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Data from cohorts, registries, randomised trials, electronic medical records and administrative claims databases have increasingly been used to inform the use of therapies for neurological diseases. While novel sophisticated methods are enabling us to use existing data to guide treatment decisions, the complexity of statistical methodology is making appraisal of clinical evidence increasingly demanding. In this narrative review, we provide a brief overview of the most commonly used methods for evaluation of treatment effectiveness in neurology. This primer discusses complementarity of randomised and non-randomised study designs, sources of observational data, different forms of bias and the appropriate mitigation strategies, statistical significance, Bayesian approaches and provides an overview of multivariable regression models, propensity score-based models, causal inference, mediation analysis and Mendelian randomisation.
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Neurología , Proyectos de Investigación , Humanos , Teorema de Bayes , Resultado del Tratamiento , CausalidadRESUMEN
BACKGROUND AND PURPOSE: Immune effector cell-associated neurotoxicity syndrome (ICANS) is an important complication of chimeric antigen receptor T-cell (CAR-T) therapy. This study aims to identify the patterns of neurotoxicity among patients with ICANS at a tertiary referral centre in Australia. METHODOLOGY: This single-centre, prospective cohort study included all consecutively recruited patients who underwent CAR-T therapy for eligible haematological malignancies. All patients underwent a comprehensive neurological assessment and cognitive screening before CAR-T infusion, during the development of ICANS, and 1 month after treatment. Baseline demographic characteristics, incidence, and neurological patterns of neurotoxicity management were evaluated. RESULTS: Over a 19-month period, 23% (12) of the 53 eligible patients developed neurotoxicity (10/12 [83%] being grade 1). All patients showed changes in handwriting and tremor as their initial presentation. Changes in cognition were manifested in most of the patients, with a more substantial drop noted in their Montreal Cognitive Assessment compared to immune effector cell-associated encephalopathy scores. All manifestations of neurotoxicity were short-lived and resolved within a 1-month period, with a mean duration of 8.2 days (range = 1-33). CONCLUSIONS: The patterns of CAR-T-related neurotoxicity often include change in handwriting, tremor, and mild confusional state, especially early in their evolution. These may remain undetected by routine neurological surveillance. These features represent accessible clinical markers of incipient ICANS.
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Receptores Quiméricos de Antígenos , Humanos , Estudios de Cohortes , Estudios Prospectivos , Temblor , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
BACKGROUND AND OBJECTIVE: Autoimmune encephalitis (AE) is a rare neuroinflammatory disease affecting the central nervous system. To examine language functions in patients with different subsets of AE consisting of seropositive and seronegative groups. METHODS: Fifty-two patients were recruited from neurology departments in Melbourne, Australia, who met clinical criteria for possible AE. Language tests include the Naming Test from the Sydney Language Battery (SydBat), the semantic fluency trial from the Controlled Oral Word Association Test (COWAT), and the Vocabulary and Similarities subtests of the Weschler Abbreviated Scale of Intelligence-Second Edition. The results were standardised with normative data. RESULTS: The mean age of our cohort was 52.5 years old, with the average time from hospital admission to recruitment being 38.41 months. At an aggregate level, none of the mean language test z-scores were below normative data. At the patient level, impairment rates were 18.37% for COWAT (animals), 28.57% for SydBat (naming), 4.65% for Similarities, and 4.55% for Vocabulary. Chi-squared goodness of fit tests indicated that observed performances were significantly below expected performances for the SydBat (naming) test (p < 0.0001) and COWAT (animals) (p = 0.004). DISCUSSION: While, on average, language functions were within normal limits in patients with AE, but a subgroup exhibited lower performance in semantic fluency and visual confrontation naming, with impairment rates below expected norms. To advance understanding of language in chronic AE patients, exploring the impact of seizure burden, antiseizure medication use, and the relationship of language functions with other cognitive functions is crucial.
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Encefalitis , Trastornos del Lenguaje , Humanos , Femenino , Masculino , Persona de Mediana Edad , Encefalitis/diagnóstico , Encefalitis/complicaciones , Encefalitis/sangre , Encefalitis/inmunología , Trastornos del Lenguaje/etiología , Trastornos del Lenguaje/diagnóstico , Adulto , Anciano , Pruebas del Lenguaje , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/complicaciones , Enfermedad de Hashimoto/sangre , Estudios de CohortesRESUMEN
OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Filamentos Intermedios , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquídeoRESUMEN
BACKGROUND: This systematic review aimed to characterise the cognitive outcomes of patients who received chimeric antigen receptor T-cell therapy. METHODS: A systematic search of the literature was performed using PubMed, PsycINFO, SCOPUS, EMBASE, Medline, and CINAHL (February 2023). Risk of bias was assessed using the JBI Checklist for Case Reports and the Risk of Bias Assessment Tool for Non-randomised Studies. RESULTS: Twenty-two studies met inclusion criteria with a total of 1104 participants. There was considerable methodological heterogeneity with differing study designs (e.g., cohort studies, clinical trials, case studies, a qualitative interview, and a focus group), measures of cognition (e.g., self-report, neuropsychological measures, clinician assessed/neurological examinations), and longest follow-up time points (i.e., five days to five years). DISCUSSION: Results of the studies were heterogenous with studies demonstrating stable, improved, or reduced cognition across differing time points. Overall, cognitive symptoms are common particularly in the acute stage (<2 weeks) post-infusion. Most deficits that arise in the acute stage resolve within one to two weeks, however, there is a subset of patients who continue to experience and self-report persistent deficits in the subacute and chronic stages. Future studies are needed to comprehensively analyse cognition using a combination of self-report and psychometric measures following chimeric antigen receptor T-cell therapy in the acute, subacute, and chronic settings.
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BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
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Personas con Discapacidad , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Progresión de la Enfermedad , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Embarazo , Femenino , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Acetato de Glatiramer/uso terapéutico , Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Natalizumab/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Dimetilfumarato/uso terapéutico , Interferón beta/uso terapéutico , RecurrenciaRESUMEN
BACKGROUND: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). OBJECTIVE: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. METHODS: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. RESULTS: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%-96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%-91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. CONCLUSION: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Modelos Estadísticos , Pronóstico , Progresión de la Enfermedad , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Recurrencia , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
OBJECTIVE: Childhood trauma has been implicated as a risk factor for the etiology of psychogenic nonepileptic seizures (PNES). Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES. Investigating childhood trauma profiles in these patient groups may identify psychological vulnerabilities that predispose to developing PNES, and aid early diagnoses, prevention, and treatment. METHODS: Data were collected from two cohorts (nRetrospective = 203; nProspective = 209) admitted to video-electroencephalography (EEG) monitoring units in Melbourne Australia. The differences in Childhood Trauma Questionnaire domain score between patient groups were investigated using standardized effect sizes and general linear mixed-effects models (GLMMs). Receiver-operating characteristic curves were used to investigate classification accuracy. RESULTS: In the retrospective cohort, patients diagnosed with PNES reported greater childhood emotional abuse, emotional neglect, physical abuse, sexual abuse, and physical neglect relative to patients with epilepsy. These differences were replicated in the prospective cohort, except for physical abuse. GLMMs revealed significant main effects for group in both cohorts, but no evidence for any group by domain interactions. Reported sexual abuse showed the best screening performance of PNES, although no psychometric scores were adequate as isolated measures. SIGNIFICANCE: Patients with PNES report a greater frequency of childhood trauma than patients with epilepsy. This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES. From a practical perspective, inquiry regarding a history of sexual abuse shows the most promise as a screening measure.
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Experiencias Adversas de la Infancia , Epilepsia , Convulsiones , Humanos , Experiencias Adversas de la Infancia/estadística & datos numéricos , Epilepsia/complicaciones , Epilepsia/epidemiología , Estudios Prospectivos , Estudios Retrospectivos , Convulsiones/epidemiologíaRESUMEN
INTRODUCTION: While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. METHODS: We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. RESULTS: Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. CONCLUSIONS: Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.
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Enfermedad de Huntington , Humanos , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Imagen por Resonancia Magnética , Lóbulo Temporal , Atrofia/patologíaRESUMEN
BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/terapia , Inmunoterapia , Modelos de Riesgos Proporcionales , RecurrenciaRESUMEN
OBJECTIVE: The appropriateness and clinical utility of neuroimaging in psychiatric populations has been long debated, and the ambiguity of guideline recommendations is well established. Most of the literature is focused on first-episode psychosis. The investigators aimed to review ordering practices and identify risk factors associated with neuroradiological MRI abnormalities and their clinical utility in a general psychiatric population. METHODS: A retrospective file review was undertaken for 100 consecutive brain MRI scans for adult psychiatric inpatients who received scanning as part of their clinical care in an Australian hospital. RESULTS: Brain MRI was abnormal in 79.0% of scans; in these cases, 72.2% of patients required further investigation or follow-up, with 17.7% requiring urgent referral within days to weeks, despite only 3.7% of admitted patients undergoing MRI during the study period. Psychiatrically relevant abnormalities were found in 32.0% of scans. Abnormalities were more likely to be found in the presence of cognitive impairment, older age, and longer duration of psychiatric disorder. Psychiatrically relevant abnormalities had further associations with older age at onset of the psychiatric disorder and a weak association with abnormal neurological examination. Multiple indications for imaging were present in 57.0% of patients; the most common indications were physical, neurological, and cognitive abnormalities. CONCLUSIONS: Brain MRI is a useful part of psychiatric management in the presence of certain neuropsychiatric risk factors. The present findings suggest that treating teams can judiciously tailor radiological investigations while limiting excessive imaging. Future research in larger cohorts across multiple centers may contribute to shaping more consistent neuroimaging guidelines in psychiatry.
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Trastornos Psicóticos , Adulto , Humanos , Estudios Retrospectivos , Australia/epidemiología , Trastornos Psicóticos/diagnóstico por imagen , Neuroimagen , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Factores de RiesgoRESUMEN
Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.
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Conectoma , Epilepsia del Lóbulo Temporal , Adulto , Atrofia/patología , Epilepsia del Lóbulo Temporal/patología , Hipocampo/patología , Humanos , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: Using objective oculomotor measures, we aimed to: (1) compare oculomotor performance in patients with drug-resistant focal epilepsy to healthy controls, and (2) investigate the differential impact of epileptogenic focus laterality and location on oculomotor performance. METHODS: We recruited 51 adults with drug-resistant focal epilepsy from the Comprehensive Epilepsy Programs of two tertiary hospitals and 31 healthy controls to perform prosaccade and antisaccade tasks. Oculomotor variables of interest were latency, visuospatial accuracy, and antisaccade error rate. Linear mixed models were performed to compare interactions between groups (epilepsy, control) and oculomotor tasks, and between epilepsy subgroups and oculomotor tasks for each oculomotor variable. RESULTS: Compared to healthy controls, patients with drug-resistant focal epilepsy exhibited longer antisaccade latencies (mean difference = 42.8 ms, P = 0.001), poorer spatial accuracy for both prosaccade (mean difference = 0.4°, P = 0.002), and antisaccade tasks (mean difference = 2.1°, P < 0.001), and more antisaccade errors (mean difference = 12.6%, P < 0.001). In the epilepsy subgroup analysis, left-hemispheric epilepsy patients exhibited longer antisaccade latencies compared to controls (mean difference = 52.2 ms, P = 0.003), while right-hemispheric epilepsy was the most spatially inaccurate compared to controls (mean difference = 2.5°, P = 0.003). The temporal lobe epilepsy subgroup displayed longer antisaccade latencies compared to controls (mean difference = 47.6 ms, P = 0.005). SIGNIFICANCE: Patients with drug-resistant focal epilepsy exhibit poor inhibitory control as evidenced by a high percentage of antisaccade errors, slower cognitive processing speed, and impaired visuospatial accuracy on oculomotor tasks. Patients with left-hemispheric epilepsy and temporal lobe epilepsy have markedly impaired processing speed. Overall, oculomotor tasks can be a useful tool to objectively quantify cerebral dysfunction in drug-resistant focal epilepsy.
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Epilepsias Parciales , Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Adulto , Movimientos Sacádicos , Movimientos Oculares , Epilepsia/complicaciones , Epilepsia/diagnóstico , Epilepsias Parciales/complicaciones , Epilepsias Parciales/diagnóstico , Tiempo de ReacciónRESUMEN
BACKGROUND AND AIMS: Neurodegeneration underpins the pathological processes of younger-onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs. METHODS: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age. RESULTS: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient-echo (FSPGR) or magnetization-prepared rapid acquisition gradient-echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = -0.402 [95% confidence interval (CI), -0.593 to -0.147], P = 0.008 and r = -0.625 [95% CI, -0.828 to -0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, -0.649 to -0.014], P = 0.017) and reduced WM in MPRAGE (r = -0.650 [95% CI, -0.777 to -0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY. CONCLUSION: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity.
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Enfermedad de Alzheimer , Trastorno Depresivo Mayor , Humanos , Estudios Retrospectivos , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Trastorno Depresivo Mayor/diagnóstico por imagen , Filamentos Intermedios , Enfermedad de Alzheimer/diagnóstico por imagen , Atrofia , BiomarcadoresRESUMEN
The transition from childhood to adolescence involves important neural function, cognition, and behavior changes. However, the links between maturing brain function and sustained attention over this period could be better understood. This study examined typical changes in network functional connectivity over childhood to adolescence, developmental differences in attention deficit/hyperactivity disorder (ADHD), and how functional connectivity might underpin variability in sustained attention development in a longitudinal sample. A total of 398 resting state scans were collected from 173 children and adolescents (88 ADHD, 85 control) at up to three timepoints across ages 9-14 years. The effects of age, sex, and diagnostic group on changes in network functional connectivity were assessed, followed by relationships between functional connectivity and sustained attention development using linear mixed effects modelling. The ADHD group displayed greater decreases in functional connectivity between salience and visual networks compared with controls. Lower childhood functional connectivity between the frontoparietal and several brain networks was associated with more rapid sustained attention development, whereas frontoparietal to dorsal attention network connectivity related to attention trajectories in children with ADHD alone. Brain network segregation may increase into adolescence as predicted by key developmental theories; however, participants with ADHD demonstrated altered developmental trajectories between salience and visual networks. The segregation of the frontoparietal network from other brain networks may be a mechanism supporting sustained attention development. Frontoparietal to dorsal attention connectivity can be a focus for further work in ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Niño , Adolescente , Humanos , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Mapeo Encefálico , Descanso , Vías Nerviosas/diagnóstico por imagen , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagenRESUMEN
BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.
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BACKGROUND: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.
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Esclerosis Múltiple , Adulto , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Estudios Prospectivos , Recurrencia , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: Around 30% of patients undergoing surgical resection for drug-resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG-PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. METHODS: Eighty two patients with drug resistant MTLE were scanned with FDG-PET pre-surgery and T1-weighted MRI pre- and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippocampal sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. RESULTS: In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug-resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow-up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75-.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59-.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. SIGNIFICANCE: Collectively, these results indicate that "acceptable" to "good" patient-specific prognostication for drug-resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.
Asunto(s)
Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Fluorodesoxiglucosa F18 , Humanos , Aprendizaje Automático , Imagen por Resonancia Magnética , Convulsiones , Resultado del TratamientoRESUMEN
Based on reported trends in relapse incidence among patients with relapsing-remitting multiple sclerosis, an original model for the response to disease modifying therapies is proposed. With a population approach and separate states for patients accounting for their risk of relapses, a system of nonlinear equations is formulated, similarly to established epidemiological models. Different parameters describe the effect of drugs and treatment switch in reducing the frequency of relapses. The model allows for a good fit to previously published data for experiments where different drugs are used. It also shows that different treatments maintain a high degree of similarity, with analogous dynamical features: a pre-treatment increment in relapse frequency leading to a distinct peak, a rapid drop after treatment switch and a plateau corresponding to a new base relapse activity, which seems dependant on the treatment chosen. A sensitivity analysis shows that the uncertainty in the initial proportions of different populations and the frequency of relapses can modify the overall dynamics of the response to treatment. Drugs are observed to induce effects that depend on patient sample's intrinsic characteristics, producing two clearly distinct and independent dynamics of relapse response. This confirms the clinical observation that certain drugs may be overall more successful in lowering the rate of relapses more significantly than others, notwithstanding the fact that patients behave differently across experiments.