Quantitative ultrasound of the tongue: Echo intensity is a potential biomarker of bulbar dysfunction in amyotrophic lateral sclerosis

Abstract Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder that affects motor neurons in the brain and spinal cord, causing progressive loss of voluntary muscle control1,2. ALS heterogeneity includes the age of manifestation, the rate of progression, and the anatomical sites of symptom onset. In addition, disease-causing mutations in specific genes have been identified and are used to catalog different subtypes of ALS3. Interestingly, several ALS-associated genes have been shown to affect immune functions, and a variety of aberrant inflammatory events have been reported in patients and mouse models4-11, suggesting that specific immune features can also account for ALS heterogeneity. ALS4 is characterized by juvenile-onset and slow progression12. After experiencing mild symptoms during their childhood, ALS4 patients show motor difficulties by their 30s, and most of them require walkers or wheelchairs by their 50s. ALS4 is caused by dominant mutations in the gene SETX. Using Setx knock-in (KI) mice carrying the ALS4 causative L389S mutation, we discovered an immunological signature consisting of clonally activated CD8 T cells specifically in the central nervous system and blood of KI animals. Expansion of antigen-specific CD8 T cells mirrors disease progression. Bone marrow transplantation experiments indicate an essential role of the immune system in ALS4 neurodegeneration. Furthermore, we found that clonally expanded CD8 T cells circulate in the peripheral blood of ALS4 patients. Our results provide evidence of an antigen-specific CD8 T cell response linked to ALS4, and can serve not only to unravel specific disease mechanisms, but as a potential biomarker of disease activity.

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Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20170032 ◽

2017 ◽

Vol 75 (5) ◽

pp. 272-276 ◽

Cited By ~ 2

Author(s):

Marcelo Chaves ◽

Mariela Bettini ◽

Maria Cecilia Fernandez ◽

Maria Jose Garcia Basalo ◽

Juan Ignacio Rojas ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Diffusion Tensor Imaging ◽

White Matter ◽

Diffusion Tensor ◽

Cognitive Profile ◽

Healthy Controls ◽

Potential Biomarker ◽

Preliminary Study ◽

Als Patients ◽

Lateral Sclerosis

ABSTRACT The objective of this preliminary study was to correlate diffusion tensor imaging (DTI) alterations with the cognitive profile of patients with amyotrophic lateral sclerosis (ALS). Methods This was a case-control study conducted from December 1, 2012 to December 1, 2014. Clinical and demographic data were recorded. A neuropsychological test battery adapted to ALS patients was used. An MRI with DTI was performed in all patients and fractional anisotropy (FA) was analyzed in the white matter using the tract based spatial statistics program. Results Twenty-four patients with ALS (15 females, mean age 66.9 + -2.3) and 13 healthy controls (four females, average age 66.9 + - 2) were included. The DTI showed white matter damage in ALS patients vs. healthy controls (p < 0.001). Discussion In our preliminary study the alterations of white matter in DTI were significantly associated with cognitive impairment in patients with ALS.

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Amyotrophic Lateral Sclerosis

Mayo Clinic Critical and Neurocritical Care Board Review ◽

10.1093/med/9780190862923.003.0095 ◽

2019 ◽

pp. 664-669

Author(s):

Jennifer M. Martinez-Thompson ◽

Nathan P. Staff

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Symptom Onset ◽

Muscle Wasting ◽

Neurodegenerative Disorder ◽

Peak Incidence ◽

Respiratory Involvement ◽

Sporadic Als ◽

Bulbar Dysfunction ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder with both upper and lower motor neuron involvement. It presents with weakness, muscle wasting, spasticity involving the limbs, bulbar dysfunction, and, typically later in the disease, respiratory involvement. Up to 20% of patients may also have a frontotemporal-type dementia. Average duration of survival is 2 to 4 years from symptom onset, and the peak incidence is between the ages of 50 and 75 years. Only 10% of patients have familial forms, and the remainder have sporadic ALS.

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Cerebral degeneration in amyotrophic lateral sclerosis

Neurology Clinical Practice ◽

10.1212/cpj.0000000000000674 ◽

2019 ◽

Vol 9 (5) ◽

pp. 400-407 ◽

Cited By ~ 4

Author(s):

Ojas Srivastava ◽

Chris Hanstock ◽

Sneha Chenji ◽

Dennell Mah ◽

Dean Eurich ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Prefrontal Cortex ◽

Motor Cortex ◽

Disease Progression ◽

Progression Rate ◽

Healthy Controls ◽

Potential Biomarker ◽

Disease Progression Rate ◽

Lateral Sclerosis ◽

Cerebral Degeneration

BackgroundWe investigated cerebral degeneration and neurochemistry in patients with amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS).MethodsWe prospectively studied 65 patients and 43 age-matched healthy controls. Participants were recruited from 4 centers as part of a study in the Canadian ALS Neuroimaging Consortium. All participants underwent single-voxel proton MRS using a protocol standardized across all sites. Metabolites reflecting neuronal integrity (total N-acetyl aspartyl moieties [tNAA]) and gliosis (myo-inositol [Ino]), as well as creatine (Cr) and choline (Cho), were quantified in the midline motor cortex and midline prefrontal cortex. Comparisons were made between patients with ALS and healthy controls. Metabolites were correlated with clinical measures of upper motor neuron dysfunction, disease progression rate, and cognitive performance.ResultsIn the motor cortex, tNAA/Cr, tNAA/Cho, and tNAA/Ino ratios were reduced in the ALS group compared with controls. Group differences in tNAA/Cr and tNAA/Cho in the prefrontal cortex displayed reduced ratios in ALS patients; however, these were not statistically significant. Reduced motor cortex ratios were associated with slower foot tapping rate, whereas only motor tNAA/Ino was associated with finger tapping rate. Disease progression rate was associated with motor tNAA/Cho. Verbal fluency, semantic fluency, and digit span forwards and backwards were associated with prefrontal tNAA/Cr.ConclusionsThis study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.

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Exosomal Angiogenin as a Potential Biomarker in Amyotrophic Lateral Sclerosis

Neurochemical Journal ◽

10.1134/s1819712420030058 ◽

2020 ◽

Vol 14 (3) ◽

pp. 321-327

Author(s):

M. V. Ivanova ◽

E. O. Chekanova ◽

B. V. Belugin ◽

I. V. Dolzhikova ◽

I. L. Tutykhina ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Potential Biomarker ◽

Lateral Sclerosis

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Predicting Early Bulbar Decline in Amyotrophic Lateral Sclerosis: A Speech Subsystem Approach

Behavioural Neurology ◽

10.1155/2015/183027 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 39

Author(s):

Panying Rong ◽

Yana Yunusova ◽

Jun Wang ◽

Jordan R. Green

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Speech Intelligibility ◽

Disease Onset ◽

Principal Component ◽

Speaking Rate ◽

Linear Mixed Effects ◽

Data Mining Approach ◽

Kaplan Meier ◽

Bulbar Dysfunction ◽

Lateral Sclerosis

Purpose. To develop a predictive model of speech loss in persons with amyotrophic lateral sclerosis (ALS) based on measures of respiratory, phonatory, articulatory, and resonatory functions that were selected using a data-mining approach.Method. Physiologic speech subsystem (respiratory, phonatory, articulatory, and resonatory) functions were evaluated longitudinally in 66 individuals with ALS using multiple instrumentation approaches including acoustic, aerodynamic, nasometeric, and kinematic. The instrumental measures of the subsystem functions were subjected to a principal component analysis and linear mixed effects models to derive a set of comprehensive predictors of bulbar dysfunction. These subsystem predictors were subjected to a Kaplan-Meier analysis to estimate the time until speech loss.Results. For a majority of participants, speech subsystem decline was detectible prior to declines in speech intelligibility and speaking rate. Among all subsystems, the articulatory and phonatory predictors were most responsive to early bulbar deterioration; and the resonatory and respiratory predictors were as responsive to bulbar decline as was speaking rate.Conclusions. The articulatory and phonatory predictors are sensitive indicators of early bulbar decline due to ALS, which has implications for predicting disease onset and progression and clinical management of ALS.

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Unstable control of breathing can lead to ineffective noninvasive ventilation in amyotrophic lateral sclerosis

ERJ Open Research ◽

10.1183/23120541.00099-2019 ◽

2019 ◽

Vol 5 (3) ◽

pp. 00099-2019 ◽

Cited By ~ 2

Author(s):

Jesús Sancho ◽

Enric Burés ◽

Santos Ferrer ◽

Ana Ferrando ◽

Pilar Bañuls ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Noninvasive Ventilation ◽

Upper Airway ◽

Control Of Breathing ◽

Controller Gain ◽

Central Origin ◽

Als Patients ◽

Bulbar Dysfunction ◽

Lateral Sclerosis

Upper airway obstruction with decreased central drive (ODCD) is one of the causes of ineffective noninvasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). The aim of this study is to determine the mechanism responsible for ODCD in ALS patients using NIV.This is a prospective study that included ALS patients with home NIV. Severity of bulbar dysfunction was assessed with the Norris scale bulbar subscore; data on upper or lower bulbar motor neuron predominant dysfunction on physical examination were collected. Polysomnography was performed on every patient while using NIV and the ODCD index (ODCDI: number of ODCD events/total sleep time) was calculated. To determine the possible central origin of ODCD, controller gain was measured by inducing a hypocapnic hyperventilation apnoea. Sonography of the upper airway during NIV was performed to determine the location of the ODCD.30 patients were enrolled; three (10%) had ODCDI >5 h−1. The vast majority of ODCD events were produced during non-rapid eye movement sleep stages and were a consequence of an adduction of the vocal folds. Patients with ODCDI >5 h−1 had upper motor neuron predominant dysfunction at the bulbar level, and had greater controller gain (1.97±0.33 versus 0.91±0.36 L·min−1·mmHg−1; p<0.001) and lower carbon dioxide (CO2) reserve (4.00±0.00 versus 10.37±5.13 mmHg; p=0.043). ODCDI was correlated with the severity of bulbar dysfunction (r= −0.37; p=0.044), controller gain (r=0.59; p=0.001) and CO2 reserve (r= −0.35; p=0.037).ODCD events in ALS patients using NIV have a central origin, and are associated with instability in the control of breathing and an upper motor neuron predominant dysfunction at the bulbar level.

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Sensitivity of brain MRI and neurological examination for detection of upper motor neurone degeneration in amyotrophic lateral sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-327269 ◽

2021 ◽

pp. jnnp-2021-327269

Author(s):

Abram D Nitert ◽

Harold HG Tan ◽

Renée Walhout ◽

Nienke L Knijnenburg ◽

Michael A van Es ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Neurological Examination ◽

Pyramidal Tract ◽

Brain Mri ◽

Symptom Burden ◽

Body Region ◽

Body Regions ◽

Potential Biomarker ◽

Lateral Sclerosis

ObjectivesTo investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS).MethodsWe studied 192 patients with ALS and 314 controls longitudinally. All patients visited our centre twice and underwent full neurological examination and brain MRI. At each visit, we assessed UMN degeneration by measuring motor cortex thickness (CT) and pyramidal tract fibre density (FD) corresponding to five body regions (bulbar region and limbs). For each body region, we measured degree of clinical UMN and lower motor neuron (LMN) symptom burden using a validated scoring system.ResultsWe found deterioration over time of CT of motor regions (p≤0.0081) and progression of UMN signs of bulbar region and left arm (p≤0.04). FD was discriminative between controls and patients with moderate/severe UMN signs (all regions, p≤0.034), but did not change longitudinally. Higher clinical UMN burden correlated with reduced CT, but not lower FD, for the bulbar region (p=2.2×10−10) and legs (p≤0.025). In the arms, we found that severe LMN signs may reduce the detectability of UMN signs (p≤0.043). With MRI, UMN degeneration was detectable before UMN signs became clinically evident (CT: p=1.1×10−10, FD: p=6.3×10−4). Motor CT, but not FD, deteriorated more than UMN signs during the study period.ConclusionsMotor CT is a more sensitive measure of UMN degeneration than UMN signs. Motor CT and pyramidal tract FD are discriminative between patients and controls. Brain MRI can monitor UMN degeneration before signs become clinically evident. These findings promote MRI as a potential biomarker for UMN progression in clinical trials in ALS.

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Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

Neurodegenerative Diseases ◽

10.1159/000490920 ◽

2018 ◽

Vol 18 (4) ◽

pp. 208-215 ◽

Cited By ~ 8

Author(s):

Leyre Martinez-Merino ◽

Marina Iridoy ◽

Arkaitz Galbete ◽

Miren Roldán ◽

Adriana Rivero ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Microglia Activation ◽

Tnf Alpha ◽

Enzyme Linked Immunosorbent Assay ◽

Specific Marker ◽

Protein Levels ◽

Potential Biomarker ◽

Significant Difference ◽

Lateral Sclerosis ◽

Exon 10

Background: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential. Objective: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers. Methods: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects. Results: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme. Conclusions: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.

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