Management of anxiety and motor symptoms in Parkinson's disease.

Anxiety may be an early non-motor feature but it is a vitally important symptom to address in the clinic as well...

Expert Rev Neurother. 2014 Aug;14(8):937-46. doi: 10.1586/14737175.2014.936388.

Coakeley S, Martens KE, Almeida QJ.

Abstract

Parkinson's disease (PD) is typically known for its cardinal motor symptoms, but a growing body of literature is recognizing a multitude of important nonmotor symptoms as well. Anxiety is one of the most common nonmotor symptoms of PD; unfortunately, neither the management of anxiety nor its influence on motor symptoms is well understood. While recent literature indicates a correlation between motor symptoms and anxiety in PD, it remains uncertain whether one symptom acts as the underlying cause of the other. This review considers the cyclic interaction between anxiety and motor symptoms in PD, each exacerbating the other when they coexist. It may be critically important to disentangle if one symptom serves as an underlying cause of the other, since this might dictate appropriate treatment. Neuroanatomical substrates as well as the treatments for both motor symptoms and anxiety are discussed in detail to consider the evidence-base for the management of PD.

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Exciting new analysis of GWAS data showing more about the heritable component of risk of PD...

Mike A Nalls, Nathan Pankratz, Christina M Lill, Chuong B Do, Dena G Hernandez, Mohamad Saad, Anita L DeStefano, Eleanna Kara, Jose Bras, Manu Sharma, Claudia Schulte, Margaux F Keller, Sampath Arepalli, Christopher Letson, Connor Edsall, Hreinn Stefansson, Xinmin Liu, Hannah Pliner, Joseph H Lee, Rong Cheng, International Parkinson's Disease Genomics Consortium (IPDGC), Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC) et al.

Nature Genetics (2014) doi:10.1038/ng.3043

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10⁻¹⁶). We also show six risk loci associated with proximal gene expression or DNA methylation.

Transcranial Sonography of the Substantia Nigra: Digital Image Analysis

Although manual measurement and digital analysis were comparable, digital analysis could help this technique be of more use in multi-centre studies, which are currently limited due to operator and machine dependency...

AJNR Am J Neuroradiol. 2014 Jul 24. [Epub ahead of print]

Skoloudík D, Jelínková M, Blahuta J, Cermák P, Soukup T, Bártová P, Langová K, Herzig R.

BACKGROUND AND PURPOSE:

Increased echogenicity of the substantia nigra is a typical transcranial sonography finding in Parkinson disease. Experimental software for digital analysis of the echogenic substantia nigra area has been developed. The aim of this study was to compare the evaluation of substantia nigra echogenicity by using digital analysis with a manual measurement in patients with Parkinson disease and healthy volunteers.

MATERIALS AND METHODS:

One hundred thirteen healthy volunteers were enrolled in the derivation cohort, and 50 healthy volunteers and 30 patients with Parkinson disease, in the validation cohort. The substantia nigra was imaged from the right and left temporal bone window by using transcranial sonography. All subjects were examined twice by using different sonographic machines by an experienced sonographer. DICOM images of the substantia nigra were encoded; then, digital analysis and manual measurement of the substantia nigra were performed. The 90th percentile of the derivation cohort values was used as a cut-point for the evaluation of the hyperechogenic substantia nigra in the validation cohort. The Spearman coefficient was used for assessment of the correlation between both measurements. The Cohen κ coefficient was used for the assessment of the correlation between both measurements and Parkinson disease diagnosis.

RESULTS:

The Spearman coefficient between measurements by using different machines was 0.686 for digital analysis and 0.721 for manual measurement (P < .0001). Hyperechogenic substantia nigra was detected in the same 26 (86.7%) patients with Parkinson disease by using both measurements. Cohen κ coefficients for digital analysis and manual measurement were 0.787 and 0.762, respectively (P < .0001).

CONCLUSIONS:

The present study showed comparable results when measuring the substantia nigra features conventionally and by using the developed software.

Tai Chi for Improvement of Motor Function, Balance and Gait in Parkinson's Disease: A Systematic Review and Meta-Analysis

PLoS One. 2014 Jul 21;9(7):e102942. doi: 10.1371/journal.pone.0102942. eCollection 2014.

Yang Y, Li XY, Gong L, Zhu YL, Hao YL.

BACKGROUND:

Recently, several studies assessed the effectiveness of Tai Chi for Parkinson's disease (PD), but the role of Tai Chi in the management of PD remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the efficacy of Tai Chi for PD.

METHODS:

Six English and Chinese electronic databases, up to April 2014, were searched to identify relevant studies. The risk of bias in eligible studies was assessed by Cochrane Collaboration's tools. The primary outcomes were motor function, balance and gait in individuals with PD. Standardized mean difference (SMD) and 95% confidence intervals (CI) of random-effect model were calculated. And heterogeneity was assessed based on the I2statistic.

RESULTS:

7 randomized controlled trials and 1 non-randomized controlled trial were eligible. The aggregated results suggested that Tai Chi showed beneficial effects in improving motor function (SMD, -0.57; 95% CI -1.11 to -0.04; p = 0.03), balance (SMD, 1.22; 95% CI 0.80 to 1.65; p<0.00001) and functional mobility (SMD, 1.06; 95% CI 0.68 to 1.44; p<0.00001) in patients with PD, but not in improving gait velocity (SMD, -0.02; 95% CI -0.58 to 0.54; p = 0.94), step length (SMD, -0.00; 95% CI -0.57 to 0.56; p = 0.99), or gait endurance (SMD, 0.53; 95% CI -0.07 to 1.12; p = 0.08). Comparing with other active therapies, however, Tai Chi only showed better effects in improving balance (SMD, 0.74; 95% CI 0.38 to 1.10; p<0.0001).

CONCLUSION:

Tai Chi should be a valid complementary and alternative therapy for PD, especially in improving motor function and balance. However, more studies with long follow-up are warrant to confirm the current finding of Tai Chi for PD.

Natural history of falls in a population-based cohort of patients with Parkinson's disease: An 8-year prospective study

Parkinsonism Relat Disord. 2014 Jul 9. pii: S1353-8020(14)00243-0. doi: 10.1016/j.parkreldis.2014.06.023. [Epub ahead of print]

Hiorth YH, Larsen JP, Lode K, Pedersen KF.

BACKGROUND:

Prospective long-term studies of falls in Parkinson's disease (PD) are scarce.

OBJECTIVE:

To examine the development of falls over 8 years in a population-based cohort of ambulatory patients with PD, and to investigate predictors of future falls in non-fallers at baseline.

METHODS:

All patients were examined at baseline and after 4 and 8 years, including the UPDRS, MMSE, Montgomery and Aaberg Depression Rating Scale, Functional Comorbidity Index, and a clinical dementia interview. Logistic regression models were applied to investigate baseline risk factors for future falls. A total of 211 patients were included at baseline, whereas 121 and 64 were re-examined at 4 and 8 years, respectively.

RESULTS:

The prevalence of falls increased from 41% (87 of 211) at baseline to 72% (46 of 64) after 8 years of prospective follow-up (disease duration 16.2 ± 4.8 years). Forty-seven non-falling patients at baseline completed all study visits, of these 68% (n = 32) changed fall status during follow-up. Predictive variables for current falling after 4 years were rare or occasional freezing of gait (OR 6.6, 95% CI 1.2-36.9), higher levodopa equivalent doses and more severe speech and axial impairment (both OR 1.3, 95% CI 1.0-1.7) in non-fallers at baseline. Higher baseline age was the only risk factor for current falling after 8 years.

CONCLUSIONS:

Nearly ¾ of the PD cohort reported falling after 8 years of follow-up. Disease-specific gait and axial impairments were the major risk factors for future falls in non-fallers at baseline. This has implications for patient education and management.

Evidence of Inflammatory System Involvement in Parkinson's Disease

Biomed Res Int. 2014;2014:308654. Epub 2014 Jun 24.

Chao Y, Wong SC, Tan EK.

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises. In vivo evidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition.

The modern pre-levodopa era of Parkinson's disease: insights into motor complications from sub-Saharan Africa

Nice to see some evidence for what is suspected in the clinic...

Brain. 2014 Jul 17. pii: awu195. [Epub ahead of print]

Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E, Fabbri M, Adjei P, Akassi J, Bonetti A, Pezzoli G.

Abstract

During the past decade, a number of large drug trials suggested that the initiation of levodopa therapy should be delayed to reduce the risk of motor complications in patients with Parkinson's disease. However, the relative contribution of the cumulative exposure to levodopa and of disease progression to the pathophysiology of motor fluctuations and dyskinesias is still poorly understood. In this 4-year multicentre study, we investigated a large cohort of patients with Parkinson's disease in a sub-Saharan African country (Ghana), where access to medication is limited and the initiation of levodopa therapy often occurs many years after onset. The primary objective was to investigate whether the occurrence of motor complications is primarily related to the duration of levodopa therapy or to disease-related factors. Study design included a cross-sectional case-control analysis of data collected between December 2008 and November 2012, and a prospective study of patients followed-up for at least 6 months after the initiation of levodopa therapy. Ninety-one patients fulfilled criteria for clinical diagnosis of idiopathic Parkinson's disease (58 males, mean age at onset 60.6 ± 11.3 years). Demographic data were compared to those of 2282 consecutive Italian patients recruited during the same period, whereas nested matched subgroups were used to compare clinical variables. Demographic features, frequency and severity of motor and non-motor symptoms were comparable between the two populations, with the only exception of more frequent tremor-dominant presentation in Ghana. At baseline, the proportion of Ghanaian patients with motor fluctuations and dyskinesias was 56% and 14%, respectively. Although levodopa therapy was introduced later in Ghana (mean disease duration 4.2 ± 2.8 versus 2.4 ± 2.1 years, P < 0.001), disease duration at the occurrence of motor fluctuations and dyskinesias was similar in the two populations. In multivariate analysis, disease duration and levodopa daily dose (mg/kg of body weight) were associated with motor complications, while the disease duration at the initiation of levodopa was not. Prospective follow-up for a mean of 2.6 ± 1.3 years of a subgroup of 21 patients who were drug-naïve at baseline [median disease duration 4.5 (interquartile range, 2.3-5) years] revealed that the median time to development of motor fluctuations and dyskinesias after initiation of levodopa therapy was 6 months. We conclude that motor fluctuations and dyskinesias are not associated with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified.

Predictors of dementia in Parkinson's disease; findings from a 5-year prospective study using the SCOPA-COG

Parkinsonism Relat Disord. 2014 Jun 26. pii: S1353-8020(14)00226-0. doi: 10.1016/j.parkreldis.2014.06.006. [Epub ahead of print]

Zhu K, van Hilten JJ, Marinus J.

OBJECTIVE:

Aim of this study was to identify risk factors for the development of dementia in patients with Parkinson's disease (PD).

METHODS:

A broad range of motor and non-motor features was assessed at baseline and the following five years in 406 PD patients. Cross-sectional analyses of baseline data and longitudinal analyses of follow-up data were performed to identify risk factors for dementia.

RESULTS:

Thirty-two percent of patients (n = 129) had dementia at baseline, while 26% of patients (n = 68) without dementia at baseline developed dementia during follow-up. Univariate survival analysis showed that higher age, fewer years of education, longer disease duration, higher age-at-onset, higher levodopa dose, higher Hoehn & Yahr stage, presence of dyskinesias, excessive daytime sleepiness (EDS), presence of hallucinations, and more severe autonomic and depressive symptoms were associated with an increased risk of dementia. Higher baseline Postural-Instability-and-Gait-Difficulty scores were also associated with an increased risk of dementia, whereas no effect of tremor severity was found. These findings largely corresponded with the variables that were associated with the presence of dementia at baseline. In a stepwise regression model, higher age at baseline, fewer years of education, higher daily levodopa dose and excessive daytime sleepiness (EDS) emerged as independent risk factors of future dementia.

CONCLUSIONS:

In this large prospective cohort study, we identified a combination of potentially interacting risk factors for dementia in PD that are associated with higher age and more advanced disease.

The association between chronic obstructive pulmonary disease and Parkinson's disease: a nationwide population-based retrospective cohort study

This surprises me given the strong negative associations with PD and smoking. In fact I can't remember ever having seen someone with PD and COPD in clinic...

QJM. 2014 Jul 14. pii: hcu136. [Epub ahead of print]

Li CH, Chen WC, Liao WC, Tu CY, Lin CL, Sung FC, Chen CH, Hsu WH.

OBJECTIVE:

Previous research has shown that patients with chronic obstructive pulmonary disease (COPD) tend to have a higher risk for cognitive impairment and dementia, a neurodegenerative disorder. The goal of this study was to examine what relationship, if any, exists between COPD and Parkinson's disease (PD), which is also a neurodegenerative disorder.

METHOD:

Our study analyzed medical data from the population of Taiwan from 1998 to 2008, with a follow-up period extending to the end of 2010. We identified patients with COPD by the Taiwan National Health Insurance Research Database (NHIRD). We selected a comparison cohort from the general population that was random frequency-matched by age (in 5-year increments), sex and index year, and further analyzed the risk of PD using Cox's regression model, including sex, age and comorbidities.

RESULTS:

The study enrolled 20 728 COPD patients (71.1% male, mean age = 68.2 years) and 41 147 controls. The risk of developing PD was 1.37 times greater in patients with COPD compared with patients without COPD after adjusting for age, sex and comorbidities. A significantly increased risk of PD was also found in patients with COPD who had any comorbidity other than diabetes.

CONCLUSION:

This nationwide retrospective cohort study demonstrates that PD risk is significantly increased in patients with COPD compared with those of the general population.

A review of the use of magnetic resonance imaging in Parkinson's disease.

Ther Adv Neurol Disord. 2014 Jul;7(4):206-20. doi: 10.1177/1756285613511507.

Pyatigorskaya N, Gallea C, Garcia-Lorenzo D, Vidailhet M, Lehericy S.

Abstract

To date, the most frequently used Parkinson's disease (PD) biomarkers are the brain imaging measures of dopaminergic dysfunction using positron emission tomography and single photon emission computed tomography. However, major advances have occurred in the development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade. Although conventional structural imaging remains normal in PD, advanced techniques have shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques such as tractography and resting state functional connectivity give access to anatomical and functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to metabolites concentrations. However, to date these techniques are not yet fully validated and standardized quantitative metrics for PD are still lacking. This review presents an overview of new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use in PD and their potential applications to improve the clinical diagnosis of Parkinsonian syndromes and the quality of clinical trials.

Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

Mov Disord. 2014 Jul 3. doi: 10.1002/mds.25952. [Epub ahead of print]

Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ; Netherlands Brain Bank, Rozemuller AJ, van de Berg WD.

Abstract

To gain a better understanding of the significance of α-synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α-synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α-synuclein pathological conditions are related to clinical measures of disease progression. Post-mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age-matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α-synuclein aggregates. The progression from Braak α-synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α-synuclein stages but did not vary across consecutive Braak α-synuclein stages. We observed a negative correlation between neuronal density and local α-synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = -0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α-synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α-synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease.