Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

OBJECTIVE: To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). METHODS: We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). RESULTS: In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. CONCLUSION: In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS.

Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis.

OBJECTIVE: To characterize the relationship between motor resting-state connectivity of the dorsal pre-motor cortex (PMd) and clinical disability in patients with multiple sclerosis (MS). MATERIALS AND METHODS: A total of 27 patients with relapsing-remitting MS (RR-MS) and 15 patients with secondary progressive MS (SP-MS) underwent functional resting-state magnetic resonance imaging. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Independent component analysis was used to characterize motor resting-state connectivity. Multiple regression analysis was performed in SPM8 between the individual expression of motor resting-state connectivity in PMd and EDSS scores including age as covariate. Separate post hoc analyses were performed for patients with RR-MS and SP-MS. RESULTS: The EDSS scores ranged from 0 to 7 with a median score of 4.3. Motor resting-state connectivity of left PMd showed a positive linear relation with clinical disability in patients with MS. This effect was stronger when considering the group of patients with RR-MS alone, whereas patients with SP-MS showed no increase in coupling strength between left PMd and the motor resting-state network with increasing clinical disability. No significant relation between motor resting-state connectivity of the right PMd and clinical disability was detected in MS. CONCLUSIONS: The increase in functional coupling between left PMd and the motor resting-state network with increasing clinical disability can be interpreted as adaptive reorganization of the motor system to maintain motor function, which appears to be limited to the relapsing-remitting stage of the disease.

Chronic cerebrospinal venous insufficiency and venous stenoses in multiple sclerosis.

OBJECTIVES: The traditional view that multiple sclerosis (MS) is an autoimmune disease has recently been challenged by the claim that MS is caused by chronic cerebrospinal venous insufficiency (CCSVI). Although several studies have questioned this vascular theory, the CCSVI controversy is still ongoing. Our aim was to assess the prevalence of CCSVI in Danish MS patients using sonography and compare these findings with MRI measures of venous flow and morphology. METHODS: We investigated cervical and cerebral veins in 24 patients with relapsing-remitting MS (RRMS) and 15 healthy controls, using extracranial high-resolution ultrasound colour Doppler (US-CD) and transcranial colour Doppler sonography (TCDS), as well as magnetic resonance imaging (MRI) and phase-contrast MR blood flow measurements (PC-MR) of the cervical veins. RESULTS: US-CD could not identify the left internal jugular vein (IJV) in one MS patient, other ultrasound examinations were normal in patients with MS. There was no difference in mean cross-sectional area of the IJV in MS patients compared with controls. Only one patient with MS and two healthy controls fulfilled one CCSVI criterion, and none fulfilled more than one CCSVI criterion. MR venography showed insignificant IJV stenosis (1-49%) in two patients with MS, whereas 50-69% IJV stenosis was detected in two healthy controls. There was no difference in PC-MR measurements of mean IJV blood flow between patients with MS and controls. CONCLUSION: Our results do not corroborate the presence of vascular pathology in RRMS and we found no evidence supporting the CCSVI hypothesis.

Anti-CD20 antibody therapy and risk of infection in patients with demyelinating diseases.

BACKGROUND: Anti-CD20 antibody therapy may be associated with an increased risk of infections. We therefore investigated risk factors for infection in patients with demyelinating diseases treated with anti-CD20 antibody therapy. METHODS: In this retrospective uncontrolled study, patients ever treated with anti-CD20 antibodies at an academic clinic were identified through the Danish Multiple Sclerosis Registry (DMSR). Data were collected from medical charts and the DMSR. We assessed occurrence of severe infections (requiring hospitalization), varicella zoster virus (VZV), major comorbidities and routine laboratory values for lymphocytes, IgG and IgM. RESULTS: A total of 447 patients ever treated with anti-CD20 antibody therapy were identified; of these 416 with 649 patient years of follow-up were still under therapy. In this group, seven patients had VZV infections, and 16 patients had been hospitalized with infections during up to three years of follow-up on anti-CD20 therapy. Comorbidity was recorded in 80 patients. The risk of severe infection was associated with comorbidities, higher age, longer duration of treatment, and higher Expanded Disability Status Scale (EDSS) scores. In multivariable analyses treatment duration, EDSS scores and presence of comorbidity were independently associated with risk of severe infections. Serum concentrations of IgG and IgM decreased with increasing duration of therapy but were not associated with risk of severe infections. Patients with VZV infection had lower lymphocyte counts and lower serum concentrations of IgM. In multivariable analyses only lymphocyte counts were independently associated with risk of VZV infection. CONCLUSIONS: In this retrospective study of patients treated with anti-CD20 antibodies, the risk of infections requiring hospitalization was independently associated with comorbidities, duration of treatment, and higher EDSS scores. Risk of VZV infection was independently associated with lymphopenia. Future studies investigating strategies for mitigating risk of infection in patients treated with anti-CD20 antibodies are warranted, especially for older patients, patients with higher levels of disability and for patients with a longer duration of treatment.

Increased socioeconomic burden in patients with primary progressive multiple sclerosis: A Danish nationwide population-based study.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is characterized by development of more chronic neurological manifestations from disease onset compared with relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) but the following socioeconomic consequences have never been described in a nation-wide patient population. OBJECTIVE: To determine if socioeconomic burden of PPMS is increased compared with RRMS and SPMS. METHODS: We included patients from The Danish Multiple Sclerosis Registry diagnosed between 1998 and 2015. Yearly average health costs, public transfers and earned income was calculated from the index diagnosis date, and each year in a five-year period before and after index diagnosis date, for the three patient groups. A regression model estimating the odds ratio (OR) with PPMS as the comparator, was used to analyze the differences between PPMS vs. RRMS and PPMS vs. SPMS controlling for age and sex. RESULTS: In total, 9563 MS patients were identified (1998-2015), with a characteristic distribution between different disease courses: 7012 patients with RRMS (73%), 1099 patients with PPMS (11%) and 1452 patients with SPMS (15%). Total health costs were lower in RRMS vs. PPMS (OR 0.76; 95% CI 0.74-0.78; p<0.0001) but not in SPMS vs. PPMS (OR 1.06; 95% CI 1.03-1.09; p<0.0001). Especially homecare costs were lower in RRMS vs. PPMS (OR 0.17; 95% CI 0.17-0.18; p<0.0001), less pronounced in SPMS vs. PPMS (OR 0.93; 95% CI 0.90-0.97; p = 0.0001). OR for health costs before and after diagnosis was significantly lower in RRMS vs. PPMS regarding most variables, less pronounced in SPMS vs. PPMS. CONCLUSION: This nation-wide population-based study show that socioeconomic burden is significantly higher in PPMS relative to RRMS, but less pronounced compared with SPMS.

Rate dependence of regional cerebral activation during performance of a repetitive motor task: a PET study.

Using repeated positron emission tomography (PET) measures of regional cerebral counts, we investigated the regional cortical activations induced in eight normal subjects performing eight different frequencies of fingertapping (0.5-4 Hz) with the right index finger. The task was auditorially cued and the performance recorded during the scanning procedure. Performance evaluation showed increased error rates, during fingertapping, of high and low frequencies, and the best tapping performance was measured in the midrange of frequencies. Significantly activated areas (p < 0.05) of normalized cerebral counts were located in the left sensorimotor cortex (MISI), right motor cortex, left thalamus, right insula, supplementary motor area (SMA), and bilaterally in the primary auditory cortex and the cerebellum. Statistical evaluation showed a significant (p < 0.01) and positive dependence of cerebral activation upon movement rate in the contralateral MISI. There was no significant rate dependence of cerebral activation in other activated motor areas. The SMA and the right cerebellar hemisphere showed a more uniform activation throughout the tapping frequency range. Furthermore, we found a stimulus rate dependence of cerebral activation in the primary auditory cortex. We believe that the present data provide useful information for the preparation and interpretation of future motor activation studies of normal human subjects and may serve as reference points for studies of pathological conditions.

A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS.

OBJECTIVE: To study the time-related changes in cerebral metabolic rate of glucose (CMRglc) in MS patients and to correlate these with changes in MRI lesion load and disability. BACKGROUND: Measurements of MRI lesion load and neurologic disability are used widely to monitor disease progression in longitudinal studies of MS patients, but little is known about the associated changes in cerebral neural function. METHODS: The authors studied 10 patients with clinically definite MS who underwent serial measurements of CMRglc, MRI T2-weighted total lesion area (TLA), and clinical evaluation of disability (Expanded Disability Status Scale [EDSS]) over a period of approximately 2 years (three examinations). CMRglc was calculated using PET and 18-fluorodeoxyglucose (FDG). RESULTS: The global cortical CMRglc decreased with time (p<0.001) and the most pronounced reductions of CMRglc were detected in frontal and parietal cortical areas. There was a statistically significant increase of disability (p<0.01) and TLA (p<0.05) measurements during the study, but changes in CMRglc were not correlated to changes in TLA and EDSS. CONCLUSIONS: Global cortical cerebral metabolism in MS is decreased significantly during a 2-year observation period, suggesting a deterioration of cortical activity with disease progression. The time-related changes of cortical CMRglc are statistically stronger than changes in TLA measurements and neurologic disability, and might be a useful secondary measure of treatment efficacy.

Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS.

OBJECTIVE: To study the association between the cortical cerebral metabolic rate of glucose (CMRglc), MRI T2-weighted total lesion area (TLA), cognitive dysfunction, and neurologic disability in MS. BACKGROUND: MRI lesion load is widely used in the clinical evaluation of the MS patient but little is known about the associated changes in cortical activation. METHODS: Twenty-three patients with clinically definite MS underwent measurements of CMRglc, TLA, motor evoked potentials (MEPs), and cognitive and neurologic disability. CMRglc was calculated using PET and 18-F-deoxyglucose and compared with nine normal control subjects. RESULTS: Reductions in CMRglc (p < 0.01) were found in the cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (Spearman rank correlation coefficient [SRCC] = -0.66, p = 0.001), and rCMRglc correlated with regional lesion load in all cerebral lobes (p < or = 0.05). Global cortical CMRglc and cognitive disability also correlated (SRCC = 0.58, p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance as well as TLA. There was no correlation between CMRglc and neurologic disability (Expanded Disability Status Scale) or MEP. CONCLUSION: Global and regional cortical CMRglc is reduced significantly in MS patients compared with normal control subjects. Furthermore, the CMRglc reductions correlate with TLA as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on cortical cerebral neural function.

Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis.

We wanted to assess whether intravenous immunoglobulin G (IVIG) decreases disease activity on MRI in relapsing MS. Previous trials of IVIG in relapsing-remitting MS demonstrated a reduction of acute relapses, but these studies did not include MRI. We treated 26 patients in a randomized, double-blind, crossover study of IVIG 1 g/kg daily or placebo on 2 consecutive days every month during two 6-month treatment periods. The primary end point was the number of gadolinium-enhancing lesions on monthly serial MRI. Secondary efficacy variables were the occurrence of exacerbations, clinical neurologic ratings, total MS lesion load on T2-weighted MRI, and multimodal evoked potentials. Eighteen patients completed the entire trial; eight patients did not. Twenty-one patients completed the first treatment period and at least two MRI examinations in the second treatment period and were included in the intention-to-treat analysis. On serial MRI, we observed fewer enhancing lesions per patient per scan during IVIG treatment (median, 0.4; range, 0 to 9.3) than during placebo treatment (median, 1.3; range, 0.2 to 25.7; p = 0.03). During IVIG treatment, 15 patients were exacerbation free compared with only 7 on placebo (p = 0.02). The total number of exacerbations in the IVIG period was 11 and in the placebo period, 19 (not significant). None of the remaining secondary efficacy measures were significantly different between the two treatment periods. The number of adverse events, in particular eczema, was significantly higher during IVIG therapy than during placebo treatment. These results suggest that IVIG treatment is beneficial to patients with relapsing MS.

No effect of pulsed magnetic stimulation on the blood-brain barrier in rats.

The impact of transcranial pulsed magnetic stimulation on blood-brain barrier permeability was studied in rats. An integral uptake technique was used to asses the blood-brain barrier permeability to the tracers [3H]sucrose, [14C]urea, and 36Cl-. From the arterial plasma concentration-time curve-integral the permeability surface-area products were calculated. A Dantec magnetic stimulator delivering a peak magnetic field of 1.9 T with a rise-time of 160 microseconds was used for transcranial stimulation of the rats. One group of rats had about 50-60 stimulations during the 15-min infusion of the tracers while another group was exposed to 50 magnetic stimulations a day for one week. A third group comprised the controls. No differences in permeability surface-area product were found for any of the three tracers in the rats exposed to magnetic stimulation as compared with the controls. It is concluded that with regard to blood-barrier integrity, pulsed magnetic stimulation of the brain can be regarded as safe.

An immunohistochemical localization of neuropeptide Y (NPY) in its amidated form in human frontal cortex.

The distribution of neuropeptide Y (NPY)-immunoreactive neurons was studied in human frontal cerebral cortex from surgical biopsy specimens by immunohistochemical techniques. NPY-containing neurons were identified in all cortical sublayers except sublayer I. The stained neurons were of the multipolar, bitufted, round or triangular form with dendritic and axonal processes. The immunoreactive neurons were considered to be cortical interneurons, due to their nonpyramidal form, and since their processes could be followed intracortically particularly in direction to superficial cortical layers. The NPY precursor molecule is processed to NPY by a dibasic cleavage, and NPY is further enzymatically amidated before release and receptor activation can be achieved. Antisera raised against Cys-NPY(32-36)amide recognize amidated NPY not cross-reacting with nonamidated NPY. These antisera and immunohistochemistry revealed the presence of a population of NPYamide-immunoreactive cells morphologically indistinguishable from the NPY-immunoreactive cells in the human frontal cortex. By comparing the number of immunoreactive cells in adjacent sections, it appears that the number of NPY-immunoreactive cells was higher than those immunoreactive to NPYamide. Also, the density of NPY fibers was much higher compared with the number stained with NPYamide antiserum. The present immunohistochemical study indicates that NPY in its amidated form is contained in a subpopulation of human cortical NPY-immunoreactive neurons and may participate as an active neurotransmitter/modulator within the human cerebral cortex.

[Reduced metabolism in cerebral cortex correlates with MRI changes and cognitive dysfunction in patients with disseminated sclerosis]. / Reduceret cerebralt stofskifte korrelerer med MRI-forandringer og kognitiv dysfunktion hos patienter med dissemineret sklerose.

INTRODUCTION: Magnetic resonance imaging (MRI) lesion load is widely used in the clinical evaluation of patients with multiple sclerosis (MS), but little is known about the associated changes in cortical activation. For this purpose, we studied the association between the corticocerebral metabolic rate of glucose (CMRglc) and the MRI T2-weighted total lesion area (TLA). In addition, we investigated the correlation between cognitive and neurological disability and CMRglc. METHODS: Twenty-three patients with clinically definite MS underwent measurements of the CMRglc, TLA, motor-evoked potentials (MEP), and cognitive and neurological disability. CMRglc was calculated with positron emission tomography (PET) and 18-F-deoxyglucose (FDG) and compared to that of nine healthy controls. RESULTS: A reduction in CMRglc (p < 0.01) was found in cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (rho = -0.66; p = 0.001), and rCMRglc correlated with the regional lesion load in all cerebral lobes (p < or = 0.05). Global cortical CMRglc and cognitive disability were also correlated (rho = 0.58; p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance, as well as the TLA. There was no correlation between CMRglc and neurological disability (expanded disability status scale [EDSS]) or MEP. CONCLUSION: Global and regional cortical CMRglc is significantly reduced in patients with MS compared to healthy controls. The reductions in CMRglc furthermore correlate with the TLA, as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on corticocerebral neural function.

A prospective PET study of patients with glioblastoma multiforme.

OBJECTIVE: To study the post-surgical metabolic and structural cerebral changes in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: We examined ten patients prospectively with newly diagnosed GBM. All patients were primarily treated with surgery, followed by chemotherapy (carmustine, cisplatine and etoposide) and radiotherapy. Positron emission tomography (PET) was used to measure tumor- and cerebral metabolism. CT or MRI was used to estimate tumor volume by measurements of tumor area. RESULTS: Tumor metabolism was not increased during chemotherapy (P = 0.71), but increased during radiotherapy (P = 0.01). CT/MRI showed similar results with no increase in tumor area during chemotherapy (P = 0.33) but increase during radiotherapy (P = 0.002). During the entire study, tumor metabolism and area increased evenly (P = 0.01). CONCLUSIONS: Our study did not show a gain of PET compared with structural imaging in the prospective evaluation of GBM. We found a difference in metabolic increase and tumor growth between the two treatment regimens, although this finding has limited relevance due to the design of the study.

Responsiveness of the Multiple Sclerosis Impairment Scale in comparison with the Expanded Disability Status Scale.

The Multiple Sclerosis Impairment Scale (MSIS) is a measure of accumulated deficits assessed by means of a standard neurological examination. We compared the responsiveness of the MSIS with that of the Expanded Disability Status Scale (EDSS). We reviewed 4300 records collected systematically from 1995 to 2003 and identified 534 patients who had clinically definite multiple sclerosis and had had at least two clinical assessments with a time interval of 2-5 years. The rate of deterioration was significantly higher on the MSIS than on the EDSS. The annualized change in EDSS exhibited a maximum at baseline EDSS 4 and a subsequent rapid decline at higher baseline EDSS, while the annualized change in MSIS was fairly stable over a wide middle range of baseline MSIS. The variance of the annualized change in EDSS fluctuated markedly between the baseline EDSS categories, being highest at baseline EDSS 2, while the variance of the annualized change in MSIS was stable. The study indicates that the responsiveness of the MSIS is better than that of the EDSS in terms of both magnitude and stability over the range of measurement

Standardization of facilitation of compound muscle action potentials evoked by magnetic stimulation of the cortex. Results in healthy volunteers and in patients with multiple sclerosis.

To establish the importance of standardization of the facilitation of central motor conduction measured by magnetic stimulation we studied the effect of increasing voluntary muscle contraction on the central motor conduction time (CMCT) and motor evoked potential (MEP) amplitudes for 3 upper and 2 lower limb muscles. MEPs were elicited by magnetic stimulation of the cortex and the spinal roots. Muscle force was indirectly assessed from the integrated electrical muscle activity and expressed as the root mean square (RMS) and was varied from 0 to 40% of maximal activity. The central motor conduction time (CMCT) decreased during increasing muscle contraction, reaching constant values at approximately 10-20% RMSmax. Similarly, the increases of MEP amplitude tapered off at about the same RMS level. For each muscle an optimal RMS level was defined. The shortening of the CMCTs at the optimal RMS levels were: the brachial biceps, 3.4 msec; the radial carpal flexor of the wrist, 2.7 msec; the first dorsal interosseus muscle of the hand, 2.9 msec; the anterior tibial, 4.2 msec; and the abductor hallucis, 2.4 msec. The standardizing procedure was applied to 10 patients with multiple sclerosis. The stimulus thresholds were higher in these patients compared with those of the normals. Only the CMCT reduction of the BB was significantly larger (8.1 msec) than in the controls. Using standardized facilitation the diagnostic value of the amplitudes seems to be only a little less than that of the CMCTs.

Significance of magnetic coil position in peripheral motor nerve stimulation.

The influences of coil position and coil-nerve distance on compound muscle action potentials (CMAPs), recorded from the first dorsal interosseus muscle during magnetic stimulation of the brachial segment of the ulnar nerve, were studied in 10 healthy volunteers. A 14-cm coil was held tangentially to the skin with the center overlying the nerve. Mapping of the CMAP latencies and amplitudes was made as the coil was displaced laterally in steps of 1 cm and in planes 0-3 cm from the skin surface. Stimulation with the coil center positioned 3 cm laterally to the nerve with the coil current directed proximally yielded the largest amplitudes with minimal variability and the most constant relationship to electrically evoked CMAPs. In this position the interindividual and intraindividual reproducibility of the magnetically evoked latencies were at least as good as those of electric stimulation when coil-skin distance was less than or equal to 2 cm.

Central motor conduction as a measure of disease progression in early multiple sclerosis.

We monitored disease progression in 27 patients with clinically or laboratory-supported definite multiple sclerosis by means of clinical assessments [expanded disability status scale (EDSS), and the neurologic rating scale (NRS)] repeated at 6 month intervals for 2 years. Each clinical assessment was accompanied by evoked potentials (EP; visual, brain stem auditory, and somatosensory evoked potentials), motor evoked potentials elicited by magnetic stimulation, and magnetic resonance imaging of the brain and brain stem. Central conduction indices were calculated for each central pathway. According to the EDSS 18 patients deteriorated, eight were unchanged and one improved. The central motor conduction index (CMCI) was the only conduction parameter which correlated significantly with both EDSS and NRS at baseline [rho=0.51 (EDSS); -0.65 (NRS)], at final investigation, and when individual changes from baseline to final investigation were addressed (rho=0.38; -0.38). Individual deteriorations or improvements of the CMCI during the 2 years correlated with changes in both EDSS and NRS (rho = 0.51; -0.38). The MRI parameters did not correlate with the clinical scores. The concordance between MRI and CMCI in detection of disease activity was 63%. We conclude that the CMCI stands out as an objective, accurate and easily obtained outcome parameter.

A double-blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: preliminary results.

We enrolled 25 patients with relapsing-remitting or relapsing progressive multiple sclerosis (MS) in a randomized placebo-controlled double-blind study of intravenous immunoglobulin G (IVIG). IVIG 1 g/kg daily for 2 days was administered every 4 weeks for 24 weeks. Seventeen patients completed the whole trial, whereas eight patients discontinued the trial; four during IVIG treatment and four on placebo. Of the 17 patients who completed the trial, 11 had no exacerbations during IVIG treatment compared with only six on placebo (P=O.05). The total number of exacerbations in the IVIG period was 11 and in the placebo period 15 (NS), and the number of severe exacerbations requiring treatment with intravenous methylprednisolone was four during treatment with IVIG and six on placebo (NS). The results suggest that IVIG treatment may be of benefit for prevention of exacerbations in patients with relapsing MS.

Cerebral metabolism in a case of multiple sclerosis with acute mental disorder.

Acute mental disorder in early Multiple Sclerosis (MS) is rare and little is known about the structural and metabolic changes in this relation. We present an MS patient with discrete motor and sensory deficits, who developed severe behavioral changes over a period of nine months during the initial course of the disease. The cerebral metabolic rate of glucose (CMRglc) was measured using positron emission tomography (PET), and the patient underwent MRI as well as a comprehensive battery of neuropsychological tests. Significantly reduced values of CMRglc were found bilaterally in the frontal and temporal cortex, the putamen, the thalamus and the hippocampus. The MRI revealed progression of MS lesions in the frontal lobes during the development of mental symptoms. Neuropsychological examination showed wide spread cognitive dysfunction, and a pronounced frontal lobe syndrome. The study demonstrates the remote metabolic effects of lesions affecting subcortical neural connections in an MS patient with severe cognitive dysfunction.

Regional differences in the CBF and BOLD responses to hypercapnia: a combined PET and fMRI study.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.