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.

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.

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.

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.

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.

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.

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.

Progressive supranuclear palsy: the relationship between ocular motor dysfunction and psychological test performance.

The performance of patients with progressive supranuclear palsy on visual search and scanning tasks was related to the pattern of ocular deficits observed in these patients during horizontal refixation. Comparisons were made to age-matched normals and patients with Parkinson disease or cerebellar damage. The poor performance of the progressive supranuclear palsy group on visual search and scanning could not be attributed to the restricted range of vertical gaze or the large number of hypometric saccades during horizontal refixation. Instead, we believe that their impaired scanning resulted from the presence of square-wave jerks during attempted fixation.

Pain prevalence, severity and impact in a clinic sample of multiple sclerosis patients.

Previous studies have reported variable prevalence of pain in multiple sclerosis (MS) and have not documented the impact of pain on daily living. In this consecutive series, we report on data collected from structured interviews with 85 patients seen within a 16-month period at a regional referral clinic. The prevalence of pain for the month preceding assessment was 53%. There were no significant differences between patients who did and those who did not report pain on the basis of patient demographics (age, gender) and disease characteristics (disease subtype, duration and neurologic symptom severity). Disease duration and neurologic symptom severity were significantly correlated with the number of hours of pain per week but were not correlated with pain severity, the number of pain sites or pain-related distress. There was wide variability in the number of pain hours/week reported with 17.6% of the sample reporting continuous pain for the month preceding assessment. Sixty-five percent of patients with pain reported taking medications for pain and 90% of these patients evaluated their medication(s) as 50% effective or better. Nevertheless, patients with pain reported poorer mental health and more social-role handicap. Discussion focuses on the need for routine assessment of pain and the comprehensive evaluation of the effectiveness of pain interventions in the therapeutic management of patients with MS.

Cognitive deficits in systemic lupus erythematosus.

Several independent studies have now demonstrated the presence of significant cognitive impairment in SLE patients. Such impairment, whether it precedes or follows overt NP events, suggests compromise of the neural substrate, irrespective of overt clinical NP symptomatology. The association between cognitive impairment and brain cross-reactive autoantibodies suggests one mechanism for CNS involvement in SLE that warrants further study; the data relating specific cognitive deficits to the presence of specific antibodies raise the intriguing possibility of system- or structure-specific immune-mediated involvement in the CNS. Whatever the mechanism, cognitive impairment in SLE may have significant implications for daily functioning of some lupus patients and requires the selection of appropriate psychosocial and somatic treatment strategies.

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.

Promotion of sheet formation in alpha-peptide strands by a beta-peptide reverse turn.

[structure: see text]We show that a tetrapeptide with a heterogeneous backbone, i.e., with two different classes of amino acid residues, adopts a hairpin conformation in which each type of residue plays a different structural role. The alpha-residues at the ends form hydrogen bonds characteristic of antiparallel beta-sheet secondary structure, while the central di-beta-peptide segment forms a reverse turn. The configuration of the turn residues is critical to sheet formation.

Drug therapy in multiple sclerosis: a study of Nova Scotia senior citizens.

We conducted a study to determine the types and costs of drugs used by Nova Scotia senior citizens with multiple sclerosis (MS) compared with the types and costs of drugs used by all senior citizens in Nova Scotia. Administrative claims databases from the Nova Scotia Seniors Pharmacare program for persons aged 65 years or older were linked to the Dalhousie Multiple Sclerosis Research Unit (DMSRU) clinical database (1980-1994). Analyses compared persons with MS aged 65 years or older who attended the DMSRU at least once with the general population of senior citizens. Not all persons with MS attended the DMSRU. In aggregate, Pharmacare costs in 1993-1994 for patients with MS aged 65 years or older (N = 52) were $975.00 Canadian per capita compared with $590.00 Canadian for all senior citizens in Nova Scotia (N = 108,646). Thus average drug costs for the senior citizens with MS were 65% greater than those for all senior citizens covered by Nova Scotia's comprehensive, publicly funded Pharmacare program. Compared with other senior citizens, those with MS more frequently received alpha-blockers, anticholinergics, cholinergics, tricyclic antidepressants, anticonvulsants, antifatigue agents, antispasticity agents, and antibiotics for bladder infections.

Improved detection of differential information-processing speed deficits between two disease-course types of multiple sclerosis.

Patients with multiple sclerosis (MS) frequently demonstrate impairments of information-processing speed (IPS) on measures such as the Paced Auditory Serial Addition Test (PASAT; D. M. A. Gronwall, 1977). The authors have previously shown that their new PASAT scoring method (mean dyad score) is better correlated in comparison with more traditional PASAT scoring method(s), with magnetic resonance imaging measurement of the total area (mm2) of white-matter sclerotic lesions (P. J. Snyder & J. C. Cappelleri, 2001). The present study reports that the mean dyad score discriminated 20 relapsing-remitting MS (RRMS) patients from 15 secondary-progressive MS (SPMS) patients noticeably better than did the standard scoring method(s). Mean dyad scores < 4.13 classified patients as having SPMS with 73% accuracy (sensitivity), whereas scores > or = 4.13 classified patients as having RRMS with 80% accuracy (specificity).

The impact of fatigue on patients with multiple sclerosis.

Although fatigue is recognized as a symptom of MS, there have been insufficient methods for evaluating this symptom. We administered the Fatigue Impact Scale to 85 MS patients and 20 hypertensive patients. Neurologic impairment, mental health, and general health status were also assessed. MS patients reported significantly higher fatigue impact than hypertensive patients. Most MS patients reported fatigue as either their worst (14%), or one of their worst (55%) symptoms. Disease classification and neurologic impairment had little bearing on Fatigue Impact Scale scores in the MS sample. The best predictive models for mental health and general health status in the MS sample both included the Fatigue Impact Scale as a significant factor. This study demonstrates that: 1) fatigue is a very prevalent and severe problem in MS, 2) fatigue impact cannot be predicted by clinical measures of neurologic impairment, 3) fatigue has a significant effect on the mental health and general health status of MS patients.

Hospital-based psychiatric service utilization and morbidity in multiple sclerosis.

BACKGROUND: Despite the common association of psychiatric morbidity and multiple sclerosis (MS), population-based prevalence estimates of these disorders are limited. Such estimates are of particular importance to those conducting trials of interventions for the treatment of MS. This study examined the prevalence of bipolar disorder, depression, and attempted suicide among hospital service utilizers in Nova Scotia and compared these measures for the MS and non-MS population. METHODS: Data regarding diagnosis and utilization were extracted from two linked databases which included all hospital separation records for Nova Scotia over a 3 year period (1992/93-1994/95). RESULTS: The prevalence of bipolar disorder in hospitalized MS patients was 1.97% and depression was 4.27%. These rates were significantly higher than the 0.92% and 2.04%, respectively, for the non-MS hospital utilizers. These diagnoses also accounted for more than half of the primary diagnostic codes for psychiatric service separations by MS patients. The proportion of total hospital utilization which was accounted for by psychiatric services did not differ between MS and non-MS utilizers. While suicide attempts were rare, the estimated frequency of suicide attempts in the total MS population was more than three times that of the general population. CONCLUSIONS: Bipolar disorder and depression were twice as prevalent in hospitalized MS patients as in the general population of hospital utilizers while the estimated frequency of suicide attempts was at least three times greater. These results illustrate that psychiatric morbidity and service utilization are important considerations in the care of MS patients.

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.

Ethical guidelines of the Alzheimer Society of Canada.

Alzheimer's disease raises numerous ethical issues which vary and evolve over the course of the illness. In recognition of the need for ongoing discussion of these issues, the Alzheimer Society of Canada established a Task Force on Ethics in 1995. Through a process of "discourse ethics" and consultation on a national scale, the Task Force produced a series of guidelines dealing with the issues of: communicating the diagnosis, driving, respecting individual choice, quality of life, participation in research, genetic testing, the use of restraints, and end-of-life care. This manuscript presents a summary of these guidelines as well as a summary of the ideas on which they were based. It was the hope of the Society that the publication of these guidelines will serve to facilitate discussion of the ethics of care of those with Alzheimer's disease.

The effects of instructions to subjects on the programming of visually directed reaching movements.

Numerous studies of human motor control have examined the effects of constraints on the programming and execution of visually directed limb movements. Only a few studies, however, have explored how the subject's objective in making the movement affects the coordinated sequence of eye and limb movements that unfolds as the subject points to or grasps an object in space. In the present study, the characteristics of the targets and the environment remained constant while the demands for speed and accuracy were varied across blocks of trials by changing the instructions to the subject. In other words, the constraints operating in the situation were kept constant, but the objective of the movement was systematically varied by changing the relative demands for speed and accuracy. All subjects were required to point to visual targets presented on a screen in front of them. Eye position was monitored by infrared reflection. The position of each subject's hand in three-dimensional space was reconstructed by a computer-assisted analysis of the images provided by two rotary-shutter video cameras. The speed and accuracy demands of the task were varied in blocks of trials by requiring the subjects to point to the target "as quickly as you can" (speed condition); "as accurately as you can" (accuracy condition); or both "quickly and accurately" (speed/accuracy condition). The time to initiate an eye movement to the target was found to be reduced by increasing either the speed or accuracy demands of the task although the time to initiate the hand movement was reduced only in the speed condition. While the duration of the acceleration phase of the reach remained constant in real time, the duration of the deceleration phase was increased with increased demands for accuracy. As expected, both variable and absolute errors were largest in the speed condition. The findings indicated that the programming of the limb movement and its coordination with the associated eye movements were affected by varying the objective of the task.