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OBJECTIVE: Irisin, released by muscles during exercise, was recently identified as a neuroprotective factor in mouse models of Alzheimer disease (AD). In a cohort of AD patients, we studied cerebrospinal fluid (CSF) and plasma irisin levels, sex interactions, and correlations with disease biomarkers. METHODS: Correlations between CSF and plasma irisin levels and AD biomarkers (amyloid ß 1-42, hyperphosphorylated tau, and total tau [t-tau]) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) were analyzed in a cohort of patients with Alzheimer dementia (n = 82), mild cognitive impairment (n = 44), and subjective memory complaint (n = 20) biologically characterized according to the recent amyloid/tau/neurodegeneration classification. RESULTS: CSF irisin was reduced in Alzheimer dementia patients (p < 0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aß42 in both female (r = 0.379, p < 0.001) and male (r = 0.262, p < 0.05) patients, and negatively with CDR-SOB (r = -0.234, p < 0.05) only in female patients. A negative trend was also observed between CSF irisin and t-tau levels in all patients (r = -0.144, p = 0.082) and in the female subgroup (r = -0.189, p = 0.084). INTERPRETATION: The results highlight the relationship between irisin and biomarkers of AD pathology, especially in females. Our findings also offer perspectives toward the use of irisin as a marker of the AD continuum. ANN NEUROL 2024;96:61-73.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Fibronectinas , Fragmentos de Peptídeos , Proteínas tau , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Feminino , Masculino , Fibronectinas/líquido cefalorraquidiano , Fibronectinas/sangue , Idoso , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Idoso de 80 Anos ou mais , Estudos de CoortesRESUMO
BACKGROUND: Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting and primary-progressive multiple sclerosis (MS). We aimed to evaluate the effectiveness of an individualized OCR extended interval dosing (EID), after switching from standard interval dosing (SID). METHODS: This was a retrospective, observational, single-centre study including MS patients regularly followed at the Neurocenter of Southern Switzerland. After a cumulative OCR dose ⩾1200 mg, stable patients were switched to EID (OCR infusions following CD19+ 27+ memory B cell repopulation). RESULTS: A total of 128 patients were included in the study, and 113 (88.3%) were switched to EID with a median interval of 9.9 (8.8-11.8) months between infusions. No clinical relapses occurred; 2 (1.8%) patients experienced disability worsening. Three (2.7%) and 2 (1.8%) patients experienced new T2 brain and spinal lesions, respectively. There was a mild decrease in IgG and IgM concentrations during both SID and EID OCR regimens (ß = -0.23, p = 0.001 and ß = -0.07, p < 0.001, respectively). CONCLUSION: Switch to personalized dosing of OCR based on CD19+ 27+ memory B cell repopulation led to a great extension of the interval between infusions, with maintained clinical and radiological efficacy. Given the potential advantages in terms of safety and health costs, EID OCR regimens should be further investigated.
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Anticorpos Monoclonais Humanizados , Células B de Memória , Humanos , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Masculino , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Células B de Memória/imunologia , Fatores Imunológicos/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Resultado do Tratamento , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologiaRESUMO
INTRODUCTION: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms. OBJECTIVES: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback. METHODS: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey. RESULTS: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant. CONCLUSION: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.
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Epilepsia , Transtornos de Enxaqueca , Enxaqueca com Aura , Humanos , Feminino , Adulto , Masculino , Enxaqueca com Aura/diagnóstico , Estudos Transversais , Cefaleia , Epilepsia/diagnósticoRESUMO
BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.
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Cladribina , Imunossupressores , Humanos , Cladribina/uso terapêutico , Feminino , Masculino , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Itália , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento , Esclerose Múltipla/tratamento farmacológicoRESUMO
BACKGROUND: Sarcopenia is an age-related clinical syndrome characterized by the progressive loss of muscle mass and muscle strength. It appears to be closely linked to dementia, particularly Alzheimer's disease (AD); however, its prevalence among AD patients remains unclear. In this study, we assessed differences in sarcopenia prevalence between non-demented individuals and AD patients. Moreover, we assessed sex-specific differences in sarcopenia prevalence and explored the diagnostic value of the Muscle Quality Index (MQI) for diagnosing sarcopenia among AD patients. METHOD: Cross-sectional study including 145 patients with probable AD and 51 older adults with normal cognition. Sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP1 and EWGSOP2) and of the Foundation for the National Institutes of Health (FNIH). The MQI was computed as the ratio of handgrip strength to skeletal muscle mass. RESULTS: No significant difference in sarcopenia prevalence was observed between AD patients and controls. Prevalence ranged from 3.4 to 23.4% in AD patients and from 2 to 11.8% in controls, depending on diagnostic criteria. Prevalence was higher using EWGSOP1 and decreased using EWGSOP2 and FNIH. Prevalence was higher in males than in females with AD. The MQI was lower in AD patients than in controls (95%CI: - 0.23, - 0.05, p < 0.001), but displayed poor diagnostic accuracy in identifying sarcopenia cases. CONCLUSIONS: AD patients and controls show comparable sarcopenia prevalence. Sarcopenia prevalence is higher in males than females among AD patients and higher when using EWGSOP1 compared to FNIH and EWGSOP2 criteria.
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Doença de Alzheimer , Sarcopenia , Masculino , Feminino , Humanos , Idoso , Estados Unidos , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Força da Mão/fisiologia , Prevalência , Estudos Transversais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , National Institutes of Health (U.S.)RESUMO
BACKGROUND: Current evidence on the safety of calcitonin gene-related peptide antagonists (CGRP-A) in pregnancy for the treatment of both episodic and chronic migraine is scarce and does not yet provide definitive information. By querying VigiBase®, the World Health Organization global pharmacovigilance database, this study aimed to detect differences in the reporting frequency between CGRP-A and triptans in relation to pregnancy. METHODS: Disproportionality analyses on de-duplicated safety reports collected in VigiBase® as of 31.05.2023 reporting exposure to CGRP-A in pregnancy with or without pregnancy outcomes. A Reporting Odds Ratio (ROR) with a 95% confidence interval (CI) was used as a measure of disproportionality and the threshold for the detection of a signal of disproportionate reporting was set with a 95% CI lower limit > 1. FINDINGS: Four hundred sixty-seven safety reports reported exposure to CGRP-A in pregnancy, mostly originating from the United States of America (360/467, 77%), more frequently reported by patients (225/467, 48%), who were mainly females (431/467, 92%), and more frequently reported exposure to CGRP-A during pregnancy (400/467, 86%). Compared to triptans, no signals of disproportionate reporting were detected with CGRP-A either for the overall reporting of pregnancy-related safety reports (ROR 0.91, 95% CI 0.78-1.06), for the reporting of pregnancy outcomes (maternal and/or foetal/neonatal, ROR 0.54, 95% CI 0.45-0.66), or for the reporting of foetal/neonatal outcomes (ROR 0.53, 95% CI 0.41-0.68). CONCLUSIONS: This study showed that, to date, there are no signals of increased reporting with CGRP-A compared to triptans in relation to pregnancy in VigiBase®. Future pharmacovigilance studies are needed to confirm these findings.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Peptídeo Relacionado com Gene de Calcitonina , Recém-Nascido , Gravidez , Feminino , Humanos , Estados Unidos , Masculino , Farmacovigilância , Bases de Dados Factuais , TriptaminasRESUMO
Background: The costs of disease-modifying therapies (DMTs) for multiple sclerosis (MS) have increased interest in generic alternatives. Methods: This prospective and observational study aims to investigate the safety, tolerability, and acceptance of switching from brand glatiramer acetate (GA) 40 mg/mL three times per week (Copaxone®) to generic GA 40 mg/mL three times per week (Glatiramyl®). Conducted at the Neurocenter of Southern Switzerland from September 2020 to September 2021, the study enrolled 27 patients; 21 completed the study. Participants reported on local and systemic side effects three months before and after the switch, and on switch acceptance by means of visual analogue scales (from 0 to 10). Results: Results indicated that those on generic GA experienced fewer local (81.0% vs. 96.3%) and systemic (33.3% vs. 59.3%) adverse events than with the brand drug. The median intensity of local adverse events was 8 (4-20) on generic GA vs. 16 (9-22) on brand GA, while the median intensity of systemic adverse events was similar between generic and brand GA [0 (0-27) vs. 0 (0-21.5), respectively]. Seventy-one percent of participants rated their acceptance of generic GA as 7/10 or higher. Conclusions: The results suggest that switching from brand to generic GA 40 mg/mL is safe, well-tolerated, and accepted by patients with MS.
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Few data are available regarding vaccine induced SARS-CoV-2 specific T cell responses over time and after booster doses in multiple sclerosis (MS) patients on different disease modifying treatments. We measured SARS-CoV-2 specific CD4+ T cell responses in 72 samples collected from 36 MS patients. The percentage of CD4+ CTVlow CD25+ ICOS+ T cells after stimulation with Spike Recombinant Protein was 29.9 (17.0-43.6) on teriflunomide, 32.4 (11.9-42.5) on ocrelizumab, but much lower (0.6 [0.3-5.9]) on sphingosine-1-phospate receptor modulators (ß = -26.35, p = 0.003). SARS-CoV-2 specific T cells were mainly of Th1 type and stable over time and after booster vaccine doses. mRNA vaccines elicit strong and persistent CD4+ T cell responses against SARS-CoV-2 in MS patients on anti-CD20 and teriflunomide, but not in those on sphingosine-1-phospate receptor modulators.
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Background: Cannabinoid oro-mucosal spray nabiximols is approved for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other antispastic medications. Few real-world data are available on the effectiveness, safety and patients' satisfaction in MS patients treated with nabiximols as monotherapy. Methods: To investigate the effectiveness, tolerability and satisfaction of nabiximols in a real-life multicentric Swiss cohort as monotherapy or with stable doses of other antispastic medications, and explore clinical features which may predict treatment response. The following data were collected at treatment start (baseline) and 12 weeks thereafter: Modified Ashworth scale (MAS), scores at numerical rating scales ranging from 0 (absent) to 10 (considerable) for effect on spasticity (sNRS), pain (pNRS), gait (gNRS), urinary symptoms (uNRS), tolerability (tNRS) as assessed by the treating neurologist, and overall treatment satisfaction (TsNRS) and tolerability (tNRS) as assessed by the patient. Results: Ninety-five patients (44 relapsing remitting, 37 secondary progressive and 14 primary progressive MS; median age = 53 (IQR 45-62); female 70%; median EDSS 6 (IQR 4-6), concomitant antispastic treatments in 54% of patients) were included. From baseline to week 12, median MAS score decreased from 3.0 to 2.0 (p < 0.001). Median scores of the each NRS also significantly decreased (p < 0.001 for all comparisons). At week 12, the median TsNRS and tTS scores were 8/10 (IQR: 6-9) and 9/10 (IQR: 7-10), respectively, and 93.7% of patients continued to use nabiximols at the average dose of six sprays/day. No clinical factors, including use of nabiximols as add on vs. monotherapy, were associated with responder status. Conclusions: Our first Swiss, multicentric, observational, real-life study supports and enhances previous finding of nabiximols as monotherapy and as add-on therapy, being an effective, safe and well-tolerated treatment option for resistant MS spasticity and spasticity-related symptoms (pain, bladder dysfunction and gait).
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The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.
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BACKGROUND: Calcitonin gene-related peptide (CGRP), implicated in migraine pain, also possesses bone anabolic properties, which leads to the possibility that monoclonal antibodies targeting CGRP (anti-CGRPs) might increase the risk of bone density abnormalities. OBJECTIVE: The objective of this study was to explore bone mineral density abnormalities in a cohort of migraine patients treated with anti-CGRPs. METHODS: This was a single-center, cross-sectional, cohort study including migraine patients who underwent a densitometry assessment during anti-CGRP treatment. We assessed the frequency of osteopenia or osteoporosis (OSTEO+ status), defined as a bone mineral density T-score of -1 to -2.5, and <-2.5 standard deviations from the young female adult mean, respectively. Additionally, the association of OSTEO+ status with anti-CGRP treatment duration and primary osteoporosis' risk factors was investigated using logistic regression models. RESULTS: Data from 51 patients (43 female, mean age 46 ± 13.9 years) were evaluated. The mean duration of anti-CGRP treatment was 15.7 (±11.8) months. Twenty-seven patients (53%) were OSTEO+ (n = 22 osteopenia; n = 5 osteoporosis). In the final model, menopause [odds ratio 11.641 (95% confidence interval 1.486-91.197), p = 0.019] and anti-seizure drug use [odds ratio 12.825 (95% confidence interval 1.162-141.569), p = 0.037] were associated with OSTEO+ status. CONCLUSIONS: In our cohort of migraine patients, no evidence of an association between anti-CGRP treatment duration and an increasing risk of bone mineral density abnormalities was found. However, these findings are preliminary and necessitate further longitudinal research with larger cohorts and extended follow-up to be validated.
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Some patients benefit from a treatment while others may do so less or do not benefit at all. We have previously developed a two-stage network meta-regression prediction model that synthesized randomized trials and evaluates how treatment effects vary across patient characteristics. In this article, we extended this model to combine different sources of types in different formats: aggregate data (AD) and individual participant data (IPD) from randomized and non-randomized evidence. In the first stage, a prognostic model is developed to predict the baseline risk of the outcome using a large cohort study. In the second stage, we recalibrated this prognostic model to improve our predictions for patients enrolled in randomized trials. In the third stage, we used the baseline risk as effect modifier in a network meta-regression model combining AD, IPD randomized clinical trial to estimate heterogeneous treatment effects. We illustrated the approach in the re-analysis of a network of studies comparing three drugs for relapsing-remitting multiple sclerosis. Several patient characteristics influence the baseline risk of relapse, which in turn modifies the effect of the drugs. The proposed model makes personalized predictions for health outcomes under several treatment options and encompasses all relevant randomized and non-randomized evidence.
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Esclerose Múltipla Recidivante-Remitente , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Algoritmos , Estudos de Coortes , Interpretação Estatística de Dados , Modelos Estatísticos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Metanálise em Rede , Prognóstico , Recidiva , Análise de Regressão , Projetos de Pesquisa , Risco , Resultado do TratamentoRESUMO
Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis. Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria. Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies. Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN gene further confirmed the diagnosis. Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults.
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Demência Frontotemporal , Feminino , Humanos , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Transtorno da Personalidade Narcisística , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , ProgranulinasRESUMO
BACKGROUND: There are limited real-world data in Switzerland examining the impact of erenumab, a fully human IgG2 monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor, on migraine-related quality of life. OBJECTIVE: This 18-month interim analysis of 172 patients with episodic or chronic migraine from the SQUARE study provides first prospective insights on the impact of mandatory erenumab treatment interruption, following Swiss-reimbursement requirements, in a real-world clinical setting in Switzerland. FINDINGS: Recruited patients receiving 70 or 140 mg erenumab underwent treatment interruption on average 11.2 months after therapy onset with a mean duration of 4 months. There were sustained improvements in mean monthly migraine days (MMD) and migraine disability (mMIDAS) during initial treatment with erenumab. Treatment interruption was associated with a temporary worsening of condition. Symptoms ameliorated upon therapy reuptake reaching improvements similar to pre-break within 3 months. CONCLUSIONS: Treatment interruption was associated with a temporary worsening of condition, which improved again after therapy restart.
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Anticorpos Monoclonais Humanizados , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Avaliação da Deficiência , Estudos Prospectivos , Resultado do Tratamento , Doença Crônica , Suíça , Qualidade de VidaRESUMO
Anterior Visual Pathway (aVP) damage may be linked to diverse inflammatory, degenerative and/or vascular conditions. Currently however, a standardized methodological framework for extracting MRI biomarkers of the aVP is not available. We used high-resolution, 3-D MRI data to generate a probabilistic anatomical atlas of the normal aVP and its intraorbital (iOrb), intracanalicular (iCan), intracranial (iCran), optic chiasm (OC), and tract (OT) subdivisions. We acquired 0.6 mm3 steady-state free-precession images from 24 healthy participants using a 3 T scanner. aVP masks were obtained by manual segmentation of each aVP subdivision. Mask straightening and normalization with cross-sectional area (CSA) preservation were obtained using scripts developed in-house. A probabilistic atlas ("aVP-24") was generated by averaging left and right sides of all subjects. Leave-one-out cross-validation with respect to interindividual variability was performed employing the Dice Similarity Index (DSI). Spatially normalized representations of the aVP subdivisions were generated. Overlapping CSA values before and after normalization demonstrate preservation of the aVP cross-section. Volume, length, CSA, and ellipticity index (ε) biometrics were extracted. The aVP-24 morphology followed previous descriptions from the gross anatomy. Atlas spatial validation DSI scores of 0.85 in 50% and 0.77 in 95% of participants indicated good generalizability across the subjects. The proposed MRI standardization framework allows for previously unavailable, geometrically unbiased biometric data of the entire aVP and provides the base for future spatial-resolved, group-level investigations.
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Doenças Vasculares , Vias Visuais , Humanos , Imageamento por Ressonância Magnética/métodos , Quiasma Óptico , Biometria , Processamento de Imagem Assistida por Computador/métodosRESUMO
The presence of parkinsonism features in primary progressive aphasia (PPA) is a subject of ongoing research. These features are usually more pronounced in the advanced stages of the disease, particularly in the non-fluent/agrammatic subtype, and are exceptionally rare in the logopenic variant (lvPPA). Here we report a case of a 63-year-old man presenting as language impairment, predominantly naming and word-finding difficulties, emerged alongside a left-sided internal tremor. Neurological examination revealed bilateral, left-side predominant rigidity, bradykinesia, and resting tremor. Notably, anosmia and constipation were present. Language assessments showed preserved single-word comprehension, object knowledge, and a minimal apraxia of speech, as well as sentence repetition issues. Neuroimaging and biomarker analysis supported a diagnosis of primary progressive logopenic aphasia with amyloid pathology co-existing with prominent and early parkinsonism. This case underlines the intricate relationship between language disorders, parkinsonism, and amyloid pathology in lvPPA.
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BACKGROUND: While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories may affect mental health and treatment adherence. Using natural language processing techniques, we investigated large-scale text data about theories that persons with MS have about the causes of their disease. We examined the topics into which their theories could be grouped and the prevalence of each theory topic. METHODS: A total of 486 participants of the Swiss MS Registry longitudinal citizen science project provided text data on their theories about the etiology of MS. We used the transformer-based BERTopic Python library for topic modeling to identify underlying topics. We then conducted an in-depth characterization of the topics and assessed their prevalence. RESULTS: The topic modeling analysis identifies 19 distinct topics that participants theorize as causal for their MS. The topics most frequently cited are Mental Distress (31.5%), Stress (Exhaustion, Work) (29.8%), Heredity/Familial Aggregation (27.4%), and Diet, Obesity (16.0%). The 19 theory topics can be grouped into four high-level categories: physical health (mentioned by 56.2% of all participants), mental health (mentioned by 53.7%), risk factors established in the scientific literature (genetics, Epstein-Barr virus, smoking, vitamin D deficiency/low sunlight exposure; mentioned by 47.7%), and fate/coincidence (mentioned by 3.1%). Our study highlights the importance of mental health issues for theories participants have about the causes of their MS. CONCLUSIONS: Our findings emphasize the importance of communication between healthcare professionals and persons with MS about the pathogenesis of MS, the scientific evidence base and mental health.
Multiple sclerosis (MS) is a disease that affects the brain and spinal cord, causing a wide range of symptoms. Our study investigated what people living with the disease think causes MS. We analyzed the replies given by 486 people who were questioned about their MS to look for patterns in the responses. We identified 19 distinct themes, notably mental and work-related stress, genetics, and dietary factors, which we grouped into 4 categories: physical health, mental health, established scientific risk factors, and chance. We found that mental health problems were viewed as a key factor for MS. Our work highlights the need for healthcare professionals to have transparent conversations with people with MS about what is known about the disease course and potential causes. In addition, it highlights the importance of fully informing and supporting people with MS regarding their mental health.
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BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Feminino , Criança , Masculino , Estudos de Coortes , Estudos Transversais , Encéfalo/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Doença CrônicaRESUMO
Introduction: Frontotemporal dementia (FTD) is an extremely heterogeneous and complex neurodegenerative disease, exhibiting different phenotypes, genetic backgrounds, and pathological states. Due to these characteristics, and to the fact that clinical symptoms overlap with those of other neurodegenerative diseases or psychiatric disorders, the diagnosis based only on the clinical evaluation is very difficult. The currently used biomarkers help in the clinical diagnosis, but are insufficient and do not cover all the clinical needs. Methods: By the means of a new immunoassay, we have measured and analyzed the proNGF levels in 43 cerebrospinal fluids (CSF) from FTD patients, and compared the results to those obtained in CSF from 84 Alzheimer's disease (AD), 15 subjective memory complaints (SMC) and 13 control subjects. Results: A statistically significant difference between proNGF levels in FTD compared to AD, SMC and controls subjects was found. The statistical models reveal that proNGF determination increases the accuracy of FTD diagnosis, if added to the clinically validated CSF biomarkers. Discussion: These results suggest that proNGF could be included in a panel of biomarkers to improve the FTD diagnosis.
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Introduction: Pure hereditary spastic paraplegia (SPG) type 4 (SPG4) is caused by mutations of SPAST gene. This study aimed to analyze SPAST variants in SPG4 patients to highlight the occurrence of splicing mutations and combine functional studies to assess the relevance of these variants in the molecular mechanisms of the disease. Methods: We performed an NGS panel in 105 patients, in silico analysis for splicing mutations, and in vitro minigene assay. Results and discussion: The NGS panel was applied to screen 105 patients carrying a clinical phenotype corresponding to upper motor neuron syndrome (UMNS), selectively affecting motor control of lower limbs. Pathogenic mutations in SPAST were identified in 12 patients (11.42%), 5 missense, 3 frameshift, and 4 splicing variants. Then, we focused on the patients carrying splicing variants using a combined approach of in silico and in vitro analysis through minigene assay and RNA, if available. For two splicing variants (i.e., c.1245+1G>A and c.1414-2A>T), functional assays confirm the types of molecular alterations suggested by the in silico analysis (loss of exon 9 and exon 12). In contrast, the splicing variant c.1005-1delG differed from what was predicted (skipping exon 7), and the functional study indicates the loss of frame and formation of a premature stop codon. The present study evidenced the high splice variants in SPG4 patients and indicated the relevance of functional assays added to in silico analysis to decipher the pathogenic mechanism.