#Parkinson’s disease (PD)

[tacitusauxilium]

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[blueoaknx]

Mitochondrial Dysfunction in the Pathogenesis of Parkinson’s Disease

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily affecting motor function due to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. The pathogenesis of PD is multifactorial, with emerging evidence pointing to mitochondrial dysfunction as a pivotal event in the onset and progression of the disease. This article provides a comprehensive technical analysis of the role of mitochondrial dysfunction in PD, focusing on key molecular mechanisms, genetic factors, and potential therapeutic strategies.

Mitochondria and Their Cellular Roles

Mitochondria are essential organelles that generate the majority of the cell's ATP via oxidative phosphorylation in the electron transport chain (ETC). In addition to their role in energy production, mitochondria are involved in maintaining cellular homeostasis by regulating calcium signaling, apoptosis, and reactive oxygen species (ROS) production. The proper functioning of mitochondria is crucial for neurons, particularly dopaminergic neurons, which have a high metabolic demand.

Mitochondrial Dysfunction and Parkinson's Disease Pathogenesis

Mitochondrial dysfunction in PD primarily manifests through alterations in mitochondrial bioenergetics, increased oxidative stress, defective mitophagy, and calcium dysregulation. These abnormalities converge on exacerbating neuronal injury, particularly in dopaminergic neurons.

1. Impaired Mitochondrial Complex I Activity

One of the hallmark features of mitochondrial dysfunction in PD is the impairment of mitochondrial complex I, the first enzyme complex in the ETC. Complex I is responsible for transferring electrons from NADH to ubiquinone, a critical step in ATP synthesis. Studies consistently show that PD patients exhibit significant reductions in complex I activity in the substantia nigra, which leads to defective ATP production. This mitochondrial dysfunction results in energy deficits, rendering dopaminergic neurons more susceptible to stressors.

Inhibition of complex I activity is not limited to genetic mutations; environmental toxins such as rotenone and paraquat, which inhibit complex I, have been implicated in Parkinsonian syndromes. Furthermore, complex I dysfunction increases the production of ROS, exacerbating oxidative stress in neurons and contributing to mitochondrial damage.

2. Oxidative Stress and ROS Generation

Mitochondria are both the primary source and target of ROS. The process of oxidative phosphorylation inevitably generates ROS as byproducts, particularly superoxide anion, hydrogen peroxide, and hydroxyl radicals. Under normal conditions, ROS are detoxified by endogenous antioxidant systems. However, in PD, mitochondrial dysfunction leads to an imbalance between ROS production and the cell’s antioxidant defenses.

The substantia nigra, which is particularly vulnerable in PD, is exposed to elevated ROS levels due to the high metabolic rate of dopaminergic neurons and the catabolism of dopamine, which generates additional ROS via the action of monoamine oxidase (MAO). Accumulation of ROS results in lipid peroxidation, protein misfolding, and mitochondrial DNA (mtDNA) mutations, all of which contribute to neuronal death and the progression of Parkinson’s pathology.

3. Mitophagy and Dysfunctional Quality Control Mechanisms

Mitophagy, a selective autophagic process that removes damaged or dysfunctional mitochondria, is crucial for maintaining mitochondrial quality and function. In PD, mitophagy is impaired, leading to the accumulation of damaged mitochondria within neurons. The PINK1-parkin pathway plays a pivotal role in the initiation of mitophagy. PINK1, a mitochondrial kinase, accumulates on depolarized mitochondria and recruits the E3 ubiquitin ligase parkin, which ubiquitinates outer mitochondrial membrane proteins to tag them for autophagic degradation.

Mutations in the PINK1 and parkin genes, which are associated with autosomal recessive forms of PD, disrupt this process and contribute to the accumulation of dysfunctional mitochondria. This failure to remove damaged mitochondria exacerbates oxidative stress and promotes the activation of apoptotic signaling pathways. As mitochondrial dysfunction progresses, neuronal survival becomes increasingly compromised, accelerating disease progression.

4. Calcium Homeostasis and Mitochondrial Regulation

Mitochondria play a critical role in buffering cytosolic calcium levels. Neurons, due to their high metabolic activity, are particularly dependent on mitochondrial calcium buffering to prevent cytotoxic calcium overload. However, in PD, mitochondrial dysfunction leads to impaired calcium handling, resulting in an increase in cytosolic calcium concentrations.

Elevated calcium levels activate a variety of calcium-dependent enzymes, such as calpains and phospholipases, that further damage cellular structures. Additionally, excessive calcium in mitochondria can activate the mitochondrial permeability transition pore (mPTP), leading to mitochondrial depolarization, the release of pro-apoptotic factors such as cytochrome c, and eventual cell death.

Genetic Factors in Mitochondrial Dysfunction in PD

Genetic mutations that directly affect mitochondrial function have been identified in familial forms of PD. These mutations often impair mitochondrial dynamics, quality control, and bioenergetics, contributing to the pathogenesis of the disease.

PINK1 and Parkin Mutations: Mutations in the PINK1 gene and the parkin gene, both involved in the regulation of mitophagy, lead to impaired mitochondrial quality control. PINK1, a serine/threonine kinase, normally accumulates on damaged mitochondria and recruits parkin to initiate mitophagy. Loss of PINK1 or parkin function results in the accumulation of dysfunctional mitochondria, contributing to neuronal degeneration.

LRRK2 Mutations: The LRRK2 gene encodes a large protein kinase involved in multiple cellular processes, including mitochondrial dynamics and autophagy. Mutations in LRRK2 are the most common genetic cause of PD, particularly in late-onset forms. LRRK2 is implicated in the regulation of mitochondrial fission and fusion, processes that control mitochondrial morphology and function. Dysregulation of these processes leads to the fragmentation of mitochondria, impaired mitochondrial function, and increased susceptibility to oxidative stress.

Alpha-Synuclein and Mitochondrial Interaction: Alpha-synuclein, the protein most notably associated with Lewy body formation in PD, has also been shown to interact with mitochondrial membranes. Aggregation of alpha-synuclein disrupts mitochondrial dynamics, leading to decreased mitochondrial respiration and increased ROS production. This interaction exacerbates mitochondrial dysfunction and accelerates neurodegeneration.

Environmental Toxins and Mitochondrial Dysfunction

Environmental exposures, particularly to pesticides like rotenone and paraquat, have been shown to inhibit mitochondrial complex I, leading to oxidative stress and mitochondrial dysfunction. These toxins induce PD-like symptoms in animal models, supporting the hypothesis that environmental factors contribute to the pathogenesis of the disease.

Therapeutic Approaches Targeting Mitochondrial Dysfunction

Given the central role of mitochondrial dysfunction in PD, therapeutic strategies aimed at restoring mitochondrial function are being actively explored. These include:

Antioxidant Therapies: Antioxidants such as coenzyme Q10 (CoQ10) have been proposed to alleviate oxidative stress by scavenging ROS. CoQ10 functions as an electron carrier in the ETC and may help restore mitochondrial bioenergetics in PD. Clinical trials, however, have shown mixed results, necessitating further research.

Gene Therapy: Gene therapy approaches aimed at correcting genetic defects that impair mitochondrial function are under investigation. For example, restoring PINK1 or parkin function in neurons may enhance mitophagy and mitigate mitochondrial damage.

Mitochondrial Replacement Therapy: Mitochondrial replacement or mitochondrial transplantation holds promise as a therapeutic strategy for restoring mitochondrial function in PD. Early-stage studies are exploring the feasibility of mitochondrial transplantation into dopaminergic neurons to restore cellular function.

Exercise and Lifestyle Interventions: Regular physical exercise has been shown to stimulate mitochondrial biogenesis and improve mitochondrial function. Exercise-induced upregulation of mitochondrial regulators such as PGC-1α may provide neuroprotective benefits in PD by enhancing mitochondrial turnover and reducing oxidative damage.

Conclusion

Mitochondrial dysfunction is a central event in the pathogenesis of Parkinson's disease, contributing to the degeneration of dopaminergic neurons through mechanisms such as impaired mitochondrial complex I activity, oxidative stress, defective mitophagy, and disrupted calcium homeostasis. Genetic mutations in key mitochondrial regulators such as PINK1, parkin, and LRRK2 exacerbate these defects, while environmental toxins further contribute to mitochondrial damage. Targeting mitochondrial dysfunction through antioxidant therapies, gene therapy, and lifestyle interventions holds promise for mitigating the progression of Parkinson's disease. Understanding the intricate molecular mechanisms linking mitochondrial dysfunction to neurodegeneration in PD will be crucial for developing effective therapeutic strategies.

[billloguidice]

New research shows effects of antimicrobial exposure on the risk of Parkinson's disease

New research shows effects of antimicrobial exposure on the risk of Parkinson's disease #parkinsons #research #antifungal #brain #pd #study

Publishing in the journal, Parkinsonism & Related Disorders, researchers used a nested case-control study design to evaluate the impact of antimicrobial exposure on the risk of developing Parkinson’s disease (PD), a movement disorder that manifests as tremors, stiffness, and balance issues. The study found that in a large UK-representative population, the risk of PD was modestly lower among…

[courtyard01]

Understanding the progression of Parkinson's disease is key to providing the right care. This blog explains the 5 stages of Parkinson's disease, from early symptoms to advanced stages. Learn how each stage affects daily life and what to expect as the condition evolves, helping caregivers and families prepare for the future with more awareness and support.

[stellasstones]

Haiku for Parkinson's: Introduction

The new project of The Haiku Foundation, Haiku for Parkinson’s was launched on the 17th of December 2023! I very much look forward to seeing it develop along the various themes and issues arising from Parkinson’s. The Introduction to the feature can be read by clicking here I have copied it on this site too, see below. Haiku for Parkinson’s is a feature of The Haiku Foundation, introducing…

[revdrjamesjshowersjr]

So help Us God.. Amen, Ameen, Amun, Amin, Aum..

[loubie364]

April 11

  World Parkinson’s Day – April 11 A very brief background of the red tulip and the day? (more…) “”

[3liza]

Apart from the prescription of transcutaneous nicotine application as a substitute for weaning smokers, the transcutaneous application of this substance has been investigated in clinical trials evaluating its therapeutic effects on neurologic or gastrointestinal disorders in non-smoking patients; these investigations showed no substantial side effects (Newhouse et al. 2012; Sandborn 1997; Pullan et al. 1994). Using very high dosages of nicotine (up to 107 mg/day), however, led nearly every patient with more than 90 mg/day to present with frequent nausea and vomiting (Villafane et al. 2007). Nonetheless, all individuals in a trial investigating the ameliorative effects of nicotine on Parkinson’s disease (PD) showed improved motor scores under reduced dopaminergic treatment (Villafane et al. 2007). In contrast to the well-known addictive potential linked to the chronic inhalation of nicotine, none of the trials could show a nicotine dependency after the withdrawal of transcutaneous nicotine application at the end of the investigations (Newhouse et al. 2012; Sandborn 1997; Pullan et al. 1994; Villafane et al. 2007).

Furthermore, among the severe and fatal cases of COVID-19, the proportion of nicotine consumers was significantly lower than non-consumers of nicotine (Miyara, et al. 2020).

CIGARETTES CONFIRMED FOR HEALTHY. CIGARETTES CURE LONG COVID im kidding but nicotine therapy is actually showing a lot of promise check it out

[afeelgoodblog]

The Best News of Last Week

⚡ - Charging Towards a More Electrifying Future

1. The Kissimmee River has been brought back to life—and wildlife is thriving

The Kissimmee River in Florida was straightened in the 1960s, causing a sharp decline in wildlife and ecological problems. But in the 1990s, a $1 billion restoration project was initiated to restore the river's natural state.

Today, nearly half of the river has been restored, wetlands have been reestablished and rehydrated, and wildlife has returned, including rare and threatened species. Already the biological impact of the project has become clear. As the wetlands have come back, so have the birds.

2. Plastic wrap made from seaweed withstands heat and is compostable

A cling film made from an invasive seaweed can withstand high temperatures yet is still easily compostable. The material could eventually become a sustainable choice for food packaging.

Scientists started with a brown seaweed called sargassum. Sargassum contains long, chain-like molecules similar to those that make up conventional plastic, which made it a good raw material. The researchers mixed it with some acids and salts to get a solution full of these molecules, then blended in chemicals that thickened it and made it more flexible and pliable.

3. An Eagle Who Adopted a Rock Becomes a Real Dad to Orphaned Eaglet

Murphy, a bald eagle that had been showing fatherly instincts, has been sharing an enclosure with an eaglet that survived a fall from a tree during a storm in Ste. Genevieve. Murphy, his rock gone by then, took his role as foster parent seriously. He soon began responding to the chick’s peeps, and protecting it.

And when, as a test, the keepers placed two plates of food in front of the birds — one containing food cut into pieces that the chick could eat by itself, and another with a whole fish that only Murphy could handle — the older bird tore up the fish and fed it to the eaglet.

4. World's largest battery maker announces major breakthrough in energy density

In one of the most significant battery breakthroughs in recent years, the world’s largest battery manufacturer CATL has announced a new “condensed” battery with 500 Wh/kg which it says will go into mass production this year.

“The launch of condensed batteries will usher in an era of universal electrification of sea, land and air transportation, open up more possibilities of the development of the industry, and promote the achieving of the global carbon neutrality goals at an earlier date,” the company said in a presentation at Auto Shanghai on Thursday.

This could be huge. Electric jets and cargo ships become very possible at this point.

5. Cat with '100% fatal' feline coronavirus saved by human Covid-19 medicine

A beloved household cat has made an “astonishing” recovery from a usually fatal illness, thanks to a drug made to treat Covid-19 in humans – and a quick-thinking vet.

Anya​, the 7-year-old birman cat, was suffering from feline infectious peritonitis (FIP), a “100% fatal” viral infection caused by feline coronavirus. That was, until Auckland vet Dr Habin Choi​ intervened, giving Anya an antiviral used to treat Covid-19 called molnupiravir.

6. Kelp forests capture nearly 5 million tonnes of CO2 annually

Kelp forests provide an estimated value of $500 billion to the world and capture 4.5 million tonnes of carbon dioxide from seawater each year. Most of kelp’s economic benefits come from creating habitat for fish and by sequestering nitrogen and phosphorus.

7. Medical Marijuana Improved Parkinson’s Disease Symptoms in 87% of Patients

Medical cannabis (MC) has recently garnered interest as a potential treatment for neurologic diseases, including Parkinson's disease (PD). 87% of patients were noted to exhibit an improvement in any PD symptom after starting medical cannabis. Symptoms with the highest incidence of improvement included cramping/dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor.

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That's it for this week :)

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[willowreader]

I know someone diagnosed with Parkinsons disease just lately. I am sure there are many causes, but that research shows it could be Covid related is worth noting.

[covid-safer-hotties]

Reference archived on our website

ABSTRACT Background Viral induction of neurological syndromes has been a concern since parkinsonian‐like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection with those observed after pandemic influenza, there is a question whether a similar syndrome of postencephalic parkinsonism could follow coronavirus disease 2019 infection.

Objective The goal of this study was to determine whether prior infection with SARS‐CoV‐2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism.

Methods K18‐hACE2 mice were infected with SARS‐CoV‐2 to induce mild‐to‐moderate disease. After 38 days of recovery, mice were administered a non‐lesion‐inducing dose of the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and euthanized 7 days later. Subsequent neuroinflammation and substantia nigra pars compacta (SNpc) dopaminergic (DA) neuron loss were determined and compared with SARS‐CoV‐2 or MPTP alone.

Results K18‐hACE2 mice infected with SARS‐CoV‐2 or MPTP showed no SNpc DA neuron loss after MPTP. In mice infected and recovered from SARS‐CoV‐2 infection, MPTP induced a 23% or 19% greater loss of SNpc DA neurons than SARS‐CoV‐2 or MPTP, respectively (P < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in both the SNpc and striatum of the SARS‐CoV‐2 + MPTP group compared with SARS‐CoV‐2 or MPTP alone.

Conclusions Our observations have important implications for long‐term public health, given the number of people who have survived SARS‐CoV‐2 infection, as well as for future public policy regarding infection mitigation. However, it will be critical to determine whether other agents known to increase risk for PD also have synergistic effects with SARS‐CoV‐2 and are abrogated by vaccination.

Keywords: COVID‐19, MPTP, Parkinson's disease

[blueoaknx]

Mitochondrial Dysfunction Drives Cognitive Decline

Introduction

Mitochondria, often referred to as the powerhouses of the cell, are crucial organelles responsible for energy production through adenosine triphosphate (ATP) synthesis. Beyond their well-known role in energy metabolism, mitochondria regulate a wide range of cellular processes, including calcium homeostasis, reactive oxygen species (ROS) generation, and apoptosis. When mitochondria malfunction, the consequences can be far-reaching, especially for energy-intensive organs like the brain. Recent research highlights mitochondrial dysfunction as a central factor in cognitive decline, contributing to neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. This article explores the mechanisms by which mitochondrial dysfunction impacts cognitive function and discusses potential therapeutic strategies.

The Brain's Energy Demands and Mitochondrial Function

The human brain, despite accounting for only about 2% of body weight, consumes approximately 20% of the body’s energy. Neurons, the primary cells of the nervous system, rely heavily on mitochondrial ATP to sustain synaptic activity, ion gradient maintenance, and neurotransmitter synthesis. Efficient mitochondrial function is critical for maintaining neuronal health and connectivity, which are foundational for learning, memory, and other cognitive processes.

Mechanisms of Mitochondrial Dysfunction in Cognitive Decline

Reduced ATP Production: Mitochondria produce ATP through oxidative phosphorylation (OXPHOS) in the electron transport chain (ETC). Damage to ETC components, often caused by genetic mutations or oxidative stress, can reduce ATP production. Energy-starved neurons may fail to maintain synaptic function, leading to cognitive impairments.

Excessive ROS Generation: While ROS are natural byproducts of mitochondrial activity and play roles in cell signaling, excessive ROS can damage mitochondrial DNA (mtDNA), proteins, and lipids. This oxidative damage exacerbates mitochondrial dysfunction, creating a vicious cycle that contributes to neuronal degeneration.

Impaired Calcium Regulation: Mitochondria help buffer intracellular calcium levels, which are critical for neurotransmitter release and synaptic plasticity. Dysfunctional mitochondria may fail to regulate calcium, leading to excitotoxicity—a condition where excessive calcium causes neuronal injury and death.

Mitochondrial Dynamics: Mitochondria constantly undergo fission (division) and fusion (joining) to adapt to cellular demands and maintain their integrity. Imbalances in these processes can result in fragmented or overly fused mitochondria, impairing their function and transport within neurons.

Mitochondrial Transport Defects: Neurons have long axons and dendrites that require efficient transport of mitochondria to regions of high energy demand, such as synaptic terminals. Dysfunction in mitochondrial transport mechanisms can disrupt synaptic activity and contribute to cognitive decline.

Mitochondrial Dysfunction in Neurodegenerative Diseases

Alzheimer’s Disease (AD): Mitochondrial dysfunction is a hallmark of AD. Amyloid-beta plaques and tau tangles, characteristic of AD, have been shown to impair mitochondrial function. Elevated ROS levels and reduced ATP production exacerbate neuronal loss and cognitive decline in AD.

Parkinson’s Disease (PD): PD is associated with mutations in genes like PINK1 and PARKIN, which regulate mitochondrial quality control. Impaired mitophagy—the process of removing damaged mitochondria—leads to their accumulation, contributing to dopaminergic neuron degeneration and motor as well as cognitive deficits.

Huntington’s Disease (HD): In HD, mutant huntingtin protein interferes with mitochondrial dynamics and function, resulting in energy deficits and increased oxidative stress. These mitochondrial abnormalities contribute to the progressive cognitive and motor decline observed in HD patients.

Diagnostic and Therapeutic Approaches

Biomarkers of Mitochondrial Dysfunction: Advances in molecular biology have identified potential biomarkers, such as altered mtDNA levels, ROS, and metabolites associated with mitochondrial pathways. These biomarkers can aid in early diagnosis and monitoring of neurodegenerative diseases.

Pharmacological Interventions:

Antioxidants: Compounds like coenzyme Q10, vitamin E, and MitoQ target mitochondrial ROS, reducing oxidative damage and preserving mitochondrial function.

Mitochondrial Biogenesis Enhancers: Agents like resveratrol and PGC-1α activators promote the production of new mitochondria and improve mitochondrial health.

Calcium Modulators: Drugs that stabilize calcium levels, such as memantine, may protect neurons from excitotoxicity.

Gene Therapy: Gene-editing tools like CRISPR/Cas9 offer potential to correct mtDNA mutations or enhance the expression of genes involved in mitochondrial quality control. For example, boosting PINK1 or PARKIN expression could improve mitophagy in PD.

Lifestyle Interventions:

Dietary Interventions: Ketogenic diets and intermittent fasting have been shown to enhance mitochondrial function by promoting efficient energy utilization and reducing ROS.

Exercise: Regular physical activity stimulates mitochondrial biogenesis and reduces oxidative stress, offering neuroprotective benefits.

Sleep Optimization: Adequate sleep is essential for mitochondrial repair and the clearance of damaged proteins, such as amyloid-beta.

Future Directions in Research

Understanding the interplay between mitochondrial dysfunction and cognitive decline opens new avenues for research and therapy. Emerging technologies, such as single-cell transcriptomics and advanced imaging, allow for detailed exploration of mitochondrial dynamics in neurons. Additionally, the development of mitochondria-targeted drugs and nanotechnologies holds promise for precise therapeutic interventions.

Conclusion

Mitochondrial dysfunction plays a pivotal role in driving cognitive decline and is implicated in the pathogenesis of various neurodegenerative diseases. Addressing mitochondrial health through targeted therapies, lifestyle modifications, and early diagnostic measures offers hope for mitigating cognitive impairments and improving quality of life. As our understanding of mitochondrial biology deepens, so too does the potential for innovative treatments that could transform the landscape of neurodegenerative disease management.

[mcatmemoranda]

SUMMARY AND RECOMMENDATIONS

●Classification – Clinical classification of tremor is based on history, tremor characteristics, associated neurologic and systemic signs, and, in some cases, additional testing. A vast number of diseases, disorders, medications, toxins, and substances cause tremor. Etiologies can be broadly classified as genetic, acquired, and idiopathic.

●Rest versus action – The activating conditions that give rise to a tremor are a key distinguishing feature (table 1). Rest tremor occurs in a body part that is fully supported and not voluntarily activated, whereas action tremor occurs with voluntary muscle contraction. Action tremors can be further characterized as kinetic, postural, and isometric.

●Causes of rest tremor – Parkinson disease (PD) and other parkinsonian syndromes are the most common causes of rest tremor (table 2).

●Causes of action tremor – Examples of isolated tremor syndromes in which action tremor can be the sole neurologic symptom include (table 2):

•Enhanced physiologic tremor (table 4)

•Essential tremor (ET) (table 5)

•Task-specific tremors (eg, writing tremor)

•Orthostatic tremor

Examples of combined tremor syndromes in which action tremor may be seen in association with other neurologic or systemic signs and symptoms include:

•Cerebellar tremor

•Neuropathic tremor

•Dystonic tremor

•Functional tremor

●Evaluation – A detailed neurologic examination is important to identify specific features of the tremor (including its frequency, amplitude, pattern, and body distribution), activating conditions, and other neurologic findings, if present.

The routine laboratory evaluation of tremor should include tests of thyroid function, diagnostic studies to exclude Wilson disease, and, rarely, screening for heavy metal poisoning such as mercury or arsenic if an environmental cause is suspected. Brain imaging is usually not indicated in patients with classic presentations of ET, PD, enhanced physiologic tremor, or drug-induced tremor (algorithm 1).

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Algorithm 1:

TSH: thyroid-stimulating hormone; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

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●Treatment – Physical and occupational therapy may be of benefit in patients with limb tremor to help identify coping mechanisms and compensatory strategies. Some forms of tremor are responsive to symptomatic pharmacotherapy.