Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

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.

Diagnostic utility of transcranial magnetic stimulation for neurodegenerative disease: a critical review.

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.

Limited value of serum neurofilament light chain in diagnosing amyotrophic lateral sclerosis.

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.

Efficacy of botulinum toxin type a in the targeted treatment of sleep bruxism: a double-blind, randomised, placebo-controlled, cross-over study.

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.

Creatine kinase and prognosis in amyotrophic lateral sclerosis: a literature review and multi-centre cohort analysis.

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.

Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain.

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 ( = 258), other neurological diseases ( = 80) and healthy control participants ( = 101), were recruited and followed at intervals of 3-6 months for up to 30 months.

Genetic testing in motor neurone disease.

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.

Effect of racial background on motor cortical function as measured by threshold tracking transcranial magnetic stimulation.

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.

Cortical Excitability across the ALS Clinical Motor Phenotypes.

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.

Apathy is associated with parietal cortical-subcortical dysfunction in ALS.

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.

Motor cortical excitability predicts cognitive phenotypes in amyotrophic lateral sclerosis.

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.

Improving clinical trial outcomes in amyotrophic lateral sclerosis.

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.

Cortical inexcitability defines an adverse clinical profile in amyotrophic lateral sclerosis.

Background And Purpose: In amyotrophic lateral sclerosis, studies using threshold-tracking transcranial magnetic stimulation (TMS) have identified corticomotoneuronal dysfunction as a key pathogenic mechanism. Some patients, however, display no motor response at maximal TMS intensities, termed here an 'inexcitable' motor cortex. The extent to which this cortical difference impacts clinical outcomes remains unclear.

Early focality and spread of cortical dysfunction in amyotrophic lateral sclerosis: A regional study across the motor cortices.

Objective: To characterise the regional cortical patterns underlying clinical symptomatology in amyotrophic lateral sclerosis (ALS).

Methods: 138 patients prospectively underwent transcranial magnetic stimulation studies from hand and leg cortical regions of each hemisphere, obtaining motor evoked potentials from all four limbs. Patients were categorised by clinical phenotype and underwent clinical and peripheral evaluation of disease.

The effect of coil type and limb dominance in the assessment of lower-limb motor cortex excitability using TMS.

Purpose: Clinical application of transcranial magnetic stimulation (TMS) has rapidly increased but the majority of studies have targeted upper limb muscles, with few exploring the lower-limb. Differences of coil choice have added to methodological difficulties of lower-limb studies and have challenged consistent interpretation of these parameters. The aims of this study were to determine the optimal coil choice for assessing lower-limb cortical excitability and assess laterality of normal cortical function.

Functional Biomarkers for Amyotrophic Lateral Sclerosis.

The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on determination of progressive dysfunction of both cortical as well as spinal and bulbar motor neurons. However, the variable mix of upper and lower motor neuron signs result in the clinical heterogeneity of patients with ALS, resulting frequently in delay of diagnosis as well as difficulty in monitoring disease progression and treatment outcomes particularly in a clinical trial setting. As such, the present review provides an overview of recently developed novel non-invasive electrophysiological techniques that may serve as biomarkers to assess UMN and LMN dysfunction in ALS patients.

Utility of threshold tracking transcranial magnetic stimulation in ALS.

Upper motor neuron [UMN] and lower motor neuron [LMN] dysfunction, in the absence of sensory features, is a pathognomonic feature of amyotrophic lateral sclerosis [ALS]. Although the precise mechanisms have yet to be elucidated, one leading hypothesis is that UMN precede LMN dysfunction, which is induced by anterograde glutamatergic excitotoxicity. Transcranial magnetic stimulation (TMS) is a neurophysiological tool that provides a non-invasive and painless assessment of cortical function.

Motor neurone disease.

Motor neurone disease (MND) patients exhibit poor gait, balance, and postural control, all of which significantly increases their risk of falling. Falls are frequent in the MND population, and are associated with an increased burden of disease. The complex interplay of both motor and extramotor manifestations in this disease contributes to the heterogeneous and multifactorial causes of such dysfunction.

Fasciculation intensity and disease progression in amyotrophic lateral sclerosis.

Objective: To investigate the association between the frequency and intensity of fasciculations with clinical measures of disease progression in amyotrophic lateral sclerosis (ALS).

Methods: Twenty-four consecutive patients with ALS underwent clinical review and neuromuscular ultrasound assessment to detect intensity of fasciculations. Results were correlated with clinical markers of disease severity, as measured by the ALS Functional Rating Scale-revised (ALSFRS-R) and rate of disease progression (ΔFS), in addition to assessment of cortical motor function.

Comparison of cross-sectional areas and distal-proximal nerve ratios in amyotrophic lateral sclerosis.

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.

Primary lateral sclerosis and the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

Aim: To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum of diseases.

Methods: Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS-FTD (n = 12). Clinical features, Addenbrooke's Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented.