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OBJECTIVE: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. METHODS: A follow-up study was conducted to reassess patients from a phase III trial of interferon beta-1a (IFNbeta-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. RESULTS: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. CONCLUSIONS: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.

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BACKGROUND: Interferon beta-1a (IFNbeta-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFNbeta preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFNbeta-1a slowed disease progression in SP-MS. METHODS: A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFNbeta-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). RESULTS: Median MSFC Z-score change was reduced 40.4% in IFNbeta-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFNbeta-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFNbeta-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFNbeta-1a-treated subjects. CONCLUSIONS: IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

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BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS. OBJECTIVE: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure. DESIGN: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization. RESULTS: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS. CONCLUSIONS: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

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OBJECTIVE: To determine whether the MS Functional Composite (MSFC) can predict future disease progression in patients with relapsing remitting MS (RR-MS). BACKGROUND: The MSFC was recommended by the Clinical Outcomes Assessment Task Force of the National MS Society as a new clinical outcome measure for clinical trials. The MSFC, which contains a test of walking speed, arm dexterity, and cognitive function, is expressed as a single score on a continuous scale. It was thought to offer improved reliability and responsiveness compared with traditional clinical MS outcome measures. The predictive value of MSFC scores in RR-MS has not been determined. METHODS: The authors conducted a follow-up study of patients with RR-MS who participated in a phase III study of interferon beta-1a (AVONEX) to determine the predictive value of MSFC scores. MSFC scores were constructed from data obtained during the phase III trial. Patients were evaluated by neurologic and MRI examinations after an average interval of 8.1 years from the start of the clinical trial. The relationships between MSFC scores during the clinical trial and follow-up status were determined. RESULTS: MSFC scores from the phase III clinical trial strongly predicted clinical and MRI status at the follow-up visit. Baseline MSFC scores, and change in MSFC score over 2 years correlated with both disability status and the severity of whole brain atrophy at follow-up. There were also significant correlations between MSFC scores during the clinical trial and patient-reported quality of life at follow-up. The correlation with whole brain atrophy at follow-up was stronger for baseline MSFC than for baseline EDSS. CONCLUSION: MSFC scores in patients with RR-MS predict the level of disability and extent of brain atrophy 6 to 8 years later. MSFC scores may prove useful to assign prognosis, monitor patients during early stages of MS, and to assess treatment effects.

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BACKGROUND: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value. METHODS: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis. RESULTS: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months. CONCLUSIONS: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

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Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNbeta-1a (Avonex) in relapsing- remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing--remitting MS.

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BACKGROUND AND OBJECTIVE: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS: The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

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BACKGROUND: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. OBJECTIVES: To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients. METHODS: A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b. RESULTS: In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. CONCLUSIONS: NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

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This randomized, double-blind, placebo-controlled study was aimed at detecting cerebrovascular effects of isradipine and enalapril in patients with moderate hypertension depending on the presence and grade on unilateral stenosis of internal carotid artery (ICA). We evaluated carotid vascular resistance by using Doppler analysis and regional cerebral blood flow (rCBF) by using 133Xe-clearance technique before and after a single 5-mg oral dose of isradipine, enalapril, or placebo. Their effects were randomly and consecutively tested in 73 patients with essential hypertension subdivided into three groups: without carotid occlusive lesions, with moderate (50-75%), and with severe (76-99%) unilateral asymptomatic ICA stenosis. There were no differences in age, gender, and antihypertensive effects of the drugs between these three subgroups. Three major variants of cerebrovascular drug effects were observed: absence of changes (variant I), decrease in carotid vascular resistance with increase in rCBF and elimination of side-to-side asymmetry (variant II), and increase in carotid vascular resistance with further reduction of rCBF ipsilaterally ICA stenosis, and increased side-to-side asymmetry (variant III). Frequency of variant III was significantly higher in patients with severe ICA stenosis. Enalapril produced variant I of cerebrovascular effects in most patients examined; variant III was observed only in 13% of patients with severe ICA stenosis. Isradipine produced variant I of cerebrovascular effects much less frequently than did enalapril. For this drug, variant II was most typical in patients without ICA stenosis and with moderate ICA stenosis. In 43.5% of patients with severe ICA stenosis, however, isradipine produced reduction of cerebral perfusion. Presumably the presence of ICA stenosis, especially >75%, increases the risk of cerebrovascular disorders in antihypertensive therapy. In patients with severe ICA stenosis, treatment with enalapril appears to be safer than that with isradipine.

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BACKGROUND AND OBJECTIVE: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. METHODS: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. RESULTS: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFN beta-1a was observed when > or = 2.0 point worsening from baseline EDSS was required or when worsening was required to persist for > or = 1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN beta-1a recipients who reached the primary study outcome. (3) Significantly fewer IFN beta-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0 (unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFN beta-1a treatment. CONCLUSIONS: The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

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Regional cerebral blood flow (rCBF) in 75 patients with arterial hypertension and symptoms of chronic ischemic cerebrovascular disorders was studied by using the 133Xenon infusion technique and a 30-detector setup. A baseline decrease in the mean hemispheric blood flow (rCBFh) with elevated deviations of rCBF from rCBFh were observed in the hemispheres. A single oral dose of either nifedipine or nicardipine induced various changes in rCBF. The drug effects regarding changes in the mean value of the hemispheric blood flow and the flow distribution were classified into 4 types. A decrease in the deviation of rCBF from the hemispheric mean CBF accompanied by an increase in the total brain blood flow was considered to be the most beneficial drug effect. This positive reaction was found more frequently when patients were given nicardipine. In some patients both drugs induced nonbeneficial changes in rCBF with an increase in the number of ischemic and hyperemic regions. It was hypothesized that such variants of drug effects may result in the deterioration of brain perfusion, contributing to development of focal brain ischemic damages. The effects of drugs were similar after both single doses and 2-week monotherapy. It is suggested that the analysis of drug effects on regional CBF distribution may be useful for estimating clinical importance of changes in cerebral hemodynamics during antihypertensive therapy.

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Growing evidence suggests that non-N-methyl-D-aspartate receptor activation may contribute to neuronal death in both acute and chronic neurological diseases. The intracellular processes that mediate this form of neuronal death are poorly understood. We have previously characterized a model of kainic acid neurotoxicity using cerebellar granule cell neurons in vitro and we sought to determine the mechanism of kainic acid-induced neuronal degeneration. We found DNA laddering by agarose gel electrophoresis, cellular DNA fragmentation by in situ end labeling of DNA, and chromatin condensation using a fluorescent DNA intercalating dye, in cerebellar granule cells following exposure to kainic acid (100 microM). Aurintricarboxylic acid protected cerebellar granule cells from kainic acid-induced death. While the morphological and biochemical features of neuronal death induced by kainic acid resembled low K(+)-induced apoptosis in cerebellar granule cells, the time interval from the institution of the death promoting condition to neuronal death was shorter with kainic acid and did not require new protein or RNA synthesis. These results demonstrate that kainic acid receptor activation can induce transcription-independent apoptosis in neurons. This in vitro model should be useful in identifying the intracellular pathways that link kainic acid receptor activation with apoptosis.

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Growing evidence suggests that non-N-methyl-D-aspartate receptor activation may contribute to neuronal death in both acute and chronic neurological diseases. The intracellular processes that mediate this form of neuronal death are poorly understood. We have previously characterized a model of kainate neurotoxicity using cerebellar granule cell neurons in vitro and we sought to determine the mechanism of kainate-induced neurons degeneration. We found DNA, and chromatin condensation using a fluorescent DNA intercalating dye, in cerebellar granule cells following exposure to kainate (100 microM). Aurintricarboxylic acid protected cerebellar granule cells from kainate-induced death. While the morphological and biochemical features of neuronal death induced by kainate resembled low-K(+)-induced apoptosis in cerebellar granule cells; the time interval from the institution of the death-promoting condition to neuronal death was briefer with kainate and did not require new protein or RNA synthesis. These results demonstrate that kainate receptor activation can induce transcription-independent apoptosis in neurons. This in vitro model should be useful in identifying the intracellular pathways that link kainate receptor activation with apoptosis.

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BACKGROUND AND PURPOSE: This study was performed to study the dynamics of polymorphonuclear leukocyte (PMNL) accumulation in human cerebral infarction and its association with neurological outcome and brain lesion. METHODS: A total of 88 patients diagnosed as having hemispheric ischemic stroke were examined. PMNL accumulation was studied using technetium-99m hexamethylpropyleneamine oxime (99mTc HMPAO)-labeled leukocyte brain single-photon emission computed tomography (SPECT). Volume of brain infarction was evaluated by CT scan. The Mathew Scale was used for neurological assessment. Dynamics of PMNL accumulation was studied at 3 to 6, 6 to 12, and 12 to 24 hours and 6 to 9, 28 to 30, and 90 days after stroke onset. In parallel, at admission, at 6 to 9 days, and at 28 to 30 days neurological outcome and infarction volume were evaluated. RESULTS: Generally, PMNL accumulation progressively increased during 6 to 24 hours after stroke, remained at a high level up to 6 to 9 days and then declined. With the use of cluster analysis, all patients were subdivided into three groups: patients with severe PMNL accumulation that dramatically increased within 12 hours after stroke onset and persisted even at 28 to 30 days (group A); those with moderate PMNL accumulation that significantly decreased at 30 days (group B); and those with mild PMNL accumulation that decreased at 6 to 9 days (group C). Baseline neurological deficit and brain tissue damage at admission appear to be at a similar level for all groups of patients. In dynamics, however, in patients with severe PMNL accumulation, neurological outcome was worse and infarction volume larger than in patients with less marked PMNL accumulation. CONCLUSIONS: The present clinical study confirms that PMNLs intensively accumulate in the regions of cerebral infarction. The present study revealed that this accumulation correlated with the severity of the brain tissue damage and poor neurological outcome.

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Oxidative stress refers to the cytopathologic consequences of a mismatch between the production of free radicals and the ability of the cell to defend against them. Growing data from experimental models and human brain studies suggest oxidative stress may play an important role in neuronal degeneration in diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Mitochondrial oxidative metabolism, nitric oxide, phospholipid metabolism, and proteolytic pathways are potential sources of intracellular free radicals. Alterations in free radical defense systems may also contribute to oxidative stress. A net increase in reactive oxygen species can produce damage to lipids, proteins, and DNA and induce necrosis or apoptosis. Elucidating the pathways important in the production of and defense from free radicals may be important in devising new pharmacologic strategies to slow or halt neuronal degeneration.

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While a correlation exists at the regional level between the distribution of neurofibrillary tangles and the predicted sites of brain dysfunction based on clinical and functional neuroimaging studies, the relationship between neurofibrillary tangles and neuronal dysfunction is poorly understood. Using cytochrome oxidase activity as a marker of neuronal functional activity, we found reductions in metabolic activity both in a hippocampal subfield with a high density of neurofibrillary tangles (CA1) as well as in subfields relatively spared (CA3, dentate granule cells). In contrast, we found no reduction in activity in primary visual cortex. Using in situ hybridization, we found a selective reduction in a mitochondrial-encoded cytochrome oxidase mRNA transcript with sparing of a nuclear-encoded transcript. These results suggest that the reduction in cytochrome oxidase activity in Alzheimer's disease brain may be related to an alteration in mitochondrial gene expression. The absence of a direct correlation between structural pathology and cytochrome oxidase activity suggests that neurons that remain structurally intact in Alzheimer's disease may nonetheless undergo substantial changes in metabolic activity.

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Positron emission tomography (PET) studies measuring glucose utilization have demonstrated cerebral hypometabolism in Alzheimer's disease (AD). The anatomic and biochemical basis for this observation remains unknown. We have examined the distribution in the hippocampal formation of the neuron-specific glucose transporter 3 (Glut3) protein. Using quantitative immunohistochemistry, we find a large reduction (49.5%) in Glut3 immunoreactivity in the outer portion of the molecular layer of the dentate gyrus in AD brains. This region corresponds to the terminal zone of the perforant pathway, whose cells of origin in layer II of the entorhinal cortex are selectively destroyed in AD. Because glucose uptake reflects metabolic demand, these results suggest a decrement of functional activity in the deafferented dentate gyrus granule cells. Generalizing from this observation, decreased glucose uptake seen on PET studies may reflect, in part, decreased glucose transport and utilization in functionally deafferented cortical fields.

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