Neurological signs in relation to white matter hyperintensity volumes in memory clinic patients.

PURPOSE: To determine the frequency of neurological signs in a memory clinic population and to explore their associations with white matter hyperintensity (WMH). METHODS: We included patients with Alzheimer disease (AD; n = 210), vascular dementia (VaD; n = 34), mild cognitive impairment (MCI; n = 86) and subjective complaints (n = 153). The presence of extrapyramidal and unilateral signs was assessed from medical charts. On MRI, WMH volumes were extracted automatically. RESULTS: Extrapyramidal signs were found in 10% and unilateral signs in 12% of the patients. Age- and sex-adjusted extrapyramidal signs occurred more often in VaD compared to patients with subjective complaints. Unilateral signs were more prevalent in all groups compared to patients with subjective complaints. Two-way analysis of variance (ANOVA) with WMH as the dependent variable showed a main effect of diagnosis (p < 0.001), but not of extrapyramidal signs (p = 0.62). In contrast, 2-way ANOVA showed main effects of diagnosis (p < 0.001) and unilateral signs (p = 0.001). Furthermore, there was an interaction between these factors (p = 0.04); if unilateral signs were present, patients with subjective complaints and VaD showed more WMH, whereas there was no relation in AD and MCI. CONCLUSION: Extrapyramidal and unilateral signs are common in memory clinic patients, but are only modestly related to WMH.

Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study.

BACKGROUND: Suppressing the antigen-presenting capacity of glial cells could represent a novel way of reducing inflammatory activity in multiple sclerosis (MS). AIMS: To evaluate the effects of fluoxetine on new lesion formation in patients with relapsing MS. METHODS: In a double-blind, placebo-controlled exploratory study, 40 non-depressed patients with relapsing remitting or relapsing secondary progressive MS were randomised to oral fluoxetine 20 mg or placebo daily for 24 weeks. New lesion formation was studied by assessing the cumulative number of gadolinium-enhancing lesions on brain MRI performed on weeks 4, 8, 16 and 24. RESULTS: Nineteen patients in both groups completed the study. The mean (SD) cumulative number of new enhancing lesions during the 24 weeks of treatment was 1.84 (2.9) in the fluoxetine group and 5.16 (8.6) in the placebo group (p = 0.15). The number of scans showing new enhancing lesions was 25% in the fluoxetine group versus 41% in the placebo group (p = 0.04). Restricting the analysis to the past 16 weeks of treatment showed that the cumulative number of new enhancing lesions was 1.21 (2.6) in the fluoxetine group and 3.16 (5.3) in the placebo group (p = 0.05). The number of patients without enhancing lesions was 63% in the fluoxetine group versus 26% in the placebo group (p = 0.02). CONCLUSIONS: This proof-of-concept study shows that fluoxetine tends to reduce the formation of new enhancing lesions in patients with MS. Further studies with this compound are warranted. TRIAL REGISTRATION: Number: ISRCTN65586975.

Lobar distribution of changes in gray matter and white matter in memory clinic patients: detected using magnetization transfer imaging.

BACKGROUND AND PURPOSE: Previous studies have shown involvement of both gray matter (GM) and white matter (WM) in mild cognitive impairment (MCI) and Alzheimer disease (AD). In this study, we assessed the lobar distribution of the GM and WM pathology over the brain and the association of lobar distribution with global cognitive decline. MATERIALS AND METHODS: Fifty-five patients with AD, 19 patients with MCI, and 43 subjects with normal cognitive function participated in this study. GM and WM were segmented on dual fast spin-echo and fluid-attenuated inversion recovery MR images. A custom template representing anatomic areas was applied. Magnetization transfer imaging (MTI) peak height and mean magnetization transfer ratio (MTR) provided measures for structural brain damage. RESULTS: Both mean MTR and MTI peak height showed that patients with AD had more structural brain damage in the GM of all lobes compared with controls. Patients with MCI had lower GM peak height compared with controls for the temporal and frontal lobe. WM peak height was lower for all lobes investigated for patients with both AD and MCI. WM mean MTR was lower in the frontal, parietal, and temporal lobes for patients with AD compared with controls. Age and both temporal GM peak height and mean MTR were the only parameters that predicted cognition. CONCLUSION: This study shows that in addition to more focal GM MTI changes in the temporal and frontal lobes, widespread WM changes are present in the earliest stages of AD. This might point to an important role for WM pathology in the earliest stage of AD.

Intracranial compartment volumes in normal pressure hydrocephalus: volumetric assessment versus outcome.

BACKGROUND AND PURPOSE: Although enlargement of the cerebral ventricles plays a central role in the diagnosis of normal pressure hydrocephalus (NPH), there are no reports on the use of volumetric assessment to distinguish between patients who respond to ventriculoperitoneal shunt surgery and those who do not. The purpose of this study is to explore the association between preoperative intracranial compartment volumes and postoperative improvement. METHODS: Twenty-six patients (17 men; mean age, 75 years [range, 54-87 years]) with a clinical or radiologic suspicion of NPH were included in the study. Gait, cognition, and bladder function were evaluated by clinical rating. MR imaging of the brain was acquired at 0.5 T and 1.5 T. Total intracranial volume, ventricular volume, brain volume, and pericerebral CSF volume were determined by volumetric assessment. Four imaging variables were determined: ventricular volume ratio, brain volume ratio, pericerebral CSF volume ratio, and the ratio of ventricular volume to pericerebral CSF volume. All patients underwent ventriculoperitoneal shunt surgery. RESULTS: Clinical follow-up was assessed 1 year after shunt surgery. No difference in the mean ventricular volume ratio, the mean brain volume ratio, the mean pericerebral CSF volume ratio, and the mean ratio between ventricular and pericerebral CSF volume was found between subjects who improved on gait or cognition or bladder function and those who did not. CONCLUSION: Volumetric assessment has no predictive value in differentiating between NPH patients who respond to ventriculoperitoneal shunt surgery and those who do not.

Measuring longitudinal white matter changes: comparison of a visual rating scale with a volumetric measurement.

BACKGROUND AND PURPOSE: Detection of longitudinal changes in white matter hyperintensities (WMH) by using visual rating scales is problematic. We compared a widely used visual rating scale with a volumetric method to study longitudinal white matter changes. METHODS: WMH were assessed with the visual Scheltens scale and a volumetric method in 100 elderly subjects aged 70-81 years for whom repetitive MR images were available with an interval of 33 (SD, 1.4) months. Reliability was determined by intraclass correlation coefficients. To examine the sensitivity of both the visual and volumetric method, we calculated Spearman rank correlations of WMH ratings and volume measurements with age. RESULTS: Reliability of the visual rating scale was good, whereas reliability of the volumetric measurement was excellent. For baseline measurements of WMH, we found weaker associations between WMH and age when assessed with the visual scale (r = 0.20, P = .045) than with the volumetric method (r = 0.31, P = .002). Longitudinal evaluation of WMH assessments showed regression in 26% of the subjects when analyzed with the visual rating scale against 12% of the subjects when using volumetric measurements. Compared with the visual rating, the correlation between progression in WMH and age was twice as high when using the volumetric measurement (r = 0.19, P = .062 and r = 0.39, P < .001, respectively). CONCLUSION: Volumetric measurements of WMH offer a more reliable, sensitive, and objective alternative to visual rating scales in studying longitudinal white matter changes.

Magnetization transfer imaging of gray and white matter in mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: To assess whether structural brain damage as detected by magnetization transfer imaging (MTI) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) is located in the gray matter (GM) and/or the white matter (WM). METHODS: Fifty-five AD patients, 19 MCI patients and 43 subjects with normal cognitive function participated in this study. GM and WM segmentations were generated from dual fast spin-echo MR images. These masks were co-registrated to MT images for volumetric MTI-analysis of the GM and WM. RESULTS: AD patients had a lower GM volume than controls. Both MCI and AD patients had more structural brain damage in both GM and WM than subjects with normal cognition. Cerebral lesion load in both GM and WM was associated with the degree of cognitive impairment. CONCLUSION: Using MTI, structural brain changes that are related to cognitive impairment could be demonstrated in both GM and WM of patients with AD and MCI. These results suggest that cerebral changes are present in GM and WM even before patients are clinically demented.

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population.

OBJECTIVE: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. METHODS: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. RESULTS: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. CONCLUSION: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

Sources of variation in multi-centre brain MTR histogram studies: body-coil transmission eliminates inter-centre differences.

OBJECT: 1. Identify sources of variation affecting Magnetisation Transfer Ratio (MTR) histogram reproducibility between-centres. 2. Demonstrate complete elimination of inter-centre difference. MATERIALS AND METHODS: Six principle sources of variation were summarised and analysed. These are: the imager coil used for radiofrequency (RF) transmission, imager stability, the shape and other parameters describing the Magnetisation Transfer (MT) pulse, the MT sequence used (including its parameters), the image segmentation methodology, and the histogram generation technique. Transmit field nonuniformity and B1 errors are often the largest factors. PLUMB (Peak Location Uniformity in MTR histograms of the Brain) plots are a convenient way of visualising differences. Five multi-centres studies were undertaken to investigate and minimise differences. RESULTS: Transmission using a body coil, with a close-fitting array of surface coils for reception, gave the best uniformity. Differences between two centres, having MR imagers from different manufacturers, were completely eliminated by using body coil excitation, making a small adjustment to the MT pulse flip angle, and carrying out segmentation at a single centre. Histograms and their peak location and height values were indistinguishable. CONCLUSIONS: Body coil excitation is preferred for multi-centre studies. Analysis (segmentation and histogram generation) should ideally be carried out at a single site.

A randomized crossover study of bee sting therapy for multiple sclerosis.

BACKGROUND: Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. METHODS: In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). RESULTS: During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. CONCLUSIONS: In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.

Fully automatic segmentation of white matter hyperintensities in MR images of the elderly.

The role of quantitative image analysis in large clinical trials is continuously increasing. Several methods are available for performing white matter hyperintensity (WMH) volume quantification. They vary in the amount of the human interaction involved. In this paper, we describe a fully automatic segmentation that was used to quantify WMHs in a large clinical trial on elderly subjects. Our segmentation method combines information from 3 different MR images: proton density (PD), T2-weighted and fluid-attenuated inversion recovery (FLAIR) images; our method uses an established artificial intelligent technique (fuzzy inference system) and does not require extensive computations. The reproducibility of the segmentation was evaluated in 9 patients who underwent scan-rescan with repositioning; an inter-class correlation coefficient (ICC) of 0.91 was obtained. The effect of differences in image resolution was tested in 44 patients, scanned with 6- and 3-mm slice thickness FLAIR images; we obtained an ICC value of 0.99. The accuracy of the segmentation was evaluated on 100 patients for whom manual delineation of WMHs was available; the obtained ICC was 0.98 and the similarity index was 0.75. Besides the fact that the approach demonstrated very high volumetric and spatial agreement with expert delineation, the software did not require more than 2 min per patient (from loading the images to saving the results) on a Pentium-4 processor (512 MB RAM).

Interaction of medial temporal lobe atrophy and white matter hyperintensities in AD.

The authors investigated the interaction between medial temporal lobe (MTL) atrophy and white matter hyperintensities (WMH) in Alzheimer disease (AD). They measured the MTL and WMH on MRI in 58 AD patients and 28 controls. MTL atrophy was associated with an increased risk of AD (OR = 6.2), but there was no significant association between WMH and AD. Moreover, there was an interaction between MTL and WMH (p = 0.045). These results suggest that vascular and Alzheimer-type pathology act in synergy in the clinical syndrome of AD.

Selective gray matter damage in neuropsychiatric lupus.

OBJECTIVE: Damage of brain parenchyma in patients with primary diffuse neuropsychiatric systemic lupus erythematosus (NPSLE) has been indicated by magnetization transfer imaging (MTI). However, the location of MTI abnormalities is unknown. This study was undertaken to assess the distribution of MTI abnormalities over gray matter (GM) and white matter (WM) in SLE patients with a history of NP symptoms without explanatory magnetic resonance imaging (MRI) evidence of focal disease. METHODS: MTI was performed in 24 female SLE patients with a history of diffuse NP symptoms and 24 healthy female controls. Magnetization transfer ratio (MTR) maps were calculated for GM and WM separately, and GM and WM MTR histograms were generated. Univariate and multivariate analyses with age as an additional covariate were performed on the histogram parameters peak location (PL), peak height (PH), and mean MTR. RESULTS: Compared with controls, significantly reduced PH (mean +/- SD 136 +/- 22 arbitrary units versus 151 +/- 13 arbitrary units) and mean MTR (33.3 +/- 1.0 percent units versus 33.6 +/- 0.5 percent units) were found in the GM of NPSLE patients (P = 0.002 and P = 0.033, respectively, in multivariate analyses). No significant differences were observed for WM MTR parameters. CONCLUSION: This is the first study to demonstrate, using MTI, that in SLE patients with a history of NP symptoms and without explanatory focal abnormalities on MRI, the GM is particularly affected. These findings support the hypothesis that neuronal injury may underlie central nervous system manifestations in NPSLE.

Different progression rates for deep white matter hyperintensities in elderly men and women.

The authors investigated the progression of white matter hyperintensities (WMHs) in a large population of elderly men and women. After 3 years of follow-up, women had accumulated approximately twice as much deep WMH (DWMH) as men. The progression of periventricular WMH was the same for men and women. Gender differences may affect the pathogenesis of DWMH, which in turn may result in different clinical consequences in women.