Repeat expansion in C9ORF72 is not a major cause of amyotrophic lateral sclerosis among Iranian patients

Neurobiol Aging. 2013 Aug 17. pii: S0197-4580(13)00321-7. doi: 10.1016/j.neurobiolaging.2013.07.016. [Epub ahead of print]

Alavi A, Nafissi S, Rohani M, Shahidi G, Zamani B, Shamshiri H, Safari I, Elahi E.

Source

School of Biology, College of Science, University of Tehran, Tehran, Iran.

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in populations of European descent. It was recently found that a hexanucleotide repeat expansion in C9ORF72 is its most common cause in these populations. The contribution of C9ORF72 to ALS is notably lower in the Far East, but its role in other populations is unknown. Results of C9ORF72 screening in 78 unrelated Iranian ALS patients are reported here. The repeat expansion was observed in only 1 (5.9%) of the familial and 1 (1.6%) of the sporadic cases. These figures are to be compared, respectively, with 30% and 6.9% among patients of European ethnicity. Screenings of C9ORF72 in other Middle East countries will reveal whether the low contribution of C9ORF72 to ALS is a feature of the entire region. During the screenings, it was noted that in a single family, 3 individuals affected with ALS, Parkinson's disease, or frontotemporal dementia all carried the repeat expansion. The finding suggests the mutation does rarely contribute to the etiology of Parkinson's disease.

The timing between REM sleep behavior disorder and Parkinson's disease

Sleep Breath. 2013 Aug 21. [Epub ahead of print]

Ferri R, Cosentino FI, Pizza F, Aricò D, Plazzi G.

Source

Sleep Research Centre, Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via C. Ruggero 73, 94018, Troina, Italy

Abstract

PURPOSE:

In Parkinson's disease (PD) patients, REM sleep behavior disorder (RBD) might precede PD or develop with or after the onset of PD. No previous study has explored differences between these two groups. The aim of this study was therefore to compare clinical features and REM sleep chin electromyographic patterns between patients in whom RBD heralded PD and those in whom RBD occurrence coincided with or followed the clinical manifestations of PD.

METHOD:

Twenty-seven consecutive PD patients (mean age 67.9 years) were enrolled. Detailed clinical, laboratory, and polysomnographic studies were obtained in all participants.

RESULTS:

Sixteen of the 27 patients were affected by RBD. These had a significantly higher stage of PD and took significantly higher doses of dopaminergic therapy; their disease duration tended to be longer, and their cognitive status tended to be lower. PD patients in whom RBD preceded PD (n = 6) did not differ from PD patients without RBD in disease parameters, while PD patients in whom RBD developed with or after PD (n = 10) showed a significantly higher disease stage, took significantly higher dopaminergic therapy, and had a longer disease duration.

CONCLUSION:

Our findings are compatible with the hypothesis that patients in whom RBD precedes, or does not precede, PD might constitute two possibly distinct clinical and physiopathological groups, based on different progressive neuropathological sequences of events.

PREDICT-PD baseline results publication now Open Access

http://jnnp.bmj.com/content/early/2013/08/18/jnnp-2013-305420.long

J Neurol Neurosurg Psychiatry. 2013 Aug 18. doi: 10.1136/jnnp-2013-305420. [Epub ahead of print]

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

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

Source

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

Abstract

OBJECTIVES:

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

METHODS:

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

RESULTS:

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

CONCLUSIONS:

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

Outcomes of rotigotine clinical trials: effects on motor and nonmotor symptoms of Parkinson's disease

Neurol Clin. 2013 Aug;31(3 Suppl):S51-9. doi: 10.1016/j.ncl.2013.04.011. Epub 2013 Jun 14.

Lyons KE, Pahwa R.

Source

Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Boulevard, MS 2012, Kansas City, KS 66160, USA.

Abstract

Rotigotine transdermal system is a nonergot, 24-hour dopamine agonist approved for the treatment of early and advanced Parkinson's disease (PD). Recent studies have demonstrated significant improvements with rotigotine in motor function in early PD and significant improvements in daily off-time and motor function in advanced PD. In addition to motor improvements, nonmotor symptoms have been shown to be improved with rotigotine in both early and advanced PD. Rotigotine has been shown in large, controlled studies to be safe and efficacious for the treatment of motor and some nonmotor symptoms of early and advanced PD.

Inhaled Apomorphine in Patients with 'on-off' Fluctuations: A Randomized, Double-blind, Placebo-controlled, Clinic and Home Based, Parallel-group Study

J Parkinsons Dis. 2013;3(1):31-7. doi: 10.3233/JPD-120142.

Grosset KA, Malek N, Morgan F, Grosset DG.

Source

Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow.

Abstract

Background: In later stages of Parkinson's disease, treatment of 'off' periods with subcutaneous apomorphine is helpful but requires injection; inhaled apomorphine would be potentially more convenient. Objectives: To identify optimal efficacy, safety and tolerability for inhaled apomorphine in reversing Parkinson's disease 'off' periods. Methods: A randomized, double-blind, 2:1 active:placebo, parallel-group, ascending dose titration study was conducted at 16 centres in 3 countries. Inhaled apomorphine was administered under observation, at escalating fine particle doses of 1.5, 2.5, 3.5 and 4.5 mg. This was followed by at-home patient self-treatment for 2 to 4 weeks, assessed from 'on-off' diaries. Results: In 55 patients, mean age 65.6 years (range 47-79), mean disease duration 12 years (range 5-22), the mean improvement in the unified PD rating scale part 3 (UPDRS 3) was significantly greater for apomorphine (mean dose 2.3 mg) at 19.5 (standard deviation 13.6) than for placebo at 9.9 (9.6), least squares mean difference 8.4 (95% confidence interval 1.2 to 15.5, p = 0.023). During at-home testing, mean 'off' time per day was reduced by 139.8 minutes (standard deviation 149.6) for apomorphine versus 68.0 (108.6) minutes for placebo, least squares mean difference not significant at 100.5 minutes (95% confidence interval -12.0 to 212.9, p = 0.078). The onset of action was faster for apomorphine (mean 8.1 SD 6.2 minutes) than placebo (mean 13.1 SD 6.6 minutes) (p < 0.0001). Reversal of 'off' episodes was significantly more likely for episodes treated with apomorphine than those treated with placebo: apomorphine 64.6% SD 32.3 of episodes versus placebo 11.1% SD 15.3 (p < 0.0001). During at-home treatment, 36% of apomorphine and 20% of placebo patients experienced adverse events. Conclusions: Inhaled apomorphine in the dose range 1.5 to 4.5 mg, significantly improved UPDRS 3 scores in the clinic, and aborted a greater proportion of 'off' periods at-home, compared to placebo. However, daily 'off' time was not significantly reduced by the use of inhaled apomorphine.

Research on the Pre-Motor Symptoms of Parkinson's Disease: Clinical and Etiological Implications

Environ Health Perspect. 2013 Aug 9. [Epub ahead of print]

Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J.

Source

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

Abstract

BACKGROUND:

The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.

OBJECTIVES:

To discuss the promise and pitfalls of research on pre-motor symptoms of PD and to develop priorities and strategies to understand their clinical and etiological implications.

METHODS:

This review was based on a workshop held on June 7-8, 2012 at the National Institute of Environmental Health Sciences.

DISCUSSION:

Research on pre-motor symptoms of PD may offer an excellent opportunity to characterize higher-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of pre-motor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these pre-motor symptoms and their relevance to PD pathogenesis are poorly understood.

CONCLUSION:

This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple pre-motor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will help understand the biology of these non-motor symptoms and test novel etiological hypothesis.

The heterogeneity of early Parkinson's disease: a cluster analysis on newly diagnosed untreated patients

PLoS One. 2013 Aug 1;8(8):e70244. doi: 10.1371/journal.pone.0070244. Print 2013.

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

Source

Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL), London, United Kingdom.

Abstract

BACKGROUND:

The variability in the clinical phenotype of Parkinson's disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients.

METHODS:

We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored.

RESULTS:

THE DATA DRIVEN APPROACH IDENTIFIED FOUR DISTINCT GROUPS OF PATIENTS, WE HAVE LABELED: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant.

CONCLUSION:

Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies.

Prevalence and clinical course of olfactory hallucinations in idiopathic Parkinson's disease

J Parkinsons Dis. 2012;2(3):199-205. doi: 10.3233/JPD-2012-012086.

McAuley JH, Gregory S.

Source

Department of Neurology, King George Hospital, Barking Havering & Redbridge University Hospitals Trust, Romford, Essex, UK Department of Neurosciences, Royal London Hospital, Whitechapel, UK.

Abstract

Background: Olfactory hallucinations are known to occur in idiopathic Parkinson's disease (IPD) but are much less well-described than visual hallucinations. Objective: To report the prevalence, clinical features, response to treatment and prognosis of olfactory hallucinations in IPD. Methods: 205 consecutively reviewed IPD patients and 205 non-IPD control patients attending the local hospital were surveyed for the presence of olfactory hallucinations by specific questioning; the IPD patients were followed up for at least three years. Results: Of 188 patients who had a clinical course remaining consistent with IPD, four were initially found to have olfactory hallucinations, yielding a prevalence of 2.1% (95% confidence interval 0.4-5.4%). Two further patients developed such hallucinations later during the study. Olfactory hallucinations were not always accompanied by other hallucination modalities. The patients had a long duration of disease treated with dopaminergic medication, loss of sense of smell typical for IPD, no dementia or features suggestive of non-idiopathic PD after three years follow-up, a lack of insight into their hallucinations with consequent failure to report them spontaneously, and a good and lasting response to modest doses of atypical antipsychotics. Conclusions: This study confirms the significant prevalence of olfactory hallucinations, describes their clinical features and indicates that they may occur in isolation and not predict other psychotic or dementing features. The nuisance that such hallucinations cause, their ease of treatment and their failure to be volunteered as a symptom means that specific questioning for their presence should be included in routine assessment of patients with IPD.

Colonic Neuropathology is Independent of Olfactory Dysfunction in Parkinson's Disease

J Parkinsons Dis. 2011;1(4):389-94. doi: 10.3233/JPD-2011-11061.

Lebouvier T, Pouclet H, Coron E, Drouard A, N'guyen JM, Roy M, Vavasseur F, Bruley des Varannes S, Damier P, Neunlist M, Derkinderen P, Rouaud T.

Source

Inserm, U913, Nantes, France Inserm, CIC-04, Nantes, France University Nantes, Nantes, France CHU Nantes, Department of Neurology, Nantes, France CHU Nantes, Institut des Maladies de l'Appareil Digestif, Nantes, France.

Abstract

Olfactory dysfunction (OD) and constipation are two frequent and early non-motor features of Parkinson's disease (PD). Colonic PD neuropathology, the putative cause of constipation, can be analyzed and quantified using routine colonic biopsies and parallels disease severity. The present study was aimed at investigating whether the severity of neuropathology in the colon in PD is related to OD. Twenty-six PD patients were included. Colonic neuropathology, i.e., the density of Lewy pathology and the number of submucosal neurons, was unrelated to OD as assessed using the University of Pennsylvania Smell Identification. This suggests that unlike colonic Lewy pathology, OD is unrelated to disease severity.

Cognitive behavioral therapy for depression and anxiety in Parkinson's disease: a clinical review

J Parkinsons Dis. 2012;2(2):135-51. doi: 10.3233/JPD-2012-12080.

Armento ME, Stanley MA, Marsh L, Kunik ME, York MK, Bush AL, Calleo JS.

Source

Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey VA Medical Center, Houston, TX, USA Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA VA South Central Mental Illness, Research, Education, and Clinical Center (MIRECC), Houston, TX, USA.

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is generally defined by its progressive motor features; but increased attention is being paid to its non-motor neuropsychiatric symptoms, which profoundly impact quality of life for patients and caregivers. Anxiety and depression are particularly problematic and are the strongest predictors of quality of life in PD. Recent research has focused on non-pharmacological approaches to treating depression and anxiety in patients with PD. Cognitive-behavioral therapy (CBT) is a potentially efficacious non-pharmacological treatment for mood and anxiety symptoms associated with PD. Accordingly, this review examines empirical studies of CBT-based treatments for depression and anxiety symptoms in PD. Medical Subject Headings were used in searches of PsychInfo and PubMed of English-language articles published in peer-reviewed journals, resulting in the identification of 10 articles. Four additional articles were identified from the references of these articles and upon the suggestions of experts, for 15 articles in all. Results of individual studies varied significantly; however, the randomized controlled trials showed encouraging results and support the need for further investigation of the utility of CBT for depressed and anxious patients with PD. CBT is potentially a useful treatment for patients with PD and comorbid depression and/or anxiety, but more systematic research will be necessary to measure its effects.

Declining quality of life in Parkinson disease before and after diagnosis

J Parkinsons Dis. 2012;2(2):153-60. doi: 10.3233/JPD-2012-12083.

Palacios N, Gao X, Schwarzschild M, Ascherio A.

Source

Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.

Abstract

We sought to assess the quality of life in PD patients before the diagnosis, in comparison to age-matched individuals free of PD, among participants in two large prospective cohorts of men and women. Components of the Short-Form Health Status Survey (SF36) were administered to all participants in 1996 and 2008 in the Health Professionals Follow-up Study (HPFS), and in 1992, 1996, 2000 and 2004 in the Nurses' Health Study (NHS). We used scores in 7 health-related quality of life-dimensions, that were rated from 1(worst) to 100(best) points. We fitted a multivariate mixed-effect model with repeated measures to estimate the expected decline with age and compared that to the decline observed among PD cases by time to diagnosis. 454 men and 414 women with PD contributed data to the analyses. A decline in physical function in PD patients relative to the whole cohort began approximately 7.5 years prior to diagnosis in women and 3 years prior to diagnosis in men, and continued to decline thereafter with a rate of 2.35 and 1.43 points per year in women and men respectively (p < 0.001 for both). For comparison, the average yearly decline in individuals without PD was 0.42 and 0.23 points per year in women and men respectively. Other measures of quality of life (only available in women) declined in a similar pattern to physical function. In summary, the quality of life in PD patients begins to decline years before the diagnosis.