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A minority (10%-15%) of cases of amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease (MND), are currently attributable to pathological variants in a single identifiable gene. With the emergence of new therapies targeting specific genetic subtypes of ALS, there is an increasing role for routine genetic testing for all those with a definite diagnosis. However, potential harm to both affected individuals and particularly to asymptomatic relatives can arise from the indiscriminate use of genetic screening, not least because of uncertainties around incomplete penetrance and variants of unknown significance. The most common hereditary cause of ALS, an intronic hexanucleotide repeat expansion in C9ORF72, may be associated with frontotemporal dementia independently within the same pedigree. The boundary of what constitutes a possible family history of MND has therefore extended to include dementia and associated psychiatric presentations. Notwithstanding the important role of clinical genetics specialists, all neurologists need a basic understanding of the current place of genetic testing in MND, which holds lessons for other neurological disorders.
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Expansão das Repetições de DNA , Demência Frontotemporal , Proteína C9orf72/genética , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Testes Genéticos , Humanos , Proteínas/genéticaRESUMO
A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.
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Esclerose Lateral Amiotrófica/etnologia , Potencial Evocado Motor , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana/normas , Adulto , Esclerose Lateral Amiotrófica/fisiopatologia , Braço/fisiologia , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nervos Periféricos/fisiologia , População BrancaRESUMO
INTRODUCTION: This study explored potential diagnostic markers of nerve ultrasound in differentiating amyotrophic lateral sclerosis (ALS) from mimic disorders. METHODS: Ultrasound of the median, ulnar, and tibial nerves was conducted in 53 patients with ALS, 32 patients with ALS-mimic disorders, and 30 controls. Nerve cross-sectional area (CSA) and distal-proximal ratios were calculated. RESULTS: The median nerve CSA in the upper arm was decreased (7.9 ± 1.3 mm2 vs. 9.0 ± 1.4 mm2 , P < 0.05), and the median nerve wrist-upper arm ratio was increased in ALS patients compared with controls (1.3 ± 0.4 vs. 1.1 ± 0.2; P < 0.01). In differentiating ALS from mimic presentations, assessment of median nerve CSA in the upper arm and comparison of a median and ulnar nerve CSA distal-proximal ratio provide diagnostic potential. DISCUSSION: Assessment of nerve CSA combined with calculation of nerve CSA distal-proximal ratio provides a useful marker to aid in the diagnosis of ALS. Muscle Nerve 58:777-783, 2018.
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Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Nervo Mediano/diagnóstico por imagem , Nervos Espinhais/diagnóstico por imagem , Adulto , Idoso , Eletromiografia , Feminino , Antebraço/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Curva ROC , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Ultrassonografia , Punho/inervaçãoRESUMO
INTRODUCTION: This study seeks to elucidate the optimal scan time to detect fasciculations by using ultrasound in the diagnosis of amyotrophic lateral sclerosis (ALS). METHODS: The intervals between fasciculations were recorded from tongue, abdominal, and limb muscles in ALS patients, incorporating assessment of the cumulative probability of 2 fasciculations occurring. RESULTS: From prospective studies of 228 muscles from 19 ALS patients, fasciculations were detectable in 68% of patients. The longest interfasciculation interval recorded was 81.4 s in the hand muscle. The cumulative probability of 2 fasciculations occurring was calculated as ≥0.9 in all muscles during a period of 60 s. DISCUSSION: A definition of 2 or more fasciculations occurring during a scan time of 60 s reliably allowed detection of fasciculations in ALS. Muscle Nerve, 2017.
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Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/fisiopatologia , Fasciculação/diagnóstico por imagem , Fasciculação/fisiopatologia , Gravação em Vídeo/normas , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Estudos Prospectivos , Fatores de Tempo , Ultrassonografia/normas , Gravação em Vídeo/métodosRESUMO
Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.
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Comunicação Interdisciplinar , Doença dos Neurônios Motores/terapia , Padrão de Cuidado , Austrália , Prática Clínica Baseada em Evidências , Testes Genéticos , Terapia Genética , Humanos , Neuroproteção , Ventilação não Invasiva , Apoio Nutricional , Aceitação pelo Paciente de Cuidados de Saúde , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante de Células-TroncoRESUMO
PURPOSE OF REVIEW: Although there is no cure for motor neurone disease (MND), the advent of multidisciplinary care and neuroprotective agents has improved treatment interventions and enhanced quality of life for MND patients and their carers. RECENT FINDINGS: Evidence-based multidisciplinary care, respiratory management and disease-modifying therapy have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the quality of life for MND patients. SUMMARY: Recent progress in the understanding of the clinical, pathophysiological and genetic heterogeneity of MND has improved the approach of clinicians to treatment. Notwithstanding improvement to care and quality of life, survival benefit has become evident with the advent of a multidisciplinary care framework, early treatment with riluzole and noninvasive ventilation. Weight maintenance remains critical, with weight loss associated with more rapid disease progression. The end-of-life phase is poorly defined and treatment is challenging, but effective symptom control through palliative care is achievable and essential. Encouragingly, current progress of clinical trials continues to close the gap towards the successful development of curative treatment in MND.
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Gerenciamento Clínico , Doença dos Neurônios Motores/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Qualidade de Vida , Progressão da Doença , Medicina Baseada em Evidências , Humanos , Doença dos Neurônios Motores/diagnóstico , Ventilação não InvasivaAssuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Metaloendopeptidases/genética , Mutação/genética , Paraplegia/diagnóstico por imagem , Paraplegia/genética , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.
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Esclerose Lateral Amiotrófica , Doença dos Neurônios Motores , Neurônios Motores , Estimulação Magnética Transcraniana , Humanos , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/diagnóstico , Estimulação Magnética Transcraniana/métodos , Doença dos Neurônios Motores/fisiopatologia , Doença dos Neurônios Motores/diagnóstico , Neurônios Motores/fisiologia , Potencial Evocado Motor/fisiologia , Córtex Motor/fisiopatologia , Córtex Motor/diagnóstico por imagemRESUMO
A biomarker specific for the diagnosis of amyotrophic lateral sclerosis must be sensitive across a spectrum of clinical heterogeneity. Neurofilament light chain levels in amyotrophic lateral sclerosis correlate with the rate of disability progression. Previous attempts to establish a diagnostic role for neurofilament light chain have been limited to comparison with healthy individuals or controls with alternative diagnoses unlikely to be confused with amyotrophic lateral sclerosis in real-world clinical practice. In a tertiary amyotrophic lateral sclerosis referral clinic, at first visit, serum was taken for neurofilament light chain measurement after prospectively recording the clinical diagnosis as 'amyotrophic lateral sclerosis', 'primary lateral sclerosis', 'alternative' or 'currently uncertain'. Of 133 referrals, 93 patients were diagnosed with amyotrophic lateral sclerosis (median neurofilament light chain 218.1â pg/ml, interquartile range 130.7-311.9), three primary lateral sclerosis (65.6, 51.5-106.9) and 19 alternative diagnoses (45.2, 13.5-71.9) at first visit. Of 18 initially uncertain diagnoses, eight were subsequently diagnosed with amyotrophic lateral sclerosis (98.5, 45.3-300.1). Neurofilament light chain ≥110.9â pg/ml had a positive predictive value of 0.92 for amyotrophic lateral sclerosis; <110.9â pg/ml had a negative predictive value of 0.48. In a specialized clinic, neurofilament light chain is largely confirmatory to clinical judgement in diagnosing amyotrophic lateral sclerosis and has limited ability to exclude alternative diagnoses. The current, important, value of neurofilament light chain is its potential to stratify patients with amyotrophic lateral sclerosis by disease activity and as a biomarker in therapeutic trials.
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Neurodegenerative diseases pose significant challenges due to their impact on brain structure, function, and cognition. As life expectancy rises, the prevalence of these disorders is rapidly increasing, resulting in substantial personal, familial, and societal burdens. Efforts have been made to optimize the diagnostic and therapeutic processes, primarily focusing on clinical, cognitive, and imaging characterization. However, the emergence of non-invasive brain stimulation techniques, specifically transcranial magnetic stimulation (TMS), offers unique functional insights and diagnostic potential. TMS allows direct evaluation of brain function, providing valuable information inaccessible through other methods. This review aims to summarize the current and potential diagnostic utility of TMS in investigating neurodegenerative diseases, highlighting its relevance to the field of cognitive neuroscience. The findings presented herein contribute to the growing body of research focused on improving our understanding and management of these debilitating conditions, particularly in regions with limited resources and a pressing need for innovative approaches.
As doenças neurodegenerativas representam desafio significativo por seu impacto na estrutura cerebral, função e cognição. À medida que a expectativa de vida aumenta, a prevalência dessas doenças cresce rapidamente, resultando em substanciais encargos pessoais, familiares e sociais. Esforços têm sido feitos para otimizar os processos diagnósticos e terapêuticos, com foco principal na caracterização clínica, cognitiva e de imagem. No entanto, o surgimento de técnicas de estimulação cerebral não invasivas, especificamente a estimulação magnética transcraniana (EMT), oferece compreensão funcional e potencial diagnóstico únicos. A TMS permite a avaliação direta da função cerebral, fornecendo informações valiosas inacessíveis por outros métodos. Esta revisão teve como objetivo resumir a utilidade diagnóstica atual e potencial da EMT na investigação de doenças neurodegenerativas, destacando sua relevância para o campo da neurociência cognitiva. As conclusões aqui apresentadas contribuem para o crescente corpo de investigação centrado na melhoria da nossa compreensão e gestão dessas condições debilitantes, particularmente em regiões com recursos limitados e necessidade premente de abordagens inovadoras.
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Background: Intramuscular injections of botulinum toxin A (BTX-A) have been used in the treatment of sleep bruxism (SB) however controlled trials are limited and the optimal injection strategy and dose is not known. Methods: This double-blind, randomised, placebo-controlled, cross-over study evaluated the efficacy and safety of BTX-A in participants with SB. Average bruxism events per hour of sleep (Bruxism Index, BI) was calculated using surface electromyography. Participants with BI >5 were included and randomised by order of injection (active or placebo with the opposite 20 weeks later) and into one of three differing treatment groups: bilateral masseter (60 units(U)), bilateral masseter and temporalis (90U) and bilateral masseter, temporalis and medial pterygoid muscles (120U). Change in BI and subjective measures of headache, pain, and bruxism at 4 and 12 weeks was calculated following intervention, and differences between treatment groups analysed. Results: 41 participants were recruited, 35 randomised and data from 22 participants (14 female) were analysed. BI was significantly lower at 4 weeks after active treatment when compared with placebo (mean=-1.66, p=0.003), not sustained at 12 weeks. The difference was greater with higher doses injected and among those with greater baseline BI. There was no difference in subjective measures at any time point. Five participants injected had mild, transient side effects. Discussion: Targeted BTX-A injection is a safe and effective treatment for SB. A greater benefit may be achieved by administering BTX-A into more muscles and at higher total doses and among those with higher baseline BI. Trial registration number: ACTRN12618001430224.
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BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a prognostically heterogeneous neurodegenerative disease. Blood creatine kinase (CK) level has been inconsistently reported as a prognostic biomarker and raised levels in some ALS patients have been presumed to reflect muscle wasting, which is also variable. METHODS: MEDLINE was systematically searched for papers related to CK in ALS and the relevant studies were reviewed. Using data from 222 ALS patients in a multi-centre, prospective, longitudinal cohort, survival analyses using Kaplan-Meier and Cox proportional hazards models were undertaken in relation to CK and other prognostic factors. RESULTS: Twenty-five studies investigating CK in ALS were identified, of which 10 specifically studied the link between CK and survival. Five studies observed no association, four found that higher CK levels were associated with longer survival and one, the opposite. In our cohort (n = 222), 39% of patients had a CK level above the laboratory reference range. Levels were higher in males compared to females (p < 0.001), in patients with limb versus bulbar onset of symptoms (p < 0.001) and in patients with higher lower motor neuron burden (p < 0.001). There was no significant trend in longitudinal CK values. Although a higher standardised log (CK) at first visit was associated with longer survival in univariate analysis (hazard ratio 0.75, p = 0.003), there was no significant association after adjusting for other prognostic covariates. CONCLUSION: While raised CK levels in ALS do reflect lower motor neuron denervation to a large extent, they are not independently associated with survival when measured in the symptomatic phase of the disease.
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Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Esclerose Lateral Amiotrófica/complicações , Estudos de Coortes , Creatina Quinase , Feminino , Humanos , Masculino , Doenças Neurodegenerativas/complicações , Prognóstico , Estudos ProspectivosRESUMO
The routine clinical integration of individualized objective markers of disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise the leading candidate biofluid biomarkers in the stratification and potential therapeutic assessment of those with amyotrophic lateral sclerosis. Incident patients diagnosed with amyotrophic lateral sclerosis (n = 258), other neurological diseases (n = 80) and healthy control participants (n = 101), were recruited and followed at intervals of 3-6 months for up to 30 months. Cerebrospinal fluid neurofilament light chain and chitotriosidase 1 and blood neurofilament light chain, creatine kinase, ferritin, complement C3 and C4 and C-reactive protein were measured. Blood neurofilament light chain, creatine kinase, serum ferritin, C3 and cerebrospinal fluid neurofilament light chain and chitotriosidase 1 were all significantly elevated in amyotrophic lateral sclerosis patients. First-visit plasma neurofilament light chain level was additionally strongly associated with survival (hazard ratio for one standard deviation increase in log10 plasma neurofilament light chain 2.99, 95% confidence interval 1.65-5.41, P = 0.016) and rate of disability progression, independent of other prognostic factors. A small increase in level was noted within the first 12 months after reported symptom onset (slope 0.031 log10 units per month, 95% confidence interval 0.012-0.049, P = 0.006). Modelling the inclusion of plasma neurofilament light chain as a therapeutic trial outcome measure demonstrated that a significant reduction in sample size and earlier detection of disease-slowing is possible, compared with using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. This study provides strong evidence that blood neurofilament light chain levels outperform conventional measures of disease activity at the group level. The application of blood neurofilament light chain has the potential to radically reduce the duration and cost of therapeutic trials. It might also offer a first step towards the goal of more personalized objective disease activity monitoring for those living with amyotrophic lateral sclerosis.
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Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.
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Apathy is the core behavioural feature of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS). Initiation and emotional manifestations of apathy significantly affect patients and carers, particularly in terms of quality of life. As such, the primary aim of the present study was to investigate the prevalence and neural correlates of initiation, and emotional subtypes of apathy in ALS. A total of 109 participants were recruited from a specialised, tertiary referral ALS/FTD clinic. Overall rates of apathy, including cognitive, initiation and emotion subtypes as assessed by the Dimensional Apathy Scale (DAS), were examined and correlated with brain volumes, including voxel-based morphometry on high resolution MRI. Clinically significant apathy ranged between 49% (patient-rated DAS) and 64% (carer-rated DAS), with the most common apathy subtypes being initiation (84-96%) and emotional (74-75%) apathy. The results of the two-way repeated measures ANOVA revealed significant differences across the DAS executive, emotional and initiation subscales (p = .0001). Multivariate analysis using a logistic regression model showed that only initiation; (odds ratio = 3.08, p = .004) and emotional (odds ratio = 2.40, p = .008) apathy were predictive of clinically significant apathy, controlling for education and depression. Increased initiation apathy correlated with reduced grey matter within bilateral superior frontal gyrus and increased emotional apathy correlated with reduced grey matter in prefrontal cortices and right anterior cingulate, previously implicated in apathy. Additional correlations were identified including the angular gyrus (or the temporo-parietal junction), important in reward valuation and subsequent goal-directed behaviour. Taken together, results from the present series highlight the frequency and multi-dimensionality of apathy in ALS. The pathophysiological mechanisms of apathy in ALS may be critically underpinned by neurodegeneration across a distributed brain network, with key roles in task initiation, emotion, reward processing and subsequent goal-directed behaviour.
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Esclerose Lateral Amiotrófica , Apatia , Demência Frontotemporal , Emoções , Humanos , Qualidade de VidaRESUMO
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke's cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p < 0.005), while ALS-Cog (63.3 ± 12.7) and ALS (60.8 ± 13.9, not significant) were similar to controls. Short interval intracortical inhibition (SICI) was reduced across all ALS groups compared to controls, indicating hyperexcitability. On receiver operating characteristic curve analysis, RMT differentiated ALS-FTD from ALS (area under the curve AUC = 0.745, p = 0.011). The present study has identified a distinct pattern of cortical excitability across cognitive phenotypes in ALS. As such, assessment of cortical physiology may provide more precise clinical prognostication in ALS.
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Esclerose Lateral Amiotrófica/fisiopatologia , Cognição/fisiologia , Excitabilidade Cortical/fisiologia , Córtex Motor/fisiopatologia , Idoso , Comportamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Curva ROC , Estimulação Magnética TranscranianaRESUMO
Objective: This study aimed to establish (1) the pattern and severity of neuropsychiatric symptoms and other non-motor symptoms of sleep and mood, across ALS phenotypes in comparison to bvFTD and (2) the contribution of non-modifiable factors including age, sex and disease state to the severity of symptoms experienced by ALS patients. Methods: Consecutive participants were recruited to the study and underwent a detailed clinical, cognitive, behavioral and neuroimaging assessment. Neuropsychiatric and other non-motor symptoms were determined using the Cambridge Behavioral Inventory, the CBI-R. The scores were converted to define impairment in terms of mild, moderate and severe symptoms for each subscale. Rate, severity and contribution of King's staging and modifiable factors were also determined and a regression model identified predictors of symptom severity. Results: In total, 250 participants (115 ALS, 98 bvFTD, and 37 ALS-FTD patients) were recruited. A similar pattern of neuropsychiatric symptom severity was identified (apathy, disinhibition and stereotypic behavior) for all behavioral phenotypes of ALS compared to bvFTD (all p > 0.05). Neuropsychiatric symptoms were also present in cases defined as ALSpure and the cognitive phenotype of ALS (ALSci) although they occurred less frequently and were at the milder end of the spectrum. Disordered sleep and disrupted mood were common across all phenotypes (all p < 0.05). The severity of sleep dysfunction was influenced by both sex and age (all p < 0.05). Neuropsychiatric symptoms, sleep and mood disorders were common early in the disease process and deteriorated in line with progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; all p < 0.05). Diagnostic phenotype, disease duration and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments. Conclusion: The current findings reveal strikingly similar patterns of changes across the subgroups of ALS and bvFTD, supporting the concept of the ALS-FTD spectrum. The findings further highlight the impact of non-motor and neuropsychiatric symptoms in patients with ALS, that are often as severe as that seen in ALS-FTD and bvFTD. This study advances understanding across the ALS-FTD spectrum that may accelerate the early identification of patient needs, to ensure prompt recognition of symptoms and thereby to improve clinical awareness, patient care and management.
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Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.