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Movement Disorders : Official Journal... Jul 2023Loss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Loss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease-modifying therapy. LTI-291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase.
OBJECTIVES
This first-in-patient study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of 28 daily doses of LTI-291 in GBA-PD.
METHODS
This was a randomized, double-blind, placebo-controlled trial in 40 GBA-PD participants. Twenty-eight consecutive daily doses of 10, 30, or 60 mg of LTI-291 or placebo were administered (n = 10 per treatment allocation). Glycosphingolipid (glucosylceramide and lactosylceramide) levels were measured in peripheral blood mononuclear cells (PBMCs), plasma, and cerebrospinal fluid (CSF), and a test battery of neurocognitive tasks, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale and the Mini-Mental State Exam, were performed.
RESULTS
LTI-291 was generally well tolerated, no deaths or treatment-related serious adverse events occurred, and no participants withdrew due to adverse events. C , and AUC of LTI-291 increased in a dose-proportional manner, with free CSF concentrations equal to the free fraction in plasma. A treatment-related transient increase in intracellular glucosylceramide (GluCer) in PBMCs was measured.
CONCLUSION
These first-in-patient studies demonstrated that LTI-291 was well tolerated when administered orally for 28 consecutive days to patients with GBA-PD. Plasma and CSF concentrations that are considered pharmacologically active were reached (ie, sufficient to at least double GCase activity). Intracellular GluCer elevations were detected. Clinical benefit will be assessed in a larger long-term trial in GBA-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Glucosylceramidase; Leukocytes, Mononuclear; Glucosylceramides; Double-Blind Method; Mutation
PubMed: 37195859
DOI: 10.1002/mds.29346 -
Parkinsonism & Related Disorders May 2024Since the original description by James Parkinson, Parkinson's disease (PD) has intrigued us for over 200 years. PD is a progressive condition that is incurable so far,... (Review)
Review
Since the original description by James Parkinson, Parkinson's disease (PD) has intrigued us for over 200 years. PD is a progressive condition that is incurable so far, and affects millions of people worldwide. Over the years, our knowledge has expanded tremendously, and a range of criteria have been put forward and used to try to define PD. However, owing to the complexity of the problem, it is still not consensual how to diagnose and classify a disease that manifests with diverse features, and that responds differently to existing therapies and to those under development. We are now living a time when 'biological' information is becoming abundant, precise, and accessible enabling us to attempt to incorporate different sources of information to classify different forms of PD. These refinements are essential for basic science, as they will enable us to develop improved models for studying PD, and to implement new findings into clinical practice, as this will be the path towards effective personalized medicine.
Topics: Humans; Parkinson Disease; Biomarkers
PubMed: 38472075
DOI: 10.1016/j.parkreldis.2024.106078 -
Journal of the Neurological Sciences Jan 2024Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its... (Review)
Review
Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its indications have been expanding beyond neurologic and ophthalmologic disorders. This article is a narrative review of the therapeutic use of BoNT in tremors, dystonia, sialorrhea, bladder and other autonomic symptoms, levodopa-induced dyskinesia and other problems occuring in the setting of parkinsonism. Though FDA approval is lacking for some of these indications, expert experiences have shown that BoNT is often beneficial in this group of patients.
Topics: United States; Humans; Botulinum Toxins; Parkinson Disease; Parkinsonian Disorders; Tremor; Dystonic Disorders; Botulinum Toxins, Type A
PubMed: 38056063
DOI: 10.1016/j.jns.2023.122810 -
Current Neurology and Neuroscience... Sep 2023To critically review recent research in the development of non-pharmacological interventions to improve cognitive functioning in individuals with Alzheimer's disease... (Review)
Review
PURPOSE OF REVIEW
To critically review recent research in the development of non-pharmacological interventions to improve cognitive functioning in individuals with Alzheimer's disease (AD) or Parkinson's disease (PD).
RECENT FINDINGS
Cognitive interventions can be grouped into three categories: cognitive stimulation (CS), cognitive training (CT), and cognitive rehabilitation (CR). CS confers temporary, nonspecific benefits and might slightly reduce dementia risk for neurologically healthy individuals. CT can improve discrete cognitive functions, but durability is limited and real-world utility is unclear. CR treatments are holistic and flexible and, therefore, most promising but are difficult to simulate and study under rigorous experimental conditions. Optimally effective CR is unlikely to be found in a single approach or treatment paradigm. Clinicians must be competent in a variety of interventions and select those interventions best tolerated by the patient and most relevant to their needs and goals. The progressive nature of neurodegenerative disease necessitates that treatment be consistent, open-ended in duration, and sufficiently dynamic to meet the patient's changing needs as their disease progresses.
Topics: Humans; Neurodegenerative Diseases; Alzheimer Disease; Parkinson Disease; Cognition; Cognitive Behavioral Therapy
PubMed: 37428401
DOI: 10.1007/s11910-023-01283-1 -
Parkinsonism & Related Disorders Dec 2023Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example,...
INTRODUCTION
Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example, atypical parkinsonisms like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Seed amplification assays (SAA), developed for the detection of α-synuclein (αSyn) aggregates in CSF, have been successful when used as a biomarker evaluation for synucleinopathies. In this study, we investigated the potential of this assay to not only detect αSyn seeds in CSF, but also discriminate between movement disorders.
METHODS
The αSyn-SAA was tested in a Scandinavian cohort composed of 129 CSF samples from patients with PD (n = 55), MSA (n = 27), CBD (n = 7), and PSP (n = 16), as well as healthy controls (HC, n = 24).
RESULTS
The αSyn seed amplification assay (αSyn-SAA) was able to correctly identify all PD samples as positive (sensitivity of 100%) while also discriminating the PD group from HC (70.8% specificity, p < 0.0001) and tauopathies [CBD (71% specificity) and PSP (75% specificity), p < 0.0001)]. The αSyn-SAA was also able to identify almost all MSA samples as positive for αSyn aggregation (sensitivity of 92.6%). In general, this assay is able to discriminate between the synucleinopathies and tauopathies analyzed herein (p < 0.0001) despite the overlapping symptoms in these diseases.
CONCLUSION
These findings suggest the αSyn-SAA is a useful diagnostic tool for differentiating between different parkinsonian disorders, although further optimization may be needed.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Parkinsonian Disorders; Parkinson Disease; Multiple System Atrophy; Tauopathies
PubMed: 37591709
DOI: 10.1016/j.parkreldis.2023.105807 -
Journal of Parkinson's Disease 2024Several dietary patterns and nutritional supplements have been linked to the development, progression, and symptomatic treatment of Parkinson's disease (PD). Most of the... (Review)
Review
Several dietary patterns and nutritional supplements have been linked to the development, progression, and symptomatic treatment of Parkinson's disease (PD). Most of the evidence, at this point, is preliminary and based largely on observational studies. Interventional studies are scarce, so the evidence on effectiveness remains inconclusive. Dietary interventions could, analogous to exercise, potentially have a beneficial effect on disease symptoms as well as on the progression of the disease and should therefore be researched in high quality studies. Further work is also needed to study whether dietary interventions, when applied to an at-risk population, have any potential to postpone the onset of manifest PD. In this paper, we summarize all ongoing clinical trials on dietary interventions in PD. We found 10 ongoing studies, all aimed at a different intervention. These studies are mostly exploratory in nature or represent phase I or phase II trials focusing on safety, biological responses, and symptomatic effects. Taken together, we conclude that research on dietary interventions in persons with PD is still in its early days. The results of the various ongoing trials are expected to generate new hypotheses and will help to shape the agenda for future research on this important topic.
Topics: Humans; Parkinson Disease
PubMed: 38277304
DOI: 10.3233/JPD-230366 -
Parkinsonism & Related Disorders Jun 2024The clinical features and outcomes of post-COVID parkinsonism have not been organized systematically, and the possible correlations between COVID-19 and parkinsonism... (Review)
Review
BACKGROUND
The clinical features and outcomes of post-COVID parkinsonism have not been organized systematically, and the possible correlations between COVID-19 and parkinsonism have not been elucidated. This scoping review addresses these two unmet needs.
METHODS
We searched two databases (Pubmed, Embase) for all published cases of post-COVID parkinsonism. Data were extracted from eligible studies using standardized forms and predefined inclusion and exclusion criteria. The patients' clinical features, their diagnosis and outcomes were assessed objectively.
RESULTS
Twenty-six cases of post-COVID parkinsonism were reported in 17 publications. Their presenting features were grouped into three clinical syndromes: typical parkinsonian motor syndrome (12 patients), parkinsonism with postural instability and gait disorder (three), or encephalopathy with parkinsonism (10). Patients had the following diagnoses: clinically established Parkinson's disease (PD, three cases), clinically probable PD (eight), clinically probable multiple system atrophy (one), acquired parkinsonism (six), unclassified parkinsonism (eight). Isolated parkinsonian motor syndromes typically followed uncomplicated COVID-19 illness or pneumonia; instead, encephalopathy with parkinsonism was observed following a wide spectrum of COVID-19-related presentations, including severe forms. PD cases mainly occurred following uncomplicated COVID-19, whereas acquired or unclassified parkinsonism were reported following different COVID-19 presentations.
CONCLUSIONS
Patients with uncomplicated COVID-19 are more likely to present PD and no signs of encephalopathy. There is no demonstration of a causative role of COVID-19, which can be coincidental in several cases. Patients with encephalopathy and parkinsonism constitute a distinct subset, suggesting a potentially different pathogenic role of SARS-CoV-2 infection. These findings provide a basis for further studies in the post-pandemic phase.
Topics: Humans; COVID-19; Parkinsonian Disorders; Aged; Middle Aged; Parkinson Disease; Female; Male
PubMed: 38480080
DOI: 10.1016/j.parkreldis.2024.106066 -
Neurological Sciences : Official... Oct 2023Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of... (Review)
Review
Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of Parkinson's disease, the most common cause of parkinsonism, and atypical parkinsonian disorders. However, parkinsonism can be a manifestation of complex neurological and neurodegenerative genetically determined disorders, which have a vast and heterogeneous motor and non-motor phenotypic features. Hereditary dementias, adult-onset ataxias and spastic paraplegias represent only few of this vast group of neurogenetic diseases. This review will provide an overview of parkinsonism's clinical features within adult-onset neurogenetic diseases which a neurologist could face with. Understanding parkinsonism and its characteristics in the context of the aforementioned neurological conditions may provide insights into pathophysiological mechanisms and have important clinical implications, including diagnostic and therapeutic aspects.
Topics: Adult; Humans; Parkinsonian Disorders; Paraplegia; Parkinson Disease; Ataxia; Dementia
PubMed: 37648940
DOI: 10.1007/s10072-023-07044-9 -
Journal of Religion and Health Dec 2023This issue of JORH presents the first of a two-part series specifically exploring suicide. Research relating to moral injury is also included-a topic which has...
This issue of JORH presents the first of a two-part series specifically exploring suicide. Research relating to moral injury is also included-a topic which has previously been discussed within earlier editions of JORH and an issue that is increasingly recognised as being associated with suicide. Other topic areas explored within this issue are Parkinson's Disease, Diabetes, and Haemodialysis. Finally, readers are once again reminded of the 9th European Congress on Religion, Spirituality and Health (ECRSH) to be held in May 2024, 16-18th at the Paracelsus Medical University in Salzburg, Austria. We would also like to announce a proposed inaugural International Moral Injury and Wellbeing Conference (IMIWC), 19-20 September 2024, Brisbane Exhibition and Convention Centre, Australia.
Topics: Humans; Stress Disorders, Post-Traumatic; Parkinson Disease; Renal Dialysis; Suicide; Diabetes Mellitus; Spirituality; Religion
PubMed: 37947998
DOI: 10.1007/s10943-023-01940-2 -
Neurotherapeutics : the Journal of the... Jul 2023Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be...
Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.
Topics: Animals; Mice; Apoptosis; Dopaminergic Neurons; Lipids; Mice, Inbred C57BL; Parkinson Disease; Parkinsonian Disorders; Phenotype; Reactive Oxygen Species; Humans
PubMed: 37133631
DOI: 10.1007/s13311-023-01382-4