Reference: January 2025 | Issue 1 | Vol 11 | Page 11
Trial finds continuous intracerebroventricular A-dopamine safe
Continuous intracerebroventricular (ICV) infusion of anaerobic dopamine (A-dopamine) is a feasible and safe treatment option for patients with Parkinson’s disease (PD) experiencing complications with traditional dopamine medications, according to a new trial presented at the International Congress of Parkinson’s Disease and Movement Disorders in Philadelphia, US, in September.
Continuous administration of levodopa has numerous pharmacokinetic and pharmacodynamic drawbacks, leading to L-dopa-related complications (LDRC). Continuous circadian compensation of dopamine deficiency in the nigro-striatal pathway represents an ideal treatment for PD.
To prevent dopamine oxidation, a novel concept of continuous ICV administration of an anaerobic dopamine formulation has previously been proven to be safe and effective in two rodent models and in a chronic non-human primate model.
This new human study involving 10 participants found that one month of A-dopamine administration resulted in a significant reduction in medication side effects compared to one month of standard oral dopaminergic medication.
All individuals on A-dopamine showed a significant reduction in percentage over target, off time, and dyskinesias on home diaries, compared with the best medical treatment. There were also reductions in the Dyskinesia Rating Score and Unified Parkinson’s Disease Rating Scale parts III and IV. A-dopamine alone induced no dyskinesias and no adverse impact on behaviour. All patients requested long-term treatment.
While this study is small and the long-term risks of continuous ICV A-dopamine administration remain unknown, these promising results warrant further investigation. This novel approach could ultimately offer superior outcomes compared to existing therapies.
Reference
Moreau C, Odou P, Demailly A, et al. Pharmacological neuromodulation with intracerebroventricular administration of anaerobic dopamine for Parkinson’s disease. Abstract 675. International Congress of Parkinson’s Disease and Movement Disorders. Philadelphia, US. September 27-October 1, 2024.
First randomised controlled trial of a probiotic for anxiety in Parkinson’s disease
There is a lack of dedicated randomised controlled trials of any treatment for anxiety in Parkinson’s disease (PD). Growing evidence supports the role of gut microbiota dysbiosis in PD, anxiety, and depressive disorders. Probiotics have been shown to improve constipation in PD, but their effect on anxiety remains largely unexplored.
At the 2024 International Congress of Parkinson’s Disease and Movement Disorders, a team from Canada presented the results of the first randomised, double-blind, placebo-controlled trial to test the effects of a probiotic on anxiety in patients with PD.
The trial included 61 PD patients with anxiety, diagnosed according to the Parkinson Anxiety Scale and the Mini International Neuropsychiatric Interview.
Patients were randomised 1:1 to receive either placebo (n=31) or a nine-strain probiotic (Winclove’s Ecologic® Barrier) twice daily (n=30) for 12 weeks.
Pre- and post-intervention measures for the primary outcome of anxiety, as well as the secondary outcomes of depression, fatigue, apathy, cognition, and motor symptoms, were compared using intention-to-treat analysis. Faecal samples were analysed using shallow shotgun sequencing.
Both groups showed a significant reduction in anxiety, depression, and MDS-Unified Parkinson’s Disease Rating Scale part I scores following the intervention, with no significant between-group differences found.
Interestingly, the probiotic group showed a significant within-group improvement in Montreal Cognitive Assessment (MoCA) scores. Between-group comparison using analysis of covariance revealed that the probiotic significantly improved
MoCA scores.
There were no differences between the groups in alpha and beta diversity indices and differential abundances of bacterial taxa post-intervention. Volatility analysis demonstrated a greater degree of change in the microbiome in the probiotic group, although the difference was not significant.
These findings align with trials of the same probiotic in people with depression which showed that the intervention improved cognitive reactivity in depressed individuals without affecting depressive symptoms or gut microbiota, and enhanced working memory under stress in healthy individuals. A dedicated trial using sensitive and specific cognitive measures for PD is now under way.
Reference
Lam J, Uzelman P, Zhu J, Meng D, Pio F, Appel-Cresswell S. A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic for anxiety in Parkinson’s disease. Abstract 714. International Congress of Parkinson’s Disease and Movement Disorders. Philadelphia, US. September 27-October 1, 2024.
New disorder identified: Childhood dementia, ataxia, and neuropathy
There is growing knowledge of the role of the CAPRIN1 gene in the pathogenesis of neurological disorders. CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNA encoding proteins important for cell proliferation and migration in multiple cell types. CAPRIN1 loss is associated with reduced neuronal processes, overall disruption of neuronal organisation, and increased neuronal degeneration.
In 2023, a paper published in Brain reported 12 cases of an autosomal dominant disorder associated with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterised by language impairment/speech delay, intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). Affected individuals also had respiratory problems, limb/skeletal anomalies, developmental delay, feeding difficulties, seizures, and ophthalmologic problems.
At this year’s conference, a team from Italy reported the case of a 13-year-old
girl with a severe neurodegenerative disorder characterised by childhood dementia, myoclonus-ataxia, and sensorimotor neuropathy.
The patient was the only child of non-consanguineous parents. Her clinical history was silent until the age of eight years, when she presented with an insidious onset of motor clumsiness, leading to progressive gait disturbances by the age of 10 years. At this time, she showed mild intellectual disability, and speech and writing disturbances.
By the age of 11 years, she developed myoclonus-ataxia, axial hypotonia, bradykinesia, sensorimotor neuropathy, and diffuse muscle atrophy. The condition continues to progress and, at the last follow-up, she showed worsening neurological symptoms, with loss of independent walking.
Brain MRI, performed at 10 years, showed atrophy of the frontal cortex and cerebellar hemispheres. Extensive metabolic work-up and next generation sequencing (NGS) panels for genetic ataxias, epilepsies, and mitochondrial diseases were negative.
Electron microscopy of skin biopsy showed swelling of the rough endoplasmic reticulum (ER) and mitochondrial damage. EEG showed diffuse epileptic abnormalities, and electroneurography confirmed an axonal neuropathy.
Whole-exome sequencing disclosed a missense pathogenic variant in CAPRIN1 gene (c.1535C>T; p.Pro512Leu). The P512L substitution is thought to cause a neurodegenerative phenotype by acting as a gain-of-function, leading to protein misfolding and aggregation.
CAPRIN1 haploinsufficiency has now been described in 14 patients with neurodevelopmental disorders. Two cases of progressive ataxia and sensorimotor axonal neuropathy carrying the same variant have also been reported.
This case contributes to the clinical spectrum of CAPRIN1 mutations, supporting its role in the pathogenesis of neurodegenerative disorders.
Reference
Bove R, Torella A, Ricciardi G, Pollini L, Novelli M, Pisani F, Nigro V, Leuzzi V, Galosi S. CAPRIN1 defect: A new severe neurodegenerative disorder with childhood dementia, myoclonus-ataxia, and sensorimotor neuropathy. Abstract 1325. International Congress of Parkinson’s Disease and Movement Disorders. Philadelphia, US. September 27-October 1, 2024.
New tool improves accuracy of Parkinson’s resting tremor diagnosis
A team of Danish researchers has developed a novel tool to diagnose Parkinson’s disease (PD) resting tremor, which has been shown to be significantly more accurate than current methods.
Resting tremor is a primary indicator of PD. Currently, diagnosis is based on subjective measures and it is widely recognised that there is a need for objective, digitally-quantifiable tools to enhance PD diagnosis and treatment.
The team analysed and compared surface electromyography (sEMG) data from 10 PD patients who exhibited resting tremors and a control group within the same age range. Data corresponding to the flexor carpi radialis (FCR) muscle underwent further processing, including filtering, rectification, and normalisation, and were examined in both time and frequency domains.
A Hill-type musculoskeletal model representing the FCR was developed using the processed data as muscle activation information in simulations to model the FCR muscle’s dynamics and properties.
Both biological (from sEMG) and synthetic (from simulations) data features were analysed. The analysis revealed distinct key biological biomarkers for assessing resting tremor, including the mean absolute value (MAV), root mean square (RMS) and mean frequency derived from sEMG signals.
Synthetic biomarkers, such as pennation angular velocity and fibre velocity obtained from simulations of the developed FCR muscle, were also extracted to assess resting tremor. The integration of these features into the linear discriminant analysis (LDA) model resulted in classification accuracy of 93.2 per cent, surpassing that of individual biological (87.8%) or synthetic (89.5%) markers alone. This enhancement was observed in 70 per cent of the cases.
The results, presented at the International Congress, demonstrate a novel method for PD tremor symptom evaluation by merging sEMG data with musculoskeletal simulations to pinpoint relevant biomarkers for resting tremors.
Although further studies with larger datasets are required for comprehensive validation, this approach could provide a more objective and rapid diagnostic method, potentially surpassing existing practices in PD diagnosis.
Reference
Rey Vilches JRV and Tolu ST. Combining EMG and simulation-based biomarkers to enhance Parkinson’s resting tremor diagnosis. Abstract 1566. International Congress of Parkinson’s Disease and Movement Disorders. Philadelphia, USA. September 27-October 1, 2024.
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