Parkinsonism & Related Disorders - Articles in Press

Fibroblast growth factor 20 (FGF20) polymorphism is a risk factor for Parkinson’s disease in Chinese population - Corrected Proof

2012-02-20

Abstract: The etiology of Parkinson’s disease (PD) is not well established. Genetic variation in fibroblast growth factor 20 (FGF20) might influence the risk of PD occurrence and development. In this study, Two DNA polymorphisms at genetic variation in FGF20, rs2720208 (C/T) and rs1721100 (C/G), were genotyped by direct sequencing in Han Chinese population, including 394 PD patients and 383 healthy controls. Stastistical analyses revealed that for rs1721100 (C/G) polymorphism, there were significant differences in genotype distribution between PD and healthy-matched controls. For rs12720208 (C/T) polymorphism, there was no significant difference in genotype distribution and gender and age-related differences between PD and control group. Results in this study revealed that the rs1721100(C/G) polymorphism is a risk factor for PD in Han Chinese population, while rs12720208(C/T) polymorphism is not significantly associated with PD.

SNP rs356219 of the α-synuclein (SNCA) gene is associated with Parkinson’s disease in a Chinese Han population - Corrected Proof

2012-02-20

Abstract: Background: Over the last decades, increasing knowledge about the genetic architecture of Parkinson’s disease(PD) has provided novel insights into the pathogenesis of the disorder. Recently, several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs356219, which is located in the 3′UTR of the SNCA gene. In this study, we aimed to verify these findings and to explore further the nature of the association in a subset of Chinese Han PD patients.Methods: Four hundred and three unrelated patients with sporadic PD and 315 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and normal controls were genotyped for SNCA rs356219 variant by ligase detection reaction (LDR).Results: A statistically significant difference was found in the frequencies of the single alleles of rs356219 (χ2 = 12.986,P = 0.002) between PD patients and normal subjects. The distribution of A > G genotypes was different between patients and controls (χ2 = 13.243, P < 0.001). The OR for subjects with the variant genotypes (AG and GG) was 1.88 (95%CI = 1.27–2.78, P = 0.001). The frequencies of the homozygous genotype for this variant was 42.2% (170 patients), which was significantly higher than that in controls (32.4%, P < 0.001).Conclusion: The results suggested that SNCA rs356219 variant might have an increased risk of susceptibility to PD in a Chinese Han population. Further studies are needed to replicate the association that we found.

Change in fatigue after bilateral subthalamic nucleus deep brain stimulation for Parkinson’s disease - Corrected Proof

Kelvin L. Chou, Carol C. Persad, Parag G. Patil — 2012-02-16

Abstract: Background: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) improves motor function in patients with medically intractable Parkinson’s disease (PD), but the effects of STN DBS on fatigue are unknown. The purpose of this study was to examine the effects of STN DBS on fatigue scores in patients with PD.Methods: Twenty PD patients underwent bilateral STN DBS surgery at our institution from 2007 to 2009. Only data from the 17 patients who completed the Parkinson Fatigue Scale (PFS) and Unified PD Rating Scale (UPDRS) before and approximately 6 months after surgery were analyzed. Other evaluations included the Geriatric Depression Scale (GDS), Apathy Evaluation Scale (AES), and Epworth Sleepiness Scale (ESS).Results: When the cohort was analyzed as a whole, there was no significant change in the mean or binary PFS score from baseline to the 6 month evaluation. However, the fatigue response of individual subjects was variable. Six of 12 subjects with fatigue before surgery were not fatigued post-operatively, while 3/5 subjects without fatigue before surgery became fatigued after DBS surgery. Fatigue in 8 subjects remained unchanged. Change in fatigue scores correlated significantly with change in the motor UPDRS, GDS and AES. Improvement in PFS also correlated with a higher PFS baseline score and higher baseline UPDRS motor off score.Conclusions: Changes in fatigue severity were not observed in our cohort as a whole, but there were changes in fatigue on an individual level. These changes appear to be related to the effects of STN DBS on motor improvement and mood.

SETX gene novel mutations in a non-French Canadian with ataxia-oculomotor apraxia type 2 - Corrected Proof

Sadik Ghrooda, Andrew Borys, Elizabeth Spriggs, Madhuri Hegde, Aizeddin Mhanni — 2012-02-16

The patient is a 24-year-old college-graduate male who presented with an insidious and a protracted course of balance difficulties since seven years of age. His initial symptoms were very mild however these slowly progressed through his junior and senior school years preventing him from participating in many sports activities. By 20 years of age, his symptoms advanced to a noticeably unsteady gait with occasional falls and deterioration in manual dexterity. The patient was born to a healthy non-consanguineous couple of English descent on the father’s side and Ukrainian ethnic background on the mother’s side. He has a younger healthy brother and there is no family history of ataxia.

Factors related to orthostatic hypotension in Parkinson's disease - Corrected Proof

2012-02-15

Abstract: Introduction: Orthostatic hypotension (OH), a frequent feature of Parkinson's disease (PD) can contribute to falls and is usually related to the disease itself and/or to drugs.Objectives: To explore factors related to OH and to assess the concordance between abnormal blood pressure (BP) fall after standing and the presence of orthostatic symptoms.Methods: Non-demented, non-operated idiopathic PD out-patients were questioned about the presence of orthostatic symptoms. Afterward, BP was measured 5-min after lying down and for 3-min after standing up. OH was defined as systolic and/or diastolic BP fall ≥20 and/or 10mmHg after standing. Patients were further evaluated by the Unified PD Rating Scale (UPDRS) and their medications were recorded.Results: 103 patients were included in this study (mean age=66±1 years, mean disease duration=9±1 years; mean UPDRS II+III in ON-state=37±2 points). Forty-one subjects (40%) reported the presence of orthostatic symptoms during the previous week and 38 (37%) had OH according to manometric definition. Independent factors related to OH, as assessed by logistic regression were age >68 years (OR, 95% CI=3.61, 1.31–9.95), polypharmacy (defined as intake of >5 medications, OR=3.59, 1.33–9.69), amantadine (7.45, 1.91–29.07) or diuretics (5.48, 1.10–54.76), whereas the consumption of entacapone was protective (0.20, 0.05–0.76). The agreement between abnormal BP fall and presence of orthostatic symptoms was poor (kappa=0.12±0.1, p=0.23).Conclusion: OH was significantly related to older age, polypharmacy and amantadine or diuretics intake, while entacapone exposure appeared to reduce the risk of OH. Low concordance between OH and orthostatic symptoms was observed.

Long-term safety and tolerability of rotigotine transdermal system in patients with early-stage idiopathic Parkinson’s disease: A prospective, open-label extension study - Corrected Proof

Lawrence W. Elmer, Erwin Surmann, Babak Boroojerdi, Joseph Jankovic — 2012-02-13

Abstract: Purpose: This prospective, open-label extension (SP702; NCT00594165) of a 6-month double-blind, randomized study investigated the long-term safety and tolerability of rotigotine transdermal system in early Parkinson’s disease (PD).Methods: Patients with early-stage idiopathic PD received transdermal rotigotine for up to 6 years at optimal dose (up to 16mg/24h). Adjunctive levodopa was allowed. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Other outcomes included time to levodopa, incidence of dyskinesias, and efficacy using the Unified Parkinson’s Disease Rating Scale (UPDRS) II+III total score.Results: Of 217 patients entering the open-label study, 47% were still in the study upon closure; 24% withdrew because of AEs and 6% because of lack of efficacy. The median exposure to rotigotine was 1910 days (∼5 years, 3 months; range 1–2188 days). Most common AEs were somnolence (23% per patient-year), falls (17%), peripheral edema (14%), nausea (12%), and application site reactions (ASRs; 12%). 3% withdrew because of ASRs. 26% patients did not initiate levodopa; of those who did, fewer than half started levodopa in the first year. Dyskinesias were reported by 25% patients; the majority (83%) reported their first episode after initiating levodopa. Mean UPDRS II+III total scores remained below double-blind baseline for up to 2 years of open-label treatment.Conclusion: This is the longest interventional study of rotigotine conducted to date. Transdermal rotigotine was generally well tolerated for up to 6 years; AEs reported were similar to those observed in shorter studies and led to discontinuation in only 24% patients.

Annual report 2011 - Corrected Proof

Zbigniew K. Wszolek, Ronald F. Pfeiffer — 2012-02-13

We are not sure whether it is an indication of being very busy, very forgetful, or simply being very proficient procrastinators following the advice of Mark Twain to “never put off until tomorrow what you can do the day after tomorrow”, but we recently were surprised and chagrined to realize that we never managed to deliver the Editorial Annual Report for 2010 and now it is time for the 2011 edition! Luckily, with our tremendously capable Associate Editors (Vincenzo Bonifati, Jonathan Carr, Robert Rodnitzky, Eng-King Tan) and Managing Editor (Susan Calne), as well as the very fine and capable team at Elsevier (Virginia Prada Lopez, Peter Bakker, Frankee Woodham-Kay, Charlotte Hayes and Ulrike Wiechern), the Journal functions much more efficiently than its Editors-in-Chief.

Pardoprunox as adjunct therapy to levodopa in patients with Parkinson’s disease experiencing motor fluctuations: Results of a double-blind, randomized, placebo-controlled, trial - Corrected Proof

2012-02-10

Abstract: Aims: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson’s disease (PD) experiencing motor fluctuations.Methods: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale).Results: Pardoprunox significantly reduced OFF time versus placebo (−1.62 h/day versus −0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid.Conclusions: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.

The development and validation of a quality of life measure for the carers of people with Parkinson’s disease (the PDQ-Carer) - Corrected Proof

2012-02-10

Abstract: Background: Parkinson’s disease (PD) can have substantial effects not only on the quality of life of those diagnosedwith the condition but also upon the informal carers who provide support and assistance to them. However, to date no well-validated carer specific quality of life measure has been developed for carers of people with PD.Objective: This paper documents the development and validation of a PD specific carer quality of life scale.Methods: In depth interviews were undertaken with carers of people with PD. The interviews were transcribed and analysed thematically to derive a pool of potential items for the questionnaire. A pilot survey was used to refine the initial version of the questionnaire. A developmental survey was undertaken and the results analysed to produce the final 29-item measure. A validation survey was then undertaken to assess the construct validity and reliability of the measure.Results: Survey results suggest a 29-item questionnaire tapping four dimensions of quality of life (Social and Personal Activities, Anxiety and Depression, Self care, and Strain). Internal consistency reliability was found to be high for all domains. Data completeness was high. Construct validity (assessed by correlations with a generic measure of quality of life) confirmed prior hypotheses.Conclusion: The 29-item Parkinson Disease Questionnaire for Carers (PDQ-Carer) is a short, meaningful quality of life instrument, which taps areas of specific salience and concern to PD carers.

123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: A systematic review and meta-analysis - Corrected Proof

Satoshi Orimo, Masahiko Suzuki, Akira Inaba, Hidehiro Mizusawa — 2012-02-10

Abstract: Objectives: Differential diagnosis of Parkinson’s disease (PD) and other neurodegenerative parkinsonism by clinical consensus criteria and diagnostic imaging is often difficult. 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy is a useful imaging tool for differentiating PD from other parkinsonism. The purpose of the present study is to systematically review and perform a meta-analysis of studies on the diagnostic performance of 123I-MIBG myocardial scintigraphy for the differential diagnosis of PD and other neurodegenerative parkinsonism, specifically multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration.Methods: A computer literature search of the PubMED/MEDLINE database was conducted to find relevant published articles on 123I-MIBG myocardial scintigraphy for the differential diagnosis of PD and other neurodegenerative parkinsonism. We used the bivariate random-effects model to obtain the pooled estimates of the sensitivity and specificity and the corresponding 95% confidence intervals.Results: Thirteen studies comprising 845 patients including 625 PD and 220 other neurodegenerative parkinsonism were analyzed. The pooled sensitivity and specificity to differentiate PD from other neurodegenerative parkinsonism by the early heart-to-mediastinum (H/M) ratio were 82.6% and 89.2%, respectively, and those by the delayed H/M ratio were 89.7% and 82.6%, respectively. When PD was limited to early stage (Hoehn-Yahr stage 1 or 2), the pooled sensitivity and specificity by the delayed H/M ratio were 94.1% and 80.2%, respectively.Conclusions: The present meta-analysis confirmed high sensitivity and specificity of 123I-MIBG myocardial scintigraphy for differentiating PD from other neurodegenerative parkinsonism in both early and delayed imaging phases. Furthermore, 123I-MIBG myocardial scintigraphy was highly effective for distinguishing early PD.

Boxing and Parkinson disease: A link or a myth? An 18F-FDOPA PET/CT study in retired Thai traditional boxers - Corrected Proof

2012-02-10

The possible relationship between head trauma and Parkinson’s disease (PD) has been a subject of debate since James Parkinson’s original description in 1817 . Recent studies indicated that the age-adjusted prevalence rate of PD in retired Thai traditional boxers is comparable to that in the general population; however, it is the number of professional bouts undertaken by a boxer that pose a risk factor, suggesting that repetitive head traumas pose additional risk to certain individuals who are already susceptible to PD .

Statistical analysis and mapping of the unified Parkinson’s Disease rating scale to Hoehn and Yahr staging - Corrected Proof

2012-02-10

Parkinson’s disease (PD) symptom severity is typically quantified using clinical metrics, where a medical rater assesses the subject’s condition and ability to perform a range of tasks. Two of the most commonly used PD metrics are the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) scale . UPDRS quantifies PD symptom severity, and H&Y quantifies disease stage; there have been few attempts to correlate these metrics. Recently, some mathematical formulas have been proposed expressing H&Y as a function of UPDRS using intuitive rules based upon H&Y evaluation guidelines . However, these formulas have not been tested against PD databases to assess how accurately H&Y might be predicted in general. In this letter, we (a) systematically study the statistical relationship between the two metrics, (b) optimize the previously proposed formulas by refining their parameters, and (c) test these formulas using a large, publicly available, PD database. The present study’s findings provide (a) an optimized formula exhibiting 9% improvement in H&Y estimation compared to the formulas in Refs. , (b) insight into the statistical association between the two most commonly used clinical metrics in PD, (c) a technique for substituting missing H&Y data in prospective clinical studies, and (d) an approach to harmonizing data in retrospective clinical studies.

Essential tremor is not dependent upon cerebellar Purkinje cell loss - Corrected Proof

A.H. Rajput, C.A. Robinson, M.L. Rajput, S.L. Robinson, A. Rajput — 2012-02-06

Abstract: The pathophysiology of essential tremor (ET) is unknown but recent studies report that the majority of ET cases has cerebellar Purkinje cell (PC) degeneration and its sequelae.Objective: To perform PC counts in ET, and normal and Parkinson's disease (PD) controls to determine the relationship of PC loss to ET.Methods: All ET cases and PD controls were followed at our clinic. Normal controls had no history of neurological disease and had normal standard neuropathological studies. The PC counts were done by a neuropathologist who was blinded to the clinical diagnosis. Three different methods were used for counting PC; section through any part of the PC, through any part of the PC nucleus, and through any part of PC nucleolus. The counts were done in five non-contiguous microscopic fields.Results: 59 brains were studied. These included 12 ET, 41 PD controls, and six normal controls. The mean age at death was 82.7 in ET, 79.1 in PD, and 75.7 years in the normal controls. The mean duration of symptoms was 34 years in ET and 15.7 years in the PD cases. The mean PC counts through any part of the neuron were 64.8 in ET, 56.2 in PD, and 58.0 in normal controls. Differences were not significant.Conclusion: Cerebellar PC loss does not distinguish ET from controls. It is concluded that PC loss is neither a pathological basis for, nor the distinctive feature of ET.

Parkinson’s disease and risk of hip fracture: An 8-year follow-up study in Taiwan - Corrected Proof

Yen-Yu Chen, Pei-Yu Cheng, Shey-Lin Wu, Chien-Hsu Lai — 2012-02-02

Abstract: Background: Patients with Parkinson’s disease (PD) are subject to posture instability and falling. However, PD was not included as one of the risk factors in commonly used fracture risk calculation tools and the fracture rate in patients with PD was rarely reported. The aim of this study was to evaluate the risk of hip fracture in patients with PD.Methods: Data were collected from the National Health Insurance Research Database of Taiwan. The study group included 394 patients with PD diagnosed in 1999–2000. The comparison cohort was comprised of 3940 age- and sex-matched patients from the same enrollment period. All patients were tracked from their index visits for eight years.Results: Hip fracture developed in 10.4% of patients with PD and 4.1% of patients in the comparison cohort during the follow-up period. Log-rank test analysis showed a significantly higher rate of hip fracture in PD. The Cox proportional regression model showed an adjusted hazard ratio of 2.71 (95% confidence interval = 1.92–3.83, P < 0.001) for patients with PD.Conclusion: The hip fracture rate was as high as 10.4% in PD patients during 8 years follow-up period. While assessing the risk of hip fracture, PD should be taken into consideration. For those very high risk patients (elderly women with PD, osteoporosis, diabetes and diabetic neuropathy), many efforts should be made to prevent fracture.

Diffusion tensor imaging: Tract based spatial statistics study in essential tremor - Corrected Proof

2012-02-01

Abstract: Introduction: Essential tremor (ET) is a common movement disorder with motor and non-motor symptoms. We aimed to investigate the neurodegenerative changes in the brain white matter of patients with ET using Diffusion Tensor Imaging (DTI).Methods: Clinical and MRI data from 20 patients (5 women and 15 men; age-38.2 ± 16.5 yrs) with ET and 17 controls (3 women and 14 men; age-40.7 ± 16.5 yrs) were collected prospectively. The DTI data were analyzed using tract based spatial statistics (TBSS) software for tract wise analysis. Further region of interest (ROI) analysis was carried out in the genu of corpus callosum, anterior limb of internal capsule (ALIC), corticospinal tract (CS), and cerebellar peduncles. Effect of tremor severity, disease duration and age of onset on DTI metrics was also studied.Results: Patients with ET in comparison to controls showed significant (Pcorrected < 0.05) increase of mean diffusivityand radial diffusivity in right frontoparietal white matter. Axial diffusivity increase was seen in bilateral cerebral hemispheres, thalamus, brainstem and cerebellar hemisphere white matter. No significant change in fractional anisotropy of the white matter was seen. ROI analysis also revealed abnormalities in the ALIC and cerebellar peduncles. There was no correlation between the severity of white matter changes and clinical tremor severity score as well as disease duration.Conclusions: This study provides in vivo evidence for axonal disintegration of the cerebral and cerebellar white matter fibres in patients with ET.

Photobiomodulation enhances nigral dopaminergic cell survival in a chronic MPTP mouse model of Parkinson’s disease - Corrected Proof

2012-01-30

Abstract: We have shown previously that photobiomodulation or near-infrared light (NIr) treatment protects dopaminergic cells of the substantia nigra pars compacta (SNc) in an acute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson’s disease (PD). In this study, we tested the protective and rescue action of NIr treatment in a chronic MPTP model, developed to resemble more closely the slow progressive degeneration in PD patients. We examined three regions of dopaminergic cells, the SNc, periaqueductal grey matter (PaG) and zona incerta-hypothalamus (ZI-Hyp). BALB/c mice had MPTP or saline injections over five weeks, followed by a three-week survival. NIr treatment was applied either at the same time as (simultaneous series) or after (post-treatment series) the MPTP insult. There were four groups within each series; Saline, Saline-NIr, MPTP and MPTP-NIr. Brains were processed for tyrosine hydroxylase (TH) immunochemistry and cell number was analysed using the optical fractionator method. In the SNc, there was a significant reduction (∼45%) in TH+ cell number in the MPTP groups compared to the saline controls of both series. In the MPTP-NIr groups of both series, TH+ cell number was significantly higher (∼25%) than in the MPTP groups, but lower than in the saline controls (∼20%). By contrast in the PaG and ZI-Hyp, there were no significant differences in TH+ cell number between the MPTP an MPTP-NIr groups of either series. In summary, exposure to NIr either at the same time or well after chronic MPTP insult saved many SNc dopaminergic cells from degeneration.

Apomorphine injections: Predictors of initial common adverse events and long term tolerability - Corrected Proof

William G. Ondo, Christine Hunter, Joseph M. Ferrara, Giovanni Mostile — 2012-01-27

Abstract: Background: Apomorphine injections effectively abort “off” episodes in Parkinson’s disease (PD). However, their use is limited by actual and perceived adverse events (AE). To our knowledge, no study has evaluated for predictors of these problems.Objectives: To assess predictors of initial common AE and long-term tolerability of apomorphine injections in PD.Methods: We prospectively monitored for AE in 28 consecutive PD patients receiving initial apomorphine injections. Sequential visual analogue scale scores for nausea and in standing systolic blood pressure drops at baseline (mean of 2 assessments), 10, 20, and 40min post-injection were acquired. Assessed historic variables included patient demographics and clinical data, treatment histories, previous AE to other dopaminergic treatments and whether patients received the recommended three day pre-treatment dose of trimethobenzamide. We also correlated the L-dopa equivalent doses with apomorphine dose needed to turn “on”.Results: No patient demographic or previous history of dopaminergic AE predicted nausea, except for baseline pre-injection nausea that day at baseline. Three days of trimethobenzamide, as recommended, was actually associated with more nausea than a single dose or no dose, even though a lack of association after matched analysis was found. A younger patient age was associated with hypotension. L-dopa equivalent dose modestly correlated with final apomorphine dose to turn “on”.Conclusion: A previous history of nausea and hypotension, and older age should not dissuade a trial of apomorphine if clinically justified. A three day pre-treatment dose of trimethobenzamide, as recommended in the United States, does not reduce nausea.

Movement orientation switching with the eyes and lower limb in Parkinson disease - Corrected Proof

Corey A. Lohnes, Gammon M. Earhart — 2012-01-20

Abstract: Difficulty switching between motor programs is a proposed cause of motor blocks in Parkinson disease (PD). Switching from one movement to another has been studied in the upper extremity and during postural control tasks, but not yet in the eyes and lower limb in PD. The purpose of this study was to compare movement orientation switching ability between people with PD and age-matched controls (CON) and to determine if switching ability is correlated between the eyes and lower limb. Twenty-six persons with PD and 19 age-matched controls participated. Movement orientation switching was studied in a seated position with the head fixed in a chinrest. In response to a randomly generated tone, participants switched from a continuous back-and-forth movement in either the horizontal or vertical orientation to the opposite orientation as quickly as possible. Lower limb movements were performed with the great toe pointing back and forth between targets positioned on a 45° angled floor platform. Eye movements were back and forth between the same targets. Eye and lower limb switch time was reduced in PD (p<0.01), but after normalizing switch time to movement velocity, no differences existed between PD and CON. Eye and lower limb switch times were correlated in PD (r=0.513, p<0.01) but not in CON. In PD, switch time and movement velocity of the lower limb, but not the eyes, correlated with bradykinesia and postural instability/gait. Our results suggest that individuals with PD experience movement-switching deficits with both the eyes and lower limb, perhaps driven by overall bradykinesia.

Magnetization transfer and adiabatic R1ρ MRI in the brainstem of Parkinson’s disease - Corrected Proof

2012-01-20

Abstract: Background: In addition to classic midbrain pathology, Parkinson’s disease (PD) is accompanied by changes in pontine and medullary brainstem structures. These additional abnormalities may underlie non-motor features as well as play a role in motor disability. Methods: Using novel magnetic resonance imaging (MRI) methods based on rotating frame adiabatic R1ρ (i.e., measurements of longitudinal relaxation during adiabatic full passage pulses) and modified magnetization transfer (MT) MRI mapping, we sought to identify brainstem alterations in nine individuals with mild-moderate PD (off medication) and ten age-matched controls at 4 T. Results: We discovered significant differences in MRI parameters between midbrain and medullary brainstem structures in control subjects as compared to PD patients. Conclusions: These findings support the presence of underlying functional/structural brainstem changes in mild-moderate PD.

Falling short: Underestimation of fracture risk in atypical parkinsonian syndromes - Corrected Proof

Alison J. Yarnall, Gordon W. Duncan, Tien K. Khoo, David J. Burn — 2012-01-20

Falls are a prominent feature of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Falls and osteoporosis are common in the older population with up to 30% of the community dwelling elderly falling at least once per year . An excess of hip fractures has been previously noted in Parkinson’s disease (PD) patients, perhaps due to the mechanism of falling . In a retrospective review of bradykinetic-rigid syndromes, 28.6% people with PSP and 11% of those with MSA sustained a fracture following a fall, with overall falls recorded in 77.5% of subjects .

The Q10 questionnaire for detection of wearing-off phenomena in Parkinson’s disease - Corrected Proof

Pablo Martinez-Martin, Basilio Hernandez, on behalf of the Q10 Study Group — 2012-01-13

Abstract: In Parkinson’s disease (PD), wearing-off can be difficult to detect as it is very variable and may affect motor and non-motor symptoms. The Wearing-Off Questionnaire, WOQ-32 (Stacy et al., 2005), was introduced to help identify wearing-off and proved to be very efficient. Two short versions of the questionnaire (WOQ-19 or QUICK and WOQ-9) were later developed to decrease the respondent burden without loss of efficacy in terms of sensitivity. The objective of the present study was to check the ability of a new 10-item QUICK version, Q10, to identify patients with wearing-off. Q10 items were selected from the QUICK validation study data set through statistical analysis and it was then tested on a sample of 162 PD patients, 64.8% with wearing-off. Sensitivity, specificity, and accuracy were 96%, 63%, and 85% respectively with one positive response and 90%, 70%, and 83% respectively with two positive responses. The correlation with the gold standard (neurologist diagnosis of wearing-off) was substantial (kappa = 0.62–0.64). Comparison with the QUICK and WOQ-9 shows that the Q10 can be a new tool for detection of wearing-off with satisfactory properties and a good balance between brevity and performance.

A DNA resequencing array for genes involved in Parkinson’s disease - Corrected Proof

2012-01-13

Abstract: Parkinson’s disease (PD) is aetiologically complex with both familial and sporadic forms. Familial PD results from rare, highly penetrant pathogenic mutations whereas multiple variants of low penetrance may contribute to the risk of sporadic PD. Common variants implicated in PD risk appear to explain only a minor proportion of the familial clustering observed in sporadic PD. It is therefore plausible that combinations of rare and/or common variants in genes already implicated in disease pathogenesis may help to explain the genetic basis of PD.We have developed a CustomSeq Affymetrix resequencing array to enable high-throughput sequencing of 13 genes (44 kb) implicated in the pathogenesis of PD. Using the array we sequenced 269 individuals, including 186 PD patients and 75 controls, achieving an overall call rate of 96.5% and 93.6%, for two respective versions of the array, and >99.9% accuracy for five samples sequenced by capillary sequencing in parallel. We identified modest associations with common variants in SNCA and LRRK2 and a trend suggestive of an overrepresentation of rare variants in cases compared to controls for several genes. We propose that this technology offers a robust and cost-effective alternative to targeted sequencing using traditional sequencing methods, and here we demonstrate the potential of this approach for either routine clinical investigation or for research studies aimed at understanding the genetic aetiology of PD.

Genetic analysis of HLA-DRA region variation in Taiwanese Parkinson’s disease - Corrected Proof

2012-01-13

Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder comprising both motor and cognitive disability. The pathogenesis of the disease is still unclear; however, neuroinflammation seemed to play a role. A recent genome-wide association study (GWAS) reported an association between HLA-DRA rs3129882 and the development of PD in Caucasian populations. In this study, we observe no association between this single nucleotide polymorphism and PD in a Taiwanese population. The possible reasons include different ethnicity with genomic differences and environmental factors in different geographical regions.

Pregnancy in patients with Sydenham’s Chorea - Corrected Proof

2012-01-12

Abstract: Background: Sydenham’s Chorea is a frequent cause of chorea during pregnancy, chorea gravidarum. The aim of this article is to describe the effect of pregnancy in a consecutive series of patients with diagnosis of Sydenham’s Chorea.Methods: A chart review was performed of all patients with the diagnosis of Sydenham’s Chorea followed up at our institution from 07/1993 through 08/2010 and who became pregnant.Results: From 66 patients, 20 became pregnant. Of these 20 patients, 15 (75%) developed chorea gravidarum. Generalized chorea was found in 67% of these 15 patients, focal or multifocal chorea was identified in 20% and 13.4% developed hemichorea. In 80% of cases chorea began in the first 6 months of gestation. Three women with previous persistent chorea experienced worsening of the movement disorder during pregnancy. Remission occurred after delivery in 11 patients whereas the other four remained with non-disabling chorea during the first 12 months after delivery. Abortion occurred in two patients (13%). All patients with chorea gravidarum subsequently treated with oral contraceptives developed recurrence of chorea.Conclusions: Chorea gravidarum is a frequent complication of pregnancy in patients with previous history of Sydenham’s Chorea and an increased risk of miscarriage should be considered. Our findings confirm the notion that chorea gravidarum results from hormonal changes acting on previously dysfunctional basal ganglia.

Assessment of appropriate medication administration for hospitalized patients with Parkinson’s disease - Corrected Proof

2012-01-11

Abstract: Background: For Parkinson’s disease (PD) patients, adherence to a regular PD medication schedule is important in achieving optimal symptom control. There are few published studies quantifying PD medication administrations in hospitalized PD patients.Methods: Hospitalization records for 100 veterans with idiopathic PD and admitted to our center were reviewed to determine the on time rate and contraindicated medication doses. A barcode based computerized medication administration system within the electronic medical record provided information of the exact time the medication was given to a patient.Results: Eighty-nine idiopathic PD patients met study inclusion criteria. Among them, 87 were on levodopa monotherapy or in combination with other PD medications. Two patients were on dopamine agonists only. A total of 3873 doses of PD medications were prescribed during hospitalization. Among 675 incorrect medication administrations, 322 doses were omitted, 300 doses late by ≥30 min, and 53 doses given early by ≥30 min. Contraindicated medications were prescribed for 19 patients. The correct administration percentage was lower during the first 2 days post-admission compared to subsequent days (mean 74.6% vs. 82.8%) and higher for patients who had neurological consultations (mean 85.5% vs. 76.5%). Correct administration rates were better for patient-based medication schedules (85.6%) than with hospital-based schedules (77.5%), but did not achieve statistical significance.Conclusion: Adherence to regular PD medication dosing schedules during hospitalization is problematic, but improves with specialist consultation. Staff involved in the admission process for PD patients should work to safeguard against disruption of the prescribed home dosing schedule.

Assessment of the Scopa-Aut questionnaire in multiple system atrophy: Relation to UMSARS scores and progression over time - Corrected Proof

2012-01-11

Abstract: Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression – that is the Unified MSA Rating Scale (UMSARS) – were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials.

Validation of a new scale to assess olfactory dysfunction in patients with Parkinson’s disease - Corrected Proof

2012-01-09

Abstract: Bakckground: Olfactory dysfunction is present in up to 90% of Parkinson’s disease (PD) patients. It is usually evaluated by means of objective standardized tests; however no self-administered scales have been developed for olfactory dysfunction bedside assessment. We present validation of a new scale to assess this symptom in PD patients.Methods: Seventy-five PD patients and 25 control subjects were evaluated using a Hyposmia Rating Scale developed in-house, combined with the extended Sniffin’ Sticks test.Results: Total score of the 6-item Hyposmia Rating Scale showed significant correlation with threshold, discrimination, identification and total Sniffin’ Sticks test scores (r = 0.53; r = 0.60; r = 0.57; r = 0.65 respectively, p < 0.001 for all values). Area under the curve of the receiver operating curve for the ability of Hyposmia Rating Scale to discriminate patients with Sniffin’ Sticks test total scores below or above the cut-off point was 80 ± 6% (p < 0.001). Considering Sniffin’ Sticks test as the gold standard method for olfactory dysfunction detection, an affirmative response to a single screening question about smelling ability problems showed 35% sensitivity (95%CI = 23–47%) and 100% specificity. The best cut-off point for Hyposmia Rating Scale was 22.5 with a sensitivity of 70% (60–81%) and a specificity of 85% (65–100%).Conclusion: The Hyposmia Rating Scale here presented may offer a simple, cost-effective, time-saving and reliable approach to evaluate olfactory dysfunction in PD patients.

Do patients with rapid eye movement sleep behavior disorder have a disease-specific personality? - Corrected Proof

Taeko Sasai, Yuichi Inoue, Masato Matsuura — 2012-01-09

Abstract: Objectives: Rapid eye movement sleep behavior disorder (RBD) occurs idiopathically (iRBD), frequently representing a prodromal phase of Parkinson’s disease (PD). Previous reports have described that patients with PD have premorbid personality profiles such as industriousness, inflexibility, cautiousness, and lack of novelty seeking. As well, psychological stress often aggravates RBD symptoms. These phenomena encouraged us to investigate personality profiles in iRBD patients.Methods: In this study, 53 patients with iRBD and 49 age and sex-matched healthy controls (HC) were enrolled. We used the revised version of the NEO Personality Inventory (NEO-PIR) to measure the personality of these subjects, and the 5 domains and the 30 facets of the NEO-PIR were compared between the two groups. Within the iRBD group, we investigated the association between RBD variables, e.g. the proportion of REM sleep without atonia (RWA/REM), length of RBD morbidity, frequency of vocalization or abnormal behavior, and the variables of NEO-PIR.Results: In the patients, olfactory function was significantly lower than that of healthy controls, but the inventory differences were not significant. The inventory showed no association with any RBD variable, or the existence of aggravation of these symptoms triggered by psychological stress, or olfactory dysfunction.Conclusion: These results suggest that RBD patients do not have a personality profile that might predict PD development. The personality profile itself cannot explain the psychological-stress-dependent aggravation of RBD symptoms.

The GAG deletion in Tor1A (DYT1) is a rare cause of complex musician’s dystonia - Corrected Proof

2012-01-06

Focal dystonia is the most common form of primary dystonia characterized by involuntary twisting, abnormal postures and repetitive movements in a specific body part. Musician’s dystonia (MD) is a type of focal task-specific dystonia that presents with loss of voluntary motor control of extensively trained movements when a musician is playing his instrument. The pathophysiology of focal dystonia remains largely unknown, however, we have recently reported an aggregation of different types of movement disorders in the families of MD patients suggesting a genetic contribution to the disease .

Apolipoprotein E gene (APOE) genotype in Wilson’s disease: Impact on clinical presentation - Corrected Proof

T. Litwin, G. Gromadzka, A. Członkowska — 2012-01-05

Abstract: Background: Wilson’s disease (WD), an inherited copper metabolism disorder that leads to pathological tissue copper accumulation and secondary organ damage, is caused by mutations in the ATP-ase 7B gene (ATP7B). The apolipoprotein E gene (APOE) alleles ε2, ε3, and ε4 produce three different apoE isoforms with different biological effects, which can determine risks of many human diseases, including neurodegenerative and liver disease. This study aimed to evaluate the impact of APOE genotype on the variability of WD phenotypic expression.Methods: We analyzed data on 383 WD consecutive patients in the WD registry. The APOE genotypes (APOE ε3/ε3 (wild-type), APOE ε2-positive, and APOE ε4-positive) were determined and the APOE genotype effect on the phenotypic WD presentation was assessed in all symptomatic WD patients, as well as in patient subgroups divided according to sex and ATP7B genotype.Results: APOE genotype had no impact on WD presentation in the general population of symptomatic patients. However, APOE ε4-positive women tended to present WD symptoms earlier than women possessing the wild-type APOE ε3/ε3 genotype (24.2 vs. 27.9 years; p = 0.08). The effect of the APOE ε4-positive genotype was more pronounced in ATP7B p.H1069Q homozygous women, in whom disease symptoms started almost 6 years earlier (23.6 vs. 29.9 years; p < 0.05) than in APOE ε3/ε3 women.Conclusions: In women, APOE ε4-positive genotype is associated with earlier onset of WD symptoms, particularly among ATP7B p.H1069Q homozygous patients. Further studies are needed to understand the mechanisms of these gender-dependent phenotypic effects.

Essential tremor: Beyond the motor features - Corrected Proof

Vijay Chandran, Pramod Kumar Pal — 2012-01-04

Abstract: There is a growing evidence to suggest that apart from motor features, patients with Essential Tremor (ET) may have significant non-motor features. This review critically analyzes the available evidence of the various non-motor symptoms in patients with ET. Apart from tremor, patients with ET have been reported to have: (i) cognitive abnormalities characterized by mild frontal dysfunction that may have a functional impact, (ii) an association with dementia (both prevalent and incident) among those with late onset of tremor (>65 years), (iii) a higher prevalence of anxiety and an anxious and worrisome personality type, (iv) depressive symptomatology and may even have depression as a premotor symptom, (v) poor sleep quality and (vi) subjective hearing impairment. It is controversial whether olfactory dysfunction occurs in ET and its utility as a diagnostic aid. The biological basis for each of these observations requires further clarification and some findings need confirmation in population-based studies. However the available evidence is sufficient to support the notion that ET can no longer be considered as a pure motor disorder and further studies of these non-motor aspects will go a long way in understanding and comprehensively treating ET.

Gastroparesis and Parkinson’s disease: A systematic review - Corrected Proof

Zaid S. Heetun, Eamonn M.M. Quigley — 2012-01-03

Abstract: Some of the gastrointestinal (GI) symptoms commonly experienced by patients with Parkinson’s disease (PD) have been attributed to gastroparesis; however, the precise prevalence and relevance of gastric emptying delay in PD is unclear. The definition of gastroparesis varies; currently the most widely accepted definition (from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium) is the presence of appropriate symptoms (including nausea, retching, vomiting, stomach fullness, and inability to finish a meal) for ≥12 weeks, together with delayed gastric emptying on scintigraphy and the absence of any obstructive lesions on upper GI endoscopy. In PD patients, gastroparesis has the potential to affect nutrition and quality of life, as well as the absorption of PD medications, including L-dopa. This reduced absorption of L-dopa has implications for the control of the PD motor symptoms for which it is administered. We performed a systematic review of the literature on gastroparesis in PD with the aim of developing an evidence-based approach to its management. Based on this review, we conclude that while gastric emptying has been reported to be frequently delayed in PD, the existing data do not permit definitive conclusions concerning its true prevalence, relationship to the underlying disease process, relevance to PD management, or the optimal therapy of related GI symptoms. Further study of these important issues is, therefore, required.

Incidence and mortality of Parkinson’s disease in older Canadians - Corrected Proof

2011-12-26

Abstract: Objective: To estimate the age-specific incidence of Parkinson’s disease (PD) in elderly persons in the Canadian province of British Columbia (BC). All-cause and injury mortalities and relative risk of death for those persons with PD were also examined.Methods: A historical cohort study was conducted using 5 provincial administrative databases from 1991/92 to 2000/2001. A series of algorithms based on the databases were created for case ascertainment of PD for persons 65 years or older. Crude and age-specific incidence and mortality rates were calculated using person-years of follow-up as the denominator. The impact of PD on all-cause and injury mortalities was examined using multivariate Cox regression models to provide adjusted hazard ratios.Results: 10,910 incidence cases over 6,051,682 person-years of follow-up were identified. The crude annual incidence rate was 252 per 100,000 person-years. Over the nine year period, age standardized incidence for males ranged from 207 to 396 per 100,000 person-years and 127 to 259 per 100,000 person-years for females. Persons with PD were at a 43% greater risk of all-cause mortality and specifically, 51% greater risk of injury mortality.Conclusions: Incidence of PD is substantially higher in advanced age with age adjusted increases for both all-cause and injury mortalities. These findings also highlight falls as a primary factor for injury mortality in PD.

Treatment of advanced Parkinson’s disease with levodopa/carbidopa intestinal gel is associated with improvements in Hoehn and Yahr stage - Corrected Proof

A. Munro Neville, Richard W. Parsons, Håkan Askmark, Dag Nyholm — 2011-12-26

Assessment of symptoms in Parkinson’s disease (PD) is important in clinical trials and in the clinical setting for optimal management and care of patients. There are a number of disease severity and disability measures for PD patients. Some are disease specific, including the Schwab and England Activities of Daily Living scale, Unified Parkinson’s Disease Rating Scale, Hoehn and Yahr (HY) scale. Some relate to non-motor aspects of PD, including Mini-Mental State Examination, the Beck Depression Inventory and the Non-Motor Symptom Scale.

Group I nonreciprocal inhibition in restless legs syndrome secondary to chronic renal failure - Corrected Proof

2011-12-26

Abstract: Background: Neurophysiological investigations disclosed spinal cord hyperexcitability in primary restless legs syndrome (p-RLS). Uremic RLS (u-RLS) is the most common secondary form, but its pathophysiological mechanisms remain unsettled. Aim of this study was to explore spinal cord excitability by evaluating group I nonreciprocal (Ib) inhibition in u-RLS patients in comparison with p-RLS patients and healthy subjects.Methods: Eleven u-RLS patients undergoing long-term hemodialysis treatment, nine p-RLS patients and ten healthy subjects were studied. Soleus H reflex latency (HR-L), ratio, and Ib inhibition were evaluated. Ib inhibition was tested measuring the amplitude changes in soleus H reflex following stimulation of the synergist gastrocnemius medialis (GM) nerve at rest. Nerve conduction studies were performed in the uremic patients.Results: The ratio did not differ in the three groups. The u-RLS patients showed a normal Ib inhibition comparable with the healthy group, whereas the p-RLS group had evidence of a reduced active inhibition compared with both u-RLS patients (P = 0.04) and controls (P = 0.007), prominently at 5 ms (P = 0.007) and at 6 ms (P = 0.02) of conditioning-test interval. Neurophysiological examination disclosed abnormalities ranging from higher HR-L to clear-cut polyneuropathy in most u-RLS patients.Conclusions: Unlike p-RLS patients, u-RLS patients had normal Ib inhibition, suggesting a regular supraspinal control of Ib spinal interneurons. Subclinical peripheral nerve abnormalities were detected in most uremic patients. Peripherally disrupted sensory modulation may represent the major pathophysiological determinant of uremic RLS.

Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson’s disease in Brazilian patients - Corrected Proof

2011-12-23

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder that has a complex etiology which involves gene-environment interactions. Genetic involvement has been substantiated by the discovery of several disease-causing genes and risk factors. These genetic causes are mainly characterized by mutations within the genes SNCA, LRRK2, Parkin, DJ1, PINK1, ATP13A2, PLA2G6 and FBXO7. The genes UCHL1, GIGYF2, HTRA2 and EIF4G1 may also be associated to PD but their pathogenicity is still unclear. In addition, multiple susceptibility genes have been observed as important genetic factors. Among them, mutations within the GBA gene have been proven to be well-established risk factors for PD .

Withdrawal of visual feedback in essential tremor - Corrected Proof

A. Gironell, R. Ribosa-Nogué, J. Pagonabarraga — 2011-12-22

We read with interest the review article on non-pharmacological interventions for essential tremor (ET) by O’Connor and Kini . The authors concluded that many rehabilitation interventions are of little efficacy and that evidence is poor. One form of physical therapy not mentioned in this review is withdrawal of visual feedback. Many patients with ET report improvements when they withdraw their vision when tremor interferes with an activity they are performing.

An evidence-based approach in the treatment of Huntington’s disease - Corrected Proof

T.A. Mestre, J.J. Ferreira — 2011-12-19

Abstract: Huntington’s disease (HD) is a neurodegenerative disease with diverse symptoms for which there is no curative or disease-modifying treatment available. Currently, tetrabenazine is the only drug approved for HD by a regulatory agency, and only for the treatment of chorea. In the current review, we present updated results from recent clinical trials and ongoing clinical research efforts to find effective and safe treatments for HD motor, and neuropsychiatric and cognitive symptoms. We used a systematic review approach that included data from well-designed randomised controlled trials. The authors conclude that there is weak evidence to support most of the treatment decisions in HD and thus clinicians may be guided only by expert opinion-based therapeutic recommendations. Ongoing research is considerable and is expected to have an impact in the management of HD in upcoming years.

Direct costs and survival of medicare beneficiaries with early and advanced parkinson’s disease - Corrected Proof

2011-12-19

Abstract: Background: No recent analysis details Parkinson’s Disease (PD) costs or survival for Medicare beneficiaries. This study assesses excess direct costs and survival in Medicare beneficiaries with early and advanced PD.Methods: Patients with ≥2 PD diagnoses (ICD-9-CM: 332.0), ≥age 65, continuously enrolled in Parts A&B during one-year baseline and study periods were selected from the Medicare 5% sample (N = 3.2 million, 1999–2008). Newly diagnosed patients were defined as having no baseline claims for movement disorder, dementia, Alzheimer’s, bipolar disorder, psychosis, falls or related injuries, ambulatory assistance device (walker or wheelchair), or skilled nursing facility. Controls without PD were demographically matched 1:1. Costs to Medicare were compared via Wilcoxon rank-sum tests and inverse probability weighted multivariate regression. Survival was assessed via Cox proportional hazards analysis.Results: Costs in the year post-diagnosis were higher for newly diagnosed patients (N = 9,201, $7423) than controls ($5024), resulting in excess PD-associated costs of $2399 (p < 0.001). Cumulative excess costs were $28,422 from the year prior to index quarter to five years following (p < 0.01). PD patients receiving their first claim for an ambulatory assistance device (N = 11,294) had excess cumulative costs of $50,923 (p < 0.001) over the same period; those receiving their first claim for a skilled nursing facility (N = 10,152) had excess costs of $102,750 (p < 0.001). Hazard rates of mortality were higher among newly diagnosed PD (1.43, p < 0.001), ambulatory assistance device (2.37, p < 0.001) and skilled nursing facility (3.34, p < 0.001) cohorts than in corresponding non-PD groups.Conclusions: Medicare beneficiaries with PD have substantially and progressively higher costs and mortality compared with controls.

Short and valid assessment of apraxia in Parkinson’s disease - Corrected Proof

2011-12-19

Abstract: Background: Valid assessment of apraxia in usually non-apraxic Parkinson’s disease helps to delineate atypical parkinsonism frequently associated with apraxia. Furthermore, in a subgroup of late Parkinson’s disease apraxia, typically the ideomotor subtype, may gradually superimpose onto parkinsonian motor symptoms contributing to defective manual skill. Here we evaluate the utility of a brief, standardized test, the apraxia screen of TULIA (AST).Methods: Seventy five Parkinson’s disease patients were tested with the AST. Parkinsonian motor deficits were measured using Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III and difficulties in activities of daily living (ADL) by modified MDS-UPDRS part II (eating, dressing, personal hygiene, and writing).Results: No association was found between the AST and MDS-UPDRS part III, indicating that AST discriminates well (discriminative validity) between apraxia and parkinsonism. Furthermore, AST was associated with ADL and Hoehn & Yahr stage (convergent validity).Conclusions: AST is a short and valid test to rule out or detect apraxia in Parkinson’s disease.

The aging striatal dopamine function - Corrected Proof

Olivier Darbin — 2011-12-16

Abstract: Movement disorders are prevalent in the elderly and may have both central and peripheral origins. Age-related parkinsonism often results in movement disorders identical to some of the cardinal symptoms of typical Parkinson's disease (TPD). Nevertheless, there may be limited similarity in the underlying dysfunction of the sensory-motor circuitry since these two conditions exhibit different changes in the nigro-striatal pathway. In this short review, we highlight some of the key distinctions between aging and TPD regarding striatal dopaminergic activity and discuss them in the context of therapeutic strategies to alleviate motor decline in the elderly.

Hippocampal-sparing Alzheimer’s disease presenting as corticobasal syndrome - Corrected Proof

Roneil G. Malkani, Dennis W. Dickson, Tanya Simuni — 2011-12-15

Corticobasal syndrome (CBS) is a progressive neurodegenerative condition characterized by focal cortical dysfunction (apraxia, alien limb phenomenon, cortical sensory loss, neglect, myoclonus, and aphasia) and focal extrapyramidal dysfunction (dystonia and rigidity unresponsive to levodopa) . Corticobasal degeneration (CBD) is a specific pathological entity defined by focal cortical neuronal loss in the frontal, parietal, and/or temporal region and tau-positive neuronal and glial inclusions, especially astrocytic plaques and threads . CBS is most commonly associated with CBD; however, some patients may have an alternate underlying pathology . We present a case with typical CBS in which the underlying pathology was Alzheimer’s disease (AD).

Common polymorphisms in dystonia-linked genes and susceptibility to the sporadic primary dystonias - Corrected Proof

2011-12-15

Abstract: Genes involved in familial dystonia syndromes (DYT genes) are ideal candidates for investigating whether common genetic variants influence the susceptibility to sporadic primary dystonia. To date, there have been few candidate gene studies for primary dystonia and only two DYT genes, TOR1A and THAP1, have been assessed. We therefore employed a haplotype-tagging strategy to comprehensively assess if common polymorphisms in eight DYT genes (TOR1A, TAF1, GCH1, THAP1, MR-1 (PNKD), SGCE, ATP1A3 and PRKRA) confer risk for sporadic primary dystonia. The 230 primary dystonia cases were matched for age and gender to 228 controls, recruited from movement disorder clinics in Brisbane, Australia and the Australian electoral roll. All subjects were genotyped for 56 tagging SNPs and genotype associations were investigated. Modest genotypic associations (P<0.05) were observed for three GCH1 SNPs (rs12147422, rs3759664 and rs10483639) when comparing all cases against controls. Associations were also seen when the cases were stratified based on presentation. Overall, our findings do not support the hypothesis that common TOR1A variants affect susceptibility for sporadic primary dystonia, and that it is unlikely that common variants around the DYT genes confer substantial risk for sporadic primary dystonia. Further work is warranted to follow up the GCH1 SNPs and the subgroup analyses.

Apathy and depression in Parkinson’s disease: The Belgrade PD study report - Corrected Proof

Lj Ziropadja, E. Stefanova, M. Petrovic, T. Stojkovic, V.S. Kostic — 2011-12-14

Abstract: Apathy and depression are among the most common psychiatric and behavioral disorders associated with Parkinson’s disease (PD). The objective of this study was to examine the prevalence and demographic and clinical correlates of apathy and depression in a clinical population-based sample of patients with PD and to assess whether apathy may present as a primary behavioral disturbance independent from depression and cognitive impairment. A series of 360 PD patients underwent psychiatric investigation with the Starkstein’s Apathy Scale (AS), and the 17-item Hamilton Depression Rating Scale (HDRS-17), motor scoring with Hoehn and Yahr (HY) staging, and the Unified Parkinson’s Disease Rating Scale (UPDRS); and cognitive screening with the Mini-Mental State Examination (MMSE) on the same day. Apathy coexisted with depression in 133 (36.9%) of PD patients, compared with depression without apathy in 16 (4.4%), apathy without depression in 84 (23%), and neither apathy nor depression in 127 PD patients (35.2%). Apathy was associated with higher axial UPDRS impairment score, lower MMSE score, higher l-dopa dosage, and earlier HY stages, while depression was predicted by the more advanced HY stages and younger age of PD patients. These findings suggest that apathy and depression may be separable in PD, although both are common in patients with PD. Therefore these two conditions should be systematically screened and considered in the care and management of PD.

Acceleration of syllable repetition in Parkinson's disease is more prominent in the left-side dominant patients - Corrected Proof

Andrea Flasskamp, Sonja A. Kotz, Uwe Schlegel, Sabine Skodda — 2011-12-14

Abstract: Background: In Parkinson's disease (PD), abnormalities of speech rate have been observed in spontaneous speech, reading tasks and syllable repetition tasks. Impaired temporal speech patterns have been contributed to dysfunctional basal ganglia circuits, but little is known about a possible differential role of right and left basal ganglia concerning speech production, although neurodegeneration in PD typically follows an asymmetrical pattern. The aim of our study was to reveal a possible influence of lateralized basal ganglia dysfunction on speech timing in PD.Patients and methods: 60 patients with PD (30 with predominant symptoms on the left-side PD_L and 30 with predominant symptoms on the right side PD_R) and 40 healthy controls were tested. Participants had to repeat a single syllable in a self chosen steady pace. Additionally, the participants performed a reading task in order to measure speaking rate related to connected speech.Results: Syllable repetition showed a significant instability in both PD groups as compared to controls. However, the PD_L group performed in a much higher pace with further significant pace acceleration in the course of the syllable repetition task. This pattern showed a further correlation to axial motor symptoms. No correlations were seen between parameters of syllable repetition and the reading task.Conclusions: Lateralization of basal ganglia dysfunction in PD seems to differentially impact the stability of spontaneous syllable repetition pace. Our data suggest a crucial role of the right basal ganglia in the maintenance of isochronous speech rhythms at least in patients with additional axial motor symptoms.

Sweeping as trick for chronic motor tics - Corrected Proof

P.J. Garcia-Ruiz, Javier del Val — 2011-12-12

Gestes antagonistes can be defined as gestes or maneuvers involving tactile or propioceptive stimulation that can relieve/diminish dystonia . Gestes antagonistes or sensory tricks are very well known in focal dystonia and in fact are often used to support the diagnosis. However, sensory tricks can also be found in other movement disorders including tics .

Albert Schweitzer: A patient with writer’s cramp - Corrected Proof

P. Tacik, C. Schrader, E. Weber, D. Dressler — 2011-12-08

Abstract: Albert Schweitzer (1875–1965) the world-famous philosopher, theologian, concert organist, musicologist, philanthropist and winner of the 1952 Nobel Peace Prize suffered throughout most of his life from severe and painful muscle cramps in his right upper extremity which were triggered exclusively by handwriting. They led to tonic finger flexion and wrist extension and produced slow and clumsy handwriting of a reduced character size. Other motor functions including Schweitzer’s highly skilful and famous organ playing were not affected. Inheritance from his mother is likely. Schweitzer applied several coping strategies including a specific holding pattern for pens, usage of special pens, avoidance of handwriting and slowing of handwriting. With all these features Schweitzer presents as a classical case of action-specific dystonia in the form of a simple tonic writer’s cramp.Interestingly, Schweitzer never received a medical diagnosis, although writer’s cramp had already been identified and described as a medical condition. Impairment of his handwriting but not his organ playing may give insight into the multifactorial aetiology of writer’s cramp.

Restless legs syndrome in Chinese elderly people of an urban suburb in Shanghai: A community-based survey - Corrected Proof

2011-12-08

Summary: Objective: The aim of the study is to investigate the prevalence rate of restless legs syndrome (RLS) in elderly Chinese people over 50 years of age in an urban suburb of Shanghai by a community-based study.Methods: A 3-step survey was adopted including two telephone-based interviews and one face-to-face interview. We used questions based on four diagnostic criteria for RLS to perform the first telephone interview. The second telephone interview was performed by a sleep specialist to rule out the ‘mimics’ and secondary RLS. The final face-to-face interview was performed in the clinic for confirmation and examination.Results: There were 2609 inhabitants in the Wuli Bridge suburb of Shanghai who responded to the first telephone interview (men 68.55±10.13 years of age and women 65.34±10.52 years of age, mean±SD). Eighteen people were finally diagnosed with RLS. In this sample, the overall prevalence rate of RLS was about 0.69% (95% confidence interval (CI): 0.41–1.09).Conclusion: Our study provided the first data about the prevalence rate of RLS in an urban suburb of Shanghai from mainland China, which is consistent with the low prevalence rate reported in other Asian countries.

First neuropathological description of a patient with Parkinson’s disease and LRRK2 p.N1437H mutation - Corrected Proof

2011-12-08

Abstract: The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson’s disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.

A serial MRI study in a patient with progressive supranuclear palsy with cerebellar ataxia - Corrected Proof

2011-12-07

Several clinical variants of progressive supranuclear palsy (PSP) have been identified . We have recently defined a variant of patients designated PSP with cerebellar ataxia (PSP-C) . Because these patients develop cerebellar ataxia as the initial and principal symptom, they might be clinically misdiagnosed as having spinocerebellar degeneration (SCD). To distinguish PSP-C from SCD, magnetic resonance imaging (MRI) may be useful.