The latest medical research on Motor Neuron Disease
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Request AccessCan resting lung function predict the response of a person living with motor neuron disease to a hypoxic challenge test?
Amyotrophic Lat Scler Frontotemporal DegenPeople living with MND (PlwMND) are at risk of altitude-related hypoxia during flight. The Hypoxic Challenge Test (HCT) determines whether in-flight oxygen is required but can be expensive and inaccessible. To assist with travel recommendations, we investigated the relationship between altitude simulation-induced hypoxemia and baseline lung function.
Retrospective audit of clinical database of PlwMND who had HCT and lung function. Pearson's correlation assessed relationships between oxygen saturation at altitude (AltSpO2) and lung function. Univariate logistic regression analysis and receiver operator characteristic (ROC) curves determined associations between lung function and HCT pass or fail.
Between 2004-2023, 50 PlwMND were identified (median (IQR) diagnosis to HCT = 11.6 (16.9) months, mean ± SD forced vital capacity (FVC) = 2.4 ± 0.9 liters). Ten patients dropped below 85% SpO2 during testing (HCT fail). Baseline SpO2 was associated with AltSpO2 (r = 0.64) and predicted HCT pass or fail (OR 2.0 [95% CI 1.2-3.4], area under ROC curve (AUC) =0.8 [0.6-1.0]), as did FVC (AUC = 0.8 [0.6-0.9]). PlwMND with a FVC > 2.7L or a resting SpO2 > 97% are likely to pass HCT, whereas all those with FVC < 1L and SpO2 < 92% failed.
PlwMND with FVC >2.7L or SpO2 >97% are unlikely to require oxygen or ventilatory supports for airline travel. A FVC below 2.7L will require a HCT to confidently determine HCT outcome, with testing still required for FVC <1L or baseline SpO2 <92%, to provide evidence to the airlines for in-flight respiratory support.
The "Hedgehog-Halo Sign" Is Associated with Gait Symptom Severity and Tap Response in Normal Pressure Hydrocephalus.
"Movement Disorders Clinical PracticeReduced cerebrospinal fluid (CSF) clearance may play a vital role in the pathogenesis of normal pressure hydrocephalus (NPH), but the radiologic marker is yet to be elucidated.
This open-label study presents two novel neuroimaging biomarkers based on enlarged perivascular spaces (ePVS) of the sub-insular territory: the Hedgehog and Hedgehog-Halo (H-H) sign, designed to predict gait symptom severity and tap response in NPH.
We retrospectively reviewed 203 patients with possible NPH with baseline magnetic resonance imaging and gait analyses before and after lumbar puncture (LP). The Hedgehog/H-H sign was scored using T2-weighted images. The clinical severity at baseline and post-tap gait improvement was compared in patients with and without Hedgehog/H-H sign. The association between Hedgehog/H-H sign and post-tap gait outcomes was assessed using multivariate regression. The diagnostic performance of Hedgehog/H-H sign was compared with conventional radiological markers.
Patients with H-H showed higher global disability and more severe gait impairment than those without any signs. Following LP, patients with Hedgehog/H-H sign significantly improved in various gait parameters, unlike those with neither sign. Additionally, sub-insular ePVS was significantly associated with post-tap gait improvement after adjusting covariates. Finally, the Hedgehog/H-H sign showed a higher performance than conventional markers in predicting post-tap gait response.
The Hedgehog/H-H sign is a useful neuroimaging biomarker related to the severity and tap response in NPH. This biomarker can be readily applied in clinical practice before undergoing LP, independent of conventional radiological signs. Further research is warranted to determine applicability in predicting post-shunt gait response.
Identifying and Predicting Risk for Hospital Admission among Patients with Parkinsonism.
"Movement Disorders Clinical PracticePatients with parkinsonism are more likely than age-matched controls to be admitted to hospital. It may be possible to reduce the cost and negative impact by identifying patients at highest risk and intervening to reduce hospital-related costs. Predictive models have been developed in nonparkinsonism populations.
The aims were to (1) describe the reasons for admission, (2) describe the rates of hospital admission/emergency department attendance over time, and (3) use routine data to risk stratify unplanned hospital attendance in people with parkinsonism.
This retrospective cohort study used Clinical Practice Research Datalink GOLD, a large UK primary care database, linked to hospital admission and emergency department attendance data. The primary diagnoses for nonelective admissions were categorized, and the frequencies were compared between parkinsonism cases and matched controls. Multilevel logistic and negative binomial regression models were used to estimate the risk of any and multiple admissions, respectively, for patients with parkinsonism.
There were 9189 patients with parkinsonism and 45,390 controls. The odds of emergency admission more than doubled from 2010 to 2019 (odds ratio [OR] 2.33; 95% confidence interval [CI] 1.96, 2.76; P-value for trend <0.001). Pneumonia was the most common reason for admission among cases, followed by urinary tract infection. Increasing age, multimorbidity, parkinsonism duration, deprivation, and care home residence increased the odds of admission. Rural location was associated with reduced OR for admission (OR 0.79; 95% CI 0.70, 0.89).
Our risk stratification tool may enable empirical targeting of interventions to reduce admission risk for parkinsonism patients.
Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.
Motor Neuron DiseaseAmyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a n...
Respiratory Dysfunction and Abnormal Hypoxic Ventilatory Response in Mild to Moderate Parkinson's Disease.
"Movement Disorders Clinical PracticeRespiratory dysfunction is an important contributor to morbidity and mortality in advanced Parkinson's disease (PD), but it is unclear what parameters are sensitive to diagnose and monitor respiratory dysfunction across disease phases.
We aimed to characterize respiratory dysfunction in mild to moderate PD.
In 20 individuals without cardiopulmonary comorbidity, pulmonary and inspiratory muscle function testing were performed ON-medication. Subsequently, the acute ventilatory response to hypoxia (HVR) was assessed by gradually decreasing FIO2 from 0.209 (room air) to 0.127, which was compared to eight age- and sex-matched healthy controls under arterial blood gas monitoring. Lastly, on different days, the same 20 individuals with PD underwent six blinded exposures to 45-min normobaric hypoxia at FiO2 0.163 and 0.127 or placebo OFF-medication to assess breathing responses.
At rest, individuals with greatest PD severity had a lower tidal volume (pairwise comparisons: 0.59 vs. 0.74, P = 0.038-0.050) and tended to have a higher breathing frequency (17.7 vs. 14.4, P = 0.076), despite normal pulmonary function. A 45-min exposure to hypoxia induced a significantly lower acute HVR in individuals with PD compared to controls (-0.0489 vs. 0.133 L.min/%, P = 0.0038). Acute HVR was reduced regardless of disease severity. Subacute HVR in individuals with milder disease tended to be higher compared to those with more advanced disease (P = 0.079).
Respiratory dysfunction is present in individuals with PD, including those with relatively mild disease severity, and is characterized by altered breathing patterns at rest, as well as a lower HVR, despite normal pulmonary and inspiratory muscle function testing.
Predicting Post-Mortem α-Synuclein Pathology by the Combined Presence of Probable REM sleep behavior disorder and Hyposmia.
"Movement Disorders Clinical PracticeIdiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α-synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post-mortem LTS.
To assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post-mortem presence of LTS in a broader, less-selected, volunteer elderly population.
We studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test.
Histological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P < 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P < 0.001) or cases with a low UPSIT score only (69.4%) (P < 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden's index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%.
PRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post-mortem presence of LTS. The combination of both measures may provide a cost-effective means of predicting LTS in a broader community.
Different intensities of physical activity for amyotrophic lateral sclerosis and Parkinson disease: A Mendelian randomization study and meta-analysis.
Motor Neuron DiseaseThe causal relationships between amyotrophic lateral sclerosis (ALS), Parkinson disease and different intensities of physical activity (PA) are still inconclusive. To evaluate the causal impact of PA on ALS and Parkinson disease (PD), this study integrates evidence from Mendelian randomization (MR) using a meta-analysis approach.
MR analyses on genetically predicted levels of PA (compose of self-reported moderate-to-vigorous physical activity [MVPA], self-reported vigorous physical activity [VPA], and strenuous sports or other exercises [SSOE]) regarding ALS and PD published up to July 27, 2024, were obtained from PubMed, Scopus, Web of Science, and Embase. De novo MR studies were analyzed utilizing publicly accessible datasets from genome-wide association studies and then meta-analyses were performed to pool the results.
Meta-analyses of results of 12 de novo MR studies analyses and 2 published MR studies indicated that genetic predicted levels of MVPA (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.08-1.38), VPA (OR: 1.32, 95% CI: 1.08-1.60), and SSOE (OR: 1.35, 95% CI: 1.07-1.70) were related to a raised risk of ALS, but not causally with PD.
Our findings showed no causal relationships between MVPA, VPA, SSOE, and PD, while MVPA, VPA, and SSOE were associated with increased ALS risk, highlighting the need for targeted PA recommendations for disease management.
Lack of habituation in somatosensory cortex but not in visual cortex of ALS patients.
Amyotrophic Lat Scler Frontotemporal DegenAmyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS.
Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. "Habituation" and "lack of habituation" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups.
Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p = 0.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p = 0.239) which indicated lack of habituation.
Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.
Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.
Motor Neuron DiseaseNo ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.
We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.
Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience.
Molecular NeurodegenerationApolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood.
APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank.
A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers.
We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.
Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.
Motor Neuron DiseaseClintrials.gov ID:NCT04322149.
In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.
Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.
Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations.
Motor Neuron DiseaseOver 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS...