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Pathophysiology Of Basal Ganglia Motor Control

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Disruption of normal dopaminergic output from the substantia nigra interferes with the basal ganglia motor circuit. This circuit is involved in the facilitation of both voluntary and involuntary movement. The connections within the motor circuit are complex and not fully understood.Reference Wichmann, Watts and Koller28

Figure 1. Basal ganglia circuitry normal and in Parkinson’s disease. Black arrows indicate inhibitory output, and white arrows indicate excitatory output. GPe, globus pallidus externa GPi, globus pallidus interna STN, subthalamic nuclei SNc, substantia nigra compacta SNr, substantia nigra reticulata VL, ventrolateral thalamus.

Striatonigral dopaminergic projections connect into the circuit via both a direct and an indirect pathway. The direct pathway involves D1 receptors and acts to reduce the inhibitory output from the globus pallidus interna , mediated by -aminobutyric acid . The indirect pathway involves D2 receptors. This pathway acts via the globus pallidus externa and the subthalamic nucleus, again to reduce inhibitory output from the GPi.Reference Gerfen, Engber, Mahan, Suzel, Chase, Monsma and Sibley29 In Parkinson’s disease, the brake on the GPi is diminished, resulting in increased inhibitory output into the thalamocortical motor circuit.

Csf Tau As A Biomarker For Pd

PD can be subcategorized into different clinical subtypes based on etiology and clinical manifestations . Extensive investigations have attempted to develop biomarkers for the early and precise diagnosis of PD . Although many studies have shown that CSF -Syn levels are lower in PD patients, a lack of association with the severity of disease and considerable overlap of values between control and diseased groups hamper the use of CSF -Syn as a diagnostic marker . Hence, biomarkers that are more sensitive and specific are urgently needed to facilitate early and precise diagnosis and to track progression of the disease. Many investigations have explored the association between CSF Tau levels and the risk of developing PD or its clinical manifestations. Please see Table 2 for an overview of the literature.

Table 2 Clinical evidence supporting the role of Tau in PD pathophysiology

Effects Of Physical Exercise On The Treatment Of Parkinsons Disease

Other therapeutic strategies have been evaluated clinically and scientifically in recent years in the search for an action to reduce clinical problems of PD, such as, non-pharmacological interventions like physiotherapy and physical exercise . Rehabilitation through physical therapy has a variety of goals and methods that generally promote benefits in parkinsonian mobility, posture, and balance. However, some limitations have been observed in a consensual way by some researchers in two topics: in relation to the benefits that seem to be more immediate , and the variety and low methodological quality of the studies . Other nonpharmacological approaches to rehabilitation in Parkinson’s disease are the practice of different modalities of physical exercises such as walking, running, strength training, whole body vibration and functional exercises, which are related to the reduction in the risk of falls, decreased motor symptoms, motor performance improvements, balance and gait improvements, positive repercussions in quality of life and executive functions .

Kurtais et al. investigated the effects of six weeks of supervised treadmill walking, three times a week for 40 minutes in patients with mild to moderate PD, and observed significant improvements in lower limb functional parameters such as walking, balance, and agility, and in related parameters, the adaptations promoted by aerobic exercise as increase of peak VO2 and caloric expenditure in METs .

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Caregiver Strain In Singapore

Caregivers in this Singapore sample reported a mean ZBI score of 23 out of 88. The personal strain and role strain domains are shown in Table 3. In order to interpret the relative intensity of burden experienced by caregivers of people living with PD, the following cut-off values were used: 020 little strain 2140 mild to moderate strain 4160 moderate to severe strain 6188 severe strain . Some caregivers reported little burden 37 caregivers had mild to moderate burden and 11 caregivers reported moderate to severe levels of burden.

Table 3. Zarit burden interview mean scores.

Data Source And Sample Size

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In 93 out of 209 studies , original data were collected from human participants. In 108 studies , data used were from public repositories and databases, including University of California at Irvine Machine Learning Repository , Parkinson’s Progression Markers Initiative , PhysioNet , HandPD dataset , mPower database , and 6 other databases .

Table 2. Source of data of the included studies.

In 3 studies, data from public repositories were combined with data from local databases or participants . In the remaining studies, data were sourced from another study , collected at another institution , obtained from the authors’ institutional database , collected postmortem , or commercially sourced .

The 209 studies had an average sample size of 184.6 , with a smallest sample size of 10 , and a largest sample size of 2,289 . For studies that recruited human participants , data from an average of 118.0 participants were collected . For other studies , an average sample size of 238.1 was reported . For a description of average accuracy reported in these studies in relation to sample size, see Figure 2C.

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Global Analysis Of Caregiver Strain

Table 4 summarizes data from our evaluation of key recent international studies of PD caregiver strain. The results show world-wide data demonstrating that care-giver strain is challenging and common, with many shared features between south-east Asia and other regions of the globe, as seen in the world-wide literature .

Table 4. Summary data from key recent international PD studies of caregiver strain.

Restoration Of Dopaminergic Deficits

Treatment of many of the motor symptoms of PD can be achieved through restoration of striatal dopaminergic tone. This may be accomplished through targeted delivery of dopamine-producing cells, or the use of viruses to deliver genes encoding the enzymes required for dopamine biosynthesis into the striatum. Targeting these regenerative treatments to the striatum, the site of greatest dopamine loss in PD, would minimize the off-target effects seen with oral dopamine-replacement.

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Diagnosis And Treatment Of Parkinson Disease: Molecules To Medicine

1Institute for Cell Engineering, 2Department of Neurology, 3Department of Neuroscience, and 4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Ted M. Dawson, Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, BRB Suite 731, Baltimore, Maryland 21205, USA. Phone: 614-3359 Fax: 614-9568 E-mail: .

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1Institute for Cell Engineering, 2Department of Neurology, 3Department of Neuroscience, and 4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Ted M. Dawson, Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, BRB Suite 731, Baltimore, Maryland 21205, USA. Phone: 614-3359 Fax: 614-9568 E-mail: .

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1Institute for Cell Engineering, 2Department of Neurology, 3Department of Neuroscience, and 4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Ted M. Dawson, Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, BRB Suite 731, Baltimore, Maryland 21205, USA. Phone: 614-3359 Fax: 614-9568 E-mail: .

J Clin Invest.

Role Of The Vagus Nerve

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Several groups have now reported that the entire gastrointestinal tract might be affected in PD, often well before the motor symptoms occur, which is in line with the evidence of prodromal NMS. Shannon et al analysed biopsies from the colonic mucosa of untreated patients with PD and showed that all were positive for alpha-synuclein. They also reported on three cases with biopsies positive for alpha-synuclein and who, on follow-up, developed PD. As a consequence, it has been speculated that the GIT possibly acts as an entry for environmental factors that then further lead to PD, although others have disputed this finding. Another theory suggests that PD starts from the brainstem as originally suggested by seminal work from Braak and colleagues. Ulusoy et al were able to reproduce PD-like alpha-synuclein spreading, starting in the lower brainstem and moving towards more rostral regions in a rat brain. Furthermore, Holmquist et al showed that by injecting a toxic lysate of alpha-synuclein into the GIT, the vagus nerve is subsequently affected and the toxin actively spreads via the vagus nerve to the dorsal motor nucleus of the vagus nerve and further travels to the substania nigra. It is, therefore, not surprising to speculate that PD might, at least in part, be caused by an ingested pathogen working its way through the GIT, through the vagus nerve into the medulla.

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General Approach To Management

The primary goal in the management of PD is to treat the symptomatic motor and nonmotor features of the disorder, with the objective of improving the patients overall quality of life. Appropriate management requires an initial evaluation and diagnosis by a multidisciplinary team consisting of neurologists, primary care practitioners, nurses, physical therapists, social workers, and pharmacists., It is also important that the patient and his or her family have input into management decisions.

Effective management should include a combination of nonpharmacological and pharmacological strategies to maximize clinical outcomes. To date, therapies that slow the progression of PD or provide a neuroprotective effect have not been identified., Current research has focused on identifying biomarkers that may be useful in the diagnosis of early disease and on developing future disease-modifying interventions.,

Stability Of Tsallis Entorphy Estimates And Intra

From a subset of patients, slightly > 360s of EEG were available after pre-processing, corresponding to approximately double the epoch length of 180s used in this analysis. For three such patients, global TE of the -band was re-calculated a total of 100 times in a random re-sampling setting, where each randomly selected epoch had a length of exactly 180s. shows the results of the re-sampling procedure. Overall, the global TE estimates show very little variance over randomly selected epochs, which potentially makes global TE, estimated with the procedure proposed by , a robust measure of signal complexity of EEG.

Stability of Tsallis entropy estimates. For three study participants, EEG with more than twice the epoch length of 180s used in this analysis was available. From these recordings, 100 epochs, each with a length of 180s, were randomly sampled and the global TE of the -band was estimated. The results show a very low variance across TE of the different sample epochs, making global TE of the -band a robust feature with low intra-subject variability.

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Mitochondrial Dysfunction: A Pivotal Pathological Mechanism Of Parkinsons Disease

Mitochondria are complex cytosolic organelles of eukaryotic cells whose primary function is the generation of cellular energy in the form of ATP by oxidative phosphorylation. Mammalian mitochondria contain between 2 and 10 mitochondrial DNA molecules encoding 22 transfer RNAs, two ribosomal RNAs, and 13 polypeptides, each of which is part of the respiratory chain and the oxidative phosphorylation system . The mitochondrial respiratory chain contains four protein complexes that form the site of oxidative phosphorylation. This site is responsible for NADH and FADH2 oxidation, co-occurring with the movement of protons from the matrix into the intermembrane space. This movement produces an electrochemical gradient denoted as mitochondrial membrane potential . This gradient stimulates the ATP synthase to reduce molecular oxygen and synthesize ATP. This step is fundamental in aerobic metabolism and constitutes the primary provider of ATP at the final stage of cellular respiration . Nevertheless, the biological function of mitochondria goes far beyond energy production and includes the metabolism of lipids and amino acids and the support of intermediate metabolic pathways, such as the Krebs cycle.

Exercise Prescription Based On Evidence For Parkinsons Disease

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It is possible to assume that patients with Parkinson’s disease should benefit in the majority of cases with different strategies, which should be prescribed based on a careful clinical evaluation, functional capacity, mental health and cardiorespiratory function. With these data in hand, the physical education or physiotherapy professional will be able to choose the type of training, duration, intensity and other variables to be worked out in order to promote the benefits of exercise to the patients.

The American College of Sports Medicine has published recommendations for the prescription of exercises for parkinsonians . These recommendations are a good guide on what exercises to prescribe for this population and how to do it. One of the key information in this guide is that exercise recommendations for adult health fitness can be applied to parkinsonians, with caveats to the condition and physical limitations that the person presents. Adults with Parkinson’s disease may present improvements similar to those of healthy adults in the variables of physical fitness , with direct impact on improving functional capacity .

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Machine Learning Methods Applied To The Diagnosis Of Pd

We divided 448 machine learning models from the 209 studies into 8 categories: support vector machine and variants , neural networks , ensemble learning , nearest neighbor and variants , regression , decision tree , naïve Bayes , and discriminant analysis . A small percentage of models used did not fall into any of the categories .

On average, 2.14 machine learning models per study were applied to the diagnosis of PD. One study may have used more than one category of models. For a full description of data types used to train each type of machine learning models and the associated outcomes, see Supplementary Materials and Supplementary Figure 2.

Iii Oropharyngeal Swallowing Abnormalities

Some persons with PD also exhibit a delay in triggering the pharyngeal swallow., Although the delay is usually mild, any delay in triggering the pharyngeal swallow is associated with increased risk of aspiration. Once the pharyngeal swallow triggers, pharyngeal wall contraction and posterior tongue base retraction may be reduced, resulting in residue in the valleculae and pyriform sinuses after the swallow., Just as a delay in triggering the pharyngeal swallow is associated with increased risk of aspiration, pharyngeal residue also increases the likelihood of aspiration, as the residual material may fall into the open airway after the pharyngeal swallow is complete. Decreased laryngeal elevation coupled with poor tongue base and pharyngeal wall motion can result in cricopharyngeal dysfunction wherein material is unable to pass into the esophagus. Laryngeal closure also may be incomplete during the pharyngeal stage of the swallow, and cough which is crucial for clearing the airway of foreign material is frequently impaired in PD. Cognitive impairment, upper extremity impairment, and impulsive feeding behavior sometimes apparent in persons with more advanced PD also can exacerbate oropharyngeal dysphagia. Finally, while there is a great deal of variability in the nature and severity of dysphagia PD, it is important to reiterate that oral and pharyngeal stage impairments and even aspiration are frequently observed in patients who have no complaints of dysphagia.

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Pd Pathophysiology And Diagnosis

Currently, the molecular mechanisms underlying the pathophysiology of PD remain largely unknown. To date, -Syn accumulation, mitochondrial dysfunction, oxidative stress, and excitotoxicity are thought to play crucial roles in PD pathophysiology .

The accumulation of -Syn progresses predictably throughout the brain, typically known as the Braak stage. The lesions initially begin from the dorsal motor nucleus of the glossopharyngeal and vagal nerves and the anterior olfactory nucleus. They then ascend to the brain stem and finally to the neocortex . The reasons why -Syn, an intrinsically disordered protein, misfolds and deposits in the brain are still obscure. The currently accepted explanation is imbalance between its synthesis and clearance . SNCA gene duplication, triplication, or mutation aggravates the accumulation of misfolded -Syn . Moreover, the collapse of any pathways involved in -Syn clearance and degradation results in the accumulation of -Syn . For instance, disruption of the lysosomal degradation pathway promotes the formation of -Syn inclusions in cells .

Predictors Of The Change In The Pdq

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Finally, similar results were observed in both groups, the whole cohort and the early PD subgroup, when a linear regression model was considered . To be a female and change in UPDRS-III , FOGQ , and NMSS scores provided the highest contribution to the model in the whole cohort. In early PD patients, the variables associated with HRQoL change at the 2-year follow-up were the same . When the ADLS score was included in the model, the results were similar but with the ADLS as an independent variable associated with HRQoL change too .

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A Swallowing And Medication

As previously mentioned, levadopa treatment tends to have the most predictable effects on limb symptoms in PD. Nonetheless, certain aspects of eating and swallowing may be enhanced by medication. It therefore is recommended that patients time their meals and medication in such a way that they receive maximum medication effect during meals so as to facilitate upper extremity control and possibly oral and pharyngeal function. Similarly, some patients may show improvement in swallowing when medication is changed. Thus, in patients who have changed medication, the clinician may opt to wait several weeks to begin swallow therapy especially in the form of active range of motion exercises to determine whether the medication benefits the patients swallow. Some patients experience xerostomia as a side effect of pharmacologic treatment for PD. Depending on the existence of other swallowing and eating difficulties, taking frequent sips of water, throat lozenges or lemon drops, as well as synthetic saliva may prove helpful.

Changes In Assessments From V0 To V2

After the 2-year follow-up, GQoL did not change significantly in PD patients or in the control group . The mean PDQ-39SI was significantly increased in PD patients by 21.6% at V2 . By domains, the score of all domains of the PDQ-39SI at V2 was significantly higher than at V0 except for domain 4 . The change in the score of other scales from V0 to V2 in PD patients and controls is shown in Table .

Fig. 1: Change in PDQ-39SI, PQ-10, and EUROHIS-QOL8 scores from V0 to V2 in PD patients and/or controls.

Data are presented as box plots, with the box representing the median and the two middle quartiles . p-values were computed using the Wilcoxon-signed rank test. Mild outliers are data points that are more extreme than Q1 1.5 * IQR or Q3 + 1.5 * IQR. EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8-Item Index PDQ-39SI, 39-item Parkinsons Disease Quality of Life Questionnaire Summary Index.

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