies. Last, future studies should utilize DTI in exploring poststroke patients, severe deep WMC predicted poststroke the mechanisms of cognitive decline and as a surrogate depression [145]. And concurrent atrophy of left inferior marker for disease progression in therapeutic trials. frontal gyrus was associated with depressive symptoms in poststroke patients with severe WMC [146]. Vascular 6.2. Gait Disturbance and PD. Both cross-sectional and depression hypothesis proposed that WMC causes depres- longitudinal studies have found that WMC were associated sion by disrupting fiber tracts within frontostriatal circuits with gait disturbance and falls [114–121]. Tasmanian Study [142]. Because of their involvement in the regulation of Journal of Aging Research 5 mood, disruption of frontostriatal circuits might lead to a 8.1. BP Lowing Therapy. The Epidemiology of Vascular disconnection syndrome that corresponded to the clinical Ageing MRI study has shown a positive linear relationship and neuropsychological profile of depression [142]. A DTI between BP and severity of WMC [28]. Dufouil et al. study study also found that frontolimbic neural pathways might retrospectively found subjects receiving regular treatment of contribute to the pathophysiology of depression [147]. hypertension had less severe PVWMC than those receiving no or irregular treatment of hypertension. Due to its cross-sectional design, the treatment effect of hypertension 6.5. Stroke and Death. The WMC increased the risk for on WMC progression cannot be examined in this study. stroke [8, 95, 148, 149]and death[149–151]. A recent meta- The Perindopril Protection against Recurrent Stroke Study analysis revealed that stroke yielded a significant association (PROGRESS) MRI substudy [178] was a longitudinal ran- of WMC with incident stroke (HR 3.5 (2.5–4.9), P< 0.001) domized placebo-controlled trail investigating the BP lowing and increased risk of death (HR 2.0 (1.6–2.7), P< 0.001) therapy using perindopril or perindopril plus indapamide [92]. In patients treated with thrombolysis for acute stroke, on WMC progression. 192 participants were followed up the rate of symptomatic intracerebral hemorrhage increased for 36 months, the mean total volume of new WMC was by 10% in patients with severe WMC and multiple lacunes significantly lower in the active treatment group compared [152]. WMC were found to be independent determinants for with the placebo group, and the difference was greatest for intracerebral hemorrhage after controlling for age and other patients with severe WMC at entry [178]. risk factors [152, 153]. An open-label study [179] and a post hoc analysis of WMC were not benign but predict poor clinical and a randomized trial [180] showed some beneficial effects of functional outcomes. Some studies also indicated that they, nimodipine in patients with subcortical vascular dementia. especially DWMC, were associated with migraine [154, 155]. A recent randomized placebo-controlled trial also found And brain stem WMC were associated with dizziness [156]. that the calcium antagonist nimodipine could slow down More studies are in need to explore the clinical significance global cognitive decline in patients with small vessel disease of WMC. related vascular dementia [181]. A recent review in vascular cognitive impairment indicated that nicardipine has been 7. Chemical Biomarkers investigated in more than 6000 patients, with improvement of cognitive deterioration in more than 60% of patients Homocysteine is a dietary sulphur-containing amino acid treated [182]. The antihypertensive activity of nicardipine derived as an intermediate during the metabolism of methio- and its safety and effectiveness in cognitive domain suggested nine [157]. Nutritional deficiencies in the vitamin cofactors reconsidering this drug in the treatment of cognitive impair- (folate, vitamin B ,and vitaminB ) required for homo- 12 6 ment of vascular origin and for reducing the risk of recurrent cysteine metabolism may promote hyperhomocyst(e)inemia stroke in patients at high risk of it [182]. Further randomized [158]. Perini et al. study found that the hyperhomocys- double-blind placebo-controlled trail is needed to explore teinemia in acute stoke stage was associated with higher the efficacy and safety of nimodipine and nicardipine upon risk of small artery disease subtype of stroke [159]. Many WMC progression. studies had indicated that hyperhomocysteinemia was an Although most studies paid attention to lower BP in independent predictor for WMC independent of smoking, hypertension, noted that low BP was a risk factor for WMC hypertension, or age [160–172]. as well [60]. Another study found that nocturnal BP dipping Inflammatory biomarkers as intercellular adhesion was associated with WMC [183]. Thus, a randomized molecule-1 (ICAM-1) [173, 174], and high sensitive C- controlled study dedicated to examine the effects of BP reactive protein (Hs CRP) [175–177] were also reported lowering therapy upon progression of WMC is needed. to be associated with WMC load. However, these studies were cross-sectional so that causal relationship cannot be 8.2. Statins. Statins have long been demonstrated to reduce determined. Longitudinal studies are needed to study the cardiovascular events and ischemic stroke among patients relationship between progression of inflammatory factors with coronary heart disease [184]. Whether statins affect with progression of WMC. progression of WMC is still controversial. The PROSPER (Prospective Study of Pravastatin in Elderly at Risk) study examined the effect of pravastatin 40 mg daily on the 8. Treatment of WMC progression of WMC in 270 placebo-treated subjects and 265 The WMC are predictors for poor clinical outcomes and active subjects within a period of 33 months. The study failed important substrates for vascular dementia. The European to demonstrate an overall beneficial effect of statins upon Task Force on age-related WMC recommended that clinical WMC progression. However, data on proportions of subjects trials on cerebral small vessel disease should target those with having different WMC severity are lacking, and stratified severe WMC and use its progression as surrogate marker analysis based on WMC severity was not performed in the in clinical trials [49]. Albeit WMC are clinically important, study. In the Cardiovascular Health Study, 3334 community very few clinical studies had been conducted so far to participants were followedup over an average observational evaluate treatments for WMC. In this part, studies on treat- period of 7 years [185]. Patients treated with statins were ments for WMC- and WMC- related vascular dementia are observed to have slightly less cognitive decline than untreated reviewed. subjects. This significant cognitive benefit was associated 6 Journal of Aging Research with reduced progression in cerebral infarcts among the and rivastigmine) and memantine in patients with vas- treated subjects, whereas progression of WMC was not cular dementia [188]. Yet, given the potential benefit of memantine upon subcortical vascular dementia based on statistically different between these two groups. Although the findings may suggest that statins exert cognitive benefits post hoc analysis and its favorable safety profile, conducting a randomized study evaluating its efficacy in subcortical independent of WMC progression, the visual rating scale vascular dementia may be worthwhile. used in that study was unlikely to be sensitive in detecting WMC progression [38]. The ROCAS (Regression of Cerebral Cerebral autosomal dominant arteriopathy with sub- Artery Stenosis) study evaluated simvastatin on WMC cortical infarcts and leucoencephalopathy (CADASIL) is a progression in patients with asymptomatic middle cerebral genetic form of subcortical vascular dementia. A recent artery stenosis [38]. Two hundred and eight randomized sub- multicentre, 18-week, placebo-controlled, double-blind, jects were assigned to either placebo (n = 102) or simvastatin randomized parallel-group trial using donepezil in 168 20 mg daily (n = 106) for 2 years. Simvastatin group did not CADASIL patients revealed that donepezil had no effect on slow the progression of WMC volume compared with the the vascular ADAS-cog score in CADASIL patients with cog- nitive impairment. Improvements were noted only on several placebo group, but in those with severe WMC at baseline, the median volume increase in the simvastatin group (1.9 cm ) measures of executive function, which might possibly suggest that cholinergic pathways were involved in the executive was less compared with that in the placebo group (3.0 cm ; function [190]. Overall, findings of this study are similar to P = 0.047). However, in this study, treatment probably that of previous studies using acetylcholinesterase inhibitors prevented WMC progression among those with severe WMC in that acetylcholinesterase inhibitors might only induce sub- at baseline was based only on subgroup analysis upon a small tle cognitive benefits among patients with vascular dementia. subset of subjects. Furthermore, the subjects of this study belonged to a high-risk group in that all our subjects had Another more recent randomized, international, multi- concurrent MCA stenosis. Hence, the findings may not be center, 24-week trial in 974 probable or possible vascular applicable to patients with less vascular burden or to those dementia patients who received donepezil 5 mg/d or placebo found that donepezil improved the vascular ADAS-cog score with WMC but without concurrent MCA stenosis. but not global function [191]. However, subgroup analysis Furthermore, a recent cross-sectional study showed that on the effects of donepezil upon subcortical type of vascular low cholesterol had more severe WMC in acute stroke dementia was not performed in this study. patients [10]. Other studies found that low cholesterol was associated with intracerebral hemorrhage and high mortality in these patients [186, 187]. Hence, effects of 8.4. Homocysteine Lowering Therapy. Lines of evidence have stains and cholesterol control upon WMC progression are shown that hyperhomocysteinemia was associated with still uncertain, and randomized clinical trials are needed to WMC through endothelial dysfunction [160–172]. Whether address this issue. homocysteine lowering therapy by means of multivitamins retards the progression of WMC or not is uncertain. A randomized double-blind, parallel, placebo-controlled trial 8.3. Acetylcholinesterase Inhibitors and N -Methysl-D-Aspar- on homocysteine lowering therapy is the VITAmins TO tate (NMDA) Receptor Antagonists. Acetylcholinesterase in- Prevent Stroke (VITATOPS) study. 8164 patients with recent hibitors (donepezil, galantamine, and rivastigmine) and N- stroke or transient ischaemic attack (within the past 7 methyl-D-aspartate (NMDA) receptor antagonists (meman- months) received one tablet daily of placebo (n = 4089) tine) have been approved for treatment of AD. Kavirajan or B vitamins (2 mg folic acid, 25 mg vitamin B ,and and Schneider reviewed three donepezil, two galantamine, 0.5 mg vitamin B , n = 4075) with a median followed- one rivastigmine, and two memantine placebo-controlled, up duration of 3.4 years. Although vitamin treatment was randomized, double blinded trials, it showed that cogni- not significantly more effective than placebo in reducing tive effects on the AD assessment scale-cognitive subscale the incidence of the composite primary endpoint of stroke, (ADAS-cog) were significant for all drugs, and post hoc myocardial infarction, or vascular death, in the subgroup analyses of donepezil tails suggested greater improvement analyses, homocysteine lowering might have preferential in patients with cortical and territorial lesions compared benefit in small vessel disease patients (risk ratio 0.80 (95% with those with predominantly subcortical small vessel CI : 0.67–0.96)) [192]. The VITATOPS MRI substudy is disease related lesions [188]. By contrast, cognitive benefits currently underway to evaluate whether vitamins can slow in the memantine trials appeared to be more pronounced WMC progression and/or cognitive decline. for patients with small vessel disease than for those with large vessel disease and such benefits derived largely from worsening in patients in the placebo-treated groups who 9. Conclusion predominantly had small vessel disease [188, 189]. With regards to safety profile, use of cholinesterase inhibitor WMC are common in elderly, and they are not benign. More significantly increased the odds of having adverse events extensive WMC are associated with a host of poor clinical (e.g., anorexia, nausea, vomiting, and diarrhea), while outcomes. Although WMC have been shown to be associated memantine was found to be well tolerable and safe. Overall, with small vessel disease, age, and other vascular risk factors, the data is insufficient to support the widespread use the exact mechanisms explaining such association are still of acetylcholinesterase inhibitors (donepezil, galantamine, uncertain. To date, dataon the effectiveness of various Journal of Aging Research 7 treatments (e.g., BP lowering, statins) in preventing WMC [14] S. J. Lee, J. S. Kim, K. S. Lee et al., “The severity of leukoa- raiosis correlates with the clinical phenotype of Parkinson’s progression were derived mainly from subgroup analyses. disease,” Archives of Gerontology and Geriatrics, vol. 49, no. 2, Randomized studies dedicated in evaluating treatments for pp. 255–259, 2009. preventing WMC progression and its clinical correlates are [15] J. Slawek, D. Wieczorek, M. Derejko et al., “The influence thus urgently needed. Although some studies have suggested of vascular risk factors and white matter hyperintensities the efficacy of nimodipine, nicardipine, and memantine on the degree of cognitive impairment in Parkinson’s in subcortical vascular dementia, further randomized disease,” Neurologia i Neurochirurgia Polska, vol. 42, no. 6, controlled studies are needed to clarify their effectiveness pp. 505–512, 2008. and safety. [16] Y. H. Sohn and J. S. Kim, “The influence of white matter hyperintensities on the clinical features of parkinson’s dis- ease,” Yonsei Medical Journal, vol. 39, no. 1, pp. 50–55, 1998. References [17] H. S. Jorgensen, H. Nakayama, H. O. Raaschou, and T. S. [1] L. Pantoni, “Cerebral small vessel disease: from pathogenesis Olsen, “Leukoaraiosis in stroke patients: the Copenhagen and clinical characteristics to therapeutic challenges,” The stroke study,” Stroke, vol. 26, no. 4, pp. 588–592, 1995. Lancet Neurology, vol. 9, no. 7, pp. 689–701, 2010. [18] D. Liao, L. Cooper, J. Cai et al., “The prevalence and severity [2] W. T. Longstreth Jr., T. A. Manolio, A. Arnold et al., “Clinical of white matter lesions, their relationship with age, ethnicity, correlates of white matter findings on cranial magnetic gender, and cardiovascular disease risk factors: the ARIC resonance imaging of 3301 elderly people: the cardiovascular study,” Neuroepidemiology, vol. 16, no. 3, pp. 149–162, 1997. health study,” Stroke, vol. 27, no. 8, pp. 1274–1282, 1996. [19] H. Henon, O. Godefroy, C. Lucas, J. P. Pruvo, and D. Leys, [3] D. Liao, L. Cooper, J. Cai et al., “Presence and severity of “Risk factors and leukoaraiosis in stroke patients,” Acta cerebral white matter lesions and hypertension, its treatment, Neurologica Scandinavica, vol. 94, no. 2, pp. 137–144, 1996. and its control: the ARIC study,” Stroke, vol. 27, no. 12, pp. [20] A. M. Basile, L. Pantoni, G. Pracucci et al., “Age, 2262–2270, 1996. hypertension, and lacunar stroke are the major determinants [4] F.E.deLeeuw,J.C.deGroot,E.Achtenetal., “Prevalenceof of the severity of age-related white matter changes. The cerebral white matter lesions in elderly people: a population LADIS (Leukoaraiosis and Disability in the Elderly) study,” based magnetic resonance imaging study. The Rotterdam Cerebrovascular Diseases, vol. 21, no. 5-6, pp. 315–322, 2006. Scan Study,” Journal of Neurology Neurosurgery and Psychi- [21] J. C. vanSwieten,G.G.Geyskes,M.M.Derix et al., atry, vol. 70, no. 1, pp. 9–14, 2001. “Hypertension in the elderly is associated with white matter [5] W. Wen, P. S. Sachdev, J. J. Li, X. Chen, and K. J. Anstey, lesions and cognitive decline,” Annals of Neurology, vol. 30, “White matter hyperintensities in the forties: their prevalence no. 6, pp. 825–830, 1991. and topography in an epidemiological sample aged 44–48,” [22] H. S. Choi, Y. M. Cho, J. H. Kang, C. S. Shin, K. S. Park, and Human Brain Mapping, vol. 30, no. 4, pp. 1155–1167, 2009. H. K. Lee, “Cerebral white matter hyperintensity is mainly [6] L.J.Launer, K. Berger,M.M.B.Breteleretal., “Regional associated with hypertension among the components of variability in the prevalence of cerebral white matter lesions: metabolic syndrome in Koreans,” Clinical Endocrinology, vol. an MRI study in 9 European countries (CASCADE),” 71, no. 2, pp. 184–188, 2009. Neuroepidemiology, vol. 26, no. 1, pp. 23–29, 2005. [23] M. K. Park, I. Jo, M. H. Park, T. K. Kim, S. A. Jo, and C. Shin, [7] R. Mantyla, H. J. Aronen, O. Salonen et al., “The prevalence “Cerebral white matter lesions and hypertension status in and distribution of white-matter changes on different MRI the elderly Korean: the Ansan Study,” Archives of Gerontology pulse sequences in a post-stroke cohort,” Neuroradiology, vol. and Geriatrics, vol. 40, no. 3, pp. 265–273, 2005. 41, no. 9, pp. 657–665, 1999. [24] E. J. van Dijk, M. M. Breteler, R. Schmidt et al., “The asso- [8] J. H. Fu, C. Z. Lu, Z. Hong, Q. Dong, Y. Luo, and K. S. Wong, ciation between blood pressure, hypertension, and cerebral “Extent of white matter lesions is related to acute subcortical white matter lesions: cardiovascular determinants of demen- infarcts and predicts further stroke risk in patients with first tia study,” Hypertension, vol. 44, no. 5, pp. 625–630, 2004. ever ischaemic stroke,” Journal of Neurology, Neurosurgery [25] F. E. de Leeuw, J. C. de Groot, M. Oudkerk et al., “Hyper- and Psychiatry, vol. 76, no. 6, pp. 793–796, 2005. tension and cerebral white matter lesions in a prospective [9] W. K. Tang, S. S. Chan, H. F. Chiu et al., “Frequency and cohort study,” Brain, vol. 125, no. 4, pp. 765–772, 2002. determinants of poststroke dementia in Chinese,” Stroke, vol. [26] C. Sierra, “Cerebral white matter lesions in essential 35, no. 4, pp. 930–935, 2004. hypertension,” Current Hypertension Reports,vol. 3, no.5, [10] J. Jimenez-Conde, A. Biffi, R. Rahman et al., “Hyperlipidemia pp. 429–433, 2001. and reduced white matter hyperintensity volume in patients [27] L. H. Kuller, K. L. Margolis, S. A. Gaussoin et al., with ischemic stroke,” Stroke, vol. 41, no. 3, pp. 437–442, “Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the [11] J. Aharon-Peretz, J. L. Cummings, and M. A. Hill, “Vascular Women’s Health Initiative Memory Study (WHIMS)—MRI dementia and dementia of the Alzheimer type. Cognition, trial,” Journal of Clinical Hypertension, vol. 12, no. 3, pp. ventricular size, and leuko-araiosis,” Archives of Neurology, 203–212, 2010. vol. 45, no. 7, pp. 719–721, 1988. [28] C. Dufouil, A. de Kersaint-Gilly, V. Besancon et al., [12] F. E. de Leeuw, F. Barkhof, and P. Scheltens, “White matter “Longitudinal study of blood pressure and white matter lesions and hippocampal atrophy in Alzheimer’s disease,” hyperintensities: the EVA MRI cohort,” Neurology, vol. 56, Neurology, vol. 62, no. 2, pp. 310–312, 2004. no. 7, pp. 921–926, 2001. [13] M. Targosz-Gajniak, J. Siuda, S. Ochudlo, and G. Opala, “Cerebral white matter lesions in patients with dementia— [29] T. Jeerakathil, P. A. Wolf, A. Beiser et al., “Stroke risk profile from MCI to severe Alzheimer’s disease,” Journal of the predicts white matter hyperintensity volume: the Framing- Neurological Sciences, vol. 283, no. 1-2, pp. 79–82, 2009. ham study,” Stroke, vol. 35, no. 8, pp. 1857–1861, 2004. 8 Journal of Aging Research [30] M. Vuorinen, A. Solomon, S. Rovio et al., “Changes in [45] W. D. Taylor,D.C.Steffens, J. R. MacFall et al., “White vascular risk factors from midlife to late life and white matter matter hyperintensity progression and late-life depression lesions: a 20-year follow-up study,” Dementia and Geriatric outcomes,” Archives of General Psychiatry, vol. 60, no. 11, pp. Cognitive Disorders, vol. 31, no. 2, pp. 119–125, 2011. 1090–1096, 2003. [46] J. Y. Streifler, M. Eliasziw, O. R. Benavente et al., [31] A. M. Brickman,C.Reitz,J.A.Luchsinger et al., “Long-term “Development and progression of leukoaraiosis in patients blood pressure fluctuation and cerebrovascular disease in with brain ischemia and carotid artery disease,” Stroke, vol. an elderly cohort,” Archives of Neurology, vol. 67, no. 5, pp. 564–569, 2010. 34, no. 8, pp. 1913–1916, 2003. [47] P. Sachdev, W. Wen, X. Chen, and H. Brodaty, “Progression [32] D. Carmelli, C. DeCarli, G. E. Swan et al., “Evidence for of white matter hyperintensities in elderly individuals over 3 genetic variance in white matter hyperintensity volume years,” Neurology, vol. 68, no. 3, pp. 214–222, 2007. in normal elderly male twins,” Stroke,vol. 29, no.6,pp. [48] E. J. van Dijk, N. D. Prins, H. A. Vrooman, A. Hofman, P. 1177–1181, 1998. J. Koudstaal, and M. M. Breteler, “Progression of cerebral [33] F. E. de Leeuw, F. Richard, J. C. de Groot et al., “Interaction small vessel disease in relation to risk factors and cognitive between hypertension, apoE, and cerebral white matter consequences: Rotterdam Scan study,” Stroke, vol. 39, no. 10, lesions,” Stroke, vol. 35, no. 5, pp. 1057–1060, 2004. pp. 2712–2719, 2008. [34] K. Kohara, M. Fujisawa, F. Ando et al., “MTHFR gene [49] R. Schmidt, P. Scheltens, T. Erkinjuntti et al., “White matter polymorphism as a risk factor for silent brain infarcts and lesion progression: a surrogate endpoint for trials in cerebral white matter lesions in the Japanese general population: the small-vessel disease,” Neurology, vol. 63, no. 1, pp. 139–144, NILS-LSA study,” Stroke, vol. 34, no. 5, pp. 1130–1135, 2003. [35] L. H. Henskens,A.A.Kroon,M.P.van Boxtel,P.A.Hofman, [50] E. J. Burton,I.G.McKeith,D.J.Burn, M. J. Firbank, and and P. W. De Leeuw, “Associations of the angiotensin II type J. T. O’Brien, “Progression of white matter hyperintensities 1 receptor A1166C and the endothelial NO synthase G894T in Alzheimer disease, dementia with lewy bodies, and gene polymorphisms with silent subcortical white matter Parkinson disease dementia: a comparison with normal lesions in essential hypertension,” Stroke,vol. 36, no.9,pp. aging,” American Journal of Geriatric Psychiatry, vol. 14, no. 1869–1873, 2005. 10, pp. 842–849, 2006. [36] L. Paternoster, W. Chen, and C. L. Sudlow, “Genetic [51] D. M. van den Heuvel, F. Admiraal-Behloul, V. H. ten Dam determinants of white matter hyperintensities on brain et al., “Different progression rates for deep white matter scans: a systematic assessment of 19 candidate gene hyperintensities in elderly men and women,” Neurology, vol. polymorphisms in 46 studies in 19,000 subjects,” Stroke, vol. 63, no. 9, pp. 1699–1701, 2004. 40, no. 6, pp. 2020–2026, 2009. [52] A. Brun and E. Englund, “A white matter disorder in [37] L. J. Podewils, E. Guallar, N. Beauchamp, C. G. Lyketsos, dementia of the Alzheimer type: a pathoanatomical study,” L. H. Kuller, and P. Scheltens, “Physical activity and white Annals of Neurology, vol. 19, no. 3, pp. 253–262, 1986. matter lesion progression: assessment using MRI,” Neurology, [53] L. Pantoni, “Pathophysiology of age-related cerebral vol. 68, no. 15, pp. 1223–1226, 2007. white matter changes,” Cerebrovascular Diseases, vol. 13, [38] V. C. Mok, W. W. Lam, Y. H. Fan et al., “Effects of statins supplement 2, pp. 7–10, 2002. on the progression of cerebral white matter lesion : post [54] L. Pantoni, D. Inzitari, G. Pracucci et al., “Cerebrospinal fluid hoc analysis of the ROCAS (Regression of Cerebral Artery proteins in patients with leucaraiosis: possible abnormalities Stenosis) study,” Journal of Neurology, vol. 256, no. 5, pp. in blood-brain barrier function,” Journal of the Neurological 750–757, 2009. Sciences, vol. 115, no. 2, pp. 125–131, 1993. [39] A. A. Gouw, W. M. van der Flier, F. Fazekas et al., [55] A. Wallin, M. Sjogren, A. Edman, K. Blennow, and B. “Progression of white matter hyperintensities and incidence Regland, “Symptoms, vascular risk factors and blood-brain of new lacunes over a 3-year period: the leukoaraiosis and barrier function in relation to CT white-matter changes in disability study,” Stroke, vol. 39, no. 5, pp. 1414–1420, 2008. dementia,” European Neurology, vol. 44, no. 4, pp. 229–235, [40] L. O. Wahlund, O. Almkvist, H. Basun, and P. Julin, “MRI in successful aging, a 5-year follow-up study from the eighth [56] R. Topakian, T. R. Barrick, F. A. Howe, and H. S. Markus, to ninth decade of life,” Magnetic Resonance Imaging, vol. 14, “Blood-brain barrier permeability is increased in normal- no. 6, pp. 601–608, 1996. appearing white matter in patients with lacunar stroke [41] J. H. Veldink, P. Scheltens, C. Jonker, and L. J. Launer, and leucoaraiosis,” Journal of Neurology, Neurosurgery and “Progression of cerebral white matter hyperintensities on Psychiatry, vol. 81, no. 2, pp. 192–197, 2010. MRI is related to diastolic blood pressure,” Neurology, vol. [57] J. E. Simpson, S. B. Wharton, J. Cooper et al., “Alterations 51, no. 1, pp. 319–320, 1998. of the blood-brain barrier in cerebral white matter lesions [42] R. Schmidt, F. Fazekas, P. Kapeller, H. Schmidt, and H. in the ageing brain,” Neuroscience Letters, vol. 486, no. 3, pp. P. Hartung, “MRI white matter hyperintensities: three- 246–251, 2010. year follow-up of the Austrian Stroke Prevention Study,” [58] F. Fazekas, R. Kleinert, H. Olfenbacher et al., “Pathologic Neurology, vol. 53, no. 1, pp. 132–139, 1999. correlates of incidental MRI white matter signal hyperinten- [43] G. T. Whitman, T. Tang, A. Lin, and R. W. Baloh, “A sities,” Neurology, vol. 43, no. 9, pp. 1683–1689, 1993. prospective study of cerebral white matter abnormalities in [59] J. E. Simpson, P. G. Ince, C. E. Higham et al., “Microglial older people with gait dysfunction,” Neurology, vol. 57, no. activation in white matter lesions and nonlesional white 6, pp. 990–994, 2001. matter of ageing brains,” Neuropathology and Applied Neurobiology, vol. 33, no. 6, pp. 670–683, 2007. [44] R. Schmidt, C. Enzinger, S. Ropele, H. Schmidt, and F. Fazekas, “Progression of cerebral white matter lesions: 6-Year [60] L. Pantoni and J. H. Garcia, “The significance of cerebral results of the Austrian Stroke Prevention Study,” The Lancet, white matter abnormalities 100 years after Binswanger’s vol. 361, no. 9374, pp. 2046–2048, 2003. report: a review,” Stroke, vol. 26, no. 7, pp. 1293–1301, 1995. Journal of Aging Research 9 [61] S. M. Manschot, G. J. Biessels, G. E. Rutten, R. P. Kessels, [77] A. Nitkunan, T. R. Barrick, R. A. Charlton, C. A. Clark, and W. H. Gispen, and L. J. Kappelle, “Peripheral and central H. S. Markus, “Multimodal MRI in cerebral small vessel neurologic complications in type 2 diabetes mellitus: no disease: its relationship with cognition and sensitivity to association in individual patients,” Journal of the Neurological change over time,” Stroke, vol. 39, no. 7, pp. 1999–2005, 2008. Sciences, vol. 264, pp. 157–162, 2008. [78] F. Fazekas, F. Barkhof, L. O. Wahlund et al., “CT and MRI [62] V. Novak, D. Last, D. C. Alsop et al., “Cerebral blood flow rating of white matter lesions,” Cerebrovascular Diseases, vol. velocity and periventricular white matter hyperintensities in 13, supplement 2, pp. 31–36, 2002. type 2 diabetes,” Diabetes Care, vol. 29, no. 7, pp. 1529–1534, [79] F. Fazekas, J. B. Chawluk, A. Alavi, H. I. Hurtig, and R. A. Zimmerman, “MR signal abnormalities at 1.5 T in [63] J. E. Simpson, O. Hosny, S. B. Wharton et al., “Microarray Alzheimer’s dementia and normal aging,” American Journal RNA expression analysis of cerebral white matter lesions of Roentgenology, vol. 149, no. 2, pp. 351–356, 1987. reveals changes in multiple functional pathways,” Stroke, vol. [80] P. Scheltens, F. Barkhof, D. Leys et al., “A semiquantitative 40, no. 2, pp. 369–375, 2009. rating scale for the assessment of signal hyperintensities on [64] H. Xu, B. Stamova, G. Jickling et al., “Distinctive RNA magnetic resonance imaging,” Journal of the Neurological expression profiles in blood associated with white matter Sciences, vol. 114, no. 1, pp. 7–12, 1993. hyperintensities in brain,” Stroke, vol. 41, no. 12, pp. [81] L. O. Wahlund, F. Barkhof, F. Fazekas et al., “A new rating 2744–2749, 2010. scale for age-related white matter changes applicable to MRI [65] J. H. Fu, C. Z. Lu, Z. Hong, Q. Dong, D. Ding, and K. S. and CT,” Stroke, vol. 32, no. 6, pp. 1318–1322, 2001. Wong, “Relationship between cerebral vasomotor reactivity [82] V. Hachinski, C. Iadecola, R. C. Petersen et al., “National and white matter lesions in elderly subjects without large Institute of Neurological Disorders and Stroke-Canadian artery occlusive disease,” Journal of Neuroimaging, vol. 16, Stroke Network vascular cognitive impairment harmoniza- no. 2, pp. 120–125, 2006. tion standards,” Stroke, vol. 37, no. 9, pp. 2220–2241, 2006. [66] Y. Isaka, M. Okamoto, K. Ashida, and M. Imaizumi, [83] Y. Xiong, V. Mok, A. Wong et al., “The age-related white “Decreased cerebrovascular dilatory capacity in subjects with matter changes scale correlates with cognitive impairment,” asymptomatic periventricular hyperintensities,” Stroke, vol. European Journal of Neurology, vol. 17, no. 12, pp. 1451–1456, 25, no. 2, pp. 375–381, 1994. [67] S. L. Bakker,F.E.deLeeuw,J.C.deGroot,A.Hofman, [84] Y. Xiong, J. Yang, A. Wong et al., “Operational definitions P. J. Koudstaal, and M. M. Breteler, “Cerebral vasomotor improve reliability of the age-related white matter changes reactivity and cerebral white matter lesions in the elderly,” scale,” European Journal of Neurology,vol. 18, no.5,pp. Neurology, vol. 52, no. 3, pp. 578–583, 1999. 744–749, 2011. [68] R. Ohtani, H. Tomimoto, T. Kawasaki et al., “Cerebral [85] N. D. Prins,E.C.van Straaten,E.J.van Dijk et al., vasomotor reactivity to postural change is impaired in “Measuring progression of cerebral white matter lesions on patients with cerebrovascular white matter lesions,” Journal MRI: visual rating and volumetrics,” Neurology, vol. 62, no. of Neurology, vol. 250, no. 4, pp. 412–417, 2003. 9, pp. 1533–1539, 2004. [69] G. M. Kozera, M. Dubaniewicz, T. Zdrojewski et al., [86] A. A. Gouw, W. M. van der Flier, E. C. van Straaten et al., “Cerebral vasomotor reactivity and extent of white matter “Reliability and sensitivity of visual scales versus volumetry lesions in middle-aged men with arterial hypertension: a for evaluating white matter hyperintensity progression,” pilot study,” American Journal of Hypertension, vol. 23, no. Cerebrovascular Diseases, vol. 25, no. 3, pp. 247–253, 2008. 11, pp. 1198–1203, 2010. [87] N. D. Prins,E.J.van Dijk,T.den Heijer et al., “Cerebral [70] C. P. Chung and H. H. Hu, “Pathogenesis of leukoaraiosis: small-vessel disease and decline in information processing role of jugular venous reflux,” Medical Hypotheses, vol. 75, speed, executive function and memory,” Brain, vol. 128, no. no. 1, pp. 85–90, 2010. 9, pp. 2034–2041, 2005. [71] L. Pantoni and J. H. Garcia, “Pathogenesis of leukoaraiosis: [88] V. C. Mok, A. Wong, W. W. Lam et al., “Cognitive a review,” Stroke, vol. 28, no. 3, pp. 652–659, 1997. impairment and functional outcome after stroke associated [72] W. R. Brown, D. M. Moody, C. R. Thore, and V. R. with small vessel disease,” Journal of Neurology, Neurosurgery Challa, “Apoptosis in leukoaraiosis,” American Journal of and Psychiatry, vol. 75, no. 4, pp. 560–566, 2004. Neuroradiology, vol. 21, no. 1, pp. 79–82, 2000. [89] C. Junque, J. Pujol, P. Vendrell et al., “Leuko-araiosis on mag- [73] G. Jickling, A. Salam, A. Mohammad et al., “Circulating netic resonance imaging and speed of mental processing,” endothelial progenitor cells and age-related white matter Archives of Neurology, vol. 47, no. 2, pp. 151–156, 1990. changes,” Stroke, vol. 40, no. 10, pp. 3191–3196, 2009. [90] R. Ylikoski, A. Ylikoski, T. Erkinjuntti, R. Sulkava, R. Rain- [74] A. Hassan, B. J. Hunt, M. O’Sullivan et al., “Markers of inko, and R. Tilvis, “White matter changes in healthy elderly endothelial dysfunction in lacunar infarction and ischaemic persons correlate with attention and speed of mental process- leukoaraiosis,” Brain, vol. 126, no. 2, pp. 424–432, 2003. ing,” Archives of Neurology, vol. 50, no. 8, pp. 818–824, 1993. [75] J. C. de Groot, F. E. de Leeuw, M. Oudkerk et al., “Cerebral [91] W. M. van der Flier, E. C. Van Straaten, F. Barkhof et al., white matter lesions and cognitive function: the Rotterdam “Small vessel disease and general cognitive function in Scan study,” Annals of Neurology, vol. 47, no. 2, pp. 145–151, nondisabled elderly: the LADIS study,” Stroke, vol. 36, no. 2000. 10, pp. 2116–2120, 2005. [76] D. K. Jones, D. Lythgoe, M. A. Horsfield, A. Simmons, S. [92] S. Debette and H. S. Markus, “The clinical importance of C. Williams, and H. S. Markus, “Characterization of white white matter hyperintensities on brain magnetic resonance matter damage in ischemic leukoaraiosis with diffusion imaging: systematic review and meta-analysis,” British tensor MRI,” Stroke, vol. 30, no. 2, pp. 393–397, 1999. Medical Journal, vol. 341, Article ID c3666, 2010. 10 Journal of Aging Research [93] D. M. vanden Heuvel,V.H.ten Dam, A. J. de Craenet [109] S. E. Vermeer, W. T. Longstreth Jr., and P. J. Koudstaal, “Silent al., “Increase in periventricular white matter hyperintensities brain infarcts: a systematic review,” The Lancet Neurology, parallels decline in mental processing speed in a non- vol. 6, no. 7, pp. 611–619, 2007. demented elderly population,” JournalofNeurology,Neuro- [110] J. A. Pettersen, G. Sathiyamoorthy, F. Q. Gao et al., “Microb- surgery and Psychiatry, vol. 77, no. 2, pp. 149–153, 2006. leed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the sunnybrook dementia study,” [94] N. D. Prins,E.J.van Dijk,T.den Heijer et al., “Cerebral Archives of Neurology, vol. 65, no. 6, pp. 790–795, 2008. white matter lesions and the risk of dementia,” Archives of Neurology, vol. 61, no. 10, pp. 1531–1534, 2004. [111] S. E. Vermeer, N. D. Prins, T. den Heijer, A. Hofman, P. J. Koudstaal, and M. M. Breteler, “Silent brain infarcts and the [95] S. E. Vermeer, M. Hollander, E. J. van Dijk, A. Hofman, risk of dementia and cognitive decline,” New England Journal P. J. Koudstaal, and M. M. Breteler, “Silent brain infarcts of Medicine, vol. 348, no. 13, pp. 1215–1222, 2003. and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study,” Stroke, vol. 34, no. [112] Y. Yakushiji, M. Nishiyama, S. Yakushiji et al., “Brain microb- leeds and global cognitive function in adults without neuro- 5, pp. 1126–1129, 2003. logical disorder,” Stroke, vol. 39, no. 12, pp. 3323–3328, 2008. [96] R. Schmidt, S. Ropele, C. Enzinger et al., “White matter [113] J. A. Schneider, “Brain microbleeds and cognitive function,” lesion progression, brain atrophy, and cognitive decline: the Stroke, vol. 38, no. 6, pp. 1730–1731, 2007. Austrian stroke prevention study,” Annals of Neurology, vol. [114] R. Camicioli, M. M. Moore, G. Sexton, D. B. Howieson, and 58, no. 4, pp. 610–616, 2005. J. A. Kaye, “Age-related brain changes associated with motor [97] D. Mungas,B.R.Reed,W.J.Jagustetal., “Volumetric function in healthy older people,” Journal of the American MRI predicts rate of cognitive decline related to AD and Geriatrics Society, vol. 47, no. 3, pp. 330–334, 1999. cerebrovascular disease,” Neurology,vol. 59, no.6,pp. [115] C. R. Guttmann, R. Benson, S. K. Warfield et al., “White 867–873, 2002. matter abnormalities in mobility-impaired older persons,” [98] D. Mungas, D. Harvey, B. R. Reed et al., “Longitudinal Neurology, vol. 54, no. 6, pp. 1277–1283, 2000. volumetric MRI change and rate of cognitive decline,” [116] C. Rosano, J. Brach, W. T. Longstreth Jr., and A. B. Newman, Neurology, vol. 65, no. 4, pp. 565–571, 2005. “Quantitative measures of gait characteristics indicate [99] D. Mungas, W. J. Jagust, B. R. Reed et al., “MRI predictors prevalence of underlying subclinical structural brain ab- of cognition in subcortical ischemic vascular disease normalities in high-functioning older adults,” Neuroe- and Alzheimer’s disease,” Neurology, vol. 57, no. 12, pp. pidemiology, vol. 26, no. 1, pp. 52–60, 2006. 2229–2235, 2001. [117] B. E. Maki, “Gait changes in older adults: predictors of falls [100] A. T. Du, N. Schuff, L. L. Chao et al., “White matter lesions or indicators of fear,” Journal of the American Geriatrics are associated with cortical atrophy more than entorhinal Society, vol. 45, no. 3, pp. 313–320, 1997. and hippocampal atrophy,” Neurobiology of Aging, vol. 26, [118] C. Rosano, J. Brach, S. Studenski, W. T. Longstreth Jr., and A. no. 4, pp. 553–559, 2005. B. Newman, “Gait variability is associated with subclinical [101] C. DeCarli, D. G. Murphy, M. Tranh et al., “The effect of brain vascular abnormalities in high-functioning older white matter hyperintensity volume on brain structure, adults,” Neuroepidemiology, vol. 29, no. 3-4, pp. 193–200, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults,” Neurology, vol. 45, no. 11, pp. [119] H. Baezner, C. Blahak, A. Poggesi et al., “Association of gait 2077–2084, 1995. and balance disorders with age-related white matter changes: [102] M. Tullberg, E. Fletcher, C. DeCarli et al., “White matter the LADIS Study,” Neurology, vol. 70, no. 12, pp. 935–942, lesions impair frontal lobe function regardless of their location,” Neurology, vol. 63, no. 2, pp. 246–253, 2004. [120] D. P. Briley, M. Wasay, S. Sergent, and S. Thomas, “Cerebral [103] C. Eckerstrom, E. Olsson, N. Klasson et al., “High white white matter changes (leukoaraiosis), stroke, and gait matter lesion load is associated with hippocampal atrophy disturbance,” Journal of the American Geriatrics Society, vol. in mild cognitive impairment,” Dementia and Geriatric 45, no. 12, pp. 1434–1438, 1997. Cognitive Disorders, vol. 31, no. 2, pp. 132–138, 2011. [121] H. C. Chui, C. Zarow, W. J. Mack et al., “Cognitive impact [104] E. E. Smith, S. Egorova, D. Blacker et al., “Magnetic resonance of subcortical vascular and Alzheimer’s disease pathology,” imaging white matter hyperintensities and brain volume in Annals of Neurology, vol. 60, no. 6, pp. 677–687, 2006. the prediction of mild cognitive impairment and dementia,” [122] V. Srikanth, R. Beare, L. Blizzard et al., “Cerebral white Archives of Neurology, vol. 65, no. 1, pp. 94–100, 2008. matter lesions, gait, and the risk of incident falls: a [105] M. W. Vernooij, M. A. Ikram, H. A. Vrooman et al., “White prospective population-based study,” Stroke,vol. 40, no.1, matter microstructural integrity and cognitive function in pp. 175–180, 2009. a general elderly population,” Archives of General Psychiatry, [123] V. Srikanth, T. G. Phan, J. Chen, R. Beare, J. M. Stapleton, vol. 66, no. 5, pp. 545–553, 2009. and D. C. Reutens, “The location of white matter lesions and [106] A. G. van Norden, K. F. de Laat, E. J. van Dijk et al., “Diffusion gait—A voxel-based study,” Annals of Neurology, vol. 67, no. tensor imaging and cognition in cerebral small vessel disease. 2, pp. 265–269, 2010. The RUN DMC study,” Biochimica et Biophysica Acta.In [124] R. A. Bhadelia, L. L. Price, K. L. Tedesco et al., “Diffusion press. tensor imaging, white matter lesions, the corpus callosum, [107] K. B. Boone, B. L. Miller, I. M. Lesser et al., “Neuro- and gait in the elderly,” Stroke, vol. 40, no. 12, pp. 3816–3820, psychological correlates of white-matter lesions in healthy 2009. elderly subjects: a threshold effect,” Archives of Neurology, [125] K. F. de Laat, A. M. Tuladhar, A. G. van Norden, D. G. vol. 49, no. 5, pp. 549–554, 1992. Norris, M. P. Zwiers, and F. E. de Leeuw, “Loss of white matter integrity is associated with gait disorders in cerebral [108] V. Mok, W. Lam, Y. Chan, and K. Wong, Poststroke Dementia and Imaging, Nova Science Publishers, 2008. small vessel disease,” Brain, vol. 134, no. 1, pp. 73–83, 2011. Journal of Aging Research 11 [126] K. F. de Laat, A. G. van Norden, R. A. Gons et al., “Diffusion [143] J. J. Vattakatuchery and J. Joy, “Hyperintensities on MRI: tensor imaging and gait in elderly persons with cerebral white matter and depression,” British Medical Journal, vol. small vessel disease,” Stroke, vol. 42, pp. 373–379, 2011. 341, Article ID c4611, 2010. [127] K. Iseki, T. Hanakawa, K. Hashikawa et al., “Gait disturbance [144] P. J. Olesen, D. R. Gustafson, M. Simoni et al., “Temporal associated with white matter changes: a gait analysis and lobe atrophy and white matter lesions are related to major blood flow study,” NeuroImage, vol. 49, no. 2, pp. 1659–1666, depression over 5 years in the elderly,” Neuropsychopharma- cology, vol. 35, no. 13, pp. 2638–2645, 2010. [128] K. A. Jellinger, “The pathology of Parkinson’s disease,” [145] W. K. Tang, Y. K. Chen, J. Y. Lu et al., “White matter Advances in Neurology, vol. 86, pp. 55–72, 2001. hyperintensities in post-stroke depression: a case control [129] N. I. Bohnen and R. L. Albin, “White matter lesions in study,” Journal of Neurology, Neurosurgery & Psychiatry, vol. Parkinson disease,” Nature Reviews Neurology, vol. 7, no. 4, 81, no. 12, pp. 1312–1315, 2010. pp. 229–236, 2011. [146] J. H. Fu, K. Wong, V. Mok et al., “Neuroimaging predictors [130] L. C. Silbert and J. Kaye, “Neuroimaging and cognition in for depressive symptoms in cerebral small vessel disease,” Parkinson’s disease dementia,” Brain Pathology, vol. 20, no. International Journal of Geriatric Psychiatry, vol. 25, no. 10, 3, pp. 646–653, 2010. pp. 1039–1043, 2010. [131] H. K. Kuo and L. A. Lipsitz, “Cerebral white matter changes [147] K. R. Cullen, B. Klimes-Dougan, R. Muetzel et al., “Altered and geriatric syndromes: is there a link?” Journals of white matter microstructure in adolescents with major Gerontology, vol. 59, no. 8, pp. 818–826, 2004. depression: a preliminary study,” Journalofthe American [132] G. A. Kuchel, N. Moscufo, C. R. Guttmann et al., Academy of Child and Adolescent Psychiatry,vol. 49, no.2, “Localization of brain white matter hyperintensities and pp. 173–183, 2010. urinary incontinence in community-dwelling older adults,” [148] J. F. Buyck, C. Dufouil, B. Mazoyer et al., “Cerebral white Journals of Gerontology, vol. 64, no. 8, pp. 902–909, 2009. matter lesions are associated with the risk of stroke but not [133] K. Sonohara, K. Kozaki, M. Akishita et al., “White matter with other vascular events: the 3-city dijon study,” Stroke, lesions as a feature of cognitive impairment, low vitality vol. 40, no. 7, pp. 2327–2331, 2009. and other symptoms of geriatric syndrome in the elderly,” [149] H. Bokura, S. Kobayashi, S. Yamaguchi et al., “Silent brain Geriatrics and Gerontology International,vol. 8, no.2,pp. infarction and subcortical white matter lesions increase the 93–100, 2008. risk of stroke and mortality: a prospective cohort study,” [134] A. Poggesi, G. Pracucci, H. Chabriat et al., “Urinary Journal of Stroke and Cerebrovascular Diseases, vol. 15, no. 2, complaints in nondisabled elderly people with age-related pp. 57–63, 2006. white matter changes: the Leukoaraiosis And DISability [150] N. K. Oksala, A. Oksala, T. Pohjasvaara et al., “Age (LADIS) Study,” Journal of the American Geriatrics Society, related white matter changes predict stroke death in long vol. 56, no. 9, pp. 1638–1643, 2008. term follow-up,” Journal of Neurology, Neurosurgery and [135] Y. Y. Sitoh, Y. Y. Sitoh, and S. Sahadevan, “Clinical Psychiatry, vol. 80, no. 7, pp. 762–766, 2009. significance of cerebral white matter lesions in older [151] D. Inzitari, M. Cadelo, M. L. Marranci, G. Pracucci, and L. Asians with suspected dementia,” Age and Ageing, vol. 33, Pantoni, “Vascular deaths in elderly neurological patients no. 1, pp. 67–71, 2004. with leukoaraiosis,” Journal of Neurology Neurosurgery and [136] S. D. Tadic, D. Griffiths, A. Murrin, W. Schaefer, H. J. Psychiatry, vol. 62, no. 2, pp. 177–181, 1997. Aizenstein, and N. M. Resnick, “Brain activity during [152] V. Palumbo, J. M. Boulanger, M. D. Hill, D. Inzitari, and A. bladder filling is related to white matter structural changes in M. Buchan, “Leukoaraiosis and intracerebral hemorrhage older women with urinary incontinence,” NeuroImage, vol. after thrombolysis in acute stroke,” Neurology, vol. 68, no. 51, no. 4, pp. 1294–1302, 2010. 13, pp. 1020–1024, 2007. [137] I. M. Lesser, E. Hill-Gutierrez, B. L. Miller, and K. B. [153] T. Neumann-Haefelin, S. Hoelig, J. Berkefeld et al., Boone, “Late-onset depression with white matter lesions,” “Leukoaraiosis is a risk factor for symptomatic intracerebral Psychosomatics, vol. 34, no. 4, pp. 364–367, 1993. hemorrhage after thrombolysis for acute stroke,” Stroke, vol. [138] R. D. Nebes, C. F. Reynolds Jr., F. Boada et al., “Longitudinal 37, no. 10, pp. 2463–2466, 2006. increase in the volume of white matter hyperintensities in [154] R. H. Swartz and R. Z. Kern, “Migraine is associated with late-onset depression,” International Journal of Geriatric magnetic resonance imaging white matter abnormalities: Psychiatry, vol. 17, no. 6, pp. 526–530, 2002. a meta-analysis,” Archives of Neurology, vol. 61, no. 9, pp. [139] D. C. Steffens, H. B. Bosworth, J. M. Provenzale, and J. R. 1366–1368, 2004. MacFall, “Subcortical white matter lesions and functional [155] M. C. Kruit, M. A. van Buchem, L. J. Launer, G. M. impairment in geriatric depression,” Depression and Anxiety, Terwindt, and M. D. Ferrari, “Migraine is associated with vol. 15, no. 1, pp. 23–28, 2002. an increased risk of deep white matter lesions, subclinical [140] A. Teodorczuk, J. T. O’Brien, M. J. Firbank et al., “White posterior circulation infarcts and brain iron accumulation: matter changes and late-life depressive symptoms: the population-based MRI CAMERA study,” Cephalalgia, longitudinal study,” British Journal of Psychiatry, vol. vol. 30, no. 2, pp. 129–136, 2010. 191, no. 3, pp. 212–217, 2007. [141] O. Godin, C. Dufouil, P. Maillard et al., “White matter lesions [156] N. Colledge, S. Lewis, G. Mead, R. Sellar, J. Wardlaw, and J. Wilson, “Magnetic resonance brain imaging in people with as a predictor of depression in the elderly: the 3C-dijon dizziness: a comparison with non-dizzy people,” Journal of study,” Biological Psychiatry, vol. 63, no. 7, pp. 663–669, 2008. Neurology Neurosurgery and Psychiatry,vol. 72, no.5,pp. [142] L. L. Herrmann, M. Le Masurier, and K. P. Ebmeier, “White 587–589, 2002. matter hyperintensities in late life depression: a systematic review,” Journal of Neurology, Neurosurgery and Psychiatry, [157] G. J. Hankey and J. W. Eikelboom, “Homocysteine and vascu- vol. 79, no. 6, pp. 619–624, 2008. lar disease,” The Lancet, vol. 354, no. 9176, pp. 407–413, 1999. 12 Journal of Aging Research [158] G. N. Welch and J. Loscalzo, “Homocysteine and athero- [173] H. S. Markus, B. Hunt, K. Palmer, C. Enzinger, H. Schmidt, thrombosis,” New England Journal of Medicine, vol. 338, no. and R. Schmidt, “Markers of endothelial and hemostatic 15, pp. 1042–1050, 1998. activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke [159] F. Perini, E. Galloni, I. Bolgan et al., “Elevated plasma Prevention Study,” Stroke, vol. 36, no. 7, pp. 1410–1414, 2005. homocysteine in acute stroke was not associated with severity [174] J. H. Han, K. S. Wong, Y. Y. Wang, J. H. Fu, D. Ding, and and outcome: stronger association with small artery disease,” Z. Hong, “Plasma level of sICAM-1 is associated with the Neurological Sciences, vol. 26, no. 5, pp. 310–318, 2005. extent of white matter lesion among asymptomatic elderly [160] S. E. Vermeer, E. J. van Dijk, P. J. Koudstaal et al., subjects,” Clinical Neurology and Neurosurgery, vol. 111, no. “Homocysteine, silent brain infarcts, and white matter 10, pp. 847–851, 2009. lesions: the Rotterdam scan study,” Annals of Neurology, vol. [175] R. Schmidt, H. Schmidt, M. Pichler et al., “C-reactive 51, no. 3, pp. 285–289, 2002. protein, carotid atherosclerosis, and cerebral small-vessel [161] C. Dufouil, A. Alperovitch, V. Ducros, and C. Tzourio, disease: results of the austrian stroke prevention study,” “Homocysteine, white matter hyperintensities, and cognition Stroke, vol. 37, no. 12, pp. 2910–2916, 2006. in healthy elderly people,” Annals of Neurology, vol. 53, no. 2, [176] E. J. van Dijk, N. D. Prins, S. E. Vermeer et al., “C-reactive pp. 214–221, 2003. protein and cerebral small-vessel disease: the Rotterdam scan [162] W. T. Longstreth Jr., R. Katz, J. Olson et al., “Plasma total study,” Circulation, vol. 112, no. 6, pp. 900–905, 2005. homocysteine levels and cranial magnetic resonance imaging [177] M. Fornage, Y. A. Chiang, E. S. Omeara et al., “Biomarkers findings in elderly persons: the cardiovascular health study,” of inflammation and MRI-defined small vessel disease of the Archives of Neurology, vol. 61, no. 1, pp. 67–72, 2004. brain: the cardiovascular health study,” Stroke, vol. 39, no. 7, pp. 1952–1959, 2008. [163] A. Hassan, B. J. Hunt, M. O’Sullivan et al., “Homocysteine [178] C. Dufouil, J. Chalmers, O. Coskun et al., “Effects of blood is a risk factor for cerebral small vessel disease, acting via pressure lowering on cerebral white matter hyperintensities endothelial dysfunction,” Brain, vol. 127, no. 1, pp. 212–219, in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic [164] P. Sachdev, R. Parslow, C. Salonikas et al., “Homocysteine Resonance Imaging Substudy,” Circulation, vol. 112, no. 11, and the brain in midadult life: evidence for an increased risk pp. 1644–1650, 2005. of leukoaraiosis in men,” Archives of Neurology, vol. 61, no. 9, [179] L. Pantoni, M. Carosi, S. Amigoni, M. Mascalchi, and pp. 1369–1376, 2004. D. Inzitari, “A preliminary open trial with nimodipine in [165] T. M. Scott, K. L. Tucker, A. Bhadelia et al., “Homocysteine patients with cognitive impairment and leukoaraiosis,” Clin- and B vitamins relate to brain volume and white-matter ical Neuropharmacology, vol. 19, no. 6, pp. 497–506, 1996. changes in geriatric patients with psychiatric disorders,” [180] L. Pantoni, R. Rossi, D. Inzitari et al., “Efficacy and safety American Journal of Geriatric Psychiatry,vol. 12, no.6,pp. of nimodipine in subcortical vascular dementia: a subgroup 631–638, 2004. analysis of the Scandinavian Multi-Infarct Dementia Trial [166] C. B. Wright, M. C. Paik, T. R. Brown et al., “Total ,” Journal of the Neurological Sciences, vol. 175, no. 2, pp. homocysteine is associated with white matter hyperintensity 124–134, 2000. volume: the Northern Manhattan study,” Stroke, vol. 36, no. [181] L. Pantoni, T. del Ser, A. G. Soglian et al., “Efficacy and 6, pp. 1207–1211, 2005. safety of nimodipine in subcortical vascular dementia: a [167] A. Wong, V. Mok, Y. H. Fan, W. W. Lam, K. S. Liang, and K. S. randomized placebo-controlled trial,” Stroke,vol. 36, no.3, Wong, “Hyperhomocysteinemia is associated with volumet- pp. 619–624, 2005. ric white matter change in patients with small vessel disease,” [182] F. Amenta, A. Lanari, F. Mignini, G. Silvestrelli, E. Traini, Journal of Neurology, vol. 253, no. 4, pp. 441–447, 2006. and D. Tomassoni, “Nicardipine use in cerebrovascular disease: a review of controlled clinical studies,” Journal of the [168] B. Censori, T. Partziguian, O. Manara, and M. Poloni, Neurological Sciences, vol. 283, no. 1-2, pp. 219–223, 2009. “Plasma homocysteine and severe white matter disease,” [183] K. Kario, T. Matsuo, H. Kobayashi, M. Imiya, M. Matsuo, Neurological Sciences, vol. 28, no. 5, pp. 259–263, 2007. and K. Shimada, “Nocturnal fall of blood pressure and silent [169] J. L. Fuh, “Homocysteine, cognition and brain white matter cerebrovascular damage in elderly hypertensive patients: hyperintensities,” Acta Neurologica Taiwanica, vol. 19, no. 3, advanced silent cerebrovascular damage in extreme dippers,” pp. 150–152, 2010. Hypertension, vol. 27, no. 1, pp. 130–135, 1996. [170] S. Seshadri, P. A. Wolf, A. S. Beiser et al., “Association of [184] T. R. Pedersen, “Randomised trial of cholesterol lowering in plasma total homocysteine levels with subclinical brain 4444 patients with coronary heart disease: the Scandinavian injury: cerebral volumes, white matter hyperintensity, and Simvastatin Survival Study (4S),” The Lancet, vol. 344, no. silent brain infarcts at volumetric magnetic resonance 8934, pp. 1383–1389, 1994. imaging in the Framingham Offspring Study,” Archives of [185] C. Bernick, R. Katz, N. L. Smith et al., “Statins and cognitive Neurology, vol. 65, no. 5, pp. 642–649, 2008. function in the elderly: the Cardiovascular Health Study,” [171] F. Anan, T. Masaki, H. Tatsukawa et al., “The role of Neurology, vol. 65, no. 9, pp. 1388–1394, 2005. homocysteine as a significant risk factor for white matter [186] D. Woo, B. M. Kissela, J. C. Khoury et al., “Hyper- lesions in Japanese women with rheumatoid arthritis,” cholesterolemia, HMG-CoA reductase inhibitors, and risk of Metabolism, vol. 58, no. 1, pp. 69–73, 2009. intracerebral hemorrhage: a case-control study,” Stroke, vol. [172] Y. L. Tseng, Y. Y. Chang, J. S. Liu, C. S. Su, S. L. Lai, 35, no. 6, pp. 1360–1364, 2004. [187] J. Roquer, A. Rodriguez Campello, M. Gomis, A. Ois, E. and M. Y. Lan, “Association of plasma homocysteine concentration with cerebral white matter hyperintensity on Munteis, and P. Bohm, “Serum lipid levels and in-hospital magnetic resonance images in stroke patients,” Journal of the mortality in patients with intracerebral hemorrhage,” Neurological Sciences, vol. 284, no. 1-2, pp. 36–39, 2009. Neurology, vol. 65, no. 8, pp. 1198–1202, 2005. Journal of Aging Research 13 [188] H. Kavirajan and L. S. Schneider, “Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials,” The Lancet Neurology, vol. 6, no. 9, pp. 782–792, 2007. [189] H. J. Mobius and A. Stoffler, “New approaches to clinical trials in vascular dementia: memantine in small vessel disease,” Cerebrovascular Diseases, vol. 13, supplement 2, pp. 61–66, 2002. [190] M. Dichgans, H. S. Markus, S. Salloway et al., “Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL,” The Lancet Neurology, vol. 7, no. 4, pp. 310–318, 2008. [191] G. C. Roman, S. Salloway, S. E. Black et al., “Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size,” Stroke, vol. 41, no. 6, pp. 1213–1221, 2010. [192] The VITATOPS Trial Study Group, “B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial,” The Lancet Neurology, vol. 9, no. 9, pp. 855–865, 2010. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Aging Research Hindawi Publishing Corporation

Age-Related White Matter Changes

Journal of Aging Research , Volume 2011 – Aug 23, 2011

Loading next page...
 
/lp/hindawi-publishing-corporation/age-related-white-matter-changes-lwsT3llP2i

References (200)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2011 Yun Yun Xiong and Vincent Mok. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2090-2204
eISSN
2090-2212
DOI
10.4061/2011/617927
Publisher site
See Article on Publisher Site

Abstract

SAGE-Hindawi Access to Research Journal of Aging Research Volume 2011, Article ID 617927, 13 pages doi:10.4061/2011/617927 Review Article Yun Yun Xiong and Vincent Mok Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Shatin 999077, Hong Kong Correspondence should be addressed to Vincent Mok, vctmok@cuhk.edu.hk Received 5 May 2011; Revised 28 June 2011; Accepted 28 June 2011 Academic Editor: Leonardo Pantoni Copyright © 2011 Y. Y. Xiong and V. Mok. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Age-related white matter changes (WMC) are considered manifestation of arteriolosclerotic small vessel disease and are related to age and vascular risk factors. Most recent studies have shown that WMC are associated with a host of poor outcomes, including cognitive impairment, dementia, urinary incontinence, gait disturbances, depression, and increased risk of stroke and death. Although the clinical relevance of WMC has been extensively studied, to date, only very few clinical trials have evaluated potential symptomatic or preventive treatments for WMC. In this paper, we reviewed the current understanding in the pathophysiology, epidemiology, clinical importance, chemical biomarkers, and treatments of age-related WMC. 1. Introduction Further searches on bibliographies in the main articles and relevant papers were performed. Age-related white matter changes (WMC) are prevalent findings among the elderly. WMC are considered to be 2. Prevalence and Risk Factors etiologically related to cerebral small vessel disease and are important substrates for cognitive impairment and WMC are almost endemic in community elderly with functional loss in the elderly [1]. Although extensive studies prevalence ranging from 50% to 98% [2–6]. In stroke have investigated various aspects on WMC, controversies still patients, prevalence of WMC varies from 67% to 98% [7– exist in the pathophysiology and clinical phenotypes, and 10]. In Alzheimer’s disease, WMC are also common with consensus regarding to treatments for WMC has not been prevalence ranges from 28.9% to 100% [11–13]. About 30– reached. In this paper, we aimed to provide an update review 55% of patients with Parkinson’s disease (PD) also harbor on the epidemiology, pathophysiology, neuroimaging, clini- WMC [14–16]. Age [2, 4, 6, 17–20]and hypertension cal importance, chemical biomarkers, and treatments of age- [3, 18, 20–30] are established risk factors for WMC. A related WMC. recent Manhattan study in community elderly found that The literature search was conducted using the National compared with individuals with low blood pressure (BP) Center for Biotechnology Information (NCBI) PubMed/ and low fluctuations in BP, the risk of WMC increased with Medline to identify relevant articles related to WMC that higher BP and BP fluctuations [31]. Associations of diabetes were published until June 2011. We used the following mellitus (DM), cholesterol, smoking, and homocysteine are keywords for the search: white matter, white matter changes, less consistent between studies. Although past studies had white matter lesions, leukoaraiosis, white matter hyperinten- suggested that WMC are highly heritable [32] and that sities, and small vessel disease. several polymorphisms in various candidate genes, such as The articles were included in this paper if (1) the journal apolipoprotein E (epsilon 4±), methylenetetrahydrofolate article was published in English and (2) they were related reductase (677 cytosine/thymine polymorphism (C/T)), and to epidemiology, pathophysiology, neuroimaging, genetics, angiotensinogen (Met235Thr), were found to be associated clinical phenotypes, biomarkers, and treatment of WMC. with WMC, [33–35] a recent meta-analyses failed to show 2 Journal of Aging Research convincing evidence for an association between WMC and to disruption of the ependymal lining with subependymal the candidate genetic polymorphisms [36]. widening of the extracellular space resulting from disruption of the blood brain barrier, whereas the DWMC were mainly related to incomplete ischemic arteriolosclerosis [58, 59]. 3. Progression of WMC Vascular risk factors, especially hypertension, cause lipo- Age-related WMC are not static lesions. The lesions may hyalinosis of the media and thickening of the vessel walls, progress, or even regress, over time. Several longitudinal which attributes to narrowing of the lumen of the small studies have investigated the rate and predictors for progres- perforating arteries and arterioles nourishing the deep white sion of WMC [37–47]. Perhaps the most consistent predictor matter [60]. The perforating vessels, which originate from for progression of WMC is the baseline severity of WMC [44, cortical and leptomeningeal arteries, have a relatively poor 47, 48]. Patients with punctate WMC usually have minimal anastomotic system, which makes the white matter vulnera- progression of WMC, whereas those with early confluent and ble to cerebral ischemia. Hypertension can also cause distur- confluent WMC at baseline have rapid progression of WMC bances in the blood-brain barrier and lead to WMC by cere- [44, 49]. In the Austrian Stroke Prevention Study, the median bral edema, activation of astrocytes, or destructive enzymes (interquartile range) volume increase over the 6-year period or other poisons which pass through the damaged vessel 3 3 was 0 cm in subjects with no lesions, 0.2 (0.0–1.1) cm in walls [60]. DM alters the glucose and insulin transfer across subjects with punctuate lesions, 2.7 (0.5–5.9) cm in subjects the blood-brain barrier, thus affects regional metabolism with early confluent lesions, and 9.3 (7.1–21.0) cm for indi- and microcirculation. Chronic hyperglycemia, which further viduals with confluent WMC at baseline [44]. In AD and PD alters membrane permeability and decreases regional blood patients, the baseline severity of WMC also predicted lesion flow, might lead to permanent cell damage. Therefore, progression, AD median WMC progression was 0.08%, while DM seems to be associated with progressive metabolic PD dementia was 0.07% [50]. Sachdev et al. study in 51 disturbance in the cerebrovascular bed that may affect blood healthy subjects with follow-up duration of 6 years found flow and accelerate the white matter ischemia [61, 62]. that increase in DWMC volume (43.8%) was greater than Recently, postmortem Medical Research Council Cog- that of PVWMC (29.7%) [47]. Furthermore, female may nitive Function and Ageing Study using RNA microarray have more lesion progression than male. A longitudinal and pathway analysis found that 8 major pathways in which study in 554 elders (313 men, 241 women) aged 70 to 82 multiple genes showed altered RNA transcription (immune years indicated that women had significantly higher DWMC regulation, cell cycle, apoptosis, proteolysis, ion transport, volume than men at baseline; after 3 years followup, they had cell structure, electron transport, metabolism) and WMC accumulated approximately twice as much DWMC as men, represented areas with a complex molecular phenotype [63]. whereas their progression of PVWMC was similar to men Xu et al. study revealed that 241 genes specific for WMC [51]. Other factors associated with faster decline in WMC are expression were associated with inflammation, oxidative higher age, cigarette smoking, and elevated BP [48]. stress, detoxification, and hormonal responses, included genes associated with brain repair, long-term potentiation, and axon guidance, and included genes associated with 4. Pathology and Physiology oligodendrocyte proliferation, axon repair, long-term poten- Pathologically, WMC are characterized by partial loss of tiation, and neurotransmission [64]. These neurogenetic myelin, axons, and oligodendroglial cells; mild reactive findings support the ischemia, blood-brain barrier dysfunc- tion, systemic oxidative stress, and inflammation in the astrocytic gliosis; sparsely distributed macrophages as well as stenosis resulting from hyaline fibrosis of arterioles and pathogenesis of WMC, as well as other potential processes smaller vessels [52]. Nowadays, the most accepted opinion is in the pathogenesis which warrant future research. that WMC represents incomplete ischemia mainly related to Other mechanisms hypothesized to be involved in the cerebral small vessel arteriolosclerosis [53]. pathophysiology of WMC encompassing dysfunction of Another mechanism is blood-brain barrier dysfunction. vasomotor reactivity and autoregulation [65–69], chronic Small vessel alterations could lead to damage of the blood- edema [70, 71], apoptosis [72], and endothelial dysfunction brain barrier and chronic leakage of fluid and macro- [73, 74]. Therefore, the pathophysiology of WMC is complex and molecules in the white matter [53]. Increased concentration of cerebrospinal fluid albumin and IgG values were found may be multifactorial. Further studies should address more in patients with CT-detected WMC [54, 55]. A recent MRI on how these different pathways interact with each other. study even found that blood-brain barrier permeability increased in normal-appearing white matter in patients 5. Neuroimaging Assessment with WMC and its presence in normal-appearing white matter would be consistent with it playing a causal role WMC are ill defined hypodensities on CT. On MRI, which in disease pathophysiology [56]. Moreover, a pathological is more sensitive than CT on delineating the lesions, they study showed that albumin extravasation was widespread in appear as hypointensities on T1-weighted imaging and the ageing brain and enhanced in WMC [57]. According hyperintensities on T2-weighted imaging, proton density to the location of the lesions, WMC can be divided into and fluid-attenuated inversion recovery sequences (FLAIR) periventricular WMC (PVWMC) and deep WMC (DWMC). (Figure 1). The FLAIR sequence is probably the best to Pathological studies have shown that PVWMC were related assess the severity of WMC because of clear distinction Journal of Aging Research 3 6row (a) (b) (c) (d) (e) Figure 1: WMC on CT and MRI. (a) Hypodensities on CT; (b) hypointensities on T1-weighted MRI; (c, d, e) hyperintensities on T2- weighted MRI, proton-density, and FLAIR sequences, respectively. (d) The lower arrow shows the PVWMC, and the upper one shows the DWMC. between ventricles and the PVWMC. Lesions are defined as it has been validated against volumetric measurement and PVWMC when their largest diameters are adjacent to the cognitive impairment [83]. The operationalized ARWMC ventricles, otherwise they are considered as DWMC [75]. scale further gave operational definitions on ARWMC scale The more recent diffusion tensor imaging (DTI) technique and improved interrater reliability on CT [84]. Noteworthy provides information on the integrity of white matter tracts is that visual rating scale for assessing the progression of by estimation of the diffusion trace (mean diffusivity) WMC is lacking. Both the Rotterdam progression scale [85] and the directionality-fractional anisotropy (FA). In WMC, and Schmidt progression scale [42]werecorrelatedwith mean diffusivity is elevated and FA is reduced [76], which volumetric measurements. The Rotterdam progression scale suggests impaired white matter integrity. Measures of DTI had moderate to good reliability (weighted Cohen’s = 0.63 are probably more sensitive than WMC volume in detecting (intraobserver), 0.59 (interobserver)), whereas the Schmidt cognitive changes over time [77]. progression scale was less reliable [85, 86]. Nowadays, fully automated techniques and semiauto- As to the assessment of WMC severity, various visual mated segmentation methods become increasingly available. rating scales have been proposed. The visual rating scales Different from the visual rating scales, volumetric measure- are quick and easy to perform on different quality of scans ment is more accurate and provides continuous data without [78]. However, they varied from each other, and data is not ceiling effect. However, it is more time-consuming with quantitative and has ceiling effect. In addition, discrepancies higher requirement of expertise and excellent quality of MRI, between the various scales may lead to inconsistent findings. which limits its use for research purpose. Overall, volumetric Two most popular visual rating scales are Fazekas scale [79] method is preferred over visual rating scales for longitudinal which has been validated histopathologically and Scheltens studies. scale [80] which is detail with good reliability but relatively time-consuming. To unite the visual rating for WMC, the vascular cognitive impairment harmonization standard rec- 6. Clinical Importance ommends the age-related WMC (ARWMC) scale [81] as the preferred visual rating scale [82]. This scale can be applied to 6.1. Cognitive Impairment and Decline. Large amounts of both MRI and CT with moderate to excellent reliability, and evidence shows that WMC are associated with cognitive 4 Journal of Aging Research impairment (executive function [2, 87, 88], mental pro- of Cognition and Gait study showed that the risk of cessing speed [89, 90], and global cognition [2, 91]) and incident falls was doubled in people with WMC volumes long-term cognitive decline in both community and stroke in the highest quintile of its distribution compared with patients [92]. Although some inconsistent results exist, part the lowest (adjusted relative risk 2.32, 95% confidence of the discrepancies stem from different sensitivities of rating interval: 1.28–4.14) [122]. Regardings the WMC location on scales for WMC, small sample size, and use of different gait, Tasmanian Study of Cognition and Gait study found neuropsychological tests [60]. Longitudinal studies have that bilateral frontal and periventricular WMC-affected demonstrated that WMC progression parallels cognitive voxels corresponded to major anterior projection fibers decline [92]. Baseline PVWMC volume was longitudinally (thalamic radiations, corticofugal motor tracts) and adjacent associated with reduced mental processing speed [93]and association fibers (corpus callosum, superior frontooccipital increased the risk of dementia [94, 95]. In some studies, fasciculus, short association fibers) showed the greatest when brain atrophy was added into the predicting models, covariance with poorer gait [123]. A DTI study also found influence of WMC became insignificant whereas global white matter integrity in the genu of corpus callosum and/or regional atrophy (i.e., medial temporal lobe atrophy, was an important marker of gait in the elderly [124]. cortical gray matter (cGM) and hippocampus atrophy) Another two recent DTI studies revealed that in elderly exerted greater influence upon cognitive decline [96–98]. subjects with small vessel disease, widespread disruption These studies also showed that whole brain or cGM atrophy of white matter integrity, predominantly in the normal- was related to severity of WMC. It was thus proposed appearing white matter, was involved in gait disturbances that cognitive decline in patients with WMC was mediated [125, 126]. Iseki et al. study using single-photon emission- by brain atrophy [96]. The hypothesized mechanisms of computed tomography suggested that abnormalities in the how WMC induce cortical atrophy include demyelination basal ganglia-thalamocortical loops partly explained gait of axons leading to cortical-subcortical deafferentation and disturbance in WMC [127]. Thus, accumulating evidence subsequent secondary cortical neuronal loss, [99, 100] suggests that the disruptions in motor network may account hypoperfusion, and hypometabolism [101, 102], as well as for gait disturbance in WMC. concomitant cortical microinfarct, which its detection is WMC correlate with gait disturbance in community beyond the ability of current neuroimaging techniques [102]. residents, and some of these abnormalities overlap with A recent study also showed that severe WMC were associated features of PD. In postmortem study with 700 parkinsonism with hippocampus atrophy [103]. Moreover, Smith et al. cases, 27 brains (3.9%) showed WMC and/or lacunes in study in community residents revealed that WMC progres- the basal ganglia, white matter, or brainstem, without sion might predict normal to mild cognitive impairment, significant nigral lesions [128]. Studies also found that WMC whereas global atrophy predicted mild cognitive impairment contributed to dementia in PD patients [16, 129, 130]. Albeit to dementia [104]. With the development of DTI technique, inconclusive, evidences accumulating that cognitive effects of studies indicated that microstructural integrity of both WMC tend to preferentially affect executive functions and WMC and normal-appearing white matter was associated may reflect frontal lobe WMC [129]. with cognitive function, regardless of white matter atrophy, WMC volume, and lacunar infarcts [105, 106]. 6.3. Urinary Incontinence. Studies had shown that WMC Certain factors need to be considered in the evaluation were associated with urgency urinary incontinence [131– of the relationship between WMC and cognitive impair- 135]. A community study found that among 100 residents, ment. First, the relationship between WMC and cognitive 64% of them had urinary incontinence. The presence of impairment may not be linear, and a threshold effect was WMC in right inferior frontal regions and selected WM proposed [107]. Second, cognitive impact of WMC may vary tracts predicted incontinence, incontinence severity, and with its location. PVWMC may affect cognition more than degree of bother. The study confirmed a critical role for the DWMC. Thus, studies evaluating total WMC may dilute the cingulum in bladder control and suggested potential involve- cognitive influence of region-specific WMC [108]. Third, ment of anterior corona radiata and superior frontooccipital psychometric tests in studies may not be comprehensive fasciculus [132]. A study in old women indicated that the for the assessment of executive function; hence, the impact presence of WMC in specific pathways (anterior thalamic of WMC may be underestimated [108]. Forth, silent brain radiation and superior longitudinal fasciculus) might affect infarcts and microbleeds were reported to be associated with continence control [136]. cognitiveimpairmentaswell[109–113], and brain atrophy (cGM, hippocampus and medial temporal lobe atrophy) may be a confounder between WMC and cognitive impairment, 6.4. Depression. Lines of evidence suggested that WMC these neuroimaging measures were not assessed in some are associated with late life depression [45, 137–144]. In studies. Last, future studies should utilize DTI in exploring poststroke patients, severe deep WMC predicted poststroke the mechanisms of cognitive decline and as a surrogate depression [145]. And concurrent atrophy of left inferior marker for disease progression in therapeutic trials. frontal gyrus was associated with depressive symptoms in poststroke patients with severe WMC [146]. Vascular 6.2. Gait Disturbance and PD. Both cross-sectional and depression hypothesis proposed that WMC causes depres- longitudinal studies have found that WMC were associated sion by disrupting fiber tracts within frontostriatal circuits with gait disturbance and falls [114–121]. Tasmanian Study [142]. Because of their involvement in the regulation of Journal of Aging Research 5 mood, disruption of frontostriatal circuits might lead to a 8.1. BP Lowing Therapy. The Epidemiology of Vascular disconnection syndrome that corresponded to the clinical Ageing MRI study has shown a positive linear relationship and neuropsychological profile of depression [142]. A DTI between BP and severity of WMC [28]. Dufouil et al. study study also found that frontolimbic neural pathways might retrospectively found subjects receiving regular treatment of contribute to the pathophysiology of depression [147]. hypertension had less severe PVWMC than those receiving no or irregular treatment of hypertension. Due to its cross-sectional design, the treatment effect of hypertension 6.5. Stroke and Death. The WMC increased the risk for on WMC progression cannot be examined in this study. stroke [8, 95, 148, 149]and death[149–151]. A recent meta- The Perindopril Protection against Recurrent Stroke Study analysis revealed that stroke yielded a significant association (PROGRESS) MRI substudy [178] was a longitudinal ran- of WMC with incident stroke (HR 3.5 (2.5–4.9), P< 0.001) domized placebo-controlled trail investigating the BP lowing and increased risk of death (HR 2.0 (1.6–2.7), P< 0.001) therapy using perindopril or perindopril plus indapamide [92]. In patients treated with thrombolysis for acute stroke, on WMC progression. 192 participants were followed up the rate of symptomatic intracerebral hemorrhage increased for 36 months, the mean total volume of new WMC was by 10% in patients with severe WMC and multiple lacunes significantly lower in the active treatment group compared [152]. WMC were found to be independent determinants for with the placebo group, and the difference was greatest for intracerebral hemorrhage after controlling for age and other patients with severe WMC at entry [178]. risk factors [152, 153]. An open-label study [179] and a post hoc analysis of WMC were not benign but predict poor clinical and a randomized trial [180] showed some beneficial effects of functional outcomes. Some studies also indicated that they, nimodipine in patients with subcortical vascular dementia. especially DWMC, were associated with migraine [154, 155]. A recent randomized placebo-controlled trial also found And brain stem WMC were associated with dizziness [156]. that the calcium antagonist nimodipine could slow down More studies are in need to explore the clinical significance global cognitive decline in patients with small vessel disease of WMC. related vascular dementia [181]. A recent review in vascular cognitive impairment indicated that nicardipine has been 7. Chemical Biomarkers investigated in more than 6000 patients, with improvement of cognitive deterioration in more than 60% of patients Homocysteine is a dietary sulphur-containing amino acid treated [182]. The antihypertensive activity of nicardipine derived as an intermediate during the metabolism of methio- and its safety and effectiveness in cognitive domain suggested nine [157]. Nutritional deficiencies in the vitamin cofactors reconsidering this drug in the treatment of cognitive impair- (folate, vitamin B ,and vitaminB ) required for homo- 12 6 ment of vascular origin and for reducing the risk of recurrent cysteine metabolism may promote hyperhomocyst(e)inemia stroke in patients at high risk of it [182]. Further randomized [158]. Perini et al. study found that the hyperhomocys- double-blind placebo-controlled trail is needed to explore teinemia in acute stoke stage was associated with higher the efficacy and safety of nimodipine and nicardipine upon risk of small artery disease subtype of stroke [159]. Many WMC progression. studies had indicated that hyperhomocysteinemia was an Although most studies paid attention to lower BP in independent predictor for WMC independent of smoking, hypertension, noted that low BP was a risk factor for WMC hypertension, or age [160–172]. as well [60]. Another study found that nocturnal BP dipping Inflammatory biomarkers as intercellular adhesion was associated with WMC [183]. Thus, a randomized molecule-1 (ICAM-1) [173, 174], and high sensitive C- controlled study dedicated to examine the effects of BP reactive protein (Hs CRP) [175–177] were also reported lowering therapy upon progression of WMC is needed. to be associated with WMC load. However, these studies were cross-sectional so that causal relationship cannot be 8.2. Statins. Statins have long been demonstrated to reduce determined. Longitudinal studies are needed to study the cardiovascular events and ischemic stroke among patients relationship between progression of inflammatory factors with coronary heart disease [184]. Whether statins affect with progression of WMC. progression of WMC is still controversial. The PROSPER (Prospective Study of Pravastatin in Elderly at Risk) study examined the effect of pravastatin 40 mg daily on the 8. Treatment of WMC progression of WMC in 270 placebo-treated subjects and 265 The WMC are predictors for poor clinical outcomes and active subjects within a period of 33 months. The study failed important substrates for vascular dementia. The European to demonstrate an overall beneficial effect of statins upon Task Force on age-related WMC recommended that clinical WMC progression. However, data on proportions of subjects trials on cerebral small vessel disease should target those with having different WMC severity are lacking, and stratified severe WMC and use its progression as surrogate marker analysis based on WMC severity was not performed in the in clinical trials [49]. Albeit WMC are clinically important, study. In the Cardiovascular Health Study, 3334 community very few clinical studies had been conducted so far to participants were followedup over an average observational evaluate treatments for WMC. In this part, studies on treat- period of 7 years [185]. Patients treated with statins were ments for WMC- and WMC- related vascular dementia are observed to have slightly less cognitive decline than untreated reviewed. subjects. This significant cognitive benefit was associated 6 Journal of Aging Research with reduced progression in cerebral infarcts among the and rivastigmine) and memantine in patients with vas- treated subjects, whereas progression of WMC was not cular dementia [188]. Yet, given the potential benefit of memantine upon subcortical vascular dementia based on statistically different between these two groups. Although the findings may suggest that statins exert cognitive benefits post hoc analysis and its favorable safety profile, conducting a randomized study evaluating its efficacy in subcortical independent of WMC progression, the visual rating scale vascular dementia may be worthwhile. used in that study was unlikely to be sensitive in detecting WMC progression [38]. The ROCAS (Regression of Cerebral Cerebral autosomal dominant arteriopathy with sub- Artery Stenosis) study evaluated simvastatin on WMC cortical infarcts and leucoencephalopathy (CADASIL) is a progression in patients with asymptomatic middle cerebral genetic form of subcortical vascular dementia. A recent artery stenosis [38]. Two hundred and eight randomized sub- multicentre, 18-week, placebo-controlled, double-blind, jects were assigned to either placebo (n = 102) or simvastatin randomized parallel-group trial using donepezil in 168 20 mg daily (n = 106) for 2 years. Simvastatin group did not CADASIL patients revealed that donepezil had no effect on slow the progression of WMC volume compared with the the vascular ADAS-cog score in CADASIL patients with cog- nitive impairment. Improvements were noted only on several placebo group, but in those with severe WMC at baseline, the median volume increase in the simvastatin group (1.9 cm ) measures of executive function, which might possibly suggest that cholinergic pathways were involved in the executive was less compared with that in the placebo group (3.0 cm ; function [190]. Overall, findings of this study are similar to P = 0.047). However, in this study, treatment probably that of previous studies using acetylcholinesterase inhibitors prevented WMC progression among those with severe WMC in that acetylcholinesterase inhibitors might only induce sub- at baseline was based only on subgroup analysis upon a small tle cognitive benefits among patients with vascular dementia. subset of subjects. Furthermore, the subjects of this study belonged to a high-risk group in that all our subjects had Another more recent randomized, international, multi- concurrent MCA stenosis. Hence, the findings may not be center, 24-week trial in 974 probable or possible vascular applicable to patients with less vascular burden or to those dementia patients who received donepezil 5 mg/d or placebo found that donepezil improved the vascular ADAS-cog score with WMC but without concurrent MCA stenosis. but not global function [191]. However, subgroup analysis Furthermore, a recent cross-sectional study showed that on the effects of donepezil upon subcortical type of vascular low cholesterol had more severe WMC in acute stroke dementia was not performed in this study. patients [10]. Other studies found that low cholesterol was associated with intracerebral hemorrhage and high mortality in these patients [186, 187]. Hence, effects of 8.4. Homocysteine Lowering Therapy. Lines of evidence have stains and cholesterol control upon WMC progression are shown that hyperhomocysteinemia was associated with still uncertain, and randomized clinical trials are needed to WMC through endothelial dysfunction [160–172]. Whether address this issue. homocysteine lowering therapy by means of multivitamins retards the progression of WMC or not is uncertain. A randomized double-blind, parallel, placebo-controlled trial 8.3. Acetylcholinesterase Inhibitors and N -Methysl-D-Aspar- on homocysteine lowering therapy is the VITAmins TO tate (NMDA) Receptor Antagonists. Acetylcholinesterase in- Prevent Stroke (VITATOPS) study. 8164 patients with recent hibitors (donepezil, galantamine, and rivastigmine) and N- stroke or transient ischaemic attack (within the past 7 methyl-D-aspartate (NMDA) receptor antagonists (meman- months) received one tablet daily of placebo (n = 4089) tine) have been approved for treatment of AD. Kavirajan or B vitamins (2 mg folic acid, 25 mg vitamin B ,and and Schneider reviewed three donepezil, two galantamine, 0.5 mg vitamin B , n = 4075) with a median followed- one rivastigmine, and two memantine placebo-controlled, up duration of 3.4 years. Although vitamin treatment was randomized, double blinded trials, it showed that cogni- not significantly more effective than placebo in reducing tive effects on the AD assessment scale-cognitive subscale the incidence of the composite primary endpoint of stroke, (ADAS-cog) were significant for all drugs, and post hoc myocardial infarction, or vascular death, in the subgroup analyses of donepezil tails suggested greater improvement analyses, homocysteine lowering might have preferential in patients with cortical and territorial lesions compared benefit in small vessel disease patients (risk ratio 0.80 (95% with those with predominantly subcortical small vessel CI : 0.67–0.96)) [192]. The VITATOPS MRI substudy is disease related lesions [188]. By contrast, cognitive benefits currently underway to evaluate whether vitamins can slow in the memantine trials appeared to be more pronounced WMC progression and/or cognitive decline. for patients with small vessel disease than for those with large vessel disease and such benefits derived largely from worsening in patients in the placebo-treated groups who 9. Conclusion predominantly had small vessel disease [188, 189]. With regards to safety profile, use of cholinesterase inhibitor WMC are common in elderly, and they are not benign. More significantly increased the odds of having adverse events extensive WMC are associated with a host of poor clinical (e.g., anorexia, nausea, vomiting, and diarrhea), while outcomes. Although WMC have been shown to be associated memantine was found to be well tolerable and safe. Overall, with small vessel disease, age, and other vascular risk factors, the data is insufficient to support the widespread use the exact mechanisms explaining such association are still of acetylcholinesterase inhibitors (donepezil, galantamine, uncertain. To date, dataon the effectiveness of various Journal of Aging Research 7 treatments (e.g., BP lowering, statins) in preventing WMC [14] S. J. Lee, J. S. Kim, K. S. Lee et al., “The severity of leukoa- raiosis correlates with the clinical phenotype of Parkinson’s progression were derived mainly from subgroup analyses. disease,” Archives of Gerontology and Geriatrics, vol. 49, no. 2, Randomized studies dedicated in evaluating treatments for pp. 255–259, 2009. preventing WMC progression and its clinical correlates are [15] J. Slawek, D. Wieczorek, M. Derejko et al., “The influence thus urgently needed. Although some studies have suggested of vascular risk factors and white matter hyperintensities the efficacy of nimodipine, nicardipine, and memantine on the degree of cognitive impairment in Parkinson’s in subcortical vascular dementia, further randomized disease,” Neurologia i Neurochirurgia Polska, vol. 42, no. 6, controlled studies are needed to clarify their effectiveness pp. 505–512, 2008. and safety. [16] Y. H. Sohn and J. S. Kim, “The influence of white matter hyperintensities on the clinical features of parkinson’s dis- ease,” Yonsei Medical Journal, vol. 39, no. 1, pp. 50–55, 1998. References [17] H. S. Jorgensen, H. Nakayama, H. O. Raaschou, and T. S. [1] L. Pantoni, “Cerebral small vessel disease: from pathogenesis Olsen, “Leukoaraiosis in stroke patients: the Copenhagen and clinical characteristics to therapeutic challenges,” The stroke study,” Stroke, vol. 26, no. 4, pp. 588–592, 1995. Lancet Neurology, vol. 9, no. 7, pp. 689–701, 2010. [18] D. Liao, L. Cooper, J. Cai et al., “The prevalence and severity [2] W. T. Longstreth Jr., T. A. Manolio, A. Arnold et al., “Clinical of white matter lesions, their relationship with age, ethnicity, correlates of white matter findings on cranial magnetic gender, and cardiovascular disease risk factors: the ARIC resonance imaging of 3301 elderly people: the cardiovascular study,” Neuroepidemiology, vol. 16, no. 3, pp. 149–162, 1997. health study,” Stroke, vol. 27, no. 8, pp. 1274–1282, 1996. [19] H. Henon, O. Godefroy, C. Lucas, J. P. Pruvo, and D. Leys, [3] D. Liao, L. Cooper, J. Cai et al., “Presence and severity of “Risk factors and leukoaraiosis in stroke patients,” Acta cerebral white matter lesions and hypertension, its treatment, Neurologica Scandinavica, vol. 94, no. 2, pp. 137–144, 1996. and its control: the ARIC study,” Stroke, vol. 27, no. 12, pp. [20] A. M. Basile, L. Pantoni, G. Pracucci et al., “Age, 2262–2270, 1996. hypertension, and lacunar stroke are the major determinants [4] F.E.deLeeuw,J.C.deGroot,E.Achtenetal., “Prevalenceof of the severity of age-related white matter changes. The cerebral white matter lesions in elderly people: a population LADIS (Leukoaraiosis and Disability in the Elderly) study,” based magnetic resonance imaging study. The Rotterdam Cerebrovascular Diseases, vol. 21, no. 5-6, pp. 315–322, 2006. Scan Study,” Journal of Neurology Neurosurgery and Psychi- [21] J. C. vanSwieten,G.G.Geyskes,M.M.Derix et al., atry, vol. 70, no. 1, pp. 9–14, 2001. “Hypertension in the elderly is associated with white matter [5] W. Wen, P. S. Sachdev, J. J. Li, X. Chen, and K. J. Anstey, lesions and cognitive decline,” Annals of Neurology, vol. 30, “White matter hyperintensities in the forties: their prevalence no. 6, pp. 825–830, 1991. and topography in an epidemiological sample aged 44–48,” [22] H. S. Choi, Y. M. Cho, J. H. Kang, C. S. Shin, K. S. Park, and Human Brain Mapping, vol. 30, no. 4, pp. 1155–1167, 2009. H. K. Lee, “Cerebral white matter hyperintensity is mainly [6] L.J.Launer, K. Berger,M.M.B.Breteleretal., “Regional associated with hypertension among the components of variability in the prevalence of cerebral white matter lesions: metabolic syndrome in Koreans,” Clinical Endocrinology, vol. an MRI study in 9 European countries (CASCADE),” 71, no. 2, pp. 184–188, 2009. Neuroepidemiology, vol. 26, no. 1, pp. 23–29, 2005. [23] M. K. Park, I. Jo, M. H. Park, T. K. Kim, S. A. Jo, and C. Shin, [7] R. Mantyla, H. J. Aronen, O. Salonen et al., “The prevalence “Cerebral white matter lesions and hypertension status in and distribution of white-matter changes on different MRI the elderly Korean: the Ansan Study,” Archives of Gerontology pulse sequences in a post-stroke cohort,” Neuroradiology, vol. and Geriatrics, vol. 40, no. 3, pp. 265–273, 2005. 41, no. 9, pp. 657–665, 1999. [24] E. J. van Dijk, M. M. Breteler, R. Schmidt et al., “The asso- [8] J. H. Fu, C. Z. Lu, Z. Hong, Q. Dong, Y. Luo, and K. S. Wong, ciation between blood pressure, hypertension, and cerebral “Extent of white matter lesions is related to acute subcortical white matter lesions: cardiovascular determinants of demen- infarcts and predicts further stroke risk in patients with first tia study,” Hypertension, vol. 44, no. 5, pp. 625–630, 2004. ever ischaemic stroke,” Journal of Neurology, Neurosurgery [25] F. E. de Leeuw, J. C. de Groot, M. Oudkerk et al., “Hyper- and Psychiatry, vol. 76, no. 6, pp. 793–796, 2005. tension and cerebral white matter lesions in a prospective [9] W. K. Tang, S. S. Chan, H. F. Chiu et al., “Frequency and cohort study,” Brain, vol. 125, no. 4, pp. 765–772, 2002. determinants of poststroke dementia in Chinese,” Stroke, vol. [26] C. Sierra, “Cerebral white matter lesions in essential 35, no. 4, pp. 930–935, 2004. hypertension,” Current Hypertension Reports,vol. 3, no.5, [10] J. Jimenez-Conde, A. Biffi, R. Rahman et al., “Hyperlipidemia pp. 429–433, 2001. and reduced white matter hyperintensity volume in patients [27] L. H. Kuller, K. L. Margolis, S. A. Gaussoin et al., with ischemic stroke,” Stroke, vol. 41, no. 3, pp. 437–442, “Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the [11] J. Aharon-Peretz, J. L. Cummings, and M. A. Hill, “Vascular Women’s Health Initiative Memory Study (WHIMS)—MRI dementia and dementia of the Alzheimer type. Cognition, trial,” Journal of Clinical Hypertension, vol. 12, no. 3, pp. ventricular size, and leuko-araiosis,” Archives of Neurology, 203–212, 2010. vol. 45, no. 7, pp. 719–721, 1988. [28] C. Dufouil, A. de Kersaint-Gilly, V. Besancon et al., [12] F. E. de Leeuw, F. Barkhof, and P. Scheltens, “White matter “Longitudinal study of blood pressure and white matter lesions and hippocampal atrophy in Alzheimer’s disease,” hyperintensities: the EVA MRI cohort,” Neurology, vol. 56, Neurology, vol. 62, no. 2, pp. 310–312, 2004. no. 7, pp. 921–926, 2001. [13] M. Targosz-Gajniak, J. Siuda, S. Ochudlo, and G. Opala, “Cerebral white matter lesions in patients with dementia— [29] T. Jeerakathil, P. A. Wolf, A. Beiser et al., “Stroke risk profile from MCI to severe Alzheimer’s disease,” Journal of the predicts white matter hyperintensity volume: the Framing- Neurological Sciences, vol. 283, no. 1-2, pp. 79–82, 2009. ham study,” Stroke, vol. 35, no. 8, pp. 1857–1861, 2004. 8 Journal of Aging Research [30] M. Vuorinen, A. Solomon, S. Rovio et al., “Changes in [45] W. D. Taylor,D.C.Steffens, J. R. MacFall et al., “White vascular risk factors from midlife to late life and white matter matter hyperintensity progression and late-life depression lesions: a 20-year follow-up study,” Dementia and Geriatric outcomes,” Archives of General Psychiatry, vol. 60, no. 11, pp. Cognitive Disorders, vol. 31, no. 2, pp. 119–125, 2011. 1090–1096, 2003. [46] J. Y. Streifler, M. Eliasziw, O. R. Benavente et al., [31] A. M. Brickman,C.Reitz,J.A.Luchsinger et al., “Long-term “Development and progression of leukoaraiosis in patients blood pressure fluctuation and cerebrovascular disease in with brain ischemia and carotid artery disease,” Stroke, vol. an elderly cohort,” Archives of Neurology, vol. 67, no. 5, pp. 564–569, 2010. 34, no. 8, pp. 1913–1916, 2003. [47] P. Sachdev, W. Wen, X. Chen, and H. Brodaty, “Progression [32] D. Carmelli, C. DeCarli, G. E. Swan et al., “Evidence for of white matter hyperintensities in elderly individuals over 3 genetic variance in white matter hyperintensity volume years,” Neurology, vol. 68, no. 3, pp. 214–222, 2007. in normal elderly male twins,” Stroke,vol. 29, no.6,pp. [48] E. J. van Dijk, N. D. Prins, H. A. Vrooman, A. Hofman, P. 1177–1181, 1998. J. Koudstaal, and M. M. Breteler, “Progression of cerebral [33] F. E. de Leeuw, F. Richard, J. C. de Groot et al., “Interaction small vessel disease in relation to risk factors and cognitive between hypertension, apoE, and cerebral white matter consequences: Rotterdam Scan study,” Stroke, vol. 39, no. 10, lesions,” Stroke, vol. 35, no. 5, pp. 1057–1060, 2004. pp. 2712–2719, 2008. [34] K. Kohara, M. Fujisawa, F. Ando et al., “MTHFR gene [49] R. Schmidt, P. Scheltens, T. Erkinjuntti et al., “White matter polymorphism as a risk factor for silent brain infarcts and lesion progression: a surrogate endpoint for trials in cerebral white matter lesions in the Japanese general population: the small-vessel disease,” Neurology, vol. 63, no. 1, pp. 139–144, NILS-LSA study,” Stroke, vol. 34, no. 5, pp. 1130–1135, 2003. [35] L. H. Henskens,A.A.Kroon,M.P.van Boxtel,P.A.Hofman, [50] E. J. Burton,I.G.McKeith,D.J.Burn, M. J. Firbank, and and P. W. De Leeuw, “Associations of the angiotensin II type J. T. O’Brien, “Progression of white matter hyperintensities 1 receptor A1166C and the endothelial NO synthase G894T in Alzheimer disease, dementia with lewy bodies, and gene polymorphisms with silent subcortical white matter Parkinson disease dementia: a comparison with normal lesions in essential hypertension,” Stroke,vol. 36, no.9,pp. aging,” American Journal of Geriatric Psychiatry, vol. 14, no. 1869–1873, 2005. 10, pp. 842–849, 2006. [36] L. Paternoster, W. Chen, and C. L. Sudlow, “Genetic [51] D. M. van den Heuvel, F. Admiraal-Behloul, V. H. ten Dam determinants of white matter hyperintensities on brain et al., “Different progression rates for deep white matter scans: a systematic assessment of 19 candidate gene hyperintensities in elderly men and women,” Neurology, vol. polymorphisms in 46 studies in 19,000 subjects,” Stroke, vol. 63, no. 9, pp. 1699–1701, 2004. 40, no. 6, pp. 2020–2026, 2009. [52] A. Brun and E. Englund, “A white matter disorder in [37] L. J. Podewils, E. Guallar, N. Beauchamp, C. G. Lyketsos, dementia of the Alzheimer type: a pathoanatomical study,” L. H. Kuller, and P. Scheltens, “Physical activity and white Annals of Neurology, vol. 19, no. 3, pp. 253–262, 1986. matter lesion progression: assessment using MRI,” Neurology, [53] L. Pantoni, “Pathophysiology of age-related cerebral vol. 68, no. 15, pp. 1223–1226, 2007. white matter changes,” Cerebrovascular Diseases, vol. 13, [38] V. C. Mok, W. W. Lam, Y. H. Fan et al., “Effects of statins supplement 2, pp. 7–10, 2002. on the progression of cerebral white matter lesion : post [54] L. Pantoni, D. Inzitari, G. Pracucci et al., “Cerebrospinal fluid hoc analysis of the ROCAS (Regression of Cerebral Artery proteins in patients with leucaraiosis: possible abnormalities Stenosis) study,” Journal of Neurology, vol. 256, no. 5, pp. in blood-brain barrier function,” Journal of the Neurological 750–757, 2009. Sciences, vol. 115, no. 2, pp. 125–131, 1993. [39] A. A. Gouw, W. M. van der Flier, F. Fazekas et al., [55] A. Wallin, M. Sjogren, A. Edman, K. Blennow, and B. “Progression of white matter hyperintensities and incidence Regland, “Symptoms, vascular risk factors and blood-brain of new lacunes over a 3-year period: the leukoaraiosis and barrier function in relation to CT white-matter changes in disability study,” Stroke, vol. 39, no. 5, pp. 1414–1420, 2008. dementia,” European Neurology, vol. 44, no. 4, pp. 229–235, [40] L. O. Wahlund, O. Almkvist, H. Basun, and P. Julin, “MRI in successful aging, a 5-year follow-up study from the eighth [56] R. Topakian, T. R. Barrick, F. A. Howe, and H. S. Markus, to ninth decade of life,” Magnetic Resonance Imaging, vol. 14, “Blood-brain barrier permeability is increased in normal- no. 6, pp. 601–608, 1996. appearing white matter in patients with lacunar stroke [41] J. H. Veldink, P. Scheltens, C. Jonker, and L. J. Launer, and leucoaraiosis,” Journal of Neurology, Neurosurgery and “Progression of cerebral white matter hyperintensities on Psychiatry, vol. 81, no. 2, pp. 192–197, 2010. MRI is related to diastolic blood pressure,” Neurology, vol. [57] J. E. Simpson, S. B. Wharton, J. Cooper et al., “Alterations 51, no. 1, pp. 319–320, 1998. of the blood-brain barrier in cerebral white matter lesions [42] R. Schmidt, F. Fazekas, P. Kapeller, H. Schmidt, and H. in the ageing brain,” Neuroscience Letters, vol. 486, no. 3, pp. P. Hartung, “MRI white matter hyperintensities: three- 246–251, 2010. year follow-up of the Austrian Stroke Prevention Study,” [58] F. Fazekas, R. Kleinert, H. Olfenbacher et al., “Pathologic Neurology, vol. 53, no. 1, pp. 132–139, 1999. correlates of incidental MRI white matter signal hyperinten- [43] G. T. Whitman, T. Tang, A. Lin, and R. W. Baloh, “A sities,” Neurology, vol. 43, no. 9, pp. 1683–1689, 1993. prospective study of cerebral white matter abnormalities in [59] J. E. Simpson, P. G. Ince, C. E. Higham et al., “Microglial older people with gait dysfunction,” Neurology, vol. 57, no. activation in white matter lesions and nonlesional white 6, pp. 990–994, 2001. matter of ageing brains,” Neuropathology and Applied Neurobiology, vol. 33, no. 6, pp. 670–683, 2007. [44] R. Schmidt, C. Enzinger, S. Ropele, H. Schmidt, and F. Fazekas, “Progression of cerebral white matter lesions: 6-Year [60] L. Pantoni and J. H. Garcia, “The significance of cerebral results of the Austrian Stroke Prevention Study,” The Lancet, white matter abnormalities 100 years after Binswanger’s vol. 361, no. 9374, pp. 2046–2048, 2003. report: a review,” Stroke, vol. 26, no. 7, pp. 1293–1301, 1995. Journal of Aging Research 9 [61] S. M. Manschot, G. J. Biessels, G. E. Rutten, R. P. Kessels, [77] A. Nitkunan, T. R. Barrick, R. A. Charlton, C. A. Clark, and W. H. Gispen, and L. J. Kappelle, “Peripheral and central H. S. Markus, “Multimodal MRI in cerebral small vessel neurologic complications in type 2 diabetes mellitus: no disease: its relationship with cognition and sensitivity to association in individual patients,” Journal of the Neurological change over time,” Stroke, vol. 39, no. 7, pp. 1999–2005, 2008. Sciences, vol. 264, pp. 157–162, 2008. [78] F. Fazekas, F. Barkhof, L. O. Wahlund et al., “CT and MRI [62] V. Novak, D. Last, D. C. Alsop et al., “Cerebral blood flow rating of white matter lesions,” Cerebrovascular Diseases, vol. velocity and periventricular white matter hyperintensities in 13, supplement 2, pp. 31–36, 2002. type 2 diabetes,” Diabetes Care, vol. 29, no. 7, pp. 1529–1534, [79] F. Fazekas, J. B. Chawluk, A. Alavi, H. I. Hurtig, and R. A. Zimmerman, “MR signal abnormalities at 1.5 T in [63] J. E. Simpson, O. Hosny, S. B. Wharton et al., “Microarray Alzheimer’s dementia and normal aging,” American Journal RNA expression analysis of cerebral white matter lesions of Roentgenology, vol. 149, no. 2, pp. 351–356, 1987. reveals changes in multiple functional pathways,” Stroke, vol. [80] P. Scheltens, F. Barkhof, D. Leys et al., “A semiquantitative 40, no. 2, pp. 369–375, 2009. rating scale for the assessment of signal hyperintensities on [64] H. Xu, B. Stamova, G. Jickling et al., “Distinctive RNA magnetic resonance imaging,” Journal of the Neurological expression profiles in blood associated with white matter Sciences, vol. 114, no. 1, pp. 7–12, 1993. hyperintensities in brain,” Stroke, vol. 41, no. 12, pp. [81] L. O. Wahlund, F. Barkhof, F. Fazekas et al., “A new rating 2744–2749, 2010. scale for age-related white matter changes applicable to MRI [65] J. H. Fu, C. Z. Lu, Z. Hong, Q. Dong, D. Ding, and K. S. and CT,” Stroke, vol. 32, no. 6, pp. 1318–1322, 2001. Wong, “Relationship between cerebral vasomotor reactivity [82] V. Hachinski, C. Iadecola, R. C. Petersen et al., “National and white matter lesions in elderly subjects without large Institute of Neurological Disorders and Stroke-Canadian artery occlusive disease,” Journal of Neuroimaging, vol. 16, Stroke Network vascular cognitive impairment harmoniza- no. 2, pp. 120–125, 2006. tion standards,” Stroke, vol. 37, no. 9, pp. 2220–2241, 2006. [66] Y. Isaka, M. Okamoto, K. Ashida, and M. Imaizumi, [83] Y. Xiong, V. Mok, A. Wong et al., “The age-related white “Decreased cerebrovascular dilatory capacity in subjects with matter changes scale correlates with cognitive impairment,” asymptomatic periventricular hyperintensities,” Stroke, vol. European Journal of Neurology, vol. 17, no. 12, pp. 1451–1456, 25, no. 2, pp. 375–381, 1994. [67] S. L. Bakker,F.E.deLeeuw,J.C.deGroot,A.Hofman, [84] Y. Xiong, J. Yang, A. Wong et al., “Operational definitions P. J. Koudstaal, and M. M. Breteler, “Cerebral vasomotor improve reliability of the age-related white matter changes reactivity and cerebral white matter lesions in the elderly,” scale,” European Journal of Neurology,vol. 18, no.5,pp. Neurology, vol. 52, no. 3, pp. 578–583, 1999. 744–749, 2011. [68] R. Ohtani, H. Tomimoto, T. Kawasaki et al., “Cerebral [85] N. D. Prins,E.C.van Straaten,E.J.van Dijk et al., vasomotor reactivity to postural change is impaired in “Measuring progression of cerebral white matter lesions on patients with cerebrovascular white matter lesions,” Journal MRI: visual rating and volumetrics,” Neurology, vol. 62, no. of Neurology, vol. 250, no. 4, pp. 412–417, 2003. 9, pp. 1533–1539, 2004. [69] G. M. Kozera, M. Dubaniewicz, T. Zdrojewski et al., [86] A. A. Gouw, W. M. van der Flier, E. C. van Straaten et al., “Cerebral vasomotor reactivity and extent of white matter “Reliability and sensitivity of visual scales versus volumetry lesions in middle-aged men with arterial hypertension: a for evaluating white matter hyperintensity progression,” pilot study,” American Journal of Hypertension, vol. 23, no. Cerebrovascular Diseases, vol. 25, no. 3, pp. 247–253, 2008. 11, pp. 1198–1203, 2010. [87] N. D. Prins,E.J.van Dijk,T.den Heijer et al., “Cerebral [70] C. P. Chung and H. H. Hu, “Pathogenesis of leukoaraiosis: small-vessel disease and decline in information processing role of jugular venous reflux,” Medical Hypotheses, vol. 75, speed, executive function and memory,” Brain, vol. 128, no. no. 1, pp. 85–90, 2010. 9, pp. 2034–2041, 2005. [71] L. Pantoni and J. H. Garcia, “Pathogenesis of leukoaraiosis: [88] V. C. Mok, A. Wong, W. W. Lam et al., “Cognitive a review,” Stroke, vol. 28, no. 3, pp. 652–659, 1997. impairment and functional outcome after stroke associated [72] W. R. Brown, D. M. Moody, C. R. Thore, and V. R. with small vessel disease,” Journal of Neurology, Neurosurgery Challa, “Apoptosis in leukoaraiosis,” American Journal of and Psychiatry, vol. 75, no. 4, pp. 560–566, 2004. Neuroradiology, vol. 21, no. 1, pp. 79–82, 2000. [89] C. Junque, J. Pujol, P. Vendrell et al., “Leuko-araiosis on mag- [73] G. Jickling, A. Salam, A. Mohammad et al., “Circulating netic resonance imaging and speed of mental processing,” endothelial progenitor cells and age-related white matter Archives of Neurology, vol. 47, no. 2, pp. 151–156, 1990. changes,” Stroke, vol. 40, no. 10, pp. 3191–3196, 2009. [90] R. Ylikoski, A. Ylikoski, T. Erkinjuntti, R. Sulkava, R. Rain- [74] A. Hassan, B. J. Hunt, M. O’Sullivan et al., “Markers of inko, and R. Tilvis, “White matter changes in healthy elderly endothelial dysfunction in lacunar infarction and ischaemic persons correlate with attention and speed of mental process- leukoaraiosis,” Brain, vol. 126, no. 2, pp. 424–432, 2003. ing,” Archives of Neurology, vol. 50, no. 8, pp. 818–824, 1993. [75] J. C. de Groot, F. E. de Leeuw, M. Oudkerk et al., “Cerebral [91] W. M. van der Flier, E. C. Van Straaten, F. Barkhof et al., white matter lesions and cognitive function: the Rotterdam “Small vessel disease and general cognitive function in Scan study,” Annals of Neurology, vol. 47, no. 2, pp. 145–151, nondisabled elderly: the LADIS study,” Stroke, vol. 36, no. 2000. 10, pp. 2116–2120, 2005. [76] D. K. Jones, D. Lythgoe, M. A. Horsfield, A. Simmons, S. [92] S. Debette and H. S. Markus, “The clinical importance of C. Williams, and H. S. Markus, “Characterization of white white matter hyperintensities on brain magnetic resonance matter damage in ischemic leukoaraiosis with diffusion imaging: systematic review and meta-analysis,” British tensor MRI,” Stroke, vol. 30, no. 2, pp. 393–397, 1999. Medical Journal, vol. 341, Article ID c3666, 2010. 10 Journal of Aging Research [93] D. M. vanden Heuvel,V.H.ten Dam, A. J. de Craenet [109] S. E. Vermeer, W. T. Longstreth Jr., and P. J. Koudstaal, “Silent al., “Increase in periventricular white matter hyperintensities brain infarcts: a systematic review,” The Lancet Neurology, parallels decline in mental processing speed in a non- vol. 6, no. 7, pp. 611–619, 2007. demented elderly population,” JournalofNeurology,Neuro- [110] J. A. Pettersen, G. Sathiyamoorthy, F. Q. Gao et al., “Microb- surgery and Psychiatry, vol. 77, no. 2, pp. 149–153, 2006. leed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the sunnybrook dementia study,” [94] N. D. Prins,E.J.van Dijk,T.den Heijer et al., “Cerebral Archives of Neurology, vol. 65, no. 6, pp. 790–795, 2008. white matter lesions and the risk of dementia,” Archives of Neurology, vol. 61, no. 10, pp. 1531–1534, 2004. [111] S. E. Vermeer, N. D. Prins, T. den Heijer, A. Hofman, P. J. Koudstaal, and M. M. Breteler, “Silent brain infarcts and the [95] S. E. Vermeer, M. Hollander, E. J. van Dijk, A. Hofman, risk of dementia and cognitive decline,” New England Journal P. J. Koudstaal, and M. M. Breteler, “Silent brain infarcts of Medicine, vol. 348, no. 13, pp. 1215–1222, 2003. and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study,” Stroke, vol. 34, no. [112] Y. Yakushiji, M. Nishiyama, S. Yakushiji et al., “Brain microb- leeds and global cognitive function in adults without neuro- 5, pp. 1126–1129, 2003. logical disorder,” Stroke, vol. 39, no. 12, pp. 3323–3328, 2008. [96] R. Schmidt, S. Ropele, C. Enzinger et al., “White matter [113] J. A. Schneider, “Brain microbleeds and cognitive function,” lesion progression, brain atrophy, and cognitive decline: the Stroke, vol. 38, no. 6, pp. 1730–1731, 2007. Austrian stroke prevention study,” Annals of Neurology, vol. [114] R. Camicioli, M. M. Moore, G. Sexton, D. B. Howieson, and 58, no. 4, pp. 610–616, 2005. J. A. Kaye, “Age-related brain changes associated with motor [97] D. Mungas,B.R.Reed,W.J.Jagustetal., “Volumetric function in healthy older people,” Journal of the American MRI predicts rate of cognitive decline related to AD and Geriatrics Society, vol. 47, no. 3, pp. 330–334, 1999. cerebrovascular disease,” Neurology,vol. 59, no.6,pp. [115] C. R. Guttmann, R. Benson, S. K. Warfield et al., “White 867–873, 2002. matter abnormalities in mobility-impaired older persons,” [98] D. Mungas, D. Harvey, B. R. Reed et al., “Longitudinal Neurology, vol. 54, no. 6, pp. 1277–1283, 2000. volumetric MRI change and rate of cognitive decline,” [116] C. Rosano, J. Brach, W. T. Longstreth Jr., and A. B. Newman, Neurology, vol. 65, no. 4, pp. 565–571, 2005. “Quantitative measures of gait characteristics indicate [99] D. Mungas, W. J. Jagust, B. R. Reed et al., “MRI predictors prevalence of underlying subclinical structural brain ab- of cognition in subcortical ischemic vascular disease normalities in high-functioning older adults,” Neuroe- and Alzheimer’s disease,” Neurology, vol. 57, no. 12, pp. pidemiology, vol. 26, no. 1, pp. 52–60, 2006. 2229–2235, 2001. [117] B. E. Maki, “Gait changes in older adults: predictors of falls [100] A. T. Du, N. Schuff, L. L. Chao et al., “White matter lesions or indicators of fear,” Journal of the American Geriatrics are associated with cortical atrophy more than entorhinal Society, vol. 45, no. 3, pp. 313–320, 1997. and hippocampal atrophy,” Neurobiology of Aging, vol. 26, [118] C. Rosano, J. Brach, S. Studenski, W. T. Longstreth Jr., and A. no. 4, pp. 553–559, 2005. B. Newman, “Gait variability is associated with subclinical [101] C. DeCarli, D. G. Murphy, M. Tranh et al., “The effect of brain vascular abnormalities in high-functioning older white matter hyperintensity volume on brain structure, adults,” Neuroepidemiology, vol. 29, no. 3-4, pp. 193–200, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults,” Neurology, vol. 45, no. 11, pp. [119] H. Baezner, C. Blahak, A. Poggesi et al., “Association of gait 2077–2084, 1995. and balance disorders with age-related white matter changes: [102] M. Tullberg, E. Fletcher, C. DeCarli et al., “White matter the LADIS Study,” Neurology, vol. 70, no. 12, pp. 935–942, lesions impair frontal lobe function regardless of their location,” Neurology, vol. 63, no. 2, pp. 246–253, 2004. [120] D. P. Briley, M. Wasay, S. Sergent, and S. Thomas, “Cerebral [103] C. Eckerstrom, E. Olsson, N. Klasson et al., “High white white matter changes (leukoaraiosis), stroke, and gait matter lesion load is associated with hippocampal atrophy disturbance,” Journal of the American Geriatrics Society, vol. in mild cognitive impairment,” Dementia and Geriatric 45, no. 12, pp. 1434–1438, 1997. Cognitive Disorders, vol. 31, no. 2, pp. 132–138, 2011. [121] H. C. Chui, C. Zarow, W. J. Mack et al., “Cognitive impact [104] E. E. Smith, S. Egorova, D. Blacker et al., “Magnetic resonance of subcortical vascular and Alzheimer’s disease pathology,” imaging white matter hyperintensities and brain volume in Annals of Neurology, vol. 60, no. 6, pp. 677–687, 2006. the prediction of mild cognitive impairment and dementia,” [122] V. Srikanth, R. Beare, L. Blizzard et al., “Cerebral white Archives of Neurology, vol. 65, no. 1, pp. 94–100, 2008. matter lesions, gait, and the risk of incident falls: a [105] M. W. Vernooij, M. A. Ikram, H. A. Vrooman et al., “White prospective population-based study,” Stroke,vol. 40, no.1, matter microstructural integrity and cognitive function in pp. 175–180, 2009. a general elderly population,” Archives of General Psychiatry, [123] V. Srikanth, T. G. Phan, J. Chen, R. Beare, J. M. Stapleton, vol. 66, no. 5, pp. 545–553, 2009. and D. C. Reutens, “The location of white matter lesions and [106] A. G. van Norden, K. F. de Laat, E. J. van Dijk et al., “Diffusion gait—A voxel-based study,” Annals of Neurology, vol. 67, no. tensor imaging and cognition in cerebral small vessel disease. 2, pp. 265–269, 2010. The RUN DMC study,” Biochimica et Biophysica Acta.In [124] R. A. Bhadelia, L. L. Price, K. L. Tedesco et al., “Diffusion press. tensor imaging, white matter lesions, the corpus callosum, [107] K. B. Boone, B. L. Miller, I. M. Lesser et al., “Neuro- and gait in the elderly,” Stroke, vol. 40, no. 12, pp. 3816–3820, psychological correlates of white-matter lesions in healthy 2009. elderly subjects: a threshold effect,” Archives of Neurology, [125] K. F. de Laat, A. M. Tuladhar, A. G. van Norden, D. G. vol. 49, no. 5, pp. 549–554, 1992. Norris, M. P. Zwiers, and F. E. de Leeuw, “Loss of white matter integrity is associated with gait disorders in cerebral [108] V. Mok, W. Lam, Y. Chan, and K. Wong, Poststroke Dementia and Imaging, Nova Science Publishers, 2008. small vessel disease,” Brain, vol. 134, no. 1, pp. 73–83, 2011. Journal of Aging Research 11 [126] K. F. de Laat, A. G. van Norden, R. A. Gons et al., “Diffusion [143] J. J. Vattakatuchery and J. Joy, “Hyperintensities on MRI: tensor imaging and gait in elderly persons with cerebral white matter and depression,” British Medical Journal, vol. small vessel disease,” Stroke, vol. 42, pp. 373–379, 2011. 341, Article ID c4611, 2010. [127] K. Iseki, T. Hanakawa, K. Hashikawa et al., “Gait disturbance [144] P. J. Olesen, D. R. Gustafson, M. Simoni et al., “Temporal associated with white matter changes: a gait analysis and lobe atrophy and white matter lesions are related to major blood flow study,” NeuroImage, vol. 49, no. 2, pp. 1659–1666, depression over 5 years in the elderly,” Neuropsychopharma- cology, vol. 35, no. 13, pp. 2638–2645, 2010. [128] K. A. Jellinger, “The pathology of Parkinson’s disease,” [145] W. K. Tang, Y. K. Chen, J. Y. Lu et al., “White matter Advances in Neurology, vol. 86, pp. 55–72, 2001. hyperintensities in post-stroke depression: a case control [129] N. I. Bohnen and R. L. Albin, “White matter lesions in study,” Journal of Neurology, Neurosurgery & Psychiatry, vol. Parkinson disease,” Nature Reviews Neurology, vol. 7, no. 4, 81, no. 12, pp. 1312–1315, 2010. pp. 229–236, 2011. [146] J. H. Fu, K. Wong, V. Mok et al., “Neuroimaging predictors [130] L. C. Silbert and J. Kaye, “Neuroimaging and cognition in for depressive symptoms in cerebral small vessel disease,” Parkinson’s disease dementia,” Brain Pathology, vol. 20, no. International Journal of Geriatric Psychiatry, vol. 25, no. 10, 3, pp. 646–653, 2010. pp. 1039–1043, 2010. [131] H. K. Kuo and L. A. Lipsitz, “Cerebral white matter changes [147] K. R. Cullen, B. Klimes-Dougan, R. Muetzel et al., “Altered and geriatric syndromes: is there a link?” Journals of white matter microstructure in adolescents with major Gerontology, vol. 59, no. 8, pp. 818–826, 2004. depression: a preliminary study,” Journalofthe American [132] G. A. Kuchel, N. Moscufo, C. R. Guttmann et al., Academy of Child and Adolescent Psychiatry,vol. 49, no.2, “Localization of brain white matter hyperintensities and pp. 173–183, 2010. urinary incontinence in community-dwelling older adults,” [148] J. F. Buyck, C. Dufouil, B. Mazoyer et al., “Cerebral white Journals of Gerontology, vol. 64, no. 8, pp. 902–909, 2009. matter lesions are associated with the risk of stroke but not [133] K. Sonohara, K. Kozaki, M. Akishita et al., “White matter with other vascular events: the 3-city dijon study,” Stroke, lesions as a feature of cognitive impairment, low vitality vol. 40, no. 7, pp. 2327–2331, 2009. and other symptoms of geriatric syndrome in the elderly,” [149] H. Bokura, S. Kobayashi, S. Yamaguchi et al., “Silent brain Geriatrics and Gerontology International,vol. 8, no.2,pp. infarction and subcortical white matter lesions increase the 93–100, 2008. risk of stroke and mortality: a prospective cohort study,” [134] A. Poggesi, G. Pracucci, H. Chabriat et al., “Urinary Journal of Stroke and Cerebrovascular Diseases, vol. 15, no. 2, complaints in nondisabled elderly people with age-related pp. 57–63, 2006. white matter changes: the Leukoaraiosis And DISability [150] N. K. Oksala, A. Oksala, T. Pohjasvaara et al., “Age (LADIS) Study,” Journal of the American Geriatrics Society, related white matter changes predict stroke death in long vol. 56, no. 9, pp. 1638–1643, 2008. term follow-up,” Journal of Neurology, Neurosurgery and [135] Y. Y. Sitoh, Y. Y. Sitoh, and S. Sahadevan, “Clinical Psychiatry, vol. 80, no. 7, pp. 762–766, 2009. significance of cerebral white matter lesions in older [151] D. Inzitari, M. Cadelo, M. L. Marranci, G. Pracucci, and L. Asians with suspected dementia,” Age and Ageing, vol. 33, Pantoni, “Vascular deaths in elderly neurological patients no. 1, pp. 67–71, 2004. with leukoaraiosis,” Journal of Neurology Neurosurgery and [136] S. D. Tadic, D. Griffiths, A. Murrin, W. Schaefer, H. J. Psychiatry, vol. 62, no. 2, pp. 177–181, 1997. Aizenstein, and N. M. Resnick, “Brain activity during [152] V. Palumbo, J. M. Boulanger, M. D. Hill, D. Inzitari, and A. bladder filling is related to white matter structural changes in M. Buchan, “Leukoaraiosis and intracerebral hemorrhage older women with urinary incontinence,” NeuroImage, vol. after thrombolysis in acute stroke,” Neurology, vol. 68, no. 51, no. 4, pp. 1294–1302, 2010. 13, pp. 1020–1024, 2007. [137] I. M. Lesser, E. Hill-Gutierrez, B. L. Miller, and K. B. [153] T. Neumann-Haefelin, S. Hoelig, J. Berkefeld et al., Boone, “Late-onset depression with white matter lesions,” “Leukoaraiosis is a risk factor for symptomatic intracerebral Psychosomatics, vol. 34, no. 4, pp. 364–367, 1993. hemorrhage after thrombolysis for acute stroke,” Stroke, vol. [138] R. D. Nebes, C. F. Reynolds Jr., F. Boada et al., “Longitudinal 37, no. 10, pp. 2463–2466, 2006. increase in the volume of white matter hyperintensities in [154] R. H. Swartz and R. Z. Kern, “Migraine is associated with late-onset depression,” International Journal of Geriatric magnetic resonance imaging white matter abnormalities: Psychiatry, vol. 17, no. 6, pp. 526–530, 2002. a meta-analysis,” Archives of Neurology, vol. 61, no. 9, pp. [139] D. C. Steffens, H. B. Bosworth, J. M. Provenzale, and J. R. 1366–1368, 2004. MacFall, “Subcortical white matter lesions and functional [155] M. C. Kruit, M. A. van Buchem, L. J. Launer, G. M. impairment in geriatric depression,” Depression and Anxiety, Terwindt, and M. D. Ferrari, “Migraine is associated with vol. 15, no. 1, pp. 23–28, 2002. an increased risk of deep white matter lesions, subclinical [140] A. Teodorczuk, J. T. O’Brien, M. J. Firbank et al., “White posterior circulation infarcts and brain iron accumulation: matter changes and late-life depressive symptoms: the population-based MRI CAMERA study,” Cephalalgia, longitudinal study,” British Journal of Psychiatry, vol. vol. 30, no. 2, pp. 129–136, 2010. 191, no. 3, pp. 212–217, 2007. [141] O. Godin, C. Dufouil, P. Maillard et al., “White matter lesions [156] N. Colledge, S. Lewis, G. Mead, R. Sellar, J. Wardlaw, and J. Wilson, “Magnetic resonance brain imaging in people with as a predictor of depression in the elderly: the 3C-dijon dizziness: a comparison with non-dizzy people,” Journal of study,” Biological Psychiatry, vol. 63, no. 7, pp. 663–669, 2008. Neurology Neurosurgery and Psychiatry,vol. 72, no.5,pp. [142] L. L. Herrmann, M. Le Masurier, and K. P. Ebmeier, “White 587–589, 2002. matter hyperintensities in late life depression: a systematic review,” Journal of Neurology, Neurosurgery and Psychiatry, [157] G. J. Hankey and J. W. Eikelboom, “Homocysteine and vascu- vol. 79, no. 6, pp. 619–624, 2008. lar disease,” The Lancet, vol. 354, no. 9176, pp. 407–413, 1999. 12 Journal of Aging Research [158] G. N. Welch and J. Loscalzo, “Homocysteine and athero- [173] H. S. Markus, B. Hunt, K. Palmer, C. Enzinger, H. Schmidt, thrombosis,” New England Journal of Medicine, vol. 338, no. and R. Schmidt, “Markers of endothelial and hemostatic 15, pp. 1042–1050, 1998. activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke [159] F. Perini, E. Galloni, I. Bolgan et al., “Elevated plasma Prevention Study,” Stroke, vol. 36, no. 7, pp. 1410–1414, 2005. homocysteine in acute stroke was not associated with severity [174] J. H. Han, K. S. Wong, Y. Y. Wang, J. H. Fu, D. Ding, and and outcome: stronger association with small artery disease,” Z. Hong, “Plasma level of sICAM-1 is associated with the Neurological Sciences, vol. 26, no. 5, pp. 310–318, 2005. extent of white matter lesion among asymptomatic elderly [160] S. E. Vermeer, E. J. van Dijk, P. J. Koudstaal et al., subjects,” Clinical Neurology and Neurosurgery, vol. 111, no. “Homocysteine, silent brain infarcts, and white matter 10, pp. 847–851, 2009. lesions: the Rotterdam scan study,” Annals of Neurology, vol. [175] R. Schmidt, H. Schmidt, M. Pichler et al., “C-reactive 51, no. 3, pp. 285–289, 2002. protein, carotid atherosclerosis, and cerebral small-vessel [161] C. Dufouil, A. Alperovitch, V. Ducros, and C. Tzourio, disease: results of the austrian stroke prevention study,” “Homocysteine, white matter hyperintensities, and cognition Stroke, vol. 37, no. 12, pp. 2910–2916, 2006. in healthy elderly people,” Annals of Neurology, vol. 53, no. 2, [176] E. J. van Dijk, N. D. Prins, S. E. Vermeer et al., “C-reactive pp. 214–221, 2003. protein and cerebral small-vessel disease: the Rotterdam scan [162] W. T. Longstreth Jr., R. Katz, J. Olson et al., “Plasma total study,” Circulation, vol. 112, no. 6, pp. 900–905, 2005. homocysteine levels and cranial magnetic resonance imaging [177] M. Fornage, Y. A. Chiang, E. S. Omeara et al., “Biomarkers findings in elderly persons: the cardiovascular health study,” of inflammation and MRI-defined small vessel disease of the Archives of Neurology, vol. 61, no. 1, pp. 67–72, 2004. brain: the cardiovascular health study,” Stroke, vol. 39, no. 7, pp. 1952–1959, 2008. [163] A. Hassan, B. J. Hunt, M. O’Sullivan et al., “Homocysteine [178] C. Dufouil, J. Chalmers, O. Coskun et al., “Effects of blood is a risk factor for cerebral small vessel disease, acting via pressure lowering on cerebral white matter hyperintensities endothelial dysfunction,” Brain, vol. 127, no. 1, pp. 212–219, in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic [164] P. Sachdev, R. Parslow, C. Salonikas et al., “Homocysteine Resonance Imaging Substudy,” Circulation, vol. 112, no. 11, and the brain in midadult life: evidence for an increased risk pp. 1644–1650, 2005. of leukoaraiosis in men,” Archives of Neurology, vol. 61, no. 9, [179] L. Pantoni, M. Carosi, S. Amigoni, M. Mascalchi, and pp. 1369–1376, 2004. D. Inzitari, “A preliminary open trial with nimodipine in [165] T. M. Scott, K. L. Tucker, A. Bhadelia et al., “Homocysteine patients with cognitive impairment and leukoaraiosis,” Clin- and B vitamins relate to brain volume and white-matter ical Neuropharmacology, vol. 19, no. 6, pp. 497–506, 1996. changes in geriatric patients with psychiatric disorders,” [180] L. Pantoni, R. Rossi, D. Inzitari et al., “Efficacy and safety American Journal of Geriatric Psychiatry,vol. 12, no.6,pp. of nimodipine in subcortical vascular dementia: a subgroup 631–638, 2004. analysis of the Scandinavian Multi-Infarct Dementia Trial [166] C. B. Wright, M. C. Paik, T. R. Brown et al., “Total ,” Journal of the Neurological Sciences, vol. 175, no. 2, pp. homocysteine is associated with white matter hyperintensity 124–134, 2000. volume: the Northern Manhattan study,” Stroke, vol. 36, no. [181] L. Pantoni, T. del Ser, A. G. Soglian et al., “Efficacy and 6, pp. 1207–1211, 2005. safety of nimodipine in subcortical vascular dementia: a [167] A. Wong, V. Mok, Y. H. Fan, W. W. Lam, K. S. Liang, and K. S. randomized placebo-controlled trial,” Stroke,vol. 36, no.3, Wong, “Hyperhomocysteinemia is associated with volumet- pp. 619–624, 2005. ric white matter change in patients with small vessel disease,” [182] F. Amenta, A. Lanari, F. Mignini, G. Silvestrelli, E. Traini, Journal of Neurology, vol. 253, no. 4, pp. 441–447, 2006. and D. Tomassoni, “Nicardipine use in cerebrovascular disease: a review of controlled clinical studies,” Journal of the [168] B. Censori, T. Partziguian, O. Manara, and M. Poloni, Neurological Sciences, vol. 283, no. 1-2, pp. 219–223, 2009. “Plasma homocysteine and severe white matter disease,” [183] K. Kario, T. Matsuo, H. Kobayashi, M. Imiya, M. Matsuo, Neurological Sciences, vol. 28, no. 5, pp. 259–263, 2007. and K. Shimada, “Nocturnal fall of blood pressure and silent [169] J. L. Fuh, “Homocysteine, cognition and brain white matter cerebrovascular damage in elderly hypertensive patients: hyperintensities,” Acta Neurologica Taiwanica, vol. 19, no. 3, advanced silent cerebrovascular damage in extreme dippers,” pp. 150–152, 2010. Hypertension, vol. 27, no. 1, pp. 130–135, 1996. [170] S. Seshadri, P. A. Wolf, A. S. Beiser et al., “Association of [184] T. R. Pedersen, “Randomised trial of cholesterol lowering in plasma total homocysteine levels with subclinical brain 4444 patients with coronary heart disease: the Scandinavian injury: cerebral volumes, white matter hyperintensity, and Simvastatin Survival Study (4S),” The Lancet, vol. 344, no. silent brain infarcts at volumetric magnetic resonance 8934, pp. 1383–1389, 1994. imaging in the Framingham Offspring Study,” Archives of [185] C. Bernick, R. Katz, N. L. Smith et al., “Statins and cognitive Neurology, vol. 65, no. 5, pp. 642–649, 2008. function in the elderly: the Cardiovascular Health Study,” [171] F. Anan, T. Masaki, H. Tatsukawa et al., “The role of Neurology, vol. 65, no. 9, pp. 1388–1394, 2005. homocysteine as a significant risk factor for white matter [186] D. Woo, B. M. Kissela, J. C. Khoury et al., “Hyper- lesions in Japanese women with rheumatoid arthritis,” cholesterolemia, HMG-CoA reductase inhibitors, and risk of Metabolism, vol. 58, no. 1, pp. 69–73, 2009. intracerebral hemorrhage: a case-control study,” Stroke, vol. [172] Y. L. Tseng, Y. Y. Chang, J. S. Liu, C. S. Su, S. L. Lai, 35, no. 6, pp. 1360–1364, 2004. [187] J. Roquer, A. Rodriguez Campello, M. Gomis, A. Ois, E. and M. Y. Lan, “Association of plasma homocysteine concentration with cerebral white matter hyperintensity on Munteis, and P. Bohm, “Serum lipid levels and in-hospital magnetic resonance images in stroke patients,” Journal of the mortality in patients with intracerebral hemorrhage,” Neurological Sciences, vol. 284, no. 1-2, pp. 36–39, 2009. Neurology, vol. 65, no. 8, pp. 1198–1202, 2005. Journal of Aging Research 13 [188] H. Kavirajan and L. S. Schneider, “Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials,” The Lancet Neurology, vol. 6, no. 9, pp. 782–792, 2007. [189] H. J. Mobius and A. Stoffler, “New approaches to clinical trials in vascular dementia: memantine in small vessel disease,” Cerebrovascular Diseases, vol. 13, supplement 2, pp. 61–66, 2002. [190] M. Dichgans, H. S. Markus, S. Salloway et al., “Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL,” The Lancet Neurology, vol. 7, no. 4, pp. 310–318, 2008. [191] G. C. Roman, S. Salloway, S. E. Black et al., “Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size,” Stroke, vol. 41, no. 6, pp. 1213–1221, 2010. [192] The VITATOPS Trial Study Group, “B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial,” The Lancet Neurology, vol. 9, no. 9, pp. 855–865, 2010. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

Journal of Aging ResearchHindawi Publishing Corporation

Published: Aug 23, 2011

There are no references for this article.