Diffusion-weighted magnetic resonance imaging for assessment of lung lesions: repeatability of the apparent diffusion coefficient measurement.

PURPOSE: To establish repeatability of apparent diffusion coefficients (ADCs) acquired from free-breathing diffusion-weighted magnetic resonance imaging (DW-MRI) in malignant lung lesions and investigate effects of lesion size, location and respiratory motion. METHODS: Thirty-six malignant lung lesions (eight patients) were examined twice (1- to 5-h interval) using T1-weighted, T2-weighted and axial single-shot echo-planar DW-MRI (b = 100, 500, 800 s/mm(2)) during free-breathing. Regions of interest around target lesions on computed b = 800 s/mm(2) images by two independent observers yielded ADC values from maps (pixel-by-pixel fitting using all b values and a mono-exponential decay model). Intra- and inter-observer repeatability was assessed per lesion, per patient and by lesion size (> or <2 cm) or location. RESULTS: ADCs were similar between observers (mean ± SD, 1.15 ± 0.28 × 10(-3) mm(2)/s, observer 1; 1.15 ± 0.29 × 10(-3) mm(2)/s, observer 2). Intra-observer coefficients of variation of the mean [median] ADC per lesion and per patient were 11% [11.4%], 5.7% [5.7%] for observer 1 and 9.2% [9.5%], 3.9% [4.7%] for observer 2 respectively; inter-observer values were 8.9% [9.3%] (per lesion) and 3.0% [3.7%] (per patient). Inter-observer coefficient of variation (CoV) was greater for lesions <2 cm (n = 20) compared with >2 cm (n = 16) (10.8% vs 6.5% ADCmean, 11.3% vs 6.7% ADCmedian) and for mid (n = 14) vs apical (n = 9) or lower zone (n = 13) lesions (13.9%, 2.7%, 3.8% respectively ADCmean; 14.2%, 2.8%, 4.7% respectively ADCmedian). CONCLUSION: Free-breathing DW-MRI of whole lung achieves good intra- and inter-observer repeatability of ADC measurements in malignant lung tumours. KEY POINTS: • Diffusion-weighted MRI of the lung can be satisfactorily acquired during free-breathing • DW-MRI demonstrates high contrast between primary and metastatic lesions and normal lung • Apparent diffusion coefficient (ADC) measurements in lung tumours are repeatable and reliable • ADC offers potential in assessing response in lung metastases in clinical trials.

Darwin v. 2.0: an interpreted computer language for the biosciences.

MOTIVATION: We announce the availability of the second release of Darwin v. 2.0, an interpreted computer language especially tailored to researchers in the biosciences. The system is a general tool applicable to a wide range of problems. RESULTS: This second release improves Darwin version 1.6 in several ways: it now contains (1) a larger set of libraries touching most of the classical problems from computational biology (pairwise alignment, all versus all alignments, tree construction, multiple sequence alignment), (2) an expanded set of general purpose algorithms (search algorithms for discrete problems, matrix decomposition routines, complex/long integer arithmetic operations), (3) an improved language with a cleaner syntax, (4) better on-line help, and (5) a number of fixes to user-reported bugs. AVAILABILITY: Darwin is made available for most operating systems free of char ge from the Computational Biochemistry Research Group (CBRG), reachable at http://chrg.inf.ethz.ch. CONTACT: darwin@inf.ethz.ch

Stress and course of disease in multiple sclerosis.

In this prospective study, 96 healthy controls and 101 multiple sclerosis patients were followed up for as many as 6 years, and self-reported stressful events and health status were assessed. The authors evaluated (a) whether patients reported more stressful life events than healthy controls and (b) the bidirectional relationship between stress and functional deterioration among patients. Healthy controls reported more life events than patients, Odds ratio (OR) = 1.13, p < .0001; and this relationship was attributable to healthy controls' reporting more neutral/positive events than patients. A bidirectional relationship was confirmed between stress and illness: there was an increased risk of disease progression when rate of reported stressful events was higher, OR = 1.13, p < .0003, and an increased risk of reported stressful events when rate of disease progression was higher, OR = 2.13, p < .0001. There were no differences in reported stress by level of baseline disability. The authors concluded that multiple sclerosis patients demonstrate a vicious cycle between stress and disease progression.

The development, standardization, and initial validation of the Chicago Multiscale Depression Inventory.

Current self-report depression scales may overestimate depression symptoms in medical patients by including items measuring symptoms inherent to many medical conditions. They may therefore reflect a patient's medical rather than psychological state. We present the Chicago Multiscale Depression Inventory (CMDI), a factorially derived self-report depression scale that includes Mood, Evaluative, and Vegetative subscales. The CMDI and its subscales were designed to be used separately or combined; we posit that the nonvegetative CMDI subscales are the most accurate means of examining depression in medical patients. In this study we outline the development, standardization, and initial validation of the CMDI, a multistep process that required a total sample of 1,062 adults. We show the CMDI and each of its subscales to be internally consistent, reliable, and valid. Confirmatory factor analysis supports the CMDI factor structure. Finally, we report standardization scores for each of the CMDI scales, derived from an age-, race- and gender-stratified standardization sample of 420 adults.

Executive functions in multiple sclerosis: an analysis of temporal ordering, semantic encoding, and planning abilities.

Previous studies have consistently demonstrated impairments in conceptual reasoning and set-shifting abilities in patients with multiple sclerosis (MS). Other executive functions have been less frequently examined. We compared 44 MS patients and 48 demographically matched controls on a temporal-ordering and semantic-encoding task and on a test of planning (Tower of Hanoi). Compared with controls, MS patients experienced deficient semantic encoding and planning but unimpaired temporal-order memory. For both tasks, post hoc analyses indicated that chronic-progressive MS patients contributed most to the group differences. A combination of poor planning and slowed information-processing speed was hypothesized to have contributed to MS patients' impaired Tower of Hanoi performance. Further research is needed to explore the possible relationship between semantic-encoding and planning deficits in MS and social and occupational disabilities.

Mood disturbance versus other symptoms of depression in multiple sclerosis.

We administered the Multiscale Depression Inventory (MDI) and the Beck Depression Inventory (BDI) to 84 multiple sclerosis (MS) patients, 101 patients diagnosed with major depression and 87 nonmedical, nonpsychiatric controls. The MDI consists of three separate depression scales measuring mood, vegetative, and evaluative symptoms. We found that: (a) MS patients did not significantly differ from the controls in mood symptoms, (b) the depression prevalence rate in MS patients was significantly lower when measured by the mood scale (17.7%) than by the BDI (30.5%) or MDI total score (26.6%), and (c) MS patients showed significantly less mood disturbance than a non-MS comparison group matched on BDI measured depression severity. We suggest that the inclusion of nonmood symptoms in self-report depression scales may artificially raise both prevalence rates and severity ratings of MS related depression and that the most valid measure of depression in MS is mood disturbance.

Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis.

Conceptual reasoning deficits are common in patients with multiple sclerosis (MS) and are typically associated with focal lesions involving the frontal lobes. In this study, we predicted that MS patients with frontal white matter lesions (MS-F) would be more impaired on a standard conceptual reasoning task (Wisconsin Card Sorting Test; WCST) than patients with minimal frontal lesions (MS-NF), even if the total cerebral lesion area (TLA), measured from MRI, was equivalent across groups. We subdivided 43 definite MS patients into three groups based on MRI findings: seven in the MS-F group (mean TLA = 41.4 cm2) and seven in the MS-NF group (mean TLA = 50.0 cm2); 29 MS patients served as a low lesion burden control group (MS-C; mean TLA = 6.4 cm2). The groups did not differ with regard to demographic and illness characteristics. Although the three subgroups obtained comparable scores on a measure of global cognitive functioning (verbal intelligence), the MS-F group achieved significantly fewer categories and made more total errors on the WCST than did the MS-NF and MS-C groups. The MS-F group made significantly more perseverative responses than the MS-C group and nonsignificantly more than the MS-NF group. These results suggest that the pattern of cognitive decline in MS is a function of the location of demyelinating lesions within the cerebral hemispheric white matter. Finally, we supplement the group study results with a case report of an MS patient who was studied serially with MRI and cognitive testing.

Automatic memory processes in patients with multiple sclerosis.

To better understand the nature of the memory deficit in patients with multiple sclerosis, we designed a study to compare automatic vs effortful memory processes. Forty-one patients with definite multiple sclerosis and 45 demographically matched normal control subjects were administered two tasks designed to assess both automatic (monitoring frequency and modality) and effortful (free and cued-recall) processing. Results indicated that patients with multiple sclerosis, as expected, were significantly impaired on memory measures requiring effort, but performed normally on automatic measures. Performance on the memory indexes did not correlate with self-reported depression. The implications of these findings for delineating the locus of the memory impairment in multiple sclerosis is discussed.

Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction.

Previous frequency estimates of cognitive dysfunction in multiple sclerosis have ranged from 54 to 65 percent. These studies may overestimate the frequency in the general MS population, since the patients in these studies were recruited from clinic populations. In the present study, we administered a comprehensive neuropsychological test battery to 100 community-based MS patients and 100 demographically matched healthy controls. Of 31 cognitive test indices examined, 48 MS patients and five controls were impaired on four or more test indices, yielding an overall frequency rate of 43% for the MS group. The pattern of cognitive decline was not uniform: MS patients were more frequently impaired on measures of recent memory, sustained attention, verbal fluency, conceptual reasoning, and visuospatial perception, and less frequently impaired on measures of language and immediate and remote memory. We developed a brief (20-minute) screening battery empirically by selecting the four most sensitive test indices from the comprehensive battery. The brief battery yielded a sensitivity value of 71% and a specificity value of 94% in discriminating cognitively intact from impaired MS patients, as defined by the comprehensive battery. Cognitive impairment was not significantly associated with illness duration, depression, disease course, or medication usage, but was significantly (albeit weakly) correlated with physical disability.

Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning.

We designed a study to assess the specific contribution of cognitive dysfunction to multiple sclerosis patients' problems in daily living. Based on the results of a comprehensive neuropsychological test battery, we classified 100 MS patients as either cognitively intact (N = 52) or cognitively impaired (N = 48). In addition to a neurologic examination, MS patients completed questionnaires on mood and social functioning, underwent a comprehensive in-home occupational therapy evaluation, and were rated by a close relative or friend regarding specific personality characteristics. While there were no significant differences between the two groups on measures of physical disability and illness duration, patients in the cognitively impaired group were less likely to be working, engaged in fewer social and avocational activities, reported more sexual dysfunction, experienced greater difficulty in performing routine household tasks, and exhibited more psychopathology than cognitively intact patients. These findings suggest that cognitive dysfunction is a major factor in determining the quality of life of patients with MS.

Cerebral disconnection in multiple sclerosis. Relationship to atrophy of the corpus callosum.

Left ear suppression to dichotically presented verbal stimuli has been observed in patients with multiple sclerosis (MS). Rubens and coworkers have suggested that a disconnection of the auditory callosal pathways may account for this finding. To examine this proposal, we compared the performance of 28 MS patients with significant corpus callosum atrophy (CCA) on midsagittal magnetic resonance scans, 16 MS patients without significant CCA, and 64 demographically matched normal control subjects on two laterality tasks: verbal dichotic listening (consonant-vowel syllables) and tachistiscopic object-naming latency. Results indicated that left ear suppression was found only in the MS patients with CCA. Likewise, patients in the MS group with CCA were slow in responding to stimuli presented in the left visual field; this effect was not observed in patients without CCA. These findings support the hypothesis that efficiency of cross-callosal information flow is reduced in MS patients with CCA.

Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis.

Previous research has suggested that cerebral lesions observed on magnetic resonance imaging (MRI) of MS patients are clinically "silent." We examined the validity of this assertion by correlating neuropsychological test performance with MRI findings in 53 MS patients. We used a semiautomated quantitation system to measure three MRI variables: total lesion area (TLA), ventricular-brain ratio (VBR), and size of the corpus callosum (SCC). Stepwise multiple regression analyses indicated that TLA was a robust predictor of cognitive dysfunction, particularly for measures of recent memory, abstract/conceptual reasoning, language, and visuospatial problem solving. SCC predicted test performance on measures on mental processing speed and rapid problem solving, while VBR did not independently predict cognitive test findings. These findings suggest that cerebral lesions in MS produce cognitive dysfunction and that MRI may be a useful predictor of cognitive dysfunction.

Neuropsychological test findings in subjects with leukoaraiosis.

Focal periventricular white-matter changes (leukoaraiosis) have been identified incidentally on brain imaging in normal healthy individuals and more commonly in the elderly and in hypertensive individuals. It has been suggested that leukoaraiosis represents the early stages of Binswanger's leukoencephalopathy, a dementing process thought to be related to hypertensive cerebrovascular disease. To test this hypothesis, extensive neuropsychological tests were administered to 50 consecutive normotensive, middle-aged, healthy volunteers. Ten subjects (20%) had white-matter changes on magnetic resonance scans; 40 subjects (80%) had normal scans. The differences observed on neuropsychological testing between subjects with and without leukoaraiosis were not significant. While this study argues against a link between leukoaraiosis and dementia, prospective longitudinal studies are needed to determine the value of leukoaraiosis in predicting future cognitive decline.