Striatal Dopamine Depletion Induced By Reserpine
Dopamine levels were pharmacologically depleted by two i.p. injections of reserpine separated by an interval of 48h, as shown in and . Controls received 0.1% glacial acetic acid ., Reserpine inhibits the vesicular monoamine transporter 2 leading to a loss of storage capacity of monoamines in synaptic vesicles, causing depletion in the brain and peripheral monoamines levels. For additional drugs detail, see the Supplementary material.
Effect of levodopa treatment on physical performance and cataleptic scores in reserpinized mice. Protocol design 2. For details, see Materials and Methods. Mouse physical performance on treadmill exhaustion test . Vertical and horizontal workloads during exhaustion test . Blood lactate levels . Cataleptic scores . Results are presented as mean ± SEM. except for the cataleptic test, which are presented as median ± interquartile range.
Anxiety And Depressive Symptoms
The level of anxiety and depressive symptoms of Parkinsons disease patients were assessed by applying the adapted version for Brazilians of the psychometric scale HADS. HADS is a widely used 14-item scale divided into subscales with seven items for anxiety and seven items for depression, resulting in a final score from 0 to 21 in each subscale. Higher scores indicate more symptoms of anxiety and depression.
Criteria For Considering Reviews For Inclusion
We included all Cochrane reviews that assessed the effects of an intervention on fatigue and/or unintentional weight loss in adults with advanced progressive illness in the overview. Systematic reviews published outside The Cochrane Library would not be included, nor would systematic reviews which only included children.
Types of studies
We included Cochrane systematic reviews of interventions with fatigue and/or unintentional weight loss as primary treatment intent.
Types of participants
Adults 18 years or older with an advanced progressive illness known to have clinically significant fatigue and/or weight loss in the latter stages of illness. These conditions include degenerative neurological conditions, such as multiple sclerosis, Parkinson’s disease and dementia, irreversible organ failure, cancer with distant metastasis and acquired immune deficiency syndrome .
Types of outcome measure
Clinically significant improvements in fatigue and/or unintentional weight loss.
Improvements in quality of life of people who have fatigue and/or unintentional weight loss.
Withdrawals due to adverse events.
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Potential Modifiers Of Disease Progression
Less is known about lifestyle associations with PD progression, primarily due to the heterogeneous nature of symptoms unique to individuals, in addition to the absence of sensitive and reliable biomarkers. Moreover, given the extensive neuronal damage at diagnosis, lifestyle behaviours after the diagnosis are more likely to impact the quality of life than dopamine levels, the latter of which may be measured via imaging techniques. PD progression is generally assessed by clinical evaluations of motor function, a stable medication dose, and surveys on quality of life and non-motor symptoms. The limitations of clinical and self-assessments as primary measures of health outcomes include composite scores of multiple outcome domains, variability in performance assessments due to assessor subjectivity and possibly medication effects, and the lack of sensitivity to detect small changes which may not be clinically relevant.
Fatigue In Parkinson’s Disease And Potential Interventions Rocaltrol
2018 99:20410.Robinson BC. Insomnia is also common with Parkinson’s, which can make tiredness during the day worse.
2009 Nov-Dec 32:305-10. doi: 10.1097/WNF.0b013e3181aa916a.Elbers RG, Verhoef J, van Wegen EE, Berendse HW, Kwakkel G.Cochrane Database Syst Rev. By using this website, you agree to our The analysis of articles, which were selected on subjective grounds, was used to review the current knowledge of pathophysiology and treatment outcomes in studies focused on fatigue in PD.Clinical and experimental findings support the view that fatigue is a primary manifestation of PD. doi: 10.1002/14651858.CD010925.pub2.Martino D, Tamburini T, Zis P, Rosoklija G, Abbruzzese G, Ray-Chaudhuri K, Pelosin E, Avanzino L.Parkinsonism Relat Disord.
Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinsons disease.
2015 Oct 8 :CD010925. According to the index, the threshold for a high level of caregiver stress was7 [The new finding in this study relates to the identification of the VAFS as a potential reliable estimate of assessing the overall sensation of excessive fatigue experienced by individuals with PD.
Fatigue is 1 of the most common, although frequently unrecognized, symptoms in Parkinson’s disease , with a prevalence from 33% to 81%.
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These studies provide some insights on the design of future larger clinical trials.
Organization, C. Execution 2.
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Fatigue In Parkinsons Disease And Potential Interventions
Article type: Review Article
Affiliations: Dr. Roger Gilbertson Endowed Chair in Neurology, and Department of Neurology, University of North Dakota School of Medicine and Health Science and Sanford Health, Fargo, ND, USA
Correspondence: Address for correspondence: Jau-Shin Lou, MD, PhD, MBA, Sanford Neuroscience Clinic, 700 1st Avenue S, Fargo, ND 58103,USA. Tel.: +503 887 6983 Fax: +701 2344151
Keywords: Parkinsons disease, fatigue, fatigability, force generation, Attention Network Test, modafinil, methylphenidate, rasagiline, exercise
Journal: NeuroRehabilitation, vol. 37, no. 1, pp. 25-34, 2015
How The Intervention Might Work
The mechanism of action for included interventions was through primary and secondary intervention strategies.
Primary intervention strategies for fatigue may have included those which help preserve muscle mass and maintain energy reserves through interventions such as exercise, activity pacing, relaxation and support services.
For unintentional weight loss primary intervention strategies may have included those which help preserve body weight through interventions such as nutritional supplementation to produce positive energy balance, weightbearing exercise to increase lean body mass, pharmacological agents to downregulate inflammatory processes and improve nitrogen balance and psychological and social interventions that increase desire to eat.
Secondary intervention strategies may have included strategies to adapt to functional decline and weight loss rather than seeking to alleviate them, such as counselling and complementary therapy support.
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Pain Management Principles In Parkinson’s Disease
Non-pharmacologic methods with a multidisciplinary pain team should be utilized to provide optimal multimodal treatment in patients with PD.4 Muscle relaxation exercises and walking regularly can improve flexibility and dampen experiences of pain associated with motor symptoms.6 Rehabilitation with a physical therapist can improve gait and balance, targeting pain caused by motor symptoms. Surgical interventions, such as deep brain stimulation or an implanted spinal cord stimulator, may be appropriate for those patients experiencing pain with PD who do not respond to pharmacologic or rehabilitation interventions.1,6,9
Optimization of treatment with levodopa and other antiparkinsonian medications should be the first pharmacological step in managing PD-related pain.6,8 Beyond this recommendation, no evidence encourages the use of specific analgesic agents in any stepwise order, making patient input and assessment of pain type critical to appropriate treatment.
Patients should be prescribed analgesics if optimization of dopaminergic agents is not effective on its own .4
Optimization of Dopaminergic Agents
Safinamide is a selective, reversible MAO-B inhibitor that reduces degradation and reuptake of dopamine to increase levels in the striatum.19 Safinamide also has non-dopaminergic properties that modulate glutamate release via inhibition of voltage-gated sodium channels. This dual mechanism may mitigate pain, especially during off periods.
Data Collection And Analysis
Selection of reviews
Two overview authors independently applied the selection criteria to reviews. We included reviews studying interventions with fatigue and/or unintentional weight loss as primary treatment intent. We listed reviews identifying interventions impacting on fatigue and/or unintentional weight loss in advanced progressive illness, where the treatment of these symptoms was not the primary indication for the intervention within excluded studies. We resolved disagreements through discussion. For this version of the overview it was not deemed necessary by the authors to seek additional information from the authors of the included systematic reviews.
Data extraction and management
Two overview authors extracted the data independently using a data extraction form. Disagreements were arbitrated by the third overview author and we reached a majority decision by discussion. The data extraction form summarised key characteristics of the review including the date on which the review content was last assessed as up to date, the review objectives, information on participants, interventions examined, comparisons performed, outcomes assessed, comparisons performed and review limitations. Due to the heterogeneity of the included systematic reviews, comparisons and data grouping were not possible. The data are grouped according to condition, intervention and/or symptom as appropriate.
Assessment of methodological quality of included reviews
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Exercise And Medical Interventions
Research has demonstrated the benefits of exercise for patients with PD. Not only have exercise programs been shown to improve motor function and reduce the risk of falls, but they also improve overall quality of life and possibly slow the course of the disease.
Fatigue is associated with lower diastolic blood pressureFatigue is a common debilitating symptom in PD. A 2019 study by researchers at the VA Ann Arbor Health Care System and University of Michigan found that symptoms of fatigue in PD patients were associated with small reductions in diastolic blood pressure throughout the day. Diastolic blood pressure measures pressure in the arteries when the heart rests between beats.
The investigators assessed hourly home blood pressures in 35 people with PD. They then asked the study participants to describe any symptoms of fatigue. The patients with fatigue symptoms had lower mean diastolic blood pressure than those without. The differences in pressure were most notable in the morning.
Fatigue is a complex condition. Understanding the mechanisms that underlie PD fatigue can help scientists find new treatment approaches, wrote the researchers. Fatigue experienced by PD patients could be a clinical manifestation of low blood pressure, they say.
Researchers taught an adapted version of the Argentine tango to 20 people with mild to moderate PD. Over three weeks, participants completed 15 dance lessons, each lasting 90 minutes.
Coping With Fatigue In Pd
Fatigue can make motor symptoms, like tremors, seem like they are worst when they are not. Dr. De León has a list of eight things you can do to prevent or improve fatigue, If you still have severe fatigue discuss it with your physician because there are some medications which can help. The key is well adjusted medications, exercise, good nutrition, and rest at least 5 minutes every day.
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Quality Of The Evidence
Five of the included systematic reviews had their last systematic literature search completed more than five years ago and this may mean that the conclusions are no longer reflective of current research findings. Conflicts of interest are not routinely reported within systematic reviews for included studies. It would be helpful for this information to be part of the standard reporting process to ensure adequate allowance for potential biases in outcomes and conclusions drawn for research.
Many of the systematic reviews had small numbers of included studies and participants and there were high attrition rates in many of the included studies in both intervention and control groups. Results were often not reported as an intentiontotreat analysis. The systematic review authors also reported a large variation in methodological quality across the included studies.
A standard quality assessment tool was not used routinely for all the included systematic reviews. Where authors chose the same quality tool there were also differing interpretations of what constituted a high versus lowquality trial. These limitations led to difficulties in comparing methodological quality across the systematic reviews.
Whilst it is particularly difficult, if not impossible on occasions, to blind participants to interventions aimed at managing symptoms of fatigue and/or weight loss, the methodological quality of trials could have been improved with the blinding of outcome assessors.
Approaches To Pain Assessment
When assessing pain in patients with PD, using a validated pain scale that targets symptoms specific to PD whenever possible will more accurately categorize pain type. The first pain tool designed specifically for patients with PD is the Kings PD Pain Scale .4,12 This scale has 14 questions that measure severity and frequency of different types of pain specific to PD. A complementary patient screening tool, the Kings College PD Pain Questionnaire , is designed for assessing whether or not specific pain types are present. All questions on the KPPQ correspond with a specific question on the KPPS. Screening patients with the KPPQ can facilitate identifying pain types that correspond to the KPPS assessment tool.
If unable to assess pain with scales specific to PD, validated general pain scales, such as the Likert scale, can be utilized to determine quality and severity of any type of pain.18 Using PD-specific pain scales may better characterize a patients pain symptoms, however, which may lead to more targeted treatment options.
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Description Of The Condition
In this overview, advanced progressive illnesses are defined as conditions for which there is no cure and which have significant morbidity in the latter stages of illness. These conditions include degenerative neurological conditions, irreversible organ failure, cancer with metastatic spread and acquired immune deficiency syndrome . The underlying medical condition can affect both the speed of functional decline and the potential for health improvements with appropriate interventions .
Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness and can be of great concern to those affected and of even greater concern to formal and informal caregivers . Altered metabolism, inadequate intake of nutrients, muscle deconditioning and poor energy management have all been implicated in the development and exacerbation of these symptoms . Other common symptoms within advanced illness such as pain, anxiety and depression are not the focus of this review.
Cognitive: inability to concentrate, lack of attention, poor memory, difficulty thinking and impaired decision making .
The National Council for Palliative Care state that interventions to control symptoms such as fatigue and unintentional weight loss can bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress .
Fatigue In Parkinsons Disease: Report From A Multidisciplinary Symposium
A summary of a symposium in October, 2014, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from other disorders in which fatigue figures prominently, and concluding with focused recommendations to enhance understanding and treatment of fatigue in Parkinsons disease.
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Can Reduce Muscle Fatigue
Evidence SummaryFew researchers include fatigue in their review parameters but 2 RCTs have shown benefits to fatigue levels in Parkinsons .Aerobic walking performed over 45 minutes 3 times a week over 6 months was found to be safe well tolerated and improved muscle fatigue over time .Most reviews have centred around medication changes for fatigue alleviation in Parkinsons but activity programs may also be effective .1 study looked at a novel high intensity combination activities and the effects within muscle as well as the perceived effects by people with Parkinsons . Individuals with Parkinsons were capable of training at an intensity, volume, and frequency sufficient to achieve robust adaptations in skeletal muscle. Currently, most investigational treatments for Parkinsons-related fatigue and fatigability centre on the use of various drugs, whereas results of this study indicate intensive training effectively reduces fatigue severity to an FSS score below that indicative of significant fatigue . This is a particularly valuable finding because until now it was unknown whether activity would improve or exacerbate Parkinsons-related fatigue. By 16 weeks, the magnitude of improvement exceeded what we found in healthy older adults after resistance training suggesting the exercise training program induced remarkable alterations in motor unit recruitment patterns among Parkinsons.More research with larger numbers is required related to Parkinsons specific fatigue.
Physiology And Biomarkers For Fatigue In Pd
The physiology underlying fatigue symptoms in PD is unknown, whereas much is known about the mechanisms of motor fatigability. The only published study of physiological differences between fatigued and nonfatigued PD patients found no measurable differences in oxygen utilization during exercise, but some studies have suggested that exercising improves fatigue.,,, Whether fatigue fluctuates with motor fluctuations was looked at in one study. Subjects were assessed during their off, whereas all other studies used the subjects experience over a preceding time interval of weeks. Eighty-eight percent of their subjects were fatigued, and fatigue increased with motor ”off.” Too few subjects were nonfatigued to determine how often fatigue occurred only during motor ”off.” The physiological implications are unclear, as many other nonmotor symptoms also increased during the ”off” period.
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Description Of Included Reviews
See: ‘Characteristics of included systematic reviews’ in and ‘Characteristics of excluded systematic reviews’ in .
The initial handsearch of the Cochrane Database of Systematic Reviews in March 2010 and a subsequent followup search in September 2010 yielded 520 titles of potential interest. We reviewed abstracts of these titles and identified 185 for further consideration with full papers being obtained. We identified 110 papers as having objectives and outcomes of interest to the overview. Two overview authors independently categorised the remaining papers for their relevance to the overview. After considerable debate we included systematic reviews where quality of life was a primary outcome measure, with fatigue or weight outcome measures separately reported. We also included systematic reviews reporting fatigue and/or unintentional weight loss as secondary outcomes if these were primary outcomes for the majority of the considered studies. We included 27 systematic reviews in the review and these are described in the ‘Characteristics of included systematic reviews’ in . Systematic reviews of interventions which impacted on the management of fatigue and weight loss in advanced illness but for which treatment of these conditions was not a primary intent of the intervention are listed in the ‘Characteristics of excluded systematic reviews’ in .
Fatigue In Parkinsons Disease Associates With Lower Ambulatory Diastolic Blood Pressure
Article type: Research Article
Affiliations: Department of Neurology, University of Michigan, Ann Arbor, MI, USA | Veterans Affairs Ann Arbor Health System and GRECC, Ann Arbor, MI, USA | University of Michigan Morris K. Udall Center of Excellence for Parkinsons Disease Research, Ann Arbor, MI, USA | Department of Radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor, MI, USA
Correspondence: Correspondence to: Vikas Kotagal, MD MS, Building 14, North Campus Research Center, 2800 Plymouth Road, Ann Arbor MI, 48109, USA. Tel.: +1 734 936 9010 Fax: +1 734 615 4991 E-mail: .
Keywords: Autonomic symptoms, blood pressure, fatigue, hypotension, Parkinsons disease
Journal: Journal of Parkinson’s Disease, vol. 9, no. 3, pp. 575-581, 2019
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