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.