Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial fingerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidentified mutations (undSOD1), compared with age/sex matched controls. Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classification. Pooled analysis revealed that undSOD1 patients had statistically higher glycolytic ATP production rate and lower Tfam protein content compared to controls, which were also the experimental features highlighted by multidimensional analysis. Metabolic phenotypic profiles in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation profiles. For most parameters, different patterns of variation were found between cohorts, which may be due to age or sex. In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor and, although a high heterogeneity of results was found, we identified specific metabolic and mitochondrial fingerprints that may have a diagnostic and therapeutic interest.

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Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

10.1101/2020.11.28.402065 ◽

2020 ◽

Author(s):

David Bayer ◽

Stefano Antonucci ◽

Hans-Peter Müller ◽

Luc Dupuis ◽

Tobias Boeckers ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Cortex ◽

Mouse Model ◽

Lateral Hypothalamus ◽

Large Scale ◽

Energy Homeostasis ◽

Metabolic Phenotype ◽

Metabolic Disturbances ◽

Als Patients ◽

Lateral Sclerosis

AbstractIncreased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.Significance statementWe provide a circuit perspective of the recently identified and medically relevant hyper-metabolic phenotype of Amyotrophic Lateral Sclerosis. We demonstrate the selective involvement of orbitofrontal, insular and motor cortex projections to hypothalamus in murine ALS models and in human patients. The enhanced pipeline for large-scale registration, segmentation projections mapping, the identification of new circuits target of neurodegeneration, and the relevance of these circuits in metabolic disturbances make this work relevant not only for the investigation of ALS but also for other neurodegenerative disease as well as for all conditions characterized by systemic energy imbalances.

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Cerebrospinal Fluid TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Patients with and without the C9ORF72 Hexanucleotide Expansion

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000444788 ◽

2016 ◽

Vol 6 (1) ◽

pp. 142-149 ◽

Cited By ~ 20

Author(s):

Anna Junttila ◽

Mari Kuvaja ◽

Päivi Hartikainen ◽

Maritta Siloaho ◽

Seppo Helisalmi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Frontotemporal Lobar Degeneration ◽

Rapid Progression ◽

Carrier Status ◽

C9orf72 Expansion ◽

Main Protein ◽

Als Patients ◽

T Tau ◽

Lateral Sclerosis

Background: TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables. Methods: The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, Aβ1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits. Results: There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort). Conclusion: CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.

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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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Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200583 ◽

2021 ◽

pp. 1-5

Author(s):

João Morgadinho ◽

Ana Catarina Pronto-Laborinho ◽

Vasco A. Conceição ◽

Marta Gromicho ◽

Susana Pinto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Creatinine Level ◽

Cox Regression ◽

Functional Decline ◽

Plasma Creatinine ◽

Plasma Creatinine Level ◽

Decline Rate ◽

Respiratory Outcome ◽

Als Patients ◽

Lateral Sclerosis

In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, or their decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

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Coping strategies among amyotrophic lateral sclerosis (ALS) patients: an integrative review

Journal of Neurology ◽

10.1007/s00415-021-10472-2 ◽

2021 ◽

Author(s):

Georgiana Soares Leandro ◽

Mário Emílio Teixeira Dourado Júnior ◽

Glauciane Costa Santana ◽

Luan Samy Xavier Dantas

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Coping Strategies ◽

Integrative Review ◽

Als Patients ◽

Lateral Sclerosis

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Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

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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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Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

Neurological Sciences ◽

10.1007/s10072-021-05188-0 ◽

2021 ◽

Author(s):

Fabiola De Marchi ◽

◽

Claudia Carrarini ◽

Antonio De Martino ◽

Luca Diamanti ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Time Course ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Multisystem Disorder ◽

Behavioral Impairment ◽

Behavioral Impairments ◽

Als Patients ◽

Disease Stages ◽

Lateral Sclerosis

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

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Critical Review of Complementary and Alternative Medicine Use in Amyotrophic Lateral Sclerosis: Prevalence and Users’ Profile, Decision-Making, Information Seeking, and Disclosure in the Face of a Lack of Efficacy

Neurodegenerative Diseases ◽

10.1159/000492946 ◽

2018 ◽

Vol 18 (4) ◽

pp. 225-232 ◽

Cited By ~ 2

Author(s):

Jon Adams ◽

Michael Lee ◽

Wenbo Peng

Keyword(s):

Decision Making ◽

Amyotrophic Lateral Sclerosis ◽

Alternative Medicine ◽

Complementary And Alternative Medicine ◽

Information Seeking ◽

Disease Process ◽

Cam Use ◽

Als Patients ◽

Lateral Sclerosis ◽

Complementary And Alternative

Background: Despite a lack of evidence of clinical efficacy for complementary and alternative medicine (CAM) use in amyotrophic lateral sclerosis (ALS), these medicines remain popular around the world. Objective: To examine the prevalence and cost of CAM use in ALS and CAM users’ profile, decision-making, information seeking, and disclosure among ALS patients. Methods: A comprehensive literature search was conducted of MEDLINE, CINAHL/SCOPUS, and AMED databases from their inception to April 2018. This review followed PRISMA guidelines and employed a quality scoring system to assess the included papers. Results: Seven papers met the inclusion criteria and were thematically analysed. ALS patients utilized a range of CAM therapies and/or products, with acupuncture and vitamins being the most frequently reported. CAM modalities were often employed concurrently with conventional medications throughout the disease process. Although some ALS patients reported positive experience regarding CAM use, many were reluctant to disclose their CAM use to their clinicians. Research focusing on CAM use in ALS remains ad hoc and restricted to only a few countries. The rigour and quality of this research field to date has been varied, predominantly drawing upon regional/localized data and failing to report CAM users’ characteristics. Conclusion: A proportion of ALS patients report utilizing CAM concurrently with conventional treatments. Such use, set amidst a dearth of evidence for the efficacy of CAM in ALS, poses potential direct and indirect risks to patient care, and medical providers should be mindful of and enquire about CAM use when treating ALS patients.

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