Voxel‐wise meta‐analysis of gray matter abnormalities in idiopathic Parkinson’s disease

Structural neuroimaging studies on idiopathic Parkinson’s disease (IPD) with voxel‐based morphometry (VBM) yielded variable and conflicting findings. A systematic review of VBM studies of patients with IPD and healthy control (HC) subjects published in PubMed, ISI Web of Science, Embase, and Medline databases from 1995 to 25 October 2010 was conducted. Coordinates were extracted from clusters of significant gray matter (GM) difference between patients with IPD and HC subjects. Meta‐analysis was performed using signed differential mapping. A total of 17 VBM studies involving 498 patients with IPD and 375 HC subjects met the inclusion criteria. A significant regional GM volume decrease was detected in the left inferior frontal gyrus (BA47) extending to the left superior temporal gyrus (BA38) and the left insula (BA13) of patients with IPD compared with HC subjects. The findings of this study remain largely unchanged in quartile and jackknife sensitivity analyses and in subgroup analyses. Robust GM reductions in the inferior frontal/orbitofrontal gyrus (BA47) are implicated in IPD, and the reductions may be related to the mediation of the non‐motor IPD symptoms, such as cognitive, emotional, and autonomic functions. Further studies must be conducted to determine whether the findings are specific to all IPD subtypes or different from the atypical Parkinsonism.     

The effectiveness of exercise interventions for people with Parkinson's disease: A systematic review and meta‐analysis

Parkinson's disease (PD) is a neurodegenerative disorder affecting the physical, psychological, social, and functional status of individuals. Exercise programs may be an effective strategy to delay or reverse functional decline for people with PD and a large body of empirical evidence has emerged in recent years. The objective is to systematically review randomized controlled trials (RCTs) reporting on the effectiveness of exercise interventions on outcomes (physical, psychological or social functioning, or quality of life) for people with PD. RCTs meeting the inclusion criteria were identified by systematic searching of electronic databases. Key data were extracted by two independent researchers. A mixed methods approach was undertaken using narrative, vote counting, and random effects meta‐analysis methods. Fourteen RCTs were included and the methodological quality of most studies was moderate. Evidence supported exercise as being beneficial with regards to physical functioning, health‐related quality of life, strength, balance and gait speed for people with PD. There was insufficient evidence support or refute the value of exercise in reducing falls or depression. This review found evidence of the potential benefits of exercise for people with PD, although further good quality research is needed. Questions remain around the optimal content of exercise interventions (dosing, component exercises) at different stages of the disease. © 2008 Movement Disorder Society     

Hyperhomocysteinemia recurrence in levodopa‐treated Parkinson’s disease patients

Background: Patients with Parkinson’s disease (PD) and chronically treated with L‐DOPA exhibit, in a percentage of 10–30%, supra‐physiological levels of plasma total homocysteinemia (tHcy). In this study, we have investigated, in a group of hyper‐homocysteinemic PD patients, the time of hyper‐tHcy recurrence after discontinuation of 1‐month folate supplementation given to normalize plasma tHcy levels. Methods: Plasma tHcy, cobalamin and folate were assayed before and after 1‐month folate supplementation (5 mg/day), and after 2 and 4 months after folate discontinuation in 29 PD patients (16M/13F, mean age 69.4 ± 6.9 years) stabilized on a mean L‐DOPA dose of 509.4 ± 312.1 mg/day. Results: After folate supplementation, plasma tHcy levels fell within the normal range in all patients. At the 2‐month control after folate discontinuation, plasma tHcy remained within physiological values in 25 out of 29 patients. Conversely, 4 months after folate discontinuation, all patients exhibited hyper‐tHcy. Conclusions: One‐month intake of 5 mg/day folate normalizes plasma tHcy levels in all hyper‐homocysteinemic PD patients. Following folate discontinuation, hyper‐tHcy recurs in all patients within 4 months. Knowledge of this time interval is useful to optimize pulses of folate therapy in hyper‐homocysteinemic patients with PD.     

Calbindin‐1 association and Parkinson’s disease

Background and purpose: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson’s disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient–control series. Methods: We genotyped rs1805874 in four independent Caucasian patient–control series (1543 PD patients, 1771 controls). Results: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82–1.31, P = 0.74). Discussion: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.     

Neurotransmission in Parkinson’s disease: beyond dopamine

Parkinson’s disease (PD) is most frequently associated with characteristic motor symptoms that are known to arise with degeneration of dopaminergic neurons. However, patients with this disease also experience a multitude of non‐motor symptoms, such as sleep disturbances, fatigue, apathy, anxiety, depression, cognitive impairment, dementia, olfactory dysfunction, pain, sweating and constipation, some of which can be at least as debilitating as the movement disorders and have a major impact on patients’ quality of life. Many of these non‐motor symptoms may be evident prior to the onset of motor dysfunction. The neuropathology of PD has shown that complex, interconnected neuronal systems, regulated by a number of different neurotransmitters in addition to dopamine, are involved in the aetiology of motor and non‐motor symptoms. This review focuses on the non‐dopaminergic neurotransmission systems associated with PD with particular reference to the effect that their modulation and interaction with dopamine has on the non‐motor symptoms of the disease. PD treatments that focus on the dopaminergic system alone are unable to alleviate both motor and non‐motor symptoms, particularly those that develop at early stages of the disease. The development of agents that interact with several of the affected neurotransmission systems could prove invaluable for the treatment of this disease.     

Oro‐buccal symptoms (dysphagia,dysarthria, and sialorrhea) in patients with Parkinson’s disease: preliminary analysis from the French COPARK cohort

Introduction: Abnormal oro‐buccal functions including dysarthria, sialorrhea and dysphagia commonly affect patients with Parkinson’s disease (PD). Objectives: To estimate the prevalence of such oro‐buccal symptoms at baseline in the first 419 patients with PD included in the COPARK cohort and to analyze their correlations with patients’ demographics, clinical characteristics, and drugs consumption. Methods: Patients were assessed using the Unified PD Rating Scale, the Hospital Anxiety and Depression Scale, and the PDQ‐39. Dysarthria, sialorrhea, and dysphagia were defined as UPDRS items 5, 6, or 7 ≥ 1. Results: Dysarthria, sialorrhea, or dysphagia were present in 51%, 37%, or 18% out of the 419 patients, respectively. At least one of these symptom was present in 267/419 patients (65%), whilst a combination of symptoms was present in 136/419 (33%). Logistic regression showed that the presence of each of the three oro‐buccal symptoms was significantly correlated with that of the two others. Other correlations included male gender, hallucinations, disease severity, levodopa use and lack of opiates consumption for dysarthria; disease severity, orthostatic hypotension and absence of antidepressants consumption for sialorrhea; female gender, motor fluctuations, and depressive symptoms for dysphagia. None of the three oro‐buccal symptoms were associated with a reduced PDQ‐39 score. Conclusion: Oro‐buccal symptoms were present in two of three patients with moderate PD, the presence of each symptoms being significantly correlated with that of the two others.     

Early versus delayed initiation of entacapone in levodopa‐treated patients with Parkinson’s disease: a long‐term,retrospective analysis

Background: We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing‐off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long‐term outcomes than delayed entacapone treatment. Methods: Post‐hoc analysis of pooled data from three randomized, double‐blind, placebo‐controlled studies and their long‐term, open‐label extension phases. In all three studies, patients on levodopa/dopa‐decarboxylase inhibitor (DDCI) were first randomized to entacapone (‘early‐start’ group) or placebo (‘delayed‐start’ group) for the initial 6‐month double‐blind phase, after which all patients received open‐label levodopa/DDCI and entacapone treatment for up to 5 years. Results: A total of 488 PD patients with wearing‐off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of ?1.66 (95% confidence intervals [?3.01, ?0.31]) points compared with the delayed‐start treatment group (P < 0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early‐start group. Conclusions: These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing‐off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.     

Assessment of sexual dysfunction in patients with Parkinson’s disease: a case–control study

Background: Sexual dysfunction (SD) in patients with Parkinson’s disease (PD) has not been very well studied, as most of the research has methodological restrictions like having no control group, using invalid assessment tools, unidimensional investigation of sexual functions and inclusion of males/females only. This study aimed to examine different sexual functions in patients with PD and compare with matched non‐parkinsonian controls by using a valid instrument. Predicting factors of SD in PD were also investigated. Methods: The sample consisted of 45 patients with PD and 45 age‐ and sex‐matched healthy controls. Sexual functions were evaluated by Arizona Sexual Experiences Scale (ASEX). Results: Female patients had reduced sexual drive and they were less satisfied with orgasm, while male patients had easier orgasms than did the controls. Regression analysis identified increased age and female sex predictive of reduced sexual drive and sexual arousal. Ability to reach orgasm and satisfaction with orgasm were associated with female sex, while erection/lubrication was associated with marital status. The severity and duration of PD, as well as the severity of anxiety and depression were not associated with SD. Conclusion: Using ASEX in the detection of SD in PD might be important in directing patients to further evaluation and treatment.     

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

Cognitive function in early Parkinson’s disease: a population‐based study

Background and purpose: The study aims to describe the frequency, pattern and determinants of cognitive function in patients with newly diagnosed Parkinson’s disease (PD); to compare patients with impaired cognition to patients with intact cognition; and to compare to matched healthy controls. Methods: Patients were identified in a longitudinal population based study of idiopathic non‐drug induced parkinsonism. Eighty‐eight newly diagnosed patients with PD and no dementia were included during a four year period. The patients and 30 age‐ and sex‐matched healthy control subjects underwent a comprehensive neuropsychological assessment. Results: Patients performed significantly worse than healthy controls in a majority of neuropsychological tests. Test results in attention, psychomotor function, episodic memory (free recall), executive function and category fluency were significantly lower in the patient group. Comparison with normative data revealed that 30% of the patients had deficits in ≥1 cognitive domain (episodic memory, executive function and verbal function). Seventy per cent of the patients had normal performance. Unified Parkinson's Disease Rating Scale (UPDRS) III sub scores; speech, facial expression, rigidity and bradykinesia were significantly higher, and disease duration shorter amongst the cognitively impaired than amongst the cognitively intact patients. Tremor showed no difference. Education level was an independent predictor of dysfunction in patients with ≥2 cognitive domains affected. Conclusion: Cognitive dysfunction is common in untreated patients in early PD, affecting attention, psychomotor function, episodic memory, executive function and category fluency. Education level was an independent predictor of severe cognitive dysfunction.     

Prevalence of Parkinson’s disease in Korea

The prevalence of neurodegenerative disorders is not well documented in Korea. We assessed the prevalence of Parkinson's disease in an elderly population in a newly industrialized city in a rural region. Subjects for this study were randomly selected from a community-based cohort study. The sample in the cohort represented approximately 1.3% (4700) of 362 625 adults (age>18 years) listed in the city register in 1998. Among this group, 4218 subjects (1086 subjects aged>60 years) agreed to be interviewed and underwent a physical examination and neuropsychological tests administered by a neurologist and neuropsychologist. All participants were examined. Participants who had bradykinesia and at least one other possible cardinal sign of parkinsonism at the neurologic screening, and those who reported that they had Parkinson's disease, or were taking antiparkinsonian drugs were identified. In our study, 16 subjects showed evidence of Parkinson's disease. The prevalence in this population was 0.37%. Prevalence increased with age, and prevalence was 1.47% for those aged older than 60 years. Postural instability and gait disturbance were more common in the older age group. The results of neuropsychological tests were as follows: (1) only two subjects had low scores (<20) in the Korea-version mini-mental status examination; (2) seven subjects scored 0.5, one subject scored 2 and the other eight subjects scored 0 in the clinical dementia rating. The results of our prevalence study are similar to those of studies carried out in Western countries. Age is a risk factor for Parkinson's disease in Korea.     

Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease

Background: The 24‐week, double‐blind Efficacy and Safety Evaluation in PD–Adjunct (EASE‐PD Adjunct) study randomized patients with advanced Parkinson’s disease (PD) suboptimally controlled with levodopa to once‐daily placebo or adjunctive ropinirole prolonged release (2–24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Methods: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Results: Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake ‘off’ time, reduced night‐time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Conclusions: Once‐daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance.     

A deformation‐based morphometry study of patients with early‐stage Parkinson’s disease

Background and purpose: Previous volumetric magnetic resonance imaging (MRI) studies of Parkinson’s disease (PD) utilized primarily voxel‐based morphometry (VBM), and investigated mostly patients with moderate‐ to late‐stage disease. We now use deformation‐based morphometry (DBM), a method purported to be more sensitive than VBM, to test for atrophy in patients with early‐stage PD. Methods: T1‐weighted MRI images from 24 early‐stage PD patients and 26 age‐matched normal control subjects were compared using DBM. Two separate studies were conducted, where two minimally‐biased nonlinear intensity‐average were created; one for all subjects and another for just the PD patients. The DBM technique creates an average population‐based MRI‐average in an iterative hierarchical fashion. The nonlinear transformations estimated to match each subject to the MRI‐average were then analysed. Results: The DBM comparison between patients and controls revealed significant contraction in the left cerebellum, and non‐significant trends towards frontal, temporal and cingulate sulcal expansions with frontal and temporal white matter contractions. Within the patient group, the unified PD rating scores were highly correlated with local expansions in or near sulci bordering on frontal and temporal cortex. Conclusion: Our results suggest that DBM could be a sensitive method for detecting morphological changes in early‐stage PD.     

Transcranial magnetic stimulation and Parkinson’s disease

While motor cortical areas are the main targets of the integrative activity of basal ganglia, their main output consists of the corticospinal system. Transcranial magnetic stimulation (TMS), a relatively new method to investigate corticospinal physiology, has been widely used to assess possible changes secondary to Parkinson’s disease (PD). The use of single- and paired-pulse TMS, two varieties of the original technique, disclosed multiple functional alterations of the corticospinal pathway. For instance, when the latter was tested at ‘rest’, or in response to somesthetic afferents, it showed excess excitability or reduced inhibition. In turn, during production of a voluntary output, its activation was defective, or inadequately modulated. One major mechanism may be a dysfunction of the interneurons mediating the level of excitation within cortical area 4. For instance, there is a shortening of the so-termed ‘central silent period’, which is a complex, TMS-induced, inhibitory phenomenon possibly mediated by activation of GABA_B receptors. The so-called ‘short-interval intracortical inhibition’, which is possibly mediated by GABA_A receptors, is also diminished. Levodopa restores these and other TMS alterations, thus demonstrating that cortical area 4 is sensitive to dopamine modulation. Overall, TMS has provided substantial new pathophysiological insights, which point to a central role of the primary motor cortex in the movement disorder typical of PD. Repetitive (r-)TMS, another form of TMS, has been studied as a treatment for PD motor signs. Although some reports are favorable, others are not, and have raised the problem of appropriate control experiments. Although extremely interesting, the potential therapeutic role of r-TMS in PD needs further evaluation.     

Genetic analysis of LRRK2 functional domains in Brazilian patients with Parkinson’s disease

Background and purpose: Mutations in the leucine‐rich repeat kinase 2 gene (LRRK2) have been associated with Parkinson’s disease (PD), and the majority of the pathogenic variants are located in the ROC and MAPKKK domains. Methods: Exons 29–31 and 38–44 (ROC and MAPKKK domains) were sequenced in 204 patients with PD, mostly Brazilian. Results: We identified four polymorphisms, a novel silent variant p.R1398R and four substitutions: p.T1410M, p.G2019S, p.Y2189C and the novel variant p.C2139S. Conclusions: The most prevalent mutation was the p.G2019S (2.4%). We consider that the p.T1410M and the p.Y2189C variants are probably polymorphisms and that the p.C2139S mutation is potentially pathogenic.     

Economic burden of Parkinson’s disease in Singapore

Background: This study was carried out to evaluate the economic burden of Parkinson’s disease (PD) and factors independently associated with individual components of total cost in Singapore. Methods: A consecutive sample of 195 patients with PD (mean age: 68.2, men: 51.8%) attending a tertiary neuroscience clinic were identified and interviewed using standardized questionnaires including a financial burden questionnaire, two Health Related Quality of Life (HRQoL) questionnaires and the Beck Depression Inventory questionnaire. Results: Annual total cost of PD from a societal perspective was SGD11345 (USD10129) per patient, with direct cost accounted for 38.5% and indirect cost 61.5%. The main cost components for direct medical cost, direct non‐medical cost, and indirect cost was pharmacotherapy (50.4%), home care (76.1%), and productivity loss (97.9%), respectively. In multiple linear regression analysis, higher education, younger age and longer duration of PD were associated with higher total cost. Conclusions: Parkinson’s disease exerts a considerable burden on patients, health care system and society in Singapore. As productivity loss accounts for a large share of the economic burden imposed by PD, treatments and health care programmes with potential for returning patients to higher productivity are urgently needed.