Therapeutic trials in amyotrophic lateral sclerosis: past, present and future

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

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Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-317138 ◽

2017 ◽

Vol 89 (3) ◽

pp. 239-247 ◽

Cited By ~ 33

Author(s):

Petra Steinacker ◽

Federico Verde ◽

Lubin Fang ◽

Emily Feneberg ◽

Patrick Oeckl ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Underlying Disease ◽

Therapeutic Trials ◽

Sporadic Als ◽

Jakob Disease ◽

Diagnostic Sensitivity And Specificity ◽

Lateral Sclerosis

ObjectivesNeurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1).MethodsAltogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression.ResultsIn ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68).ConclusionsCHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.

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Blood Biomarkers for Amyotrophic Lateral Sclerosis: Myth or Reality?

BioMed Research International ◽

10.1155/2014/525097 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 30

Author(s):

Laura Robelin ◽

Jose Luis Gonzalez De Aguilar

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Multiple Testing ◽

Low Cost ◽

Cellular Level ◽

Point Of View ◽

Metabolic Dysfunction ◽

Therapeutic Trials ◽

Electrophysiological Findings ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal condition primarily characterized by the selective loss of upper and lower motor neurons. At present, the diagnosis and monitoring of ALS is based on clinical examination, electrophysiological findings, medical history, and exclusion of confounding disorders. There is therefore an undeniable need for molecular biomarkers that could give reliable information on the onset and progression of ALS in clinical practice and therapeutic trials. From a practical point of view, blood offers a series of advantages, including easy handling and multiple testing at a low cost, that make it an ideal source of biomarkers. In this review, we revisited the findings of many studies that investigated the presence of systemic changes at the molecular and cellular level in patients with ALS. The results of these studies reflect the diversity in the pathological mechanisms contributing to disease (e.g., excitotoxicity, oxidative stress, neuroinflammation, metabolic dysfunction, and neurodegeneration, among others) and provide relatively successful evidence of the usefulness of a wide-ranging panel of molecules as potential biomarkers. More studies, hopefully internationally coordinated, would be needed, however, to translate the application of these biomarkers into benefit for patients.

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Moving Toward Multicenter Therapeutic Trials in Amyotrophic Lateral Sclerosis: Feasibility of Data Pooling Using Different Translocator Protein PET Radioligands

Journal of Nuclear Medicine ◽

10.2967/jnumed.119.241059 ◽

2020 ◽

Vol 61 (11) ◽

pp. 1621-1627 ◽

Cited By ~ 4

Author(s):

Donatienne Van Weehaeghe ◽

Suma Babu ◽

Joke De Vocht ◽

Nicole R. Zürcher ◽

Sheena Chew ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Translocator Protein ◽

Data Pooling ◽

Therapeutic Trials ◽

Lateral Sclerosis

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The Gold Coast criteria increases the diagnostic sensitivity for amyotrophic lateral sclerosis in a Chinese population

Translational Neurodegeneration ◽

10.1186/s40035-021-00253-2 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Dongchao Shen ◽

Xunzhe Yang ◽

Yanying Wang ◽

Di He ◽

Xiaohan Sun ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Final Diagnosis ◽

Gold Coast ◽

Diagnostic Sensitivity ◽

College Hospital ◽

Medical College ◽

Diagnostic Categories ◽

Therapeutic Trials ◽

Als Patients ◽

Lateral Sclerosis

Abstract Objectives The aim of this study was to assess and compare the diagnostic utility of a new diagnostic criteria for amyotrophic lateral sclerosis (ALS), abbreviated as the ‘Gold Coast Criteria’, with the revised El Escorial (rEEC) and Awaji criteria. Methods Clinical and electrophysiological data of 1185 patients from January 2014 to December 2019 in the Peking Union Medical College Hospital ALS database were reviewed. The sensitivity of the Gold Coast criteria was compared to that of the possible rEEC and Awaji criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS). Results A final diagnosis of ALS was recorded in 1162 patients. The sensitivity of the Gold Coast criteria (96.6%, 95% confidence interval [CI] = 95.3%–97.5%) was greater than that of the rEEC (85.1%, 95%CI = 82.9%–87.1%) and Awaji (85.3%, 95%CI = 83.2%–87.3%). In addition, the sensitivity of the novel criteria maintained robust across subgroups, and the advantage was more prominent in limb-onset ALS patients and those who completed electromyographic tests. In those who did not achieve any of the rEEC diagnostic categories, the sensitivity of Gold Coast criteria was 84.4%. Conclusions The current study demonstrated that the Gold Coast criteria exhibited greater diagnostic sensitivity than the rEEC and Awaji criteria in a Chinese ALS population. The application of the Gold Coast criteria should be considered in clinical practice and future therapeutic trials.

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The natural history of amyotrophic lateral sclerosis and the use of natural history controls in therapeutic trials

Neurology ◽

10.1212/wnl.43.4.751 ◽

1993 ◽

Vol 43 (4) ◽

pp. 751-751 ◽

Cited By ~ 51

Author(s):

J. Pradas ◽

L. Finison ◽

P. L. Andres ◽

B. Thornell ◽

D. Hollander ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Natural History ◽

Therapeutic Trials ◽

History Of ◽

Lateral Sclerosis

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Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials

Aging and Disease ◽

10.14336/ad.2013.0400295 ◽

2013 ◽

Vol 04 (05) ◽

pp. 295-310 ◽

Cited By ~ 148

Author(s):

Paul Gordon ◽

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Clinical Features ◽

Therapeutic Trials ◽

Lateral Sclerosis

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Automated Acoustic Analysis of Oral Diadochokinesis to Assess Bulbar Motor Involvement in Amyotrophic Lateral Sclerosis

Journal of Speech Language and Hearing Research ◽

10.1044/2019_jslhr-19-00178 ◽

2020 ◽

Vol 63 (1) ◽

pp. 59-73 ◽

Cited By ~ 3

Author(s):

Panying Rong

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Acoustic Analysis ◽

Speaking Rate ◽

Disease Stage ◽

Healthy Controls ◽

Tongue Movement ◽

Major Barrier ◽

Syllable Repetition ◽

Oral Diadochokinesis ◽

Lateral Sclerosis

Purpose The purpose of this article was to validate a novel acoustic analysis of oral diadochokinesis (DDK) in assessing bulbar motor involvement in amyotrophic lateral sclerosis (ALS). Method An automated acoustic DDK analysis was developed, which filtered out the voice features and extracted the envelope of the acoustic waveform reflecting the temporal pattern of syllable repetitions during an oral DDK task (i.e., repetitions of /tɑ/ at the maximum rate on 1 breath). Cycle-to-cycle temporal variability (cTV) of envelope fluctuations and syllable repetition rate (sylRate) were derived from the envelope and validated against 2 kinematic measures, which are tongue movement jitter (movJitter) and alternating tongue movement rate (AMR) during the DDK task, in 16 individuals with bulbar ALS and 18 healthy controls. After the validation, cTV, sylRate, movJitter, and AMR, along with an established clinical speech measure, that is, speaking rate (SR), were compared in their ability to (a) differentiate individuals with ALS from healthy controls and (b) detect early-stage bulbar declines in ALS. Results cTV and sylRate were significantly correlated with movJitter and AMR, respectively, across individuals with ALS and healthy controls, confirming the validity of the acoustic DDK analysis in extracting the temporal DDK pattern. Among all the acoustic and kinematic DDK measures, cTV showed the highest diagnostic accuracy (i.e., 0.87) with 80% sensitivity and 94% specificity in differentiating individuals with ALS from healthy controls, which outperformed the SR measure. Moreover, cTV showed a large increase during the early disease stage, which preceded the decline of SR. Conclusions This study provided preliminary validation of a novel automated acoustic DDK analysis in extracting a useful measure, namely, cTV, for early detection of bulbar ALS. This analysis overcame a major barrier in the existing acoustic DDK analysis, which is continuous voicing between syllables that interferes with syllable structures. This approach has potential clinical applications as a novel bulbar assessment.

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