Cortical thinning associated with mild cognitive impairment in Parkinson's disease.

Mov Disord. 2014 Aug 7. doi: 10.1002/mds.25982. [Epub ahead of print]

Segura B, Baggio HC, Marti MJ, Valldeoriola F, Compta Y, Garcia-Diaz AI, Vendrell P, Bargallo N, Tolosa E, Junque C.

Abstract

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual-visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains.

Gene-Gene and Gene-Environment Interaction on the Risk of Parkinson's Disease.

Curr Aging Sci. 2014 Aug 5. [Epub ahead of print]

Singh NK, Banerjee BD, Bala K, Basu M, Chhillar N.

Abstract

Background: Even with numerous studies the cause of Parkinson's disease (PD) remains elusive. It has been hypothesized that interactions between genetic and environmental factors may play an important role in the pathogenesis of PD. Objectives: To examine the gene-gene and gene-environment interaction on PD risk with respect to gene polymorphism of cytochrome P450 2D6 (CYP2D6) and glutathione S-transferases pi 1 (GSTP1), organochlorine pesticides (OCPs) and metals. Methods: This study included 70 patients of PD and 100 age-matched controls. The restriction fragment length polymorphism was used for analysis of genetic polymorphism. OCPs and serum metal levels were estimated by using gas chromatography and an autoanalyser respectively. Results: The CYP2D6*4 mt and GSTP1 *B allelic variants were significantly associated with increase in PD risk. We found a statistically significant difference in β-hexachlorocyclohexane (β-HCH), dieldrin, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (pp'-DDE) and copper levels between the patients and controls. We found significantly high levels of β-HCH, dieldrin and pp'-DDE in the CYP2D6*4 mt allelic variants, β-HCH and pp'-DDE in the GSTP1*B allelic variants and dieldrin in the GSTP1*C allelic variants when comparing CYP2D6*4 non-mt, GSTP1 non-*B and GSTP1 non-*C allelic variants in patients of PD respectively. Conclusion: This study demonstrates that the CYP2D6*4 and GSTP1 genes may be considered as candidate genes for PD and they may also interact with β- HCH, dieldrin and pp'-DDE to influence the risk for PD.

REM sleep behavior disorder: Association with motor complications and impulse control disorders in Parkinson's disease

Parkinsonism Relat Disord. 2014 Apr 1. pii: S1353-8020(14)00132-1. doi: 10.1016/j.parkreldis.2014.03.022. [Epub ahead of print]

Kim YE, Jeon BS, Yang HJ, Ehm G, Yun JY, Kim HJ, Kim JM.

OBJECTIVE:

Clinical phenotypes such as old age, longer disease duration, motor disability, akineto-rigid type, dementia and hallucinations are known to be associated with REM sleep behavior disorder (RBD) in Parkinson's disease (PD). However, the relationship between motor fluctuations/impulse control and related behaviors (ICRB) and RBD is not clear. We designed this study to elucidate the clinical manifestations associated with RBD to determine the implications of RBD in PD.

DESIGN:

In a cross-sectional study, a total of 994 patients with PD were interviewed to determine the presence of RBD and their associated clinical features including motor complications and ICRB.

RESULTS:

Of the 944 patients, 578 (61.2%) had clinical RBD. When comparing the clinical features between patients with RBD (RBD group) and without RBD (non-RBD group), older age, longer disease duration, higher Hoehn and Yahr stage (H&Y stage), higher levodopa equivalent daily dose (LEDD), and the existence of wearing off, dyskinesia, freezing, and ICRB, especially punding, were associated with the RBD group compared to the non-RBD group (P < .05 in all). Multivariate analysis showed that motor complications including wearing off, peak dose dyskinesia, and diphasic dyskinesia were the only relevant factors for RBD after adjusting for age and disease duration.

CONCLUSION:

Motor complications and ICRB are more frequent in patients with RBD than in patients without RBD. In addition, motor complications are related to RBD even after adjusting for age and disease duration.

Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study

Brain. 2014 Jul 30. pii: awu201. [Epub ahead of print]

Nombela C, Rowe JB, Winder-Rhodes SE, Hampshire A, Owen AM, Breen DP, Duncan GW, Khoo TK, Yarnall AJ, Firbank MJ, Chinnery PF, Robbins TW, O'Brien JT, Brooks DJ, Burn DJ; the ICICLE-PD study group, Barker RA.

Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.

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.