scholarly journals Motor cortical excitability predicts cognitive phenotypes in amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Smriti Agarwal ◽  
Elizabeth Highton-Williamson ◽  
Jashelle Caga ◽  
James Howells ◽  
Thanuja Dharmadasa ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cortical Excitability ◽  
Characteristic Curve ◽  
Short Interval ◽  
Surrogate Marker ◽  
Area Under The Curve ◽  
Distinct Pattern ◽  
Cortical Hyperexcitability ◽  
Resting Motor Threshold ◽  
Lateral Sclerosis

AbstractAmyotrophic 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.

Imbalance of cortical facilitatory and inhibitory circuits underlies hyperexcitability in ALS

Neurology ◽  
2018 ◽  
Vol 91 (18) ◽  
pp. e1669-e1676 ◽  
Author(s):  
Mehdi A.J. Van den Bos ◽  
Mana Higashihara ◽  
Nimeshan Geevasinga ◽  
Parvathi Menon ◽  
Matthew C. Kiernan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Functional Disability ◽  
Rating Scale ◽  
Cortical Excitability ◽  
Short Interval ◽  
Silent Period ◽  
Cortical Function ◽  
Cortical Hyperexcitability ◽  
Intracortical Circuits ◽  
Lateral Sclerosis

ObjectiveTo determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS).MethodsIn this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits.ResultsThere was a significant increase in SICF (ALS −18.51 ± 1.56%, controls −8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score (R2 = 0.335, p = 0.002).ConclusionsThe present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.

scholarly journals Neuron-specific enolase level is a useful biomarker for distinguishing amyotrophic lateral sclerosis from cervical spondylotic myelopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Akihiro Tsukahara ◽  
Takafumi Hosokawa ◽  
Daisuke Nishioka ◽  
Takuya Kotani ◽  
Shimon Ishida ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cervical Spondylotic Myelopathy ◽  
Characteristic Curve ◽  
Neuron Specific Enolase ◽  
Area Under The Curve ◽  
Diagnostic Value ◽  
Control Group ◽  
Chemiluminescent Immunoassay ◽  
And Control ◽  
Lateral Sclerosis

AbstractThe current study aimed to evaluate whether cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels are elevated in amyotrophic lateral sclerosis (ALS) and are effective in distinguishing ALS from cervical spondylotic myelopathy (CSM). We retrospectively evaluated 45 patients with ALS, 23 with CSM, 28 controls, and 10 with Parkinson’s disease (PD) who underwent analysis of CSF NSE levels. The control group comprised patients aged above 45 years who underwent lumbar puncture because of suspected neurological disorders that were ruled out after extensive investigations. CSF NSE levels were evaluated using the electro-chemiluminescent immunoassay. The ALS group had significantly higher CSF NSE levels than the CSM and control groups (P < 0.001 for both comparisons). The CSM, control, and PD groups did not significantly differ in terms of CSF NSE levels. A receiver-operating characteristic curve analysis was performed to assess the diagnostic value of CSF NSE levels in distinguishing ALS from CSM. The area under the curve for CSF NSE levels was 0.86. The optimal cutoff value was 17.7 ng/mL, with a specificity of 87% and a sensitivity of 80%. Hence, CSF NSE levels are elevated in ALS and are effective in distinguishing ALS from CSM.

scholarly journals Clinical Controversies in Amyotrophic Lateral Sclerosis

EMJ Neurology ◽  
2020 ◽  
pp. 80-92
Author(s):  
Ruaridh Cameron Smail ◽  
Neil Simon
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cortical Excitability ◽  
Target Population ◽  
New Techniques ◽  
Cortical Hyperexcitability ◽  
Suitable Target ◽  
Active Research ◽  
Relevant Finding ◽  
Cell Disorder ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a devastating neurodegenerative condition with few effective treatments. Current research is gathering momentum into the underlying pathology of this condition and how components of these pathological mechanisms affect individuals differently, leading to the broad manifestations encountered in clinical practice. We are moving away from considering this condition as merely an anterior horn cell disorder into a framework of a multisystem neurodegenerative condition in which early cortical hyperexcitability is key. The deposition of TAR DNA-binding protein 43 is also a relevant finding given the overlap with frontotemporal dysfunction. New techniques have been developed to provide a more accurate diagnosis, earlier in the disease course. This goes beyond the traditional nerve conduction studies and needle electromyography, to cortical excitability studies using transcranial magnetic stimulation, and the use of ultrasound. These ancillary tests are proposed for consideration of future diagnostic paradigms. As we learn more about this disease, future treatments need to ensure efficacy, safety, and a suitable target population to improve outcomes for these patients. In this time of active research into this condition, this paper highlights some of the areas of controversy to induce discussion surrounding these topics.

Association of Cortical Hyperexcitability and Cognitive Impairment in Patients with ALS

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011798
Author(s):  
Mana Higashihara ◽  
Nathan Pavey ◽  
Mehdi van den Bos ◽  
Parvathi Menon ◽  
Matthew C. Kiernan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cortical Excitability ◽  
Short Interval ◽  
Motor Evoked Potential ◽  
Intracortical Inhibition ◽  
Cognitively Impaired ◽  
Cortical Hyperexcitability ◽  
Multivariable Regression ◽  
Als Patients ◽  
Lateral Sclerosis

Objective:To determine whether cortical hyperexcitability was more prominent in cognitively impaired amyotrophic lateral sclerosis (ALS) patients.Methods:Threshold tracking transcranial magnetic stimulation (TMS) was utilised to assess cortical excitability, while cognitive function determined by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Cognitive impairment was defined by ECAS<105. ALS patients, defined by the Awaji criteria, were prospectively recruited. Patients unable to undergo TMS, or in whom TMS indices were compromised by coexistent medical conditions were excluded. Cortical hyperexcitability was defined by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation (SICF), index of excitability (IE) and motor evoked potential (MEP) amplitude. Student t-test determined differences between groups, while multivariable regression modelling was utilised to assess association between cognitive, clinical and TMS parameters. TMS results were compared to 42 controls.Results:Cognitive impairment was evident in 36% of the 40 ALS patents (23 males, mean age 62.1 years). Cortical hyperexcitability was more prominent in cognitively impaired patients as indicated by an increase in SICF (ECAS≥105 -15.3±1.7%; ECAS<105 -20.6±1.2%, P<0.01), IE (ECAS ≥105 80.9±7.8; ECAS <105 95.0±4.5, P<0.01) and MEP amplitude (ECAS≥105 28.7±3.3%; ECAS<105 43.1±5.9%, P<0.05). SICF was independently associated with the ECAS score (β=2.410, P<0.05). Reduced SICI was evident in ALS, being more prominent in patients with reduced executive score (ECASexecutive score>33 6.2±1.3%; ECASexecutive score<33 1.5±2.1%, P<0.01).Conclusion:Cortical hyperexcitability was more prominent in cognitively impaired ALS patients. Given that ECAS is a valid predictor of TDP-43 pathology, the increase in cortical hyperexcitability may be associated with TDP-43 accumulation.

scholarly journals Elevated CSF Neuron-specific Enolase Levels in Amyotrophic Lateral Sclerosis (Als): A Useful Biomarker for Distinguishing ALS From Cervical Spondylotic Myelopathy

2021 ◽  
Author(s):  
Akihiro Tsukahara ◽  
Takafumi Hosokawa ◽  
Daisuke Nishioka ◽  
Takuya Kotani ◽  
Shimon Ishida ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cervical Spondylotic Myelopathy ◽  
Characteristic Curve ◽  
Neuron Specific Enolase ◽  
Area Under The Curve ◽  
Diagnostic Value ◽  
Control Group ◽  
Control Groups ◽  
And Control ◽  
Lateral Sclerosis

Abstract The current study aimed to evaluate whether cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels are elevated in amyotrophic lateral sclerosis (ALS) and are effective in distinguishing ALS from cervical spondylotic myelopathy (CSM). We retrospectively evaluated 45 patients with ALS, 23 with CSM, and 28 controls who underwent analysis of CSF NSE levels. The control group comprised patients aged above 45 years who underwent lumbar puncture because of suspected neurological disorders that were ruled out after extensive investigations. CSF NSE levels were evaluated using the electro-chemiluminescent immunoassay. The ALS group had significantly higher CSF NSE levels than the CSM and control groups (P < 0.001 for both comparisons). The CSM and control groups did not significantly differ in terms of CSF NSE levels. A receiver-operating characteristic curve analysis was performed to assess the diagnostic value of CSF NSE levels in distinguishing ALS from CSM. The area under the curve for CSF NSE levels was 0.86. The optimal cutoff value was 17.7 ng/mL, with a specificity of 87% and a sensitivity of 80%. Hence, CSF NSE levels are elevated in ALS and are effective in distinguishing ALS from CSM.

scholarly journals Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 906
Author(s):  
Nimeshan Geevasinga ◽  
Mehdi Van den Bos ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cortical Excitability ◽  
Muscular Atrophy ◽  
Close Relationship ◽  
Bulbar Onset ◽  
Als Patients ◽  
Transcranial Magnetic Simulation ◽  
Cortical Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

Amyotrophic lateral sclerosis diagnostic index

Neurology ◽  
2019 ◽  
Vol 92 (6) ◽  
pp. e536-e547 ◽  
Author(s):  
Nimeshan Geevasinga ◽  
James Howells ◽  
Parvathi Menon ◽  
Mehdi van den Bos ◽  
Kazumoto Shibuya ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Confidence Interval ◽  
Diagnostic Accuracy ◽  
Neuromuscular Disorders ◽  
Area Under The Curve ◽  
Disease Process ◽  
Diagnostic Utility ◽  
Training Cohort ◽  
Diagnostic Index ◽  
Lateral Sclerosis

ObjectiveThe aim of the study was to assess the utility of a novel amyotrophic lateral sclerosis (ALS) diagnostic index (ALSDI).MethodsA prospective multicenter study was undertaken on patients presenting with suspected ALS. The reference standard (Awaji criteria) was applied to all patients at recruitment. Patients were randomly assigned to a training (75%) and a test (25%) cohort. The ALSDI was developed in the training cohort and its diagnostic utility was subsequently assessed in the test cohort.ResultsA total of 407 patients were recruited, with 305 patients subsequently diagnosed with ALS and 102 with a non-ALS mimicking disorder. The ALSDI reliably differentiated ALS from neuromuscular disorders in the training cohort (area under the curve 0.92, 95% confidence interval 0.89–0.95), with ALSDI ≥4 exhibiting 81.6% sensitivity, 89.6% specificity, and 83.5% diagnostic accuracy. The ALSDI diagnostic utility was confirmed in the test cohort (area under the curve 0.90, 95% confidence interval 0.84–0.97), with ALSDI ≥4 exhibiting 83.3% sensitivity, 84% specificity, and 83.5% diagnostic accuracy. In addition, the diagnostic utility of the ALSDI was confirmed in patients who were Awaji negative at recruitment and in those exhibiting a predominantly lower motor neuron phenotype.ConclusionThe ALSDI reliably differentiates ALS from mimicking disorders at an early stage in the disease process.Classification of evidenceThis study provides Class I evidence that for patients with suspected ALS, the ALSDI distinguished ALS from neuromuscular mimicking disorders.

Inflammatory markers in cerebrospinal fluid: independent prognostic biomarkers in amyotrophic lateral sclerosis?

2019 ◽  
pp. jnnp-2018-319586 ◽  
Author(s):  
Benjamin Gille ◽  
Maxim De Schaepdryver ◽  
Lieselot Dedeene ◽  
Janne Goossens ◽  
Kristl G Claeys ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Progression ◽  
Inflammatory Markers ◽  
Cox Regression ◽  
Characteristic Curve ◽  
Progression Rate ◽  
Cox Regression Analysis ◽  
Lateral Sclerosis ◽  
Discriminatory Performance

ObjectiveInflammation is a key pathological hallmark in amyotrophic lateral sclerosis (ALS), which seems to be linked to the disease progression. It is not clear what the added diagnostic and prognostic value are of inflammatory markers in the cerebrospinal fluid (CSF) of patients with ALS.MethodsChitotriosidase-1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) were measured in CSF and serum of patients with ALS (n=105), disease controls (n=102) and patients with a disease mimicking ALS (n=16). The discriminatory performance was evaluated by means of a receiver operating characteristic curve analysis. CSF and serum levels were correlated with several clinical parameters. A multivariate Cox regression analysis, including eight other established prognostic markers, was used to evaluate survival in ALS.ResultsIn CSF, CHIT1, YKL-40 and MCP-1 showed a weak discriminatory performance between ALS and ALS mimics (area under the curve: 0.79, p<0.0001; 0.72, p=0.001; 0.75, p=0.001, respectively). CHIT1 and YKL-40 correlated with the disease progression rate (ρ=0.28, p=0.009; ρ=0.34, p=0.002, respectively). CHIT1 levels were elevated in patients with a higher number of regions displaying motor neuron degeneration (one vs three regions: 4248 vs 13 518 pg/mL, p = 0.0075). In CSF, YKL-40 and MCP-1 were independently associated with survival (HR: 29.7, p=0.0003; 6.14, p=0.001, respectively).ConclusionsOur findings show that inflammation in patients with ALS reflects the disease progression as an independent predictor of survival. Our data encourage the use of inflammatory markers in patient stratification and as surrogate markers of therapy response in clinical trials.

scholarly journals Non-invasive measurement of fasciculation frequency demonstrates diagnostic accuracy in amyotrophic lateral sclerosis

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Arina Tamborska ◽  
James Bashford ◽  
Aidan Wickham ◽  
Raquel Iniesta ◽  
Urooba Masood ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Confidence Interval ◽  
Biceps Brachii ◽  
Delayed Diagnosis ◽  
Area Under The Curve ◽  
Motor Neuropathy ◽  
Healthy Individuals ◽  
Non Invasive ◽  
Lateral Sclerosis ◽  
Invasive Measurement

Abstract Delayed diagnosis of amyotrophic lateral sclerosis prevents early entry into clinical trials at a time when neuroprotective therapies would be most effective. Fasciculations are an early hallmark of amyotrophic lateral sclerosis, preceding muscle weakness and atrophy. To assess the potential diagnostic utility of fasciculations measured by high-density surface electromyography, we carried out 30-min biceps brachii recordings in 39 patients with amyotrophic lateral sclerosis, 7 patients with benign fasciculation syndrome, 1 patient with multifocal motor neuropathy and 17 healthy individuals. We employed the surface potential quantification engine to compute fasciculation frequency, fasciculation amplitude and inter-fasciculation interval. Inter-group comparison was assessed by Welch’s analysis of variance. Logistic regression, receiver operating characteristic curves and decision trees discerned the diagnostic performance of these measures. Fasciculation frequency, median fasciculation amplitude and proportion of inter-fasciculation intervals &lt;100 ms showed significant differences between the groups. In the best-fit regression model, increasing fasciculation frequency and median fasciculation amplitude were independently associated with the diagnosis of amyotrophic lateral sclerosis. Fasciculation frequency was the single best measure predictive of the disease, with an area under the curve of 0.89 (95% confidence interval 0.81–0.98). The cut-off of more than 14 fasciculation potentials per minute achieved 80% sensitivity (95% confidence interval 63–90%) and 96% specificity (95% confidence interval 78–100%). In conclusion, non-invasive measurement of fasciculation frequency at a single time-point reliably distinguished amyotrophic lateral sclerosis from its mimicking conditions and healthy individuals, warranting further research into its diagnostic applications.

scholarly journals CSF chitinase proteins in amyotrophic lateral sclerosis

2019 ◽  
Vol 90 (11) ◽  
pp. 1215-1220 ◽  
Author(s):  
Alexander G Thompson ◽  
Elizabeth Gray ◽  
Alexander Bampton ◽  
Dominika Raciborska ◽  
Kevin Talbot ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Area Under The Curve ◽  
Neuronal Loss ◽  
Progression Rate ◽  
Healthy Controls ◽  
Reactive Protein ◽  
Classifier Performance ◽  
Disease Progression Rate ◽  
Csf Levels ◽  
Lateral Sclerosis

ObjectiveTo evaluate the classifier performance, clinical and biochemical correlations of cerebrospinal fluid (CSF) levels of the chitinase proteins Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1) and Chitinase-3-like protein 2 (CHI3L2) in amyotrophic lateral sclerosis (ALS).MethodsCSF levels of CHIT1, CHI3L1, CHI3L2, phosphorylated neurofilament heavy chain (pNFH) and C-reactive protein were measured by ELISA in a longitudinal cohort of patients with ALS (n=82), primary lateral sclerosis (PLS, n=10), ALS-mimic conditions (n=12), healthy controls (n=25) and asymptomatic carriers of ALS-causing genetic mutations (AGC; n=5).ResultsCSF CHIT1, CHI3L1 and CHI3L2 were elevated in patients with ALS compared with healthy controls (p<0.001) and ALS-mimics (CHIT1, p<0.001; CHI3L1, p=0.017; CHI3L2, p<0.001). CHIT1 and CHI3L2 were elevated in ALS compared with PLS (CHIT1, p=0.021; CHI3L1, p=0.417; CHI3L2, p<0.001). Chitinase levels were similar in AGCs and healthy controls. Chitinase proteins distinguished ALS from healthy controls (area under the curve (AUC): CHIT1 0.92; CHI3L1 0.80; CHI3L2 0.90), mimics (AUC: CHIT1 0.84; CHI3L1 0.73; CHI3L2 0.88) and, to a lesser extent, PLS (AUC: CHIT 0.73; CHI3L1 0.51; CHI3L2 0.82) but did not outperform pNFH. CHIT1 and CHI3L2 correlated with disease progression rate (Pearson’s r=0.49, p<0.001; r=0.42, p<0.001, respectively). CHI3L1 correlated with degree of cognitive dysfunction (r=−0.25, p=0.038). All chitinases correlated with pNFH. CHIT1 levels were associated with survival in multivariate models. Chitinase levels were longitudinally stable.ConclusionsCSF chitinase proteins may have limited value as independent diagnostic and stratification biomarkers in ALS, but offer a window into non-autonomous mechanisms of motor neuronal loss in ALS, specifically in assessing response to therapies targeting neuroinflammatory pathways.

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