Simple decision aid for those newly diagnosed with Parkinson's

"I prepared this graph to help newly diagnosed Parkinson's patients share their treatment choices with their doctor. Happy to hear feedback - is it helpful or unhelpful?"

- Alastair Noyce

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy-a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

Sleep Med. 2013 Jul 22. pii: S1389-9457(13)00175-5. doi: 10.1016/j.sleep.2013.02.016. [Epub ahead of print]

Schenck CH, Montplaisir JY, Frauscher B, Hogl B, Gagnon JF, Postuma R, Sonka K, Jennum P, Partinen M, Arnulf I, Cochen de Cock V, Dauvilliers Y, Luppi PH, Heidbreder A, Mayer G, Sixel-Döring F, Trenkwalder C, Unger M, Young P, Wing YK, Ferini-Strambi L, Ferri R, Plazzi G, Zucconi M, Inoue Y, Iranzo A, Santamaria J, Bassetti C, Moeller JC, Boeve BF, Lai YY, Pavlova M, Saper C, Schmidt P, Siegel JM, Singer C, St Louis E, Videnovic A, Oertel W.

Source

Minnesota Regional Sleep Disorders Center, Department of Psychiatry, Hennepin County Medical Center and University of Minnesota Medical School, Minneapolis, MN, USA.

Abstract

OBJECTIVES:

We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD.

METHODS:

The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]).

RESULTS:

Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies.

CONCLUSIONS:

The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Drug-induced Parkinson`s disease. A clinical review

Neurosciences (Riyadh). 2013 Jul;18(3):215-21.

Bohlega SA, Al-Foghom NB.

Source

Section of Neurology, Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia.

Abstract

Drug-induced Parkinsonism must always be suspected when parkinsonian symptom like rigidity, tremor, or postural instability appear in patients receiving drug treatment. Indeed, drug-induced Parkinsonism is a frequent etiology of secondary Parkinsonism. The main causative drugs are antipsychotic, other neuroleptic drugs, and calcium-channel entry blockers. The risk associated with antipsychotics is often dose dependent and related to dopamine D2 striatal occupancy. The risk is less for the second-generation atypical antipsychotic. The other treatments rarely involved are antidepressants, antivirals, anti-arrhythmics, lithium, valproic acid, and others. Regression of symptom will be observed in most cases after a mean delay of 3 months after cessation of treatment. In one-tenth of cases, symptoms persist after drug withdrawal leading to the diagnosis of underlined idiopathic Parkinson`s disease.

Update on diffusion MRI in Parkinson's disease and atypical parkinsonism

J Neurol Sci. 2013 Jul 15. pii: S0022-510X(13)00310-9. doi: 10.1016/j.jns.2013.06.032. [Epub ahead of print]

Meijer FJ, Bloem BR, Mahlknecht P, Seppi K, Goraj B.

Source

Radboud University Nijmegen Medical Centre, Department of Radiology, Nijmegen, The Netherlands. 

Abstract

Differentiating Parkinson's disease (PD) from other types of neurodegenerative atypical parkinsonism (AP) can be challenging, especially in early disease stages. Routine brain magnetic resonance imaging (MRI) can show atrophy or signal changes in several parts of the brain with fairly high specificity for particular forms of AP, but the overall diagnostic value of routine brain MRI is limited. In recent years, various advanced MRI sequences have become available, including diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI). Here, we review available literature on the value of diffusion MRI for identifying and quantifying different patterns of neurodegeneration in PD and AP, in relation to what is known of underlying histopathologic changes and clinical presentation of these diseases. Next, we evaluate the value of diffusion MRI to differentiate between PD and AP and the potential value of serial diffusion MRI to monitor disease progression. We conclude that diffusion MRI may quantify patterns of neurodegeneration which could be of additional value in clinical use. Future prospective clinical cohort studies are warranted to assess the added diagnostic value of diffusion MRI.

Relationship of olfactory function with olfactory bulbus volume, disease duration and Unified Parkinson's disease rating scale scores in patients with early stage of idiopathic Parkinson's disease

J Clin Neurosci. 2013 Jul 16. pii: S0967-5868(13)00109-4. doi: 10.1016/j.jocn.2012.11.017. [Epub ahead of print]

Hakyemez HA, Veyseller B, Ozer F, Ozben S, Bayraktar GI, Gurbuz D, Cetin S, Yildirim YS.

Source

Haseki Training and Research Hospital, Department of Neurology, Istanbul, Turkey.

Abstract

We aimed to investigate the relationship between olfactory function and olfactory bulbus (OB) volume, disease duration and Unified Parkinson's disease rating scale (UPDRS) scores in early stage idiopathic Parkinson's disease patients. The University of Pennsylvania Smell Identification Test (UPSIT) was used for the evaluation of olfactory function. UPSIT scores for patients with Parkinson's disease were significantly lower than controls. There was no significant difference between stage 1 and stage 2 patients. OB volumes were higher in stage 1 and 2 patients than controls, but there was no statistical difference between the three groups. No significant correlation was found between UPSIT and UPDRS total scores, nor between UPSIT scores and disease duration in stage 1 and 2 patients. According to our results, we propose UPSIT be used as a screening test to diagnose presymptomatic patients, but not OB volumes.

Nicotine increases lifespan and rescues olfactory and motor deficits in a Drosophila model of Parkinson's disease

Behav Brain Res. 2013 Jul 16. pii: S0166-4328(13)00419-1. doi: 10.1016/j.bbr.2013.07.020. [Epub ahead of print]

Chambers RP, Call GB, Meyer D, Smith J, Techau JA, Pearman K, Buhlman LM.

Source

Department of Biomedical Sciences, College of Health Sciences, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, United States.

Abstract

Drosophila melanogaster is an attractive model of familial Parkinson's disease, as flies with loss-of-function mutations of the parkin gene exhibit many pathologies observed in PD patients. Progressive motor deficits found in homozygous parkin mutants seem to result from mitochondrial pathology that causes indirect flight muscle and dopaminergic neuronal degeneration [1,2]. We have found that heterozygous parkin mutants have decreased lifespan, generally progressive motor dysfunction and olfactory deficits compared to control flies, suggesting that mutation of this gene produces a dominant phenotype. Tobacco smokers are dose-dependently less likely to develop PD [3-5]; subsequent in vitro and in vivo studies show that nicotine is protective in models of sporadic PD [6]. Literature addressing the potential protection by nicotine in Parkin loss-of-function models spans limited concentrations and selected time points in the organism's lifespan. We have found that parkin heterozygotes have late-onset climbing and flying deficits as well as decreased viability and olfactory deficits that precede motor defects. While chronic nicotine exposure decreases lifespan and climbing and flying abilities in control flies, it can improve viability and flying capability as well as rescue climbing and olfactory deficits in parkin heterozygotes. Dopaminergic neurons are spared in the parkin heterozygote, perhaps because this phenotype is less severe than in the homozygous parkin mutants. Nicotine pretreatment may be protective in sporadic PD patients and models; however, timely diagnosis remains to be an obstacle. Our results suggest that nicotine also may be protective in familial PD patients, who can be easily identified before motor symptoms occur.

Parkinson's disease-cognitive rating scale: Psychometrics for mild cognitive impairment

Mov Disord. 2013 Jul 19. doi: 10.1002/mds.25568. [Epub ahead of print]

Fernández de Bobadilla R, Pagonabarraga J, Martínez-Horta S, Pascual-Sedano B, Campolongo A, Kulisevsky J.

Source

Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Barcelona, Spain; Movement Disorders Section, Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.

Abstract

Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinson's disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD-Cognitive Rating Scale (PD-CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD-NC) group and a PD with MCI (PD-MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale-2 (MDRS-2). The discriminative power of the PD-CRS for PD-MCI was examined in a representative sample of 234 patients (145 in the PD-NC group; 89 in the PD-MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD-CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution-based and anchor-based approaches) was explored in a 6-month observational multicenter trial involving a subset of 120 patients (PD-NC, 63; PD-MCI, 57). Regression analysis demonstrated that PD-CRS total scores (P < 0.001) and age (P = 0.01) independently differentiated PD-NC from PD-MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80-0.90) indicated that a score ≤81 of 134 was the optimal cutoff point on the total score for the PD-CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD-CRS total score was indicative of clinically significant change. These findings suggest that the PD-CRS is a useful tool to identify PD-MCI and to track cognitive changes in nondemented patients with PD.

Mild cognitive impairment in Parkinson's disease.

Age Ageing. 2013 Jul 17. [Epub ahead of print]

Yarnall AJ, Rochester L, Burn DJ.

Source

Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, Tyne and Wear NE4 5PL, UK.

Abstract

The concept of mild cognitive impairment (MCI) in the general population has received increased attention over recent years, and is associated with risk of progression to Alzheimer's disease. Within Parkinson's disease (PD), MCI (PD-MCI) is also now recognised to be relatively common, with certain subtypes predicting progression to Parkinson's disease dementia (PDD). Recently, criteria to better characterise PD-MCI and its subtypes have been produced by the Movement Disorder Society. In contrast to the population as a whole, where amnestic MCI is the most common subtype, non-amnestic PD-MCI dominates, with prominent executive and attention dysfunction. Although the pathophysiology of PD-MCI is poorly understood and encompasses both PD and non-PD pathology, it is most likely the result of a complex interaction between neurotransmitter dysfunction, synaptic pathology, protein aggregation and neuronal damage. Determining the factors that influence the progression of these pathologies in PD and the individuals at risk of ultimately developing PDD is critical for targeted intervention and drug discovery studies. Further work is required, however, to determine the significance of PD-MCI and also to validate the diagnostic criteria. This would be best delivered in the form of longitudinal studies in homogenous cohorts of PD participants, to allow prognostication and generalisation among the PD population. At the present time, no drug therapies are available for PD-MCI. Management includes screening for the disorder, excluding treatable causes of cognitive decline and cautious use of dopamine agonists and medications such as anticholinergics.

Acute complications of movement disorders surgery: Effects of age and comorbidities

Mov Disord. 2013 Jul 16. doi: 10.1002/mds.25610. [Epub ahead of print]

Rughani AI, Hodaie M, Lozano AM.

Source

Neuroscience Institute, Maine Medical Center, Portland, Maine, United States.

Abstract

The most common indication for movement disorder surgery is Parkinson's disease (PD), and the incidence of PD increases with age. The analysis reported here was undertaken with the primary goal of examining whether there is a relationship between peri-operative complications and age. The Nationwide Inpatient Sample (Agency for Healthcare Research and Quality, Rockville, MD, USA) was queried for 10 years beginning in 1999 for patients undergoing deep brain stimulator insertion, pallidotomy, and thalamotomy for treatment of PD, essential tremor, and dystonia. Inpatient complications, including death, stroke (both ischemic and hemorrhagic), and other overall complications were examined. The relative risks associated with advanced age; primary diagnosis; treatment modality; the diagnoses of hypertension, diabetes, and nicotinism; and the cumulative number of comorbidities were examined. There were 5464 patients who met inclusion criteria, including 4145 patients treated for PD and 4961 patients treated with deep brain stimulation (DBS). Overall in-hospital mortality was 0.26%, with 0.15% related to surgical factors. There was a correlation between in-hospital mortality, increasing age, and number of medical comorbidities. After multivariate regression no factor remained predictive of mortality. Having more than 1 medical comorbidity or PD increased the risk of in-hospital complications. Patients with PD were more likely to suffer hemorrhage or stroke. Hypertension, diabetes, nicotinism, and modality of treatment were not associated with increased mortality, hemorrhage or stroke risk, or in-hospital mortality in univariate or multivariate analysis. Both age and medical comorbidity are correlated with in-hospital complications, but age appears to serve as a surrogate for comorbidity. Surgery for PD appears to carry an increased risk of hemorrhage or stroke and in-hospital complications.

Measurement of costs and scales for outcome evaluation in health economic studies of Parkinson's disease

Mov Disord. 2013 Jul 16. doi: 10.1002/mds.25571. [Epub ahead of print]

Dodel R, Jönsson B, Reese JP, Winter Y, Martinez-Martin P, Holloway R, Sampaio C, Růžička E, Hawthorne G, Oertel W, Poewe W, Stebbins G, Rascol O, Goetz CG, Schrag A.

Source

Department of Neurology, Philipps-University Marburg, Marburg, Germany.

Abstract

Health economic studies in Parkinson's disease (PD) have become increasingly common in recent years. Because several methodologies and instruments have been used to assess cost and outcomes in PD, the Movement Disorder Society (MDS) commissioned a Task Force to assess their properties and make recommendations regarding their use. A systematic literature review was conducted to explore the use of those instruments in PD and to determine which should be selected for this review. We assessed approaches to evaluate cost of illness (COI), cost effectiveness, and cost utilities, which include the use of direct (standard gamble, time trade-off. and visual analogue scales) and indirect instruments to measure health status and utilities. No validated instruments/models were identified for the evaluation of COI or cost-effectiveness in patients with PD; therefore, no instruments in this group are recommended. Among utility instruments, only a few of these outcome instruments have been used in the PD population, and only limited psychometric data are available for these instruments with respect to PD. Because psychometric data for further utility instruments in conditions other than PD already exist, the standard gamble and time trade-off methods and the EQ-5D (a European quality-of-life health states instrument) and Health Utility Index instruments met the criteria for scales that are "recommended (with limitations)," but only the EQ-5D has been assessed in detail in PD patients. The MDS Task Force recommends further study of these instruments in the PD population to establish core psychometric properties. For the assessment of COI, the Task Force considers the development of a COI instrument specifically for PD, like that available for Alzheimer's disease.

Rasagiline adjunct therapy in patients with Parkinson's disease: Post hoc analyses of the PRESTO and LARGO trials

Parkinsonism Relat Disord. 2013 Jul 9. pii: S1353-8020(13)00219-8. doi: 10.1016/j.parkreldis.2013.06.001. [Epub ahead of print]

Elmer LW.

Source

Department of Neurology, University of Toledo College of Medicine, Toledo, OH 43614, USA.

Abstract

BACKGROUND:

Rasagiline was safe and effective when used as adjunct therapy with levodopa in patients with moderate-to-advanced Parkinson's disease (PD) in the phase III PRESTO and LARGO studies.

OBJECTIVE:

To assess clinical effects of rasagiline 1 mg/day on cardinal PD symptoms and motor fluctuations in defined patient subgroups using pooled data from PRESTO and LARGO.

METHODS:

Both double-blind, randomized, and placebo-controlled studies included PD patients with motor fluctuations despite optimized therapy with levodopa, with or without concomitant dopamine agonists (DA) or catechol-O-methyltransferase inhibitor (COMT-I) treatment. These post hoc analyses measured effects of rasagiline 1 mg vs placebo on individual cardinal PD symptoms during ON time and mean change from baseline in daily OFF time in subgroups of patients who at baseline were receiving only levodopa, were considered "mild fluctuators" (daily OFF time ≤ 4 h), and who were or were not receiving concomitant DA or COMT-I therapy.

RESULTS:

Compared with placebo, rasagiline significantly improved all cardinal PD symptoms and significantly reduced adjusted mean daily OFF time when used as first adjunct therapy in levodopa-treated patients and in patients with mild motor fluctuations. Significant improvement in motor fluctuations was reported with rasagiline regardless of concomitant DA or COMT-I use. Overall incidence of dopaminergic adverse events did not increase with concomitant DA or COMT-I use.

CONCLUSION:

Rasagiline was an effective first adjunct therapy in levodopa-treated patients; benefited patients with signs of early "wearing off"; improved all cardinal PD symptoms; and further improved symptoms in patients already receiving other adjunctive dopaminergic treatment.

Advances in the genetics of Parkinson disease

Nat Rev Neurol. 2013 Jul 16. doi: 10.1038/nrneurol.2013.132. [Epub ahead of print]

Trinh J, Farrer M.

Source

Department of Medical Genetics, UBC Pavillion Hospital, 2nd floor, Room S-132 Koerner Building, VCHRI, 2211 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

Abstract

Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies.

A Single-Center, Cross-Sectional Prevalence Study of Impulse Control Disorders in Parkinson Disease: Association With Dopaminergic Drugs

J Clin Psychopharmacol. 2013 Jul 12. [Epub ahead of print]

Poletti M, Logi C, Lucetti C, Del Dotto P, Baldacci F, Vergallo A, Ulivi M, Del Sarto S, Rossi G, Ceravolo R, Bonuccelli U.

Source

From the *Department of Neuroscience, University of Pisa, Pisa; †Neurology Unit, Hospital of Viareggio, USL 12 Toscana; and ‡Unit of Epidemiology and Biostatistics, Institute of Clinical Physiology, National Research Council, Pisa, Italy.

Abstract

The current study aimed at establishing the prevalence of impulse control disorders (ICDs) in patients with Parkinson disease (PD) and their association with demographic, drug-related, and disease-related characteristics. We performed a single-center cross-sectional study of 805 PD patients. Impulse control disorders were investigated with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease; also comorbid neuropsychiatric complications (dementia, delusions, visual hallucinations) were investigated with clinical interviews and ad hoc instruments (Parkinson Psychosis Questionnaire and Neuropsychiatry Inventory). Impulse control disorders were identified in 65 patients (prevalence, 8.1%), with pathological gambling and hypersexuality the most frequent. Impulse control disorders were present in 57 of 593 cognitively preserved patients (prevalence, 9.6%) and in 8 of 212 demented patients (prevalence, 3.8%). Impulse control disorders were significantly associated with dopamine agonists (odds ratio [OR], 5.50; 95% confidence interval [CI], 2.60-12.46; P < 0.0001) and levodopa (OR, 2.43; 95% CI, 1.06-6.35; P = 0.034). Impulse control disorders frequency was similar for pramipexole and ropinirole (16.6% vs 12.5%; OR, 1.45; 95% CI, 0.79-2.74; P = 0.227). Additional variables associated with ICDs were male sex and younger age. These findings suggested that dopaminergic treatments in PD are associated with increased odds of having an ICD, but also other demographic and clinical variables are associated with ICDs, suggesting the multifactorial nature of the ICD phenomenon in PD.

C9ORF72 Intermediate Repeat Copies Are a Significant Risk Factor for Parkinson Disease

Ann Hum Genet. 2013 Jul 12. doi: 10.1111/ahg.12033. [Epub ahead of print]

Nuytemans K, Bademci G, Kohli MM, Beecham GW, Wang L, Young JI, Nahab F, Martin ER, Gilbert JR, Benatar M, Haines JL, Scott WK, Züchner S, Pericak-Vance MA, Vance JM.

Source

University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, 1501 NW 10th Ave, Miami, FL, 33136, USA.

Abstract

We set out to determine whether expansions in the C9ORF72 repeat found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) families are associated with Parkinson disease (PD). We determined the repeat size in a total of 889 clinically ascertained patients (including PD and essential tremor plus Parkinsonism (ETP)) and 1144 controls using a repeat-primed PCR assay. We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk. However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls. Overall, 14 cases (13 PD, 1 ETP) and three controls had >20 repeat copies (Fisher's exact test p = 0.002). Further, seven cases and no controls had >23 repeat copies (p = 0.003). Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP. This also suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease. Further studies are needed to elucidate the contribution of the C9ORF72 repeat in the overall PD population and to determine whether other common genetic risk factors exist between these neurodegenerative disorders.

Imaging of Dopamine in PD and Implications for Motor and Neuropsychiatric Manifestations of PD

Front Neurol. 2013 Jul 9;4:90. Print 2013.

de la Fuente-Fernández R.

Source

Section of Neurology, Hospital A. Marcide, Complejo Hospitalario Universitario de Ferrol (CHUF) , Ferrol , Spain.

Abstract

Parkinson's disease (PD) is characterized by dopamine depletion in the putamen, which leads to motor dysfunction. As the disease progresses, a substantial degree of dopamine depletion also occurs in caudate and nucleus accumbens. This may explain a number of neuropsychiatric manifestations, including depression, apathy, and cognitive decline. Dopamine replacement therapy partially restores motor function but long-term treatment is often associated with motor complications (motor fluctuations and dyskinesias). Positron emission tomography (PET) studies suggest that the dopamine release rate is substantially higher in PD subjects with motor complications compared to stable responders. Notably, this differential pattern of dopamine release is already present in the early stages of the disease, before motor complications become clinically apparent. Converging evidence suggests that striatal dopamine depletion in PD leads to reduced plasticity in the primary motor cortex and, presumably, in non-motor cortical areas as well. Although dopamine replacement therapy tends to restore physiological plasticity, treatment-induced motor, and neuropsychiatric complications could be related to abnormalities in corticostriatal synaptic plasticity.

Alcohol Consumption, Types of Alcohol, and Parkinson's Disease

PLoS One. 2013 Jun 19;8(6):e66452. Print 2013.

Liu R, Guo X, Park Y, Wang J, Huang X, Hollenbeck A, Blair A, Chen H.

Source

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.

Abstract

BACKGROUND:

The epidemiologic evidence on alcohol consumption and Parkinson's disease (PD) is equivocal. We prospectively examined total alcohol consumption and consumption of specific types of alcoholic beverage in relation to future risk of PD.

METHODS:

The study comprised 306,895 participants (180,235 male and 126,660 female) ages 50-71 years in 1995-1996 from the NIH-AARP Diet and Health Study. Consumption of alcoholic beverages in the past 12 months was assessed in 1995-1996. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models.

RESULTS:

A total of 1,113 PD cases diagnosed between 2000 and 2006 were included in the analysis. Total alcohol consumption was not associated with PD. However, the association differed by types of alcoholic beverages. Compared with non-beer drinkers, the multivariate ORs for beer drinkers were 0.79 (95% CI: 0.68, 0.92) for <1 drink/day, 0.73 (95% CI: 0.50, 1.07) for 1-1.99 drinks/day, and 0.86 (95% CI: 0.60, 1.21) for ≥2 drinks/day. For liquor consumption, a monotonic increase in PD risk was suggested: ORs (95% CI) were 1.06 (0.91, 1.23), 1.22 (0.94, 1.58), and 1.35 (1.02, 1.80) for <1, 1-1.99, and ≥2 drinks/day, respectively (P for trend <0.03). Additional analyses among exclusive drinkers of one specific type of alcoholic beverage supported the robustness of these findings. The results for wine consumption were less clear, although a borderline lower PD risk was observed when comparing wine drinkers of 1-1.99 drinks/day with none drinkers (OR = 0.74, 95% CI: 0.53, 1.02).

CONCLUSIONS:

OUR RESULTS SUGGEST THAT BEER AND LIQUOR CONSUMPTION MAY HAVE OPPOSITE ASSOCIATIONS WITH PD: low to moderate beer consumption with lower PD risk and greater liquor consumption with higher risk. These findings and potential underlying mechanisms warrant further investigations.

Repetitive transcranial magnetic stimulation improves handwriting in Parkinson's disease

Parkinsons Dis. 2013;2013:751925. doi: 10.1155/2013/751925. Epub 2013 May 8.

Randhawa BK, Farley BG, Boyd LA.

Source

Graduate Program in Rehabilitation Sciences, University of British Columbia, 212-2177 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.

Abstract

Background. Parkinson disease (PD) is characterized by hypometric movements resulting from loss of dopaminergic neurons in the substantia nigra. PD leads to decreased activation of the supplementary motor area (SMA); the net result of these changes is a poverty of movement. The present study determined the impact of 5 Hz repetitive transcranial magnetic stimulation (rTMS) over the SMA on a fine motor movement, handwriting (writing cursive "l"s), and on cortical excitability, in individuals with PD. Methods. In a cross-over design, ten individuals with PD were randomized to receive either 5 Hz or control stimulation over the SMA. Immediately following brain stimulation right handed writing was assessed. Results. 5 Hz stimulation increased vertical size of handwriting and diminished axial pressure. In addition, 5 Hz rTMS significantly decreased the threshold for excitability in the primary motor cortex. Conclusions. These data suggest that in the short term 5 Hz rTMS benefits functional fine motor task performance, perhaps by altering cortical excitability across a network of brain regions. Further, these data may provide the foundation for a larger investigation of the effects of noninvasive brain stimulation over the SMA in individuals with PD.

PREDICT-PD: Identifying risk of Parkinson's disease in the community: methods and baseline results.

J Neurol Neurosurg Psychiatry. 2013 Jul 4. [Epub ahead of print]

Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Knowles CH, Hardy J, Giovannoni G, Nageshwaran S, Osborne C, Lees AJ, Schrag A.

Source

Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, , London, UK.

Abstract

OBJECTIVES:

To present methods and baseline results for an online screening tool to identify increased risk for Parkinson's disease (PD) in the UK population.

METHODS:

Risk estimates for future PD were derived from the results of a systematic review of risk factors and early features of PD. Participants aged 60-80 years without PD were recruited by self-referral. They completed an online survey (including family history, non-motor symptoms and lifestyle factors), a keyboard-tapping task and the University of Pennsylvania Smell Identification Test. Risk scores were calculated based on survey answers. Preliminary support for the validity of this algorithm was assessed by comparing those estimated to be higher risk for PD with those at lower risk using proxies, including smell loss, REM-sleep behaviour disorder and reduced tapping speed, and by assessing associations in the whole group.

RESULTS:

1324 eligible participants completed the survey and 1146 undertook the keyboard-tapping task. Smell tests were sent to 1065 participants. Comparing the 100 highest-risk participants and 100 lowest-risk participants, median University of Pennsylvania Smell Identification Test scores were 30/40 versus 33/40 (p<0.001), mean number of key taps in 30 s were 55 versus 58 (p=0.045), and 24% versus 10% scored above cut-off for REM-sleep behaviour disorder (p=0.008). Regression analyses showed increasing risk scores were associated with worse scores in the three proxies across the whole group (p≤0.001).

CONCLUSIONS:

PREDICT-PD is the first study to systematically combine risk factors for PD in the general population. Validity to predict risk of PD will be tested through longitudinal follow-up of incident PD diagnosis.

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems.

Maturitas. 2013 Jul 1. pii: S0378-5122(13)00182-5. doi: 10.1016/j.maturitas.2013.05.019. [Epub ahead of print]

Garbayo E, Ansorena E, Blanco-Prieto MJ.

Source

Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain.

Abstract

Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.

Drivers with Parkinson's disease: are the symptoms of PD associated with restricted driving practices?

J Neurol. 2013 Jul 3. [Epub ahead of print]

Crizzle AM, Myers AM, Roy EA, Almeida QJ.

Source

School of Public Health and Health Systems, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, ON, N2L 3G1, Canada

Abstract

This study examined whether symptoms (motor, cognitive, vision, sleepiness, depression) of Parkinson's disease (PD) were associated with restricted driving practices. To quantify driving practices, electronic devices were installed in the vehicles of 27 drivers with PD (78 % men; M = 71.6, SD = 6.6; Unified Parkinson's Disease Rating Scale (UPDRS) motor score M = 30.1, SD = 8.6; disease duration M = 3.9, SD = 2.8 years) and 20 controls (80 % men; M = 70.6, SD = 7.9) for 2 weeks. Participants completed measures of sleepiness, depression, quality of life, and assessments of motor, cognitive and visual functions. The PD group had significantly slower brake response times (p < 0.05), poorer cognitive and quality of life scores (p < 0.01) and greater depression (p < 0.05) compared to controls. Slower reaction time was significantly related to reduced driving; specifically, fewer trips (r = -0.46; p < 0.05), distance (r = -0.54, p < 0.01) and duration at night (r = -0.58, p < 0.01). Better cognitive scores were associated with driving less often in difficult situations such as bad weather and rush hour (p < 0.05), as well as reduced speed on city streets, but only for the control group. While most drivers with PD rated their overall health as good or excellent, the five PD drivers who rated their health more poorly had significantly worse clinical symptoms (UPDRS motor scores, contrast sensitivity, depression, brake response time) and more restricted driving patterns. These findings show that drivers with PD who perceive their health poorly have greater symptomatology and were more likely to restrict their driving, possibly due to noticeable declines in multiple driving-related abilities.

Recent developments in biomarkers in Parkinson disease

Curr Opin Neurol. 2013 Aug;26(4):395-400. doi: 10.1097/WCO.0b013e3283633741.

Schapira AH.

Source

Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.

Abstract

PURPOSE OF REVIEW:

Parkinson disease is the second most common neurodegenerative disease after Alzheimer disease, and current demographic trends indicate a life-time risk approaching 4% and predict a doubling of prevalence by 2030. Strategies are being developed to apply recent advances in our understanding of the cause of Parkinson disease to the development of biomarkers that will enable the identification of at-risk individuals, enable early diagnosis and reflect the progression of disease. The latter will be particularly important for the testing of disease-modifying therapies. This review summarizes recent advances in Parkinson disease biomarker development.

RECENT FINDINGS:

Recent reports continue to reflect the application of a variety of clinical, imaging or biochemical measurements, alone or in combination, to general Parkinson disease populations. Probably the most promising is the assay of alpha-synuclein in the diagnosis and evolution of Parkinson disease. At present, detection techniques are still being refined, but once accurate and reproducible assays are available, it will be important to define the relationship of these to early diagnosis and progression. Alpha-synuclein concentrations may also be modulated by certain disease-modifying agents in development and so may represent a measure of their efficacy. It has to be accepted that no single measure currently fulfils all the necessary criteria for a biomarker in Parkinson disease, but combinations of measures are more likely to deliver benefit.

SUMMARY:

The Parkinson disease biomarker field is approaching a stage when certain combinations of clinical, imaging and biochemical measures may identify a proportion of individuals at risk for developing the disease. However, their general applicability may be limited. Attention is now turning to stratification of Parkinson disease into certain at-risk groups defined by genotype. The application of multimodal screening to these populations may be more rewarding in the short term.

Different β-amyloid binding patterns in Alzheimer and Parkinson diseases: It's the network!

Neurology. 2013 Jul 3. [Epub ahead of print]

Eidelberg D, Martin W.

Source

From the Center for Neurosciences (D.E.), The Feinstein Institute for Medical Research, Manhasset, NY; and the Department of Medicine (Neurology) (W.M.), University of Alberta, Edmonton, Canada.

Abstract

11C-Pittsburgh compound B (PiB) PET is a sensitive and increasingly popular imaging tool for assessing the deposition of fibrillar β-amyloid aggregates in the brains of living patients with Alzheimer disease (AD). Increased cortical PiB binding also occurs in dementia with Lewy bodies, but rarely in cognitively impaired individuals with Parkinson disease (PD).1,2 To date, most PiB PET studies have focused on identifying significant group differences in radiotracer binding in single brain regions or in the cortex overall. However, recent evidence suggests that the deposition of protein aggregates in neurodegenerative disorders evolves at the systems level, with involvement of discrete sets of interconnected brain regions.3,4 In this regard, techniques of pattern analysis based upon principal component analysis (PCA) and other multivariate procedures are increasingly used to quantify disease-related circuit changes in functional brain images.5.

Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus

J Neurol Neurosurg Psychiatry. 2013 Jun 29. [Epub ahead of print]

Vriend C, Raijmakers P, Veltman DJ, van Dijk KD, van der Werf YD, Foncke EM, Smit JH, Berendse HW, van den Heuvel OA.

Source

Department of Psychiatry, VU University Medical Center, , Amsterdam, The Netherlands.

Abstract

BACKGROUND:

Depression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD.

METHODS:

In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non-demented PD patients (median Hoehn & Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [123I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT).

RESULTS:

Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients.

CONCLUSIONS:

These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatal-thalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression.

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Neuropathy in Parkinson's Disease Patients with Intestinal Levodopa Infusion versus Oral Drugs

PLoS One. 2013 Jun 20;8(6):e66639. Print 2013.

Jugel C, Ehlen F, Taskin B, Marzinzik F, Müller T, Klostermann F.

Source

Department of Neurology, Charité - University Medicine, Campus Benjamin Franklin, Berlin, Germany.

Abstract

BACKGROUND:

Severe polyneuropathy has been observed in a number of patients treated for Parkinson's disease with Levodopa/Carbidopa intestinal gel infusion. This may reflect a rare individual complication or a systematic side effect.

OBJECTIVE:

To investigate whether peripheral nerve function differed between patients with oral treatment versus Levodopa/Carbidopa intestinal gel infusion.

METHODS:

In an observational design, data from median, tibial, and peroneal neurography were prospectively assessed and compared between patients with conventional drug treatment (n = 15) and with Levodopa/Carbidopa intestinal gel infusion (n = 15). The groups were matched for age and disease duration. In view of the medical risk profile for polyneuropathy, comorbidity and basic serological parameters were assessed.

RESULTS:

Axonal neuropathy was common in both patient groups. However, although group differences in risk factors for polyneuropathy were not evident, neurographic abnormalities were more severe in the patients treated with Levodopa/Carbidopa intestinal gel infusion than in the orally treated patients. In the group with Levodopa/Carbidopa intestinal gel infusion, the degree of neuropathic change correlated with weight lost since therapy initiation and with the drug dose. In contrast to the axonal abnormalities, conduction velocity was found normal in both groups.

CONCLUSION:

The results are compatible with the promotion of axonal neuropathy by Levodopa/Carbidopa intestinal gel infusion. This could be due to the intrinsically high levodopa doses associated with the therapy and/or malnutritional effects from intestinal drug application. The results should be corroborated by a larger longitudinal and controlled trial.

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CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer's disease

Acta Neuropathol. 2013 Jun 29. [Epub ahead of print]

Toledo JB, Korff A, Shaw LM, Trojanowski JQ, Zhang J.

Source

Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Abstract

Alzheimer's disease (AD) and Lewy body diseases (LBD), e.g., Parkinson's disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of α-synuclein (α-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau181 (p-tau181), and amyloid beta1-42 (Aβ1-42) in subjects of the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between α-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson's Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF α-syn levels was observed in the ADNI cohort, with high levels of α-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between α-syn and p-tau181, there was a mismatch (α-syn-p-tau181-Mis), i.e., higher p-tau181 levels accompanied by lower α-syn levels in a subset of ADNI patients. We hypothesize that this α-syn-p-tau181-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF α-syn and calculation of α-syn-p-tau181-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.

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Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation.

Mov Disord. 2013 Jul 1. doi: 10.1002/mds.25535. [Epub ahead of print]

Angeli A, Mencacci NE, Duran R, Aviles-Olmos I, Kefalopoulou Z, Candelario J, Rusbridge S, Foley J, Pradhan P, Jahanshahi M, Zrinzo L, Hariz M, Wood NW, Hardy J, Limousin P, Foltynie T.

Source

Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, United Kingdom.

Abstract

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

© 2013 The Authors. Movement Disorders published by Wiley on behalf of The Movement Disorder Society.

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Clinical, genetic, and brain sonographic features related to Parkinson's disease in Gaucher disease

J Neurol. 2013 Jun 29. [Epub ahead of print]

Böttcher T, Rolfs A, Meyer B, Grossmann A, Berg D, Kropp P, Benecke R, Walter U.

Source

Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Rostock, Germany.

Abstract

Homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause Gaucher disease. Moreover, heterozygous glucocerebrosidase gene mutations represent the most common genetic risk factor for Parkinson's disease (PD) known so far. Substantia nigra (SN) hyperechogenicity, a sonographic feature thought to reflect iron accumulation, has been described in both PD and Gaucher disease patients. Here we studied how clinical, genetic, and brain sonographic findings relate to the occurrence of PD in Gaucher disease. Sixteen Gaucher disease patients, 12 PD patients, and 32 control subjects were enrolled. The glucocerebrosidase genotypes were identified by DNA sequencing. All subjects underwent transcranial ultrasound, and eight Gaucher disease patients additionally MRI for comparison with SN ultrasound findings. SN hyperechogenicity and reduced echogenicity of brainstem raphe were more frequent in Gaucher disease patients (62, 37 %) than in controls (12, 12 %; p < 0.001, p < 0.05). SN hyperechogenicity in Gaucher disease patients was unrelated to type or severity of glucocerebrosidase gene mutation, but correlated with iron-sensitive MRI-T2 hypointensity of SN pars compacta, and with age at start of enzyme replacement therapy. While none of the five Gaucher disease patients with signs of PD (definite PD, n = 4; early PD, n = 1) had severe glucocerebrosidase gene mutations known to cause neuronopathic Gaucher disease, all carried a N370S allele, previously reported to predict non-neuronopathic Gaucher disease. Hyposmia, higher non-motor symptoms score (constipation, depression, executive dysfunction), and SN hyperechogenicity were characteristic features of Gaucher disease-related PD. We conclude that the combined clinical, genetic, and transcranial sonographic assessment may improve the PD risk evaluation in Gaucher disease.

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Five-year fracture risk estimation in patients with Parkinson's disease

Bone. 2013 Jun 22. pii: S8756-3282(13)00236-6. doi: 10.1016/j.bone.2013.06.018. [Epub ahead of print]

Pouwels S, Bazelier MT, de Boer A, Weber WE, Neef CK, Cooper C, de Vries F.

Source

Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, Netherlands. Electronic address: s.pouwels@uu.nl.

Abstract

BACKGROUND:

Previous studies have shown that patients with Parkinson's Disease (PD) are at increased risk of fractures. However, no specific prediction model for fracture estimation among PD patients is currently available. Therefore, the aim of this study was to develop a simple score for estimating the 5-year osteoporotic and hip fracture risk among patients with PD.

METHODS:

The UK Clinical Practice Research Datalink (1987-2011) was used to identify incident PD patients. Cox proportional-hazards models were used to calculate the 5-year risk of osteoporotic and hip fracture among PD patients. The regression model was fitted with various risk factors for fracture and the final Cox model was converted into integer risk scores.

RESULTS:

We identified 4,411 incident PD patients without a history of osteoporotic treatment. The 5-year risks of osteoporotic and hip fracture were plotted in relation to the risk score. Risk scores increased with age, female gender, history of renal disease and history of dementia. The C-statistic, which is a parameter to test the internal validity of the model, was reasonable for the prediction of osteoporotic fracture (0.69) and hip fracture (0.73).

CONCLUSION:

In this study, we developed a simple model to estimate 5-year fracture risk among incident PD patients. It may be useful in daily practice after external validation.