Prodrome in relapsing-remitting and primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The multiple sclerosis prodrome remains poorly understood. We aimed to examine the prodrome in people with relapsing remitting multiple sclerosis at onset (RMS) and primary progressive multiple sclerosis (PPMS). METHODS: We conducted a matched cohort study using clinical and linked health administrative data in two Canadian provinces. We identified people with RMS, PPMS and age- sex- and geographically-matched population controls, and compared the number of physician encounters (total number, per International Classification of Diseases chapter, and per physician speciality) in the five years before symptom onset. Negative binomial regression models were sex, age, socioeconomic status and calendar year adjusted. RESULTS: We identified 1887 RMS, 171 PPMS cases, and 9837 matched population controls. No difference existed in the total number of encounters in the five years before index between RMS and PPMS, or between the phenotypes and their respective controls. Compared to RMS cases, PPMS cases had more nervous system-related encounters (adjusted rate ratio, 3.00; 95% confidence interval, 1.06-8.49) and fewer encounters with dermatologists (adjusted rate ratio 0.53; 95% confidence interval, 0.30-0.96). CONCLUSION: Findings suggest that people with RMS and PPMS may both experience a prodrome, although aspects may differ.

Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease.

AIMS: After the diagnosis of immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA), the incidence of psychiatric comorbidity is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of IMID as compared with the general population. METHODS: Using population-based administrative health data from the Canadian province of Manitoba, we identified all persons with incident IBD, MS and RA between 1989 and 2012, and cohorts from the general population matched 5 : 1 on year of birth, sex and region to each disease cohort. We identified members of these groups with at least 5 years of residency before and after the IMID diagnosis date. We applied validated algorithms for depression, anxiety disorders, bipolar disorder, schizophrenia, and any psychiatric disorder to determine the annual incidence of these conditions in the 5-year periods before and after the diagnosis year. RESULTS: We identified 12 141 incident cases of IMID (3766 IBD, 2190 MS, 6350 RA) and 65 424 matched individuals. As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the IMID cohort as compared with the matched cohort. Similar results were obtained for each of the IBD, MS and RA cohorts. The incidence of bipolar disorder was elevated beginning 3 years before IMID diagnosis (IRR 1.63; 95% CI 1.10-2.40). CONCLUSION: The incidence of psychiatric comorbidity is elevated in the IMID population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and IMID, a shared final common inflammatory pathway or other aetiology.

Lateralized microstructural changes in early-stage Parkinson's disease in anterior olfactory structures, but not in substantia nigra.

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor symptoms as well as severe deficits in olfactory function and microstructural changes in olfactory brain regions. Because of the evidence of asymmetric neuropathological features in early-stage PD, we examined whether lateralized microstructural changes occur in olfactory brain regions and the substantia nigra in a group of early-stage PD patients. Using diffusion tensor imaging (DTI) and the University of Pennsylvania Smell Identification Test (UPSIT), we assessed 24 early-stage PD patients (Hoehn and Yahr stage 1 or 2) and 26 healthy controls (HC). We used DTI and a region of interest (ROI) approach to study the microstructure of the left and right anterior olfactory structures (AOS; comprising the olfactory bulbs and anterior end of the olfactory tracts) and the substantia nigra (SN). PD patients had reduced UPSIT scores relative to HC and showed increased mean diffusivity (MD) in the SN, with no lateralized differences. Significant group differences in fractional anisotropy (FA) and MD were seen in the AOS, but these differences were restricted to the right side and were not associated with the primary side of motor symptoms amongst PD patients. No associations were observed between lateralized motor impairment and lateralized microstructural changes in AOS. Impaired olfaction and microstructural changes in AOS are useful for early identification of PD but asymmetries in AOS microstructure seem unrelated to the laterality of PD motor symptoms.

Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus.

AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of ß-amyloid (Aß) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Aß plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi-quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE-associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE-associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD.

Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis.

BACKGROUND: Depression and anxiety are common in persons with multiple sclerosis (MS), and adversely affect fatigue, medication adherence, and quality of life. Though effective treatments for depression and anxiety exist in the general population, their applicability in the MS population has not been definitively established. OBJECTIVE: To determine the overall effect of psychological and pharmacological treatments for depression or anxiety in persons with MS. METHODS: We searched the Medline, EMBASE, PsycINFO, PsycARTICLES Full Text, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and Scopus databases using systematic review methodology from database inception until March 25, 2015. Two independent reviewers screened abstracts, extracted data, and assessed risk of bias and strength of evidence. We included controlled clinical trials reporting on the effect of pharmacological or psychological interventions for depression or anxiety in a sample of persons with MS. We calculated standardized mean differences (SMD) and pooled using random effects meta-analysis. RESULTS: Of 1753 abstracts screened, 21 articles reporting on 13 unique clinical trials met the inclusion criteria. Depression severity improved in nine psychological trials of depression treatment (N=307; SMD: -0.45 (95%CI: -0.74, -0.16)). The severity of depression also improved in three pharmacological trials of depression treatment (SMD: -0.63 (N=165; 95%CI: -1.07, -0.20)). For anxiety, only a single trial examined psychological therapy for injection phobia and reported no statistically significant improvement. CONCLUSION: Pharmacological and psychological treatments for depression were effective in reducing depressive symptoms in MS. The data are insufficient to determine the effectiveness of treatments for anxiety.

Comorbidity is associated with pain-related activity limitations in multiple sclerosis.

BACKGROUND: Comorbidities are common in multiple sclerosis (MS). The high prevalence of pain in MS is well-established but the influence of comorbidities on pain, specifically, pain-related interference in activity is not. OBJECTIVE: To examine the relationship between comorbidity and pain in MS. METHODS: We recruited 949 consecutive patients with definite MS from four Canadian centres. Participants completed the Health Utilities Index (HUI-Mark III) and a validated comorbidity questionnaire at 3 visits over 2 years. The HUI's pain scale was dichotomized into two groups: those with/without pain that disrupts normal activities. We used logistic regression to assess the association of pain with each comorbidity individually at baseline and over time. RESULTS: The incidence of disruptive pain over two years was 31.1 per 100 persons. Fibromyalgia, rheumatoid arthritis, irritable bowel syndrome, migraine, chronic lung disease, depression, anxiety, hypertension, and hypercholesterolemia were associated with disruptive pain (p<0.006). Individual-level effects on the presence of worsening pain were seen for chronic obstructive pulmonary disease (odds ratio [OR]: 1.50 95% CI: 1.08-2.09), anxiety (OR: 1.49 95% CI: 1.07-2.08), and autoimmune thyroid disease (OR: 1.40 95% CI: 1.00-1.97). CONCLUSION: Comorbidity is associated with pain in persons with MS. Closer examination of these associations may provide guidance for better management of this disabling symptom in MS.

Performance of administrative case definitions for comorbidity in multiple sclerosis in Manitoba and Nova Scotia.

INTRODUCTION: As the population ages and the prevalence of comorbid conditions increases, the need for feasible, validated methods of comorbidity surveillance in chronic diseases such as multiple sclerosis (MS) increases. METHODS: Using kappa (k) statistics, we evaluated the performance of administrative case definitions for comorbidities commonly observed in MS by comparing agreement between Manitoba (MB) administrative data and self-report (n = 606) and Nova Scotia (NS) administrative data and self-report (n = 1923). RESULTS: Agreement between the administrative definitions and self-report was substantial for hypertension (k = 0.69 [NS], 0.76 [MB]) and diabetes (k = 0.70 [NS], 0.66 [MB]); moderate for hyperlipidemia (k = 0.53 [NS], 0.51 [MB]) and heart disease (k = 0.42 [NS], 0.51 [MB]) and fair for anxiety (k = 0.27 [NS], 0.26 [MB]). In NS, agreement was substantial for inflammatory bowel disease (k = 0.71) and moderate for epilepsy (k = 0.48). CONCLUSION: Administrative definitions for commonly observed comorbidities in MS performed well in 2 distinct jurisdictions. This suggests that they could be used more broadly across Canada and in national studies.

TITRE: Performance des définitions administratives de cas pour les affections concomitantes de la sclérose en plaques au Manitoba et en Nouvelle-Écosse. INTRODUCTION: Au fur et à mesure du vieillissement de la population et de l'augmentation de la prévalence d'affections concomitantes, le recours à des méthodes fiables et efficaces de surveillance des affections concomitantes de maladies chroniques telles que la sclérose en plaques (SP) s'avère de plus en plus nécessaire. MÉTHODOLOGIE: Nous avons évalué, au moyen de la statistique kappa (k), la performance des définitions administratives de cas pour les affections concomitantes fréquemment observées en lien avec la SP en comparant les concordances entre les données administratives et les données provenant d'autodéclarations au Manitoba (MB) (n = 606) et en Nouvelle-Écosse (NS) (n = 1 923). RÉSULTATS: Les concordances entre les définitions administratives et les autodéclarations étaient bonnes pour l'hypertension (k = 0,69 [NS] et 0,76 [MB]) et le diabète (k = 0,70 [NS] et 0,66 [MB]), modérées pour l'hyperlipidémie (k = 0,53 [NS] et 0,51 [MB]) et la cardiopathie (k = 0,42 [NS] et 0,51 [MB]) et médiocres pour l'anxiété (k = 0,27 [NS] et 0,26 [MB]). La concordance était bonne en Nouvelle-Écosse pour la maladie inflammatoire chronique de l'intestin (k = 0,71) et modérée pour l'épilepsie (k = 0,48). CONCLUSION: Les définitions administratives étaient performantes dans les deux provinces pour plusieurs affections concomitantes fréquemment observées en lien avec la SP. À la lumière de ces résultats, il semble que ces définitions puissent être utilisées plus largement au Canada et dans les études nationales.

Disease progression among multiple sclerosis patients before and during a disease-modifying drug program: a longitudinal population-based evaluation.

Randomized controlled trials have demonstrated the efficacy of disease-modifying drugs (DMDs) in persons with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS with superimposed relapses. However, these brief studies of selected patients have focused mainly on reducing attacks and must be complemented by evaluations in 'realworld' clinical settings to establish the effectiveness of DMD programs in slowing disease progression and to inform health policy and program decision-making. We assessed the effectiveness of DMDs as administered in a comprehensive publicly funded drug insurance program that provides DMDs to a geographically defined population of MS patients who meet specific eligibility criteria. Data from 1752 MS patients (10,312 assessments) seen between 1980 and 2004 at a regional MS Clinic serving the entire population of Nova Scotia, Canada were analysed. Using survival methods we observed a statistically significant reduction in disease progression to specific Expanded Disability Status Scale endpoints following the introduction of this program. Subgroup analyses of patients eligible for treatment using hierarchical linear regression methods also suggested that disease progression was slowed in patients treated with the first DMD prescribed. These findings provide evidence supporting DMD program effectiveness that can be used to inform the broader implementation of such programs.

Social anxiety in a multiple sclerosis clinic population.

BACKGROUND: Little is known about social anxiety in MS. OBJECTIVE: We estimated the prevalence of social anxiety symptoms and their association with demographic and clinical features in a clinic-attending sample of patients with MS. METHODS: Patients attending the Dalhousie MS Research Unit for regularly scheduled visits completed the Social Phobia Inventory (SPIN), the Hospital Anxiety and Depression Scale (HADS), and the Health Utilities Index (HUI). Neurological disability was determined by ratings on the Expanded Disability Status Scale (EDSS). RESULTS: A total of 251 patients completed self-report scales of anxiety and depression symptoms. In all, 245 (98%) provided sufficient data for analysis. In all, 30.6% (n=75) had clinically significant social anxiety symptoms as defined by a SPIN threshold score of 19. Half of those with social anxiety had general anxiety (HADSA>or=11) and a quarter had depression (HADSD>or=11). Severity of social anxiety symptoms was associated with reduced health-related quality of life and not related to neurological disability. CONCLUSIONS: Social anxiety symptoms are common in persons with MS, contribute to overall morbidity, but are unrelated to the overall severity of neurologic disability. Greater awareness and routine systematic inquiry of social anxiety symptoms is an important component of comprehensive care for persons with MS.

Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination.

A failure of autoreactive T cells to undergo apoptosis may contribute to the pathogenesis of multiple sclerosis (MS). The role of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins such as X-linked IAP (XIAP), human inhibitor of apoptosis-1 (HIAP-1), human inhibitor of apoptosis-2 (HIAP-2), neuronal apoptosis inhibitory protein (NAIP) and Survivin in relapsing-remitting, secondary-progressive, primary-progressive or benign forms of MS is unclear. We report here that expression of the IAP family of genes in peripheral blood samples and brain tissues from MS cases support a role for differential regulation of these potent anti-apoptotic proteins in the pathology of MS. XIAP mRNA and protein levels were elevated in peripheral blood mononuclear cells from patients with active disease relative to normal subjects. In patients with active MS, HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood. In post-mortem MS brain tissue, XIAP and HIAP-1 in myelin lesions were co-localized with microglia and T cells, respectively. Only in primary-progressive patients was Survivin expression elevated suggestive of a distinct pathological basis for this subtype of MS. Taken together, these results suggest that patterns of inhibitor of apoptosis expression in immune cells may have value in distinguishing between MS subtypes and offer insight into the mechanisms responsible for their distinct clinical courses.

How effective are disease-modifying drugs in delaying progression in relapsing-onset MS?

OBJECTIVE: Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying multiple sclerosis (MS) disability progression in relapsing-onset (R-onset) definite MS patients under "real-world" conditions. METHODS: Treatment effect size, for DMDs as a class, was estimated in absolute terms and relative to MS natural history. A basic model estimated annual Expanded Disability Status Scale (EDSS) change before and after treatment. An expanded model estimated annual EDSS change in pretreatment years, treatment years on first drug, treatment years after drugs were switched, and in years after treatment stopped. Models were populated with 1980 through 2004 clinical data, including 1988 through 2004 data for all Nova Scotians treated with DMDs. Estimates were made for relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and R-onset groups. RESULTS: Estimated pretreatment annual EDSS increases were approximately 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group, and 0.16 for the R-onset group. Estimates of EDSS increase avoided per treatment year on the first drug were significant for the RRMS group (-0.103, 0.000), the SPMS group (-0.065, 0.011), and the R-onset group (-0.162, 0.000); relative effect size estimates were 112%, 21%, and 105%. Estimated EDSS progression was faster in years after drug switches and treatment stops. CONCLUSIONS: Our estimates of disease-modifying drug (DMD) relative treatment effect size, in the context of "real-world" clinical practice, are similar to DMD treatment efficacy estimates in pivotal trials, though our findings attained statistical significance. DMDs, as a class, are effective in delaying Expanded Disability Status Scale progression in patients with relapsing-onset definite multiple sclerosis (MS) (90%), although effectiveness is much better for relapsing-remitting MS than for secondary progressive MS groups.

Comparison of cognitive functions between people with silent and wild-type butyrylcholinesterase.

In the human brain, butyrylcholinesterase (BuChE) is expressed in neurons and glia. For example, many nuclei in the human thalamus, with projections to the cerebral cortex, contain a large number of neurons with intense BuChE activity. Thalamocortical projections subserve a variety of cognitive functions. Due to genetic mutations, there are individuals who do not have detectable BuChE activity (silent BuChE). While the prevalence of silent BuChE is only 1:100,000 in European and American populations, it is 1:24 in the Vysya community in Coimbatore, India. To examine whether there are differences in cognitive functions between individuals with silent BuChE and those expressing normal BuChE (wild-type), twelve healthy individuals with silent BuChE and thirteen healthy individuals with wild-type BuChE, all from the Vysya community in Coimbatore, were tested for cognitive function using the Automated Neuropsychological Assessment Metrics test battery. The silent BuChE group was slightly faster on simple reaction tasks, but slower on a visual perceptual matching task. Furthermore, discriminant function analyses correctly classified 11/12 silent and 8/13 wild-type BuChE subjects (76% correct classification overall) based on BuChE status. Different profiles of cognitive test performance between individuals with silent and wild-type BuChE were observed. These observations suggest a function for BuChE in cognition.

Outcomes of incident mild cognitive impairment in relation to case definition.

Definitions of mild cognitive impairment (MCI) vary, yielding conflicting results. For example, case definitions affect prevalence but not outcomes in prevalent cases. Our objective was to determine whether variation in case definitions affects outcomes in incident cases of MCI. The 5 year risks of death, institutionalisation, and dementia were evaluated in clinically examined incident MCI cases in the Canadian Study of Health and Aging. The definition of MCI was varied so as to include or relax combinations of diagnostic features from consensus criteria. Relative risks (RR) of each adverse outcome were highest in MCI case definitions that required subjective memory complaints (for example, RR of dementia = 26.4-38.7). Although each MCI definition conferred an increased risk of dementia, for each case definition 20-30% of survivors had no cognitive impairment at follow up. In this population based study, MCI represented a transitional state, but was heterogeneous, with substantial proportions recovering, regardless of how MCI was defined. Factors associated with recovery and non-progression in MCI require elucidation.

A comparison of health utility measures for the evaluation of multiple sclerosis treatments.

OBJECTIVES: To evaluate the practical application and psychometric properties of three health utility measures in a sample of MS patients with a broad range of neurological disability as measured by the Extended Disability Status Scale (EDSS). METHODS: Patients randomly selected from two MS clinic registries were assessed using standard clinical methods and completed three generic measures of health utility (EQ-5D, HUI Mark III, SF-6D). The proportion of missing data, test/retest reliability, and construct validity of each health utility measure were examined. RESULTS: The assessments were completed by 187 patients. Less than 10% of data were missing for the subscales of the SF-6D (< 3.2%), HUI Mark III (<1.6%), and EQ-5D (< or =7.5%). Severely disabled patients were more likely to omit physical function questions for the SF-6D (20%), and EQ-5D (43%). Retest reliability for the SF-6D (ICC = 0.83), EQ-5D (ICC = 0.81), and HUI Mark III (ICC = 0.87) were adequate for population surveys. Correlations between assessment of clinical function and each health utility measure were strongest for the HUI Mark III (HUI Mark III EDSS rho = -0.77, HUI Mark III ambulation index rho = -0.76, HUI Mark III timed 25 foot walk rho = -0.73, HUI Mark III nine hole peg test rho = -0.65). CONCLUSIONS: The health utility measures were generally feasible and reliable but the HUI Mark III demonstrated highest concordance with the EDSS across the full range of neurological disability. Of the three measures studied, the HUI Mark III may be the most appropriate for cost effectiveness evaluations of MS therapies.

Short term predictors of unemployment in multiple sclerosis patients.

BACKGROUND: Unemployment is common in people with multiple sclerosis (MS) and is associated with loss of income and impaired health related quality of life. This study determined variables associated with unemployment and risk factors for the development of unemployment in people with MS. METHODS: Ninety-six patients who were under age 65 and participated in two previous studies to measure economic costs and health related quality of life in MS were included. The baseline employment rate and variables associated with unemployment at baseline were determined. The ability of these variables to predict unemployment over the next two and a half years was then evaluated. RESULTS: At baseline 50.1% (50/96) of participants were employed. Two and a half years later only 40.6% (39/96) remained employed. This represents loss of employment for 22.0% (11/50) of those originally employed. Factors associated with unemployment at baseline included greater disability, progressive disease course, longer disease duration, and older age. Risk factors for loss of employment over the next 2.5 years included greater disability and older age. CONCLUSIONS: This study confirms the low employment rate among people with MS and confirms the association of several previously-reported factors with greater risk of unemployment. It is also the first study to confirm that some of these factors also increase the risk of future unemployment. People with MS who are over age 39 or have moderate disability and are still employed can now be identified as at risk for becoming unemployed over the next 2.5 years. They should be considered for interventions to maintain employment or to lessen the impact of unemployment.

The relation between APOE status and neuropsychological memory test performance: an analysis of the Canadian Study of Health and Aging.

This study examined the relationship between two risk factors for dementia, the apolipoprotein (APOE) epsilon4 allele and poor memory test performance. Participants were from the Canadian Study of Health and Aging, a 4-year longitudinal population-based study. Persons with no cognitive impairment who had an epsilon4 allele but whose memory was average or better were not at increased risk of developing dementia after five years. Risk was increased for those with below average memory and no epsilon4 allele, but was particularly increased for those with below average memory and an epsilon4 allele. While the APOE epsilon4 allele was associated with slightly lower memory test performance for persons without cognitive impairment at baseline, it only increased their risk of developing dementia if their memory was below average.

Evaluation of hydrogen bonding complementarity between a secondary sulfonamide and an alpha-amino acid residue.

[structure: see text] We report an initial step toward the development of sulfonamide-based complements for extended peptide strands. A molecule containing one secondary sulfonamide unit and one valine residue linked by a turn-forming segment was found by IR and NMR to exhibit a doubly hydrogen-bonded folding pattern in chloroform.

Limitations of the Paced Auditory Serial Addition Test as a measure of working memory in patients with multiple sclerosis.

The Paced Auditory Serial Addition Test (PASAT) is a commonly used procedure that combines elements of both a working memory task and a test of information processing speed. Patients with multiple sclerosis (MS) have consistently been found to be impaired on this test and it has been recommended as a core outcome measure in clinical trials. The standard score for this task is the number of correct responses at each stimulus presentation rate but a concern has been raised that subjects may ignore some test items in order to chunk the information into manageable portions and avoid performing several cognitive tasks simultaneously. To account for this strategy, one can examine the proportion of correct responses that are consecutive (termed dyads), since such responses require that the task be performed according to the instructions. We compared a group of 35 mildly to moderately disabled MS patients and matched healthy controls on the PASAT. The MS patients made significantly fewer correct responses at the 2 slowest presentation rates (2.4, 2.0 s/digit) while their scores at faster rates (1.6, 1.2 s/digit) did not discriminate them from controls as well. Nevertheless, the MS patients' percentage of dyads was significantly lower than that of the control sample across all stimulus presentation rates. While our study supports the use of the PASAT as a test that distinguishes MS patients from healthy individuals, our results also illustrate problems that lie in the interpretation of this difference in performance. It appears that a chunking strategy may be common in the PASAT, particularly as task demands increase, and that this may mask actual performance differences. If so, the total correct response score alone is limited as a measure of working memory and information processing speed. More detailed analyses of PASAT performance, coupled with other measures of information processing, may help clarify the underlying cognitive deficits of MS patients.