Extended interval dosing of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4ß1/ß7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation.

Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression.

Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions.

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

A p74 common gamma receptor chain isoform facilitates IL-2 and IL-15 responses by the myelomonocytic cell line Tf-1beta2.

Functional forms of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors require the gamma c receptor component. We have described previously a myeloid cell line called Tf-1beta, which binds IL-2 with intermediate-affinity and proliferates in response to IL-2. In this study, we characterize gamma c expression on Tf-1beta2 cells, a derivative of Tf-1beta cells stimulated exclusively with IL-2. Although Tf-1beta2 cells bind IL-2 with intermediate-affinity and proliferate in response to IL-2, this cell line does not express the p64 gamma c chain at the protein level. This result was surprising because prior studies suggest these cells should not be expected to proliferate in response to IL-2 or IL-15 in the absence of the p64 gamma c chain. A p74 protein was detected by western blot following immunoprecipitation with an anti-gamma c polyclonal antibody, and a p74 protein was identified consistently in complex with IL-2 and IL-15 on these cells. However, the gamma c gene in these Tf-1beta2 cells shows no evidence of mutation by sequence analysis. Furthermore, inhibition of glycosylation of these Tf-1beta2 cells by tunicamycin treatment yields a standard 39-kDa molecule recognized on western blot with anti-gamma c antibody, as seen for the standard 64-kDa isoform of gamma c. These results demonstrate that a 74-kDa gamma c receptor isoform was involved in the response of the Tf-1beta2 cells to cytokines which normally interact with the 64-kDa gamma c chain.

Clinical and demographic predictors of cognitive performance in multiple sclerosis. Do diagnostic type, disease duration, and disability matter?

Patients with chronic progressive multiple sclerosis often perform more poorly on cognitive tasks than do patients with the relapsing-remitting form of this disease. Whether these differences reflect an independent influence of disease type on cognitive performance is uncertain. We used multiple regression techniques to determine how well performance on a number of tasks done poorly by groups of patients with multiple sclerosis could be predicted by disease type and its confounds: age, disease duration, and disability status as well as other demographic variables. Disease types were assigned longitudinally, based on serial neurological examinations at 6-month intervals over a minimum of 2 years. None of the demographic or clinical variables predicted cognitive performance with more than minimal accuracy. These findings fail to provide support for the assertion that disease type is an important independent determinant of cognitive impairment in multiple sclerosis.

Cognitive disturbances in patients with relapsing remitting multiple sclerosis.

The performance of 42 patients with relapsing remitting (RR) multiple sclerosis was compared with that of 24 age-, education-, and gender-matched control subjects on a battery of neuropsychological tests known from previous studies to be sensitive to the impairments of patients with chronic progressive (CP) multiple sclerosis. Like CP patients, RR patients exhibited deficits on tests of information-processing speed, verbal fluency, and problem solving, and on recall measures of anterograde and remote memory. Although a few patients were mildly dysnomic, the RR patients were not generally impaired on visual confrontation naming and they did not exhibit perseverative responding on verbal fluency measures. The pattern of neuropsychological deficits exhibited by RR patients closely approximates the profile observed in other subcortical dementias and does not contain the features of cortical dementia evident in some CP patients. The impairment of RR patients on cognitive tests were less severe than those observed in CP patients in our previous studies. Differences in the age of patients in the CP and RR groups did not account for group differences in the severity of cognitive impairments, but differences in disease duration or severity of disability, as well as disease course, could explain why CP patients exhibit more serious cognitive disturbances than RR patients.

Anterograde and retrograde amnesia in patients with chronic progressive multiple sclerosis.

The performance of 38 patients with chronic progressive multiple sclerosis was compared with that of 26 age- and education-matched controls on a battery of tests of information-processing speed, verbal fluency, naming, egocentric perception, and anterograde and remote memory. Although there were marked differences in the extent and severity of cognitive disturbance among individual patients, as a group they were impaired compared with controls on all measures. Deficits were most striking on the Symbol-Digit Modalities Test and the verbal fluency measures, tests that require rapid information processing. More than 75% of the patients scored below the tenth percentile for controls on the Symbol-Digit Modalities Test, while 61% scored below the tenth percentile on verbal fluency. Memory disturbances were also common. More than 45% of the patients scored below the tenth percentile. The proportion of impaired patients was quite similar for anterograde and remote memory tests and for recall and recognition procedures. The pattern of memory disturbance and slowed information processing resembled deficits generally observed in subcortical dementias, such as Huntington's disease, but in addition, the patients with multiple sclerosis showed naming difficulties that are usually associated with cortical dementias, such as Alzheimer's disease.

Does distraction reduce pain-produced distress among college students?

College students in four experiments placed their hands in ice water (the cold-pressor task) and reported their distress. They simultaneously engaged in different reaction-time (RT) tasks that varied in the amount of attention required for successful performance. In each experiment, which differed in numerous procedural details, RT, error-rate, and self-report measures all demonstrated that the distraction tasks differed in the degree of attention required. Greater distraction, however, failed to reduce physiological, self-report, or behavioral responses to the cold-pressor task. These data call into question the hypothesis that attention mediates the process whereby distraction tasks reduce pain-produced distress.

Two-dimensional cancellation neglect a review and suggested method of analysis.

Directional bias on cancellation has thus far not been standardized. While cancellation tasks are primarily used to assess lateral performance asymmetries, they may also reveal two-dimensional (i.e., combined lateral and radial) neglect patterns. We propose a method to evaluate and report cancellation neglect regardless of whether the neglect pattern is strictly unilateral or two-dimensional. Our method establishes the location of the geographic center of all neglected stimuli relative to the page center by averaging their Cartesian coordinates. This "neglect center" is reported in polar coordinates to indicate its distance and direction from the page center. We apply our method to published examples of two-dimensional neglect. We find that neglect centers from different cancellation performances may not be statistically distinct even though they may occupy different quadrants. In addition, the net direction of neglect found by the coordinate method may differ from that inferred from measuring differences in quadrant omission totals. The suitability of the coordinate vs. the quadrant method will depend on the mechanism hypothesized for visuospatial exploration under particular test conditions. Using both approaches may detect different attentional biases operating during the same task. The coordinate method is appropriate for conventional cancellation testing. By incorporating the precise locations of all neglected stimuli and determining the net neglect direction in two dimensions, the technique may stimulate more comprehensive explanations for directional bias.

Lexical processing in Parkinson's disease and multiple sclerosis.

Patients with Parkinson's disease (PD) or multiple sclerosis (MS) were categorized as normal in naming (NN) or impaired in naming (IN) based on their performance on the Boston Naming Test. All patients scored at least 23 on the Mini-Mental State Examination. Both PDIN and MSIN patient groups exhibited poor naming performance when target words were elicited with semantic, visual or rhyming cues. They also performed poorly on the vocabulary subtest of the Wechsler Adult Intelligence Scale-Revised and had difficulty repeating sentences. PDNN and MSNN patients showed more selective deficits. These findings add to a growing literature demonstrating that language in general, and naming in particular, can be compromised in subcortical diseases even when global mental status is only mildly affected. The clinical implications of these observations are, however, unclear.

Problem solving in Parkinson's disease: comparison of performance on the Wisconsin and California Card Sorting Tests.

Previous demonstrations that problem solving deficits may occur early in the course of Parkinson's disease (PD) have been taken to support the view that disturbances in the functioning of the frontal lobes are responsible for the initial cognitive deficits in this disease. However, no specific pattern of responding associated with poor problem solving by PD patients has been observed consistently. In an effort to clarify the nature of the problem solving deficits in PD we administered the Wisconsin Card Sorting Test (WCST) and the California Card Sorting Test (CCST), a new test which provides separate measures of concept generation, concept identification, and concept execution as well as several different measures of perseveration. On both tests PD patients of lower than normal mental status performed poorly and their patterns of performance resembled those previously described for patients with focal frontal lobe lesions, but PD patients of normal mental status performed normally. Because poor problem solving in association with increased perseverative responding was only observed for patients with global cognitive deficits these findings do not necessarily support the idea that frontal dysfunction is the principal cause of impaired cognition in PD. Although the overall pattern of results was similar for the WCST and the CCST, the CCST was more sensitive for detecting deficits than was the WCST.

Picture and motor sequencing in Parkinson's disease.

A recent report found that the discrepancy between scaled scores on the Vocabulary and Picture Arrangement subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) was much larger for patients with Parkinson's disease than for healthy controls or patients with Alzheimer's disease. On this basis, it was argued that Parkinson's disease causes a specific deficit in cognitive sequencing that occurs even when the memory and speed requirements of the task are minimal. However, other work indicated that Parkinson's disease patients are almost as severely impaired on other Performance subtests from the WAIS-R that do not require sequencing. In the present study, an extremely simple, untimed test of picture sequencing and a version of the Luria three-step test of motor sequencing were employed. Parkinson's disease patients were impaired on both tasks. The extent of their impairments on picture and motor sequencing were positively correlated, and the severity of deficits on both sequencing tests was related to global mental status and to performance on the Wisconsin Card Sorting Test, but not to neurologic measures of disease severity. However, the patients' performance on the picture sequencing test but not on the motor sequencing test was related to performance on Benton's Facial Recognition Test. These results demonstrate the existence of a generalized sequencing deficit in Parkinson's disease that appears dissociable from impairment in performing simple motor acts.

Access to semantic memory in Parkinson's disease and multiple sclerosis.

The capacity to access semantic memory and the efficiency of the memory search were studied in patients with Parkinson's disease (PD) or multiple sclerosis (MS) using a modified version of the "Supermarket Test." PD and MS patients who performed normally on the Boston Naming Test generated as many specific exemplars and category labels as did controls, and these patients also searched their semantic memories as efficiently as controls. In contrast, PD and MS patients with impaired confrontational naming generated fewer specific exemplars, but a normal number of generic category labels. These naming-impaired patients searched their semantic memories less efficiently than controls. For both MS and PD patients, the efficiency of semantic memory search was significantly correlated with measures that reflect access to semantic memory (eg, performance on letter or category fluency tasks), but was not significantly related to measures of problem-solving ability derived from the Wisconsin Card Sorting Test. Inefficient search of semantic memory in MS and PD appears to arise from an inability to retrieve knowledge from semantic memory quickly or from the loss of information from semantic memory stores, rather than from impairment in the ability to formulate and deploy appropriate strategies for task solution.

Cognitive disturbances in Parkinson's disease.

To test the hypothesis that the cognitive impairments that accompany Parkinson's disease (PD) arise from frontal lobe dysfunction, patients with idiopathic PD and controls were tested on a neuropsychological battery that included measures of anterograde memory, visuospatial perception, and naming, as well as several tests that are known to be sensitive to lesions of the frontal lobes. PD patients of normal mental status as measured by the Mini-Mental State Examination performed normally on the naming, line orientation, and verbal recognition memory tests but exhibited deficits on verbal recall. On tests of frontal lobe function, these patients showed mild deficits on a category fluency task and on the Wisconsin Card Sorting Test. However, their errors on the latter were not typical of patients with frontal lesions, and they performed normally on a letter fluency task and exhibited normal release from proactive interference. Patients of lower than normal mental status performed poorly on nearly all of the cognitive tasks including confrontational naming, line orientation, and recognition memory, suggesting that their cerebral dysfunction extended beyond subcortical-frontal circuits. The present study supports the usefulness of the Mini-Mental State Examination for cognitive screening of PD patients, but does not support the hypothesis that the cognitive impairments in PD arise principally from disruption of frontal lobe functioning.

A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis.

B cells isolated from the CSF of patients with multiple sclerosis (MS) have a unique accumulation of somatic hypermutation within the B cell receptor, termed the antibody gene signature (AGS). The focus of this study was to investigate whether the AGS could also be detected in MS brain tissue. Genetic analysis of B cells isolated from post-mortem CNS tissue samples from four MS brains demonstrated that signature enriched B cells are present at the site of tissue injury as well as in the circulating CSF.

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy.

OBJECTIVE: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy. METHODS: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored. RESULTS: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed. CONCLUSION: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Problem solving by patients with multiple sclerosis: comparison of performance on the Wisconsin and California Card Sorting Tests.

Problem solving by patients with clinically definite multiple sclerosis (MS) was examined using the Wisconsin and California Card Sorting Tests (WCST and CCST). On the WCST, the MS patients achieved fewer categories and made more perseverative responses and errors than controls, confirming results of several previous studies. On the CCST, the MS patients generated and identified fewer concepts, but they performed normally when sorting was cued by the experimenter and they made no more perseverations than controls. Although findings from the WCST indicate that the problem solving deficits by MS patients closely resemble those exhibited by patients with various conditions that produce frontal lobe dysfunction, results from the CCST indicate that the problem solving difficulties exhibited by patients with MS are distinct and probably represent a primary deficit in concept formation.

Age vs. aging in the pathogenesis of senile dementia of the Alzheimer type: electrophysiological evidence.

Is senile dementia of the Alzheimer type (SDAT) the end result of aging of the brain (serial or aging-related model) or the result of some other mechanism that runs in parallel to normal aging (parallel or age-related model)? This question can be answered by comparing variables that measure biological aging (aging-dependent variables, ADVs) of normal individuals and of SDAT patients. If the serial model applies, the values of the ADVs of SDAT patients should be at the upper end of the normal ADV curves. In control individuals the power of the alpha band in the 2-Hz flash-stimulated EEG at the posterior head regions increased with age, while the power of the delta band in the resting EEG at the anterior head regions decreased. In SDAT patients the ADVs were significantly different from normal and opposite to the trend of normal aging, supporting the parallel model and suggesting that the pathogenesis of SDAT is different from normal aging.