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Biomedical subjects

F Barkhof

Publications and source records attributed to F Barkhof.

At least 37 records · Page 2Linked to original sources
PubMed2006

Classification of multiple sclerosis patients by latent class analysis of magnetic resonance imaging characteristics.

BACKGROUND: Disease heterogeneity is a major issue in multiple sclerosis (MS). Classification of MS patients is usually based on clinical characteristics. More recently, a pathological classification has been presented. While clinical subtypes differ by magnetic resonance imaging (MRI) signature on a group level, a classification of individual MS patients based purely on MRI characteristics has not been presented so far. OBJECTIVES: To investigate whether a restricted classification of MS patients can be made based on a combination of quantitative and qualitative MRI characteristics and to test whether the resulting subgroups are associated with clinical and laboratory characteristics. METHODS: MRI examinations of the brain and spinal cord of 50 patients were scored for 21 quantitative and qualitative characteristics. Using latent class analysis, subgroups were identified, for whom disease characteristics and laboratory measures were compared. RESULTS: Latent class analysis revealed two subgroups that mainly differed in the extent of lesion confluency and MRI correlates of neuronal loss in the brain. Demographics and disease characteristics were comparable except for cognitive deficits. No correlations with laboratory measures were found. CONCLUSIONS: Latent class analysis offers a feasible approach for classifying subgroups of MS patients based on the presence of MRI characteristics. The reproducibility, longitudinal evolution and further clinical or prognostic relevance of the observed classification will have to be explored in a larger and independent sample of patients.

Adult↗
PubMed2006

Cerebral white matter abnormalities in 6p25 deletion syndrome.

Submicroscopic deletion of the terminal part of the short arm of chromosome 6, including 6p25, leads to developmental retardation, hearing impairment, ocular dysgenesis, and dysmorphic features. We diagnosed 3 patients referred because of white matter abnormalities of unknown origin. MR imaging showed multifocal areas of abnormal signal and enlarged perivascular spaces in the cerebral white matter that were stable during follow-up. Multifocal white matter abnormalities are most commonly seen in static, nonmetabolic encephalopathies, including chromosomal abnormalities.

Abnormalities, Multiple↗
PubMed2006

Voxel-based analysis of quantitative T1 maps demonstrates that multiple sclerosis acts throughout the normal-appearing white matter.

BACKGROUND AND PURPOSE: Disease activity in normal-appearing white matter (NAWM) in multiple sclerosis (MS) has been demonstrated in vivo with T1 relaxation time measurements. We aimed to investigate the spatial distribution of T1 increases in MS NAWM without a priori selection of specific regions. METHODS: Whole-brain quantitative T1 maps were measured in 67 patients with one of the 3 main clinical types of MS (13 primary progressive [PP], 36 relapsing-remitting [RR], and 18 secondary progressive [SP]) and in 23 healthy control subjects. After registration to standard space and segmentation of NAWM, the maps were analyzed by using voxel-based analyses with a cluster-based corrected P threshold of .05. RESULTS: Group mean T1 relaxation times throughout NAWM increased when going from control subjects to PP to RR to SP MS. In the RR and SP MS groups, the T1 increases compared with control subjects were significant throughout the NAWM, without apparent preference for specific brain regions. In RR MS, 16% of NAWM voxels displayed a significant increase in T1 compared with control subjects, and in SP, this fraction was 49%. The comparison between RR MS and the subsequent phase SP MS revealed that, in these patients, disease progression occurs throughout the NAWM. In patients with PP MS, the spatial extent of significant T1 increases is limited. There were no correlations with clinical disability scales or brain volume in a substantial fraction of voxels. CONCLUSION: This study demonstrates that in patients with RR MS and SP MS, NAWM disease processes have no regional preferences but can occur throughout the brain.

Adult↗
PubMed2006

Normal-appearing white matter changes vary with distance to lesions in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) disease processes in normal-appearing white matter (NAWM) may be different close to MR-visible lesions than farther from these lesions. We aimed to investigate the relationship of NAWM changes to the distance to the lesions. METHODS: We measured B(1)-corrected T1 and magnetization transfer ratio (MTR) maps in 63 patients with MS (11 primary progressive, 34 relapsing-remitting, 18 secondary progressive). We used histogram analyses to assess the global properties of lesions, of 4 consecutive 1-mm pixel layers of NAWM around the lesions, and of distant NAWM located at least 4-mm from lesions in all directions. In 22 healthy controls, we measured white matter MTR and T1 histograms. Histogram parameters were statistically analyzed by using a linear mixed model. RESULTS: The first and second NAWM pixel layers around the lesions had a significantly lower MTR histogram peak position than distant NAWM, whereas T1 histogram peak position was similar between all types of NAWM. Furthermore, MTR histograms of distant NAWM were statistically indistinguishable from those of control white matter, whereas T1 histograms of distant NAWM had significantly decreased peak height for relapsing-remitting MS and secondary progressive MS and significantly increased peak position for secondary progressive MS. CONCLUSION: Our results may suggest that axonal damage and demyelination in NAWM mainly arise as a secondary result of visible lesions, with the largest effect close to these lesions. NAWM disease farther from the lesions may be mainly characterized by subtle blood-brain barrier damage, with leakage of fibrinogen into the parenchyma and microplaque formation, processes that are detected with T1 but not with MTR.

Adult↗
PubMed2005

Hippocampal atrophy on MRI in frontotemporal lobar degeneration and Alzheimer's disease.

BACKGROUND: Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer's disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD). OBJECTIVE: To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer's disease, using volumetry and a visual rating scale. METHODS: 42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non-fluent aphasia), 103 patients with Alzheimer's disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy. RESULTS: Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer's disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer's disease. No significant hippocampal atrophy was detected in non-fluent progressive aphasia. CONCLUSIONS: Hippocampal atrophy is not only a characteristic of Alzheimer's disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.

Aged↗
PubMed2005

Predicting gadolinium enhancement status in MS patients eligible for randomized clinical trials.

BACKGROUND: Gadolinium enhancement is often used in randomized clinical trials to evaluate the efficacy of new drugs in multiple sclerosis (MS). Knowledge about predictors of enhancement status is important for the selection of patients for MRI monitored trials. METHODS: Data from 17 trials were available in anonymized format through the Sylvia Lawry Centre for MS Research. In an open part containing 1,328 (non primary progressive) patients, two logistic regression analyses were explored, including demographic, clinical, and MRI predictors. The authors examined the area under the curve (AUC) and the increase in positive predictive value (PPV). The final selection of models was validated in a closed part of 848 comparable patients. RESULTS: Age at onset, disease duration, and disease course (CIS/RR/SP) were important predictors from the multivariate models. Further, a multivariate model including T2 burden of disease was more predictive than one with only clinical predictors (AUC 0.719 vs 0.625, p < 0.001). For the model with T2 burden of disease, the PPV was 66.8%, compared to 58.5% for the model without (a priori chance 46.4%). These findings were unequivocally confirmed in the closed part of the database. CONCLUSION: Gadolinium status can be predicted by a set of baseline variables, certainly when T2 burden of disease is included. These findings may benefit the design and statistical power of future randomized clinical trials.

Adult↗
PubMed2005

Long-term clinical outcome of primary progressive MS: predictive value of clinical and MRI data.

The authors sought to identify clinical and MRI predictors of outcome in primary progressive multiple sclerosis (PPMS). Clinical and MRI assessments were performed at baseline and 2 and 5 years (clinical only). At baseline, disease duration, expanded disability status scale (EDSS) and brain volume predicted outcome. Adding short-term change variables, baseline EDSS, changes in T2* lesion load and cord area, and number of new lesions were predictive. Clinical and MRI variables predict long-term outcome in PPMS.

Atrophy↗
PubMed2005

Patterns of enhancing lesion evolution in multiple sclerosis are uniform within patients.

BACKGROUND: Histopathologic studies suggest that lesion development differs between patients with multiple sclerosis (MS), but that all lesions appear similar within patients. It is unclear whether the same applies to the evolution of lesions on T1-weighted MRI. OBJECTIVE: To evaluate lesion evolution on MRI, comparing variance within and between patients, as well as the relationship between MRI lesion development and clinical characteristics. METHODS: In 48 patients, signal intensity at baseline and at follow-up on T1-weighted MRI of 789 newly enhancing lesions was studied in relationship with clinical data. Patients were included on the basis of showing at least five enhancing lesions that could be followed on monthly scans for 6 months. Variance component analysis and multilevel analysis were used to compare within-patient and between-patient variability. RESULTS: Although various types of lesion evolution could be observed within a single patient, between-patient variance was considerably larger than within-patient variance for MRI parameters used to describe lesion evolution, indicating that lesion evolution is a patient-specific phenomenon. Evolution of lesions in patients with secondary progressive disease more frequently followed a hypointense-hypointense pattern than in patients with relapsing-remitting disease (odds ratio 4.2). Patients with a benign disease course had more persistent isointense lesions at follow-up, whereas patients with aggressive disease had more hypointense lesions. CONCLUSION: Lesion evolution on MRI appears to be a patient-specific phenomenon, although the outcome seems to vary according to the phase and severity of the disease.

Central Nervous System↗
PubMed2005

Corpus callosum size correlates with asymmetric performance on a dichotic listening task in healthy aging but not in Alzheimer's disease.

Alzheimer's disease (AD) involves not only gray matter but also white matter pathology, as reflected by atrophy of the corpus callosum (CC). Since decreased CC size may indicate reduced functional interhemispheric connectivity, differences in callosal size may have cognitive consequences that may become specifically apparent in neuropsychological tasks that tap hemispheric laterality. In the present study, we examined callosal functioning with a dichotic listening task in 25 Alzheimer patients, 20 healthy elderly and 20 healthy elderly with subjective memory complaints. We found decreased performance, increased ear asymmetry, and decreased callosal size in the AD group compared to healthy elderly. As expected, in the healthy elderly, we found significant negative correlations between ear asymmetry and callosal size, specifically in the anterior and posterior callosal subareas. While the association with the posterior subareas (isthmus and splenium) points at involvement of temporal areas mediating language processing, the association with the anterior subarea (the rostrum and genu) points at involvement of frontal areas mediating attention and executive functions. Remarkably however, in contrast to the healthy elderly, callosal size was not related to ear asymmetry in the AD group. The absence of an association between callosal atrophy and ear asymmetry implies that other pathological processes, next to reduced callosal functioning, attribute to ear asymmetry in AD. Difficulties to attend specifically to the left ear during dichotic listening in some of the AD patients, points at decreased attention and executive functions and suggests that pathology of specifically the frontal areas is involved.

Aged↗
PubMed2005

Treatment with laquinimod reduces development of active MRI lesions in relapsing MS.

BACKGROUND: Laquinimod is a novel immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability, and efficacy on MRI lesions of two different doses of laquinimod compared with placebo in patients with relapsing MS. METHODS: In this multicenter, double-blind, randomized trial, patients with relapsing MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks. Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment. The primary efficacy variable was the cumulative number of active lesions over 24 weeks. Safety measures included adverse events, physical examination, and laboratory variables. RESULTS: Of 256 screened patients, 209 were randomized (67 to 74 patients per group) in 20 centers. There was a significant difference between laquinimod 0.3 mg and placebo for the primary outcome measure (mean cumulative number of active lesions reduced by 44%). In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced (52%). No differences with respect to clinical variables (relapses, disability) were found. The safety profile was favorable; there were no clinical signs of undesired inflammatory manifestations. CONCLUSION: Oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.

Administration, Oral↗
PubMed2005

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Aged↗
PubMed2005

MR spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter.

Quantitative single-voxel, short echo-time (TE) MR spectroscopy (MRS) was used to determine metabolite concentrations in the cerebral normal-appearing white matter (NAWM) of 76 patients with multiple sclerosis (MS), and the WM of 25 controls. In NAWM of all MS disease types (primary progressive, relapsing-remitting, and secondary progressive), the concentration ratio of total N-acetyl-aspartate (tNAA)/total creatine (tCr) was decreased compared to controls. Remarkably, this was entirely due to an increase of tCr in MS patients, whereas there was no difference in tNAA. Separate quantification of the two tNAA components yielded no significant difference in NAA (N-acetyl-aspartate), while the concentration of NAAG (N-acetyl-aspartyl-glutamate) was slightly-but significantly-elevated in MS patients. Myo-inositol (Ins) was strongly increased in MS patients, and choline-containing compounds (Cho) were mildly increased. There were no metabolite differences between disease types, and no correlations with disability scores. The results are supported by measures of spectral quality, which were identical for patients and controls. In conclusion, MS NAWM containing very little perilesional tissue is characterized by increased glial cell numbers (increase of Ins and tCr) without evidence of axonal dysfunction (normal NAA). Further studies should elucidate the mechanism underlying increased NAAG in MS NAWM.

Adolescent↗
PubMed2005

Progression of cerebral white matter lesions in Alzheimer's disease: a new window for therapy?

BACKGROUND: White matter lesions (WML) are a risk factor for Alzheimer's disease. Progression of WML is associated with vascular factors and cognitive decline in population based studies but the course of WML is unknown in Alzheimer's disease. OBJECTIVE: To investigate the prevalence and risk factors for progression of WML in Alzheimer's disease. SUBJECTS: 38 patients with Alzheimer's disease for whom blood pressure measurements and sequential brain MRIs were available. METHODS: The proportion of patients with progression of WML was calculated, stratified on baseline absence or presence of WML by analysis of variance. Odds ratios (OR) were calculated by age and sex adjusted logistic regression to quantify the relation between blood pressure and progression of WML. RESULTS: About 25% of the patients showed progression of WML. Patients with WML at baseline had significantly more progression than those without WML at baseline (adjusted mean difference = 1.2; 95% confidence interval (CI), 0.6 to 1.8). Diastolic blood pressure (DBP) was particularly related to progression of WML (OR = 5.9 (95% CI, 1.0 to 37.6) per 10 mm Hg DBP, p = 0.05). CONCLUSIONS: Alzheimer's disease patients with WML at baseline are at risk for rapid progression of WML. WML may offer a potential treatment target in this disease to ameliorate the rate of cognitive decline.

Aged↗
PubMed2005

Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study.

OBJECTIVE: To assess the associations of medial temporal lobe atrophy (MTA) and white matter hyperintensities (WMH) with cognitive function in a large group of independently functioning elderly people. METHODS: Data were drawn from the multicentre, multinational leukoaraiosis and disability (LADIS) project which is studying prospectively the role of WMH as an independent predictor of the transition to disability in non-disabled elderly people. In all, 639 participants were enrolled in the LADIS study. For the present analysis, data on 581 subjects were available. Cognitive function was assessed by the mini-mental state examination (MMSE). Visual ratings of WMH and MTA were undertaken on magnetic resonance images (MRI). RESULTS: The presence of either severe WMH or MTA was associated with a modest but non-significant increase in frequency of mild cognitive deficits (severe WMH: odds ratio (OR) = 1.9 (95% confidence interval (CI), 1.0 to 3.7); MTA present: OR = 1.5 (95% CI, 0.8 to 2.8)). However, subjects with the combination of MTA and severe WMH had a more than fourfold increase in frequency of mild cognitive deficits (OR = 4.1 (95% CI, 2.3 to 7.4)). Analysis of variance with post hoc Bonferroni t tests showed that subjects with both MTA and severe WMH performed worse on MMSE than those with either no MRI abnormality or a single MRI abnormality (p<0.05). CONCLUSIONS: These results provide further evidence for the combined involvement of both Alzheimer type pathology and vascular pathology in the earliest stages of cognitive decline and suggest an additive effect of WMH and MTA.

Aged↗
PubMed2005

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Adult↗
PubMed2004

MRI and CT in the diagnosis of vascular dementia.

Neuroimaging is necessary to demonstrate cerebrovascular disease (CVD) and is therefore an important examination in vascular dementia (VaD) and vascular cognitive impairment (VCI). MRI is preferred over CT because multiple planes and sequences are needed to assess various types of pathology in relevant regions. These protocols allow differentiation of VaD from other forms of dementia and sometimes identify specific underlying disorders. Different diagnostic criteria for VaD exist but the NINDS-AIREN criteria are widely used in controlled clinical trials in VaD. These criteria have relatively low sensitivity but are highly specific and include radiological requirements. The radiological criteria have poor interobserver agreement. In general, the radiological portion of the diagnostic criteria for VaD needs revision and refinement to include bone fide cases of VaD not currently accepted by imaging rules, and for the early detection of patients with VCI.

Cerebral Amyloid Angiopathy↗