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Journal of Parkinson's Disease 2022Fueled by aging populations and continued environmental contamination, the global burden of Parkinson's disease (PD) is increasing. The disease, or more appropriately... (Review)
Review
Fueled by aging populations and continued environmental contamination, the global burden of Parkinson's disease (PD) is increasing. The disease, or more appropriately diseases, have multiple environmental and genetic influences but no approved disease modifying therapy. Additionally, efforts to prevent this debilitating disease have been limited. As numerous environmental contaminants (e.g., pesticides, metals, industrial chemicals) are implicated in PD, disease prevention is possible. To reduce the burden of PD, we have compiled preclinical and clinical research priorities that highlight both disease prediction and primary prevention. Though not exhaustive, the "PD prevention agenda" builds upon many years of research by our colleagues and proposes next steps through the lens of modifiable risk factors. The agenda identifies ten specific areas of further inquiry and considers the funding and policy changes that will be necessary to help prevent the world's fastest growing brain disease.
Topics: Humans; Parkinson Disease; Pesticides
PubMed: 34719434
DOI: 10.3233/JPD-212922 -
Journal of Parkinson's Disease 2021Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from... (Review)
Review
Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.
Topics: Animals; Humans; Mitochondrial Diseases; Parkinson Disease
PubMed: 33074190
DOI: 10.3233/JPD-201981 -
Journal of Parkinson's Disease 2022Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety... (Review)
Review
Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson's disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.
Topics: Diagnosis, Differential; Humans; Middle Aged; Neurologists; Parkinson Disease; Parkinsonian Disorders
PubMed: 34569973
DOI: 10.3233/JPD-212815 -
Journal of Parkinson's Disease 2020Orthostatic hypotension (OH) is a common non-motor feature of Parkinson's disease that may cause unexplained falls, syncope, lightheadedness, cognitive impairment,... (Review)
Review
Orthostatic hypotension (OH) is a common non-motor feature of Parkinson's disease that may cause unexplained falls, syncope, lightheadedness, cognitive impairment, dyspnea, fatigue, blurred vision, shoulder, neck, or low-back pain upon standing. Blood pressure (BP) measurements supine and after 3 minutes upon standing screen for OH at bedside. The medical history and cardiovascular autonomic function tests ultimately distinguish neurogenic OH, which is due to impaired sympathetic nerve activity, from non-neurogenic causes of OH, such as hypovolemia and BP lowering drugs. The correction of non-neurogenic causes and exacerbating factors, lifestyle changes and non-pharmacological measures are the cornerstone of OH treatment. If these measures fail, pharmacological interventions (sympathomimetic agents and/or fludrocortisone) should be introduced stepwise depending on the severity of symptoms. About 50% of patients with neurogenic OH also suffer from supine and nocturnal hypertension, which should be monitored for with in-office, home and 24 h-ambulatory BP measurements. Behavioral measures help prevent supine hypertension, which is eventually treated with non-pharmacological measures and bedtime administration of short-acting anti-hypertensive drugs in severe cases. If left untreated, OH impacts on activity of daily living and increases the risk of syncope and falls. Supine hypertension is asymptomatic, but often limits an effective treatment of OH, increases the risk of hypertensive emergencies and, combined with OH, facilitates end-organ damage. A timely management of both OH and supine hypertension ameliorates quality of life and prevents short and long-term complications in patients with Parkinson's disease.
Topics: Accidental Falls; Antihypertensive Agents; Blood Pressure; Disease Management; Humans; Hypotension, Orthostatic; Parkinson Disease; Risk Reduction Behavior
PubMed: 32716319
DOI: 10.3233/JPD-202036 -
Journal of Parkinson's Disease 2023The pathophysiology of Parkinson's disease (PD) tremor remains incompletely understood and there is a lack of clinical trials specifically addressing its pharmacological... (Review)
Review
The pathophysiology of Parkinson's disease (PD) tremor remains incompletely understood and there is a lack of clinical trials specifically addressing its pharmacological treatment. Levodopa is the most efficacious drug for most patients and should be used as primary approach to control troublesome tremor. While the efficacy of oral dopamine agonists on PD tremor has been demonstrated in controlled trials, there is no evidence of greater antitremor efficacy compared to levodopa. The magnitude of the antitremor effect of anticholinergics is generally lower than that of levodopa. Due to their adverse effects, anticholinergics have a limited role in selected young and cognitively intact patients. Propranolol may improve resting and action tremor and may be considered as an adjunct in patients with insufficient tremor response to levodopa and this also applies to clozapine, despite its unfavorable adverse effect profile. Treating motor fluctuations with MAO-B and COMT inhibitors, dopamine agonists, amantadine, or on-demand treatments such as subcutaneous or sublingual apomorphine and inhaled levodopa as well as with continuous infusions of levodopa or apomorphine will improve off period tremor episodes. For patients with drug-refractory PD tremor despite levodopa optimization deep brain stimulation and focused ultrasound are first-line considerations. Surgery can also be highly effective for the treatment medication-refractory tremor in selected patients without motor fluctuations. The present review highlights the clinical essentials of parkinsonian tremor, critically examines available trial data on the effects of medication and surgical approaches and provides guidance for the choice of treatments to control PD tremor in clinical practice.
Topics: Humans; Parkinson Disease; Levodopa; Tremor; Dopamine Agonists; Antiparkinson Agents; Apomorphine; Cholinergic Antagonists
PubMed: 36847017
DOI: 10.3233/JPD-225060 -
Journal of Parkinson's Disease 2021Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and tremor. Recently, there has been a growing focus on the relationship between the gut and the development of PD. Emerging to the forefront, an interesting concept has developed suggesting that the initial pathophysiological changes occur in the gastrointestinal tract before changes are seen within the brain. This review is aimed at highlighting the relationship between PD and the gastrointestinal tract, along with the supporting evidence for this. Firstly, we will focus on the gastrointestinal conditions and symptoms which commonly affects patients, including both upper and lower gastrointestinal issues. Secondly, the impact of nutrition and diet on neurological health and PD physiology, with particular emphasis on commonly consumed items including macronutrients and micronutrients. Finally, variability of the gut microbiome will also be discussed and its link with both the symptoms and signs of PD. The evidence presented in this review highly suggests that the initial pathogenesis in the gut may proceed the development of prodromal PD subtypes, and therefore building on this further could be imperative and lead to earlier diagnosis with new and improved therapeutics.
Topics: Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Microbiota; Neurodegenerative Diseases; Parkinson Disease
PubMed: 34250955
DOI: 10.3233/JPD-212707 -
International Journal of Molecular... Jan 2020In recent years, therapeutic strategies [...].
In recent years, therapeutic strategies [...].
Topics: Animals; Disease Susceptibility; Humans; Parkinson Disease; Research
PubMed: 31991804
DOI: 10.3390/ijms21030793 -
Journal of Parkinson's Disease 2020Over the past two decades, aerobic exercise has emerged as a mainstream recommendation to aid in treating Parkinson's disease (PD). Despite the acknowledgement of the... (Review)
Review
Over the past two decades, aerobic exercise has emerged as a mainstream recommendation to aid in treating Parkinson's disease (PD). Despite the acknowledgement of the benefits of exercise for people with PD (PwPD), frequently, exercise recommendations lack specificity in terms of frequency, intensity and duration. Additionally, conflating physical activity with exercise has contributed to providing vague exercise recommendations to PwPD. Therefore, the beneficial effects of exercise may not be fully realized in PwPD. Data provided by animal studies and select human trials indicate aerobic exercise may facilitate structural and functional changes in the brain. Recently, several large human clinical trials have been completed and collectively support the use of aerobic exercise, specifically high-intensity aerobic exercise, in improving PD motor symptoms. Data from these and other studies provide the basis to include aerobic exercise as an integral component in treating PD. Based on positive clinical findings and trials, it is advised that PwPD perform aerobic exercise in the following dose: 3x/week, 30-40-minute main exercise set, 60-80% of heart rate reserve or 70-85% of heart rate max. In lieu of heart rate, individuals can achieve an intensity of 14-17 on a 20-point RPE scale. Ongoing clinical trials, SPARX3 and CYCLE-II, have potential to further develop patient-specific exercise recommendations through prognostic modeling.
Topics: Animals; Exercise; Exercise Therapy; Humans; Parkinson Disease; Prescriptions
PubMed: 32925109
DOI: 10.3233/JPD-202100 -
Journal of Parkinson's Disease 2020In people with young onset Parkinson's disease (YOPD), onset of symptoms is between 21 and 40 years of age. The distinction between YOPD and late-onset Parkinson's... (Review)
Review
In people with young onset Parkinson's disease (YOPD), onset of symptoms is between 21 and 40 years of age. The distinction between YOPD and late-onset Parkinson's disease is supported by genetic differences (a genetic etiology is more common in people with YOPD) and clinical differences (e.g., dystonia and levodopa-induced dyskinesias are more common inYOPD). Moreover, people with YOPD tend to have different family and societal engagements compared to those with late-onset PD. These unique features have implications for clinical management, and call for a tailored multidisplinary approach involving shared-decision making.
Topics: Adult; Age of Onset; Disease Management; Dystonia; Female; Humans; Male; Parkinson Disease; Pregnancy; Pregnancy Complications; Social Interaction; Work Schedule Tolerance; Young Adult
PubMed: 32651336
DOI: 10.3233/JPD-202135 -
Journal of Parkinson's Disease 2020There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.
BACKGROUND
There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.
OBJECTIVE
To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease.
METHODS
A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls.
RESULTS
Qualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson's patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson's disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson's disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET.
CONCLUSION
Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson's disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson's disease modification therapy.
Topics: Aged; Beta Rhythm; Biomarkers; Dopamine Plasma Membrane Transport Proteins; Electroencephalography; Electroencephalography Phase Synchronization; Female; Humans; Machine Learning; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Positron-Emission Tomography
PubMed: 32116262
DOI: 10.3233/JPD-191844