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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.

Clinical analyses of patients with acquired dysgraphia provide unique opportunities to understand the cognitive and neural organization of written language production. We report J.B., a 50-year-old woman with peripheral dysgraphia who had prominent dissociations in her ability to write in lowercase versus uppercase and print versus cursive. We gave J.B. a series of tasks that evaluated her skills at writing uppercase and lowercase print and cursive, spelling aloud and in writing, writing numbers and symbols, and visual letter recognition and imagery. She was impaired in printing letters, with lowercase more affected than uppercase, but her cursive writing was relatively intact. This pattern was consistent across letter, word, and nonword writing tasks. She was unimpaired on tasks assessing her visual recognition and imagery of lowercase and uppercase letters. Her writing of numbers was preserved. J.B.'s handwriting disorder was accompanied by a central phonological dysgraphia. Our findings indicate functional independence of graphomotor programs for print and cursive letter styles and for letters and numbers. We discuss the relationship between peripheral and central writing disorders.

The oral Symbol Digit Modalities Test (SDMT) has been recommended to assess cognition for multiple sclerosis (MS) patients. However, the lack of adequate normative data has limited its clinical utility. Recently published regression-based norms may resolve this limitation but, because these norms were derived from a relatively small sample, their stability is unclear. We aimed to evaluate the stability of regression-based SDMT norms by comparing existing norms to a cross-validation dataset. First, regression-based normative data were created from a similarly-sized, independent, control sample (n = 94). Next the original and cross-validation norms were compared for equivalency, management of demographic influences, construct validity, and impairment classification rates in a mildly affected MS sample (n = 70). Lastly, similar comparisons were made for a large, representative MS clinic sample (n = 354). We found construct validity and management of demographic influences were equivalent for the two sets of regression-based norms but lower T-scores were obtained using the original dataset, resulting in discrepancies in impairment classification. In conclusion, regression-based norms for the oral SDMT attenuate demographic influences and possess adequate construct validity. However, norms generated using small samples may yield unreliable classification of cognitive impairment. Larger, representative databases will be necessary to improve the clinical utility of regression-based norms.

Background: Impairments in information processing speed are common in multiple sclerosis (MS), with affected individuals demonstrating slower responses and more intraindividual variability (IIV) in their performance on timed tasks. Evidence suggesting that IIV provides novel information about cognitive deficits in MS is accumulating; however, little is known about the stability of IIV across multiple assessments. In this study, we investigated IIV in response speed in persons with MS across 6 monthly sessions using the Attention Network Test-Interaction (ANT-I)., Method: Individuals with relatively mild relapsing remitting MS and healthy controls completed the ANT-I at 6 monthly intervals. Clinical assessments (Sessions 1 and 6) and conventional magnetic resonance imaging (MRI) studies (Sessions 1-6) were examined for individuals with MS., Results: The MS group's clinical and neuroimaging measures were stable during the 6-month period. Individuals with MS were slower and more variable in reaction time performance on the ANT-I than were controls. Differences in IIV between groups were maintained across the 6 sessions, with IIV demonstrating less susceptibility to across-session practice effects than mean latency scores., Conclusions: IIV provides a stable measure of cognitive performance in mildly affected persons with MS who are clinically and radiologically stable. Further studies exploring its utility as a clinical outcome are warranted.

Background: Estimates of incidence and prevalence are needed to determine disease risk and to plan for health service needs. Although the province of Nova Scotia, Canada is located in a region considered to have a high prevalence of multiple sclerosis (MS), epidemiologic data are limited., Objective: We aimed to validate an administrative case definition for MS and to use this to estimate the incidence and prevalence of MS in Nova Scotia., Methods: We used provincial administrative claims data to identify persons with MS. We validated administrative case definitions using the clinical database of the province's only MS Clinic; agreement between data sources was expressed using a kappa statistic. We then applied these definitions to estimate the incidence and prevalence of MS from 1990 to 2010., Results: We selected the case definition using ≥7 hospital or physician claims when >3 years of data were available, and ≥3 claims where less data were available. Agreement between data sources was moderate (kappa = 0.56), while the positive predictive value was high (89%). In 2010, the age-standardized prevalence of MS per 100,000 population was 266.9 (95% CI: 257.1- 277.1) and incidence was 5.17 (95% CI: 3.78-6.56) per 100,000 persons/year. From 1990-2010 the prevalence of MS rose steadily but incidence remained stable., Conclusions: Administrative data provide a valid and readily available means of estimating MS incidence and prevalence. MS prevalence in Nova Scotia is among the highest in the world, similar to recent prevalence estimates elsewhere in Canada., Incidence et prévalence de la sclérose en plaques en Nouvelle-Écosse, Canada.

Background: Multiple sclerosis (MS) is the most common cause of neurological disability in young adults worldwide and approximately half of those affected are in Europe. The assessment of differential incidence and prevalence across populations can reveal spatial, temporal and demographic patterns which are important for identifying genetic and environmental factors contributing to MS. However, study methodologies vary and the quality of the methods can influence the estimates. This study aimed to systematically review European studies of incidence and prevalence of MS and to provide a quantitative assessment of their methodological quality., Methods: A comprehensive literature search was performed to obtain all original population-based studies of MS incidence and prevalence in European populations conducted and published between January 1985 and January 2011. Only peer-reviewed full-text articles published in English or French were included. All abstracts were screened for eligibility and two trained reviewers abstracted the data and graded the quality of each study using a tool specifically designed for this study., Results: There were 123 studies that met the inclusion criteria. The study estimates were highly heterogeneous, even within regions or countries. Quality was generally higher in the more recent studies, which also tended to use current diagnostic criteria. Prevalence and incidence estimates tended to be higher in the more recent studies and were higher in the Nordic countries and in northern regions of the British Isles. With rare exceptions, prevalence and incidence estimates were higher in women with ratios as high as 3:1. Few studies examined ethnicity. Epidemiological data at the national level was uncommon and there were marked geographical disparities in available data, with large areas of Europe unrepresented and other regions well-represented in the literature. Only 37% of the studies provided standardized estimates., Conclusions: Despite the breadth of the literature on the epidemiology of MS in Europe, inter-study comparisons are hampered by the lack of standardization. Further research should focus on regions not yet studied and the evaluation of ethnic differences in MS prevalence and incidence. National-level studies using current diagnostic criteria, validated case definitions and similar age- and sex-standardization would allow better geographical comparisons.

Slowed information processing speed is commonly reported in persons with multiple sclerosis (MS), and is typically investigated using clinical neuropsychological tests, which provide sensitive indices of mean-level information processing speed. However, recent studies have demonstrated that within-person variability or intra-individual variability (IIV) in information processing speed may be a more sensitive indicator of neurologic status than mean-level performance on clinical tests. We evaluated the neural basis of increased IIV in mildly affected relapsing-remitting MS patients by characterizing the relation between IIV (controlling for mean-level performance) and white matter integrity using diffusion tensor imaging (DTI). Twenty women with relapsing-remitting MS and 20 matched control participants completed the Computerized Test of Information Processing (CTIP), from which both mean response time and IIV were calculated. Other clinical measures of information processing speed were also collected. Relations between IIV on the CTIP and DTI metrics of white matter microstructure were evaluated using tract-based spatial statistics. We observed slower and more variable responses on the CTIP in MS patients relative to controls. Significant relations between white matter microstructure and IIV were observed for MS patients. Increased IIV was associated with reduced integrity in more white matter tracts than was slowed information processing speed as measured by either mean CTIP response time or other neuropsychological test scores. Thus, despite the common use of mean-level performance as an index of cognitive dysfunction in MS, IIV may be more sensitive to the overall burden of white matter disease at the microstructural level. Furthermore, our study highlights the potential value of considering within-person fluctuations, in addition to mean-level performance, for uncovering brain-behavior relationships in neurologic disorders with widespread white matter pathology.

The Attention Network Test (ANT) assesses the networks of attention (alerting, orienting, and executive control). The utility of measuring attention network performances with the repeated administration of the ANT in clinical populations has not yet been explored. In the present study, we administered a variant of the ANT (ANT-I) to 11 multiple sclerosis (MS) patients and 11 controls over six monthly sessions to examine the stability, isolability, robustness, and reliability of the ANT-I. Participants responded through button presses to indicate the direction of a target arrow presented either above or below a fixation cross. The target was accompanied by distracting arrows, pointing either in the same or opposite direction of the target arrow. Target arrows were preceded in some trials by alerting auditory signals and/or by uninformative visual cues. Network scores were calculated using orthogonal subtractions of performance under selected conditions. The MS patients were slower than the controls, though group differences in network performance were rare. Even after five test sessions, the network scores remained stable, despite some practice effects that were the largest under conditions that tested the executive network. The reliabilities of the orienting and executive network effects were good in both groups and increased across sessions, especially with the MS patients. The alerting network was the least reliable, especially for MS patients, but it also became more reliable across sessions. The results suggest that the ANT-I can be used to measure the integrity of attention networks for MS patients in applications that require repeated testing., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Impairments in attention and information processing speed are common in multiple sclerosis (MS) and may contribute to impairments of other cognitive abilities. This study examined attentional efficiency, information processing speed and intra-individual variability in response speed using the Attention Network Test-Interactions (ANT-I) in mildy-affected patients with MS. Thirty-one patients with relapsing-remitting MS and 30 age, sex, and education-matched controls completed the ANT-I, as well as the Paced Auditory Serial Attention Test (PASAT), as a standard clinical measure of information processing efficiency. As expected, patients with MS were slower in reaction time performance on the ANT-I and had poorer performance on the PASAT compared to controls. Patients with MS also demonstrated poorer efficiency in their executive control of attention on the ANT-I, suggesting difficulties with top-down allocation of attention. In addition, the MS group demonstrated greater intra-individual variability in the responses to the ANT-I even when their slower overall response time and other factors such as practice were accounted for. Intra-individual variability was found to best predict group membership compared to PASAT scores and other ANT-I scores. These results suggest that intra-individual variability may provide sensitive, unique and important information regarding cognitive functioning in early MS.

Background: While mental comorbidity is considered common in multiple sclerosis (MS), its impact is poorly defined; methods are needed to support studies of mental comorbidity. We validated and applied administrative case definitions for any mental comorbidities in MS., Methods: Using administrative health data we identified persons with MS and a matched general population cohort. Administrative case definitions for any mental comorbidity, any mood disorder, depression, anxiety, bipolar disorder and schizophrenia were developed and validated against medical records using a a kappa statistic (k). Using these definitions we estimated the prevalence of these comorbidities in the study populations., Results: Compared to medical records, administrative definitions showed moderate agreement for any mental comorbidity, mood disorders and depression (all k ≥ 0.49), fair agreement for anxiety (k = 0.23) and bipolar disorder (k = 0.30), and near perfect agreement for schizophrenia (k = 1.0). The age-standardized prevalence of all mental comorbidities was higher in the MS than in the general populations: depression (31.7% vs. 20.5%), anxiety (35.6% vs. 29.6%), and bipolar disorder (5.83% vs. 3.45%), except for schizophrenia (0.93% vs. 0.93%)., Conclusions: Administrative data are a valid means of surveillance of mental comorbidity in MS. The prevalence of mental comorbidities, except schizophrenia, is increased in MS compared to the general population.

Objective: Fibromyalgia adversely affects quality of life, yet little is known of the epidemiology of this condition in MS. We aimed to validate and apply administrative case definitions for fibromyalgia in MS., Methods: Using administrative health data we identified persons with MS and an age-, sex- and geographically-matched general population (GP) cohort. Case definitions for fibromyalgia were developed using ICD-9/10 codes, validated against medical records, and applied to evaluate the incidence and prevalence of fibromyalgia., Results: The case definition for fibromyalgia with ≥5 hospital or physician claims in 3 years had a sensitivity of 60%, specificity of 98%, and agreed moderately with medical records (κ=0.48). In 2005, the age-standardized prevalence of fibromyalgia was 6.82% (95% CI: 5.91-7.72) in the MS population and 3.04% (95% CI: 2.77-3.32) in the GP. After adjustment for age, sex and year, the incidence of fibromyalgia was 44% higher in the MS than the GP (IRR 1.44; 95% CI: 1.01-2.07). The incidence of fibromyalgia increased slightly over time in both populations., Conclusion: The incidence and prevalence of fibromyalgia are higher in the MS population than the general population. Fibromyalgia should be considered in the management of pain in persons with MS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Frailty can be defined as the presence of multiple, interacting medical and functional problems. Frailty is associated with psychiatric conditions but its relation to psychological well-being is unclear. A "frailty identity crisis" has been proposed as a maladaptive response to the sense of self as health deficits accumulate. We evaluated this so-called identity crisis by investigating associations between well-being, frailty, and mortality in community-dwelling older Canadians., Methods: In this secondary analysis of the Canadian Study of Health and Aging (N = 5,703; age 70+), frailty was defined by an index of 33 health deficits. Psychological well-being was measured using Ryff's 18-item scale, with six domains (autonomy, personal growth, environmental mastery, positive relations, purpose in life, and self-acceptance). Cognition was measured using the Modified Mini-Mental State Examination. Associations between well-being, frailty, and mortality were measured using linear regression, adjusting for age, sex, education, cognition, and mental health., Results: For each additional frailty-defining deficit, the psychological well-being score worsened by 0.3 points (0.29, 95% CI: 0.22-0.36, p < 0.001), independent of age, sex, education, cognition, and mental health. Among the six domains of well-being, only "purpose in life" and "autonomy" were not associated with frailty (all others, p < 0.001). Worse psychological well-being was associated with five-year mortality independent of age, sex, education, frailty, and mental health; this association was not statistically significant when adjusting for baseline cognition., Conclusions: Frailty was associated with low levels of well-being. Psychological well-being impaired by a frailty identity crisis may play an important role in defining subjective health in older adults.

Objective: We examined the association between responses on a screening questionnaire and objective performance on a computer-administered test of cognitive abilities in systemic lupus erythematosus (SLE)., Methods: The Cognitive Symptom Inventory (CSI) and Hospital Anxiety and Depression Scales (HADS) questionnaires were compared in patients with SLE or rheumatoid arthritis (RA). The Automated Neuropsychological Assessment Metrics (ANAM) was used to evaluate cognitive performance in patients with SLE. Efficiency of performance was measured by "throughput" (number of correct responses per minute) and "inverse efficiency" (response speed/proportion of correct responses). Linear regression was applied to log-transformed CSI scores to examine their associations with ANAM scores and other factors., Results: Patients with SLE (n = 68) or RA (n = 33) were similar in age, sex, ethnicity, and education status (p > 0.05). Patients with SLE had higher total CSI scores (33.6 ± 10.5 vs 29.4 ± 6.8, respectively; p = 0.041) and attention/concentration subscale CSI scores (15.7 ± 5.3 vs 13.3 ± 3.4; p = 0.016) compared to patients with RA. In patients with SLE there was a positive association between CSI scores and neuropsychiatric (NP) events at the time of testing (p = 0.0006), HADS anxiety (p < 0.0001), and depression (p < 0.0001) scores. After adjustment for age, education, disease duration, and NP events at the time of testing, there was no significant association (p > 0.05) between ANAM and CSI scores in patients with SLE. The results were similar using either "throughput" or "inverse efficiency" or the number of impaired ANAM subscales after adjustment for simple reaction time., Conclusion: The CSI self-report questionnaire of cognitive symptoms does not reliably screen for efficiency of cognitive processing in patients with SLE. Rather, cognitive complaints reported in the CSI are influenced by the presence of anxiety and depression.

Deficits in information processing speed are among the most commonly reported impairments in multiple sclerosis (MS) and are generally assessed by evaluating mean-level performance on time-limited tests. However, this approach to assessing performance ignores potential within-subject differences in MS patients that may be useful for characterizing cognitive difficulties in MS. An alternative method of measuring performance is by examining the degree of within-subject variability, termed intra-individual variability (IIV). Intra-individual variability provides information about the characteristics of a person's performance over time and may provide novel information about cognitive functioning in MS. This study examined IIV in performance on the Computerized Test of Information Processing (CTIP) using two within-subject variability methods: individual standard deviation and coefficient of variation. Eighteen females with relapsing-remitting MS and 18 healthy female controls completed the CTIP. Consistent with previous research, MS patients demonstrated slower overall mean performance on the CTIP compared with controls, with patients becoming increasingly slower than controls as cognitive demands increased across the tasks. Furthermore, MS patients demonstrated greater IIV as measured by individual standard deviations on all subtests of the CTIP, even with mean-level group differences as well as practice and learning effects controlled. These between-group differences were not found when the coefficient of variation, a more coarse measure of within-subject variability, was used. Intra-individual variability was also found to be a better predictor of neurologic status than mean-level performance. These results suggest that IIV may provide unique insight into cognitive functioning in MS.

Accumulation of central nervous system (CNS) pathology affects cognitive processing speed and efficiency and is thought to underlie attentional and executive deficits in multiple sclerosis (MS). Most clinical neuropsychological tests are multifactorial and are limited in their sensitivity to specific cognitive processes. This may, in part, account for the low to moderate correlations between clinical test results and magnetic resonance imaging (MRI) indices of brain pathology. We compared the ability of a clinical and an experimental test of cognitive processing speed to differentiate domain-specific cognitive changes in MS, and examined relations between test performance and MRI measures of brain pathology. Twelve MS patients and 12 controls completed the Paced Auditory Serial Addition Test (PASAT) and the Attention Networks Test-Interactions (ANT-I), a computerized response latency task. Subjects also had MRI scans that included T1, T2, and fluid-attenuated inversion recovery (FLAIR) sequences that provided global and localized volumetric measures. Patients made more errors on the PASAT and were slower on the ANT-I. The ANT-I also revealed specific deficits in response inhibition. In addition, ANT-I performance was associated with changes in a number of MRI measures, which was not the case for the PASAT. Reaction time paradigms that manipulate within-task demands on distinct cognitive functions may provide meaningful markers of brain disease burden in MS.

Purpose: The purpose of this study was to describe the factors influencing healthy aging from the perspective of the older person with multiple sclerosis (MS) in order to build curricula for MS self-management programs., Method: We sourced participants, older than 55 years with MS for more than 20 years, from a database of MS clinic and outpatient rehabilitation visits. Recruitment continued until data saturation was reached (n = 18). Semi-structured interviews explored perspectives on aging and health and lifestyle habits. Demographic, lifestyle and perceived health status information was also gathered. We analyzed the transcribed text for themes and theme relationships., Results: Work and social engagement, effective and accessible health care, healthy lifestyle habits, and maintaining independence at home were found to be critical proximal factors for healthy aging. The presence of financial flexibility, social support, cognitive and mental health, and resilience provided a supporting foundation to these critical proximal factors. These factors comprised a two-tiered model of healthy aging with MS., Conclusions: This two-tiered conceptual model of health aging, based on the perspectives of older persons with MS, provides a potential framework for the development of MS self-management program curricula aimed at optimizing quality of life. Further empirical testing may validate its utility in predicting healthy aging with MS.

Evidence from imaging, clinical studies, and pathology suggests that Parkinson's disease is preceded by a prodromal stage that predates clinical diagnosis by several years but there is no established method for detecting this stage. Olfactory impairment, which is common in Parkinson's disease and often predates clinical diagnosis, may be a useful biomarker for early Parkinson's. Evidence is emerging that diffusion imaging parameters might be altered in olfactory tract and substantia nigra in the early stages of clinical Parkinson's disease, possibly reflecting pathological changes. However, no study has examined olfaction and diffusion imaging in olfactory tract and substantia nigra in the same group of patients. The present study compared newly diagnosed Parkinson's disease patients with a matched control group using both olfactory testing and diffusion tensor imaging of the substantia nigra and anterior olfactory structures. Fourteen patients with stage 1-2 Hoehn & Yahr Parkinson's disease were matched to a control group by age and sex. All subjects then completed the University of Pennsylvania Smell Identification Test, as well as a series of MRI scans designed to examine diffusion characteristics of the olfactory tract and the substantia nigra. Olfactory testing revealed significant impairment in the patient group. Diffusion tensor imaging revealed significant group differences in both the substantia nigra and anterior olfactory region, with fractional anisotropy of the olfactory region clearly distinguishing the Parkinson's subjects from controls. This study suggests that there may be value in combining behavioral (olfaction) and MRI testing to identify early Parkinson's disease. Since loss of olfaction often precedes the motor symptoms in Parkinson's disease, the important question raised is "will the combination of olfactory testing and MRI (DTI) testing identify pre-motor Parkinson's disease?"

Background: Prefrontal cortical lobe function is related to social behavior in humans. We investigated whether performance on tests of prefrontal cortical function was associated with social vulnerability. Associations with non-frontal cognitive function were investigated for comparison., Methods: 1216 participants aged 70+ of the Canadian Study of Health and Aging-2 screening examination, who also underwent detailed neuropsychological testing, comprised the study sample. Performance on WAIS-R abstraction, WAIS-R comprehension, Trails B, FAS and category verbal fluency, Block construction, Token Test and Wechsler Memory Scale Information Subset was tested in relation to the participant's level of social vulnerability using regression models adjusted for age, education, sex, frailty, MMSE score, diagnosis of depression, and use of psychoactive medications. Social vulnerability was measured by an index comprising many social problems or "deficits"., Results: The most socially vulnerable group had worse performance on FAS verbal fluency, generating 4.1 fewer words (95% CI: 1.8-6.4, p<0.001) than those in the least socially vulnerable group; those with intermediate social vulnerability generated 2.6 fewer words (95% CI: 0.4-4.8, p = 0.02). Social vulnerability was also associated, though less strongly, with category verbal fluency. The most socially vulnerable people had impaired performance on the Trails B, taking 37 seconds longer (95% CI: 11-63, p = 0.005). These results were independent of age, education, sex, frailty, MMSE score, depression, and psychoactive medications. Social vulnerability was not associated with performance on WAIS-R abstraction, WAIS-R comprehension, Block Design, Token Test or Wechsler Memory Scale tests., Conclusions: High social vulnerability was associated with impaired performance on verbal fluency and set shifting but not with common sense judgment, abstraction, long-term memory, constructional ability, or language comprehension. The association between social functioning and the cognitive functions subserved by prefrontal cortex warrants further study.

Background: A brain atrophy and lesion index (BALI) based on high-field magnetic resonance imaging (MRI) has recently been validated to evaluate structural changes in the aging brain. The present study investigated the two-year progression of brain structural deficits in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI), and in healthy control older adults (HC) using the BALI rating., Methods: T1-weighted high-resolution anatomical imaging data using 3 Tesla MRI at baseline (AD = 39, MCI = 82, HC = 58) and at 24-months were obtained from the Alzheimer's disease Neuroimaging Initiative database. Lesions in various brain structures, including the infratentorial and basal ganglia areas, and the periventricular and deep white matter and global atrophy, were evaluated and combined into the BALI scale., Results: Mean progression of brain deficits over two years was evident in all diagnostic groups (p < 0.001) and was statistically greater in MCI-AD converters than in the non-converters (p = 0.044). An increase in the BALI score was significantly associated with cognitive test scores (p = 0.008 for the Mini-Mental State Examination MMSE and p = 0.013 for the Alzheimer's Disease Assessment Scale-Cognitive Subscale ADAS-cog) in a model that adjusted for age, sex, and education., Conclusion: The BALI rating quantified the progression of brain deficits over two years, which is associated with cognitive decline. BALI ratings may be used to help summarize AD-associated structural variations.

Purpose: The Fatigue Impact Scale (FIS) has been used extensively to assess the impact of fatigue on health-related quality of life (HRQOL) in multiple sclerosis (MS). The objective of this study was to estimate the minimally important difference (MID) of the FIS to facilitate the interpretation of the scale in patients with MS., Methods: Data came from a cross-sectional study of 184 patients with MS. Anchor-based estimates of the MID were evaluated using patients' ratings of their own health and a clinical rating of MS severity. Using the proportional odds model, estimates of the MID were evaluated by finding FIS score differences that corresponded to a 50% increase in the odds of poorer health. Convergence between distribution- and anchor-based estimates was assessed., Results: Nineteen items met the selection criteria for anchors. Triangulation of the anchor- and distribution-based approaches indicated that the MID of the FIS ranged between 10 and 20 points, approximately., Conclusion: A common metric of meaningful difference of FIS was defined across anchors measuring a broad range of HRQOL domains. The MID estimates in the current study can be used for sample size calculation in the planning of future studies and to aid researchers and clinicians in interpreting FIS score differences in patients with MS.

Butyrylcholinesterase (BuChE) is an enzyme capable of hydrolysing a wide variety of esters including acetylcholine, a molecule involved in neurotransmission and modulation of immune cell activity. In the brain, BuChE is expressed in white matter and certain populations of neurons and glia. Multiple sclerosis (MS) is an autoimmune disease affecting white matter characterized by neuroinflammation and neurodegeneration in the central nervous system. Here we demonstrate alterations in BuChE activity in MS white matter lesions, including diminished enzyme activity associated with myelin and an increased activity in cells with microglial morphology. Increased BuChE activity within MS lesions could contribute to the pro-inflammatory immune responses through hydrolysis of acetylcholine and to demyelination through hydrolytic deacylation of myelin proteins such as proteolipid protein. This suggests that BuChE could be a potential target for novel disease-modifying strategies for MS., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: Computerized neuropsychological testing may facilitate screening for cognitive impairment in systemic lupus erythematosus (SLE). This study was undertaken to compare patients with SLE, patients with rheumatoid arthritis (RA), and patients with multiple sclerosis (MS) with healthy controls using the Automated Neuropsychological Assessment Metrics (ANAM)., Methods: Patients with SLE (n = 68), RA (n = 33), and MS (n = 20) were compared with healthy controls (n = 29). Efficiency of cognitive performance on 8 ANAM subtests was examined using throughput (TP), inverse efficiency (IE), and adjusted IE scores. The latter is more sensitive to higher cognitive functions because it adjusts for the impact of simple reaction time on performance. The results were analyzed using O'Brien's generalized least squares test., Results: Control subjects were the most efficient in cognitive performance. MS patients were least efficient overall (as assessed by TP and IE scores) and were less efficient than both SLE patients (P = 0.01) and RA patients (P < 0.01), who did not differ. Adjusted IE scores were similar between SLE patients, RA patients, and controls, reflecting the impact of simple reaction time on cognitive performance. Thus, 50% of SLE patients, 61% of RA patients, and 75% of MS patients had impaired performance on >or=1 ANAM subtest. Only 9% of RA patients and 11% of SLE patients had impaired performance on >or=4 subtests, whereas this was true for 20% of MS patients., Conclusion: ANAM is sensitive to cognitive impairment. While such computerized testing may be a valuable screening tool, our results emphasize the lack of specificity of slowed performance as a reliable indicator of impairment of higher cognitive function in SLE patients.

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.

Objective: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS) compared to best supportive care in the United States., Methods: Cost-effectiveness analysis was undertaken using a state transition model of disease natural history and the impact of DMTs for the representative Medicare beneficiary with MS. Costs and outcomes were evaluated from the health-care payer perspective using a 50-year time horizon. Natural history data were drawn from a longitudinal cohort study. The effectiveness of the DMTs was evaluated through a systematic review. Utility data were taken from a study of patients with clinically definite MS in Nova Scotia. Resource use and cost data were derived from the Sonya Slifka database and associated literature., Results: When based on placebo-controlled evidence, the marginal cost-effectiveness of interferon beta (IFNβ) and glatiramer acetate compared to best supportive care is expected to be in excess of $100,000 per quality-adjusted life-year gained. When evidence from head-to-head trials is incorporated into the model, the cost-effectiveness of 6 MIU IFNβ-1a is expected to be considerably less favorable. Treatment discontinuation upon progression to Expanded Disability Status Scale 7.0 is expected to improve the cost-effectiveness of all DMTs., Conclusions: Further research is required to examine the long-term clinical effectiveness and cost-effectiveness of these therapies. There is no definitive guidance in the United States concerning discontinuation of DMTs; this study suggests that the prudent use of a treatment discontinuation rule may considerably improve the cost-effectiveness of DMTs.

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.

Background: Practising physicians frequently seek advice on the most effective interventions for dementia. In this article, we provide practical guidance on nonpharmacologic and pharmacologic interventions for the management of mild to moderate dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia., Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of mild to moderate stages of Alzheimer disease and other forms of dementia. Recommendations based on the literature review were drafted and voted on. Consensus required 80% or more agreement by participants. Subsequent to the conference, we searched for additional articles published from January 2006 to April 2008 using the same major keywords and secondary search terms. We graded the strength of the evidence using the criteria of the Canadian Task Force on Preventive Health Care., Results: We identified 1615 articles, of which 954 were selected for further study. From a synthesis of the evidence in these studies, we made 48 recommendations for the management of mild to moderate dementia (28) and dementia with a cerebrovascular component (8) as well as recommendations for addressing ethical issues (e.g., disclosure of the diagnosis) (12). The updated literature review did not change these recommendations. An exercise program is recommended for patients with mild to moderate dementia. Physicians should decide whether to prescribe a cholinesterase inhibitor on an individual basis, balancing anticipated benefits with the potential for harm. For mild mood and behavioural concerns, nonpharmacologic approaches should be considered first., Interpretation: Although the available therapies for dementia can help with the management of symptoms, there is a need to develop more effective interventions.

Background: The management of mild to moderate dementia presents complex and evolving challenges. Practising physicians are often uncertain about the appropriate approaches to issues such as the disclosure of the diagnosis, driving and caregiver support. In this article, we provide practical guidance on management based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia., Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of mild to moderate stages of Alzheimer disease and other forms of dementia. Recommendations based on the literature review were drafted and voted on. Consensus required 80% or more agreement by participants. Subsequent to the conference, we searched for additional articles published from January 2006 to April 2008 using the same major keywords and secondary search terms. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care., Results: We identified 1615 articles, of which 954 were selected for further study. From a synthesis of the evidence in these studies, we made 48 recommendations for the management of mild to moderate dementia (28) and dementia with a cerebrovascular component (8) as well as recommendations for addressing ethical issues (e.g., disclosure of the diagnosis) (12). The updated literature review did not change these recommendations. In brief, patients and their families should be informed of the diagnosis. Although the specifics of managing comorbid conditions might require modification, standards of care and treatment targets would not change because of a mild dementia. The use of medications with anticholinergic effects should be minimized. There should be proactive planning for driving cessation, since this will be required at some point in the course of progressive dementia. The patient's ability to drive should be determined primarily on the basis of his or her functional abilities. An important aspect of care is supporting the patient's primary caregiver., Interpretation: Much has been learned about the care of patients with mild to moderate dementia and the support of their primary caregivers. There is a pressing need for the development, and dissemination, of collaborative systems of care.

We report the development of diacid units that promote formation of a two-stranded parallel beta-sheet secondary structure between peptide segments attached via their N-termini. These linker units are formed by attaching glycine to one carboxyl group of cis-1,2-cyclohexanedicarboxylic acid (CHDA). Parallel sheet formation in water is observed when l-residue strands are attached to the CHDA-Gly unit with either of the two absolute configurations.

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.

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.

Most ethical guidelines strongly promote disclosure of a diagnosis of dementia to the affected individual, based on the principle of autonomy. Nevertheless, codes of medical ethics allow for various interpretations of this issue and surveys of clinical practice illustrate that such disclosure is by no means the rule. We argue that diagnostic disclosure for persons with dementia must be considered a process that begins when cognitive impairment is first suspected and that evolves over time as information is obtained. Whenever possible and appropriate, this process should involve not only the affected individual but also their family and/or other current or potential future care providers. Once a diagnosis is established it should be disclosed in a manner consistent with the expressed wishes of the patient, using an individualized patient-centered approach that maintains the individual's personal integrity. Diagnostic disclosure of dementia is a process that may require additional time as well as follow-up or referral to other specialists. We recommend that a progressive disclosure process be employed to address issues including: remaining diagnostic uncertainty, treatment options, future plans, financial planning, assigning power of attorney, wills and "living wills", driving privileges and the need for eventual driving cessation, available support services, and potential research participation. The potential for adverse psychological consequences to diagnostic disclosure must be assessed and these should be addressed through education and support of the patient and their family/caregivers throughout the diagnostic disclosure process. At present, few data are available regarding patients' perspectives on the diagnostic disclosure process and its consequences. This limitation and the apparent discrepancies in physician and caregiver opinions about the disclosure process, make it incumbent upon health care professionals to evaluate the diagnostic disclosure process within their practice.

This evidence-based review examines the utility of brief cognitive tests and neuropsychological testing (NPT) in the detection and diagnosis of mild cognitive impairment (MCI) and dementia. All patients presenting with cognitive complaints are recommended to have a brief screening test administered to document the presence and severity of memory/cognitive deficits. There is fair evidence to support the use of a range of new screening tests that can detect MCI and mild dementia with higher sensitivity (>or=80%) than the Mini-Mental State Exam (MMSE). NPT should be part of a clinically integrative approach to the diagnosis and differential diagnosis of dementia. It should be applied selectively to address specific clinical and diagnostic issues including: 1) The distinction between normal cognitive functioning in the aged, MCI and early dementia: there is fair evidence that NPT can document the presence of specific diagnostic criteria and provide additional useful information on the pattern of memory/cognitive impairment. 2) The evaluation of risk for Alzheimer disease (AD) or other types of dementia in persons with MCI: there is fair evidence that NPT measures or profiles can predict progression to dementia (predictive accuracy ranges from approximately 80 to 100%, sensitivities from 53 to 80%, and specificities from 67 to 99%). 3) DIFFERENTIAL DIAGNOSIS: There is fair evidence that NPT can complement clinical history and neuroimaging in determining the dementia etiology. Different dementia types have distinguishable NPT profiles though these may be stage-dependent, and increased sensitivity may be at the expense of specificity. 4) When NPT is part of a comprehensive assessment, which also entails clinical interviews and consideration of other clinical data, there is good evidence that it can contribute to management decisions in MCI and dementia, including the determination of retained and impaired cognitive abilities, their functional and vocational impact, and opportunities for cognitive rehabilitation.

Here we review issues of patient decision-making and consent to treatment and research by persons with cognitive impairment and dementia. Clinicians and researchers must recognize their primary duty to care for the individual and must clearly distinguish their role as a clinician and/or researcher. Distinctions between standard care and research must be clearly understood by everyone, as must the clinician's role in each. Both actual and perceived conflicts of interest must be avoided. At present there is insufficient evidence to recommend specific methods for determining competency for decision-making, but a diagnosis of cognitive impairment or dementia does not preclude such competence. Competency is not a unitary or static construct and must be considered as the ability to make an informed decision about participation in the particular context of the specific treatment or study. Clinicians and researchers should consider consent as a process involving both the patient with cognitive impairment and his or her family/caregiver, particularly given the potential that competency for decision-making will change over time. As the availability of advance directives remains limited, clinicians and researchers must make efforts to ensure that decisions made by proxies are based on the prior attitudes and values of the patient.

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.

We describe a 59-year-old woman, M.T., with a progressive language impairment and neuroimaging findings of decreased perfusion (SPECT) and focal atrophy (MRI) in the left temporal region. The most prominent feature of her cognitive profile was a profound and progressive impairment in naming. In spite of this, she performed normally on tests of semantic processing and phonological output. Her spontaneous speech was fluent with preserved syntax and articulation but with notable word-finding problems. All other cognitive abilities were relatively stable and intact. These features are not typical of either fluent or non-fluent forms of neurodegenerative language disturbance. The cognitive mechanisms that may underlie this case are discussed.

Clinical trials in persons with dementia bring into focus the ethical dilemmas frequently confronting the clinician-scientist. Despite the existence of various ethical guidelines, most with common underlying principles, few are specific to dementia. A particular difficulty is finding a balance between respect for the autonomy of the individual and the protection of vulnerable persons, while at the same time defining an acceptable risk/benefit ratio for the study. The availability of symptomatic treatments for Alzheimer's disease also now make it difficult to argue that withholding treatment from those in the placebo arm of a clinical trial fulfills one's duty to provide best care. Those conducting clinical trials must be knowledgeable about existing legislation and ethical guidelines in order to justify to themselves and others, the design of clinical trials and their risks. They must be prepared to educate patients and family members about dementia and research, determine each potential subject's competence to consent, and ensure that decisions about participation are in accordance with the best interests of the subject. Ethical conduct of clinical trials of new antidementia therapies will require that everyone involved understands the values and beliefs that guide their decision-making and the potentially conflicting roles facing the clinician-scientist.

Rapid adsorption kinetics have been observed for protein binding to a 800 nm aggregated nanoparticle, showing extreme sensitivity resulting from a non-linear particle plasmon response.

Objective: To determine the prevalence of circulating anti-NR2 antibodies and their association with neuropsychiatric systemic lupus erythematosus (NP-SLE), particularly cognitive function, in women with SLE., Methods: Cognitive function was assessed in 65 consecutive women with SLE from a single referral center using standardized neuropsychological tests. These were selected subtests of the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the California Verbal Learning Test, which provided information on 8 areas of cognitive function. After a mean followup of 64 (range 52-71) months, cognitive assessments were repeated. Global and domain-specific cognitive impairment was examined using predetermined decision rules, and the change in individual tests of cognitive performance over time was also examined. Overt NP-SLE was identified by clinical assessment and classified using the American College of Rheumatology nomenclature. Circulating IgG anti-NR2 and anti-dsDNA antibodies were determined by ELISA on up to 4 occasions over the study period. A positive result was defined as at least 3 standard deviations above the mean of healthy controls., Results: At enrollment, 15/65 (23%) patients had cognitive impairment. This fell to 7/54 (13%) at followup. In addition 15/65 (23%) patients had a history of clinically overt NP-SLE. Twenty-three of 65 (35%) patients had anti-NR2 antibodies and 48/65 (74%) had anti-dsDNA antibodies. Anti-NR2 antibodies were present in 18/48 (38%) patients with anti-DNA antibodies, and 18/23 patients (78%) with anti-NR2 antibodies also had anti-dsDNA antibodies. There was no association between global cognitive impairment, domain-specific cognitive impairment, or a history of clinically overt NP-SLE and either the presence or amount of anti-NR2 or anti-dsDNA antibodies (p > 0.05). When change in cognitive performance or the occurrence of new NP-SLE events over the 5-year followup period was examined, there was no significant association with persistent elevation of either antibody (p > 0.05). Similarly there was no association between a rise in autoantibodies over time and the development of overt NP events or cognitive decline (p > 0.05)., Conclusion: These results indicate that anti-NR2 antibodies occur in 35% of women with SLE and are infrequent in the absence of detectable anti-dsDNA antibodies. Their presence in the circulation is not associated with cognitive dysfunction at a single timepoint, and an increase in or persistently elevated antibody levels are not associated with a change in cognitive performance over time. There was no association with clinically overt NP-SLE. However, as our study did not examine cerebrospinal fluid samples, these results do not exclude a potential pathogenic role in selected patients for this group of autoantibodies should they penetrate the blood-brain barrier and thereby gain direct access to neuronal tissues.

We report the first thermodynamic analysis of parallel beta-sheet formation in a model system that folds in aqueous solution. NMR chemical shifts were used to determine beta-sheet population, and van't Hoff anaysis provided thermodynamic parameters. Our approach relies upon the d-prolyl-1,1-dimethyl-1,2-diaminoethane unit to promote parallel beta-sheet formation between attached peptide strands. The development of a macrocyclic reference molecule to provide chemical shift data for the fully folded state was crucial to the quantitative anaylsis.

In this paper, we present an illustrative case of Semantic Dementia (SD) and we review the literature on this relatively rare progressive neurodegenerative disorder. After reviewing the clinical, neuroimaging, neuropathological, and genetic features of SD, we propose a theoretical framework that addresses features of SD and relates them to features of other well known neuropsychiatric syndromes. Our 'on-line / off-line disconnection' model seeks to conceptualize SD as a syndrome of disconnection between two large distributed cortical networks, namely, between those networks that subserve language function and those that subserve memory function.

The pH-dependent adsorption isotherms for the charged chromophore crystal violet, CV(+), have been measured with three different bases by a free-running cavity implementation of evanescent wave cavity ring-down spectroscopy. The ratio of the maximal absorbance measurements at pH 5.10 and 9.05 is consistent with a Q2:Q3 silanol site ratio of 72.8:27.2. The adsorption isotherms have been interpreted in terms a cooperative binding adsorption allowing more than one ionic species to bind to each silanol group. The surface concentration is consistent with a silanol charge density of 1.92 +/- 0.55 nm(-2) and a total neutralized interface layer structure extending 9 nm from the surface. Binding constants and stoichiometric coefficients are derived for CV(+) to both the Q2 and Q3 sites. A variation of the adsorption isotherm with base is observed so that the isotherm at pH 9.05 adjusted with ammonium hydroxide sets up a competitive acid-base equilibrium with the SiOH groups with only 49% of the surface silanol sites dissociated. The implications for functionalized surfaces in chromatography are discussed.

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.

Objective: The cause of neurologic (N) and psychiatric (P) syndromes in patients with systemic lupus erythematosus (SLE) is mutifactorial and includes primary immunopathogenic mechanisms, nonspecific sequelae of chronic disease, and concurrent illnesses. We compared the prevalence, diversity, and clinical significance of NP syndromes in patients with SLE and rheumatoid arthritis (RA)., Methods: Fifty-three patients with SLE were matched by age and sex to 53 patients with RA attending ambulatory clinics in a single academic medical center. All fulfilled the American College of Rheumatology (ACR) classification criteria for either SLE or RA. Cumulative NP manifestations were determined using the ACR nomenclature and case definitions for 19 NP syndromes. Depression and anxiety were measured by the Hospital Anxiety and Depression Scales (HADS) and symptoms of cognitive dysfunction were assessed by the Cognitive Symptoms Inventory (CSI). Health related quality of life (HRQOL) was evaluated by the SF-36 and fatigue by a 10 point Likert scale., Results: The patients were well matched with regard to age, sex, disease duration, and years of education. There were no significant differences in self-reported HRQOL, fatigue, anxiety, depression, and cognitive symptoms between the 2 groups. The proportion of patients with cumulative NP events was higher in RA than in SLE patients (47% vs 28%; p = 0.045), and of these the occurrence of multiple NP events in individual patients was comparable in both groups (SLE 53%; RA 48%; p = 0.75). Fifty-five percent and 66% of NP events occurred prior to the diagnosis of SLE and RA, respectively. NP events common to both SLE and RA patients were headaches, mood disorders, acute confusional states, anxiety, cerebrovascular disease, and cognitive dysfunction. Seizures and demyelinating syndrome occurred only in SLE patients, but were rare. Depression scores (HADS) were significantly higher in SLE patients with a history of cumulative NP events compared to RA patients with NP events (p = 0.02). Similarly, symptoms of cognitive dysfunction (CSI) were more common in SLE patients with a history of NP manifestations (p = 0.02). However, there were no significant differences in SF-36 subscale or fatigue scores between SLE and RA patients with cumulative NP events., Conclusion: NP syndromes, regardless of etiology, are common in both SLE and RA patients. SLE patients with NP syndromes report more symptoms of depression and cognitive dysfunction compared to RA patients with NP syndromes, but do not report significantly poorer HRQOL. These results emphasize the presence of non-disease-specific causes of NP manifestations in SLE patients, which should be acknowledged in future studies of pathogenesis and treatment.

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.