Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study

Lancet Neurol. 2013 Dec 19. pii: S1474-4422(13)70293-X. doi: 10.1016/S1474-4422(13)70293-X. [Epub ahead of print]

Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, Vanagunas A, Othman AA, Widnell KL, Robieson WZ, Pritchett Y, Chatamra K, Benesh J, Lenz RA, Antonini A; for the LCIG Horizon Study Group.

Abstract

BACKGROUND:

Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube.

METHODS:

In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994.

FINDINGS:

From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1·91 h [95% CI -3·05 to -0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube.

INTERPRETATION:

Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study.

FUNDING:

AbbVie.

Characterizing mild cognitive impairment in incident Parkinson disease: The ICICLE-PD Study

Neurology. 2013 Dec 20. [Epub ahead of print]

Yarnall AJ, Breen DP, Duncan GW, Khoo TK, Coleman SY, Firbank MJ, Nombela C, Winder-Rhodes S, Evans JR, Rowe JB, Mollenhauer B, Kruse N, Hudson G, Chinnery PF, O'Brien JT, Robbins TW, Wesnes K, Brooks DJ, Barker RA, Burn DJ; On behalf of the ICICLE-PD Study Group.

Author information

From the Institute for Ageing and Health (A.J.Y., G.W.D., M.J.F., D.J.B.), Industrial Statistics Research Unit (S.Y.C.), and Institute of Genetic Medicine (G.H., P.F.C.), Newcastle University; John van Geest Centre for Brain Repair (D.P.B., J.R.E., R.A.B.), Department of Clinical Neurosciences (C.N., S.W.-R., J.B.R.), Behavioural and Clinical Neuroscience Institute (C.N., S.W.-R., J.B.R., T.W.R.), MRC Cognition and Brain Sciences Unit (C.N., S.W.-R., J.B.R.), Departments of Psychiatry (J.T.O.) and Psychology (T.W.R.), University of Cambridge, UK; School of Medicine (T.K.K.), Griffith University, Australia; Paracelsus-Elena-Klinik (B.M.), Kassel, and Göttingen University; Institute for Neuropathology (N.K.), Prion and Dementia Research Unit, University Medical Centre Göttingen, Germany; Centre for Human Psychopharmacology (K.W.), Swinburne University, Melbourne, Australia; and Department of Medicine (D.J.W.), Imperial College London, UK.

Abstract

OBJECTIVE:

To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers.

METHODS:

Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria.

RESULTS:

The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1-42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1-42 and 1-40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold.

CONCLUSIONS:

In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1-42 and 1-40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Risk of obstructive sleep apnea in Parkinson's disease: a meta-analysis

PLoS One. 2013 Dec 9;8(12):e82091. doi: 10.1371/journal.pone.0082091.

Zeng J, Wei M, Li T, Chen W, Feng Y, Shi R, Song Y, Zheng W, Ma W.

Author information

Institute of Genetic Engineering, Southern Medical University, Guangzhou, Guangdong, P. R. China.

Sleep Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China.

Department of Urology, Nanfang hospital, Southern Medical University, Guangzhou, Guangdong. P. R. China.

Abstract

STUDY OBJECTIVES:

Sleep disorders are a common symptom of Parkinson's disease (PD) and they significantly impair the sleep quality of the PD patients. However, there is no conclusive evidence to support the relation between PD and the prevalence of obstructive sleep apnea (OSA). The purpose of this meta-analysis review is to evaluate the association between PD and the prevalence of OSA.

METHODS:

A comprehensive literature search was conducted on PubMed and Embase through July 2013. Only studies that referred to PD and the prevalence of OSA and that met the selection criteria were included in the analysis. The odds ratios (ORs) were used to evaluate the relationship of PD and the prevalence of OSA by the fixed-effect model.

RESULTS:

Five eligible studies were analyzed in this study including 322 cases and 6,361 controls. The pooled-analysis showed the OR to be 0.60 (95% confidence interval (CI): 0.44 to 0.81, P = 0.001) and I(2) = 0.0% (χ(2) = 3.90, P = 0.420) in the fixed-effect model.

CONCLUSIONS:

Although we only included five small sample studies that indicated high homogeneity in the heterogeneity test, the results suggest that there is a significant negative association between PD and the prevalence of OSA; PD patients generally have a reduced prevalence of OSA. According to our analysis, these results are primarily due to the lower BMI of PD patients when compared with the general population controls.

Automatic and objective assessment of alternating tapping performance in Parkinson's disease.

Sensors (Basel). 2013 Dec 9;13(12):16965-84. doi: 10.3390/s131216965.

Memedi M, Khan T, Grenholm P, Nyholm D, Westin J.

Author information

School of Technology and Business Studies, Computer Engineering, Dalarna University, Falun SE-791 88, Sweden.

Abstract

This paper presents the development and evaluation of a method for enabling quantitative and automatic scoring of alternating tapping performance of patients with Parkinson's disease (PD). Ten healthy elderly subjects and 95 patients in different clinical stages of PD have utilized a touch-pad handheld computer to perform alternate tapping tests in their home environments. First, a neurologist used a web-based system to visually assess impairments in four tapping dimensions ('speed', 'accuracy', 'fatigue' and 'arrhythmia') and a global tapping severity (GTS). Second, tapping signals were processed with time series analysis and statistical methods to derive 24 quantitative parameters. Third, principal component analysis was used to reduce the dimensions of these parameters and to obtain scores for the four dimensions. Finally, a logistic regression classifier was trained using a 10-fold stratified cross-validation to map the reduced parameters to the corresponding visually assessed GTS scores. Results showed that the computed scores correlated well to visually assessed scores and were significantly different across Unified Parkinson's Disease Rating Scale scores of upper limb motor performance. In addition, they had good internal consistency, had good ability to discriminate between healthy elderly and patients in different disease stages, had good sensitivity to treatment interventions and could reflect the natural disease progression over time. In conclusion, the automatic method can be useful to objectively assess the tapping performance of PD patients and can be included in telemedicine tools for remote monitoring of tapping.

Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease: A Randomized Clinical Trial

JAMA Neurol. 2013 Dec 23. doi: 10.1001/jamaneurol.2013.5528. [Epub ahead of print]

The Parkinson Study Group SURE-PD Investigators, Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K.

Abstract

IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690.

Female reproductive factors, menopausal hormone use, and Parkinson's disease

Mov Disord. 2013 Dec 18. doi: 10.1002/mds.25771. [Epub ahead of print]

Liu R, Baird D, Park Y, Freedman ND, Huang X, Hollenbeck A, Blair A, Chen H.

Author information

Epidemiology Branch of the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.

Abstract

The objective of this study was to examine the associations of reproductive factors and exogenous hormone use with risk of Parkinson's disease (PD) among postmenopausal women. The study comprised 119,166 postmenopausal women aged 50 to 71 years in the NIH-AARP Diet and Health Study, who completed a baseline questionnaire in 1995-1996 and a follow-up survey in 2004-2006. A total of 410 self-reported PD diagnoses were identified between 1995 and 2006. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models. PD risk was not significantly associated with female reproductive factors including age at menarche, age at first live birth, parity, and age at menopause. For example, compared with women with natural menopause at age 50 to 54 years, the ORs were 1.18, (95% CI, 0.78-1.79) for women with natural menopause aged <45, 1.19 (95% CI, 0.88-1.61) for those aged 45 to 49, and 1.33 (95% CI, 0.91-1.93) for those aged 55 or older. We found that oral contraceptive use for ≥10 years (vs. never used) was associated with lower PD risk (OR, 0.59; 95% CI, 0.38-0.92), but shorter use showed no association. Use of menopausal hormone therapy showed inconsistent results. Compared with non-hormone users at baseline, current hormone users for <5 years showed a higher risk of PD (OR, 1.52; 95% CI, 1.11-2.08). However, no associations were observed for past hormone users or current users of ≥5 years. Overall, this large prospective study provides little support for an association between female reproductive factors and PD risk. Our findings on long-term oral contraceptive use and current hormone therapy warrant further investigations. © 2013 International Parkinson and Movement Disorder Society.

Driving errors in Parkinson's disease: moving closer to predicting on-road outcomes

Am J Occup Ther. 2014 Jan-Feb;68(1):77-85. doi: 10.5014/ajot.2014.008698.

Classen S, Brumback B, Monahan M, Malaty II, Rodriguez RL, Okun MS, McFarland NR.

Abstract

Age-related medical conditions such as Parkinson's disease (PD) compromise driver fitness. Results from studies are unclear on the specific driving errors that underlie passing or failing an on-road assessment. In this study, we determined the between-group differences and quantified the on-road driving errors that predicted pass or fail on-road outcomes in 101 drivers with PD (mean age = 69.38 ± 7.43) and 138 healthy control (HC) drivers (mean age = 71.76 ± 5.08). Participants with PD had minor differences in demographics and driving habits and history but made more and different driving errors than HC participants. Drivers with PD failed the on-road test to a greater extent than HC drivers (41% vs. 9%), χ²(1) = 35.54, HC N = 138, PD N = 99, p < .001. The driving errors predicting on-road pass or fail outcomes (95% confidence interval, Nagelkerke R² =.771) were made in visual scanning, signaling, vehicle positioning, speeding (mainly underspeeding, t(61) = 7.004, p < .001, and total errors. Although it is difficult to predict on-road outcomes, this study provides a foundation for doing so.

α-synuclein in the appendiceal mucosa of neurologically intact subjects.

Mov Disord. 2013 Dec 18. doi: 10.1002/mds.25779. [Epub ahead of print]

Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM.

Author information

Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Abstract

Parkinson's disease is characterized by the pathological aggregation of α-synuclein. The dual-hit hypothesis proposed by Braak implicates the enteric nervous system as an initial site of α-synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of α-synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade. We performed immunohistochemical staining for α-synuclein on gastrointestinal tissue from patients with no history of neurological disease using the established LB509 antibody and a new clone, MJFR1, characterized for immunohistochemistry here. We demonstrate that the vermiform appendix is particularly enriched in α-synuclein-containing axonal varicosities, concentrated in its mucosal plexus rather than the classical submucosal and myenteric plexuses. Unexpectedly, intralysosomal accumulations of α-synuclein were detected within mucosal macrophages of the appendix. The abundance and accumulation of α-synuclein in the vermiform appendix implicate it as a candidate anatomical locus for the initiation of enteric α-synuclein aggregation and permits the generation of testable hypotheses for Parkinson's disease pathogenesis.

Effect of subthalamic nucleus deep brain stimulation on driving in Parkinson disease

Neurology. 2013 Dec 18. [Epub ahead of print]

Buhmann C, Maintz L, Hierling J, Vettorazzi E, Moll CK, Engel AK, Gerloff C, Hamel W, Zangemeister WH.

Author information

From the Departments of Neurology (C.B., L.M., J.H., C.G., W.H.Z.), Medical Biometry and Epidemiology (E.V.), Neurophysiology and Pathophysiology (C.K.E.M., A.K.E.), and Neurosurgery (W.H.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Abstract

OBJECTIVE:

To examine the influence of subthalamic nucleus (STN) deep brain stimulation (DBS) on driving in patients with Parkinson disease (PD).

METHODS:

Using a driving simulator setup proven to reflect on-road driving, 2 main analyses were performed: 1) comparison of driving performance among 23 patients with deep brain surgery (DBS patients), 21 patients without surgery (no-DBS patients), and 21 controls; and 2) analysis of the effect of stimulation vs levodopa on driving performance. To this end, 3 tests were run in the medicated DBS patient cohort, with 3 different conditions: "stimulation on" (STIM) (equated to daily treatment), "stimulation off" (OFF), and "stimulation off/levodopa" (LD) (dosage aimed at maintaining motor status). Differences in driving times and errors among conditions were analyzed.

RESULTS:

Age and cognitive deficits influenced driving performance negatively. The no-DBS patient group performed worse in driving time and driving errors than controls. DBS patients drove slower than controls and no-DBS patients. Driving safety was comparable to controls but higher than in no-DBS patients. Within the DBS patient group, driving was more accurate with STIM than with LD, although motor effects did not differ. Driving with STIM, but not with LD, was superior to driving in the OFF condition.

CONCLUSION:

DBS of the STN seems to have a beneficial effect on driving ability in patients with PD, potentially because of nonmotor driving-relevant aspects. Our data suggest that driving permission for DBS-treated patients with PD should not be handled more restrictively than permissions for patients with PD in general.

CLASSIFICATION OF EVIDENCE:

This study provides Class IV evidence that STN-DBS in patients with PD is associated with a reduction in driving errors and improvements in driving accuracy in driving simulations.

MIBG myocardial scintigraphy in pre-motor Parkinson's disease: A review

Parkinsonism Relat Disord. 2013 Nov 21. pii: S1353-8020(13)00393-3. doi: 10.1016/j.parkreldis.2013.11.001. [Epub ahead of print]

Sakakibara R, Tateno F, Kishi M, Tsuyusaki Y, Terada H, Inaoka T.

Abstract

OBJECTIVES:

Detecting very early markers of neurodegeneration that predate the diagnosis of idiopathic Parkinson's disease (PD) is a crucial research topic for the development of disease-modifying therapeutic interventions. Recently 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy has become widely used for this purpose, since this test shows high sensitivity and specificity in the diagnosis of PD, based on evidence that cardiac sympathetic nerve fibers are affected early and commonly in PD. We reviewed the literature to determine the role of MIBG myocardial scintigraphy for diagnosing pre-motor PD.

METHODS:

We performed a systematic review of the literature to identify the use of MIBG myocardial scintigraphy in relation to the constellation of pre-motor symptoms in PD.

RESULTS:

Mild memory disorder, autonomic failure (constipation and postural hypotension), depression/anxiety, visual hallucination/psychosis (in the elderly), sleep disorder (REM sleep behavior disorder), and impaired olfaction are reported to appear as sole initial symptoms of PD. All clinical features except for impaired olfaction are accompanied by low MIBG uptake, suggestive of very early PD in situ.

CONCLUSION:

Identifying persons with mild memory disorder, constipation/postural hypotension, depression/anxiety, visual hallucination/psychosis (in the elderly), and REM sleep behavior disorder associated with low MIBG uptake may provide a unique opportunity to detect very early PD in situ within a pre-clinical window. Future prospective studies to investigate further the findings of these early cases are warranted.

Substantia nigra in Parkinson's disease: a multimodal MRI comparison between early and advanced stages of the disease.

Neurol Sci. 2013 Dec 11. [Epub ahead of print]

Aquino D, Contarino V, Albanese A, Minati L, Farina L, Grisoli M, Elia A, Bruzzone MG, Chiapparini L.

Author information

Neuroradiology Department, IRCCS Foundation Neurological Institute Carlo Besta, Via Celoria, 11, 20133, Milan, Italy

Abstract

This study focused on the substantia nigra (SN) in Parkinson's disease (PD). We measured its area and volume, mean diffusivity (MD), fractional anisotropy (FA) and iron concentration in early and late PD and correlated the values with clinical scores. Twenty-two early PD (EPD), 20 late PD (LPD) and 20 healthy subjects (age 64.7 ± 4.9, 60.5 ± 6.1, and 61 ± 7.2 years, respectively) underwent 1.5 T MR imaging with double-TI-IR T1-weighted, T2*-weighted and diffusion tensor imaging scans. Relative SN area, MD, FA and R2* were measured in ROIs traced on SN. Correlation with Unified Parkinson Disease Rating Scale (UPDRS) scores was assessed. In LPD, the SN area was significantly reduced with respect to EPD (p = 0.04) and control subjects (p < 0.001). In EPD, the SN area was also significantly smaller than in controls (p = 0.006). Similarly, the SN volume significantly differed between LPD and controls (p = 0.001) and between EPD and LPD (p = 0.049), while no significant differences were found between controls and EPD. Both SN area (r = 0.47, p = 0.004) and volume (r = 0.46, p = 0.005) correlated with UPDRS scores. At 1.5 T, SN morphological measurements were sensitive to early PD changes and able to track the disease progression, while MD and FA measures and relaxometry did not provide significant results.

Assessing plasma levels of selenium, copper, iron and zinc in patients of Parkinson's disease

PLoS One. 2013 Dec 10;8(12):e83060. doi: 10.1371/journal.pone.0083060.

Zhao HW, Lin J, Wang XB, Cheng X, Wang JY, Hu BL, Zhang Y, Zhang X, Zhu JH.

Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Abstract

Trace elements have been recognized to play an important role in the development of Parkinson's disease (PD). However, it is difficult to precisely identify the relationship between these elements and the progression of PD because of an insufficient number of patients. In this study, quantifications of selenium (Se), copper (Cu), iron (Fe) and zinc (Zn) by atomic absorption spectrophotometry were performed in plasma from 238 PD patients and 302 controls recruited from eastern China, which is so far the largest cohort of PD patients and controls for measuring plasma levels of these elements. We found that plasma Se and Fe concentrations were significantly increased whereas Cu and Zn concentrations decreased in PD patients as compared with controls. Meanwhile, these four elements displayed differential changes with regard to age. Linear and logistic regression analyses revealed that both Fe and Zn were negatively correlated with age in PD patients. Association analysis suggests that lower plasma Se and Fe levels may reduce the risk for PD, whereas lower plasma Zn is probably a PD risk factor. Finally, a model was generated to predict PD patients based on the plasma concentrations of these four trace elements as well as other features such as sex and age, which achieved an accuracy of 80.97±1.34% using 10-fold cross-validation. In summary, our data provide new insights into the roles of Se, Cu, Fe and Zn in PD progression.

Retinal thinning and correlation with functional disability in patients with Parkinson's disease.

Br J Ophthalmol. 2013 Nov 25. doi: 10.1136/bjophthalmol-2013-304152. [Epub ahead of print]

Satue M, Seral M, Otin S, Alarcia R, Herrero R, Bambo MP, Fuertes MI, Pablo LE, Garcia-Martin E.

Source

Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain.

Abstract

AIMS:

To determine whether there is an association between retinal thinning and functional rating scales in patients with Parkinson's disease (PD).

MATERIALS AND METHODS:

Patients with PD (n=153) and controls (n=242) underwent evaluations of the macula and retinal nerve fibre layer (RNFL) using two new-generation Fourier domain optical coherence tomography (OCT) devices (Cirrus, Carl Zeiss Meditec, Dublin, California, USA; Spectralis, Heidelberg Engineering, Heidelberg, Germany). PD severity was assessed using the Schwab-England Activities of Daily Living scale, the Unified Parkinson Disease Rating Scale, the Hoehn and Yahr (HY) scale. Retinal and RNFL thicknesses were compared between patients and controls. Correlations between structural parameters and the scores of the neurologic scales were evaluated.

RESULTS:

RNFL parameters were significantly reduced in patients with PD, especially when using the Spectralis OCT device. All macular parameters, except for foveal thickness, differed significantly between controls and patients with PD (p<0.001). HY scores were significantly and inversely correlated with all macular parameters when measured with the Spectralis OCT device (p<0.05) and with RNFL thickness when measured with the Cirrus OCT device (nasal quadrant, sectors 2 and 5).

CONCLUSIONS:

The neurodegeneration caused by PD can be detected using Fourier domain OCT. RNFL and macular thicknesses correlate with PD severity.

Early DEtection of wEaring off in Parkinson disease: The DEEP study

Parkinsonism Relat Disord. 2013 Nov 5. pii: S1353-8020(13)00390-8. doi: 10.1016/j.parkreldis.2013.10.027. [Epub ahead of print]

Stocchi F, Antonini A, Barone P, Tinazzi M, Zappia M, Onofrj M, Ruggieri S, Morgante L, Bonuccelli U, Lopiano L, Pramstaller P, Albanese A, Attar M, Posocco V, Colombo D, Abbruzzese G; DEEP study group.

Source

Department of Neurology, Institute of Research and Medical Care, IRCCS San Raffaele, Rome, Italy. Electronic address: fabrizio.stocchi@tin.it.

Abstract

OBJECTIVE:

Assessing the frequency of Wearing-Off (WO) in Parkinson's disease (PD) patients, and its impact on Quality of Life (QoL).

METHODS:

Consecutive ambulatory patients, who were on dopaminergic treatment for ≥1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores ≥ 2. QoL was evaluated by the 8-item Parkinson's Disease Questionnaire (PDQ-8).

RESULTS:

617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a <2.5 years disease duration, WO was diagnosed in 12 subjects (21.8%) by neurologists and in 23 subjects (41.8%) by the WOQ-19. The most frequent WO symptoms, as identified by WOQ-19, were "slowness of movements" (55.8%) and "reduced dexterity" (48.8%). Younger age, female gender, Unified Parkinson's Disease Rating Scale (UPDRS) part II score and duration of anti-Parkinson treatment were found significantly associated with WO. The number of motor (p < 0.0001) and non-motor (p < 0.0001) WO symptoms correlated with PDQ-8 total score.

CONCLUSIONS:

WO is common already at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of WO symptoms, both motor and non motor, increases along with disease duration and has a negative impact on patients QoL.

Objective measurement of daytime napping, cognitive dysfunction and subjective sleepiness in Parkinson's disease

PLoS One. 2013 Nov 21;8(11):e81233. doi: 10.1371/journal.pone.0081233.

Bolitho SJ, Naismith SL, Salahuddin P, Terpening Z, Grunstein RR, Lewis SJ.

Source

Parkinson's Disease Clinic, Brain and Mind Research Institute, The University of Sydney, Sydney, New South Wales, Australia.

Abstract

INTRODUCTION:

Sleep-wake disturbances and concomitant cognitive dysfunction in Parkinson's disease (PD) contribute significantly to morbidity in patients and their carers. Subjectively reported daytime sleep disturbance is observed in over half of all patients with PD and has been linked to executive cognitive dysfunction. The current study used daytime actigraphy, a novel objective measure of napping and related this to neuropsychological performance in a sample of PD patients and healthy, age and gender-matched controls. Furthermore this study aimed to identify patients with PD who may benefit from pharmacologic and behavioural intervention to improve these symptoms.

METHODS:

Eighty-five PD patients and 21 healthy, age-matched controls completed 14 days of wrist actigraphy within two weeks of neuropsychological testing. Objective napping measures were derived from actigraphy using a standardised protocol and subjective daytime sleepiness was recorded by the previously validated Epworth Sleepiness Scale.

RESULTS:

Patients with PD had a 225% increase in the mean nap time per day (minutes) as recorded by actigraphy compared to age matched controls (39.2 ± 35.2 vs. 11.5 ± 11.0 minutes respectively, p < 0.001). Significantly, differences in napping duration between patients, as recorded by actigraphy were not distinguished by their ratings on the subjective measurement of excessive daytime sleepiness. Finally, those patients with excessive daytime napping showed greater cognitive deficits in the domains of attention, semantic verbal fluency and processing speed.

CONCLUSION:

This study confirms increased levels of napping in PD, a finding that is concordant with subjective reports. However, subjective self-report measures of excessive daytime sleepiness do not robustly identify excessive napping in PD. Fronto-subcortical cognitive dysfunction was observed in those patients who napped excessively. Furthermore, this study suggests that daytime actigraphy, a non-invasive and inexpensive objective measure of daytime sleep, can identify patients with PD who may benefit from pharmacologic and behavioural interventions to improve these symptoms.

A prospective study of depression in French patients with Parkinson's disease. The Depar study

Eur J Neurol. 1995 Nov;2(5):455-461. doi: 10.1111/j.1468-1331.1995.tb00155.x.

Davous P, Auquier P, Grignon S, Neukirch HC.

Source

The Collège National de Neurologie des Hôpitaux Généraux, FranceDepartment of Neurology, Centre Hospitalier Victor Dupouy, ArgenteuilLaboratoire de Santé Publique, Faculté de Médecine, MarseilleClinique Universitaire de Psychiatrie, CHU La Timone, MarseilleSchering Plough France, Levallois, France.

Abstract

To investigate the prevalence and symptomatology of depression in Parkinson's disease (PD), we have studied 506 unselected patients attending the neurology services in French general hospitals during a 5 month period defined for prospective inclusion. 246 patients (48.6%) were suspected of depression according to different methods of evaluation and 168 (33.2%) were defined as definite or probable depression. According to the Montgomery and Asberg scale, 46 cases (9%) had a severity score suggestive of major depression. As a function of the cut-off score defined for severity, these patients represented from 23.2 to 43.7% of the depressive population with PD. There was no significant difference between depressed and non depressed PD patients as a function of the patient's current age or age at onset of PD. A significantly higher rate of depression was found among women with PD. A past history of depression was a risk factor for mood disorder after onset of PD. The severely depressed patients had a significantly longer duration of PD and a higher score of cognitive impairment than mildly or moderately depressed and non depressed patients with PD. Depressed patients had a significantly more advanced stage of disability than non-depressed patients with PD.

Use of Hyposmia and Other Non-Motor Symptoms to Distinguish between Drug-Induced Parkinsonism and Parkinson's Disease

Objective smell testing should be used more routinely in clinical practice. Perhaps this will change when the 2006 NICE guidelines are updated - Alastair Noyce

J Parkinsons Dis. 2013 Nov 27. [Epub ahead of print]

Morley JF, Duda JE.

Source

Parkinson's Disease Research, Education and Clinical Center, Philadelphia VA Medical Center, PA, USA.

Abstract

Drug-induced Parkinsonism (DIP) secondary to antipsychotics and other dopamine antagonists is common and can be clinically indistinguishable from idiopathic Parkinson's disease (PD). Making the correct diagnosis is essential as it has important implications both for management of the underlying psychiatric condition and potentially lifelong therapy with antiparkinsonian agents. Additionally, because Parkinsonism does not always resolve with withdrawal of the offending agent or can recur years later, DIP may sometimes represent unmasking of incipient PD. The problem is increasing in scope as antipsychotic drugs are prescribed for a widening variety of indications, and understanding the factors that distinguish pharmacologic from degenerative Parkinsonism represents a significant unmet need. In this review, we discuss the rationale and evidence for using pre-clinical manifestations of PD, particularly non-motor symptoms, to distinguish between the conditions.

The effects of dopaminergic medication on dynamic decision making in Parkinson's disease

Neuropsychologia. 2013 Nov 19. pii: S0028-3932(13)00386-2. doi: 10.1016/j.neuropsychologia.2013.10.024. [Epub ahead of print]

Osman M, Ryterska A, Karimi K, Tu L, Obeso I, Speekenbrink M, Jahanshahi M.

Source

Biological and Experimental Psychology Centre, School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom; Sobell Department of Motor Neuroscience and Movement Disorders, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, 33 Queen Square, London WC1N 3 BG, United Kingdom; Cognitive, Perceptual and Brain Sciences, University College London, 26 Bedford Way, London WC1H 0AP, United Kingdom.

Abstract

In the present study we address the following questions: (1) How is performance affected when patients with Parkinson's Disease (PD) perform a dynamic decision making task? (2) Does dopaminergic medication differentially affect dynamic decision making? Participants were trained with different goals during learning: either they made intervention-based decisions or prediction-based decisions during learning. The findings show that overall there is an advantage for those trained to intervene over those trained to predict. In addition, the results are the first demonstration that PD patients 'ON' (N=20) compared to 'OFF' L-Dopa (N=15) medication and also relative to healthy age matched controls (N=16) showed lower levels of relative improvement in the accuracy of their decisions in a dynamic decision making task, and tended to use sub-optimal strategies. These findings provide support for the 'Dopamine Overdose' hypothesis using a novel decision making task, and suggest that executive functions such as decision making can be adversely affected by dopaminergic medication in PD.

Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease

A recent article has re-ignited the debate on the role of the gastro-intestinal tract in the earliest stages of Parkinson’s and whether tissue biopsies routinely taken during gastroscopy or colonoscopy tests could be used to help diagnose the disease. Hilton et al analysed 117 previously collected samples of gut using antibodies against abnormal alpha-synuclein protein. This marker of disease could be detected in samples taken up to 8 years before the diagnosis of Parkinson’s was made. This adds weight to the ‘Braak Hypothesis’ that the disease process could begin in the gastrointestinal tract before affecting the brain, however, it also supports the emerging idea that gastrointestinal tissue samples could help diagnose early Parkinson’s (or at least identify people who could go on to develop the disease). This is clearly a fascinating area of Parkinson’s research however these markers of disease could only be found in a minority of patients and more work is needed to determine if such tests can reliably detect the disease in the general population.

Hilton D, Stephens M, Kirk L, Edwards P, Potter R, Zajicek J, Broughton E, Hagan H, Carroll C.

Acta Neuropathologica, 17th November 2013.

Abstract: Parkinson's disease primarily affects the central nervous system, but autopsy and small patient studies have revealed autonomic nervous system pathology in most cases. We looked for α-synuclein pathology in routinely acquired biopsies from patients and matched controls. Immunocytochemistry was performed and assessed blind to the clinical diagnoses. One hundred and seventeen gastrointestinal tissue samples from 62 patients, and 161 samples from 161 controls, were examined. Twelve biopsies from seven patients showed accumulation of α-synuclein within mucosal and submucosal nerve fibres, and ganglia, which was more extensive with an antibody to phosphorylated, than with an antibody to non-phosphorylated, α-synuclein. These included gastric, duodenal and colonic biopsies, and were taken up to 8 years prior to the onset of motor symptoms. All patients with positive biopsies had early autonomic symptoms and all controls were negative. This large scale study demonstrates that accumulation of α-synuclein in the gastrointestinal tract is a highly specific finding that could be used to confirm a clinical diagnosis of Parkinson's disease. We have shown that α-synuclein accumulation occurs prior to the onset of motor symptoms in the upper, as well as the lower gastrointestinal tract, remains present in serial biopsies until the onset of motor symptoms and is predominantly composed of phosphorylated α-synuclein. Accumulation of α-synuclein in the bowel therefore offers an accessible biomarker which allows further study of the early stages of the disease and could be of value in the assessment of disease modifying treatments.­­

Effects of sleep disorders on the non-motor symptoms of Parkinson disease

J Clin Sleep Med. 2013 Nov 15;9(11):1119-29. doi: 10.5664/jcsm.3148.

Neikrug AB, Maglione JE, Liu L, Natarajan L, Avanzino JA, Corey-Bloom J, Palmer BW, Loredo JS, Ancoli-Israel S.

Source

SDSU/UCSD Joint Doctoral Program in Clinical Psychology, San Diego, CA ; Veterans Medical Research Foundation, San Diego, CA.

Abstract

STUDY OBJECTIVES:

To evaluate the impact of sleep disorders on non-motor symptoms in patients with Parkinson disease (PD).

DESIGN:

This was a cross-sectional study. Patients with PD were evaluated for obstructive sleep apnea (OSA), restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and REM sleep behavior disorder (RBD). Cognition was assessed with the Montreal Cognitive Assessment and patients completed self-reported questionnaires assessing non-motor symptoms including depressive symptoms, fatigue, sleep complaints, daytime sleepiness, and quality of life.

SETTING:

Sleep laboratory.

PARTICIPANTS:

86 patients with PD (mean age = 67.4 ± 8.8 years; range: 47-89; 29 women).

INTERVENTIONS:

N/A.

MEASUREMENTS AND RESULTS:

Having sleep disorders was a predictor of overall non-motor symptoms in PD (R(2) = 0.33, p < 0.001) while controlling for age, PD severity, and dopaminergic therapy. These analyses revealed that RBD (p = 0.006) and RLS (p = 0.014) were significant predictors of increased non-motor symptoms, but OSA was not. More specifically, having a sleep disorder significantly predicted sleep complaints (ΔR(2) = 0.13, p = 0.006), depressive symptoms (ΔR(2) = 0.01, p = 0.03), fatigue (ΔR(2) = 0.12, p = 0.007), poor quality of life (ΔR(2) = 0.13, p = 0.002), and cognitive decline (ΔR(2) = 0.09, p = 0.036). Additionally, increasing number of sleep disorders (0, 1, or ≥ 2 sleep disorders) was a significant contributor to non-motor symptom impairment (R(2) = 0.28, p < 0.001).

CONCLUSION:

In this study of PD patients, presence of comorbid sleep disorders predicted more non-motor symptoms including increased sleep complaints, more depressive symptoms, lower quality of life, poorer cognition, and more fatigue. RBD and RLS were factors of overall increased non-motor symptoms, but OSA was not.

Lewy body extracts from parkinson's disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys

This is an interesting article which supports the templating hypothesis of Parkinson's and cell-to-cell transfer of pathology. Protein (alpha-synuclein) was gathered from 3 Parkinson's patients who donated their brains for research. This was injected into mice and monkeys. When the brains of the animals were examined later abnormal collections of protein were found both near the injection sites and further away in connected brain areas, suggesting the ability to spread. These findings may be vitally important to our understanding of the processes that go on in Parkinson's.

Ann Neurol. 2013 Nov 16. doi: 10.1002/ana.24066. [Epub ahead of print]

Recasens A, Dehay B, Bové J, Carballo-Carbajal I, Dovero S, Pérez A, Fernagut PO, Blesa J, Parent A, Perier C, Fariñas I, Obeso JA, Bezard E, Vila M.

Source

Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.

Abstract

Objective: Mounting evidence suggest that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson's disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans. 

Methods: Nigral LB-enriched fractions containing pathological α-synuclein were purified from post-mortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. 

Results: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. 

Interpretation: α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and pre-synaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.

OnabotulinumtoxinA Office Treatment for Neurogenic Bladder Incontinence in Parkinson's Disease

Urology. 2013 Nov 11. pii: S0090-4295(13)01180-1. doi: 10.1016/j.urology.2013.09.017. [Epub ahead of print]

Anderson RU, Orenberg EK, Glowe P.

Source

Department of Urology, Stanford University School of Medicine, Stanford, CA.

Abstract

OBJECTIVE:

To evaluate safety and effectiveness of low-dose (100 U) onabotulinumtoxinA (onabotA) bladder injections as an office procedure with topical anesthesia only for patients with Parkinson's disease (PD) and incontinence.

METHODS:

Qualified patients who failed oral antimuscarinic agents participated in an open-label study. They discontinued antimuscarinics, provided a King's Health Questionnaire (KHQ), voiding symptom score, and 3-day voiding diary. Free uroflowmetry with post-void ultrasounds and cystometrogram pressure/flow studies were performed. Patients underwent flexible cystoscopy and injections of onabotA 100 U (10 U/mL) dispersed into 10-20 submucosal/detrusor sites of the bladder, including the trigone. Voiding diaries, questionnaires, and free uroflowmetry with post-void ultrasound residual urine measurements were repeated after 1, 3, and 6 months.

RESULTS:

Twelve men and 8 women were treated: mean age, 70.4 years; duration of disease, 10.6 years; median bladder contraction volume, 115 mL; maximum bladder pressure, 62 cm; and post-void volume, 9 mL. Moderate to marked symptom relief at 3 months and a 50% incontinence decrease over 6 months relative to pretreatment was reported in 59% patients (P ≤.02); 5 patients failed to complete the 6-month endpoint. No urinary retention required catheterization.

CONCLUSION:

Office cystoscopy with low-dose onabotA injection treatment is a potential long-term management strategy for patients with PD and urinary incontinence who fail oral antimuscarinic agents. The treatment seems to be safely utilized for older men with BPH as well as women with potential hypoactive detrusor function.

Insomnia and sleepiness in Parkinson disease: associations with symptoms and comorbidities

J Clin Sleep Med. 2013 Nov 15;9(11):1131-7. doi: 10.5664/jcsm.3150.

Chung S, Bohnen NI, Albin RL, Frey KA, Müller ML, Chervin RD.

Source

Sleep Disorders Center and Department of Neurology, University of Michigan, Ann Arbor, MI ; Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

Abstract

STUDY OBJECTIVES:

Insomnia and daytime sleepiness are common complaints in Parkinson disease (PD), but the main causes remain unclear. We examined the potential impact of both motor and non-motor symptoms of PD on sleep problems.

METHODS:

Patients with PD (n = 128) were assessed using the Insomnia Severity Index, Epworth Sleepiness Scale, Unified Parkinson Disease Rating Scale, Beck Depression Inventory, Fatigue Severity Scale, Survey of Autonomic Symptoms, and the 39-item Parkinson Disease Questionnaire. A subset of subjects (n = 38, 30%) also completed nocturnal polysomnography and a multiple sleep latency test (MSLT).

RESULTS:

Multivariate stepwise logistic regression models revealed that subjective insomnia was independently associated with depressed mood (odds ratio [OR] = 1.79; 95% confidence interval (CI) [1.01-3.19]), autonomic symptoms (1.77 [1.08-2.90]), fatigue (1.19 [1.02-1.38]), and age (0.61 [0.39-0.96]). Subjective daytime sleepiness was associated with dosage of dopaminergic medication (1.74 [1.08-2.80]) and fatigue (1.14 [1.02-1.28]). On polysomnography, longer sleep latency correlated with autonomic symptoms (rho = 0.40, p = 0.01) and part I (non-motor symptoms) of the Unified PD Rating Scale (rho = 0.38, p = 0.02). Decreased sleep efficiency correlated with autonomic symptoms (rho = -0.42, p < 0.0001). However, no significant difference emerged on polysomnography and MSLTs between patients with or without insomnia or daytime sleepiness. Higher rates of apneic events did predict shorter sleep latencies on the MSLTs.

CONCLUSIONS:

Non-motor symptoms appear to be associated with subjective insomnia, whereas fatigue and dopaminergic medication are associated with subjective daytime sleepiness. Objective sleep laboratory data provided little insight into complaints of insomnia and sleepiness, though obstructive sleep apnea predicted worsened sleepiness when measured objectively.

Chemical produced by fungi produces Parkinson Disease-like neurodegeneration in flies

 

Researchers find that a chemical produced by fungi, called 1-octen-3-ol can produce the death of dopaminergic neurons and movement disorders in flies, hinting that this chemical may be capable of causing Parkinson's Disease in humans too.

This has raised concerns raised that moulds found in damp living conditions may contribute to PD in humans. This may even help explain the higher incidence of PD in rural areas, where more moulds and fungi can be found.

Could mould like this contribute to PD?

However, showing that these fungal compounds can cause neurodegeneration in flies most certainly does not prove that living in damp, mouldy conditions causes PD. In order to establish an association between damp living conditions and PD, 'epidemiological' evidence showing that poor quality housing increases risk of PD in humans will be required.

Inamdar AA, Hossain MM, Bernstein AI, Miller GW, Richardson JR, & Bennett JW (2013). Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America PMID: 24218591

Abstract: Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism. 

Cognitive and Motor Function in Long-Duration PARKIN-Associated Parkinson Disease

JAMA Neurol. 2013 Nov 4. doi: 10.1001/jamaneurol.2013.4498. [Epub ahead of print]

Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Orbe Reilly M, Ruiz D, Louis ED, Comella CL, Nance MA, Bressman SB, Scott WK, Tanner CM, Mickel SF, Waters CH, Fahn S, Cote LJ, Frucht SJ, Ford B, Rezak M, Novak KE, Friedman JH, Pfeiffer RF, Marsh L, Hiner B, Payami H, Molho E, Factor SA, Nutt JG, Serrano C, Arroyo M, Ottman R, Pauciulo MW, Nichols WC, Clark LN, Marder KS.

Source

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York.

Abstract

IMPORTANCE Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients. OBJECTIVE Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (&gt;14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers. MAIN OUTCOMES AND MEASURES Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose. RESULTS Carriers had an earlier age at onset of PD (P &lt; .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains. CONCLUSIONS AND RELEVANCE In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

Effects of rasagiline on olfactory function in patients with parkinson's disease

Mov Disord. 2013 Nov 4. doi: 10.1002/mds.25661. [Epub ahead of print]

Haehner A, Hummel T, Wolz M, Klingelhöfer L, Fauser M, Storch A, Reichmann H.

Source

Smell & Taste Clinic, Department of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany.

Abstract

BACKGROUND:

Impairment of olfactory function is a well-recognized nonmotor manifestation of Parkinson's disease (PD). The aim of this investigation was to determine if the MAO-B inhibitor rasagiline can improve olfaction in PD patients.

METHODS:

Thirty-four PD patients participated in this single-center, prospective, randomized, controlled, double-blind study. Seventeen patients were randomly assigned to rasagiline and 17 patients to placebo. Ortho- and retronasal olfactory testing and recording of event-related potentials were performed before and after 120 days of rasagiline versus placebo intake.

RESULTS:

When comparing olfactory score differences between baseline and after 120 days between the 2 groups, the level of significance was not reached.

CONCLUSIONS:

The primary end point of the study was not reached, and therefore, a specific effect of rasagiline on olfactory function in PD could not be demonstrated. 

Risk factors and prodromal markers and the development of Parkinson's disease.

J Neurol. 2013 Nov 5. [Epub ahead of print]

Lerche S, Seppi K, Behnke S, Liepelt-Scarfone I, Godau J, Mahlknecht P, Gaenslen A, Brockmann K, Srulijes K, Huber H, Wurster I, Stockner H, Kiechl S, Willeit J, Gasperi A, Fassbender K, Poewe W, Berg D.

Source

Department of Neurodegeneration and Hertie Institute for Clinical Brain Research, Center of Neurology, University of Tuebingen, Hoppe Seyler-Strasse 3, 72076, Tübingen, Germany.

Abstract

Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.

DNAJC13 mutations in Parkinson disease

This finding seems to fit in with the pathways that are emerging as being important in idiopathic Parkinson's disease.

Carles Vilariño-Güell, Alex Rajput, Austen J. Milnerwood, Brinda Shah, Chelsea Szu-Tu, Joanne Trinh, Irene Yu, Mary Encarnacion, Lise N. Munsie, Lucia Tapia, Emil K. Gustavsson, Patrick Chou, Igor Tatarnikov, Daniel M. Evans, Frederick T. Pishotta, Mattia Volta, Dayne Beccano-Kelly, Christina Thompson, Michelle K. Lin, Holly E. Sherman, Heather J. Han, Bruce L. Guenther, Wyeth W. Wasserman, Virginie Bernard, Colin J. Ross, Silke Appel-Cresswell, A. Jon Stoessl, Christopher A. Robinson, Dennis W. Dickson, Owen A. Ross, Zbigniew K. Wszolek, Jan O. Aasly, Ruey-Meei Wu, Faycal Hentati, Rachel A. Gibson, Peter S. McPherson, Martine Girard, Michele Rajput, Ali H. Rajput and Matthew J. Farrer

Hum. Mol. Genet. (2013)

doi: 10.1093/hmg/ddt570

First published online: November 11, 2013

Abstract

A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal dominant trait, which could not be ascribed to any known mutation. DNA from three affected members were subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically-matched controls. Subsequent genotyping was performed in a multi-ethnic case control series consisting of 2,928 patients and 2,676 control subjects from Canada, Norway, Taiwan, Tunisia and the United States.

A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions.

In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2, and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

The influence of age and gender on motor and non-motor features of early Parkinson's disease: Initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort

Parkinsonism Relat Disord. 2013 Oct 12. pii: S1353-8020(13)00356-8. doi: 10.1016/j.parkreldis.2013.09.025. [Epub ahead of print]

Szewczyk-Krolikowski K, Tomlinson P, Nithi K, Wade-Martins R, Talbot K, Ben-Shlomo Y, Hu MT.

Source

Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, United Kingdom; Oxford Parkinson Disease Centre, University of Oxford, Oxford, United Kingdom.

Abstract

BACKGROUND:

Identifying factors influencing phenotypic heterogeneity in Parkinson's Disease is crucial for understanding variability in disease severity and progression. Age and gender are two most basic epidemiological characteristics, yet their effect on expression of PD symptoms is not fully defined. We aimed to delineate effects of age and gender on the phenotype in an incident cohort of PD patients and healthy controls from the Oxford Parkinson Disease Centre (OPDC).

METHODS:

Clinical features, including demographic and medical characteristics and non-motor and motor symptoms, were analyzed in a group of PD patients within 3 years of diagnosis and a group of healthy controls from the OPDC cohort. Disease features were stratified according to age and compared between genders, controlling for effects of common covariates.

RESULTS:

490 PD patients and 176 healthy controls were analyzed. Stratification by age showed increased disease severity with age on motor scales. Some non-motor features showed similar trend, including cognition and autonomic features. Comparison across genders highlighted a pattern of increased severity and greater symptom symmetricality in the face, neck and arms in men with women having more postural problems. Amongst the non-motor symptoms, men had more cognitive impairment, greater rate of REM behavior disorder (RBD), more orthostatic hypotension and sexual dysfunction.

CONCLUSIONS:

Age in PD is a strong factor contributing to disease severity even after controlling for the effect of disease duration. Gender-related motor phenotype can be defined by a vertical split into more symmetrical upper-body disease in men and disease dominated by postural symptoms in women.

Yeast Reveal a "Druggable" Rsp5/Nedd4 Network that Ameliorates a-Synuclein Toxicity in Neurons

As we have mentioned before, there are currently no therapies for PD which target the underlying neurodegenerative process. Recent research published in Science, from Susan Lindquist's group (MIT), reveals pathways which could form ideal drug targets for neuroprotective treatments for PD.

Tardiff et al. used yeast cells expressing pathogenic α-synuclein (the main disease causing protein in PD) as a model for the cellular pathology in PD. Although these cells are not neurons, the α-synuclein causes very similar intracellular problems to that those found in the neurons of patients with PD and the inhibition of growth of the yeast cells provides a simple end-point for testing potential treatments.

Using this model, the authors proved that the compound N-aryl benzimidazole (NAB) strongly protects cells from α-synuclein toxicity and identified a network of proteins through which NAB exerts its protective effects. At the centre of this network was the protein Rsp5/Nedd4 which is involved in intracellular transport. The authors then showed that α-synuclein impairs intracellular transport and that NAB rescues Rsp5/Nedd4-dependent intracellular transport processes.

Thus, this study not only identifies Rsp5/Nedd4 as a new potential target for neuroprotective treatments, but also reveals the importance of dysregulated intracellular trnaport, which may drive the other pathological processes leading to neurodegeneration in PD.

How was this compound, NAB, initially identified?

Rather than selectively targeting cellular processes known to be involved in neurodegenerative diseases, the authors ran an 'unbiased' screen, more-or-less randomly testing over 190,000 different compounds for their ability to restore the growth of yeast cells following treatment with TDP-43 (another protein implicated in neurodegenerative diseases) (Tardiff et al, 2012).

 

NAB was initially shown to have protective effects in a yeast model expressing TDP-43 (Tardiff et al, 2012) but the group subsequently found it to be even more beneficial in a model expressing AS (a model of PD)

Of course this is not very efficient, but the beauty of the yeast model is that it is very cheap and quick to run, so such huge numbers of compounds can be easily tested.

By employing this 'unbiased' approach the authors were able to identify completely new therapeutic targets, rather than being restricted to potential targets based on our (currently quite poor) knoweldge of the cellular mechanisms involved in neurodegeneration.

How was NAB shown to have protective effects in models of PD?

In the yeast model of PD, NAB  prevented the accumulation of vesicular α-synuclein foci, the generation of reactive oxygen species, the block in ER-golgi trafficking and the nitration of proteins; all of which are part of the neurodegerative process in PD.

The authors then confirmed that NAB could also rescue neurons from the effects of α-synuclein in a nematode and a rat model of PD and finally in cells taken from PD patients which were turned into stem cells (iPSCs) and then differentiated into neurons.

Interestingly, NAB had no effect on levels of α-synuclein within the cell, indicating that it worked by inhibiting the down-stream damaging effects of α-synuclein, rather than preventing the accumulation of α-synucleinitself.

What are the mechanisms through which NAB has a protective effect?

A genetic screen of mutations in thousands of different genes then identified a core network of proteins through which NAB has its effects:

 

The network of genes with which NAD interacts, as indentified through a mutation screen. Colours represent type of mutation (green = overexpression, red = SNP, blue = transposon insertion, yellow = knock-out)

At the centre of this network is the protein Rsp5 (which is called Nadd4 in mammals). Rsp5 is a 'ubiquitin ligase' which promotes endosomal transport. NAB was found to exert many of its protective effects through this central node of the network. Specifically, NAB was found to promote the Rsp5-dependent endocytosis and delivery to the vacuole of the protein Mup1 and to promote the Rsp5-dependent Golgi-to-vacuole trafficking of the protein Sna3.

In the yeast model of PD, expression of AS was found to impair endosomal transport from the plasma membrane to the vacuole, as well as trafficking from the Golgi body to vacuoles; both these processes were rescued by NAB.

Why is this work really exciting?

NAB is a very long way from clinical trials -- it has yet to be tested in animal models, let alone humans -- thus, the protective effects of this compound are, on their own, not such exciting findings.

 Rather, the most interesting finding from this study is the revelation of the importance of Rsp5/Nedd4 in endosomal and ER-Golgi transport in PD: processes which are only recently becoming recognised as key to the underlying pathological process in PD (Esposito et al, 2012).

 

Dysfunctional endosomal and ER-Golgi trafficking contribute to core PD pathology and NAB restores these protective processes via Rsp5.

Tardiff et al. speculate that the processes we often consider to be the causes of neurodegeneration in PD (such as ROS production and mitochondrial dysfunction) are in fact secondary to the core pathology of intracellular transport dysfunction. Thus, in order to curb neurodegeneration in PD, it may be more fruitful to target these direct effects of AS, rather than the downstream secondary pathologies. Either way, dysfunctional intracellular trafficking in PD is line of research which warrants further attention.

References:



Lindquist S. (2013). Yeast Reveal a "Druggable" Rsp5/Nedd4 Network that Ameliorates a-Synuclein Toxicity in Neurons Science DOI: 10.1126/science.1245321

 
D.F. Tardiff, M. L. Tucci, K. A. Caldwell, G.A. Caldwell, S. Lindquist, Different 8-hydroxyquinolines protect models of TDP-43 protein, a-synuclein and polyglutamine proteotoxicity through distinct mechanisms. J. Biol. Chem. 287, 4107-4120 (2012).


G. Esposito, F. Ana Clara, P. Verstreken, Synaptic vesicle trafficking and Parkinson's disease. Dev. Neurobiol. 72, 134-144 (2012). Tardiff DF, Jui NT, Khurana V, Tambe MA, Thompson ML, Chung CY, Kamadurai HB, Kim HT, Lancaster AK, Caldwell KA, Caldwell GA, Rochet JC, Buchwald SL,