Impairment of daily occupations in multiple sclerosis: analysis of neuroimaging, general and social cognition, and reserve.

BACKGROUND: Multiple Sclerosis (MS) can impact performance of daily occupations in both relapsing-remitting (RRMS) and secondary-progressive (SPMS) clinical courses. Work force participation decreases with advancing physical disability but the influence of non-motor factors, neuroimaging, and reserve have been scarcely investigated. We aimed to evaluate MRI, clinical, and cognitive (social and general) factors associated with impairment in different daily occupations and address whether cognitive and brain reserve have a positive impact on the ability to maintain these activities. METHODS: We prospectively enrolled persons with MS (PwMS) who underwent clinical examination (Expanded Disability Status Scale - EDSS; Timed 25-Foot Walk Test - T25FW; and the Nine Hole Peg Test - 9HPT), general neuropsychological assessment (Brief Repeatable Battery of Neuropsychological Tests - BRBN, including the Symbol Digit Modalities Test - SDMT), social cognition evaluation (Reading the Mind in the Eyes Test), cognitive reserve questionnaire, and MRI (FreeSurfer). We also enrolled healthy subjects for comparison as a control group. Daily occupations (employment, money management, and driving abilities) were assessed in all individuals with questionnaires. RESULTS: We included 62 PwMS (32 RRMS and 30 SPMS; mean age 42.8 years; median educational time 12.75 years) and 67 controls (mean age 39.7; median educational time 12.0 years) which were similar regarding demographics, education, and socioeconomic status (p > 0.1). Most PwMS (67.7%) had work-restrictions. They also reported fewer money management and driving abilities than controls (p < 0.001). Work-restriction was associated with physical disability (p = 0.006), SDMT and BRBN performance (p = 0.035 and p = 0.031, respectively), and T2-lesion volume (p = 0.022), with large effect sizes (d > 0.75). After hierarchical linear regression, money management was associated with hand dexterity, general and social cognition, and cognitive reserve (p < 0.03). Variables associated with driving abilities included fatigue, verbal fluency, striatum volume, and brain reserve (p < 0.05). CONCLUSIONS: PwMS have more frequent work-restrictions and impairment in money management and driving abilities compared to controls. Cognitive function, physical disability, and MS-lesion burden are strongly associated with work-restriction. Social cognition can also influence financial capacity. Cognitive and brain reserve can help retain some of these daily occupations.

Are we ready to define cognitive worsening in MS? How different cutoffs detect future cognitive worsening after six years of follow-up.

BACKGROUND: Although cognitive evaluation has been incorporated in recent MS clinical trials, the definition of cognitive progression is not clear and recent data are questioning the 4-point cutoff using the SDMT at the individual level. We aimed to evaluate the behavior of cognitive performance over time using different cutoffs. METHODS: Cognitive performance over six years was analyzed in a cohort of 42 relapsing-remitting MS patients and 30 controls using verbal/visual memory and information processing speed tests. Fixed cutoffs were: 10% and 20% change (all tests) and a 4- and 8-point change (SDMT). The relative cutoff established by regression-based models was a 1SD change. RESULTS: The distributions of "worsening", "stability", and "improvement" showed low concordance rates across the cutoffs (p < 0.001 for most comparisons). Most patients classified with worsening initially using fixed cutoffs had subsequent improvement in all cognitive tests, yielding a low sensitivity to predict later cognitive worsening. Using the relative cutoff, the proportion of patients with subsequent improvement was noticeably smaller. CONCLUSIONS: Fixed cutoffs classify a high proportion of patients with cognitive improvement. Most patients categorized with worsening initially presented subsequent improvement. Instead, the relative cutoff generally had a better performance. These data raise concerns about how we are defining cognitive worsening so far, especially at the individual level.

Diagnosis of Alzheimer's disease: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology.

This paper presents the consensus of the Scientific Department of Cognitive Neurology and Aging from the Brazilian Academy of Neurology on the diagnostic criteria for Alzheimer's disease (AD) in Brazil. The authors conducted a literature review regarding clinical and research criteria for AD diagnosis and proposed protocols for use at primary, secondary, and tertiary care levels. Within this clinical scenario, the diagnostic criteria for typical and atypical AD are presented as well as clinical, cognitive, and functional assessment tools and complementary propaedeutics with laboratory and neuroimaging tests. The use of biomarkers is also discussed for both clinical diagnosis (in specific conditions) and research.

Este artigo apresenta o consenso realizado pelo Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia sobre os critérios diagnósticos da Doença de Alzheimer (DA) no Brasil. Foi realizada uma revisão da literatura e dos critérios clínicos e de pesquisa para DA, sendo propostos protocolos para o diagnóstico de DA em níveis de atenção primária, secundária e terciária. Dentro deste cenário clínico, são apresentados os critérios diagnósticos para DA típica e atípica, além de instrumentos de avaliação clínica, cognitiva e funcional; bem como propedêutica complementar com exames laboratoriais e de neuroimagem. A utilização de biomarcadores é também apresentada, tanto para o diagnóstico clínico em situações específicas quanto para pesquisa.

Diagnóstico da doença de Alzheimer: recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia / Diagnosis of Alzheimer's disease: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology

RESUMO Este artigo apresenta o consenso realizado pelo Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia sobre os critérios diagnósticos da Doença de Alzheimer (DA) no Brasil. Foi realizada uma revisão da literatura e dos critérios clínicos e de pesquisa para DA, sendo propostos protocolos para o diagnóstico de DA em níveis de atenção primária, secundária e terciária. Dentro deste cenário clínico, são apresentados os critérios diagnósticos para DA típica e atípica, além de instrumentos de avaliação clínica, cognitiva e funcional; bem como propedêutica complementar com exames laboratoriais e de neuroimagem. A utilização de biomarcadores é também apresentada, tanto para o diagnóstico clínico em situações específicas quanto para pesquisa.

ABSTRACT This paper presents the consensus of the Scientific Department of Cognitive Neurology and Aging from the Brazilian Academy of Neurology on the diagnostic criteria for Alzheimer's disease (AD) in Brazil. The authors conducted a literature review regarding clinical and research criteria for AD diagnosis and proposed protocols for use at primary, secondary, and tertiary care levels. Within this clinical scenario, the diagnostic criteria for typical and atypical AD are presented as well as clinical, cognitive, and functional assessment tools and complementary propaedeutics with laboratory and neuroimaging tests. The use of biomarkers is also discussed for both clinical diagnosis (in specific conditions) and research.

Neuropsychiatric Symptoms in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease: A 12-Month Follow-Up Study.

Introduction: Neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) are highly prevalent and may complicate clinical managements. Objective: To test whether the Neuropsychiatry Inventory (NPI) could detect change in neuropsychiatric symptoms and caregiver's distress in patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) from baseline to a 12-month follow-up and to investigate possible predictors of change in NPI scores. Methods: The sample consisted of 31 patients diagnosed with bvFTD and 28 patients with AD and their caregivers. The Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination Revised (ACE-R), the INECO Frontal Screening (IFS), the Frontal Assessment Battery (FAB), the Executive Interview (EXIT-25) and the NPI were applied. Descriptive statistics, Mann-Whitney U test, Wilcoxon test, Chi square (χ2) test and Linear Regression Analysis were used. Results: NPI total and caregiver distress scores were statistically higher among bvFTD patients at both assessment points. MMSE, ACE-R scores significantly declined and NPI Total and Distress scores significantly increased in both groups. In the bvFTD group, age was the only independent predictor variable for the NPI total score at follow up. In the AD group, ACE-R and EXIT-25, conjunctively, were associated with the NPI total score at follow up. Conclusions: In 12 months, cognition declined and neuropsychiatric symptoms increased in bvFTD and AD groups. In the AD group only, cognitive impairment was a significant predictor of change in neuropsychiatric symptoms.

Associations between cognitive and clinical disability across MS subtypes: The role of the underlying brain damage.

BACKGROUND: Cognitive impairment (CI) is present in all stages and subtypes of multiple sclerosis (MS). However, the majority of studies examined relapsing-remitting (RRMS) patients, and did not address cognitive phenotyping. Is still not clear whether patients with progressive MS (PMS) have a distinct pattern of CI compared to RRMS. In addition, there is conflicting data regarding the correlation between clinical and cognitive disability. OBJECTIVE: To investigate the differences of CI between PMS and RRMS patients, evaluating cognitive phenotypes. We also aimed to analyze the association between physical and cognitive disability with MRI measures of grey-matter atrophy and lesion burden. METHODS: Thirty patients with PMS and twenty-four with RRMS underwent neurological, neuropsychological (BRB-N, Boston Naming, and Tower of London), and MRI assessments (3T). Brain volume evaluations were performed using FreeSurfer. Principal Components Analysis on neuropsychological yielded six principal cognitive domains. Cognitive deficits were classified according to three categories: no CI, impairment in isolated cognitive domain, or impairment in combined domains. RESULTS: In the overall sample, the most frequently impaired cognitive domains were information processing speed (IPS) and visual memory. PMS patients had a higher prevalence of verbal memory and verbal fluency deficits, and more frequent impairment in combined cognitive domains compared to RRMS individuals. After multivariable regression analysis with clinical variables, EDSS was associated with most cognitive domains. Nevertheless, after including T1-lesion volume in the model, it was the most consistent predictor of cognitive performance. To further analyze the interaction between EDSS and T1-lesions, we performed GLM analysis with EDSS and T1-hypointense lesion volume as covariates, and T1-lesion volume adjusted better the model for verbal memory (p = 0.013), IPS (p = 0.021) and total number of impaired cognitive domains (p = 0.021). CONCLUSIONS: RRMS and PMS patients tend to have a similar neuropsychological profile in general, but the extent of CI was greater in PMS patients. Worse cognitive performance was associated with increased physical disability, but this correlation was no longer significant after controlling for T1-lesion volume, suggesting that the underlying MS pathology might be involved in this relationship. Thalamic and T1-lesion volumes were the most consistent MRI predictors associated with cognitive disability.

Exploring the performance of outcome measures in MS for predicting cognitive and clinical progression in the following years.

BACKGROUND: The demand for better outcome measures in multiple sclerosis (MS) management has been increasingly recognized. Nevertheless, the prognostic impacts of available outcome measures for long-term clinical and especially cognitive disability have not been thoroughly investigated. We, therefore, aimed to explore the sustainability and long-term predictive value of outcome measures in MS. METHODS: We studied a cohort of 42 relapsing-remitting MS patients and 30 healthy subjects. Evaluations were performed at baseline and after two (Y2) and six years (Y6), and included neurological and neuropsychological evaluation (BRBN), MRI (3T), and quality of life assessment. Combined clinical and cognitive measures were evaluated, such as minimal and no evidence of disease activity (MEDA and NEDA, respectively). We performed logistic regression with bootstrapping and calculated the diagnostic properties to identify patients who reached six-year clinical and/or cognitive worsening. RESULTS: NEDA status was observed in up to 30.8% of patients at Y2, but only in 5% at Y6, and did not preclude cognitive decline (SDMT and BRBN). The absence of MRI activity and MEDA status at Y2 were associated with less EDSS worsening in the following years but without impact on cognition. The absence of deterioration on combined clinical/cognitive measures at Y2 (e.g., T25W+ 9HPT + BRBN) was associated with better outcomes in the following years (clinical and cognitive), with moderate to large effect sizes. For the identification of clinical worsening at Y6, best accuracies were found for MEDA (70.6%), and clinical worsening (71.4%), but only MEDA remained in the final model after multivariable logistic regression analysis (OR = 6.81, p = 0.017). For combined clinical and cognitive worsening at Y6, only T25W+ 9HPT + BRBN remained in the final model (OR = 8.5, p = 0.017). CONCLUSIONS: Early MS inflammatory disease activity is associated with future clinical disability. Nevertheless, NEDA was difficult to sustain in the long-term and did not preclude cognitive deterioration. Clinical and cognitive measures combined predicted outcomes better than each one isolated. Our data suggest that the evaluation of more than one cognitive domain yields a better predictive outcome measure.

Cognitive trajectories in relapsing-remitting multiple sclerosis: A longitudinal 6-year study.

BACKGROUND: Information concerning longitudinal cognitive trajectories in multiple sclerosis (MS) is relatively scarce. Moreover, it is unclear which factors are associated with cognitive decline and what is the clinical impact of cognitive impairment (CI) in the long run. OBJECTIVE: To investigate cognitive trajectories in relapsing-remitting multiple sclerosis (RRMS) patients, analyzing clinical and magnetic resonance imaging (MRI) predictors of cognitive decline. METHODS: We enrolled 42 patients and 30 controls. They underwent brain MRI and clinical/neuropsychological evaluation at baseline and after 1, 2, and 6 years. We evaluated cognitive domains with principal component analysis and performed multivariable regression analyzing predictors of clinical/cognitive deterioration. We also performed repeated measures analysis to assess whether clinical progression was different according to CI at baseline. RESULTS: A total of 23 (62.2%) patients deteriorated in combined cognitive domains after 6 years, most in processing speed and memory. The number of baseline impaired cognitive domains was strongly associated with 6-year cognitive (R2 = 0.452; p < 0.001) and Expanded Disability Status Scale (EDSS) deterioration (R2 = 0.263; p < 0.001). Patients with baseline CI in combined domains had worse clinical progression. CONCLUSION: Isolated CI tends to become more widespread, affecting memory and processing speed alongside. The extent of baseline CI was the best predictor of both clinical and cognitive deterioration after 6 years.

The Effect of Pelvic Floor Muscle Contraction on Detrusor Overactivity Pressure in Neurogenic and Nonneurogenic Women During Urodynamic Study: A Cross-Sectional Study.

OBJECTIVE: The aims of this study were to investigate whether detrusor overactivity can be influenced by a pelvic floor muscle contraction in multiple sclerosis-associated overactive bladder and idiopathic overactive bladder volunteers and to compare urodynamic findings between the two groups. DESIGN: Eighteen women with multiple sclerosis-associated overactive bladder and 17 women with overactive bladder responded the overactive bladder V8 questionnaire and performed urodynamic study with electromyography of pelvic floor muscle to confirm the presence of a 15-sec pelvic floor muscle contraction during a detrusor overactivity, when present. Variables were the following: overactive bladder-V8 questionnaire, maximum cystometric capacity, volume at first detrusor overactivity, maximum detrusor overactivity amplitude, and percentage of detrusor overactivity pressure reduction. RESULTS: All participants had a reduction in detrusor overactivity pressure when pelvic floor muscle contraction was requested. Multiple sclerosis-associated overactive bladder group showed significant higher detrusor overactivity amplitude than overactive bladder group (P = 0.02). Overactive bladder group had their detrusor overactivity pressure reduced in a greater extent when compared with multiple sclerosis-associated overactive bladder group (P = 0.01). CONCLUSIONS: The results suggest that pelvic floor muscle contraction is able to reduce detrusor overactivity pressure in multiple sclerosis-associated overactive bladder and overactive bladder population.

Clinical and MRI correlates of CSF neurofilament light chain levels in relapsing and progressive MS.

BACKGOUND: A major aim in MS field has been the search for biomarkers that enable accurate detection of neuronal damage. Besides MRI, recent studies have shown that neuroaxonal damage can also be tracked by neurofilament detection. Nevertheless, before widespread implementation, a better understanding of the principal contributors for this biomarker is of paramount importance. Therefore, we analyzed neurofilament light chain (NfL) in relapsing (RMS) and progressive MS (PMS), addressing which MRI and clinical variables are better related to this biomarker. METHODS: Forty-seven MS patients underwent MRI (3T) and cerebrospinal fluid (CSF) sampling. We measured NfL concentrations using ELISA (UmanDiagnostics) and performed multivariable regression analysis to assess the contribution of clinical and MRI metrics to NfL. RESULTS: NfL correlated with previous clinical activity in RMS (p < 0.001). In RMS, NfL also correlated with Gad+ and cortical lesion volumes. However, after multivariable analysis, only cortical lesions and relapses in previous 12 months remained in the final model (R2 = 0.610; p = 0.009 and p = 0.00008, respectively). In PMS, T1-hypointense lesion volume was the only predictor after multivariate analysis (R2 = 0.564; p = 0.012). CONCLUSIONS: CSF NfL levels are increased in RMS and associated with relapses and cortical lesions. Although NfL levels were correlated with Gad+ lesion volume, this association did not persist in multivariable analysis after controlling for previous clinical activity. We encourage controlling for previous clinical activity when testing the association of NfL with MRI. In PMS, the major contributor to NfL was T1-hypointense lesion volume.

Normative values of the Brief Repeatable Battery of Neuropsychological Tests in a Brazilian population sample: discrete and regression-based norms.

Objective Cognitive dysfunction is common in multiple sclerosis. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was developed to assess cognitive functions most-frequently impaired in multiple sclerosis. However, normative values are lacking in Brazil. Therefore, we aimed to provide continuous and discrete normative values for the BRB-N in a Brazilian population sample. Methods We recruited 285 healthy individuals from the community at 10 Brazilian sites and applied the BRB-N version A in 237 participants and version B in 48 participants. Continuous norms were calculated with multiple-regression analysis. Results Mean raw scores and the 5th percentile for each neuropsychological measure are provided, stratified by age and educational level. Healthy participants' raw scores were converted to scaled scores, which were regressed on age, sex and education, yielding equations that can be used to calculate predicted scores. Conclusion Our normative data allow a more widespread use of the BRB-N in clinical practice and research.

Normative values of the Brief Repeatable Battery of Neuropsychological Tests in a Brazilian population sample: discrete and regression-based norms / Valores normativos da Brief Repeatable Battery of Neuropsychological Tests (BRB-N) em uma amostra da população Brasileira: dados discretos e contínuos

ABSTRACT Objective Cognitive dysfunction is common in multiple sclerosis. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was developed to assess cognitive functions most-frequently impaired in multiple sclerosis. However, normative values are lacking in Brazil. Therefore, we aimed to provide continuous and discrete normative values for the BRB-N in a Brazilian population sample. Methods We recruited 285 healthy individuals from the community at 10 Brazilian sites and applied the BRB-N version A in 237 participants and version B in 48 participants. Continuous norms were calculated with multiple-regression analysis. Results Mean raw scores and the 5th percentile for each neuropsychological measure are provided, stratified by age and educational level. Healthy participants' raw scores were converted to scaled scores, which were regressed on age, sex and education, yielding equations that can be used to calculate predicted scores. Conclusion Our normative data allow a more widespread use of the BRB-N in clinical practice and research.

RESUMO Objetivo Disfunção cognitiva é comum em pacientes com esclerose múltipla. Por isto, a Brief Repeatable Battery of Neuropsychological Tests (BRB-N) foi desenvolvida para avaliar as funções cognitivas mais frequentemente alteradas na doença. Entretanto, estão faltando dados normativos desta bateria no Brasil. Assim, nosso objetivo foi fornecer valores normativos contínuos e discretos da BRB-N para a população brasileira. Métodos Foram recrutados 285 indivíduos sadios da comunidade em 10 centros do Brasil e aplicada a versão A em 237 e a versão B em 48 sujeitos. Normas contínuas foram calculadas com análise de regressão múltipla. Resultados Escores brutos médios e 5°percentil para cada subteste são fornecidos, estratificados por idade e nível educacional. Os escores brutos dos sujeitos sadios foram convertidos em escores de escalas e postos em regressão quanto a idade, sexo e educação, fornecendo equações que podem ser usadas para calcular escores previsíveis. Conclusão Nossos dados normativos permitem um uso mais amplo da BRB-N na prática clínica e na pesquisa, fornecendo normas para dados discretos e contínuos. Normas para dados discretos deveriam ser usadas com cuidado e escores demograficamente ajustados são geralmente preferidos quando interpretando dados neuropsicológicos.

Self, cortical midline structures and the resting state: Implications for Alzheimer's disease.

Different aspects of the self have been reported to be affected in many neurological or psychiatric diseases such as Alzheimer's disease (AD), including mainly higher-level cognitive self-unawareness. This higher sense of self-awareness is most likely related to and dependent on episodic memory, due to the proper integration of ourselves in time, with a permanent conservation of ourselves (i.e., sense of continuity across time). Reviewing studies in this field, our objective is thus to raise possible explanations, especially with the help of neuroimaging studies, for where such self-awareness deficits originate in AD patients. We describe not only episodic (and autobiographical memory) impairment in patients, but also the important role of cortical midline structures, the Default Mode Network, and the resting state (intrinsic brain activity) for the processing of self-related information.

Pelvic Floor Muscle Training With and Without Electrical Stimulation in the Treatment of Lower Urinary Tract Symptoms in Women With Multiple Sclerosis.

PURPOSE: The aim of this study was to evaluate the effect of intravaginal neuromuscular electrical stimulation (NMES) and transcutaneous tibial nerve stimulation (TTNS) on lower urinary tract symptoms (LUTS) and health-related quality of life in women undergoing pelvic floor muscle (PFM) training (PFMT) with multiple sclerosis (MS) and to compare the efficacy of these 2 approaches. DESIGN: Randomized controlled trial. METHODS: Thirty women with MS and LUTS were randomly allocated to 1 of 3 groups and received treatment for 12 weeks. Ten women in group 1 received PFMT with electromyographic (EMG) biofeedback and sham NMES. Ten women in group 2 underwent PFMT with EMG biofeedback and intravaginal NMES, and 10 subjects in group 3 received PFMT with EMG biofeedback and TTNS. Multiple assessments, performed before and after treatment, included a 24-hour pad test, 3-day bladder diary, assessment of PFM function (strength and muscle tone), urodynamic studies, and validated questionnaires including Overactive Bladder Questionnaire (OAB-V8), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and Qualiveen instrument. RESULTS: All groups showed reductions in pad weight, frequency of urgency and urge urinary incontinence episodes, improvement in all domains of the PFM assessment, and lower scores on the OAB-V8 and ICIQ-SF questionnaires following treatment. Subjects in group 2 achieved significantly greater improvement in PFM tone, flexibility, ability to relax PFMs, and OAB-V8 scores when compared to subjects in groups 1 and 3. CONCLUSION: Results suggest that PFMT alone or in combination with intravaginal NMES or TTNS is effective in the treatment of LUTS in patients with MS. The combination of PFMT and NMES offers some advantage in the reduction of PFM tone and symptoms of overactive bladder.

A spring to summer shift of pro-inflammatory cytokine production in multiple sclerosis patients.

Higher MS relapse frequency is observed during warmer months in different regions, but evidence for an underlying immunological variation is lacking. Therefore, we investigated seasonal variations of cytokine production in relapsing-remitting MS patients. Twenty-one patients and eight controls had blood samples drawn in each season, evaluating for IL-10, IL-6, TNF-α and IFN-γ. The lowest levels of cytokine production were observed in spring samples, with a significant increase from spring to summer for most cytokines, and especially IFN-γ and TNF-α. This phenomenon may underlie the higher prevalence of clinical and subclinical MS activity observed in warmer months.

No evidence of disease activity in multiple sclerosis: Implications on cognition and brain atrophy.

BACKGROUND: The concept of no evidence of disease activity (NEDA) has emerged as an important outcome measure for multiple sclerosis (MS). However, it is not known if maintaining NEDA has a positive impact on cognition or brain atrophy. OBJECTIVE: To evaluate NEDA status after two years, addressing its implications on cognition and brain atrophy. METHODS: Forty-two relapsing-remitting MS patients and 30 controls underwent MRI (3T) and cognitive evaluation (BRB-N). Forty patients performed additional evaluations, after 12 and 24 months. NEDA was defined as the absence of clinical (relapses/disability progression) and MRI activity (new T2/gadolinium-enhancing lesions). Repeated measures and multivariate analyses were performed to assess the contribution of NEDA criteria to GM atrophy. RESULTS: After two years, 30.8% of the cohort had NEDA. From these, 58.3% still had worsening in ⩾2 cognitive domains. Patients with MRI activity had more cortical thinning and slightly more thalamus volume decrease. Absence of new/enlarging T2 lesions was the only predictor of cortical thinning, subcortical GM and thalamic atrophy rates. CONCLUSIONS: NEDA status was achieved in a small proportion of our cohort, and did not preclude cognitive deterioration. Absence of MRI activity and especially of new/enlarging T2 lesions was associated with less cortical and subcortical GM atrophy.

Atrophy of reward-related striatal structures in fatigued MS patients is independent of physical disability.

BACKGROUND: MRI studies have shown gray-matter abnormalities in fatigued multiple sclerosis (MS) patients. However, given that physical disability is highly correlated to MS fatigue, it is often difficult to disentangle its effect in these MRI findings. OBJECTIVE: The objective of this research paper is to investigate gray-matter damage in mildly disabled MS patients, addressing which variables were better related to fatigue while controlling for physical disability and depression. METHODS: Forty-nine relapsing-remitting MS (RRMS) patients and 30 controls underwent MRI (3T). Fatigue was assessed using the Fatigue Severity Scale (FSS). Multivariate logistic regression was performed to assess the contribution of clinical and MRI metrics to fatigue. Statistical analyses were performed controlling for disability and depression. RESULTS: Fatigue was present in 22 (44.9%) patients. FSS score was highly correlated with EDSS (p = 0.00001). Patients with fatigue had lower brain cortical and subcortical gray-matter volumes. However, after controlling for EDSS, only the caudate and the accumbens volumes remained statistically significant. CONCLUSIONS: Fatigued MS patients have a global cortical and subcortical gray-matter atrophy that seems largely related to higher physical disability. However, striatal structures involved in effort-reward functions exhibited smaller volumes in fatigued patients, independently of physical disability and depressive symptoms, supporting the theory of cortico-striatal network impairment in MS fatigue.

Neuroimaging in normal pressure hydrocephalus / Neuroimagem na hidrocefalia de pressão normal

ABSTRACT Normal pressure hydrocephalus (NPH) is a syndrome characterized by the triad of gait disturbance, mental deterioration and urinary incontinence, associated with ventriculomegaly and normal cerebrospinal fluid (CSF) pressure. The clinical presentation (triad) may be atypical or incomplete, or mimicked by other diseases, hence the need for supplementary tests, particularly to predict postsurgical outcome, such as CSF tap-tests and computed tomography (CT) or magnetic resonance imaging (MRI). The CSF tap-test, especially the 3 to 5 days continuous external lumbar drainage of at least 150 ml/day, is the only procedure that simulates the effect of definitive shunt surgery, with high sensitivity (50-100%) and high positive predictive value (80-100%). According to international guidelines, the following are CT or MRI signs decisive for NPH diagnosis and selection of shunt-responsive patients: ventricular enlargement disproportionate to cerebral atrophy (Evans index >0.3), and associated ballooning of frontal horns; periventricular hyperintensities; corpus callosum thinning and elevation, with callosal angle between 40º and 90º; widening of temporal horns not fully explained by hippocampal atrophy; and aqueductal or fourth ventricular flow void; enlarged Sylvian fissures and basal cistern, and narrowing of sulci and subarachnoid spaces over the high convexity and midline surface of the brain. On the other hand, other imaging methods such as radionuclide cisternography, SPECT, PET, and also DTI or resting-state functional MRI, although suitable for NPH diagnosis, do not yet provide improved accuracy for identifying shunt-responsive cases.

RESUMO. A hidrocefalia de pressão normal (HPN) é uma síndrome caracterizada por alteração da marcha, transtorno mental-cognitivo e incontinência urinária, associados a ventriculomegalia e pressão liquórica normal. A apresentação clínica (tríade) pode ser atípica ou incompleta, ou pode ser mimetizada por outras doenças, daí a necessidade de testes suplementares, principalmente para predição do resultado cirúrgico, tais como teste da punção lombar e tomografia computadorizada (TC) ou ressonância magnética (MR) de crânio. O teste da punção liquórica lombar, especialmente a drenagem externa contínua (≥150 ml/dia, por 3 a 5 dias), é o único método que simula o efeito da cirurgia, com alta sensibilidade (50-100%) e alto valor preditivo positivo (80-100%). Consensos internacionais consideram os seguintes achados da TC ou RM como decisivos para o diagnóstico de HPN e a seleção de pacientes bons respondedores à cirurgia: dilatação ventricular desproporcional em relação ao grau de atrofia cerebral (índice de Evans >0.3), associada a arredondamento dos cornos frontais; hipersinal difuso periventricular; adelgaçamento e elevação do corpo caloso, com ângulo do corpo caloso entre 40º e 90º; dilatação dos cornos temporais não explicada por atrofia hipocampal; sinal do fluxo vazio no aqueduto e quarto ventrículo; dilatação das fissuras Sylvianas e cisterna basal, e estreitamento ou apagamento dos sulcos e espaços subaracnoides nas superfícies cerebrais da convexidade alta e linha média. Por outro lado, a cisternografia isotópica, SPECT, PET, e mesmo técnicas mais modernas de RM funcional e tensor de difusão, embora compatíveis com o diagnóstico de HPN, não melhoram a acurácia na identificação de casos responsivos à cirurgia.

Disruption of melatonin circadian rhythm production is related to multiple sclerosis severity: A preliminary study.

Sunlight can influence the immune system independently of vitamin D, such as through melatonin production in the pineal gland. Inflammatory disorders can suppress nocturnal melatonin production, but only a few studies have investigated melatonin status in multiple sclerosis (MS). We aimed to study melatonin production in association with clinical and immunological data in MS patients. Eleven treated relapsing-remitting MS (RRMS) patients and eight controls underwent neurological examination and were assessed for fatigue severity and depressive symptoms. Inflammatory cytokines were analyzed in blood samples and concentration of 6-sulfatoxymelatonin (6-SMT) was determined in 24h urine. Patients with an abnormal proportion of overnight 6-SMT (n=8, 72.7%) had higher disability and fatigue severity (p<0.05). Overnight 6-SMT was inversely related with fatigue severity (p=0.016), number of relapses in the previous 12 months (p=0.010) and EDSS scores (p=0.049). In conclusion, disruption of melatonin circadian rhythm production is frequent among RRMS patients and seemingly related to higher disability and fatigue scores. Future studies with larger sample size are necessary to establish melatonin status as a biomarker of disease severity in MS.