Molecular Classification and Interpretation of Amyotrophic Lateral Sclerosis Using Deep Convolution Neural Networks and Shapley Values

Amyotrophic lateral sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons to severely effect the functionality to control voluntary muscle movement. Most of the non-additive genetic aberrations responsible for ALS make its molecular classification very challenging along with limited sample size, curse of dimensionality, class imbalance and noise in the data. Deep learning methods have been successful in many other related areas but have low minority class accuracy and suffer from the lack of explainability when used directly with RNA expression features for ALS molecular classification. In this paper, we propose a deep-learning-based molecular ALS classification and interpretation framework. Our framework is based on training a convolution neural network (CNN) on images obtained from converting RNA expression values into pixels based on DeepInsight similarity technique. Then, we employed Shapley additive explanations (SHAP) to extract pixels with higher relevance to ALS classifications. These pixels were mapped back to the genes which made them up. This enabled us to classify ALS samples with high accuracy for a minority class along with identifying genes that might be playing an important role in ALS molecular classifications. Taken together with RNA expression images classified with CNN, our preliminary analysis of the genes identified by SHAP interpretation demonstrate the value of utilizing Machine Learning to perform molecular classification of ALS and uncover disease-associated genes.

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Molecular Classification and Interpretation of Amyotrophic Lateral Sclerosis Using Deep Convolution Neural Networks and Shapley Values

10.20944/preprints202110.0059.v1 ◽

2021 ◽

Author(s):

Abdul Karim ◽

Zheng Su ◽

Phillip K.West ◽

Matthew Keon ◽

The NYGC ALS Consortium ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Deep Learning ◽

Motor Neurons ◽

Class Imbalance ◽

Molecular Classification ◽

Rna Expression ◽

Minority Class ◽

Shapley Values ◽

Disease Associated Genes ◽

Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a prototypical neurodegenerative disease characterized by progressive degeneration of motor neurons to severely effect the functionality to control voluntary muscle movement. Most of the non additive genetic aberrations responsible for ALS make its molecular classification very challenging along with limited sample size, curse of dimensionality, class imbalance and noise in the data. Deep learning methods have been successful in many other related areas but have low minority class accuracy and suffer from the lack of explainailbilty when used directly with RNA expression features for ALS molecular classification. In this paper we propose a deep learning based molecular ALS classification and interpretation framework. Our framework is based on training a convolution neural network (CNN) on images obtained from converting RNA expression values into pixels based on DeepInsight similarity technique. Then we employed Shapley Additive Explanations (SHAP) to extract pixels with higher relevance to ALS classifications. These pixels were mapped back to the genes which made them up. This enabled us to classify ALS samples with high accuracy for a minority class along with identifying genes that might be playing an important role in ALS molecular classifications. Taken together with RNA expression images classified with CNN, our preliminary analysis of the genes identified by SHAP interpretation demonstrate the value of utilising Machine Learning to perform molecular classification of ALS and uncover disease-associated genes.

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Exploring molecular approaches in Amyotrophic lateral sclerosis: Drug targets from clinical and pre-clinical findings

Current Molecular Pharmacology ◽

10.2174/1566524020666200427214356 ◽

2020 ◽

Vol 13 ◽

Author(s):

Mamtaj Alam ◽

Rajeshwar Kumar Yadav ◽

Elizabeth Minj ◽

Aarti Tiwari ◽

Sidharth Mehan

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Drug Targets ◽

Therapeutic Index ◽

Experimental Models ◽

Clinical Findings ◽

Adenyl Cyclase ◽

Molecular Approaches ◽

Pharmacologically Active ◽

Lateral Sclerosis

: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterised by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age included impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% beyond 10 years of age. The limited intervention of pharmacologically active compounds that are used clinically is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, current review specially targeted in the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with up-regulation of intracellular adenyl cyclase/cAMP/CREB and mitochondrial-ETC coenzyme-Q10 activation as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

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Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

Current Neurovascular Research ◽

10.2174/1567202617666200409125227 ◽

2020 ◽

Vol 17 (3) ◽

pp. 275-285 ◽

Cited By ~ 5

Author(s):

Si Chen ◽

Qiao Liao ◽

Ke Lu ◽

Jinxia Zhou ◽

Cao Huang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rat Model ◽

Microglial Activation ◽

Transgenic Rat ◽

Intragastric Administration ◽

Behavioral Deficits ◽

Als Patients ◽

Lateral Sclerosis ◽

Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

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Cortical and Striatal Electroencephalograms and Apomorphine Effects in the FUS Mouse Model of Amyotrophic Lateral Sclerosis

Journal of Alzheimer s Disease ◽

10.3233/jad-201472 ◽

2021 ◽

pp. 1-15

Author(s):

Vasily Vorobyov ◽

Alexander Deev ◽

Frank Sengpiel ◽

Vladimir Nebogatikov ◽

Aleksey A. Ustyugov

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Neurons ◽

Primary Motor Cortex ◽

Beta Activity ◽

Systemic Injection ◽

Eeg Spectra ◽

Electroencephalogram Eeg ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1–359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in ΔFUS(1–359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

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Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽

10.1186/s12883-021-02306-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Atsuhiko Sugiyama ◽

Takahiro Takeda ◽

Mizuho Koide ◽

Hajime Yokota ◽

Hiroki Mukai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Repeat Expansion ◽

Cerebellar Hemisphere ◽

Intranuclear Inclusions ◽

Intranuclear Inclusion ◽

Neuronal Intranuclear Inclusion ◽

Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

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The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells10081865 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1865

Author(s):

Nica Borgese ◽

Nicola Iacomino ◽

Sara Francesca Colombo ◽

Francesca Navone

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Adaptor Proteins ◽

Loss Of Function ◽

Membrane Contact Sites ◽

Physiological Processes ◽

Main Driver ◽

Single Allele ◽

Induced Pluripotent ◽

Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

Journal of Personalized Medicine ◽

10.3390/jpm11070671 ◽

2021 ◽

Vol 11 (7) ◽

pp. 671

Author(s):

Oihane Pikatza-Menoio ◽

Amaia Elicegui ◽

Xabier Bengoetxea ◽

Neia Naldaiz-Gastesi ◽

Adolfo López de Munain ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Muscle Tissue ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Fine Tuning ◽

Current State ◽

The Central Nervous System ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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

Brain Sciences ◽

10.3390/brainsci11070906 ◽

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.

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Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽

10.3390/diagnostics11071210 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1210

Author(s):

Júlia Costa ◽

Marta Gromicho ◽

Ana Pronto-Laborinho ◽

Conceição Almeida ◽

Ricardo A. Gomes ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Motor Neurons ◽

Neurological Diseases ◽

Disease Diagnosis ◽

Enzyme Linked Immunosorbent Assay ◽

Progression Rate ◽

Therapeutic Trials ◽

Als Patients ◽

Lateral Sclerosis

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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