How pain arises in Parkinson's disease?

In recent years, increasing attention has centred on pain in Parkinson's disease (PD). Pain in PD is heterogeneous in quality and body distribution. To clarify how the various pain types relate to PD and to propose plausible treatment strategies, in this paper we reviewed psychophysical, neurophysiological and imaging data reported in parkinsonian patients with and without pain. Most available evidence supports abnormal central nociceptive input processing that probably reflects an impairment in the lateral and medial pain pathways. Changes in central pain processing probably underlie all the different pain types and also intervene in patients with PD without pain. Thus, altered pain processing might predispose patients with PD to spontaneous pain that is variable in quality. These background pain‐processing abnormalities may interact with additional factors (such as contractures secondary to marked rigidity/bradykinesia, dystonia and medical conditions associated with painful symptoms), thus causing pain to manifest itself clinically in various ways and providing candidate targets for pain treatment in PD.     

Why and how does light therapy offer neuroprotection in Parkinson's disease?

<正>Red and infrared light(λ=600–1,070 nm)therapy,known also as photobiomodulation,has been reported to offer neuroprotection and to improve locomotor behaviour in animal models of Parkinson’s disease,from rodents to non-human primates(Rojas and Gonzalez-Lima,2011;Hamblin,2016;Johnstone et al.,2016).The neuroprotective aspect of this therapy is particularly relevant;the saving of neurons that     

Clinical trials for neuroprotection in Parkinson's disease: overcoming angst and futility?

PURPOSE OF REVIEW: To summarize recently published results of neuroprotection trials for Parkinson's disease, and discuss them in the context of evolving concepts in clinical study design and animal models. RECENT FINDINGS: Despite compelling preclinical evidence from laboratory models suggesting potential neuroprotective benefits, the antioxidant, antiapoptotic, antiexcitotoxic, immunomodulatory and neurotrophic agents studied to date have not shown clear benefit in human studies. The futility study design, an alternative approach focused on efficiently excluding less promising compounds, has been adopted recently to investigate four candidate neuroprotectants. A delayed-start trial design has also been introduced in a study of the monoamine oxidase inhibitor rasagiline, demonstrating a possible neuroprotective effect as well as its clear symptomatic benefit. In parallel with these clinical innovations, preclinical research initiatives are identifying new animal models that more closely resemble the clinical course and pathology of Parkinson's disease. SUMMARY: Angst over disappointing results of neuroprotection trials in Parkinson's disease has engendered efforts to refine animal models at one end of the therapeutics pipeline, and to optimize clinical trial design at the other. Building on new insights into the genetics, epidemiology and pathogenesis of Parkinson's disease, these recent improvements in 'translational infrastructure' will enhance the prospects of achieving the critical goal of slowing the progression of disability.     

A new road to neuroinflammation in Parkinson's disease?

Common architecture of cytokine receptors and G-protein coupled receptors (GPCRs) may underlie pathological receptor heteromer formation and signaling. Here, we clarify how chemokines and cytokines can participate in pathogenic processes of Parkinson's disease, especially in dopaminergic neurons of substantia nigra. Possible common architecture of GPCRs and cytokine receptors suggests that they may act as molecular switches similar to the prototypical innate immune receptors: Toll-like receptors. Thus, pathological signaling (as well as trafficking and internalization) of receptors may be initiated by their incorrect dimerization depending on direct or indirect (via adaptor proteins) receptor-receptor interactions, leading to neuroinflammatory responses.     

Can overexpression of parkin provide a novel strategy for neuroprotection in Parkinson's disease?

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by selective degeneration of the dopamine producing neurons in the substantia nigra. There is currently no clinically applicable therapy for treating or preventing Parkinsonian neurodegeneration. Great effort is put behind the development of novel therapeutic approaches that aim to alter the natural progression of the disease. For example, a disease-modifying strategy based on the use of glial cell line-derived neurotrophic factor family of ligands have yielded successful results in animal models and later in initial clinical trials. More recently, identification of the gene mutations underlying the familial forms of the disease opened new frontiers in tackling the underlying neuropathological changes seen in PD brains. Overexpression of parkin, in particular, emerged as a powerful approach with complementary effects to those described with use of neurotrophic factors. In light of the fact that the mechanism of disease in the affected patient population might be significantly variable, the ability to intervene the disease process at multiple levels should be seen as a key point in devising effective treatments.     

How common are complications of Parkinson's disease?

Background Parkinson's disease (PD) can be associated with a wide range of complications of advancing disease and treatment. However, it is unclear how often these occur in the overall population of patients with PD. Objective To assess the prevalence of disease and treatment complications and their clinical correlates in a community-based sample of 124 patients with PD. Results Average current age was 72 (SD 10.9) and mean disease duration 6 (SD 4.3) years. Falls with postural instability and other axial features were among the most common complications of advancing disease in this population (64 %). Motor fluctuations and dyskinesias affected approximately 30 and 20 % of the overall sample respectively, and changes in mental state such as dementia, depression and hallucinations each affected approximately one fifth of patients. Symptoms of autonomic nervous system dysfunction occurred in the great majority of patients, but were not associated with greater disease severity, disease duration or overall disability. Conclusion In contrast to clinic-based samples, the most frequently occurring complications of PD in this community-based sample were axial features such as postural instability with falls. These factors should be more taken into account in the allocation of health care resources and the treatment of symptoms of patients with PD in the community. Received: 31 January 2001, Received in revised form: 8 August 2001, Accepted: 21 August 2001     

How Parkinson's disease patients recognize Parkinson's disease therapeutic guideline?]

The "Parkinson's disease (PD) therapeutic guideline 2002 (PGL)" was published by Societas Neurologica Japonica in Japan. The guideline, which is based on evidence-based medicine (EBM), is a good reference for making medical decisions. Although physicians recognize the usefulness of the guideline, it is unclear whether PD patients know of the its existence. We performed a survey of 42 PD patients to evaluate their thoughts on the guideline. Sixty-seven percent of the patients had no knowledge of the existence of the PGL. However, after informing them of the existence of the PGL, 93% of the patients welcomed its publication. Forty-three percent of the patients wanted to read the PGL, although they expressed reservation that the PGL might be difficult to understand. Ninety-five percent of the patients answered that they would read the PGL if an easy-to read explanation manual were provided. However, none of the patients wanted an excessively strict obedience to the PGL. Eighty-three percent of the patients wanted a flexible application of the PGL to their own therapy. The PGL seems to have been accepted by the patients. A plain-language explanation manual of the PGL for PD patients, if published, would be helpful to the patients' understanding of PD therapy and to building cooperation between patients and physicians.     

How well do caregivers detect mild cognitive change in Parkinson's disease?

Using the Cambridge Behavior Inventory‐Revised, this study evaluated the relationship between caregiver ratings of cognitive change and neuropsychological performance. In sixty‐one nondemented patients with Parkinson's Disease (PD; mean age = 64.5 years, MMSE = 28.7), 62% met criteria for mild cognitive impairment. This group were rated as having more overall change as well as memory and behavior change. Caregiver ratings were related to poorer psychomotor speed, learning/memory, language, and executive functioning. The capacity for caregivers to rate mild cognitive change in PD may be useful to assist in early screening and intervention approaches. © 2010 Movement Disorder Society     

Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson's disease?

Patients with Parkinson's disease often complain of fatigue, and although cardiac sympathetic denervation is thought to be associated with fatigue, this link remains unclear. Previously, we detected cardiac sympathetic denervation in patients with Parkinson's disease using dobutamine, a selective beta‐1 stimulant. To clarify the involvement of autonomic dysfunction in fatigue in Parkinson's disease, we conducted autonomic function tests on 33 patients with Parkinson's disease (mean age, 66.1 ± 5.6 years; 20 men, 13 women) and evaluated their relationships to fatigue. We divided patients into 2 groups, fatigued (n = 12) and nonfatigued (n = 21), based on an average score ≥ 3.3 on the Parkinson fatigue scale. Autonomic function tests included the coefficient of variation of R–R intervals, head‐up tilt test, norepinephrine and dobutamine infusion tests, and cardiac ¹²³I‐metaiodobenzylguanidine scintigraphy. The coefficient of variation of R–R intervals and the systolic blood pressure changes accompanying the head‐up tilt test did not show significant differences between the 2 groups; however, the pressor responses in the norepinephrine and dobutamine infusion tests were significantly greater in the fatigued group than in the nonfatigued group. The ¹²³I‐metaiodobenzylguanidine heart‐to‐mediastinal uptake ratio was lower in the fatigued group than in the nonfatigued group. Partial correlation analyses, using disease duration and Hoehn and Yahr stage as control variables, also demonstrated significant correlations between the Parkinson fatigue scale score and the results of the autonomic function tests and cardiac ¹²³I‐metaiodobenzylguanidine uptake. Our results suggest that autonomic dysfunction, including cardiac sympathetic denervation, is associated with fatigue in patients with Parkinson's disease. © 2011 Movement Disorder Society     

Does robotic gait training improve balance in Parkinson's disease? A randomized controlled trial

BackgroundTreadmill training (with or without robotic assistance) has been reported to improve balance skills in patients with Parkinson's disease (PD). However, its effectiveness on postural instability has been evaluated mainly in patients with mild to moderate PD (Hoehn &; Yahr stage ≤3). Patients with more severe disease may benefit from robot-assisted gait training performed by the Gait-Trainer GT1, as a harness supports them with their feet placed on motor-driven footplates. The aim of this study was to determine whether robot-assisted gait training could have a positive influence on postural stability in patients with PD at Hoehn &; Yahr stage 3–4.MethodsThirty-four patients with PD at Hoehn &; Yahr stage 3–4 were randomly assigned into two groups. All patients received twelve, 40-min treatment sessions, three days/week, for four consecutive weeks. The Robotic Training group (n = 17) underwent robot-assisted gait training, while the Physical Therapy group (n = 17) underwent a training program not specifically aimed at improving postural stability. Patients were evaluated before, immediately after and 1-month post-treatment. Primary outcomes were: Berg Balance scale; Nutt's rating.ResultsA significant improvement was found after treatment on the Berg Balance Scale and the Nutt's rating in favor of the Robotic Training group (Berg: 43.44 ± 2.73; Nutt: 1.38 ± 0.50) compared to the Physical Therapy group (Berg: 37.27 ± 5.68; Nutt: 2.07 ± 0.59). All improvements were maintained at the 1-month follow-up evaluation.ConclusionsRobot-assisted gait training may improve postural instability in patients with PD at Hoehn &; Yahr stage 3–4.     

How specific are non-motor symptoms in the prodrome of Parkinson's disease compared to other movement disorders?

The clinical diagnosis of Parkinson's disease (PD) based on motor signs is often preceded by several non-motor symptoms that can indicate early prodromal neurodegenerative processes. Such prodromal symptoms can aid the early detection of PD, but their specificity for prodromal PD in comparison to prodromes of other movement disorders is still largely unclear. We here aim to give a first insight into the published evidence of prodromal non-motor symptoms in PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Huntington's disease (HD), progressive supranuclear palsy (PSP) and spinocerebellar ataxia (SCA). REM-sleep behavior disorder (RBD) and autonomic dysfunction have been observed in the prodromes of PD, MSA, DLB and SCA. Depression and cognitive decline have been reported for prodromal PD, DLB, HD, SCA, and PSP. Olfactory loss has only been described in prodromal PD/DLB. However, estimating the specificity of prodromal non-motor symptoms in PD is so far complicated by scarce prospective evidence and study limitations. Information on marker specificity is a prerequisite for an accurate early (differential) diagnosis of prodromal diseases, as well as specific recruitment for targeted neuroprotective interventions. We here would like to raise awareness of these issues and encourage further prospective research of prodromal non-motor symptoms in neurodegenerative movement disorders and other diseases.     

Nonmotor versus motor symptoms: How much do they matter to health status in Parkinson's disease?

Evidence suggests that both motor and nonmotor symptoms contribute to health status in Parkinson's disease. Less clear is how much change in health status can be expected if these clinical variables change. In addition, anxiety, separate from depression, has rarely been examined as a predictor of health status. We used hierarchical multiple regression analysis and standardized beta coefficients in a prevalent cohort of 462 patients with Parkinson's disease to explore the relative impact on health status (measured using the Parkinson's Disease Questionnaire) of 5 well-recognized symptom domains in Parkinson's disease: motor signs, depression, anxiety, cognition, and other nonmotor symptoms. In the health status scores, 19.6% of variance was explained by age, number of comorbidities, disease duration, and levodopa equivalent dose. Younger age predicted worse health status. A full regression model containing baseline variables and all 5 symptom domains explained 56% of the variance in health status. The standardized beta coefficient for depression was 2.1, 1.6, and 1.3 times that of motor signs, anxiety, and other nonmotor symptoms, respectively. Our findings provide a ranking order of clinical variables for their relative impact on health status in Parkinson's disease and show that depression has more than twice the impact of motor signs on health status. Anxiety and other nonmotor symptoms are also important separate determinants of poor health status in Parkinson's disease. Our results will help to guide the development of individual care and service planning for patients with Parkinson's disease.     

How valid is the clinical diagnosis of Parkinson's disease in the community?

BACKGROUND: Many patients diagnosed with Parkinson's disease are later found to have an erroneous diagnosis, often only when they come to necropsy; conversely, many patients with Parkinson's disease in the community remain undiagnosed. OBJECTIVE: To assess the validity of a clinical diagnosis of parkinsonism in the general population according to strict published criteria. METHODS: As part of a population based study on the prevalence of Parkinson's disease in London, all patients were identified with a diagnosis of parkinsonism, tremor with onset over age 50 years, or who had ever received antiparkinsonian drugs. All patients who agreed to participate were diagnosed according to strict clinical diagnostic criteria, after a detailed neurological interview and examination and discussion of the findings with examination of their video recordings. Follow up information was obtained over a period of at least one year, and atypical cases were reviewed at the end of the study. RESULTS: A diagnosis of probable Parkinson's disease was confirmed in 83% of patients with this diagnosis, including three (2%) in whom atypical features were found that were insufficient to discard a diagnosis of Parkinson's disease. Two additional patients (2%) were found to have possible Parkinson's disease. However, in 15% of patients the diagnosis was unequivocally rejected. Conversely, 13 patients who had previously not been diagnosed with Parkinson's disease (19%) were found to have this disorder. CONCLUSIONS: At least 15% of patients with a diagnosis of Parkinson's disease in the population do not fulfil strict clinical criteria for the disease, and approximately 20% of patients with Parkinson's disease who have already come to medical attention have not been diagnosed as such.     

Are current recommendations to diagnose orthostatic hypotension in Parkinson's disease satisfactory?

We interviewed 50 Parkinson's disease (PD) patients using a questionnaire to verify the reliability of orthostatic symptoms in warning the presence of orthostatic hypotension (OH). OH is defined as 20 mm Hg systolic or 10 mm Hg diastolic BP fall within 3 min of tilting or standing but if this fall occurs after 3 min we called it ‘late OH’ (L‐OH). We compared if OH in Parkinson's disease (PD) was more frequent after head‐up tilt or on standing and if the period of postural challenge matters in detecting OH. Twenty‐one (42%) patients had OH that occurred twice more often after tilting (n = 20) than on standing (n = 10). OH occurred within 3 min of tilting in 9 patients (18%) and appeared beyond the currently recommended 3 min in 11 patients (55%) (L‐OH). Ten of the 20 patients developing OH on tilting were symptomatic. The 10 patients who had OH on standing were asymptomatic. Reporting of symptoms was independent of age or severity of BP fall. Most (90%) patients reporting orthostatic symptoms on standing had OH on tilting for 3 min. Orthostatic symptoms in PD have a high specificity but low sensitivity in predicting OH. In Parkinson's disease OH occurs often after tilting than on standing and is delayed (after 3 min). As OH in PD is often asymptomatic and delayed it could contribute to falls and increase morbidity. We suggest routine evaluation of OH in PD by tilting them longer than the recommended 3 minutes to detect delayed OH. © 2009 Movement Disorder Society     

What contributes to quality of life in patients with Parkinson's disease?

OBJECTIVE: To identify the factors that determine quality of life (QoL) in patients with idiopathic Parkinson's disease in a population based sample. Quality of life (QoL) is increasingly recognised as a critical measure in health care as it incorporates the patients' own perspective of their health. METHODS: All patients with Parkinson's disease seen in a population based study on the prevalence of parkinsonism were asked to complete a disease-specific QoL questionnaire (PDQ-39) and the Beck depression inventory. A structured questionnaire interview and a complete neurological examination, including the Hoehn and Yahr scale, the Schwab and England disability scale, the motor part of the unified Parkinson's disease rating scale (UPDRS part III), and the mini mental state examination were performed by a neurologist on the same day. RESULTS: The response rate was 78%. The factor most closely associated with QoL was the presence of depression, but disability, as measured by the Schwab and England scale, postural instability, and cognitive impairment additionally contributed to poor QoL. Although the UPDRS part III correlated significantly with QoL scores, it did not contribute substantially to predicting their variance once depression, disability, and postural instability had been taken into account. In addition, patients with akinetic rigid Parkinson's disease had worse QoL scores than those with tremor dominant disease, mainly due to impairment of axial features. CONCLUSION: Depression, disability, postural instability, and cognitive impairment have the greatest influence on QoL in Parkinson's disease. The improvement of these features should therefore become an important target in the treatment of the disease.