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Lancet (London, England) Jan 2024The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above... (Review)
Review
The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.
Topics: Male; Humans; Female; Aged; Parkinson Disease; Risk Factors; Causality; Incidence; Poverty
PubMed: 38245248
DOI: 10.1016/S0140-6736(23)01419-8 -
Movement Disorders : Official Journal... Aug 2023This document presents a consensus on the diagnosis and classification of isolated cervical dystonia (iCD) with a review of proposed terminology. The International... (Review)
Review
This document presents a consensus on the diagnosis and classification of isolated cervical dystonia (iCD) with a review of proposed terminology. The International Parkinson and Movement Disorder Society Dystonia Study Group convened a panel of experts to review the main clinical and diagnostic issues related to iCD and to arrive at a consensus on diagnostic criteria and classification. These criteria are intended for use in clinical research, but also may be used to guide clinical practice. The benchmark is expert clinical observation and evaluation. The criteria aim to systematize the use of terminology as well as the diagnostic process, to make it reproducible across centers and applicable by expert and non-expert clinicians. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations, which are incorporated into the current criteria. Three iCD presentations are described in some detail: idiopathic (focal or segmental) iCD, genetic iCD, and acquired iCD. The relationship between iCD and isolated head tremor is also reviewed. Recognition of idiopathic iCD has two levels of certainty, definite or probable, supported by specific diagnostic criteria. Although a probable diagnosis is appropriate for clinical practice, a higher diagnostic level may be required for specific research studies. The consensus retains elements proven valuable in previous criteria and omits aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of iCD expands, these criteria will need continuous revision to accommodate new advances. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Torticollis; Dystonic Disorders; Tremor; Consensus; International Classification of Diseases
PubMed: 36989390
DOI: 10.1002/mds.29387 -
The Lancet. Neurology Feb 2024With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically... (Review)
Review
With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.
Topics: Humans; Parkinson Disease; Neuroimaging; Precision Medicine
PubMed: 38267191
DOI: 10.1016/S1474-4422(23)00404-0 -
Expert Review of Neurotherapeutics 2023Essential Tremor (ET) is one of the most common tremor syndromes typically presented as action tremor, affecting mainly the upper limbs. In at least 30-50% of patients,... (Review)
Review
INTRODUCTION
Essential Tremor (ET) is one of the most common tremor syndromes typically presented as action tremor, affecting mainly the upper limbs. In at least 30-50% of patients, tremor interferes with quality of life, does not respond to first-line therapies and/or intolerable adverse effects may occur. Therefore, surgery may be considered.
AREAS COVERED
In this review, the authors discuss and compare unilateral ventral intermedius nucleus deep brain stimulation (VIM DBS) and bilateral DBS with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy, which comprises focused acoustic energy generating ablation under real-time MRI guidance. Discussion includes their impact on tremor reduction and their potential complications. Finally, the authors provide their expert opinion.
EXPERT OPINION
DBS is adjustable, potentially reversible and allows bilateral treatments; however, it is invasive requires hardware implantation, and has higher surgical risks. Instead, MRgFUS is less invasive, less expensive, and requires no hardware maintenance. Beyond these technical differences, the decision should also involve the patient, family, and caregivers.
Topics: Humans; Essential Tremor; Tremor; Treatment Outcome; Quality of Life; Deep Brain Stimulation
PubMed: 37288812
DOI: 10.1080/14737175.2023.2221789 -
Current Opinion in Neurology Aug 2023Since the original description of progressive supranuclear palsy (PSP) by Steele, Richardson and Olszewski, the clinical spectrum of PSP has expanded and now includes... (Review)
Review
PURPOSE OF REVIEW
Since the original description of progressive supranuclear palsy (PSP) by Steele, Richardson and Olszewski, the clinical spectrum of PSP has expanded and now includes multiple phenotypic variants linked by a common disease. In this review, we discuss the evolution of the PSP syndrome and clinical criteria, with a particular focus on the 2017 Movement Disorders Society PSP criteria, its application and limitations. We also discuss our current approach to diagnosis and treatment.
RECENT FINDINGS
There is a significant overlap between the different variants of PSP and multiple phenotypes that may be applied to the same patient simultaneously. Variant severity and predominance also evolve throughout the course of the disease. Each variant and level of certainty is associated with different specificity and sensitivity for underlying disease. The differential diagnosis of PSP is continuously evolving and includes other tauopathies, neurodegenerative, genetic, autoimmune and infectious disorders. MRI measurements can aid in the diagnosis. The first guidelines to help with clinical management of those patients have been recently published.
SUMMARY
Although much improved, clinical PSP criteria alone remain insufficient and emphasize the need for improved biomarkers to identify patients at early stages to direct appropriate therapeutic strategies and target potential research.
Topics: Humans; Supranuclear Palsy, Progressive; Movement Disorders; Tauopathies; Diagnosis, Differential; Phenotype
PubMed: 37381926
DOI: 10.1097/WCO.0000000000001163 -
The Lancet. Neurology Feb 2024Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the... (Review)
Review
Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.
Topics: Humans; alpha-Synuclein; Parkinson Disease; Lewy Body Disease; Synucleinopathies; Lewy Bodies; Syndrome
PubMed: 38267190
DOI: 10.1016/S1474-4422(23)00405-2 -
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 -
Movement Disorders : Official Journal... Mar 2024At present, clinical practice and research in movement disorders (MDs) focus on the "normalization" of altered movements. In this review, rather than concentrating on... (Review)
Review
At present, clinical practice and research in movement disorders (MDs) focus on the "normalization" of altered movements. In this review, rather than concentrating on problems and burdens people with MDs undoubtedly have, we highlight their hidden potentials. Starting with current definitions of Parkinson's disease (PD), dystonia, chorea, and tics, we outline that solely conceiving these phenomena as signs of dysfunction falls short of their complex nature comprising both problems and potentials. Such potentials can be traced and understood in light of well-established cognitive neuroscience frameworks, particularly ideomotor principles, and their influential modern derivatives. Using these frameworks, the wealth of data on altered perception-action integration in the different MDs can be explained and systematized using the mechanism-oriented concept of perception-action binding. According to this concept, MDs can be understood as phenomena requiring and fostering flexible modifications of perception-action associations. Consequently, although conceived as being caught in a (trough) state of deficits, given their high flexibility, people with MDs also have high potential to switch to (adaptive) peak activity that can be conceptualized as hidden potentials. Currently, clinical practice and research in MDs are concerned with deficits and thus the "deep and wide troughs," whereas "scattered narrow peaks" reflecting hidden potentials are neglected. To better delineate and utilize the latter to alleviate the burden of affected people, and destigmatize their conditions, we suggest some measures, including computational modeling combined with neurophysiological methods and tailored treatment. © 2024 International Parkinson and Movement Disorder Society.
Topics: Humans; Movement Disorders; Parkinson Disease; Tics; Dystonia; Chorea
PubMed: 38196315
DOI: 10.1002/mds.29706 -
JAMA Apr 2024Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple...
IMPORTANCE
Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies.
OBJECTIVE
To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF.
DESIGN, SETTING, AND PARTICIPANTS
This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis.
EXPOSURE
Skin biopsy for detection of phosphorylated α-synuclein.
MAIN OUTCOMES
Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy.
RESULTS
Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.
Topics: Aged; Female; Humans; Male; alpha-Synuclein; Biopsy; Cross-Sectional Studies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies; Phosphorylation; Skin; Pure Autonomic Failure; Reproducibility of Results; Adult; Middle Aged; Aged, 80 and over; Single-Blind Method; Prospective Studies
PubMed: 38506839
DOI: 10.1001/jama.2024.0792 -
Handbook of Clinical Neurology 2024Paraneoplastic movement disorders are diverse autoimmune neurological illnesses occurring in the context of systemic cancer, either in isolation or as part of a... (Review)
Review
Paraneoplastic movement disorders are diverse autoimmune neurological illnesses occurring in the context of systemic cancer, either in isolation or as part of a multifocal neurological disease. Movement phenomena may be ataxic, hypokinetic (parkinsonian), or hyperkinetic (myoclonus, chorea, or other dyskinetic disorders). Some disorders mimic neurodegenerative or hereditary illnesses. The subacute onset and coexisting nonclassic features of paraneoplastic disorders aid distinction. Paraneoplastic autoantibodies provide further information regarding differentiating cancer association, disease course, and treatment responses. A woman with cerebellar ataxia could have metabotropic glutamate receptor 1 autoimmunity, in the setting of Hodgkin lymphoma, a mild neurological phenotype and response to immunotherapy. A different woman, also with cerebellar ataxia, could have Purkinje cytoplasmic antibody type 1 (anti-Yo), accompanying ovarian adenocarcinoma, a rapidly progressive phenotype and persistent disabling deficits despite immune therapy. The list of antibody biomarkers is growing year-on-year, each with its own ideal specimen type for detection (serum or CSF), accompanying neurological manifestations, cancer association, treatment response, and prognosis. Therefore, a profile-based approach to screening both serum and CSF is recommended. Immune therapy trials are generally undertaken, and include one or more of corticosteroids, IVIg, plasma exchange, rituximab, or cyclophosphamide. Symptomatic therapies can also be employed for hyperkinetic disorders.
Topics: Female; Humans; Cerebellar Ataxia; Autoantibodies; Movement Disorders; Nervous System Diseases; Neoplasms
PubMed: 38494279
DOI: 10.1016/B978-0-12-823912-4.00004-9