Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer’s disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD) and segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together depressed mood and cognitive impairment are caused by different pathological correlates.
white matter lesion; gray matter atrophy; depression; mood; cognition; MRI
White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years.
In 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia.
Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia.
Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.
The objectives were first to compare the effects of subcortical ischemic vascular dementia (SIVD) and Alzheimer's disease (AD) on cerebral blood flow (CBF) and second to analyze the relationship between CBF and subcortical vascular disease, measured as volume of white matter lesions (WML).
Eight mildly demented patients with SIVD (77 ± 8 years, 26 ± 3 MMSE) and 14 patients with AD were compared to 18 cognitively normal elderly. All subjects had CBF measured using arterial spin labeling MRI and brain volumes assessed using structural MRI.
AD and SIVD showed marked CBF reductions in frontal (p = 0.001) and parietal (p = 0.001) cortex. In SIVD, increased subcortical WML were associated with reduced CBF in frontal cortex (p = 0.04) in addition to cortical atrophy (frontal: p = 0.05; parietal: p = 0.03).
Subcortical vascular disease is associated with reduced CBF in the cortex, irrespective of brain atrophy.
Magnetic Resonance Imaging; Cerebral blood flow; Subcortical ischemic vascular dementia; Alzheimer's disease; Cortex; Segmentation; White matter lesions
Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS).
From the CHS we selected 740 cognitively normal controls with a 1.5 T MRI scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software.
WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores.
Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.
White matter lesions; age; gray matter volume; cognition
This paper evaluates the relationship of blood pressure (BP) levels at Women’s Health Initiative (WHI) baseline, treatment of hypertension, and white matter abnormalities among women in conjugated equine estrogen (CEE) and medroxyprogesterone acetate and CEE-alone arms. The WHI Memory Study—Magnetic Resonance Imaging (WHIMS-MRI) trial scanned 1424 participants. BP levels at baseline were significantly positively related to abnormal white matter lesion (WML) volumes. Participants treated for hypertension but who had BP ≥140/90 mm Hg had the greatest amount of WML volumes. Women with untreated BP ≥140/90 mm Hg had intermediate WML volumes. Abnormal WML volumes were related to hypertension in most areas of the brain and were greater in the frontal lobe than in the occipital, parietal, or temporal lobes. Level of BP at baseline was strongly related to amount of WML volumes. The results of the study reinforce the relationship of hypertension and BP control and white matter abnormalities in the brain. The evidence to date supports tight control of BP levels, especially beginning at younger and middle age as a possible and perhaps only way to prevent dementia.
Lacunar lesions (LLs) and white matter lesions (WMLs) affect cognition. We assessed whether lesions located in specific white matter tracts were associated with cognitive performance taking into account total lesion burden.
Within the Second Manifestations of ARTerial disease Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed on 516 patients with manifest arterial disease. We applied an assumption-free voxel-based lesion-symptom mapping approach to investigate the relation between LL and WML locations on 1.5 Tesla brain MRI and compound scores of executive functioning, memory and processing speed. Secondly, a multivariable linear regression model was used to relate the regional volume of LLs and WMLs within specific white matter tracts to cognitive functioning.
Voxel-based lesion-symptom mapping identified several clusters of voxels with a significant correlation between WMLs and executive functioning, mostly located within the superior longitudinal fasciculus and anterior thalamic radiation. In the multivariable linear regression model, a statistically significant association was found between regional LL volume within the superior longitudinal fasciculus and anterior thalamic radiation and executive functioning after adjustment for total LL and WML burden.
These findings identify the superior longitudinal fasciculus and anterior thalamic radiation as key anatomical structures in executive functioning and emphasize the role of strategically located vascular lesions in vascular cognitive impairment.
Age-related white matter lesions (WML) are a risk factor for stroke, cognitive decline, and dementia. Different requirements are imposed on methods for the assessment of WML in clinical settings and for research purposes, but reliability analysis is of major importance. In this study, WML assessment with three different methods was evaluated. In the Gothenburg mild cognitive impairment study, MRI scans from 152 participants were used to assess WML with the Fazekas visual rating scale on T2 images, a manual volumetric method on FLAIR images, and FreeSurfer volumetry on T1 images. Reliability was acceptable for all three methods. For low WML volumes (2/3 of the patients), reliability was overall lower and nonsignificant for the manual volumetric method. Unreliability in the assessment of patients with low WML with manual volumetry may mainly be due to intensity variation in the FLAIR sequence used; hence, intensity standardization and normalization methods must be used for more accurate assessments. The FreeSurfer segmentations resulted in smaller WML volumes than the volumes acquired with the manual method and showed deviations from visible hypointensities in the T1 images, which quite likely reduces validity.
Causes of cognitive impairment in subcortical ischemic vascular disease (SIVD) are less well understood than in AD, but have been thought to result from direct effects of subcortical lacunes and white matter lesions, perhaps related to disruption of important cortical-subcortical pathways.
To examine the relation between cognitive abilities and quantitative MRI measures of subcortical cerebrovascular disease and cortical and hippocampal atrophy.
Subjects were 157 participants in a multicenter study of SIVD and AD who included cognitively normal, cognitively impaired, and demented individuals with and without subcortical lacunar infarcts. Dependent variables were neuropsychological tests of global cognitive function, memory, language, and executive function. Independent variables were quantitative MRI measures of volume of lacunar infarcts in specific subcortical structures, volume of white matter lesion (WML), volume of cortical gray matter (cGM), and total hippocampal volume (HV). Multiple regression analyses were used to identify MRI predictors of cognition.
Subcortical lacunes were not related to cognitive measures independent of effects of other MRI variables. WML was independently related to selected, timed measures. HV and cGM were strong and independent predictors of cognitive variables, with effects that did not differ in subjects with and without subcortical lacunes.
Results suggest that cognitive impairment associated with subcortical ischemic vascular disease is primarily a result of associated hippocampal and cortical changes.
Pure vascular parkinsonism without evidence of nigral Lewy body pathology may occur as a distinct clinicopathological entity, but a much more frequent occurrence is the comorbid presence of age-associated white matter lesions (WMLs) in idiopathic Parkinson disease (PD). WMLs are associated with motor and cognitive symptoms in otherwise normal elderly individuals. Comorbid WMLs are, therefore, expected to contribute to clinical symptoms in PD. Studies of WMLs in PD differ with regard to methods of assessment of WML burden and the patient populations selected for analysis, but converging evidence suggests that postural stability and gait motor functions are predominantly affected. WMLs are described to contribute to dementia in Alzheimer disease, and emerging but inconclusive evidence indicates similar effects in PD. In this article, we review the literature addressing the occurrence and impact of WMLs in PD, and suggest that WMLs may exacerbate or contribute to some motor and cognitive deficits associated with PD. We review existing and emerging methods for studying white matter pathology in vivo, and propose future research directions.
Background: White matter lesions (WML) in elderly people co-occur with hypertension, depression, and cognitive impairment. Little is known about the density and distribution of WML in normal elderly people, whether they occur randomly in the aging brain or tend to cluster in certain areas, or whether patterns of WML aggregation are linked to clinical symptoms.
Objectives: To describe patterns of WML distribution in a large representative population of elderly people using non-inferential cluster analysis; and to determine the extent to which such patterns are associated with clinical symptomatology.
Method: A population sample of 1077 elderly people was recruited. Multiple analysis of correspondence followed by automatic classification methods was used to explore overall patterns of WML distribution. Correspondence was then sought between these patterns and a range of cerebrovascular, psychiatric, and neurological symptoms.
Results: Three distinct patterns of spatial localisation within the brain were observed, corresponding to distinct clusters of clinical symptoms. In particular WML aggregation in temporal and occipital areas was associated with greater age, hypertension, late onset depressive disorder, poor global cognitive function, and overall WML frequency.
Conclusions: WML localisation is not random in the aging brain, and their distribution is associated with age and the presence of clinical symptoms. Age differences suggest there may be patterns of progression across time; however, this requires confirmation from longitudinal imaging studies.
White matter lesions (WML) and brain atrophy are important biomarkers in stroke and dementia. Stroke lesions, either acute or old, symptomatic or silent, are common in older people. Such stroke lesions can have similar signals to WML and cerebrospinal fluid (CSF) on magnetic resonance (MR) images, and may be classified accidentally as WML or CSF by MR image processing algorithms, distorting WML and brain atrophy volume from the true volume. We evaluated the effect that acute or old stroke lesions at baseline, and new stroke lesions occurring during follow-up, could have on measurement of WML volume, cerebral atrophy and their longitudinal progression.
We used MR imaging data from patients who had originally presented with acute lacunar or minor cortical ischaemic stroke symptoms, recruited prospectively, who were scanned at baseline and about 3 years later. We measured WML and CSF volumes (ml) semi-automatically. We manually outlined the acute index stroke lesion (ISL), any old stroke lesions present at baseline, and new lesions appearing de novo during follow-up. We compared baseline and follow-up WML volume, cerebral atrophy and their longitudinal progression excluding and including the acute ISL, old and de novo stroke lesions. A non-parametric test (Wilcoxon's signed rank test) was used to compare the effects.
Among 46 patients (mean age 72 years), 33 had an ISL visible on MR imaging (median volume 2.05 ml, IQR 0.88–8.88) and 7 of the 33 had old lacunes at baseline: WML volume was 8.54 ml (IQR 5.86–15.80) excluding versus 10.98 ml (IQR 6.91–24.86) including ISL (p < 0.001). At follow-up, median 39 months later (IQR 30–45), 3 patients had a de novo stroke lesion; total stroke lesion volume had decreased in 11 and increased in 22 patients: WML volume was 12.17 ml (IQR 8.54–19.86) excluding versus 14.79 ml (IQR 10.02–38.03) including total stroke lesions (p < 0.001). Including/excluding lacunes at baseline or follow-up also made small differences. Twenty-two of the 33 patients had tissue loss due to stroke lesions between baseline and follow-up, resulting in a net median brain tissue volume loss (i.e. atrophy) during follow-up of 24.49 ml (IQR 12.87–54.01) excluding versus 24.61 ml (IQR 15.54–54.04) including tissue loss due to stroke lesions (p < 0.001). Including stroke lesions in the WML volume added substantial noise, reduced statistical power, and thus increased sample size estimated for a clinical trial.
Failure to exclude even small stroke lesions distorts WML volume, cerebral atrophy and their longitudinal progression measurements. This has important implications for design and sample size calculations for observational studies and randomised trials using WML volume, WML progression or brain atrophy as outcome measures. Improved methods of discriminating between stroke lesions and WML, and between tissue loss due to stroke lesions and true brain atrophy are required.
White matter disease; Infarcts; Lacunes; Atrophy; Magnetic resonance imaging
Background: Cerebral white matter lesions (WML), evident on CT and MRI brain scans, are histopathologically heterogeneous but associated with vascular risk factors and thought mainly to indicate ischemic damage. There has been disagreement over their clinical prognostic value in predicting conversion from mild cognitive impairment (MCI) to dementia.
Methods: We scrutinised and rated CT and MRI brain scans for degree of WML in a memory clinic cohort of 129 patients with at least 1 year of follow-up. We examined the relationship between WML severity and time until conversion to dementia for all MCI patients and for amnestic (aMCI) and non-amnestic (naMCI) subgroups separately.
Results: Five-year outcome data were available for 87 (67%) of the 129 patients. The proportion of patients converting to dementia was 25% at 1 year and 76% at 5 years. Patients with aMCI converted to dementia significantly earlier than those with naMCI. WML severity was not associated with time to conversion to dementia for either MCI patients in general or aMCI patients in particular. Among naMCI patients, there was a tendency for those with a low degree of WML to survive without dementia for longer than those with a high degree of WML. However, this was not statistically significant.
Conclusions: MCI subtype is a significant independent predictor of conversion to dementia, with aMCI patients having higher risk than naMCI for conversion throughout the 5-year follow-up period. WML severity does not influence conversion to dementia for aMCI but might accelerate progression in naMCI.
survival analysis; conversion; amnestic; non-amnestic; white matter lesions; dementia; Alzheimer's disease; cerebrovascular disease
Type 2 diabetes mellitus has been associated with brain atrophy and cognitive decline, but the association with ischaemic white matter lesions is unclear. Previous neuroimaging studies have mainly used semiquantitative rating scales to measure atrophy and white matter lesions (WMLs). In this study we used an automated segmentation technique to investigate the association of type 2 diabetes, several diabetes-related risk factors and cognition with cerebral tissue and WML volumes.
Subjects and methods
Magnetic resonance images of 99 patients with type 2 diabetes and 46 control participants from a population-based sample were segmented using a k-nearest neighbour classifier trained on ten manually segmented data sets. White matter, grey matter, lateral ventricles, cerebrospinal fluid not including lateral ventricles, and WML volumes were assessed. Analyses were adjusted for age, sex, level of education and intracranial volume.
Type 2 diabetes was associated with a smaller volume of grey matter (−21.8 ml; 95% CI −34.2, −9.4) and with larger lateral ventricle volume (7.1 ml; 95% CI 2.3, 12.0) and with larger white matter lesion volume (56.5%; 95% CI 4.0, 135.8), whereas white matter volume was not affected. In separate analyses for men and women, the effects of diabetes were only significant in women.
The combination of atrophy with larger WML volume indicates that type 2 diabetes is associated with mixed pathology in the brain. The observed sex differences were unexpected and need to be addressed in further studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-007-0688-y) contains a list of members of the Utrecht Diabetic Encephalopathy Study Group, and is available to authorised users.
Brain; Diabetes mellitus type 2; Image analysis; Computer-assisted; Leukoaraiosis; Magnetic resonance imaging; White matter lesion
White matter lesions (WMLs) are associated with hypertension, an increased risk of falling, and impaired physical and cognitive performance that may affect the mechanical effect of falls.
We hypothesized that WMLs are a risk factor for hip fracture (HF). We studied a sample of 820 community-dwelling Italian persons 65 years and older from the cohort of the Progetto Veneto Anziani Study who underwent brain magnetic resonance imaging at baseline. Subjects were classified as having no lesions, focal lesions, or diffuse WMLs.
Compared with those with no lesions, participants with diffuse WMLs were older, reported more falls, and had worse physical and cognitive performance, all factors implicated in the causal pathway to HF. During 9 years of follow-up, 51 HFs occurred. Hip fracture risk associated with diffuse WMLs markedly differed between participants younger than 80 years vs those 80 years and older. After adjustment among participants younger than 80 years, diffuse WMLs compared with no lesions were associated with a 2.7-fold (95% confidence interval, 1.1-7.1) increase in the risk of HF. Focal lesions were not statistically significantly associated with an increased risk of HF in the same age group (hazard ratio, 2.0; 95% confidence interval, 0.6-7.6). No associations between diffuse WMLs, focal lesions, and HF were evident among participants 80 years and older, possibly because of the limited sample size.
White matter lesions represent an independent risk factor for HF in persons younger than 80 years. Older persons with diffuse WMLs should be considered candidates for multifactorial interventions aimed at reducing the risk of falling and fractures.
This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A. 137 depressed and 94 nondepressed subjects age 60 years or older were enrolled. Standard clinical evaluations were performed on all subjects and blood samples obtained for genotyping. 1.5T MRI was obtained at baseline and approximately two years later. These scans were processed using a semi-automated segmentation process which allowed for the calculation of WML volume at each time point. Statistical models tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume, and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without hypertension. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene-gene or gene-depression interactions were observed. Our results parallel previously observed gender differences of the relationship between other renin-angiotensin system polymorphisms and hypertension. Further work is needed to determine if these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and if antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.
MRI; Major Depressive Disorder; Volumetric Study; Cerebrovascular Disease; Renin-Angiotensin System; Genetic Polymorphisms
Limited evidence exists on the relationships between severity of white-matter lesions (WMLs) and cerebral hemodynamics in patients without major cerebral artery disease. To examine changes of cerebral blood flow (CBF), oxygen metabolism, and vascular reserve capacity associated with severity of WML in patients with lacunar stroke, we used a positron emission tomography (PET). Eighteen lacunar patients were divided into two groups according to the severity of WMLs, assessed by Fazekas classification; grades 0 to 1 as mild WML group and grades 2 to 3 as severe WML group. Rapid dual autoradiography was performed with 15O-labeled gas-PET followed by 15O-labeled water-PET with acetazolamide (ACZ) challenge. Compared with the mild WML group, the severe WML group showed lower CBF (20.6±4.4 versus 29.9±8.2 mL/100 g per minute, P=0.008), higher oxygen extraction fraction (OEF) (55.2±7.4 versus 46.7±5.3%, P=0.013), and lower cerebral metabolic rate of oxygen (CMRO2) (1.95±0.41 versus 2.44±0.42 mL/100 g per minute, P=0.025) in the centrum semiovale. There were no significant differences in the ACZ reactivity between the two groups (48.6±22.6% versus 42.5±17.2%, P=0.524). Lacunar patients with severe WMLs exhibited reduced CBF and CMRO2, and increased OEF in the centrum semiovale. The ACZ reactivity was preserved in both patients with severe and mild WMLs in each site of the brain.
acetazolamide challenge; centrum semiovale; cerebrovascular reactivity; ischemic stroke; leukoaraiosis
White matter lesions (WMLs) are a common finding in patients with dementia. This study investigates the relationship between WMLs, hyperphosphorylated tau (P-tau) in cerebrospinal fluid (CSF) and apolipoprotein E (APOE) ε4 genotype in prodromal Alzheimer's disease (AD).
Baseline levels of tau, P-tau and β-amyloid 1-42 in CSF, the presence of WMLs in the brain, and the APOE genotype were ascertained in 159 patients with mild cognitive impairment (MCI) and 38 cognitively healthy controls.
After 5.7 years, 58 patients had developed AD. In this group, patients with normal levels of CSF P-tau had higher levels of WMLs in the parietal regions than those with pathological P-tau levels (p < 0.05). Also, patients without APOE ε4 alleles had more WMLs in the parietal lobes than those with at least one allele (p < 0.05). MCI patients with pathological P-tau levels and parietal WMLs showed a greater risk of developing AD than those with just one of the two pathological parameters.
We suggest that WMLs in parietal lobes and tau pathology likely have independent but synergistic effects on the reduction of the cognitive reserve capacity of the brain. In patients with a more low-grade AD pathology, WMLs in the parietal lobes might increase the risk of developing dementia.
Alzheimer's disease; Dementia; Cerebrospinal fluid; White matter lesions; Follow-up studies
Fluid attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI) techniques have been widely used to evaluate white matter (WM) alterations associated with aging, dementia and cerebral vascular disease. The relationship between FLAIR detected WM lesions (WML) and DTI detected WM integrity changes, however, remains unclear. To investigate this association, voxelwise correlations between 4 Tesla DTI and FLAIR images from elderly subjects were performed by relating WML volume and intensity in FLAIR to fractional anisotropy (FA) and mean diffusivity (MD) in DTI. Significant DTI-FLAIR correlations were found in regions overlapping with the WML of moderate intensities in FLAIR. No significant correlations were detected in periventricular regions where the FLAIR intensities are particularly high. The findings are consistent with a transitional model for WM degeneration from normal WM to cerebrospinal fluid (CSF). The results show that the correlation between DTI and FLAIR disappears when the FLAIR intensity of WML reaches its maximum at a certain lesion severity, and that the correlations may remerge with reversed signs when the lesion severity is further increased. These results suggest that the different stages of WM degeneration in elderly subjects can be better characterized by regional DTI-FLAIR correlations than single modality alone.
correlation analysis; diffusion tensor imaging; fluid attenuated inversion recovery; white matter degeneration; white matter lesion
To prospectively assess the relation between carotid plaque characteristics and the development of new cerebral white matter lesions (WMLs) at MRI.
Fifty TIA/stroke patients with ipsilateral 30–69% carotid stenosis underwent MRI of the plaque at baseline. Total plaque volume and markers of vulnerability to thromboembolism (lipid-rich necrotic core [LRNC] volume, fibrous cap [FC] status, and presence of intraplaque hemorrhage [IPH]) were assessed. All patients also underwent brain MRI at baseline and after one year. Ipsilateral cerebral WMLs were quantified with a semiautomatic method.
Mean WML volume significantly increased over a one-year period (6.52 vs. 6.97 mm3, P = 0.005). WML volume at baseline and WML progression did not significantly differ (P>0.05) between patients with 30–49% and patients with 50–69% stenosis. There was a significant correlation between total plaque volume and baseline ipsilateral WML volume (Spearman ρ = 0.393, P = 0.005). There was no significant correlation between total plaque volume and ipsilateral WML progression. There were no significant associations between LRNC volume and WML volume at baseline and WML progression. WML volume at baseline and WML progression did not significantly differ between patients with a thick and intact FC and patients with a thin and/or ruptured FC. WML volume at baseline and WML progression also did not significantly differ between patients with and without IPH.
The results of this study indicate that carotid plaque burden is significantly associated with WML severity, but that there is no causal relationship between carotid plaque vulnerability and the occurrence of WMLs.
The determinants of cerebral complications of type 2 diabetes are unclear. The present study aimed to identify metabolic and vascular factors that are associated with impaired cognitive performance and abnormalities on brain MRI in patients with type 2 diabetes.
The study included 122 patients and 56 controls. Neuropsychological test scores were divided into five cognitive domains and expressed as standardised z values. Brain MRI scans were rated for white matter lesions (WML), cortical and subcortical atrophy, and infarcts. Data on glucose metabolism, vascular risk factors and micro- and macrovascular disease were collected.
Patients with type 2 diabetes had more cortical (p < 0.001) and subcortical (p < 0.01) atrophy and deep WML (p = 0.02) than the control group and their cognitive performance was worse. In multivariate regression analyses within the type 2 diabetes group, hypertension (p < 0.05) and a history of vascular events (p < 0.01) were associated with worse cognitive performance, while statin use was associated (p < 0.05) with better performance. Retinopathy and brain infarcts on MRI were associated with more severe cortical atrophy (both p < 0.01) and statin use with less atrophy (p < 0.05). Insulin level and brain infarcts were associated with more severe WML and statin use with less severe WML (all p < 0.05).
Type 2 diabetes is associated with modest impairments in cognition, as well as atrophy and vascular lesions on MRI. This ‘diabetic encephalopathy’ is a multifactorial condition, for which atherosclerotic (macroangiopathic) vascular disease is an important determinant. Chronic hyperglycaemia, hyperinsulinaemia and hypertension may play additional roles.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-007-0792-z) contains details of the Utrecht Diabetic Encephalopathy Study Group, which are available to authorised users.
Brain atrophy; Brain MRI; Cerebral complications; Cognitive performance; Diabetic encephalopathy; Metabolic risk factors; Neuropsychological investigation; Type 2 diabetes mellitus; Vascular risk factors; White matter lesions
Population-based studies have investigated the relation between β-amyloid levels in cerebrospinal fluid or plasma and white matter lesions (WMLs). However, these circulating levels of β-amyloid in cerebrospinal fluid or plasma may not reliably reflect the actual degree of amyloid present in the brain. Therefore, we investigated the relation between WMLs and β-amyloid plaques and amyloid angiopathy in brain tissue. WML on MRI or CT were rated in 28 nondemented patients whose neuroimaging was available prior to death. β-amyloid in plaques and arterioles were immunohistochemically stained and quantified in postmortem brain necropsies. WMLs were present in 43% of the total population. Both cortex and periventricular region showed no differences for β-amyloid deposition in either plaques or blood vessel walls in patients with WMLs compared to those without WMLs. Thus, our results indicate that there is no relation between the degree of WMLs and β-amyloid deposition in the brain.
Objective: To investigate whether the extent of white matter lesions (WML) on fluid attenuated inversion recovery (FLAIR) MRI sequences is an independent risk factor for recurrent stroke, and to document the pattern of acute cerebral infarcts using diffusion weighted imaging (DWI) in patients with different severities of WML.
Methods: In a prospective cohort study, 228 consecutive stroke patients were studied between 1999 and 2001 in a community hospital. The severity of WML was graded as 0 (no WML), 1 (mild), 2 (moderate), or 3 (severe) according to the FLAIR appearances. DWI was used to document the location and size of the infarct.
Results: 31 patients had grade 0 WML, 69 had grade 1, 59 had grade 2, and 69 had grade 3. Age was independently associated with WML on logistic regression analysis (p = 0.0001). Acute cerebral infarcts in deep white matter were correlated with increasing severity of WML. On a median follow up of 23.0 months, life table analysis showed that recurrent stroke was related to the severity of WML (recurrence rate 7.8% in grade 0, 9.3% in grade 1, 17.7% in grade 2, 43.7% in grade 3; p = 0.0001). Survival was reduced in patients with severe WML (p = 0.0068). A Cox proportional hazards model showed WML to be predictive of recurrent stroke (p = 0.000, hazard ratio = 4.177 (95% confidence interval, 2.038 to 8.564)) and also for survival (p = 0.040, hazard ratio = 2.021 (1.032 to 3.960)).
Conclusions: Patients with severe leukoaraiosis have increased risk of deep subcortical stroke and a higher risk of recurrent stroke.
The influence of organic brain changes on the development of depression in the elderly is uncertain. Cross-sectional studies, most often from clinical samples, report associations with brain atrophy and cerebrovascular disease, while longitudinal population studies have given mixed results. Our aim was to investigate whether cortical atrophy and white matter lesions (WMLs) on computed tomography (CT) predict occurrence of depression in the elderly. This is a prospective population-based study with 5-year follow-up. The baseline sample included 525 elderly subjects, aged 70–86 years, without dementia or major depression, with a score on the Mini-Mental State Examination above 25, and without dementia at follow-up. Cortical atrophy and WMLs were evaluated at baseline using CT. The main outcome measure was development of major or minor depression at follow-up according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, as evaluated using neuropsychiatric examinations and hospital discharge registers. Logistic regression was used to estimate risk. Over the period of 5 years, 20 individuals developed major and 63 minor depression. Presence of temporal lobe atrophy (odds ratio (OR)=2.81, 95% confidence interval (CI) 1.04–7.62) and moderate-to-severe WMLs (OR=3.21, 95% CI 1.00–10.26) independently predicted major, but not minor, depression after controlling for various confounders. Other brain changes did not predict occurrence of depression. Our findings suggest that temporal lobe atrophy and WMLs represent relatively independent and complementary pathways to major depression in the elderly. This may have implications for prevention, as both neurodegeneration and cerebrovascular disease have been related to preventable factors.
depression; elderly; brain atrophy; white matter lesions; population; longitudinal; aging/geriatrics; imaging, clinical or preclinical; epidemiology; depression, unipolar/bipolar; brain atrophy; longitudinal; white matter lesions; depression; population
This study is to investigate the association between single and combined vascular brain changes (white matter lesions [WMLs], lacunar infarctions) and the cognitive domains of memory, processing speed, and motor function in the elderly adults.
In a sample of 268 participants aged 65–83 years of the MEMO (Memory and Morbidity in Augsburg Elderly) population-based study in Augsburg, Germany, cerebral magnetic resonance imaging (MRI) was performed and a detailed neuropsychological test battery applied. Analysis of covariance determined the effects of vascular brain changes on domains of cognitive functioning.
Strong associations of large WMLs and of MRI-defined lacunar infarction with three different domains of cognitive function even after adjustment for age, gender, and education were found. The combined occurrence of both lesions affected about one in 10 participants and was associated with a strong decrease in cognitive function in all domains. The difference between the groups with only one lesion type (either large WMLs or MRI-defined infarction) and participants affected by both was significant in the domains of processing speed and memory, even after adjustment for important confounders such as age, gender, education, and comorbidities. The effects of both lesion types on cognitive function were not more than additive.
Our study shows that both large WMLs and MRI-defined lacunar infarction contribute to impairments in different cognitive domains. The results suggest that their combined occurrence is associated with stronger reductions in cognitive function than each of the two brain lesion types alone.
White matter lesions; Brain infarcts; Cognitive function; Elderly
The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been linked to unipolar major depressive disorder (MDD) and MRI hyperintensities. We examined the relationship between the MTHFR C677T polymorphism (C677T) and a) geriatric depression, b) MRI hyperintense lesion volume, and c) neurocognitive test performance.
Duke University Medical Center.
Depressed (N=178) and comparison (N=85) elderly subjects.
Subjects had blood drawn to assess MTHFR genotype, were imaged by MRI to determine their white (WML) and gray (GML) matter hyperintense lesion volume, and assessed using a comprehensive neurocognitive battery evaluating multiple domains of function. Linear regression models were fit to test the effect of genotype, a depression by genotype interaction, and an age by genotype interaction on both hyperintense lesion volume measures and neurocognitive task performance.
The MTHFR C677T genotype by age interaction term was significantly associated with MRI WML volume (p=0.0175), however this relationship was no longer statistically significant when WML volumes underwent a log transformation to produce a more normal distribution. The 677T allele was neither more frequent in depressed subjects nor associated with either gray matter hyperintensity volume or neurocognitive test performance.
MTHFR genotype affects the relationship between age and WML volume, where individuals who carry the 677T allele exhibit greater WML volume by age, although this relationship should be verified given the failure to replicate the finding using transformed WML volumes. Genotype was not related to GML volume, cognitive function, or presence of depression, although demographic differences could account for this negative finding.
MTHFR polymorphism; depression; white matter lesion; folate; homocysteine; elderly