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1.  The impact of vascular burden on late-life depression 
Brain research reviews  2009;62(1):19-32.
Small vessel pathology and microvascular lesions are no longer considered as minor players in the fields of cognitive impairment and mood regulation. Although frequently found in cognitively intact elders, both neuroimaging and neuropathological data revealed the negative impact on cognitive performances of their presence within neocortical association areas, thalamus and basal ganglia. Unlike cognition, the relationship between these lesions and mood dysregulation is still a matter of intense debate. Early studies focusing on the role of macroinfarct location in the occurrence of post-stroke depression (PSD) led to conflicting data. Later on, the concept of vascular depression proposed a deleterious effect of subcortical lacunes and deep white matter demyelination on mood regulation in elders who experienced the first depressive episode. More recently, the chronic accumulation of lacunes in thalamus, basal ganglia and deep white matter has been considered as a strong correlate of PSD. We provide here a critical overview of neuroimaging and neuropathological sets of evidence regarding the affective repercussions of vascular burden in the aging brain and discuss their conceptual and methodological limitations. Based on these observations, we propose that the accumulation of small vascular and microvascular lesions constitutes a common neuropathological platform for both cognitive decline and depressive episodes in old age.
PMCID: PMC2915936  PMID: 19744522
Vascular burden; Cognitive impairment; Aging; Mood; Microvascular pathology; Lacunes
2.  Late-onset Depression in the Absence of Stroke: Associated with Silent Brain Infarctions, Microbleeds and Lesion Locations 
Background: Late-onset depression (LOD) is a frequent mood disorder among elderly. Previous studies have proved that LOD is associated with cerebral silent lesions especially white matter lesions (WML) and yielded the “vascular depression” hypothesis to explain the pathogenesis of LOD. However, there were relatively few studies about the association between silent brain infarctions (SBIs), microbleeds (MBs) and the prevalence of LOD. In this study we sought to evaluate the presence, accumulation and locations of SBIs and MBs, and explore the possible association between them and LOD.
Methods: 65 patients of LOD diagnosed according to DSM-IV and 270 subjects of control group were enrolled and scanned by MRI to analyze the presence, numbers and locations of SBIs and MBs. Clinical and radiological characteristics were compared between LOD patients and control group. Logistic regression models were constructed to identify the independent risk factors for LOD.
Results: LOD patients had higher prevalence and numbers of both SBIs and MBs. SBIs and MBs in the left hemisphere, SBIs in basal ganglia and lobar MBs were all independent risk factors for LOD.
Conclusion: The presence of both SBIs and MBs were associated with a higher rate LOD. Lesions in some specific locations might be critical for the presence of LOD.
PMCID: PMC4003543  PMID: 24782647
Late-onset depression; stroke; silent brain infarctions; microbleeds.
3.  Quantitative Magnetic Resonance Imaging Differences Between Alzheimer Disease With and Without Subcortical Lacunes 
Previous reports showed that patients with Alzheimer disease (AD) frequently have coexisting vascular-related pathologies, such as cerebral infarcts and white matter lesions. The aim of this study was to determine the effects of subcortical lacunar infarcts on brain structure in patients with AD. Semi-automated tissue segmentation and volumetry of magnetic resonance imaging data were performed in 38 AD patients without lacunes (AD-L), 24 AD patients with subcortical lacunes (AD+L), and 40 age-matched cognitively healthy subjects without lacunes. The following tissue volumes were quantified, expressed as percentage of total intracranial volume: ventricular cerebrospinal fluid (CSF), sulcal CSF, cortical gray matter (GM), subcortical GM, white matter (WM), white matter signal hyperintensities (WMSH), lacunes, and hippocampus. There was no difference in the Mini-Mental State Examination between the two AD groups. AD+L patients compared with AD-L subjects had significantly greater volumes of WMSH and ventricular CSF spaces (as expected) but smaller sulcal CSF spaces and no significant increase in cortical GM atrophy (both unexpected). In the AD groups, ventricular CSF correlated inversely with cortical GM but not with WM; sulcal CSF correlated inversely with cortical GM and WM. Cognitive impairment was associated with sulcal CSF volume but not with volumes of WMSH or lacunes. In conclusion, the presence of subcortical lacunes in those with AD is associated with more WM lesions and ventriculomegaly but not with cortical atrophy.
PMCID: PMC1820852  PMID: 12040300
Alzheimer disease; Cerebral infarcts; Magnetic resonance imaging
4.  Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression 
Reduced hippocampal volume and increased prevalence of subcortical white matter lesions are associated with both recurrent early onset depression (EOD) and late onset depression (LOD). It is not clear whether these two factors differentially affect the age of onset of first depression. Therefore, we wished to investigate the relationship between age of first depression onset and hippocampal volume, with adjustment for subcortical white matter lesions.
MRI brain scans were used to compare hippocampal volumes and white matter lesions between age matched female patients (>60 years) with recurrent EOD and LOD and healthy controls.
When comparing the three groups and adjusting for age, the Mini‐Mental State Examination score, total brain volume and total hippocampal volume were significantly smaller in patients with EOD compared with controls (5.6 vs 6.1 ml; p = 0.04). The prevalence of larger subcortical white matter lesions was higher in patients with LOD compared with patients with EOD (47% vs 8%; p = 0.002). Patients with LOD did not differ in hippocampal volume from patients with EOD or from controls.
In late life depression, age of first depression onset may distinguish between different independent neuropathological mechanisms. A small hippocampus volume may be a neuranatomical marker of EOD depression and larger subcortical white matter lesions could be an intermediate between cerebrovascular disease and LOD.
PMCID: PMC2077968  PMID: 17210630
5.  Neuropathological Basis of Magnetic Resonance Images in Aging and Dementia 
Annals of neurology  2008;63(1):72-80.
Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.
This report includes 93 subjects from a longitudinally followed cohort recruited for the study of Alzheimer’s disease (AD) and subcortical cerebrovascular disease (CVD). MR images were analyzed to quantify cortical gray matter volume, hippocampal volume, white matter hyperintensities, and lacunes. Neuropathological examination quantified CVD parenchymal pathology, AD pathology (defined as Consortium to Establish a Registry for Alzheimer’s Disease scores and Braak and Braak stage), and hippocampal sclerosis. Subjects were pathologically classified as 12 healthy control subjects, 46 AD, 14 CVD, 9 mixed AD/CVD, and 12 cognitively impaired patients without significant AD/CVD pathology. Multivariate models tested associations between magnetic resonance and pathological findings across the entire sample.
Pathological correlates of cortical gray matter volume were AD, subcortical vascular pathology, and arteriosclerosis. Hippocampal volume was related to AD pathology and hippocampal sclerosis, and the effects of hippocampal sclerosis were greater for subjects with low levels of AD pathology. White matter hyperintensities were related to age and to white matter pathology. Number of MRI lacunes was related to subcortical vascular pathology.
In this clinical setting, the presence of lacunes and white matter changes provide a good signal for vascular disease. The neuropathological basis of MR defined cerebral cortical and hippocampal atrophy in aging and dementia is complex, with several pathological processes converging on similar brain structures that mediate cognitive decline.
PMCID: PMC2624571  PMID: 18157909
6.  Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease 
Neurology  2002;59(6):867-873.
To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI).
Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI.
Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability.
Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline.
Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.
PMCID: PMC1820873  PMID: 12297568
7.  Subcortical Ischemic Vascular Dementia (SIVD) 
Neurologic clinics  2007;25(3):717-vi.
Subcortical ischemic vascular dementia (SIVD) has been proposed as a subtype of vascular cognitive impairment (VCI). The syndrome is defined clinically by cognitive impairment and evidence of subcortical vascular brain injury, including lacunar infarcts and deep white matter changes. SIVD has been traditionally recognized as lacunar state, strategic infarct dementia, and Binswanger syndrome, but these clinical syndromes represent the tip of the iceberg. Proton density magnetic resonance (MRI) often discloses “silent” hyperintensities in 20-40% of community dwelling elderly. Efforts to relate MRI-measured lacunes and white matter changes to cognitive impairment have not been straightforward. The hidden possibility that concomitant Alzheimer disease pathology contributes significantly to cognitive impairment increases with age. Nonetheless, new knowledge is being gained from longitudinal MRI and systematic neuropathological studies. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL), a rare genetic disorder, provides an opportunity to study pure SIVD in the absence of AD. Dysexecutive syndrome characterized by slowing of mental processing speed, decreased working memory, and impairment of abstract reasoning are associated with lacunes and deep white matter changes. But data related to sensitivity and specificity which would support dysexecutive syndrome as diagnostic criteria are limited. Hypertension, by far the leading risk factor for sporadic SIVD, is eminently treatable. High priority must be given to reducing vascular risk profiles.
PMCID: PMC2084201  PMID: 17659187
vascular dementia; subcortical; ischemia; lacunes; white matter changes
8.  Subcortical Ischemic Vascular Dementia: Assessment with Quantitative MR Imaging and 1H MR Spectroscopy 
Subcortical ischemic vascular dementia is associated with cortical hypometabolism and hypoperfusion, and this reduced cortical metabolism or blood flow can be detected with functional imaging such as positron emission tomography. The aim of this study was to characterize, by means of MR imaging and 1H MR spectroscopy, the structural and metabolic brain changes that occur among patients with subcortical ischemic vascular dementia compared with those of elderly control volunteers and patients with Alzheimer’s disease.
Patients with dementia and lacunes (n = 11), cognitive impairment and lacunes (n = 14), and dementia without lacunes (n = 18) and healthy age-matched control volunteers (n = 20) underwent MR imaging and 1H MR spectroscopy. 1H MR spectroscopy data were coanalyzed with coregistered segmented MR images to account for atrophy and tissue composition.
Compared with healthy control volunteers, patients with dementia and lacunes had 11.74% lower N-acetylaspartate/creatine ratios (NAA/Cr) (P = .007) and 10.25% lower N-acetylaspartate measurements (NAA) in the cerebral cortex (P = .03). In white matter, patients with dementia and lacunes showed a 10.56% NAA/Cr reduction (P = .01) and a 12.64% NAA reduction (P = .04) compared with control subjects. NAA in the frontal cortex was negatively correlated with the volume of white matter signal hyperintensity among patients with cognitive impairment and lacunes (P = .002). Patients with dementia, but not patients with dementia and lacunes, showed a 10.33% NAA/Cr decrease (P = .02) in the hippocampus compared with healthy control volunteers.
Patients with dementia and lacunes have reduced NAA and NAA/Cr in both cortical and white matter regions. Cortical changes may result from cortical ischemia/infarction, retrograde or trans-synaptic injury (or both) secondary to subcortical neuronal loss, or concurrent Alzheimer’s pathologic abnormalities. Cortical derangement may contribute to dementia among patients with subcortical infarction.
PMCID: PMC1945115  PMID: 10782769
9.  Microbleeds in Late-Life Depression: Comparison of Early- and Late-Onset Depression 
BioMed Research International  2014;2014:682092.
Late-life depression could be classified roughly as early-onset depression (EOD) and late-onset depression (LOD). LOD was proved to be associated with cerebral lesions including white matter hyperintensities (WMH) and silent brain infarctions (SBI), differently from EOD. However, it is unclear whether similar association is present between LOD and microbleeds which are also silent lesions. In this study, 195 patients of late-life depression were evaluated and divided into EOD, presenile-onset depression (POD), and LOD groups; 85 healthy elderly controls were enrolled as controls. Subjects were scanned by MRI including susceptibility weighted images to evaluate white matter hyperintensities (WMH), silent brain infarctions (SBI), and microbleeds. The severity of depression was evaluated with 15-item Geriatric Depression Scale. Psychosocial factors were investigated with Scale of Life Events and Lubben Social Network Scale. Logistic regression and linear regression were performed to identify the independent risk factors for depression. Results showed that LOD patients had higher prevalence of microbleeds than EOD, POD, and control patients. The prevalence of lobar microbleeds and microbleeds in the left hemisphere was the independent risk factor for the occurrence of LOD; a high number of microbleeds were associated with severe state of LOD, whereas life events and lack of social support were more important for EOD and POD. All these results indicated that Microbleeds especially lobar microbleeds and microbleeds in the left hemisphere were associated with LOD but not with EOD.
PMCID: PMC3955674  PMID: 24719883
10.  Vascular Contributions to Cognitive Impairment and Dementia 
Background and Purpose
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
11.  Fasting Versus Post-Challenge Triglycerides and Pre-Existing Cavitating Lacunes: A Berlin “Cream & Sugar” Substudy 
Background and Purpose: Although the presence of cavitating lacunes on brain imaging may have prognostic implications, the modifiable risk factors underlying these frequently observed lesions are not completely understood. We sought to determine if fasting and post-challenge triglycerides associate with cavitating lacunes.
Methods: All first ischemic stroke patients who completed a novel combined oral triglyceride and glucose tolerance test and MRI between January 2009 and June 2012 were included. Fluid-attenuated inversion recovery or T2 MRI sequences were used to visualize cavitating lacunes and white matter hyperintensities, which were graded using the Wahlund visual scale.
Results: One hundred and ninety patients were included (median age 66, IQR 52–73; 33% female; median National Institute of Health Stroke Scale 2, IQR 1–4). A forward stepwise binary logistical regression analysis applying the Hosmer–Lemeshow goodness of fit test adjusted for parameters significant in univariate analyses (at the p < 0.10 level) revealed that Wahlund scores (Wahlund 0–4: reference; Wahlund 5–10: adjusted odds ratio, 5.1; 95% confidence interval, 1.3–20.0, p = 0.019; Wahlund>10: adjusted odds ratio 9.6; 95% CI, 1.55–59.35; p = 0.015) and the highest quartile of post-challenge triglycerides (>295 mg/dL; adjusted odds ratio, 7.36; 95% confidence interval 1.24–43.70; p = 0.028) independently associated with the presence of cavitating lacunes.
Conclusion: Post-challenge serum triglycerides are independently associated with the presence of cavitating lacunes.
PMCID: PMC3706746  PMID: 23847590
ischemia; cerebral lacunes; leukoaraiosis; white matter disease; triglycerides; glucose
12.  Executive dysfunction in subcortical ischaemic vascular disease 
Executive dysfunction has been reported in patients with subcortical-frontal pathology, even in the absence of dementia.
This study was undertaken to determine if impairments in executive functioning could be found in non-demented patients with subcortical lacunes.
Cross sectional comparison between older control subjects (n=27) and non-demented patients with one or more subcortical lacunes (n=12). All participants were administered a neuropsychological test battery incorporating three measures of executive functioning, the Stroop interference test, California card sorting test, and the initiation-perseveration subtest of the Mattis dementia rating scale.
No group differences were found on measures of recent verbal memory, language, or spatial ability. Normal controls performed better than patients with lacunes in visual memory. On the Stroop interference test, patients with lacunes performed as well as controls on the colour naming condition but slower on the interference condition. Patients with lacunes also generated fewer correct sorts on the California card sort test and achieved lower scores on the initiation-perseveration subtest. Executive measures were correlated with extent of white matter signal hyperintensity but not number of lacunes.
Subcortical ischaemic vascular disease is associated with subtle declines in executive functioning and visual memory, even in non-demented patients. The pattern of cognitive impairment after subcortical lacunes is consistent with models of subcortical-frontal circuits.
PMCID: PMC1737728  PMID: 11796772
13.  Executive dysfunction in subcortical ischaemic vascular disease 
Background: Executive dysfunction has been reported in patients with subcortical-frontal pathology, even in the absence of dementia.
Objective: This study was undertaken to determine if impairments in executive functioning could be found in non-demented patients with subcortical lacunes.
Methods: Cross sectional comparison between older control subjects (n=27) and non-demented patients with one or more subcortical lacunes (n=12). All participants were administered a neuropsychological test battery incorporating three measures of executive functioning, the Stroop interference test, California card sorting test, and the initiation-perseveration subtest of the Mattis dementia rating scale.
Results: No group differences were found on measures of recent verbal memory, language, or spatial ability. Normal controls performed better than patients with lacunes in visual memory. On the Stroop interference test, patients with lacunes performed as well as controls on the colour naming condition but slower on the interference condition. Patients with lacunes also generated fewer correct sorts on the California card sort test and achieved lower scores on the initiation-perseveration subtest. Executive measures were correlated with extent of white matter signal hyperintensity but not number of lacunes.
Conclusion: Subcortical ischaemic vascular disease is associated with subtle declines in executive functioning and visual memory, even in non-demented patients. The pattern of cognitive impairment after subcortical lacunes is consistent with models of subcortical-frontal circuits.
PMCID: PMC1737728  PMID: 11796772
14.  Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease 
Neurology  2000;55(11):1626-1635.
The cause of dementia in subcortical ischemic vascular disease (SIVD) is controversial.
To determine whether cognitive impairment in SIVD 1) correlates with measures of ischemic brain injury or brain atrophy, and/or 2) is due to concomitant AD.
Volumetric MRI of the brain was performed in 1) elderly subjects with lacunes (L) and a spectrum of cognitive impairment—normal cognition (NC+L, n = 32), mild cognitive impairment (CI+L, n = 26), and dementia (D+L, n = 29); 2) a comparison group with probable AD (n = 28); and 3) a control group with normal cognition and no lacunes (NC). The authors examined the relationship between the severity of cognitive impairment and 1) volume, number, and location of lacunes; 2) volume of white matter signal hyperintensities (WMSH); and 3) measures of brain atrophy (i.e., hippocampal, cortical gray matter, and CSF volumes).
Among the three lacune groups, severity of cognitive impairment correlated with atrophy of the hippocampus and cortical gray matter, but not with any lacune measure. Although hippocampal atrophy was the best predictor of severity of cognitive impairment, there was evidence for a second, partially independent, atrophic process associated with ventricular dilation, cortical gray matter atrophy, and increase in WMSH. Eight autopsied SIVD cases showed variable severity of ischemic and neurofibrillary degeneration in the hippocampus, but no significant AD pathology in neocortex. The probable AD group gave evidence of only one atrophic process, reflected in the severity of hippocampal atrophy. Comparison of regional neocortical gray matter volumes showed sparing of the primary motor and visual cortices in the probable AD group, but relatively uniform atrophy in the D+L group.
Dementia in SIVD, as in AD, correlates best with hippocampal and cortical atrophy, rather than any measure of lacunes. In SIVD, unlike AD, there is evidence for partial independence between these two atrophic processes. Hippocampal atrophy may result from a mixture of ischemic and degenerative pathologies. The cause of diffuse cortical atrophy is not known, but may be partially indexed by the severity of WMSH.
PMCID: PMC2733356  PMID: 11113215
15.  Predicting Symptomatic Intracerebral Hemorrhage Versus Lacunar Disease in Patients With Longstanding Hypertension 
Background and Purpose
Hypertension results in a spectrum of subcortical cerebrovascular disease. It is unclear why some individuals develop ischemia and others develop hemorrhage. Risk factors may differ for each population. We identify factors that predispose an individual to subcortical symptomatic intracerebral hemorrhage (sICH) compared with ischemia.
Demographic and laboratory data were prospectively collected for hypertensive patients presenting with ischemic stroke or sICH during an 8.5-year period. Neuroimaging was retrospectively reviewed for acute (subcortical lacunes [<2.0 cm] versus subcortical sICH) and chronic (periventricular white matter disease and cerebral microbleeds) findings. We evaluated the impact of age, race, sex, serum creatinine, erythrocyte sedimentation rate, low-density lipoprotein, presence of periventricular white matter disease or cerebral microbleeds, and other factors on the risk of sICH versus acute lacune using multivariate logistic regression.
Five hundred seventy-one patients had subcortical pathology. The presence of cerebral microbleeds (adjusted odds ratio [OR], 3.39; confidence interval [CI], 2.09–5.50) was a strong predictor of sICH, whereas severe periventricular white matter disease predicted ischemia (OR, 0.56 risk of sICH; CI, 0.32–0.98). This association was strengthened when the number of microbleeds was evaluated; subjects with >5 microbleeds had an increased risk of sICH (OR, 4.11; CI, 1.96–8.59). It remained significant when individuals with only cortical microbleeds were removed (OR, 1.77, CI, 1.13–2.76). An elevated erythrocyte sedimentation rate (OR, 1.19 per 10 mm/h increase; CI, 1.06–1.34) was significantly associated with sICH, whereas low-density lipoprotein was associated with ischemic infarct (OR, 0.93 risk of sICH per 10 mg/dL increase; CI, 0.86–0.99).
Subclinical pathology is the strongest predictor of the nature of subsequent symptomatic event. Low-density lipoprotein and erythrocyte sedimentation rate may also have a role in risk stratification.
PMCID: PMC4442011  PMID: 24811338
cerebral hemorrhage; hypertension; inflammation; stroke
16.  Clinical Characterization of Symptomatic Microangiopathic Brain Lesions 
Background: Microangiopathic brain lesions can be separated in diffuse lesions – leukoaraiosis – and focal lesions – lacunes. Leukoaraiosis and lacunes are caused by common cerebrovascular risk factors, but whether they represent a common entity is not sufficiently investigated. The present study aimed to determine the clinical profiles associated with the extent of leukoaraiosis and lacunes. Methods: Sixty-four consecutive patients with acute microangiopathic stroke were studied. Leukoaraiosis and lacunes were stratified according to their MRI-based extent. Standardized clinical assessment included clinical syndromes, cerebrovascular risk factors, cognitive performance, retinal imaging, ultrasonography, blood, and urine parameters. Results: Different clinical profiles for leukoaraiosis and lacunes were found. Regarding leukoaraiosis, the cognitive scores (SISCO, mini mental score examination, mental examination) and the presence of hyperlipidemia decreased as the severity of leukoaraiosis increased. Univariate and multivariate analysis revealed that these cognitive score values as well as the presence of hyperlipidemia correlated significantly with no or only mild leukoaraiosis. Regarding lacunes, the percentage of migraine, previous stroke events, hydrocephalus, left ventricular hypertrophy, and a higher National Institutes of Health Stroke Scale increased as the number of lacunar lesions increased. Statistical analysis revealed that these parameters correlated not significantly with the number of lacunes. Conclusions: The findings suggests that leukoaraiosis and lacunes are different microangiopathic entities potentially requiering different treatment concepts.
PMCID: PMC3178061  PMID: 21960985
microangiopathic brain lesions; leukoaraiosis; lacunar lesion; cardiovascular risk factor
17.  Three-Dimensional MRI Analysis of Individual Volume of Lacunes in CADASIL 
Background and Purpose
Three-dimensional MRI segmentation may be useful to better understand the physiopathology of lacunar infarctions. Using this technique, the distribution of lacunar infarctions volumes has been recently reported in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Whether the volume of each lacune (individual lacunar volume [ILV]) is associated with the patients’ other MRI lesions or vascular risk factors has never been investigated. The purpose of this study was to study the impact of age, vascular risk factors, and MRI markers on the ILV in a large cohort of patients with CADASIL.
Of 113 patients with CADASIL, 1568 lacunes were detected and ILV was estimated after automatic segmentation on 3-dimensional T1-weighted imaging. Relationships between ILV and age, blood pressure, cholesterol, diabetes, white matter hyperintensities load, number of cerebral microbleeds, apparent diffusion coefficient, brain parenchymal fraction, and mean and median of distribution of lacunes volumes at the patient level were investigated. We used random effect models to take into account intraindividual correlations.
The ILV varied from 4.28 to 1619 mm3. ILV was not significantly correlated with age, vascular risk factors, or different MRI markers (white matter hyperintensity volume, cerebral microbleed number, mean apparent diffusion coefficient or brain parenchymal fraction). In contrast, ILV was positively correlated with the patients’ mean and median of lacunar volume distribution (P=0.0001).
These results suggest that the ILV is not related to the associated cerebral lesions or to vascular risk factors in CADASIL, but that an individual predisposition may explain predominating small or predominating large lacunes among patients. Local anatomic factors or genetic factors may be involved in these variations.
PMCID: PMC3085999  PMID: 18948610
CADASIL; cerebral lacunes; MRI
18.  Association of Depressed Mood and Mortality in Older Adults With and Without Cognitive Impairment in a Prospective Naturalistic Study 
The American journal of psychiatry  2010;167(5):589-597.
The authors examined predictors of mortality in individuals age 50 or older with or without cognitive impairment in a 12-year prospective naturalistic study of subcortical ischemic vascular disease focusing on symptoms of depressed mood, apathy, anhedonia, or anergia.
A total of 498 participants were recruited from the community and from memory clinics into a multicenter longitudinal study of subcortical ischemic vascular disease. For baseline cognitive status, 36% of participants were assessed as cognitively intact, 31% as cognitively impaired, and 33% as demented. All participants underwent a research protocol MRI, and 41% were classified as having subcortical lacunes. Depressed mood, anhedonia, anergia, and apathy were assessed at baseline using a structured behavioral assessment. Cox regression models were used to investigate the associations between neuropsychiatric symptoms and mortality, controlling for age, gender, race, education level, cognitive status, presence of vascular lacunes, and vascular risk factors.
Of 498 participants, 175 (35%) died over the follow-up period, with a median survival time of 5.6 years. In the multivariate analyses, cognitive impairment, age, male gender, depressed mood, and the presence of lacunes predicted higher mortality. Participants with both lacunes and depressed mood had the shortest survival among all cognitive groups. The mortality hazard ratio for participants with depressed mood was 2.2 (95% CI=1.5–3.2) after adjustment for cognitive status, age, gender, education level, race, lacunes, and all vascular conditions.
These findings suggest the importance of detecting depressed mood in individuals with cerebrovascular disease and of developing more aggressive treatment and preventive interventions for this vulnerable population.
PMCID: PMC2864365  PMID: 20160005
19.  Risk Factors of Dilated Virchow-Robin Spaces Are Different in Various Brain Regions 
PLoS ONE  2014;9(8):e105505.
Background and Purpose
Few studies have reported on the risk factors of dilated Virchow-Robin Spaces (dVRS) in large samples of ischemic stroke patients. Little evidence exists regarding the relationship between dVRS and etiologic subtype of ischemic stroke or lacune. We aimed to investigate the risk factors associated with the severity of dVRS in a large sample of ischemic stroke patients.
We consecutively enrolled 1,090 patients who experienced an ischemic stroke within the past seven days and underwent a 3.0 T MRI scan in the Chinese IntraCranial AtheroSclerosis Study (ICAS). Clinical data and cranial MRI information of patients included age, sex, vascular risk factors, dVRS, leukoaraiosis, lacune, and etiologic subtype of ischemic stroke. Analyses were performed regarding the risk factors associated with the severity of dVRS by univariate analysis and multivariable ordinal logistic regression analysis.
Through multivariable ordinal logistic regression analysis, age, the severity of leukoaraiosis, lacune, admission National Institutes of Health Stroke Scale (NIHSS) ≤3, and the severity of dVRS in the white matter (WM) and hippocampus (Hip) were correlated with the severity of dVRS in basal ganglia (BG); male, history of hypertension, admission NIHSS ≤3, and the severity of dVRS in BG and Hip were correlated with the severity of dVRS in WM; female, the severity of leukoaraiosis, admission NIHSS >3, small artery occlusion subtype of ischemic stroke, and the severity of dVRS in BG and WM were correlated with the severity of dVRS in Hip.
dVRS is an indicator of cerebral small vessel diseases such as leukoaraiosis and lacune. However, the risk factors of dVRS differ in various brain regions.
PMCID: PMC4144854  PMID: 25157843
20.  Silent Microbleeds and Old Hematomas in Spontaneous Cerebral Hemorrhages 
The authors studied the risk factors of silent cerebral microbleeds (MBs) and old hematomas (OHs) and their association with concurrent magnetic resonance (MR) imaging findings in the patients of intracerebral hemorrhages (ICHs).
From April 2002 to June 2007, we retrospectively studied 234 patients of primary hemorrhagic stroke. All patients were evaluated with computed tomography (CT) and 3.0-tesla MR imaging studies within the first week of admission. MBs and OHs were assessed by using T2*-weighted gradient-echo (GRE) MR imaging. The patients were divided into 2 groups, depending on whether or not they had two GRE lesions of chronic hemorrhages. A correlation between MBs and OHs lesions were also statistically tested. Lacunes and white matter and periventricular hyperintensities (WMHs, PVHs) were checked by T1- and T2-weighted spin-echo and fluid attenuated inversion recovery sequences. Variables on the clinical and laboratory data and MR imaging abnormalities were compared between both groups with or without MBs and OHs.
MBs were observed in 186 (79.5%) patients and a total of 46 OHs were detected in 45 (19.2%) patients. MBs (39.6%), OHs (80.4%), and ICHs (69.7%) were most commonly located in the ganglionic/thalamic region. Both MBs and OHs groups were more frequently related to chronic hypertension and advanced WMHs and PVHs. The prevalence and number of MBs were more closely associated with OHs groups than non-OH patients.
This study clearly demonstrated the presence of MBs and OHs and their correlation with hypertension and cerebral white matter microangiopathy in the ICHs patients. Topographic correlation between the three lesions (MBs, OHs, and ICHs) was also noted in the deep thalamo-basal location.
PMCID: PMC2729822  PMID: 19707492
Cerebral hemorrhage; Microbleed; Magnetic resonance imaging; Leukoaraiosis; Hypertension
21.  Different patterns of N-acetylaspartate loss in subcortical ischemic vascular dementia and AD 
Neurology  2003;61(3):358-364.
1) To determine the regional pattern of reduced N-acetylaspartate (NAA) in subcortical ischemic vascular dementia (SIVD); 2) to explore the relationship between NAA reduction and subcortical vascular disease; and 3) to test if MR spectroscopic imaging (MRSI) in combination with structural MRI improves differentiation between SIVD and Alzheimer disease (AD).
Thirteen patients with SIVD (71 ± 8 years old) and 43 patients with AD of comparable age and dementia severity were studied using MRSI and MRI. Patients were compared to 52 cognitively normal subjects with and without lacunes.
Compared to controls, patients with SIVD had lower NAA by 18% (p < 0.001) in frontal cortex and by 27% (p < 0.003) in parietal cortex, but no significant NAA reduction in white matter and medial temporal lobe. Compared to patients with AD, patients with SIVD had lower NAA by 13% (p < 0.02) in frontal cortex and by 20% (p < 0.002) in left parietal cortex. Cortical NAA decreased in SIVD with increasing white matter lesions (r = 0.54, p < 0.02) and number of lacunes (r = 0.59, p < 0.02). Thalamic lacunes were associated with greater NAA reduction in frontal cortex than were lacunes outside the thalamus (p < 0.02) across groups, after adjusting for cognitive impairments. Adding parietal NAA to MRI-derived hippocampal atrophy improved separation between SIVD and AD (p < 0.02) from 79 to 89%.
These results emphasize the importance of cortical dysfunction as a factor in SIVD and indicate a characteristic pattern of metabolite change that might serve as a basis for improved diagnosis.
PMCID: PMC1820863  PMID: 12913198
22.  Temporal lobe abnormalities in dementia and depression: a study using high resolution single photon emission tomography and magnetic resonance imaging 
OBJECTIVES—Perfusion SPECT and MRI were used to test the hypothesis that late onset depression is associated with brain abnormalities.
METHODS—Forty depressed patients (DSM-III-R major depressive episode, not demented at two year follow up) were recruited who were either drug free, or on a stable dose of antidepressants for at least three weeks, as well as 22 demented patients (DSM-IIIR and NINCDS/ADRDA criteria for probable Alzheimer's disease). Patients were imaged at rest with a high resolution single slice 12 detector head scanner (SME-Neuro 900) and the cerebral perfusion marker 99mTc-exametazime (HM-PAO). Temporal lobe templates were fitted with brains pitched by 20°-30°. A subgroup of 41 patients (22 depressed) were also scanned using a Siemens Magnetron 1.0 Tesla magnetic resonance imager, using a FLAIR imaging sequence for the assessment of white matter hyperintensities, and a Turbo FLASH sequence for the measurement of medial temporal lobe width.
RESULTS—Demented patients showed reduced perfusion, particularly in the left temporoparietal cortex. In these regions of interest, patients with late onset depression tended to have perfusion values intermediate between patients with early onset depression and demented patients. Differences in changes in white matter between demented and early and late onset depressive patients did not reach conventional levels of significance. Temporal lobe width differed between demented and depressed patients, but not between early and late onset depressed patients. Perfusion and temporal lobe width were not associated, but reductions of perfusion were associated with periventricular white matter changes. Mini mental state examination scores were associated with temporal perfusion in demented patients and with changes in deep white matter in depressed patients. Finally, severity of depressive symptoms was associated with decreased perfusion in frontotemporal and basal ganglia regions of interest.
CONCLUSION—A cumulative effect of duration of illness on regional cerebral perfusion could not be confirmed. Late onset depression may show more abnormalities of deep white matter and of left temporoparietal perfusion than early onset depression, but the underlying pathology remains to be established.

PMCID: PMC2169802  PMID: 9408100
23.  The MRI brain correlates of depressed mood, anhedonia, apathy, and anergia in older adults with and without cognitive impairment or dementia 
We examined the magnetic resonance imaging (MRI) correlates of depressed mood, apathy, anhedonia, and anergia in older adults with and without cognitive impairment or dementia.
This analysis included 270 community-dwelling older adults (59% male; 79% Caucasian; mean age 74.4 years) who were recruited into a multi-center longitudinal observational study of subcortical ischemic vascular disease (SIVD).The distribution of cognitive status included: cognitively intact (38%), cognitively impaired (27%), or demented (35%). All subjects underwent MRI and 41% were classified as having subcortical lacunes. MRI measures included cortical gray and white matter volumes, lacunar volumes in subcortical white and gray matter structures, volume of white matter hyperintensities, and total hippocampal volume. Depressed mood, anhedonia, anergia, and apathy apparent at the time of assessment were assessed using a behavioral assessment Associations between neuropsychiatric symptoms and MRI variables were evaluated using logistic regression.
Subjects with neuropsychiatric symptoms were more likely to be cognitively impaired or demented than those without neuropsychiatric symptoms. In multivariate models controlling for cognitive status, age, gender, and education, higher lacunar volume in white matter was independently associated with the presence of all four neuropsychiatric symptoms.
We report an association between the lacunar volumes in the white matter and depressed mood, anhedonia, apathy, and anergia, thus supporting the role of subcortical ischemic vascular disease in the pathogenesis of late-life neuropsychiatric disorders.
PMCID: PMC2575050  PMID: 18412291
late-life neuropsychiatric symptoms; depression; apathy; anhedonia; anergia; subcortical ischemic vascular disease; hippocampal volume; magnetic resonance imaging (MRI)
24.  Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging 
Background and purpose
Most of the neuropathological studies in brain aging were based on the assumption of a symmetric right-left hemisphere distribution of both Alzheimer's disease (AD) and vascular pathology. To explore the impact of asymmetric lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts.
Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle (NFT) and Aß-deposition staging, microvascular pathology and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and CDR scores was assessed using ordered logistic regression.
Unlike Braak NFT and Aß deposition staging, vascular scores were significantly higher in the left hemisphere for all CDR scores. A negative relationship was found between Braak NFT, but not Aß, staging and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak NFT staging was the main determinant of cognitive decline followed by vascular scores and Aß deposition staging. The concomitant predominance of AD and vascular pathology in the right hemisphere was associated with significantly higher CDR scores.
Our data show that the cognitive impact of AD and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and AD burden in the right hemisphere may increase the risk for dementia in this group.
PMCID: PMC2674266  PMID: 19118241
Alzheimer; cerebral infarct; cognition; white matter disease
25.  Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease 
Brain  2011;134(11):3384-3397.
Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3′-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3′-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
PMCID: PMC3212720  PMID: 22006983
NOTCH3; cerebral small vessel disease; genetics; MRI; ageing

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