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Old 18-08-2016, 08:59 AM   #1
Jo Bowyer
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Default Premotor Symptoms as Predictors of Outcome in Parkinsons Disease: A Case-Control Study

http://journals.plos.org/plosone/art...l.pone.0161271

Abstract

Quote:
Background

To evaluate the association between the premotor symptoms and the prognosis of PD.

Methods

A total of 1213 patients who were diagnosed of PD from January 2001 to December 2008 were selected from the Taiwan’s National Health Insurance Research Database. Patients were traced back to determine the presence of premotor symptoms, including rapid eye movement sleep behavior disorder (RBD), depression, and constipation. Cox’s regression analysis was used to detect the risks between the occurrence of premotor symptoms and the outcome (including death, psychosis, accidental injury, dementia and aspiration pneumonia). In addition, the association between premotor symptoms and levodopa equivalent dosage (LED) was examined.

Results

Higher occurrence of death, dementia and aspiration pneumonia were identified in PD patients with premotor symptoms than without premotor symptoms (HR 1·69, 95% CI 1·34–2·14, p <0·001 for death; HR 1·63, 95% CI 1·20–2·22, p = 0·002 for dementia; HR 2·45, 95% CI 1·42–4·21, p = 0·001 for aspiration pneumonia). In a comorbidities-stratified analysis, PD patients with premotor symptoms showed significantly high risks of mortality and morbidity (dementia and aspiration pneumonia), especially in the absence of comorbidities. Independent predictors of mortality in PD were found to be higher age, male sex, constipation, RBD, RBD with constipation and depression, and diabetes. Furthermore, no significant differences of LED and subsequent accidental injury were noted between PD patient with or without premotor symptoms.

Conclusion

Premotor symptoms seem to be not merely risk factors, but also prognostic factors of PD.


Looking beyond the brain in Parkinson’s disease: is the answer skin deep?
http://blogs.biomedcentral.com/bmcse...ource=Teradata

Quote:
Parkinson’s disease pathology is not limited to the brain, but disrupts the function of multiple organ systems. An article recently published in BMC Neurology provides new insights into the pathological changes that occur in the skin during Parkinson’s disease, and may shed light on potential targets for a diagnostic biomarker
Update 05/04/2017



The underlying mechanism of prodromal PD: insights from the parasympathetic nervous system and the olfactory system

https://translationalneurodegenerati...ource=Teradata

Abstract

Quote:
Neurodegeneration of Parkinson’s disease (PD) starts in an insidious manner, 30–50% of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis. Prodromal stage of the disease, during which the disease pathology has started but is insufficient to result in clinical manifestations, offers a valuable window for disease-modifying therapies. The most focused underlying mechanisms linking the pathological pattern and clinical characteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons. In this review, we consider the two potential portals, the vagus nerve and the olfactory bulb, through which abnormal alpha-synuclein can access the brain. We review the clinical, pathological and neuroimaging evidence of the parasympathetic nervous system and the olfactory system in the neurodegenerative process and using the two systems as models to discuss the internal homogeneity and heterogeneity of the prodromal stage of PD, including both the clustering and subtyping of symptoms and signs. Finally, we offer some suggestions on future directions for imaging studies in prodromal Parkinson’s disease.
Quote:
According to recent Movement Disorder Society criteria, early PD can be divided into three stages: preclinical PD (neurodegeneration has started yet without evident symptoms and signs); prodromal PD (symptoms and signs are present, but are still insufficient to define PD) and clinical PD (diagnosis of PD based on classical symptoms). The criteria are based upon probability and likelihood since it is not possible to identify prodromal PD with 100% certainty; probable prodromal PD is defined as a high likelihood (greater than 80%) and possible prodromal PD as a likelihood between 30 and 80% [4, 5]. The cardinal features of prodromal PD are non-motor and include constipation, hyposmia/anosmia, depression, REM sleep behavior disorder, orthostatic hypotension, and loss of heart rate variability [6]. Notably, many of the symptoms that emerge earlier in the disease course can be attributed to dysfunction in the peripheral nervous system or the peripheral part of the central nervous system, such as the vagus nerve (e.g. constipation), the sympathetic nervous system (e.g. orthostatic hypotension), or the olfactory bulb (hyposmia).
Update 13/04/2017



Probing Possible Reasons For Smell Loss


http://neurosciencenews.com/alzheimers-olfaction-6637/

Quote:
Studies have shown that loss of the sense of smell can be among the first warning signs of diseases such as Alzheimer’s and Parkinson’s. Now a researcher at the Perelman School of Medicine at the University of Pennsylvania wants to shift the search for clues about this process back even further, to find out if there is a common factor responsible for the loss of smell that may also serve as an early warning signal for a number of neurodegenerative diseases. In a review published online in Lancet Neurology, Richard L. Doty, PhD, a professor of Otorhinolaryngology and director of the Smell and Taste Center, cites evidence that the common link could be damage to neurotransmitter and neuromodulator receptors in the forebrain – the front part of the brain.

“We need to retrace the steps of the development of these diseases,” Doty said. “We know loss of smell is an early sign of their onset, so finding common factors associated with the smell loss could provide clues as to the pre-existing processes that initiate the first stages of a number of neurodegenerative diseases. An understanding of such processes could provide novel approaches to their treatment, including ways to slow down or stop their development before irreversible damage has occurred.”

Currently, it’s is generally believed that the smell loss of various neurodegenerative diseases is caused by disease-specific pathology. In other words, different diseases can bring about the same loss of smell for different reasons. Doty’s review – the first of its kind – looked at many neurodegenerative diseases with varying degrees of smell loss and sought to find a common link that may explain such losses. He considered physiological factors as well as environmental factors like air pollution, viruses, and exposure to pesticides.

“Ultimately, as each possibility was evaluated, there were cases where these factors didn’t show up, which ruled them out as potential universal biomarkers.”

Doty did find compelling evidence for a neurological solution: Damage to the neurotransmitter and neuromodulator receptors in the forebrain – most notably, a system employing the neurochemical acetylcholine. Neurotransmitters are the chemicals that send signals throughout the brain. Neuromodulators influence the activity of neurons in the brain. The receptors receive the signals, and if they are damaged, it hurts the brain’s ability to process smells normally.

“The good news is we can assess damage to some of the systems by evaluating their function in living humans using radioactive neurochemicals and brain imaging processes such as positron emission tomography (PET),” Doty said. “Unfortunately, few data are currently available, and the historical data of damage to neurotransmitter/neuromodulator systems, including cell counts from autopsy studies, are limited to just a few diseases. Moreover, quantitative data on a patient’s olfactory status is rarely available, especially prior to disease diagnosis.”

Doty said the lack of early data is a problem across the board in the search for factors that may explain smell loss.
Update 10/05/2017


Ocular Tremor in Parkinson’s Disease: Discussion, Debate, and Controversy

http://journal.frontiersin.org/artic...017.00134/full

Quote:
The identification of ocular tremor in a small cohort of patients with Parkinson’s disease (PD) had lay somewhat dormant until the recent report of a pervasive ocular tremor as a universal finding in a large PD cohort that was, however, generally absent from a cohort of age-matched healthy subjects. The reported tremor had frequency characteristics similar to those of PD limb tremor, but the amplitude and frequency of the tremor did not correlate with clinical tremor ratings. Much controversy ensued as to the origin of such a tremor, and specifically as to whether a pervasive ocular tremor was a fundamental feature of PD, or rather a compensatory eye oscillation secondary to a transmitted head tremor, and thus a measure of a normal vestibulo-ocular reflex. In this mini review, we summarize some of the evidence for and against the case for a pervasive ocular tremor in PD and suggest future experiments that may help resolve these conflicting opinions.



Visual System Changes That May Signal Parkinson’s Disease

http://neurosciencenews.com/parkinso...-changes-7061/

Quote:
Changes in the visual systems of newly diagnosed Parkinson’s disease patients may provide important biomarkers for the early detection and monitoring of the disease, according to a new study published online in the journal Radiology.

“Just as the eye is a window into the body, the visual system is a window into brain disorders,” said lead researcher Alessandro Arrigo, M.D., a resident in ophthalmology at the University Vita-Salute San Raffaele of Milan, Italy.

Parkinson’s disease is a neurodegenerative condition caused by neuronal loss in several brain structures. Parkinson’s disease is characterized by tremors, rigidity or stiffness throughout the body, and impaired balance and coordination.

“Although Parkinson’s disease is primarily considered a motor disorder, several studies have shown non-motor symptoms are common across all stages of the disease,” Dr. Arrigo said. “However, these symptoms are often undiagnosed because patients are unaware of the link to the disease and, as a result, they may be under-treated.”

Non-motor symptoms experienced by patients with Parkinson’s disease include visual alterations such as an inability to perceive colors, a change in visual acuity, and a decrease in blinking which can lead to dry eye.

“These non-motor Parkinson’s symptoms may precede the appearance of motor signs by more than a decade,” Dr. Arrigo said.
Update 12/07/2017




Cortical and Striatal Reward Processing in Parkinson’s Disease Psychosis

http://journal.frontiersin.org/artic...017.00156/full

Quote:
Psychotic symptoms frequently occur in Parkinson’s disease (PD), but their pathophysiology is poorly understood. According to the National Institute of Health RDoc programme, the pathophysiological basis of neuropsychiatric symptoms may be better understood in terms of dysfunction of underlying domains of neurocognition in a trans-diagnostic fashion. Abnormal cortico-striatal reward processing has been proposed as a key domain contributing to the pathogenesis of psychotic symptoms in schizophrenia. This theory has received empirical support in the study of schizophrenia spectrum disorders and preclinical models of psychosis, but has not been tested in the psychosis associated with PD. We, therefore, investigated brain responses associated with reward expectation and prediction error signaling during reinforcement learning in PD-associated psychosis. An instrumental learning task with monetary gains and losses was conducted during an fMRI study in PD patients with (n = 12), or without (n = 17), a history of psychotic symptoms, along with a sample of healthy controls (n = 24). We conducted region of interest analyses in the ventral striatum (VS), ventromedial prefrontal and posterior cingulate cortices, and whole-brain analyses. There was reduced activation in PD patients with a history of psychosis, compared to those without, in the posterior cingulate cortex and the VS during reward anticipation (p < 0.05 small volume corrected). The results suggest that cortical and striatal abnormalities in reward processing, a putative pathophysiological mechanism of psychosis in schizophrenia, may also contribute to the pathogenesis of psychotic symptoms in PD. The finding of posterior cingulate dysfunction is in keeping with prior results highlighting cortical dysfunction in the pathogenesis of PD psychosis.
Update 24/04/2017



Associations between cognitive impairment and motor dysfunction in Parkinson's disease

http://onlinelibrary.wiley.com/doi/1.../brb3.719/full

Abstract

Quote:
Introduction

Numerous studies have been carried out to explore the potential association between neurologic deficits and variable clinical manifestations of Parkinson's disease (PD). The aim of our study was to investigate the association between cognitive performance and motor dysfunction in Chinese patients with PD.
Methods

Data from 96 patients with PD were obtained from the Parkinson's disease patient cohort database of Huashan Hospital. All participants underwent a comprehensive neuropsychological evaluation to assess cognitive status, that included scoring on the Mini-mental state examination (MMSE), followed by more detailed cognitive assessment on five main cognitive domains (verbal memory, nonverbal memory, visuospatial function, language and attention/executive function). Correlations between cognitive and motor scores were investigated after controlling for age, disease duration, education, and gender.
Results

We report a significant correlation between subdomains of cognitive impairment and motor dysfunction using analyses of the multiple linear regression. Notably, executive function and attention was significantly associated with bradykinesia and rigidity, while visuospatial function was associated with bradykinesia and tremor.
Conclusions

The association between motor dysfunction and cognitive decline in PD might highlight deficits represented by a shared neurochemical pathway.
Update 16/05/2017




No relevant association of kinematic gait parameters with Health-related Quality of Life in Parkinson’s disease

http://journals.plos.org/plosone/art...l.pone.0176816

Abstract

Quote:
Background

Health-related Quality of Life (HrQoL) is probably the most important outcome parameter for the evaluation and management of chronic diseases. As this parameter is subjective and prone to bias, there is an urgent need to identify objective surrogate markers. Gait velocity has been shown to be associated with HrQoL in numerous chronic diseases, such as Parkinson’s disease (PD). With the development and wide availability of simple-to-use wearable sensors and sophisticated gait algorithms, kinematic gait parameters may soon be implemented in clinical routine management. However, the association of such kinematic gait parameters with HrQoL in PD has not been assessed to date.

Methods

Kinematic gait parameters from a 20-meter walk from 43 PD patients were extracted using a validated wearable sensor system. They were compared with the Visual Analogue Scale of the Euro-Qol-5D (EQ-5D VAS) by performing a multiple regression analysis, with the International Classification of Functioning, Disability and Health (ICF) model as a framework.

Results

Use of assistive gait equipment, but no kinematic gait parameter, was significantly associated with HrQoL.

Conclusion

The widely accepted concept of a positive association between gait velocity and HrQoL may, at least in PD, be driven by relatively independent parameters, such as assistive gait equipment.
Update 26/05/2017




Pain in Parkinson’s Disease

https://noijam.com/2017/06/23/pain-i...nsons-disease/

Update 24/06/2017




Forward flexion of trunk in Parkinson's disease patients is affected by subjective vertical position

https://www.somasimple.com/forums/sh...ad.php?t=23891

Abstract

Quote:
Purpose

No method has been established to evaluate the dissociation between subjective and objective vertical positions with respect to the self-awareness of postural deformity in patients with Parkinson’s disease (PD). The purpose of this study was to demonstrate, from the relationship between an assessment of the dissociation of subjective and objective vertical positions of PD patients and an assessment based on established PD clinical evaluation scales, that the dissociation regarding vertical position is a factor in the severity of the forward flexion of trunk (FFT).

Methods

Subjects were 39 PD patients and 15 age-matched healthy individuals (control group). Posture was evaluated with measurement of FFT angle during static standing and the subjective vertical position (SV) of the patient. For evaluation of motor function, the Modified Hoehn & Yahr scale, Unified Parkinson’s Disease Rating Scale (UPDRS), 3-m Timed Up and Go Test (TUG), and Functional Reach Test (FRT) were used.

Results

In PD patients, FFT angle in the 3rd tertile of patients was 13.8±9.7°, significantly greater than those in the control group and the 1st and 2nd tertiles of PD patients (control group vs 3rd tertile, p = 0.008; 1st tertile vs 3rd tertile, p<0.001; 2nd vs 3rd tertile, p = 0.008). In multiple regression analysis for factors in the FFT angle, significant factors were SV, disease duration, and the standard deviation of each SV angle measurement.

Conclusion

The dissociation between SV and objective vertical position affects the FFT of PD patients, suggesting an involvement of non-basal ganglia pathologies.
Update 11/07/2017
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Old 18-10-2016, 04:31 AM   #2
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Default Molecular changes in the postmortem parkinsonian brain

http://onlinelibrary.wiley.com/doi/1...jnc.13696/full

Abstract

Quote:
Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by ‘reverse biochemistry’ i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD.

Parkinson's is accompanied by multiple changes in the brain that are responsible for the progression of the disease. We describe here the molecular alterations occurring in postmortem brains and classify them as: Neurotransmitters and neurotrophic factors; Lewy bodies and Parkinson's-linked genes; Transition metals, calcium and calcium-binding proteins; Inflammation; Mitochondrial abnormalities and oxidative stress; Abnormal protein removal and degradation; Apoptosis and transduction pathways.
Yesterday, I did a home visit for a patient with PD who I first met as a child. It ranks high amongst the saddest moments of my career thus far.
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Old 18-10-2016, 09:41 PM   #3
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Mitochondrial dysfunction in Parkinson's disease.
Bose A, Beal MF.
J Neurochem. 2016 Oct;139 Suppl 1:216-231. doi: 10.1111/jnc.13731. Epub 2016 Aug 21.
Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD. Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD.

This article is part of a special issue on Parkinson disease.

© 2016 International Society for Neurochemistry.
Full article:
http://onlinelibrary.wiley.com/doi/1...jnc.13731/full
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Old 18-10-2016, 10:50 PM   #4
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If your interested all 23 articles in the special issue are to be found here:

http://onlinelibrary.wiley.com/doi/1...ue-S1/issuetoc

Quote:
Journal of Neurochemistry - Special Issue: Parkinson Disease. Guest Editors: Jörg B. Schulz and John Hardy
October 2016

Volume 139, Issue Supplement S1

Pages 1–352
Just recently the effect of placebo was in (our local) news, in some patients with moderate symptoms a well delivered placebo (in this case it was a trial setting) can have
quite impressive effects on motor improvement. I had to think of a Sapolsky lecture on dopamine and behaviour/reward - however that is most likely a different dopaminergic pathway.

https://www.youtube.com/watch?v=ZIRZu1dRp8Q
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Old 19-10-2016, 01:42 AM   #5
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Thanks Marcel,

I did a lot of work with this group in the late '70s, early '80s when the pharmacological management was fairly hit and miss, so am looking forward to working with my current patient who is getting some of her meds via transdermal patch. I was told by the receptionist that a home visit was wanted because someone had been on the floor all day with acute onset low back pain. There appears to have been minimal physio input with regards to the PD.
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Old 19-10-2016, 03:36 PM   #6
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Hi Jo,

This was the trial I mentioned:

Quote:
Effects of expectation on placebo-induced dopamine release in Parkinson disease.
Lidstone SC1, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, de la Fuente-Fernández R, Phillips AG, Stoessl AJ.

Abstract

CONTEXT:
Expectations play a central role in the mechanism of the placebo effect. In Parkinson disease (PD), the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections, yet the factors that control this dopamine release are undetermined.

OBJECTIVE:
To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD.

DESIGN:
Randomized, repeated-measures study with perceived expectation as the independent between-subjects variable.

SETTING:
University of British Columbia Hospital, Vancouver, British Columbia, Canada. Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment. Intervention Verbal manipulation was used to modulate the expectations of patients, who were told that they had a particular probability (25%, 50%, 75%, or 100%) of receiving active medication when they in fact received placebo.

MAIN OUTCOME MEASURES:
The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography. The clinical response was also measured (Unified Parkinson Disease Rating Scale) and subjective responses were ascertained using patient self-report.

RESULTS:
Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at other probabilities. Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum.

CONCLUSIONS:
The strength of belief of improvement can directly modulate dopamine release in patients with PD. Our findings demonstrate the importance of uncertainty and/or salience over and above a patient's prior treatment response in regulating the placebo effect and have important implications for the interpretation and design of clinical trials.
https://www.ncbi.nlm.nih.gov/pubmed/20679593

In 2001 I had a patient with PD who mentioned a pretty particular thing: he was walking back home when he "froze" the only thing he could do that worked was walking backwards, a police car stopped because they thought he was drunk, they gave him a ride home though.
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Old 19-10-2016, 08:15 PM   #7
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he was walking back home when he "froze" the only thing he could do that worked was walking backwards,
Good thinking! I like patients who work out strategies for themselves.



Focused and Sustained Attention Is Modified by a Goal-Based Rehabilitation in Parkinsonian Patients

http://journal.frontiersin.org/artic...017.00056/full

Quote:
Rehabilitation for patients with Parkinson’s disease (PD) is based on cognitive strategies that exploit attention. Parkinsonians exhibit impairments in divided attention and interference control. Nevertheless, the effectiveness of specific rehabilitation treatments based on attention suggests that other attentional functions are preserved. Data about attention are conflicting in PD, and it is not clear whether rehabilitative treatments that entail attentional strategies affect attention itself. Reaction times (RTs) represent an instrument to explore attention and investigate whether changes in attentional performances parallel rehabilitation induced-gains. RTs of 103 parkinsonian patients in “on” state, without cognitive deficits, were compared with those of a population of 34 healthy controls. We studied those attentional networks that subtend the use of cognitive strategies in motor rehabilitation: alertness and focused and sustained attention, which is a component of the executive system. We used visual and auditory RTs to evaluate alertness and multiple choices RTs (MC RTs) to explore focused and sustained attention. Parkinsonian patients underwent these tasks before and after a 4-week multidisciplinary, intensive and goal-based rehabilitation treatment (MIRT). Unified Parkinson’s Disease Rating Scale (UPDRS) III and Timed Up and Go test (TUG) were assessed at the enrollment and at the end of MIRT to evaluate the motor-functional effectiveness of treatment. We did not find differences in RTs between parkinsonian patients and controls. Further, we found that improvements in motor-functional outcome measures after MIRT (p < 0.0001) paralleled a reduction in MC RTs (p = 0.014). No changes were found for visual and auditory RTs. Correlation analysis revealed no association between changes in MC RTs and improvements in UPDRS-III and TUG. These findings indicate that alertness, as well as focused and sustained attention, are preserved in “on” state. This explains why Parkinsonians benefit from a goal-based rehabilitation that entails the use of attention. The reduction in MC RTs suggests a positive effect of MIRT on the executive component of attention and indicates that this type of rehabilitation provides benefits by exploiting executive functions. This ensues from different training approaches aimed at bypassing the dysfunctional basal ganglia circuit, allowing the voluntary execution of the defective movements. These data suggest that the effectiveness of a motor rehabilitation tailored for PD lies on cognitive engagement.
Introduction
Quote:
In Parkinson’s disease (PD) the loss of the physiological dopaminergic modulation transforms the basal ganglia into a disruptive filter (Beeler et al., 2013) that impairs the ability to express habitual-automatic actions (Redgrave et al., 2010). Rehabilitation has been proposed as an effective and complementary approach for the treatment of PD (Goodwin et al., 2008; Keus et al., 2009; Frazzitta et al., 2010, 2012, 2015b). The great value of rehabilitation lies in the possibility of treating those disabling PD disturbances, such as balance dysfunctions, postural instability and freezing of gait, that do not respond to the standard medical or surgical treatments.

Even if implicit learning is defective in parkinsonian subjects, motor learning is feasible in PD (Nieuwboer et al., 2009). In this regard, it has been demonstrated that specific rehabilitation techniques provide benefits by using explicit cognitive strategies (Nieuwboer et al., 2009). These are bottom-up strategies, which use external cues, and/or top-down strategies, which exploit feedbacks or verbal instructions. The application of these explicit cognitive strategies requires the use of attention (Morris et al., 2010) and activates the goal-directed control system, bypassing the dysfunctional habitual, sensorimotor basal ganglia circuit (Morris, 2006; Morris et al., 2009; Redgrave et al., 2010).
I am passionate about preserving and where possible improving function, particularly in my young patients.

In Parkinson’s disease (PD) the loss of the physiological dopaminergic modulation transforms the basal ganglia into a disruptive filter (Beeler et al., 2013) that impairs the ability to express habitual-automatic actions (Redgrave et al., 2010).

my italics

Just look at what these guys are up against in terms of physiology though!! Some of the younger patients tell me in no uncertain terms that I can have no idea of what they are up against and I can't. All I can do is read the research and take lessons from patients of all ages who have passed through my hands and where indicated, pass the useful strategies on.

Update 15/04/2017
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Old 31-10-2016, 04:55 PM   #8
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Default Parkinson's disease: 4 big questions

http://www.nature.com/nature/journal...AyNTAxMzYxMQS2

Quote:
The characteristic brain pathology and motor symptoms of Parkinson's disease are well established. But the details of the disease's cause and course are much murkier.


Parkinson Disease: An Evolutionary Perspective

http://journal.frontiersin.org/artic...017.00157/full

Quote:
There are two central premises to this evolutionary view of Parkinson disease (PD). First, PD is a specific human disease. Second, the prevalence of PD has increased over the course of human history. Several lines of evidence may explain why PD appears to be restricted to the human species. The major manifestations of PD are the consequence of degeneration in the dopamine-synthesizing neurons of the mesostriatal neuronal pathway. It is of note the enormous expansion of the human dopamine mesencephalic neurons onto the striatum compared with other mammals. Hence, an evolutionary bottle neck was reached with the expansion of the massive nigrostriatal axonal arborization. This peculiar nigral overload may partly explain the selective fragility of the human dopaminergic mesencephalic neurotransmission and the unique presence of PD in humans. On the other hand, several facts may explain the increasing prevalence of PD over the centuries. The apparently low prevalence of PD before the twentieth century may be related to the shorter life expectancy and survival compared to present times. In addition, changes in lifestyle over the course of human history might also account for the increasing burden of PD. Our hunter-gatherers ancestors invested large energy expenditure on a daily basis, a prototypical physical way of life for which our genome remains adapted. Technological advances have led to a dramatic reduction of physical exercise. Since the brain release of neurotrophic factors (including brain-derived neurotrophic factor) is partially exercise related, the marked reduction in exercise may contribute to the increasing prevalence of PD.

Parkinson disease (PD), the second most prevalent neuropsychiatric neurodegenerative disorder (1–5), increases exponentially with aging (3, 4). While PD likely represents a syndrome of several molecular subtypes, with a small proportion arising from well-defined genetic abnormalities (1, 5), the data accumulated suggest two common denominators: alpha synuclein accumulation into cytoplasmic Lewy bodies and dopamine deficiency as the casualty of neuronal loss in the nigrostriatal neurons (1, 5). The convergence of diverse biological processes, including genetic, environment, and behavioral factors in the development of PD suggests that evolutionary processes may explain in part the vulnerability to this form of neurodegeneration (6). From a phylogenetic standpoint, PD is prevalent among human primates at the top of the evolutionary chain but evidence for its presence in other species is lacking.

There are two central premises to the evolutionary view of PD. First, PD is a specific human disease. Despite the importance of animal models to the understanding of potential pathogenic mechanism in PD (5), there is no naturally occurring parkinsonism in non-human species: PD is a specific human disease. Second, the prevalence of PD has increased over the course of human history (7), and probably even over the last century (8). Several converging evolutionary theories can explain these observations.
One of my patients kept his disease stable for years by walking 15 miles a day, when he became too old to do so, he relapsed within months.

Quote:
Finally, other evolutionary concepts may partially explain the increasing presence of PD in our society, including the following:

1. The apparently low prevalence of PD before the twentieth century may be related to a shorter life expectancy and survival (4, 8, 31, 34).

2. Changes in lifestyle over the course of human history might also account for the increasing burden of PD. Our hunter-gatherers ancestors invested large energy expenditure on a daily basis, a prototypical physical way of life for which our genome remains adapted (35, 36).

3. Technological advances have led to a dramatic reduction of physical exercise for daily routines (35, 36).

4. Since the brain release of neurotrophic factors is partially exercise-related (44, 45), the reduction in exercise at a societal level may contribute to the increasing prevalence of PD and other neurodegenerative disorders in our era of digital revolution.
Update 03/05/2015
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Old 31-10-2016, 11:51 PM   #9
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Interaction between subclinical doses of the Parkinson's disease associated gene, α-synuclein, and the pesticide, rotenone, precipitates motor dysfunction and nigrostriatal neurodegeneration in rats.
Naughton C. et al

Abstract

In most patients, Parkinson's disease is thought to emerge after a lifetime of exposure to, and interaction between, various genetic and environmental risk factors. One of the key genetic factors linked to this condition is α-synuclein, and the α-synuclein protein is pathologically associated with idiopathic cases. However, α-synuclein pathology is also present in presymptomatic, clinically "normal" individuals suggesting that environmental factors, such as Parkinson's disease-linked agricultural pesticides, may be required to precipitate Parkinson's disease in these individuals. In this context, the aim of this study was to assess the behavioural and neuropathological impact of exposing rats with a subclinical load of α-synuclein to subclinical doses of the organic pesticide, rotenone. Rats were randomly assigned to two groups for intra-nigral infusion of AAV2/5-GFP or AAV2/5-α-synuclein. Post viral motor function was assessed at 8, 10 and 12 weeks in the Corridor, Stepping and Whisker tests of lateralised motor function. At week 12, animals were performance-matched to receive a subsequent intra-striatal challenge of the organic pesticide rotenone (or its vehicle) to yield four final groups (Control, Rotenone, AAV2/5-α-synuclein and Combined). Behavioural testing resumed one week after rotenone surgery and continued for 5 weeks. We found that, when administered alone, neither intra-nigral AAV-α-synuclein nor intra-striatal rotenone caused sufficient nigrostriatal neurodegeneration to induce a significant motor impairment in their own right. However, when these were administered sequentially to the same rats, the interaction between the two Parkinsonian challenges significantly exacerbated nigrostriatal neurodegeneration which precipitated a pronounced impairment in motor function. These results indicate that exposing rats with a subclinical α-synuclein-induced pathology to the pesticide, rotenone, profoundly exacerbates their Parkinsonian neuropathology and dysfunction, and highlights the potential importance of this interaction in the etiology of, and in driving the pathogenesis of Parkinson's disease.
https://www.ncbi.nlm.nih.gov/pubmed/27585560

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Combination of acamprosate and baclofen as a promising therapeutic approach for Parkinson's disease.

Hajj R et al

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic nigrostriatal neurons but which involves the loss of additional neurotransmitter pathways. Mono- or polytherapeutic interventions in PD patients have declining efficacy long-term and no influence on disease progression. The systematic analysis of available genetic and functional data as well as the substantial overlap between Alzheimer's disease (AD) and PD features led us to repurpose and explore the effectiveness of a combination therapy (ABC) with two drugs - acamprosate and baclofen - that was already effective in AD animal models, for the treatment of PD. We showed in vitro that ABC strongly and synergistically protected neuronal cells from oxidative stress in the oxygen and glucose deprivation model, as well as dopaminergic neurons from cell death in the 6-hydroxydopamine (6-OHDA) rat model. Furthermore, we showed that ABC normalised altered motor symptoms in vivo in 6-OHDA-treated rats, acting by protecting dopaminergic cell bodies and their striatal terminals. Interestingly, ABC also restored a normal behaviour pattern in lesioned rats suggesting a symptomatic effect, and did not negatively interact with L-dopa. Our results demonstrate the potential value of combining repurposed drugs as a promising new strategy to treat this debilitating disease.
https://www.ncbi.nlm.nih.gov/pubmed/26542636

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Parkinson's Disease and Pesticides Exposure: New Findings From a Comprehensive Study in Nebraska, USA.
Wan N1, Lin G2.

Abstract


The association between exposure to agricultural pesticides and Parkinson's Disease (PD) has long been a topic of study in the field of environmental health. This research takes advantage of the unique Nebraska PD registry and state-level crop classification data to investigate the PD-pesticides exposure relationship.
METHODS:

First, Geographic Information System and satellite remote sensing data were adopted to calculate exposure to different pesticides for Nebraska residents. An integrated spatial exploratory framework was then adopted to explore the association between PD incidence and exposure to specific pesticide ingredients at the county level.
RESULTS:

Our results reveal similarities in geographic patterns of pesticide exposure and PD incidence. The regression analyses indicate that, for most Nebraska counties, PD incidence was significantly associated with exposure to certain pesticide ingredients such as alachlor and broxomy. However, the results also suggest that factors other than pesticide exposure may help further explain the risk of PD at the county level.
CONCLUSIONS:

We found significant associations between PD incidence and exposure to different pesticide ingredients. These results have useful implications for PD prevention in Nebraska and other agricultural states in the United States.
https://www.ncbi.nlm.nih.gov/pubmed/26515233
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Old 01-11-2016, 12:34 AM   #10
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The Role of Innate and Adaptive Immunity in Parkinson's Disease
George T. Kannarkat et al
J Parkinsons Dis. 2013; 3(4): 493–514.
doi: 10.3233/JPD-130250

Abstract

In recent years, inflammation has become implicated as a major pathogenic factor in the onset and progression of Parkinson's disease. Understanding the precise role for inflammation in PD will likely lead to understanding of how sporadic disease arises. In vivo evidence for inflammation in PD includes microglial activation, increased expression of inflammatory genes in the periphery and in the central nervous system (CNS), infiltration of peripheral immune cells into the CNS, and altered composition and phenotype of peripheral immune cells. These findings are recapitulated in various animal models of PD and are reviewed herein. Furthermore, we examine the potential relevance of PD-linked genetic mutations to altered immune function and the extent to which environmental exposures that recapitulate these phenotypes, which may lead to sporadic PD through similar mechanisms. Given the implications of immune system involvement on disease progression, we conclude by reviewing the evidence supporting the potential efficacy of immunomodulatory therapies in PD prevention or treatment. There is a clear need for additional research to clarify the role of immunity and inflammation in this chronic, neurodegenerative disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102262/
Keywords: Immune System, Parkinson's Disease, lymphocytes, inflammation, immunomodulation, adaptive immunity
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Old 03-12-2016, 10:55 PM   #11
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Default Standing Up May Unmask Cognitive Deficits in Patients With Parkinson’s

http://neurosciencenews.com/parkinso...pressure-5670/

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“Cognitive impairment is a common symptom of Parkinson’s disease,” said co-senior author Roy Freeman, MD, director of the Center for Autonomic and Peripheral Nerve Disorders at BIDMC and a professor of neurology at Harvard Medical School (HMS). “In this study, we demonstrated that the upright posture in patients with Parkinson’s disease exacerbated cognitive deficits, and that this effect is transient and reversible. Based on these results, we encourage clinicians to include cognitive testing in a variety of postures in their assessments of patients.”

Marked by characteristic tremor, rigidity and slowness of movement, Parkinson’s disease (PD) is a progressive degeneration of parts of the nervous system. It affects many aspects of movement and can cause a masklike, expressionless face, rigid limbs, and problems with walking and posture. PD is also associated with cognitive defects attributed to breakdowns in connectivity between regions of the brain. Up to 50 percent of people with Parkinson’s disease may also have orthostatic hypotension.

In a previous study, Freeman and colleagues demonstrated that orthostatic hypotension is linked to reversible cognitive impairment in patients with a rare neurological disorder called autoimmune autonomic ganglionopathy. In this new study of the far more prevalent Parkinson’s disease, the researchers investigated whether OH is linked to reversible cognitive deficits in patients with PD as well.

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Old 13-12-2016, 10:19 PM   #12
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Default Triggering neurodegeneration from the gut

http://stke.sciencemag.org/content/9...et_cid=1051985

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In Parkinson’s disease, aggregation of α-synuclein triggers the death of dopaminergic neurons, resulting in the development of motor deficits. Aggregates of α-synuclein are also found in enteric nerves, and the onset of gastrointestinal symptoms, such as constipation, often precedes that of motor deficits in Parkinson’s disease patients. Noting that Parkinson’s disease patients have dysbiosis, or altered microbiome composition, and that gut microbiota can alter signaling and function in both the gastrointestinal system and the brain, Sampson et al. investigated the link between gut microbiota and Parkinson’s disease, using mice that overexpress α-synuclein (ASO mice) and are a model for Parkinson’s disease. Compared with ASO mice with a complex microbiota, germ-free ASO mice had reduced motor deficits and normal fecal output (implying normal gastrointestinal function). Furthermore, germ-free ASO mice had reduced α-synuclein aggregation and microglia with morphology suggestive of reduced activation in the brain regions affected in Parkinson’s disease and decreased inflammatory cytokine concentrations in some brain regions. Postnatal colonization of germ-free ASO mice with a complex microbiota resulted in increased motor deficits, reduced fecal output, and increased microglial activation. In contrast, postnatal depletion of microbiota with antibiotic treatment partially or fully reversed motor deficits, gastrointestinal dysfunction, and microglial activation in ASO mice with a complex microbiota. Short-chain fatty acids released by gut bacteria during viral infection can activate microglia, and concentrations of short-chain fatty acids were lower in germ-free ASO mice than in ASO mice with a complex microbiota. Administration of short-chain fatty acids to germ-free ASO mice led to increased microglial activation and α-synuclein aggregation and to impairment of motor function. Mice that received fecal microbiota from Parkinson’s disease patients developed greater motor dysfunction than those that received microbiota from healthy controls. These results suggest that metabolites produced by the gut microbiota contribute to the microglial activation, α-synuclein aggregation, and motor deficits characteristic of Parkinson’s disease.


Could Parkinson’s Disease Start in the Gut?

http://neurosciencenews.com/parkinsons-vagotomy-6518/

Quote:
The preliminary study examined people who had resection surgery, removing the main trunk or branches of the vagus nerve. The surgery, called vagotomy, is used for people with ulcers. Researchers used national registers in Sweden to compare 9,430 people who had a vagotomy over a 40-year period to 377,200 people from the general population. During that time, 101 people who had a vagotomy developed Parkinson’s disease, or 1.07 percent, compared to 4,829 people in the control group, or 1.28 percent. This difference was not significant.

But when researchers analyzed the results for the two different types of vagotomy surgery, they found that people who had a truncal vagotomy at least five years earlier were less likely to develop Parkinson’s disease than those who had not had the surgery and had been followed for at least five years. In a truncal vagotomy, the nerve trunk is fully resected. In a selective vagotomy, only some branches of the nerve are resected.



Study Suggests Parkinson’s Could Start in Gut Endocrine Cells

http://neurosciencenews.com/study-su...docrine-cells/

Quote:
“There is abundant evidence that misfolded alpha-synuclein is found in the nerves of the gut before it appears in the brain, but exactly where this misfolding occurs is unknown,” said gastroenterologist Rodger Liddle, M.D., senior author of the paper and professor of medicine at Duke. “This is another piece of evidence that supports the hypothesis that Parkinson’s arises in the gut.”

Alpha-synuclein is the subject of much ongoing research on Parkinson’s, as it’s the main component of Lewy bodies, or toxic protein deposits that take up residence in brain cells, killing them from the inside. The clumps form when alpha-synuclein develops a kink in its normally spiral structure, making it ‘sticky,’ and prone to aggregating, Liddle said.

But how would a protein go from traveling through the inner-most ‘tube’ of the intestine, where there are no nerve cells, into the nervous system? That’s a question Liddle and colleagues sought to answer in a 2015 manuscript published in the Journal of Clinical Investigation. Although the main function of gut endocrine cells is to regulate digestion, the Duke researchers found these cells also have nerve-like properties.

Rather than using hormones to communicate indirectly with the nervous system, these gut endocrine cells physically connect to nerves, providing a pathway to communicate with the brain, Liddle said. The researchers demonstrated this in a stunning time-lapse video (2015, Journal of Clinical Investigation) in which a gut endocrine cell is placed under the microscope near a neuron. In just a few hours, the endocrine cell moves toward the neuron and fibers appear between them as they establish communication.

Liddle and other scientists were astonished at the video, he said, because the endocrine cells — which are not nerves — were behaving like them. This suggests they are able to communicate directly with the nervous system and brain.
Update 16/06/2017




A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity

https://www.karger.com/Article/FullText/477990

Abstract
Quote:
Background: Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract. Methods: We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation. Findings: We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation. Interpretation: These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
Update 28/06/2017
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Old 29-01-2017, 07:56 PM   #13
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The range and nature of non-motor symptoms in drug-naive Parkinson’s disease patients: a state-of-the-art systematic review
Panagiotis Zis, Roberto Erro, Courtney C Walton, Anna Sauerbier & Kallol Ray Chaudhuri

npj Parkinson's Disease (2015)


Non-motor symptoms (NMS) are a key component of Parkinson’s disease (PD). A range of NMS, most notably impaired sense of smell, sleep dysfunction, and dysautonomia are present from the ‘pre-motor’ phase to the final palliative stage. Theories as to the pathogenesis of PD such as those proposed by Braak and others also support the occurrence of NMS in PD years before motor symptoms start. However, research addressing the range and nature of NMS in PD has been confounded by the fact that many NMS arise as part of drug-related side effects. Thus, drug-naive PD (DNPD) patients provide an ideal population to study the differences in the presentation of NMS. The aim of this paper is therefore to systematically review all the available studies of NMS in DNPD patients. We believe this is the first review of its kind. The current review confirms the increasing research being conducted into NMS in DNPD patients as well as the necessity for further investigation into less-studied NMS, such as pain. Moreover, the data confirms non-motor heterogeneity among PD patients, and, therefore, further research into the concept of non-motor subtyping is encouraged. The review suggests that the clinical assessment of NMS should be integral to any assessment of PD in clinical and research settings.
http://www.nature.com/articles/npjparkd201513

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Pathogenesis of Parkinson disease—the gut–brain axis and environmental factors
Lisa Klingelhoefer & Heinz Reichmann

Nature Reviews Neurology 2015

Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.
http://www.nature.com/nrneurol/journ....2015.197.html

I noticed that some art. are open access for a limited time (so here the pdf's)
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