Sonography for diagnosis of Parkinson disease-from theory to practice: a study on 300 participants

Good results using a Toshiba...

J Ultrasound Med. 2014 Dec;33(12):2069-74. doi: 10.7863/ultra.33.12.2069.

Alonso-Cánovas A, López-Sendón JL, Buisán J, deFelipe-Mimbrera A, Guillán M, García-Barragán N, Corral I, Matute-Lozano MC, Masjuan J, Martínez-Castrillo JC, Walter U.

OBJECTIVES:

Hyperechogenicity of the substantia nigra on transcranial sonography is used for diagnosing Parkinson disease (PD). Cutoff values for the substantia nigra echogenic area, defining substantia nigra hyperechogenicity, vary among ultrasound systems from different manufacturers. In this study we wanted to determine the cutoff criterion for a Toshiba (Tokyo, Japan) system and to assess its diagnostic value.

METHODS:

Three hundred participants (controls, n = 138; patients with PD, n = 105; and patients with essential tremor, n = 57) underwent transcranial sonography following a standardized protocol.

RESULTS:

The substantia nigra was assessable in 92.7% of all participants. The substantia nigra echogenic area (larger of bilateral measurements) was larger in patients with PD (mean ± SD, 0.24 ± 0.05 cm(2)) than controls (0.14 ± 0.05 cm(2); P < .001) and patients with essential tremor (0.14 ± 0.04 cm(2); P < .001). Substantia nigra echogenicity was larger in male participants (0.20 ± 0.07 cm(2)) than female participants (0.15 ± 0.06 cm(2); P< .001). Age did not correlate with substantia nigra echogenicity in any group. Frontal horn width was larger and lenticular nucleus hyperechogenicity and a discontinuous raphe were more frequent in the PD group than the other groups. On multivariate analysis, only substantia nigra hyperechogenicity was associated with the diagnosis of PD. The 90th-percentile substantia nigra echogenic area in the control group, which defined marked substantia nigra hyperechogenicity, also represented the optimum cutoff value for discrimination of PD from non-PD participants on receiver operating characteristic curve analysis (area under the curve, 0.913; Youden index, 0.73). This cutoff value (≥0.21 cm(2), larger of bilateral measurements) yielded sensitivity of 83% and specificity of 90% for the diagnosis of PD.

CONCLUSIONS:

Transcranial sonography shows good diagnostic validity for diagnosis of PD when implemented according to a strictly standardized protocol.

Physical activity and risk of Parkinson's disease in the Swedish National March Cohort

http://brain.oxfordjournals.org/content/early/2014/11/16/brain.awu323.long

Brain. 2014 Nov 18. pii: awu323. [Epub ahead of print]

Yang F, Trolle Lagerros Y, Bellocco R, Adami HO, Fang F, Pedersen NL, Wirdefeldt K.

Physical exercise has been associated with neuroprotective effects in the nigrostriatal dopaminergic system. To examine the impact of physical activity on Parkinson's disease risk prospectively, we followed 43 368 individuals who provided extensive information on physical activity at baseline. We estimated hazard ratios with 95% confidence intervals using Cox proportional hazards regression. During an average of 12.6 years of follow-up, 286 incident Parkinson's disease cases were identified. In males, there was an inverse association with Parkinson's disease for total physical activity (hazard ratio 0.55, 95% confidence interval 0.35-0.87 for medium versus low level), for sum of household, commuting and leisure time exercise (hazard ratio 0.53, 95% confidence interval 0.33-0.85 for high versus low level), and for household and commuting physical activity specifically (hazard ratio 0.50, 95% confidence interval 0.31-0.81 for >6 versus <2 h per week). No association was observed for leisure time exercise or occupational physical activity with Parkinson's disease, among either males or females. Meta-analysis of the present study and five previous prospective studies showed a pooled hazard ratio of 0.66 (95% confidence interval 0.57-0.78) for highest versus lowest physical activity level. Our results indicate that a medium level of physical activity lowers Parkinson's disease risk.

CSF biomarkers and clinical progression of Parkinson disease

Neurology. 2014 Nov 19. pii: 10.1212/WNL.0000000000001098. [Epub ahead of print]

Hall S, Surova Y, Ohrfelt A, Zetterberg H, Lindqvist D, Hansson O.

OBJECTIVE:

To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD).

METHODS:

Patients and controls were recruited from hospitals in southern Sweden as part of the prospective and longitudinal Swedish BioFinder Study. In the present study, we included 42 patients with PD and 69 controls who had clinical assessment and lumbar puncture at baseline. Baseline CSF samples were analyzed for α-synuclein (αSyn), β-amyloid 1-42 (Aβ42), tau, phosphorylated tau, and neurofilament light. Associations between CSF markers at baseline and change in clinical characteristics after 2 years of follow-up were investigated using multivariate models adjusting for age, sex, disease duration, and levodopa-equivalent daily dose.

RESULTS:

Higher levels of αSyn within the PD group were associated with progression of motor symptoms and cognitive decline over 2 years, indicated by significant relationships between αSyn and change in Hoehn and Yahr (β = 0.394, p = 0.043), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (β = 0.449, p = 0.013), Timed Up and Go (β = 0.406, p = 0.023), and A Quick Test of Cognitive Speed (β = 0.423, p = 0.018). Lower levels of Aβ42 were associated with worsening of performance on delayed memory recall (F = 5.834, p = 0.022). Finally, high levels of phosphorylated tau were associated with worsening in motor symptoms (UPDRS-III, β = 0.350, p = 0.045; Hoehn and Yahr, β = 0.366, p = 0.038).

CONCLUSION:

We found evidence of a link between higher levels of αSyn at baseline and worsening of motor symptoms and cognitive speed over 2 years in PD. Increased αSyn might be a marker of more intense synaptic degeneration in PD. The results indicate that cortical amyloid pathology (low CSF Aβ42) is associated with memory decline.

A Novel 6-Item Screening Questionnaire for Parkinsonism: Validation and Comparison Between Different Instruments

Neuroepidemiology. 2014 Nov 13;43(3-4):178-193. [Epub ahead of print]

Fereshtehnejad SM, Shafieesabet M, Rahmani A, Farhadi F, Hadizadeh H, Shahidi GA, Delbari A, Lökk J.

Background: Several instruments have been developed to screen Parkinson's disease (PD); yet, there is no consensus on the items, number of questions, and diagnostic accuracy. We aimed to develop a new questionnaire combining the best items with highest validity to screen parkinsonism and to compare its diagnostic value with that of the previous instruments using the same database. 

Methods: 157 patients with parkinsonism and 110 healthy controls completed a comprehensive screening questionnaire consisting of 25 items on different PD symptoms used in previous studies. To select the optimal items, clinical utility index (CUI) was calculated and those who met at least good negative utility (CUI ≥0.64) were selected. Receiver operating characteristics (ROC) curves analysis was used to compare the area under the curve (AUC) of different screening instruments. 

Results: Six items on 'stiffness & rigidity', 'tremor & shaking', 'troublesome buttoning', 'troublesome arm swing', 'feet stuck to floor' and 'slower daily activity' demonstrated good CUI. The new screening instrument had the largest AUC (0.977) compared to other instruments. 

Conclusions: We selected a new set of six items to screen parkinsonism, which showed higher diagnostic values compared to the previously developed questionnaires. This screening instrument could be used in population-based PD surveys in poor-resource settings.

Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson DiseaseA Pooled Analysis

http://archneur.jamanetwork.com/article.aspx?articleid=1934716

JAMA Neurology

Ilir Agalliu, MD, ScD¹; Marta San Luciano, MD²; Anat Mirelman, MD³; Nir Giladi, MD^3,4; Bjorg Waro, MD^5,6; Jan Aasly, MD, PhD^5,6; Rivka Inzelberg, MD^4,7; Sharon Hassin-Baer, MD^7,8; Eitan Friedman, MD^7,8; Javier Ruiz-Martinez, MD^9,10,11; Jose Felix Marti-Masso, MD^9,10,11; Avi Orr-Urtreger, MD^8,12; Susan Bressman, MD^13,14,15; Rachel Saunders-Pullman, MD^13,14,15

Importance  Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies.

Objectives  To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies.

Design, Setting, and Participants  Clinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect.

Main Outcomes and Measures  All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer.

Results  The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers.

Conclusions and Relevance  This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

DNAJC13 genetic variants in parkinsonism

http://onlinelibrary.wiley.com/doi/10.1002/mds.26064/full

Mov Disord. 2014 Nov 12. doi: 10.1002/mds.26064. [Epub ahead of print]

Gustavsson EK, Trinh J, Guella I, Vilariño-Güell C, Appel-Cresswell S, Stoessl AJ, Tsui JK, McKeown M, Rajput A, Rajput AH, Aasly JO, Farrer MJ.

BACKGROUND:

A novel mutation (p.N855S) in DNAJC13 has been linked to familial, late-onset Lewy body parkinsonism in a Dutch-German-Russian Mennonite multi-incident kindred.

METHODS:

DNAJC13 was sequenced in 201 patients with parkinsonism and 194 controls from Canada. Rare (minor allele frequency < 0.01) missense variants identified in patients were genotyped in two Parkinson's disease case-controls cohorts.

RESULTS:

Eighteen rare missense mutations were identified; four were observed in controls, three were observed in both patients and controls, and eleven were identified only in patients. Subsequent genotyping showed p.E1740Q and p.L2170W to be more frequent in patients, and p.R1516H being more frequent in controls. Additionally, p.P336A, p.V722L, p.N855S, p.R1266Q were seen in one patient each, and p.T1895M was found in two patients.

CONCLUSION:

Although the contribution of rare genetic variation in DNAJC13 to parkinsonisms remains to be further elucidated, this study suggests that, in addition to p.N855S, other rare variants might affect disease susceptibility.

A feasibility study of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders

Hugely interesting to me, for obvious reasons...

Health Informatics J. 2014 Nov 11. pii: 1460458214556373. [Epub ahead of print]

Abdolahi A, Bull MT, Darwin KC, Venkataraman V, Grana MJ, Dorsey ER, Biglan KM.

Abstract

Remote assessments of individuals with a neurological disease via telemedicine have the potential to reduce some of the burdens associated with clinical care and research participation. We aim to evaluate the feasibility of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders. A pilot study derived from two telemedicine trials was conducted. In total, 17 individuals with movement disorders (8 with Parkinson disease and 9 with Huntington disease) had Montreal Cognitive Assessment examinations evaluated in-person and remotely via web-based video conferencing to primarily determine feasibility and potential barriers in its remote administration. Administering the Montreal Cognitive Assessment remotely in a sample of movement disorder patients with mild cognitive impairment is feasible, with only minor common complications associated with technology, including delayed sound and corrupted imaging for participants with low connection speeds. The Montreal Cognitive Assessment has the potential to be used in remote assessments of patients and research participants with movement disorders.

PERFORM: A System for Monitoring, Assessment and Management of Patients with Parkinson's Disease

Wearable technology certainly in-vogue right now in PD and movement disorders. Quite a few groups working on solutions - interesting to speculate on whose is best. I have my own thoughts, which for now I'll hold on to...

http://www.mdpi.com/1424-8220/14/11/21329

Sensors (Basel). 2014 Nov 11;14(11):21329-57. doi: 10.3390/s141121329.

Tzallas AT, Tsipouras MG, Rigas G, Tsalikakis DG, Karvounis EC, Chondrogiorgi M, Psomadellis F, Cancela J, Pastorino M, Waldmeyer MT, Konitsiotis S, Fotiadis DI.

Abstract

In this paper, we describe the PERFORM system for the continuous remote monitoring and management of Parkinson's disease (PD) patients. The PERFORM system is an intelligent closed-loop system that seamlessly integrates a wide range of wearable sensors constantly monitoring several motor signals of the PD patients. Data acquired are pre-processed by advanced knowledge processing methods, integrated by fusion algorithms to allow health professionals to remotely monitor the overall status of the patients, adjust medication schedules and personalize treatment. The information collected by the sensors (accelerometers and gyroscopes) is processed by several classifiers. As a result, it is possible to evaluate and quantify the PD motor symptoms related to end of dose deterioration (tremor, bradykinesia, freezing of gait (FoG)) as well as those related to over-dose concentration (Levodopa-induced dyskinesia (LID)). Based on this information, together with information derived from tests performed with a virtual reality glove and information about the medication and food intake, a patient specific profile can be built. In addition, the patient specific profile with his evaluation during the last week and last month, is compared to understand whether his status is stable, improving or worsening. Based on that, the system analyses whether a medication change is needed¾always under medical supervision¾and in this case, information about the medication change proposal is sent to the patient. The performance of the system has been evaluated in real life conditions, the accuracy and acceptability of the system by the PD patients and healthcare professionals has been tested, and a comparison with the standard routine clinical evaluation done by the PD patients' physician has been carried out. The PERFORM system is used by the PD patients and in a simple and safe non-invasive way for long-term record of their motor status, thus offering to the clinician a precise, long-term and objective view of patient's motor status and drug/food intake. Thus, with the PERFORM system the clinician can remotely receive precise information for the PD patient's status on previous days and define the optimal therapeutical treatment.

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study

http://onlinelibrary.wiley.com/doi/10.1002/mds.26065/full

Mov Disord. 2014 Nov 12. doi: 10.1002/mds.26065. [Epub ahead of print]

Sharp ME, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Orbe Reilly M, Ruiz D, Louis ED, Comella C, Nance M, Bressman S, Scott WK, Tanner C, Waters C, Fahn S, Cote L, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Payami H, Molho E, Factor SA, Nutt J, Serrano C, Arroyo M, Pauciulo MW, Nichols WC, Clark LN, Alcalay RN, Marder KS.

BACKGROUND:

Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS).

METHODS:

The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers.

RESULTS:

Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13).

CONCLUSIONS:

First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype.

'The clocks that time us'-circadian rhythms in neurodegenerative disorders

Nat Rev Neurol. 2014 Nov 11. doi: 10.1038/nrneurol.2014.206. [Epub ahead of print]

Videnovic A, Lazar AS, Barker RA, Overeem S.

Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep-wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep-wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep-wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases.

The link between Parkinson's disease and breast and prostate cancers: A meta-analysis

That settles that then...

Int J Neurosci. 2014 Nov 11:1-26. [Epub ahead of print]

Wang T

Purpose: Clinical observations have shown an increased morbidity for breast cancer or prostate cancer in patients with Parkinson's disease, however, other reports have noted contradictory results. This pooled analysis was utilized to test whether Parkinson's disease is associated with the risk of breast or prostate cancer. Methods: We searched PubMed, Embase and Cochrane library and conducted a meta-analysis to clarify the correlation of Parkinson's disease with breast and/or prostate cancer risk. We identified 16 eligible articles from which odds ratios with 95% confident intervals were assessed as main measures in the pooled estimation. Subgroup analyses and cumulative meta-analysis were also performed. Results: Our results showed no Parkinson's disease risk associated with breast or prostate cancer in the overall population, which was supported by the results of cumulative meta-analyses. The subgroup analyses suggested no significant risk of breast or prostate cancer in patients with Parkinson's disease within relevant subsets, i.e. gender, ethnicity, Parkinson's disease diagnosis time, or study design. No evidence of publication bias was observed across the involved studies. Conclusions: This meta-analysis indicates a lack of association between Parkinson's disease and risk of breast or prostate cancer.

Ancillary investigations to diagnose parkinsonism: a prospective clinical study

J Neurol. 2014 Nov 9. [Epub ahead of print]

Aerts MB, Esselink RA, Abdo WF, Meijer FJ, Drost G, Norgren N, Janssen MJ, Borm GF, Bloem BR, Verbeek MM.

Various ancillary investigations can assist clinicians in the differential diagnosis of patients with parkinsonism. It is unknown which test offers greatest diagnostic value in clinical practice. We included 156 consecutive patients with parkinsonism, but with an initially uncertain diagnosis. At baseline, all patients underwent extensive clinical testing and the following ancillary investigations: brain magnetic resonance imaging (MRI); 123I-iodobenzamide single photon-emission computed tomography (IBZM-SPECT); analysis of cerebrospinal fluid (CSF); and anal sphincter electromyography (EMG). The final diagnosis was established after 3-year follow-up by two movement disorder specialists, according to international consensus criteria. We determined the diagnostic value by comparing the baseline clinical parameters and ancillary studies with the final diagnosis. Out of a potential 138 parameters, univariate analysis identified 35 parameters that discriminated Parkinson's disease (PD, n = 62) and atypical parkinsonism (AP, n = 94), with AUC of 0.55-0.81. Stepwise logistic regression showed that the combination of tandem gait, axial UPDRS subscore, slow saccadic eye movements and dysphagia yielded an AUC of 0.93, adjusted for optimism. The combination of tandem gait and axial UDPRS subscore yielded an AUC of 0.90. None of the ancillary investigations alone or in combination with clinical testing improved this clinically based diagnostic accuracy, not even in a subgroup of patients with the greatest diagnostic uncertainty at baseline. Our study demonstrates that a comprehensive set of clinical tests provides good accuracy to differentiate PD from AP. Our results also suggest that routine MRI, IBZM-SPECT, CSF analysis and anal sphincter EMG do not improve this diagnostic accuracy. Future work should evaluate the possible diagnostic value of more advanced diagnostic tests.

Five-year follow-up of substantia nigra echogenicity in idiopathic REM sleep behavior disorder

This is a very helpful and timely study for all of us working in this field...

http://onlinelibrary.wiley.com/doi/10.1002/mds.26055/abstract

Mov Disord. 2014 Nov 10. doi: 10.1002/mds.26055. [Epub ahead of print]

Iranzo A, Stockner H, Serradell M, Seppi K, Valldeoriola F, Frauscher B, Molinuevo JL, Vilaseca I, Mitterling T, Gaig C, Vilas D, Santamaria J, Högl B, Tolosa E, Poewe W.

Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinson's disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow-up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty-one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20 ± 0.09 cm2 vs. 0.19 ± 0.07 cm2 ; P = 0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P = 0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow-up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains stable over time.

EuroInf: A multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease

Mov Disord. 2014 Nov 10. doi: 10.1002/mds.26067. [Epub ahead of print]

Martinez-Martin P, Reddy P, Katzenschlager R, Antonini A, Todorova A, Odin P, Henriksen T, Martin A, Calandrella D, Rizos A, Bryndum N, Glad A, Dafsari HS, Timmermann L, Ebersbach G, Kramberger MG, Samuel M, Wenzel K, Tomantschger V, Storch A, Reichmann H, Pirtosek Z, Trost M, Svenningsson P, Palhagen S, Volkmann J, Chaudhuri KR.

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required. © 2014 International Parkinson and Movement Disorder Society.

Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson's disease

J Neurol. 2014 Nov 8. [Epub ahead of print]

Compta Y, Valente T, Saura J, Segura B, Iranzo A, Serradell M, Junqué C, Tolosa E, Valldeoriola F, Muñoz E, Santamaria J, Cámara A, Fernández M, Fortea J, Buongiorno M, Molinuevo JL, Bargalló N, Martí MJ.

High-oligomeric and low-total-α-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson's disease (PD), but with inconsistent or limited data, particularly on their clinical and structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-α-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD [21 non-demented (PDND) + 20 demented (PDD)], intended to reflect the premotor-motor-dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF τ and CSF Aβ. CSF oligomeric-α-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor-motor-dementia PD continuum (iRBD + PDND + PDD). CSF total-α-synuclein positively correlated with age, CSF Aβ, and, particularly, CSF τ, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF τ. Low CSF total-α-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF τ. Conversely, the associations of high (instead of low) CSF total-α-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF τ. These findings suggest that CSF oligomeric- and total-α-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor-motor-dementia PD continuum. CSF total-α-synuclein correlations with CSF τ and Aβ support the hypothesis of an interaction among these proteins in PD, with CSF τ probably influencing the presence of high (instead of low) CSF total-α-synuclein and its correlates mostly in the setting of PD-related dementia.

Neurological outcomes associated with low-level manganese exposure in an inception cohort of asymptomatic welding trainees

Scand J Work Environ Health. 2014 Nov 7. pii: 3466. doi: 10.5271/sjweh.3466. [Epub ahead of print]

Baker MG, Criswell SR, Racette BA, Simpson CD, Sheppard L, Checkoway H, Seixas NS.

OBJECTIVE:

Long-term, high-level exposure to manganese (Mn) is associated with impaired central nervous system (CNS) function. We quantitatively explored relations between low-level Mn exposure and selected neurological outcomes in a longitudinal inception cohort of asymptomatic welder trainees.

METHODS:

Welders with no previous occupational Mn exposure were observed approximately every three months over the course of the five-quarter traineeship. Fifty-six welders were assessed for motor function using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) and Grooved Pegboard tests. A subset of 17 also had MRI scans to assess T1-weighted indices. Personal exposure to Mn in welding fume was quantitatively assessed during the study period using a mixed model to obtain estimates of subject-specific exposure level by welding type. These estimates were summed to estimate cumulative exposure at the time of each neurological outcome test.

RESULTS:

When adjusting for possible learning effects, there were no associations between cumulative exposure and UPDRS3 score or Grooved Pegboard time. T1-weighted indices of the basal ganglia (caudate, anterior putamen, posterior putamen, and combined basal ganglia, but not the pallidal index) exhibited statistically significant increases in signal intensity in relation to increased cumulative Mn exposure.

CONCLUSIONS:

This study demonstrates that T1-weighted changes can be detected in the brain even at very low levels of exposure among humans before any clinically evident deficits. This suggests that with continued follow-up we could identify a T1 threshold of toxicity at which clinical symptoms begin to manifest.

My slides from the Parkinson's UK meeting in York on 2nd November 2014

As we go past 600 respondents in this year's PREDICT-PD re-survey frantic packing of smell tests and spit kits begins

The phenotypic spectrum of progressive supranuclear palsy: A retrospective multicenter study of 100 definite cases.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26054/abstract;jsessionid=8128EAF9082E2147A7447C3D12E5B50C.f03t03

Mov Disord. 2014 Nov 5. doi: 10.1002/mds.26054. [Epub ahead of print]

Respondek G, Stamelou M, Kurz C, Ferguson LW, Rajput A, Chiu WZ, van Swieten JC, Troakes C, Al Sarraj S, Gelpi E, Gaig C, Tolosa E, Oertel WH, Giese A, Roeber S, Arzberger T, Wagenpfeil S, Höglinger GU; for the Movement Disorder Society-endorsed PSP Study Group.

Abstract

The phenotypic variability of progressive supranuclear palsy (PSP) may account for its frequent misdiagnosis, in particular in early stages of the disease. However, large multicenter studies to define the frequency and natural history of PSP phenotypes are missing. In a cohort of 100 autopsy-confirmed patients we studied the phenotypic spectrum of PSP by retrospective chart review. Patients were derived from five brain banks with expertise in neurodegenerative disorders with referrals from multiple academic hospitals. The clinical characteristics of the 100 cases showed remarkable heterogeneity. Most strikingly, only 24% of cases presented as Richardson's Syndrome (RS), and more than half of the cases either showed overlapping features of several predescribed phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. These predominance types differed significantly with regard to survival time and frequency of cognitive deficits. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-center studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition of and for making prognostic predictions for these patients. Given the limitations arising from the retrospective nature of this analysis, a systematic validation in a prospective cohort study is imperative. 

Head injury, α-synuclein genetic variability and Parkinson's disease.

Eur J Neurol. 2014 Nov 5. doi: 10.1111/ene.12585. [Epub ahead of print]

Lee PC, Bordelon Y, Bronstein J, Sinsheimer JS, Farrer M, Ritz B.

BACKGROUND AND PURPOSE:

Head injury has been linked to Parkinson's disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated.

METHODS:

From 2001 to 2012, 561 incident idiopathic PD cases and 721 population controls from central California were enrolled. Subjects reported on head injuries throughout their lifetime and were assessed for genetic variability in the SNCA 5' region (D4S3481; Rep1) and 3' untranslated region (rs356165). In unconditional logistic regression models adjusted for confounders, interactions between head injuries and genetic risk variants were investigated.

RESULTS:

Parkinson's disease risk in individuals with head injury who are carriers of at least one 263 bp allele in D4S3481 or rs356165 variants was 3-4.5-fold higher compared with non-carriers without head injuries. However, tests for interaction between head injury and SNCA D4S3481or rs356165 were not statistically significant.

CONCLUSIONS:

Our study finds some evidence that head injury and D4S3481 or rs356165 variants jointly increase the risk of PD but little evidence of interaction.

Neuroinflammation in Parkinson's disease: role in neurodegeneration and tissue repair.

Int J Neurosci. 2014 Nov 3:1-17. [Epub ahead of print]

Vivekanantham S, Shah S, Dewji R, Dewji A, Khatri C, Ologunde R.

Abstract

Neuroinflammation in Parkinson's disease [PD] is a process that occurs alongside the loss of dopaminergic neurones, and is associated with alterations to many cell types, most notably microglia. This review examines the key evidence contributing to our understanding of the role of inflammation-mediated degeneration of the dopaminergic (DA) nigrostriatal pathway in PD. It will consider the potential role inflammation plays in tissue repair within the brain, inflammation linked gene products that are associated with sporadic parkinsonian phenotypes (alpha-synuclein, parkin and Nurr 1), and developing anti-inflammatory drug treatments in PD. With growing evidence supporting the key role of neuroinflammation in PD pathogenesis, new molecular targets are being found that could potentially prevent or delay nigrostriatal DA neurone loss. Hence, this creates the opportunity for disease modifying treatment, to currently what is an incurable disease.

Clinically silent idiopathic Parkinson's disease unmasked by valproate use: a brief report.

Aging Clin Exp Res. 2014 Nov 1. [Epub ahead of print]

Athauda D, Batley R, Ellis C.

Abstract

Valproate is an important but uncommon cause of drug induced parkinsonism in the elderly. The development of symptoms after valproate onset is unpredictable, and severity of symptoms is unrelated to plasma levels. However, though the majority of cases improve after drug cessation, parkinsonian symptoms can persist and should prompt investigation into underlying degenerative parkinsonism, as valproate can unmask idiopathic Parkinson's disease in susceptible individuals. This case describes a patient on chronic valproate therapy developing a severely disabling akinetic-rigid syndrome, only partially reversed on stopping valproate. We hypothesise that an increase in valproate dosage unmasked clinically silent Parkinson's disease. The patient made an excellent recovery following cessation of valproate and commencement of dopaminergic therapy.

Functional imaging in pre-motor Parkinson's disease

Can't wait for synuclein imaging to be a reality...

Q J Nucl Med Mol Imaging. 2014 Nov 4. [Epub ahead of print]

Arnaldi D, Morbelli S, Picco A, Ferrara M, Buschiazzo A, Famà F, De Carli F, Nobili FM.

Abstract

Several non motor symptoms (NMS) can precede the onset of the classical motor Parkinson's Disease (PD) syndrome. The existence of pre--motor and even pre--clinical PD stages has been proposed but the best target population to be screened to disclose PD patients in a pre--clinical, thus asymptomatic, stage is still matter of debate. The REM sleep behavior disorder (RBD) often affects PD patients at different stages of the disease and could precede the onset of motor symptoms by several years. However, RBD could also precede other synucleinopathies (namely, dementia with Lewy bodies and multisystem atrophy), and less frequently could be related to other neurological conditions or remain idiopathic. Moreover, not all PD patients exhibit RBD. Despite these caveats, RBD probably represents the best feature to disclose pre--motor PD patients given its high--risk of developing a full motor syndrome. Other clinical clues in the pre--motor stages of PD undergoing active investigation include hyposmia, depression, and autonomic dysfunction. Effective biomarkers are needed in order to improve the diagnostic accuracy in the pre--motor stage of PD, to monitor disease progression and to plan both pharmacological and non--pharmacological intervention. Functional imaging, in particular radionuclide methodologies, has been often used to investigate dopaminergic and non--dopaminergic features as well as cortical functioning in patients with RBD in its idiopathic form (iRBD) and/or associated with PD. Recently, new tracers to image α--synuclein pathologies are under development. Functional imaging in pre--motor PD, and in particular in iRBD, could improve our knowledge about the underlying mechanisms and the neurodegenerative progress of PD.

The serum lipid profile of Parkinson's disease patients: A study from China

Int J Neurosci. 2014 Oct 23:1-14. [Epub ahead of print]

Guo X, Song W, Chen K, Chen X, Zheng Z, Cao B, Huang R, Zhao B, Wu Y, Shang HF.

Abstract

Abstract Background: The association between the fasting levels of serum lipids and Parkinson's disease (PD) in Chinese populations remains largely unknown. Methods: This study enrolled 555 sporadic PD patients and 555 age-, gender- and body mass index (BMI)-matched controls. The fasting serum lipid concentrations of all subjects, including total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglycerides (TG), were measured. Results: Total cholesterol, LDL-C, HDL-C and TG were significantly lower in PD patients than in controls. The prevalence of PD is significantly lower in subjects with the second, third and fourth quartiles of total cholesterol than in those with the first quartile of total cholesterol, regardless of gender. The prevalence of PD is significantly lower in subjects with the third and fourth quartiles of LDL-C than in those with the first quartile of LDL-C, regardless of gender. Negative correlations were found between UPDRS part III score and level of total cholesterol/LDL-C. Conclusions: PD patients are with lower levels of total cholesterol, LDL-C, HDL-C and TG than controls. Lipids may be a marker of PD severity.

α-Synuclein inclusions in the skin of Parkinson's disease and parkinsonism

More on the skin as a potential source for biomarkers in PD...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184776/

Ann Clin Transl Neurol. 2014 Jul;1(7):471-8. doi: 10.1002/acn3.78. Epub 2014 Jul 1.

Rodríguez-Leyva I, Calderón-Garcidueñas AL, Jiménez-Capdeville ME, Rentería-Palomo AA, Hernandez-Rodriguez HG, Valdés-Rodríguez R, Fuentes-Ahumada C, Torres-Álvarez B, Sepúlveda-Saavedra J, Soto-Domínguez A, Santoyo ME, Rodriguez-Moreno JI, Castanedo-Cázares JP.

OBJECTIVE:

The presence in the brain of α-synuclein containing Lewy neurites, or bodies, is the histological hallmark of Parkinson's disease (PD). The discovery of α-synuclein aggregates in nerve endings of the heart, digestive tract, and skin has lent support to the concept of PD as a systemic disease. Our goals were, first, to demonstrate the presence of α-synuclein inclusions in the skin and, second, to detect quantitative differences between patients with PD and atypical parkinsonism (AP).

METHODS:

Skin biopsies were taken from 67 patients and 20 controls. The biopsies underwent immunohistochemistry (IHC) and immunofluorescence (IF) testing for α-synuclein, whereupon its presence was quantified as the percentage of positive cells. Patients were divided into those with PD and those with AP. AP patients included AP with neurodegenerative disease (proteinopathies) and secondary AP.

RESULTS:

Sixty-seven patients (34 with PD) and 20 controls were recruited. In the PD group, α-synuclein was detected in 58% of the cells in the spinous cell layer (SCL), 62% in the pilosebaceous unit (PSU), and 58% in the eccrine glands (EG). The AP-proteinopathies group showed 7%, 7%, and 0% expression of α-synuclein, respectively. No expression was found in the skin of the control group.

CONCLUSIONS:

The expression of α-synuclein in the skin was relatively high in the PD group, scarce in AP, and null for the individuals in the control group. While these findings require further confirmation, this minimally invasive technique may aid in the improvement of the accuracy of PD diagnoses.