Matter Changes In Patients Research Articles

Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression

Early emotional stress is associated with a life-long burden of risk for later depression and stressful life events contribute to the development of depressive episodes. In this study we investigated whether childhood stress is associated with structural brain alterations in patients with major depression (MD). Forty-three patients with MD and 44 age as well as gender matched healthy control subjects were investigated using high-resolution magnetic resonance imaging (MRI). Region of interest analysis of the hippocampus, whole brain voxel-based morphometry (VBM) and assessment of childhood stress was carried out. Significantly smaller hippocampal white matter and prefrontal gray matter volume was observed in patients with MD compared to healthy controls. In particular left hippocampal white matter was smaller in patients, who had emotional childhood neglect, compared to those without neglect. For male patients this effect was seen in the left and right hippocampus. Moreover, physical neglect during childhood affected prefrontal gray matter volume in healthy subjects. Both emotional neglect and brain structural abnormalities predicted cumulative illness duration and there was a significant interaction between emotional neglect and prefrontal volumes as well as hippocampal white matter on the illness course. Childhood neglect resulted in hippocampal white matter changes in patients with major depression, pronounced at the left side and in males. Most interestingly, childhood stress and brain structure volumes independently predicted cumulative illness course. Subjects with both, structural brain changes and childhood emotional neglect seem to be at a very high risk to develop a more severe illness course.

Progressive gray matter changes in first episode schizophrenia: A 4-year longitudinal magnetic resonance study using VBM

Schizophrenia is a disabling illness, characterized by a heterogeneous course including clinical deterioration and poor outcome. Accumulating findings in schizophrenia suggest that it might involve two pathophysiologic processes, one early in life (neurodevelopmental), and one after onset of the illness (neurodegenerative). Longitudinal imaging studies after onset of the illness may help to clarify these pathophysiological aspects of schizophrenia, but so far, probably due to methodological differences, there have been no conclusive results. The present study sets out to investigate longitudinal gray matter changes in patients with first-episode schizophrenia relative to healthy subjects over the first 4 years of the illness and the relation of gray matter changes in patients with functional outcome, using an objective automatic method not biased to one particular structure to analyze gray matter changes. Methods We included 28 first-episode neuroleptic-naïve patients with DSM-IV diagnosis of schizophreniform disorder or schizophrenia, and 17 controls. 15 patients and 11 controls completed the longitudinal study and were reevaluated after four years. Gray matter changes over time were measured with voxel-based morphometry (VBM) using SPM5. Functional outcome was measured with the global assessment functioning scale (GAF). Results Excessive decrease in gray matter was found in patients as compared to healthy individuals in the left superior temporal gyrus and right orbitofrontal gyrus, and excessive increase in the bilateral lingual gyrus and right cuneus. Additionally, gray matter changes in patients in the left lingual gyrus, right insula and right cerebellum, were inversely related to functional outcome ( p < 0.001 uncorrected at voxel level, p < 0.05 family-wise-error corrected at cluster level). Conclusions There are differing longitudinal gray matter changes in patients with schizophrenia during the first years of the illness as compared to healthy individuals. Some progressive gray matter changes in patients are related to functional outcome.

End-Stage Renal Disease: In Vivo Diffusion-Tensor Imaging of Silent White Matter Damage

To characterize and compare regional differences in anisotropy in patients with end-stage renal disease (ESRD) and in control subjects to understand the effect of ESRD and hemodialysis on the microstructures of white matter. This study was approved by an institutional review board; written informed consent was obtained. From March 2007 to December 2007, 34 patients (16 men, 18 women; mean age, 40.0 years; range, 26-50 years) with ESRD who were undergoing dialysis and 35 control subjects (16 men, 19 women; mean age, 38.3 years; range, 25-49 years) were enrolled. There was no significant sex or age difference between the ESRD and control groups. By using a 1.5-T imager, fractional anisotropy (FA) data obtained at diffusion-tensor magnetic resonance (MR) imaging (echo-planar imaging, 33 directions; b value, 1000 sec/mm(2)) and at T2-weighted fluid-attenuated inversion recovery (FLAIR) MR imaging of the bilateral parietal, frontal, occipital, and temporal lobe white matter, as well as the genu and splenium of the corpus callosum, were compared. The Cognitive Abilities Screening Instrument (CASI) was administered to all participants at imaging. The ESRD group had significantly lower FA values in all regions than the control group. FA values were generally lower in older patients and in those who had been undergoing dialysis for a longer duration. Duration of dialysis was more often than age found to be correlated with differences in FA values. In areas in which there was a significant correlation between age, duration, and FA values, the regression coefficients were greater for those who had been undergoing dialysis longer than for those who were older. Patients with ESRD had significantly lower CASI scores than control subjects (P = .03). There were no significant group differences in FLAIR values (P = .25-.89). Changes in FA values may be used to follow-up white matter changes in patients with ESRD who are undergoing maintenance dialysis. http://radiology.rsnajnls.org/cgi/content/full/2523080484/DC1.

Cingulum fiber diffusivity and CSF T-tau in patients with subjective and mild cognitive impairment

Diffusion tensor imaging (DTI) and CSF biomarkers are useful diagnostic tools to differentiate patients with mild cognitive impairment (MCI) from normal controls, and may help predict conversion to dementia. Total Tau protein (T-tau) and DTI parameters are both markers for axonal damage, thus it is of interest to determine if DTI parameters are associated with elevated CSF T-tau levels in patients with cognitive impairment. For this purpose, patients with subjective cognitive impairment (SCI) and MCI were recruited from a university based memory clinic. Regions of interest were used to determine fractional anisotropy (FA), radial diffusivity (DR) and axial diffusivity (DA) in known white matter tracts in patients with MCI (n=39) and SCI (n=8) and 26 cognitively healthy controls. Significant lower FA and higher DR values were observed in patients with pathological vs. patients with normal CSF T-tau levels and vs. controls in left posterior cingulum fibers. T-tau values were negatively correlated with FA and positively correlated with DR values in the posterior cingulum fibers. Cingulum fiber diffusivity was related to T-tau pathology in SCI/MCI patients and altered DR may suggest that loss of myelin contributes to early white matter changes in patients at risk of developing Alzheimer's disease (AD).

Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma

Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.

Whole-Brain Voxel-Based Morphometry in Kallmann Syndrome Associated with Mirror Movements

There are 2 main hypotheses concerning the cause of mirror movements (MM) in Kallmann syndrome (KS): abnormal development of the primary motor system, involving the ipsilateral corticospinal tract; and lack of contralateral motor cortex inhibitory mechanisms, mainly through the corpus callosum. The purpose of our study was to determine white and gray matter volume changes in a KS population by using optimized voxel-based morphometry (VBM) and to investigate the relationship between the abnormalities and the presence of MM, addressing the 2 mentioned hypotheses. T1-weighted volumetric images from 21 patients with KS and 16 matched control subjects were analyzed with optimized VBM. Images were segmented and spatially normalized, and these deformation parameters were then applied to the original images before the second segmentation. Patients were divided into groups with and without MM, and a t test statistic was then applied on a voxel-by-voxel basis between the groups and controls to evaluate significant differences. When considering our hypothesis a priori, we found that 2 areas of increased gray matter volume, in the left primary motor and sensorimotor cortex, were demonstrated only in patients with MM, when compared with healthy controls. Regarding white matter alterations, no areas of altered volume involving the corpus callosum or the projection of the corticospinal tract were demonstrated. The VBM study did not show significant white matter changes in patients with KS but showed gray matter alterations in keeping with a hypertrophic response to a deficient pyramidal decussation in patients with MM. In addition, gray matter alterations were observed in patients without MM, which can represent more complex mechanisms determining the presence or absence of this symptom.

Neural Networks in Schizophrenia

Back to table of contents Previous article Next article EditorialFull AccessNeural Networks in SchizophreniaJohn G. Csernansky M.D.Will J. Cronenwett M.D.John G. Csernansky M.D.Search for more papers by this authorWill J. Cronenwett M.D.Search for more papers by this authorPublished Online:1 Aug 2008https://doi.org/10.1176/appi.ajp.2008.08050700AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail As methods for high-resolution MRI continue to develop, our understanding of changes in brain structure in patients with psychiatric disorders improves. In patients with schizophrenia, decreases in the gray matter volume of a variety of cortical and subcortical brain regions have been repeatedly observed (1) . Two articles in this issue of the Journal add to this literature and go further by strengthening the hypothesis that schizophrenia involves abnormalities in specific cortical-subcortical networks. Ellison-Wright et al. (2) present a meta-analysis of MRI studies that reveals different patterns of structural changes in first-episode and chronic schizophrenia. Adapting a technique developed to combine data from functional MRI studies (3) , the authors evaluated group differences in specific brain regions in reference to a three-dimensional coordinate system. The result of this adaptation, called anatomical likelihood estimation, adds to a growing literature on probabilistic approaches to neuroanatomical computation (4) . In patients with first-episode schizophrenia, Ellison-Wright et al. found evidence for decreased gray matter volume in the hippocampus, the caudate nucleus, the thalamus (mediodorsal nucleus), the insula, the anterior cingulate gyrus, the inferior frontal gyrus, and the cerebellum. Subcortical changes were similar in patients with chronic schizophrenia, but cortical changes were even more extensive. As Ellison-Wright et al. note, this pattern of abnormality implicates a neural circuit originating with limbic input to the striatum, then the thalamus, and finally to the prefrontal and cingulate cortex ( Figure 1 ). Abnormalities of thalamocortical circuitry have previously been implicated in schizophrenia, particularly in reference to the pathophysiological concept of cognitive dysmetria (5) . Figure 1. Gray Matter Deficits and Thalamocorticostriatal Circuit Dysfunction in Schizophrenia aa The diagram on the left illustrates the circuit pathways. On the right is a diagrammatic representation of thalamocorticostriatal circuits superimposed on regions of gray matter showing signal decrease in both first-episode schizophrenia (yellow) and chronic schizophrenia (red). The thalamus (blue triangle) sends thalamocortical projections to the cortex (blue arrow). Cortical regions project (green arrow) to the caudate (pink circle) and then back to the thalamus (orange arrow). Components of these circuits show anatomical changes in schizophrenia, with the caudate head showing gray matter deficits in first-episode schizophrenia and more widespread cortical changes in chronic schizophrenia. The thalamus shows gray matter deficits in both first-episode and chronic schizophrenia. Also in this issue, Friedman et al. (6) report on their use of diffusion tensor imaging to examine the pattern of white matter changes in patients with first-episode and chronic schizophrenia. Using fractional anisotropy (FA) to assess the integrity of white matter connections (7) , they found evidence in first-episode patients for decreased connectivity only in the inferior longitudinal fasciculus (at the trend level), while chronic patients showed a broader pattern of white matter disturbances ( Figure 2 ). Figure 2. Regions of Fractional Anisotropy (FA) Reductions in Schizophrenia aa Relative to healthy comparison subjects, patients with first-episode schizophrenia showed trend-level FA reductions in the left and right inferior longitudinal fasciculus. Patients with chronic schizophrenia showed significant FA reductions in the right forceps minor and the left inferior longitudinal fasciculus. ILF=inferior longitudinal fasciculus; GCC=genu of corpus callosum; SCC=splenium of corpus callosum. The results of Friedman’s study, to date the largest to directly examine FA in first-episode and chronic schizophrenia patients, suggest a number of intriguing interpretations. As they note, one explanation may be that pathological white matter abnormalities may be present but too subtle to detect with current imaging methods in first-episode schizophrenia. Alternatively, white matter changes may develop as the disease process of schizophrenia progresses.Taken together, the results of these two studies provide strong support for the hypothesis that schizophrenia involves abnormalities in networks of brain regions. They further suggest that such abnormalities may be progressive in at least some patients. If the “progression” hypothesis is confirmed in future studies, we must redouble our efforts at early and effective intervention for this potentially disabling disorder.Address correspondence and reprint requests to Dr. Csernansky, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 446 E. Ontario, Suite 7-200, Chicago, IL 60611; [email protected] (e-mail). Editorial accepted for publication May 2008 (doi: 10.1176/appi.ajp.2008.08050700).Dr. Csernansky has consulted for Eli Lilly, Sanofi-Aventis, and HoustonPharma. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships. Dr. Cronenwett reports no competing interests.

Regional Grey Matter Changes in Patients With Migraine: A Voxel-Based Morphometry Study

We used voxel-based morphometry (VBM) to compare grey matter volume (GMV) between 20 migraine patients (five with aura and 15 without aura) with normal conventional magnetic resonance imaging findings and 33 healthy controls matched for age and sex. A separate analysis was also performed to delineate a possible correlation between the GMV changes and the headache duration or lifetime headache frequency. When compared with controls, migraine patients had significant GMV reductions in the bilateral insula, motor/premotor, prefrontal, cingulate cortex, right posterior parietal cortex, and orbitofrontal cortex (P < 0.001, uncorrected for multiple comparisons at a voxel level; corrected P < 0.05 after small volume corrections). All regions of the GMV changes were negatively correlated with headache duration and lifetime headache frequency (P < 0.05, Pearson's correlation test). We found evidence for structural grey matter changes in patients with migraine. Our findings of progressive GMV reductions in relation to increasing headache duration and increasing headache frequency suggest that repeated migraine attacks over time result in selective damage to several brain regions involved in central pain processing.

Excessive Brain Volume Loss Over Time in Cannabis-Using First-Episode Schizophrenia Patients

Cerebral gray matter volume reductions have been found to progress over time in schizophrenia, with larger decreases related to poorer outcome, which has also been associated with cannabis use in schizophrenia patients. Progressive gray matter changes in patients who use cannabis may be more extensive than in those who do not. Patients with recent-onset schizophrenia (N=51) and matched healthy subjects (N=31) were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion (T0) and at 5-year follow-up (T5). Nineteen patients used cannabis but no other illicit drugs; 32 patients did not use any drugs during the 5-year follow-up. At T5, clinical outcome was measured. Cumulative amount of antipsychotic medication during the interval was calculated. At T0 and T5, total brain, gray and white matter, and lateral and third ventricle volumes were measured. Univariate analysis of covariance and pairwise comparisons were performed. Schizophrenia patients showed a larger gray matter volume decrease over time than healthy subjects. They also showed larger increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis during follow-up. This decrement was significantly more pronounced in the patients who continued to use cannabis. These differences could not be attributed to outcome or baseline characteristics. First-episode schizophrenia patients who use cannabis show a more pronounced brain volume reduction over a 5-year follow-up than patients with schizophrenia who do not use cannabis. These results may help explain some of the detrimental effects of cannabis use in schizophrenia.

P,1.e.011 Positive correlation between theory of mind deficit and gray matter changes in patients with schizophrenia

p,1.e.011 Positive correlation between theory of mind deficit and gray matter changes in patients with schizophrenia

Apolipoprotein E ɛ4 allele is associated with the volume of white matter changes in patients with lacunar infarcts

The relationship between the apolipoprotein E (APOE) exon 4 polymorphism and white matter changes (WMC) in elderly subjects or patients with Alzheimer's disease is controversial. To investigate this polymorphism in relation to WMC in patients with lacunar infarcts, we prospectively observed 67 patients with acute lacunar infarct and 134 age- and sex-matched controls. Genotypes were determined using a nested polymerase chain reaction. WMC were measured quantitatively and were divided into two groups, severe and mild, with the mean volume of WMC as the cut point. Twenty-two patients (33%) had severe WMC. There was a significant difference in the distribution of APOE epsilon2, epsilon3, and epsilon4 alleles between severe and mild WMC groups (P = 0.002). The frequency of epsilon4 alleles was higher in patients with severe WMC than in those with mild WMC (25% vs. 7%, P = 0.003). These results suggest that APOE epsilon4 may exacerbate WMC in patients with lacunar infarcts. Further studies are required to confirm this finding.

IC-P-068: Diffusion tensor imaging of normal appearing white matter in MCI and AD

Structural magnetic resonance imaging (MRI) studies on mild cognitive impairment (MCI) and Alzheimer's disease (AD) have largely focused on the brain's cortical gray matter. However, cellular degeneration in cortical structures is usually accompanied by concomitant degeneration of axonal processes from these dying neurons. Pathoanatomical and imaging studies have confirmed both macroscopic and microscopic white matter changes in patients with AD. We propose that microstructural changes in subcortical brain regions should also be detectable in MCI. To examine the microstructural integrity of subcortical white mater in subjects with amnestic MCI and mild AD using diffusion tensor imaging (DTI). Elderly subjects with normal cognition (n=5), MCI (n=6) and mild AD (n=4) were recruited from our Alzheimer's Disease Research Center. Petersen criteria were used to diagnose amnestic MCI, and NINCDS–ADRDA criteria to diagnose AD. Normal appearing white matter (NAWM) was defined by normal signal intensity on standard T1–weighted, T2–weighted and FLAIR images. DTI images were acquired using a single shot, pulsed gradient, echo planar imaging protocol with twelve non–collinear gradient directions. Fractional anisotropy (FA), axial diffusivity (DA) and radial diffusivity (DR) of NAWM regions in the frontal, temporal, parietal and occipital lobes were measured and compared across the three groups using ANOVA with post–hoc Scheffe tests. Both AD and MCI subjects demonstrated significantly lower FA in frontal and temporal NAWM compared with normal control subjects (AD/MCI/normal = 0.28/0.28/0.35 in frontal NAWM, F=6.61, df =2, p<0.01; AD/MCI/normal = 0.41/0.44/0.52 in temporal NAWM, F=14.2, df =2, p<0.001). Radial diffusivity (DR) was significantly greater in AD and MCI subjects compared to normal controls in parietal NAWM (AD/MCI/normal = 0.62/0.60/0.56, F=11.9, df=2, p<0.001). Even in NAWM, we found evidence for microstructural changes in AD and MCI. These changes were present in brain regions serving higher cortical functions (frontal, temporal and parietal lobes), but not in regions serving primary functions (occipital lobe), and are consistent with a hypothesized loss of axonal processes in affected regions.

Depressive symptoms and white matter changes in patients with dementia

The aim of the present study was to investigate if depressive symptoms in demented patients are associated with white matter changes (WMCs) in the brain. WMCs are frequently found in patients with dementia, as well as among elderly nondemented patients with depressive symptoms. However, it is less established whether or not WMCs are related to depressive symptoms in demented patients. 67 (26 men, 41 women) patients with primary degenerative dementia (Alzheimer's disease, frontotemporal dementia), vascular dementia (VaD), or mixed Alzheimer/VaD dementia were included in the study. The patients were young-old (mean 68.1, SD 7.3). All patients underwent a standardized examination procedure and MRI of the brain. The degree of WMCs was visually rated, blindly. Depressive symptoms were rated according to the Gottfries-Bråne-Steen scale (anxiety, fear-panic, depressed mood). No significant relationship was found between WMCs and depressive symptoms in the demented patients. The possible involvement of WMCs in the pathogenesis of depressive symptoms in dementia is unclear. A link between disruptions of frontal-subcortical pathways, due to WMCs, and depressive symptomatology in dementia has been hypothesised from earlier findings, which would imply common elements of pathogenesis for depressive symptomatology and cognitive impairment in dementia. However, the results of the present study do not add further support to this hypothesis.

Coping with Multiple Virulence Factors: Which Is Most Important?

Despite being a time when genomics and proteomics are becoming popular modes of scientific inquiry, most microbe-centric researchers continue to use reductionism to study virulence by identifying the microbial characteristics associated with virulence and characterizing each independently. Reductionism is a critical and remarkably powerful tool for determining the contribution of a single virulence factor to the overall virulence phenotype. However, the approach has the following limitation: most pathogenic microbes possess numerous attributes that contribute to virulence, and this virulence is a microbial trait that is expressed only in a susceptible host. Unfortunately, it is often very difficult, if not impossible with current technology, to study combinations of virulence factors simultaneously, especially at the molecular level. Hence, new tools are needed to study the larger picture of virulence in a pathogenic organism and to better understand how the host and microbe interact. And while computer modeling, genomics, and proteomics contribute much to the larger picture of virulence, a more accessible method is available via multivariate statistics. Consider two microbes: Cryptococcus neoformans and Bacillus anthracis. For C. neoformans, at least a half-dozen cellular attributes have been associated with virulence, including the polysaccharide capsule, melanin production, phospholipase secretion, mating factor, laccase, and urease [1]. Similarly, for B. anthracis the poly-D-glutamic acid capsule, lethal toxin, edema factor, and anthrolysin are each associated with the virulence phenotype [2,3]. Since immune responses to virulence factors often negate the virulence phenotype, vaccines often target virulence factors, as is the case for both C. neoformans and B. anthracis. In addition, the highly successful vaccines to Streptococcus pneumoniae and Haemophilus influenzae type B elicit antibodies to their polysaccharide capsules. In the same way, toxoid vaccines protect against tetanus and diphtheria by eliciting neutralizing antibody responses. Consequently, an investigator may want to prioritize the relative importance of virulence factors that contribute to the overall virulence phenotype, especially when designing new vaccines or antimicrobial drugs. However, to our knowledge, no methods have been developed to accomplish this. Fortunately, the goal of prioritizing virulence factors for an individual microbe is similar to problems that have been encountered and solved in other disciplines where investigators have had to confront phenomena caused by multiple components. Sophisticated statistical methods have been developed to approach these problems and are applicable to the problem of microbial virulence. A commonly used statistical tool is multivariate linear regression analysis (MLRA), which has found a myriad of uses in the social sciences, biology, and medicine. For example, MLRA has been used to study aspects of school readiness such as the prediction of learning-related skills in children [4], factors that contribute to smoking in youths [5], the degree and location of white matter changes in patients with Alzheimer disease [6], and whether hand lead contamination is associated with blood lead contamination [7]. MLRA simultaneously assesses the relationships of many independent variables to one dependent variable, and can easily be used to examine the relative contribution of microbial virulence factors to virulence. In fact, MLRA can be used to rank virulence factors in disease importance. There are three different kinds of MLRA: standard multiple regression, sequential (hierarchical) regression, and statistical regression [8]. In standard multiple regression, all independent variables are entered together so that the relative contribution of each independent variable to the dependent variable is assessed at the same time. Thus, standard regression illustrates how much of the dependent variable is explained by each of the independent variables at once. In hierarchical regression, the independent variables are entered in different steps in a specific order, with the order of entry resulting from theoretical or logical importance. Thus, hierarchical regression allows the investigator to examine the unique contribution of each independent predictor variable to the variance in the dependent variable, while taking into account the contribution of previously identified independent variables. In statistical regression, the independent variables are entered or removed in different steps, in an order that is specified by statistical criteria. Thus, statistical regression is useful for selecting which independent variables best predict the dependent variable when there is no theoretical rationale for a priori prioritization [8]. Depending on how much information is available on certain microbial virulence factors, and the focus of the research question, investigators can use any or all of the different kinds of MLRA. One limitation of MLRA is the need for an adequate sample size. A general rule of thumb is that ten data points

Bilateral thalamic gray matter changes in patients with restless legs syndrome

Restless legs syndrome (RLS) is a common neurological disorder of a primary unpleasant sensation with an urge to move the legs occurring at rest. The etiology of idiopathic RLS is unknown and structural cerebral abnormalities have so far not been detected. We studied 51 right-handed patients with an idiopathic restless legs syndrome in two independent samples ( Regensburg RLS-group: n = 28, Munich RLS-group: n = 23) and compared them to 51 sex- and age-matched healthy volunteers. High-resolution T1-weighted magnetic resonance imaging (MRI) of each subject was obtained and analyzed using voxel-based morphometry (VBM) to detect regionally specific differences in gray matter between patients and controls. Conjunction analysis was used to combine results from both centers. In patients with idiopathic RLS, both study centers observed independently a bilateral gray matter increase in the pulvinar. In the conjunction analysis including all patients and controls from both study centers, a significant gray matter increase in the pulvinar bilaterally (right: x = 16, y = −21, z = 12, Z = 4.57; left: x = −16, y = −24, z = 12, Z = 4.10) was present. This is the first demonstration of structural changes in the brain of patients with idiopathic RLS. These changes in thalamic structures are either involved in the pathogenesis of RLS or may reflect a consequence of chronic increase in afferent input of behaviorally relevant information.

White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging

Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimer's disease using diffusion tensor magnetic resonance imaging (DT-MRI). Background: Although Alzheimer's disease pathology...

Evaluation of White Matter Anisotropy in Krabbe Disease with Diffusion Tensor MR Imaging: Initial Experience

To compare diffusion tensor magnetic resonance imaging with conventional T2-weighted imaging for evaluation of white matter changes in patients with Krabbe disease. In eight patients with Krabbe disease and eight age-matched control subjects, anisotropy maps were generated with diffusion tensor data by using echo-planar imaging with diffusion gradient encoding in six directions. Anisotropy maps and T2-weighted images were visually inspected. Relative anisotropy (RA) and normalized T2-weighted signal intensity in white matter tracts and gray matter nuclei were quantitatively compared between patients and controls (paired Student t test). Loss of diffusion anisotropy appeared on anisotropy maps as areas of decreased hyperintensity in patients with Krabbe disease. Differences in RA between Krabbe disease patients and control subjects were significant in eight of nine white matter structures studied (P =.001-.01) and in basal ganglia (P =.04). T2-weighted signal intensity was also significantly different in the same white matter structures (P =.006-.049) but not in basal ganglia. In the three patients imaged after stem cell transplantation, mean RA was between the RAs of untreated patients and control subjects. Diffusion tensor-derived anisotropy maps (a) provide a quantitative measure of abnormal white matter in patients with Krabbe disease, (b) are more sensitive than T2-weighted images for detecting white matter abnormality, and (c) may be a marker of treatment response.

Impact of white matter changes on clinical manifestation of Alzheimer's disease: A quantitative study.

There have been conflicting results involving the clinical significance of white matter changes in patients with Alzheimer's disease (AD). We studied the association between the volume of white matter hyperintensities (WMHs) on T2-weighted images and cognitive, neurological, and neuropsychiatric symptoms. The subjects were 76 AD patients who had WMHs but no obvious cerebrovascular diseases. We quantified the volume of WMHs by using fast-fluid-attenuated inversion recovery images and whole brain atrophy by using 3D spoiled gradient-echo images. Effects of WMHs and brain atrophy on dementia severity, cognitive function, neuropsychiatric disturbances, and neurological findings were examined. Whole brain atrophy was significantly associated with dementia severity and cognitive disturbances, as well as with grasp reflex and some kinds of neuropsychiatric disturbances. After we controlled for the effects of brain atrophy, duration of symptoms, and demographic factors, we found that WMH volume was not associated with global cognitive disturbances or dementia severity but was significantly associated with urinary incontinence, grasp reflex, and aberrant motor behaviors. Brain atrophy and WMH volume were not significantly correlated either before or after controlling for age, sex, education, and duration of symptoms. WMH volume was associated with hypertension, but brain atrophy was not positively correlated with any vascular risk factors. Our results support the hypothesis that WMHs in AD patients are superimposed phenomena of vascular origin. WMHs contribute to specific neurological and neuropsychiatric manifestations but not to global cognitive impairment, which is more closely associated with brain atrophy.

Effect of the Apolipoprotein E ε4 Allele on White Matter Hyperintensities in Dementia

The clinical significance of the apoE epsilon4 allele in white matter changes in patients with dementia has been a subject of debate. We studied the association between the apoE epsilon4 allele and white matter hyperintensities (WMHs) before and after control for (1) potential vascular risk factors and (2) the presence of lacunar infarcts in patients with dementia. The subjects were 131 patients with dementia who had either Alzheimer's disease or vascular dementia, or a combination of these 2 types of dementia, with or without WMHs, lacunar infarcts, or both. The association of the epsilon4 allele with WMHs was examined before and after control for age, sex, duration of symptoms, education level, severity of dementia, presence of lacunar infarcts, and potential vascular risk factors, including hypertension, diabetes mellitus, lipid disorders, smoking habit, drinking habit, and cardiac diseases. WMHs were observed in 73 (55.7%) of the patients. Neither the number of apoE epsilon4 alleles nor their presence was significantly associated with WMHs before or after control for the potential confounding factors. Multiple logistic regression analyses revealed that age, the presence of hypertension, and the presence of lacunar infarcts were independently associated with WMHs. The apoE epsilon4 allele was not associated with WMHs in patients with dementia. The fact that WMHs were significantly associated with hypertension and lacunar infarcts may indicate an ischemic origin of WMHs.

Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy. Influence of CAG repeat size on MRI findings.

To elucidate how the size of the expanded CAG repeat of the gene for dentatorubral pallidoluysian atrophy (DRPLA) and other factors affect the atrophy of the brainstem and cerebellum, and the appearance of high-intensity signals on T2-weighted MRI of the cerebral white matter of patients with DRPLA, we quantitatively analyzed the MRI findings of 26 patients with DRPLA, the diagnosis of which was confirmed by molecular analysis of the DRPLA gene. When we classified the patients into two groups based on the size of the expanded CAG repeat of the DRPLA gene (group 1, number of CAG repeat units > or = 66; group 2, number of CAG repeat units < or = 65), we found strong inverse correlations between the age at MRI and the areas of midsagittal structures of the cerebellum and brainstem in group 1 but not in group 2. Multiple regression analysis, however, revealed that both the patient's age at MRI and the size of the expanded CAG repeat correlated with the areas of midsagittal structures. Involvement of the cerebral white matter as detected on T2-weighted images was observed more frequently in patients belonging to group 2 than in group 1 patients. Furthermore it was demonstrated that high-intensity signals can be detected on T2-weighted images of the cerebral white matter of patients with a largely expanded CAG repeat (group 1) in their thirties. These results suggest that patient age as well as the size of the expanded CAG repeat are related to the degree of atrophy of the brainstem and cerebellum, and the white matter changes in patients with DRPLA.