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Michael Benatar

Publications and source records attributed to Michael Benatar.

18 recordsLinked to original sources
PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention. FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University M&#xfc;nster.

Journal Article↗
PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention. FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University M&#xfc;nster.

Journal Article↗
PubMed2019

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Child↗
PubMed2006

Preventing familial amyotrophic lateral sclerosis: is a clinical trial feasible?

OBJECTIVE: To evaluate the feasibility of a clinical trial designed to delay or prevent the onset of disease amongst subjects at risk for familial amyotrophic lateral sclerosis (fALS). BACKGROUND: The success of many agents in prolonging survival in the SOD1 model of ALS has not been translated into effective therapies for patients with ALS. It is our hypothesis that a trial in fALS may reproduce the positive effects seen in fALS animals. METHODS: Pedigrees with at least two affected family members were constructed. Unaffected family members were assigned a risk status based on their relationship to affected subjects. Attitudes towards genetic testing were ascertained amongst the at-risk family members. RESULTS: We obtained data about 5,544 people (116 families) including 516 subjects with ALS (169 from SOD1 positive families) as well as 1,056 subjects "definitely" or "probably" at risk for fALS (335 from SOD1 positive families). In excess of 80% of subjects indicated an interest in participating in a future clinical trial directed at delaying the onset of the disease. Assuming the use of a therapeutic agent that will prolong the time to the onset of fALS by 50%, we estimate that a sample size of between 261 and 610 subjects 'definitely at risk' will be required (power 0.8) depending on whether patients are followed for 10 or 5 years respectively. CONCLUSIONS: A clinical trial in fALS may be feasible although such a trial would likely require prolonged follow-up and would require a therapeutic agent with a large clinical effect in order to be adequately powered.

Adolescent↗
PubMed2006

A systematic review of diagnostic studies in myasthenia gravis.

We performed a systematic review to identify studies that reported the accuracy of tests for the diagnosis of myasthenia gravis. We identified 20 studies of reasonable, although variable, methodological quality upon which to base estimates of the accuracy of the ice test, rest test, Tensilon test, acetylcholine receptor antibodies, repetitive nerve stimulation and single fiber electromyography for the diagnosis of myasthenia gravis. After examining inter-study heterogeneity for each diagnostic modality, we calculated pooled estimates of sensitivity and specificity as well as positive and negative likelihood ratios. Results are reported separately for ocular and generalized myasthenia. Studies that have examined the performance of anti-acetylcholine receptor antibody testing and single fiber electromyography were generally of better quality than those that examined other diagnostic modalities. We suggest that caution should be exercised in the interpretation of the diagnostic performance of these tests given the methodological limitations of the studies upon which test performance is based.

Cholinesterase Inhibitors↗
PubMed2006

Electrodiagnostic criteria for carpal tunnel syndrome in axonal polyneuropathy.

Median-ulnar comparative studies (MUCSs) play an important role in the electrodiagnosis of carpal tunnel syndrome (CTS), but diagnostic criteria in patients with underlying axonal polyneuropathy have not been established. We prospectively evaluated 28 patients with axonal polyneuropathy (48 hands), blindly dichotomized into CTS cases and controls, using the lumbrical-interosseous motor (LIM), mixed palmar sensory (MPS), and digit 4 sensory (D4S) MUCS. LIM, MPS, and D4S MUCS latency differences could be calculated in 98%, 69%, and 48% of hands. Based on the maximum combination of sensitivity and specificity, diagnostic cutoffs were > or = 0.8, > or = 0.5, and > or = 0.4 ms for the LIM, MPS, and D4S studies, respectively. The LIM study was the most accurate test and the only MUCS that yielded a positive likelihood ratio greater than 10 (16.25 for a cut-off value of 1 ms) and a negative likelihood ratio less than 0.1 (0.09 for a cut-off value of 0.4 ms), resulting in meaningful differences in pretest and posttest probabilities of CTS in patients with axonal polyneuropathy. These novel MUCS electrodiagnostic criteria should facilitate more accurate electrodiagnostic confirmation of CTS in this population.

Adult↗
PubMed2006

Concentric-needle single-fiber electromyography for the diagnosis of myasthenia gravis.

The goal of this study was to estimate the accuracy of concentric-needle single-fiber electromyography (CN-SFEMG) for the diagnosis of myasthenia gravis (MG). A consecutive series of patients referred for CN-SFEMG was evaluated by an investigator blinded to the results of CN-SFEMG in order to determine the presence or absence of MG using an independent reference standard. Sensitivity, specificity, predictive values, and likelihood ratios were calculated. The study population included 51 patients (21 with MG). CN-SFEMG was normal in 34 patients (67%) and abnormal in 17 (33%). The sensitivity of CN-SFEMG for the diagnosis of MG was 0.67 and the specificity was 0.96. The positive likelihood ratio was 16.8 and the negative likelihood ratio was 0.34. The positive and negative predictive values were 0.93 and 0.76, respectively. These results indicate that CN-SFEMG showing abnormal jiggle is extremely useful for confirming the diagnosis of MG, but that CN-SFEMG showing normal jiggle has limited utility in excluding the diagnosis.

Action Potentials↗
PubMed2005

Sural and radial sensory responses in healthy adults: diagnostic implications for polyneuropathy.

We prospectively performed sural and radial sensory nerve conduction studies in 92 healthy subjects, aged between 21 and 88 years, both to determine the lower limits of normal (LLN) and to assess the effects of age and body mass index (BMI) on the sural and radial sensory nerve action potential (SNAP) amplitudes and on the sural/radial amplitude ratio (SRAR). Using the nonparametric bootstrap method to calculate 95% confidence intervals, we found that the 5% LLN values for sural and radial SNAPs were 14 microV and 25.5 microV in subjects aged < or =39 years, 7 microV and 17.4 microV in subjects aged 40-59 years, and 3 microV and 12 microV in subjects aged > or =60 years. The 5% LLN for SRAR for all patients was 0.21. Sural and radial SNAP amplitudes but not SRAR were strongly and inversely correlated with age and BMI. These age-adjusted normal values and revised SRAR will aid in the electrodiagnosis of polyneuropathy.

Adult↗
PubMed2004

The spectrum of cranial neuropathy in patients with Bell's palsy.

BACKGROUND: There is controversy regarding whether, and how frequently, other cranial nerve deficits accompany Bell's palsy. We sought to determine prospectively the presence of signs indicating an associated cranial neuropathy in patients with Bell's palsy. METHODS: All subjects presenting to an emergency department with Bell's palsy over a 2-year period were evaluated. The study included 51 consecutive patients. One patient with Bell's palsy was not examined by a neurologist at the time of presentation and was excluded. The main outcome measure was presence of other cranial nerve deficits. RESULTS: We identified 4 patients with additional cranial neuropathies (contralateral trigeminal [n=1], glossopharyngeal [n=2], and hypoglossal [n=1]). We also identified 13 patients with ipsilateral facial sensory loss, suggesting an ipsilateral trigeminal neuropathy; 3 patients with a contralateral facial palsy; and 3 patients with hearing impairment. CONCLUSION: This prospective study indicates that a small percentage (approximately 8%) of patients with otherwise typical Bell's palsy may harbor additional cranial neuropathies.

Adult↗
PubMed2004

Repetitive nerve stimulation for the evaluation of peripheral nerve hyperexcitability.

OBJECTIVE: To examine the utility of repetitive nerve stimulation (RNS) in the evaluation of peripheral nerve hyperexcitability (PNH). BACKGROUND: PNH describes a group of disorders characterized by muscle cramps, twitching and stiffness. When severe, PNH may be characterized by the presence of continuous muscle fiber activity on routine needle electromyography (EMG). In milder forms of the disease, nerve hyperexcitability may be evidenced by the presence of after-discharges or cramp potentials following RNS. METHODS: Fifty-four patients were prospectively recruited and classified into one of three groups-PNH, other neuromuscular disease and controls. We recorded and quantified the after-discharges and cramp potentials following RNS at 1, 5, 10 and 30 Hz. RESULTS: The proportion of nerves with after-discharges and/or cramp potentials was significantly greater in the PNH group than the control group at both 5 Hz (p=0.03) and 10 Hz (p=0.01), as well as in the neuromuscular disease group compared to controls at 5 Hz (p=0.02). There was also a significant concordance between complaints of muscle cramps and fasciculations and the finding of after-discharges and/or cramp potentials at both 5 Hz (p=0.005) and 10 Hz (p=0.004). At a stimulation frequency of 10 Hz, the sensitivity of RNS for the diagnosis of PNH (primary or secondary) was 79% and the specificity was 88%. CONCLUSION: Our findings suggest that RNS at or below a stimulation frequency of 10 Hz (when positive) is a useful test for the diagnosis of PNH, whether it is primary or secondary.

Adult↗
PubMed2004

Laminoplasty.

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Cervical Vertebrae↗
PubMed2003

Between prophylaxis and child abuse: the ethics of neonatal male circumcision.

Opinion about neonatal male circumcision is deeply divided. Some take it to be a prophylactic measure with unequivocal and significant health benefits, while others consider it a form of child abuse. We argue against both these polar views. In doing so, we discuss whether circumcision constitutes bodily mutilation, whether the absence of the child's informed consent makes it wrong, the nature and strength of the evidence regarding medical harms and benefits, and what moral weight cultural considerations have. We conclude that nontherapeutic circumcision of infant boys is a suitable matter for parental discretion.

Analgesia↗
PubMed2002

Ictal aphasia.

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Journal Article↗