Saturday, 30 November 2013

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.

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.


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.

Friday, 29 November 2013

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.

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


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.

Wednesday, 27 November 2013

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.

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.


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.

Tuesday, 26 November 2013

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.

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.­­

Thursday, 21 November 2013

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.

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


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

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.

Sleep laboratory.

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


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).


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.

Wednesday, 20 November 2013

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.

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


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.

Tuesday, 19 November 2013

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.

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


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.

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.

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.


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.

Monday, 18 November 2013

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.

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.


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.

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).

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.


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.

Saturday, 16 November 2013

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. 

Friday, 15 November 2013

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.

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.


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.

Thursday, 14 November 2013

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.

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


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.

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.

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


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. 

Wednesday, 13 November 2013

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.

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


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.

Tuesday, 12 November 2013

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

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.

Friday, 8 November 2013

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.

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.


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).

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.

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.


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.

Thursday, 7 November 2013

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.


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, 

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

Lancet. 2013 Oct 31. pii: S0140-6736(13)62106-6. doi: 10.1016/S0140-6736(13)62106-6. [Epub ahead of print]
Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.


Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population.

In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with, number NCT01174004.

Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.

Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease.


ACADIA Pharmaceuticals.

Wednesday, 6 November 2013

Parkinson's disease patients first treated at age 75 years or older: A comparative study

Parkinsonism Relat Disord. 2013 Oct 18. pii: S1353-8020(13)00350-7. doi: 10.1016/j.parkreldis.2013.09.020. [Epub ahead of print]
Peretz C, Chillag-Talmor O, Linn S, Gurevich T, El-Ad B, Silverman B, Friedman N, Giladi N.

Department of Epidemiology, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.


Parkinson's disease (PD) first diagnosed at older age reportedly has different clinical characteristics and survival rates than when it is first diagnosed at younger age. We compared these features among PD patients who initiated anti-parkinsonian drugs at age 75-85 years (elderly) with those who started treatment at age 50-74 years (younger).

We used a population-based cohort of 4449 incident cases of PD patients aged 50-85 at treatment initiation, based on a pharmacy registry of Maccabi Health Maintenance Organization, with definite/probable/possible certainty of having PD. Mean follow-up was 3.9 ± 2.6 years. The two age groups were compared for time/risk to levodopa and to death, using Kaplan-Meier curves and Cox regression. Gender-specific standardized mortality rates (SMRs) accounting for Israeli death rates were also compared.

One-half of the entire cohort (n = 2148) were elderly (>75 years) and more likely to be given levodopa (Hazard Rate (HR) = 1.48, P < 0.05), had a significantly higher frequency of comorbidities (e.g., heart disease, hypertension and cancer), and had a 3-fold increased risk to die (HR = 2.97, P < 0.05) within the same follow-up time as the youngers. Accounting for the general Israeli population death rates, female PD patients had a significantly lower risk to die compared to males especially females who were elderly at treatment initiation (SMR = 1.53 for females vs. 1.73 for males, P < 0.05).


PD patients first diagnosed and treated at >74 years of age comprise a unique cluster for inclusion into drugs studies, mortality risk analyses and for projection of disease burden.

Tuesday, 5 November 2013

REM sleep behaviour disorder is associated with worse quality of life and other non-motor features in early Parkinson's disease

J Neurol Neurosurg Psychiatry. 2013 Nov 1. doi: 10.1136/jnnp-2013-306104. [Epub ahead of print]
Rolinski M, Szewczyk-Krolikowski K, Tomlinson PR, Nithi K, Talbot K, Ben-Shlomo Y, Hu MT.

Nuffield Department of Clinical Neurosciences, Division of Neurology, University of Oxford, Oxford, UK.


Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson's disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear.

The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors.

The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006).


pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.

Drawn by one of our PREDICT-PD participants...

... whose husband sadly passed away from Pancreatic cancer. A little reminder that there are other things out there that also need funding and research. Catching disease at the earliest possible stages can dramatically improve the outcome.

Monday, 4 November 2013

Antidepressants and REM Sleep Behavior Disorder: Isolated Side Effect or Neurodegenerative Signal?

Sleep. 2013 Nov 1;36(11):1579-85. doi: 10.5665/sleep.3102.
Postuma RB, Gagnon JF, Tuineaig M, Bertrand JA, Latreille V, Desjardins C, Montplaisir JY.

Department of Neurology, McGill University, Montreal General Hospital, Montreal, Québec, Canada ; Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada.


Antidepressants, among the most commonly prescribed medications, trigger symptoms of REM sleep behavior disorder (RBD) in up to 6% of users. Idiopathic RBD is a very strong prodromal marker of Parkinson disease and other synuclein-mediated neurodegenerative syndromes. It is therefore critically important to understand whether antidepressant-associated RBD is an independent pharmacologic syndrome or a sign of possible prodromal neurodegeneration.

Prospective cohort study.

Tertiary sleep disorders center.

100 patients with idiopathic RBD, all with diagnosis confirmed on polysomnography, stratified to baseline antidepressant use, with 45 matched controls.

Of 100 patients, 27 were taking antidepressants. Compared to matched controls, RBD patients taking antidepressants demonstrated significant abnormalities of 12/14 neurodegenerative markers tested, including olfaction (P = 0.007), color vision (P = 0.004), Unified Parkinson Disease Rating Scale II and III (P < 0.001 and 0.007), timed up-and-go (P = 0.003), alternate tap test (P = 0.002), Purdue Pegboard (P = 0.007), systolic blood pressure drop (P = 0.029), erectile dysfunction (P = 0.002), constipation (P = 0.003), depression indices (P < 0.001), and prevalence of mild cognitive impairment (13% vs. 60%, P < 0.001). All these abnormalities were indistinguishable in severity from RBD patients not taking antidepressants. However, on prospective follow-up, RBD patients taking antidepressants had a lower risk of developing neurodegenerative disease than those without antidepressant use (5-year risk = 22% vs. 59%, RR = 0.22, 95%CI = 0.06, 0.74).


Although patients with antidepressant-associated RBD have a lower risk of neurodegeneration than patients with "purely-idiopathic" RBD, markers of prodromal neurodegeneration are still clearly present. Development of RBD with antidepressants can be an early signal of an underlying neurodegenerative disease.

Saturday, 2 November 2013

Unrecognised vitamin D deficiency is common in Parkinson disease: a report from the Harvard Biomarker Study

The headline findings from this study are dramatic: patients with PD are nearly twice as likely as age matched controls to be deficient in vitamin D. Although this study does not reveal much regarding a possible causal role for vitamin D in PD, the results are clinically relevant.

An association between PD and low vitamin D levels has previously been reported in smaller observational studies (Sato et al., 1997; Evatt et al., 2008; Knekt et al., 2010) - although none of these found a correlation between vitamin D levels and disease severity. Further evidence for a causal role of vitamin D in PD come from genetic studies which have shown polymorphisms in the vitamin D receptor to be associated with increased risk of developing PD (Scherzner et al., 2007; Butler et al., 2011; Kim et al., 2005). Furthermore, in animal models of PD, vitamin D appears to have a neuroprotective effect (Wang et al., 2001). Taken together, this evidence points towards a link between vitamin D and Parkinson's disease, but up until now the studies have been small and subject to limitations.

This large case-control study provides new support for the existence of a relationship between PD and low vitamin D3 levels. Patients with PD were found to be nearly twice as likely as age matched controls to be deficient in vitamin D3 (17.6% vs 9.3%, p=0.002) and the degree of deficiency is correlated to the severity and duration of disease. However, after adjusting for age, sex, race and vitamin D3 supplementation the association between PD and vitD3 deficiency was only just statistically significant (p=0.047). As Raja Mahana points out in a response to the article, there was no adjusting for multiple statistical tests, which, if performed, may have tipped this value over the edge of the 95% cutoff for statistical significance (Mahana, 2013).

In addition, importantly, no significant association was found with total vitamin D levels, suggesting that vitamin D2 levels were not changed in patients with PD (they may even have been higher). The authors offer no explanation for these seemingly conflicting results - in fact, they do not mention this in their discussion at all.

This failure to discuss important negative findings, combined with the borderline statistical significance and the lack of correction for multiple comparisons mean this study should be treated with a degree of scepticism.

Further limitations include:
  1. Confounding - some additional, unmeasured factors may account for the association
  2. Generalisability - patients and controls were drawn entirely from two hospitals in a small area of Massachusetts and are therefore not representative of all patients with Parkinson's disease. Further studies in minority populations that may be at even higher risk of vitamin D deficiency are necessary.
  3. Correlation does not imply causation - the association found in this study could be explained if vitamin D deficiency accelerates PD pathology or if PD predisposes to vitamin D deficiency, because of a reduced tendency to go outdoors (sunlight is needed for the body to synthesise vitamin D).

Therefore it is impossible to make any claims about whether vitamin D deficiency causes Parkinson's Disease or whether Parkinson's Disease results in vitamin D deficiency from the results of this study alone.

Nonetheless, this study does show that patients with PD are at a considerably increased risk of vitamin D deficiency, whether as a result of confounding/reverse causality or not. The issues of confounding and reverse causality are only really important for scientists trying to understand whether low vitamin D has a causal role in PD. From a clinical viewpoint, all that really matters is that patients with PD have an increased risk of being vitamin D deficient and this, combined with an increased risk of falls and fractures, makes patients with PD an important population in which to consider testing of vitamin D levels and supplementation (Dobson et al, 2013). Ding H, Dhima K, Lockheart K et al. (2013). Unrecognized vitamin D3 deficiency is common in Parkinson disease Neurology DOI: 10.1212/WNL.0b013e3182a95818

Abstract: Unrecognized vitamin D3 deficiency is common in Parkinson disease

Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).

Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 6 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study.

Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values 5 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6%of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up.

Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Additional references:


Butler MW, Burt A, Edwards TL, Zuchner S, Scott WK, Martin ER, Vance JM, Wang L (2011) Vitamin D receptor gene as a candidate gene for Parkinson disease. Ann Hum Genet 75: 201-210

Dobson R, Yarnall A, Noyce AJ, Giovannoni G (2013) Bone health in chronic neurological diseases: a focus on Multiple sclerosis and Parkinsonian syndromes. Pract Neurol 13: 70-79

Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V (2008) Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 65: 1348-1352

Kim JS, Kim YI, Song C, Yoon I, Park JW, Choi YB, Kim HT, Lee KS (2005) Association of vitamin D receptor gene polymorphism and Parkinson's disease in Koreans. J Korean Med Sci 20: 495-498

Knekt P, Kilkkinen A, Rissanen H, Marniemi J, Sääksjärvi K, Heliövaara M (2010) Serum vitamin D and the risk of Parkinson disease. Arch Neurol 67: 808-811

Mehanna R (2013) Is Parkinson's disease associated with deficit in Vitamin D? Neurology

Sato Y, Iwamoto J, Honda Y (2011) Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in Parkinson's disease. Parkinsonism Relat Disord 17: 22-26

Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson's disease based on gene expression in blood. Proc Natl Acad Sci U S A 104: 955-960

Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y (2001) Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 904: 67-75


Plain English - Low body mass index and life prognosis in Parkinson's disease

Over the last few years we have seen research that suggests being underweight has a negative or detrimental effect on survival with diseases...