Does Parkinson's Disease and Type-2 Diabetes Mellitus Present Common Pathophysiological Mechanisms and Treatments?

CNS Neurol Disord Drug Targets. 2013 Sep 18. [Epub ahead of print]

Lima Mms, Targa Ads, Noseda Acd, Rodrigues LS, Delattre AM, Dos Santos Fv, Fortes MH, Maturana MJ, Ferraz AC.

Source

Universidade Federal do Paraná, Setor de Ciências Biológicas, Departamento de Fisiologia, Av. Francisco H. dos Santos s/n ZIP: 81.531 - 990, Caixa Postal: 19031, Curitiba - Paraná - Brasil. 

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease afflicting about 1% of people over 65 years old and 4-5% of people over 85 years. It is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. In this scenario, chronic systemic inflammation, as well as impaired mitochondrial metabolism, have also been suspected of playing a role in the development of type-2 diabetes, and the possibility of a shared pathophysiology of Parkinson's disease and type-2 diabetes has been proposed. The discussion about the interactions between PD and type-2 diabetes mellitus began in the 1960's and there is still controversy. Insulin and dopamine (DA) may exert reciprocal regulation hence; hypoinsulinaemia induced by streptozotocin decreased the amounts of DA transporter and tyrosine hydroxylase transcripts in the substantia nigra pars compacta (SNpc). Accordingly, DA depletion in the striatum is able to decreases insulin signaling in basal ganglia, indicating that, perhaps, PD may be considered as a risk factor for the development of type-2 diabetes mellitus. In this sense, it is described that PPAR-γ, KATP, AMPK, GLP-1 and DPP-4 are important therapeutic targets for PD and reinforces the association with diabetes. Therefore, the objective of the present review is to contextualize the mutual pathophysiological interactions between PD and type-2 diabetes mellitus, as well as the potential common treatments.

How to measure substantia nigra hyperechogenicity in Parkinson disease: detailed guide with video

J Ultrasound Med. 2013 Oct;32(10):1837-43. doi: 10.7863/ultra.32.10.1837.

Walter U.

Source

Department of Neurology, University of Rostock, Gehlsheimer Strasse 20, D-18147 Rostock, Germany.

Abstract

The detection of an enlarged echogenic size ("hyperechogenicity") of the substantia nigra on transcranial sonography is increasingly used for the early and differential diagnosis of Parkinson disease. However, the diagnostic value of substantia nigra sonography depends on the quality of its execution. This article with an accompanying video presents a step-by-step description and demonstration of ultrasound system settings, typical errors in assessment of the substantia nigra, planimetric measurement of substantia nigra echogenicity according to current guidelines, and its diagnostic implications in 2 exemplary patients with parkinsonism. Published cutoff values for grading substantia nigra hyperechogenicity with different ultrasound systems and novel technologies are reviewed.

Multiple sclerosis and risk of Parkinson's disease: a Danish nationwide cohort study

Eur J Neurol. 2013 Sep 19. doi: 10.1111/ene.12255. [Epub ahead of print]

Nielsen NM, Pasternak B, Stenager E, Koch-Henriksen N, Frisch M.

Source

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Abstract

BACKGROUND AND PURPOSE:

Case reports have observed a co-occurrence of multiple sclerosis (MS) and Parkinson's disease (PD) and it has been hypothesized that MS lesions could affect dopaminergic pathways causing parkinsonism. Our aim was to examine the association between MS and PD in a historically prospective cohort study using Danish nationwide register data.

METHODS:

Multiple sclerosis patients identified in the Multiple Sclerosis Registry were followed for PD from 1977 to 2011 in the National Patient Register. As measures of relative risk, ratios of observed to expected incidence rates of first hospitalization for PD amongst persons with MS were used, i.e. standardized incidence ratios (SIRs) with 95% confidence intervals (CIs).

RESULTS:

Amongst 15 557 MS patients 26 cases of PD were observed versus 26.51 expected, reflecting no overall increased risk of PD (SIR 0.98, 95% CI 0.67-1.44). Similar estimates were seen for female (SIR 0.99, 95% CI 0.58-1.67) and male MS patients (SIR 0.97, 95% CI 0.55-1.72). Likewise, no increased risk of PD amongst MS patients was observed in a robustness analysis backdating the date of diagnosis of PD by 5 years to account for the time lag between disease onset and first hospital contact with PD (SIR 0.57, 95% CI 0.32-1.00).

CONCLUSION:

Our data do not suggest an increased risk of PD amongst patients with MS.

Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease

PLoS One. 2013 Aug 23;8(8):e71634. doi: 10.1371/journal.pone.0071634.

Gardai SJ, Mao W, Schüle B, Babcock M, Schoebel S, Lorenzana C, Alexander J, Kim S, Glick H, Hilton K, Fitzgerald JK, Buttini M, Chiou SS, McConlogue L, Anderson JP, Schenk DB, Bard F, Langston JW, Yednock T, Johnston JA.

Source

Elan Pharmaceuticals, Research, South San Francisco, California, United States of America.

Abstract

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.

Genetic comorbidities in Parkinson's disease

"In this study lead by Professor Nalls we looked at genetic information from a large number of people with Parkinson's and a large number without. We gathered information from genetic regions associated with factors/diseases that have been previously reported to be associated with Parkinson's. We then compared the two groups to see if there were differences in these regions. We found that the Crohn's disease, which is a type of inflammatory bowel disease, and schizophrenia genetic profiles were statistically associated Parkinson's. This potentially gives us further insight into the mechanisms underlying such diseases."

"For those that follow the PREDICT-PD study you will see that the method above is the inverse of what we are doing in PREDICT. Here we are using genetic data to identify genetic risk of associated diseases in those with established PD, whereas in PREDICT we are using the associated diseases and factors to identify risk of PD (and PD genes)."

- Alastair Noyce

Hum Mol Genet. 2013 Sep 20. [Epub ahead of print]

Nalls MA, Saad M, Noyce AJ, Keller MF, Schrag A, Bestwick JP, Traynor BJ, Gibbs JR, Hernandez DG, Cookson MR, Morris HR, Williams N, Gasser T, Heutink P, Wood N, Hardy J, Martinez M, Singleton AB; for the International Parkinson's Disease Genomics Consortium (IPDGC); The Wellcome Trust Case Control Consortium 2 (WTCCC2); North American Brain Expression Consortium (NABEC); the United Kingdom Brain Expression Consortium (UKBEC).

Source

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.

Abstract

Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known GWAS loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.

http://hmg.oxfordjournals.org

Therapeutic prospects for parkinson's disease

Ann Neurol. 2013 Aug 22. doi: 10.1002/ana.24011. [Epub ahead of print]

Olanow CW, Schapira A.

Source

Departments of Neurology and Neuroscience, Mount Sinai School of Medicine.

Abstract

INTRODUCTION:

Parkinson's disease (PD) affects approximately 5 million persons globally, and prevalence is expected to markedly increase in the coming decades due to aging of the population. The disease is characterized clinically by motor features (rest tremor, rigidity, bradykinesia) and pathologically by degeneration of nigrostriatal dopamine neurons. Current therapy is primarily based on a dopamine replacement strategy using the dopamine precursor levodopa. Levodopa is effective for virtually all patients, particularly in the early stages of the disease. However, chronic treatment is associated with the development of motor complications (fluctuations in motor response and dyskinesia) in the majority of patients. Additional classes of drugs have been developed to try and enhance dopaminergic tone. These include dopamine agonists which act directly on the dopamine receptor, monoamine oxidase-B (MAO-B) inhibitors which increase synaptic dopamine levels by blocking central dopamine oxidative metabolism, and catechol-O-methyltransferase (COMT) inhibitors which increase the elimination half-life and bioavailability of levodopa by blocking its peripheral metabolism1 . Surgical therapies such as deep brain stimulation (DBS) have proven valuable in treating motor complications that cannot be satisfactorily controlled with medical therapy. However, none of these treatments provide anti-parkinsonian benefits superior to levodopa and most patients eventually develop intolerable disability. Further, non-dopaminergic features emerge that are not adequately controlled by levodopa.1 Indeed, in the levodopa era, non-dopamine features such as gait disturbance, falls, and dementia represent the major source of disability for advanced PD patients. There remains a need for new therapies that a) provide symptomatic benefits that are not associated with motor complications, b) treat the non-dopaminergic features, and c) slow, stop, or reverse disease progression. 

Incidence of Dementia With Lewy Bodies and Parkinson Disease Dementia

JAMA Neurol. 2013 Sep 16. doi: 10.1001/jamaneurol.2013.3579. [Epub ahead of print]

Savica R, Grossardt BR, Bower JH, Boeve BF, Ahlskog JE, Rocca WA.

Source

Department of Neurology, College of Medicine, Mayo Clinic, Rochester, Minnesota2Division of Epidemiology, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota.

Abstract

IMPORTANCE Epidemiologic data on dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) remain limited in the United States and worldwide. These data are essential to guide research and clinical or public health interventions. OBJECTIVE To investigate the incidence of DLB among residents of Olmsted County, Minnesota, and compare it with the incidence of PDD. DESIGN The medical records linkage system of the Rochester Epidemiology Project was used to identify all persons who developed parkinsonism and, in particular, DLB or PDD from 1991 through 2005 (15 years). A movement disorders specialist reviewed the complete medical records of each suspected patient to confirm the diagnosis. SETTING Olmsted County, Minnesota, from 1991 through 2005 (15 years). PARTICIPANTS All the residents of Olmsted County, Minnesota, who gave authorization for medical record research. MAIN OUTCOMES AND MEASURES Incidence of DLB and PDD. RESULTS Among 542 incident cases of parkinsonism, 64 had DLB and 46 had PDD. The incidence rate of DLB was 3.5 per 100 000 person-years overall, and it increased steeply with age. The incidence of PDD was 2.5 overall and also increased steeply with age. The incidence rate of DLB and PDD combined was 5.9. Patients with DLB were younger at onset of symptoms than patients with PDD and had more hallucinations and cognitive fluctuations. Men had a higher incidence of DLB than women across the age spectrum. The pathology was consistent with the clinical diagnosis in 24 of 31 patients (77.4%) who underwent autopsy. CONCLUSIONS AND RELEVANCE The overall incidence rate of DLB is lower than the rate of Parkinson disease. The incidence of DLB increases steeply with age and is markedly higher in men. This men to women difference may suggest different etiologic mechanisms. Our findings may guide health care planning and prompt new studies.

Cheek cell-derived α-synuclein and DJ-1 do not differentiate Parkinson's disease from control

Neurobiol Aging. 2013 Sep 13. pii: S0197-4580(13)00342-4. doi: 10.1016/j.neurobiolaging.2013.08.008. [Epub ahead of print]

Stewart T, Sui YT, Gonzalez-Cuyar LF, Wong DT, Akin DM, Tumas V, Aasly J, Ashmore E, Aro P, Ginghina C, Korff A, Zabetian CP, Leverenz JB, Shi M, Zhang J.

Source

Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.

Abstract

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD.

Selecting the best patient groups for clinical trials: insights from the CamPaIGN study of Parkinson’s disease

This post was inspired by a talk given by Prof Roger Barker, to whom all credit for the ideas below must be attributed. His group are also doing some very exciting work on cell based therapies and viral-RNA based therapies for PD which I plan to write about in the future.
 

In addition to identifying PD as early as possible, being able to identify those with a more severe, rapidly-progressing form of the disease would help with deciding who should be entered into clinical trials of disease-modifying therapies.

Longitudinal studies of patients with PD (such as the CamPaIGN study) have shown that while some patients with PD may have ‘good’ outcomes (no dementia or postural instability) even 10 years after their diagnosis, others may progress much more rapidly to getting dementia or postural instability [1].

This second group with a more rapidly-progressing underlying disease process, would be the ideal group with which to trial new potentially disease-modifying therapies, whereas those with a more ‘benign’ form of PD are likely to do well with dopaminergic based therapies.

Therefore, being able to predict whether a patient will have a benign or rapidly-progressing disease course is important, not only for patients’ and their families’ own information, but also to optimise who gets what treatment.

Luckily, the CamPaIGN study managed to identify a few factors which predict a rapid progression to Parkinson’s disease dementia, including:

• Age 
• Poor semantic fluency [1] – reduced ability to name as many animals as possible from memory in 90 seconds
• Poor overlapping pentagon drawing – poor ability to replicate the overlapping
• Having two copies of the H1 variant of the gene ‘MAPT’. This encodes a protein called ‘Tau’ which has been implicated in a number of neurodegenerative diseases, including Alzheimer’s [2]
• Having a single abnormal copy of the GBA gene. ALL the patients with a single GBA mutation in the CamPaiGN study developed dementia by 8 years. (GBA is a gene which causes Gaucher’s disease when two mutated copies are inherited. People with a single mutation do not develop Gaucher’s and are otherwise healthy, they are known to have an increased risk of developing PD)

 

This is a great example of how epidemiological evidence can inform clinical practice (by allowing doctors to more accurately assess prognosis), add to our understanding of the mechanisms of disease (in this case, by suggest a role for Tau in the pathology of Parkinson’s disease dementia) and help optimise our efforts to find new treatments for a disease (by helping to select the best patients for trials of new therapies).

References:

1. Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, Barker RA: The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013.

2. Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, et al.: Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 2007, 62:145-153.

Screening for early detection of parkinsonism using a self-administered questionnaire: A cross-sectional epidemiologic study

Neurotoxicology. 2013 Sep 12. pii: S0161-813X(13)00134-4. doi: 10.1016/j.neuro.2013.08.010. [Epub ahead of print]

Lundin JI, Checkoway H, Criswell SR, Hobson A, Harris RC, Swisher LM, Evanoff BA, Racette BA.

Source

University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA. Electronic address: jlundin2@uw.edu.

Abstract

BACKGROUND:

Manganese (Mn) is a common component of welding fume. Exposure to Mn fume has been associated with parkinsonism. A simple and reliable screening tool to evaluate Mn exposed workers for neurotoxic injury would have broad occupational health application.

METHODS:

This study investigated 490 occupational welders recruited from a trade union list. Subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism, intermediate, and normal groups were defined as UPDRS3 score ≥15, 6-15, and <6, respectively. Workers completed a health status questionnaire (PDQ39) and a Parkinson's disease (PD) Symptoms Questionnaire. Areas under receiver operator curve (AUC) were analyzed based on these scores, adjusted for age, smoking, race, gender, and neurologist, using normal as the reference.

RESULTS:

The AUC was 0.79 (95% confidence interval [CI]=0.73-0.84) for PDQ39 and 0.78 (95% CI=0.72-0.85) for PD Symptoms Questionnaire score. At 70% sensitivity, the specificity for PDQ39 score and PD Symptoms Questionnaire score for the prediction of parkinsonism was 73.1% and 80.1%, respectively.

CONCLUSIONS:

These results suggest the questionnaires have reasonably good sensitivity and specificity to predict parkinsonism in Mn exposed workers. These questionnaires could be a valuable first step in a tiered screening approach for Mn exposed workers.

The nucleus basalis of Meynert: A new target for deep brain stimulation in dementia?

Neurosci Biobehav Rev. 2013 Sep 11. pii: S0149-7634(13)00206-6. doi: 10.1016/j.neubiorev.2013.09.003. [Epub ahead of print]

Gratwicke J, Kahan J, Zrinzo L, Hariz M, Limousin P, Foltynie T, Jahanshahi M.

Source

Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, UK, WC1N 3BG.

Abstract

Dementia is a major cause of disability amongst the elderly and represents a serious global health issue. Current treatments for dementia are limited; at best they provide inadequate symptomatic relief. In contrast, there are a plethora of approaches that provide symptomatic relief for abnormalities of movement including surgical approaches. Deep brain stimulation has been used successfully to directly alter processing in neural networks and thereby improve movement functions. Here we describe the anatomy, intrinsic organization and connectivity of the cholinergic nucleus basalis of Meynert, a basal forebrain structure implicated in cognitive functions including memory, attention, arousal and perception. A significant body of evidence suggests that degeneration of the nucleus and its cortical projections underlies the cognitive decline seen in dementia. We review this evidence and postulate that deep brain stimulation to this nucleus may be able to improve specific cognitive functions. This could represent a novel treatment strategy for some dementias in carefully selected individuals. Controlled trials of deep brain stimulation of the nucleus basalis of Meynert for Parkinson's disease dementia and Alzheimer's disease are required to evaluate potential efficacy and the mechanisms of possible cognitive changes.

Quantitative wearable sensors for objective assessment of Parkinson's disease

Mov Disord. 2013 Sep 12. doi: 10.1002/mds.25628. [Epub ahead of print]

Maetzler W, Domingos J, Srulijes K, Ferreira JJ, Bloem BR.

Source

Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.

Abstract

There is a rapidly growing interest in the quantitative assessment of Parkinson's disease (PD)-associated signs and disability using wearable technology. Both persons with PD and their clinicians see advantages in such developments. Specifically, quantitative assessments using wearable technology may allow for continuous, unobtrusive, objective, and ecologically valid data collection. Also, this approach may improve patient-doctor interaction, influence therapeutic decisions, and ultimately ameliorate patients' global health status. In addition, such measures have the potential to be used as outcome parameters in clinical trials, allowing for frequent assessments; eg, in the home setting. This review discusses promising wearable technology, addresses which parameters should be prioritized in such assessment strategies, and reports about studies that have already investigated daily life issues in PD using this new technology.

Rotigotine for anxiety during wearing-off in Parkinson's disease with dementia

Aging Clin Exp Res. 2013 Sep 10. [Epub ahead of print]

Fanciulli A, Assogna F, Caltagirone C, Spalletta G, Pontieri FE.

Source

Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso - NeSMOS, "Sapienza" Università di Roma, Via di Grottarossa, 1035, 00189, Rome, Italy.

Abstract

BACKGROUND:

Wearing-off (WO) refers to the exacerbation of motor and/or non-motor symptoms of Parkinson's disease at the end of dose of dopaminergic medications. Treatment of WO is based on modifying drug schedule, meal timetable and/or increasing dopamine replacement therapy. In advanced and/or demented patients, management of WO is often limited by scarce compliance and by cognitive, psychiatric and dysautonomic side-effects that may accompany increased dopaminergic stimulation.

METHODS:

Here, we report 2 patients suffering from Parkinson's disease with dementia, who experienced anxiety as non-motor symptom of WO under stable levodopa therapy. In both cases, transdermal rotigotine (4 mg/day) was added to the original dopaminergic therapy.

RESULTS:

Rotigotine proved beneficial on symptoms of anxiety in both patients, without worsening cognitive and behavioral symptoms. During the 9-month follow-up period, there was a slight improvement of motor impairment, with no worsening of drug-related dyskinesia.

CONCLUSIONS:

These preliminary results suggest that rotigotine at low dose might improve non-motor symptoms of WO in elderly patients suffering from Parkinson's disease with dementia, without raising major safety issues.

Quality of life in Parkinson's disease caregivers: the contribution of personality traits

Biomed Res Int. 2013;2013:151872. doi: 10.1155/2013/151872. Epub 2013 Aug 19.

Tew EH, Naismith SL, Pereira M, Lewis SJ.

Source

Parkinson's Disease Research Clinic, Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2050, Australia.

Abstract

Parkinson's disease imposes significant demands not only on patients but also on those people living and caring for them, who often have a reduction in their quality of life. The factors that may ameliorate these effects, such as an individual's personality, are not understood. Therefore, the aim of this study was to look at the relative contribution of caregiver personality on their quality of life, specifically attempting to identify those traits, which may be protective or harmful. Two hundred and seventy-four caregivers of patients with Parkinson's disease were included in this study. Caregivers were given questionnaires to complete, including the Big Five Inventory and the World Health Organisation Quality of Life BREF version. Univariate correlations demonstrated that depression and anxiety were the largest predictors of reduced quality of life amongst caregivers. However, after controlling for these potential confounds, conscientiousness was associated with enhanced psychological quality of life and openness positively predicted benefits in the environmental domain. Neuroticism was associated with reduced quality of life in the psychological domain. Thus, screening for neuroticism may help identify those caregivers who would benefit from intervention strategies, which could in the long term help reduce the need for nursing home placement of Parkinson's disease patients.

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease

Parkinsonism Relat Disord. 2013 Aug 29. pii: S1353-8020(13)00305-2. doi: 10.1016/j.parkreldis.2013.08.011. [Epub ahead of print]

Bunzeck N, Singh-Curry V, Eckart C, Weiskopf N, Perry RJ, Bain PG, Düzel E, Husain M.

Source

Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany. 

Abstract

BACKGROUND:

In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population.

METHODS:

Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals.

RESULTS:

We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus.

CONCLUSIONS:

Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease.

Influence of Single Nucleotide Polymorphisms in COMT , MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson's Disease

Neurodegener Dis. 2013 Sep 5. [Epub ahead of print]

Cheshire P, Bertram K, Ling H, O'Sullivan SS, Halliday G, McLean C, Bras J, Foltynie T, Storey E, Williams DR.

Source

Department of Medicine (Neuroscience), Monash University (Alfred Hospital), Melbourne, Vic., Australia.

Abstract

Background: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence. Objective: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID. Methods: We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course. Results: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025). Conclusions: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation.

Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome: Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications

Nancy J. Butcher, Tim-Rasmus Kiehl, Lili-Naz Hazrati, Eva W. C. Chow, Ekaterina Rogaeva, Anthony E. Lang, Anne S. Bassett

JAMA Neurol. Published online September 09, 2013

Importance   Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition.

Objective   To evaluate a possible association between 22q11.2 deletions and PD.

Design, Setting, and Participants   An observational study of the occurrence of PD in the world’s largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.

Main Outcomes and Measures   A clinical diagnosis of PD made by a neurologist and neuropathological features of PD.

Results   Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein–positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.

Conclusions and Relevance   These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.

Comparison of once-daily versus twice-daily combination of Ropinirole prolonged release in Parkinson's disease

BMC Neurol. 2013 Sep 2;13(1):113. [Epub ahead of print]

Yun JY, Kim HJ, Lee JY, Kim YE, Kim JS, Kim JM, Jeon BS.

Abstract

BACKGROUND:

Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease.

METHODS:

This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI).

RESULTS:

A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen.

CONCLUSION:

RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.Trial registration: This study is registered with ClinicalTrials.gov, number NCT00986245.

Motor fluctuations and Helicobacter pylori in Parkinson's disease

J Neurol. 2013 Sep 4. [Epub ahead of print]

Rahne KE, Tagesson C, Nyholm D.

Source

NeuroCenter Saint Göran Hospital, Stockholm, Sweden.

Abstract

The presence of Helicobacter pylori (HP) in the gastrointestinal tract may limit the absorption of levodopa. The objectives of this study were to investigate whether HP infection may affect the clinical response to levodopa as well as levodopa dose requirement in patients with Parkinson's disease (PD) as well as to investigate whether HP infection may affect plasma levels of vitamin B12, folic acid, and homocysteine. Seventy-five patients with PD diagnosed at least 4 years ago were included. Symptom fluctuations were assessed by UPDRS-IV and the WOQ9 wearing-off-scale. Plasma levels of vitamin B12, folic acid, and homocysteine were analyzed. Screening for HP was performed with a 13C-labeled urea breath test (Diabact UBT). A propensity-matched analysis was made where each patient in the HP-infected group was matched with one patient in the non-infected group with respect to age and gender. Of the 75 included patients, 20 were HP infected (27 %). Median Hoehn & Yahr scores were 3 in both HP infected patients and the matched group (n = 20). HP-infected patients had decreased "complications of therapy" with average total UPDRS-IV score of 4.8 ± 3.0 vs. 7.7 ± 3.8 (p < 0.05), despite no significant difference in levodopa equivalent dose. Wearing-off and sleep disturbance were significantly less common in the HP group (p < 0.05). There were no differences regarding vitamin B12, folic acid, or homocysteine values. HP infection in patients with PD may result in a decreased occurrence of symptom fluctuations according to this small study. This finding may be due to altered absorption of levodopa in the gastrointestinal tract in patients with HP infection, but further studies are required.

Association of stressful life events with incident falls and fractures in older men: the Osteoporotic Fractures in Men (MrOS) Study

Age Ageing. 2013 Sep 3. [Epub ahead of print]

Fink HA, Kuskowski MA, Marshall LM.

Source

VA Medical Center, Geriatric Research Education and Clinical Center, One Veterans Drive, 11-G, Minneapolis, MN 55417, USA.

Abstract

BACKGROUND:

small, retrospective studies suggest that major life events and/or sudden emotional stress may increase fall and fracture risk. The current study examines these associations prospectively.

METHODS:

a total of 5,152 men aged ≥65 years in the Osteoporotic Fractures in Men study self-reported data on stressful life events for 1 year prior to study Visit 2. Incident falls and fractures were ascertained for 1 year after Visit 2. Fractures were centrally confirmed.

RESULTS:

a total of 2,932 (56.9%) men reported ≥1 type of stressful life event. In men with complete stressful life event, fall and covariate data (n = 3,949), any stressful life event was associated with a 33% increased risk of incident fall [relative risk (RR) 1.33, 95% confidence interval (CI) 1.19-1.49] and 68% increased risk of multiple falls (RR = 1.68, 95% CI = 1.40-2.01) in the year following Visit 2 after adjustment for age, education, Parkinson's disease, diabetes, stroke, instrumental activities of daily living (IADL) impairment, chair stand time, walk speed, multiple past falls, depressive symptoms and antidepressant use. Risk increased with the number of types of stressful life events. Though any stressful life event was associated with a 58% increased age-adjusted risk for incident fracture, this association was attenuated and no longer statistically significant after additional adjustment for total hip bone mineral density, fracture after age 50, Parkinson's disease, stroke and IADL impairment.

CONCLUSIONS:

in this cohort of older men, stressful life events significantly increased risk of incident falls independent of other explanatory variables, but did not independently increase incident fracture risk.

Integrated multidisciplinary care in Parkinson's disease: a non-randomised, controlled trial (IMPACT)

Lancet Neurol. 2013 Aug 23. pii: S1474-4422(13)70196-0. doi: 10.1016/S1474-4422(13)70196-0. [Epub ahead of print]

van der Marck MA, Munneke M, Mulleners W, Hoogerwaard EM, Borm GF, Overeem S, Bloem BR; for the IMPACT study group.

Source

Department of Neurology, Nijmegen Centre for Evidence Based Practice, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.

Abstract

BACKGROUND:

A multidisciplinary approach is thought to be the best way to manage the motor and non-motor symptoms of Parkinson's disease, but how such care should be delivered is unknown. To address this gap in knowledge, we assessed the effectiveness of an integrated multidisciplinary approach compared with usual care.

METHODS:

We recruited patients for our non-randomised controlled trial from six community hospitals in the Netherlands (two in regions where the integrated care intervention was available and four in control regions that administered usual care). Eligible patients were those with Parkinson's disease, aged 20-80 years, and without severe cognitive impairment or comorbidity. Patients in the intervention group were offered an individually tailored comprehensive assessment in an expert tertiary referral centre and subsequent referrals to a regional network of allied health professionals specialised in Parkinson's disease. Primary outcomes were activities of daily living (Academic Medical Center linear disability score [ALDS]) and quality of life (Parkinson's disease quality of life questionnaire [PDQL]) measured at 4, 6, and 8 months. Secondary outcomes included motor functioning (unified Parkinson's disease rating scale, part III [UPDRS III], at 4 months), caregiver burden (belastungsfragebogen Parkinson angehörigen-kurzversion [BELA-A-k] at 4 and 8 months), and costs (during whole study period). Primary analysis was by intention to treat and included scores over 4, 6, and 8 months, with correction for baseline score. The trial is registered at Clinicaltrials.gov, number NCT00518791.

FINDINGS:

We recruited 301 patients (150 patients in the intervention group and 151 in the control group) between August, 2007, and December, 2009, of whom 285 completed follow-up (last follow-up was July, 2010). 101 (67%) patients in the intervention group visited the expert centre; 49 (33%) opted not to visit the expert centre. The average ALDS score from months 4, 6, and 8, with correction for baseline score, was greater in the intervention group than in the control group (difference 1·3 points, 95% CI -2·1 to 2·8; corresponding raw logit score difference 0·1, 95% CI 0·003 to 0·2) as was the average PDQL score (difference 3·0 points, 0·4 to 5·6). Secondary analysis with correction for baseline disease severity showed no differences between groups for ALDS (difference 0·9 points, 95% CI -0·6 to 2·4; corresponding raw logit score difference 0·1, -0·02 to 0·3) or PDQL (difference 1·7 points, -1·2 to 4·6). Secondary outcomes did not differ between groups (UPDRS III score difference 0·6 points, 95% CI -1·4 to 2·6; BELA-A-k score difference 0·8 points, -0·2 to 1·8; cost difference €742, -€489 to €1950).

INTERPRETATION:

This integrated care approach offered only small benefits to patients with Parkinson's disease, and these disappeared after correction for baseline disease severity. These results suggest that different approaches are needed to achieve more substantial health benefits.

FUNDING:

NutsOhra Foundation, Stichting Parkinson Nederland, National Parkinson Foundation.

Gender differences in non-motor symptoms in early, drug naïve Parkinson's disease

J Neurol. 2013 Aug 30. [Epub ahead of print]

Picillo M, Amboni M, Erro R, Longo K, Vitale C, Moccia M, Pierro A, Santangelo G, De Rosa A, De Michele G, Santoro L, Orefice G, Barone P, Pellecchia MT.

Source

Department of Neurological Sciences, Federico II University, Naples, Italy.

Abstract

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ 2 exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

The Relationship between Thermoregulation and REM Sleep Behaviour Disorder in Parkinson's Disease

PLoS One. 2013 Aug 21;8(8):e72661. doi: 10.1371/journal.pone.0072661.

Zhong G, Bolitho S, Grunstein R, Naismith SL, Lewis SJ.

Source

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

Abstract

BACKGROUND:

This study explored the relationship between symptoms of rapid eye movement sleep behaviour disorder, thermoregulation and sleep in Parkinson's Disease.

METHODS:

The study group comprised 12 patients with Parkinson's Disease and 11 healthy age-matched controls. We investigated markers of thermoregulation (core-body temperature profile), circadian rhythm (locomotor actigraphy) and sleep (polysomnography).

RESULTS:

The mesor (the mean value around which the core temperature rhythm oscillates) of the core-body temperature in patients with Parkinson's Disease was significantly lower than that of controls. In addition, the nocturnal fall in CBT (the difference between the mesor and the nadir temperature) was also significantly reduced in PD patients relative to controls. Furthermore, in patients the reduction in the amplitude of their core-body temperature profile was strongly correlated with the severity of self-reported rapid eye movement sleep behaviour disorder symptom, reduction in the percentage of REM sleep and prolonged sleep latency. By contrast, these disturbances of thermoregulation and sleep architecture were not found in controls and were not related to other markers of circadian rhythm or times of sleep onset and offset.

CONCLUSIONS:

These findings suggest that the brainstem pathology associated with disruption of thermoregulation in Parkinson's disease may also contribute to rapid eye movement sleep behavioural disorder. It is possible that detailed analysis of the core-body temperature profile in at risk populations such as those patients with idiopathic rapid eye movement sleep behaviour disorder might help identify those who are at high risk of transitioning to Parkinson's Disease.