Allison Drake

Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative. MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test—retest interval of 2.3 ± 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability. All MSFCs had similar test—retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC. Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.

Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline

Cognitive dysfunction is common in multiple sclerosis (MS), yet the magnitude of change on objective neuropsychological (NP) tests that is clinically meaningful is unclear. We endeavored to determine NP markers of the transition from employment to work disability in MS, as indicated by degree of decline on individual tests. Participants were 97 employed MS patients followed over 41.3 ± 17.6 months with a NP battery covering six domains of cognitive function. Deterioration at follow-up was designated as documented and paid disability benefits (conservative definition) or a reduction in hours/work responsibilities (liberal definition). Using the conservative definition, 28.9% reported deteriorated employment status and for the liberal definition, 45.4%. The Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test, Total Learning (CVLT2-TL) measures distinguished employed and disabled patients at follow-up. Controlling for demographic and MS characteristics, the odds ratio of a deterioration based on a change of 2.0 on the CVLT2-TL was 3.7 (95% CI 1.2–11.4 and SDMT by 4.0 was 4.2 (95% CI 1.2–14.8), accounting for 86.7% of the area under the ROC curve. We conclude that decline on NP testing over time is predictive of deterioration in vocational status, establishing a magnitude of decline on NP tests that is clinically meaningful.

Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis

BackgroundThe breakdown of the blood-brain-barrier vascular endothelium is critical for entry of immune cells into the MS brain. Vascular co-morbidities are associated with increased risk of progression. Dyslipidemia, elevated LDL and reduced HDL may increase progression by activating inflammatory processes at the vascular endothelium.ObjectiveTo assess the associations of serum lipid profile variables (triglycerides, high and low density lipoproteins (HDL, LDL) and total cholesterol) with disability and MRI measures in multiple sclerosis (MS).MethodsThis study included 492 MS patients (age: 47.1 ± 10.8 years; disease duration: 12.8 ± 10.1 years) with baseline and follow-up Expanded Disability Status Score (EDSS) assessments after a mean period of 2.2 ± 1.0 years. The associations of baseline lipid profile variables with disability changes were assessed. Quantitative MRI findings at baseline were available for 210 patients.ResultsEDSS worsening was associated with higher baseline LDL (p = 0.006) and total cholesterol (p = 0.001, 0.008) levels, with trends for higher triglyceride (p = 0.025); HDL was not associated. A similar pattern was found for MSSS worsening. Higher HDL levels (p < 0.001) were associated with lower contrast-enhancing lesion volume. Higher total cholesterol was associated with a trend for lower brain parenchymal fraction (p = 0.033).ConclusionsSerum lipid profile has modest effects on disease progression in MS. Worsening disability is associated with higher levels of LDL, total cholesterol and triglycerides. Higher HDL is associated with lower levels of acute inflammatory activity.

Soluble receptor for advanced glycation end products in multiple sclerosis: a potential marker of disease severity.

Objectives To compare serum levels of the receptor for advanced glycation end products (sRAGE) between multiple sclerosis (MS) patients and healthy control subjects, and to investigate whether serum sRAGE levels correlate with MS disease severity as indicated by the Kurtzke Expanded Disability Status Scale (EDSS). Method 37 patients with clinical diagnosis of MS and 22 healthy control subjects were investigated in a cross-sectional study using enzyme-linked immunosorbent assays (ELISA). Results Serum levels of sRAGE were found to be significantly lower in MS patients compared to levels in healthy controls (p = 0.005). A trend toward lower levels of serum sRAGE was observed in female MS patients compared to their male counterparts (p = 0.05). A relationship between sRAGE and EDSS, and sRAGE and rate of clinical relapse was observed (p = 0.012). Conclusion The significant reduction of sRAGE in MS patients relative to healthy controls supports the potential role for RAGE axis in MS clinical pathology. Lower levels of sRAGE may be associated with enhanced inflammatory responses. Based on these observations, further investigations into the role of sRAGE in MS clinical pathology is warranted.

Benchmarks of meaningful impairment on the MSFC and BICAMS

Background: Cognitive and motor abilities in multiple sclerosis (MS) are typically quantified using reliable, consensus standard tests validated in the MS population. While these performance measures are associated with vocational disability in parametric analyses, translation of raw scores into anchors reflecting clinically relevant, functional impairment requires further research. Objective: To examine performance-based motor and cognitive outcomes among definitive anchors that designate varying degrees of functional impairment, thereby establishing benchmarks for score interpretation. Methods: We evaluated MS patients and healthy controls, all undergoing a brief test battery. Outcomes were derived from the MS Functional Composite (MSFC) and the Brief International Cognitive Assessment for MS (BICAMS). Functional impairment anchors were (1) disability benefits, (2) employed with negative work events, and (3) employed without problems. Results: All measures yielded statistically significant differences across all levels of work status, after accounting for the effects of age and education. Benchmark values distinguished the functional impairment groups. When evaluated in combination, the Timed 25-Foot Walk and the Symbol Digit Modalities Test were the most robust predictors of functional decline. Conclusion: We have established benchmark scores for popular motor and cognitive tests that are associated with specific degrees of impairment in work status.

Impact of Pharmacotherapy on Cognitive Dysfunction in Patients with Multiple Sclerosis

Cognitive impairment is a common symptom of multiple sclerosis (MS), adversely impacting many spheres of daily functioning. Yet the effectiveness of pharmacological interventions for cognitive impairment in MS is unclear. Clinicians and patients alike would benefit from formal guidelines regarding effective management of cognitive symptoms. We reviewed the background on the measurement, pathophysiology and risk factors for cognitive dysfunction in MS, and then examined the published clinical trials of pharmacotherapy, including both disease-modifying treatments (DMTs) and symptom-management therapies (SMTs). Our review of DMTs revealed only a single well-designed, randomized, controlled trial where intramuscular interferon (IFN)-β1a, administered once weekly, was compared with placebo. The results showed significant benefits in terms of cognitive processing speed and memory. Less convincing but promising data have shown the potential benefits of IFN-β1b and natalizumab. The literature on SMTs is replete with placebo-controlled, single-centre studies, with a failure to replicate initially promising results. The results for SMTs such as acetylcholinesterase inhibitors and psychostimulants are mixed. Some encouraging data show promise but not to a threshold of indication for standard clinical use. Numerous methodological factors hamper research in this area. Acknowledging the lack of firm conclusions, we argue that all DMTs are likely to benefit cognition and that, if otherwise safe, SMTs with some empirical support may be attempted at the discretion of the treating clinician. We offer some guidance on the assessment and monitoring of cognitive function to inform off-license treatment of cognitive impairment in MS patients.

Stable neuropsychiatric status in multiple sclerosis: a 3-year study

Personality changes and neuropsychiatric symptoms are found in multiple sclerosis (MS), but no study has evaluated decline compared to healthy controls. This study assessed personality traits and neuropsychiatric symptoms over 3 years using the NEO Five Factor Inventory and the Neuropsychiatric Inventory. Additional metrics evaluated ambulation, manual dexterity and cognitive function. Contrary to hypothesis, patients showed no significant change in personality or neuropsychiatric status relative to controls. Patients were impaired in motor and cognitive function at baseline and follow-up, but showed only slowing in ambulation over time. The findings indicate that neuropsychiatric status is stable in MS over 3 years.

Negative work events reported online precede job loss in multiple sclerosis

PURPOSE Determine if a recently validated online survey of negative work events can predict future job loss among multiple sclerosis (MS) patients. METHOD Evaluated were 284 employed individuals (63 healthy controls, 221 MS patients), every three months, using an online vocational monitoring tool. Job loss rates in MS patients were compared with the healthy controls. Survey responses from MS patients suffering job loss (n=23) were then compared to those maintaining employment. Analyses focused on the frequency of negative work events. RESULTS While 23 (10%) of MS patients lost their job after baseline, there was no job loss among the healthy controls. Compared to stably employed patients, those suffering job loss had been diagnosed with MS later in life, were more likely to report a progressive disease course, and had greater physical disability as measured by the Patient Derived Disease Steps (PDDS). Declining patients were also more likely to report negative work events within three months of job loss (e.g., verbal criticism for errors or removal of responsibilities). Stepwise logistic regression predicting MS job loss retained the PDDS, age at diagnosis, years working for employer and reporting a negative work event. CONCLUSIONS The results show that physical disability and patient reported risk factors for job loss can be monitored using an online survey tool. The tool can trigger clinical assessments to help prevent unemployment and assist patients in procuring disability benefits.

Differential effects of aging on motor and cognitive functioning in multiple sclerosis.

Background: Multiple sclerosis (MS) patients are impaired in motor and cognitive performance, but the extent to which these deficits are magnified by aging is unknown. In one prior study, differences in cognitive processing speed between MS patients and healthy individuals were of similar magnitude across the lifespan. Here, we have improved on this work by expanding assessment to multiple cognitive domains and motor functioning. Objective: To determine whether the degree of cognitive and motor dysfunction in MS is magnified with increasing age. Methods: In all, 698 MS patients (aged 29–71 years) and 226 healthy controls (HCs; aged 18–72 years) completed neuroperformance tests covering ambulation, upper extremity function, information processing speed, and memory. Results: Linear regression models predicting cognitive and motor function revealed main effects of MS/HC diagnosis, age, and education across all measures. There was also an interaction between age and diagnosis on measures of motor function, but not on cognitive outcomes. Conclusion: The progression of motor decline is amplified by aging in MS. However, the degree of cognitive impairment does not vary across the lifespan. Thus, evidence of accelerated cognitive impairment in older adults with MS may signal the presence of other age-related cognitive pathologies.

Longitudinal personality change associated with cognitive decline in multiple sclerosis

We previously reported that personality and cognition were stable over 3 years in patients with multiple sclerosis (MS). This study examined whether a longer duration would reveal evidence of emerging personality dysfunction. The NEO Five-Factor Inventory and Brief International Cognitive Assessment for MS was used to assess personality and cognition, respectively. Patients were classified as “Cog Stable” or “Cog Decline” based on cognitive deterioration over 5 years. Extraversion and Conscientiousness declined across pooled groups. Follow-up of a group by time interaction found that decline in these traits was more evident in the Cog Decline group, demonstrating a link between personality and cognitive change.