Outcome of gastrostomy in parkinsonism: A retrospective study.

OBJECTIVE: To investigate the indications and the outcomes of gastrostomy tube insertion in patients with parkinsonian syndromes. METHODS: Consecutive patients with Parkinson's disease or atypical parkinsonism, seen in two French tertiary referral movement disorders centers, that received gastrostomy tube insertion (GTI) for feeding between 2008 and 2014 were included in this retrospective study. Data regarding clinical status, indications and outcomes were retrieved from medical files. The main outcome measure was survival duration following gastrostomy insertion according to Kaplan-Meier estimate. Cox analysis was also performed to identify factors associated with survival. Finally, we described short term and long term adverse effects occurring during the follow-up period. RESULTS: We identified 33 patients with Parkinsonism that received GTI during the study period. One patient was excluded from the analysis because of missing data. Among 32 patients, 7 (22%) had Parkinson's disease and 25 (78%) had atypical parkinsonism. The median survival following the procedure was 186 days (CI 95% [62-309]). In Cox model analysis, total dependency was the only factor negatively associated with survival (HR 0.1; 95% CI [0.02-0.4], p = 0.001). Pneumonia was the most frequent adverse event. CONCLUSION: In this sample of patients with parkinsonian syndromes, survival after GTI was short particularly in totally dependent subjects. Aspiration pneumonia was not prevented by GTI. A larger prospective study is warranted to assess the potential benefits of gastrostomy, in order to identify the most appropriate indications and timing for the procedure.

Correction: Bee Venom for the Treatment of Parkinson Disease - A Randomized Controlled Clinical Trial.

[This corrects the article DOI: 10.1371/journal.pone.0158235.].

Bee Venom for the Treatment of Parkinson Disease - A Randomized Controlled Clinical Trial.

In the present study, we examined the potential symptomatic and/or disease-modifying effects of monthly bee venom injections compared to placebo in moderatly affected Parkinson disease patients. We conducted a prospective, randomized double-blind study in 40 Parkinson disease patients at Hoehn & Yahr stages 1.5 to 3 who were either assigned to monthly bee venom injections or equivalent volumes of saline (treatment/placebo group: n = 20/20). The primary objective of this study was to assess a potential symptomatic effect of s.c. bee venom injections (100 µg) compared to placebo 11 months after initiation of therapy on United Parkinson's Disease Rating Scale (UPDRS) III scores in the « off ¼ condition pre-and post-injection at a 60 minute interval. Secondary objectives included the evolution of UPDRS III scores over the study period and [123I]-FP-CIT scans to evaluate disease progression. Finally, safety was assessed by monitoring specific IgE against bee venom and skin tests when necessary. After an 11 month period of monthly administration, bee venom did not significantly decrease UPDRS III scores in the « off ¼ condition. Also, UPDRS III scores over the study course, and nuclear imaging, did not differ significantly between treatment groups. Four patients were excluded during the trial due to positive skin tests but no systemic allergic reaction was recorded. After an initial increase, specific IgE against bee venom decreased in all patients completing the trial. This study did not evidence any clear symptomatic or disease-modifying effects of monthly bee venom injections over an 11 month period compared to placebo using a standard bee venom allergy desensitization protocol in Parkinson disease patients. However, bee venom administration appeared safe in non-allergic subjects. Thus, we suggest that higher administration frequency and possibly higher individual doses of bee venom may reveal its potency in treating Parkinson disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01341431.

Executive functioning and risk-taking behavior in Parkinson's disease patients with impulse control disorders.

Impulse control disorders (ICD) are common in Parkinson's disease (PD) and are associated with dopaminergic medication. The purpose of this study was to investigate executive function and risk-taking behavior in PD patients with ICD. 17 PD patients with ICD (ICD-PD) were compared to 20 PD patients without ICD (CTRL-PD) using neuropsychological and experimental tasks. Executive functions were assessed using standard executive testing (Conner's Performance Test, Modified Wisconsin Card Sorting Test, Trail Making Test and phonological verbal fluency). Subjects were also submitted to an experimental gambling task consisted of three decks of money cards: neutral deck (equal opportunity for gains as losses), winning deck (small amount of money with a positive balance) and loser deck (high amount of money with a negative balance), evaluating risk-taking behavior (number of cards picked in each deck) and valuation of the reward (subjective appreciation of the value of each deck). There was no significant difference in executive functioning between groups. Both groups selected more cards in the losing deck (high amount of money) as compared to the neutral deck (Mann-Whitney test, ICD-PD, p = 0.02; CTRL-PD, p = 0.003) and to the winning deck (Mann-Whitney test, ICD-PD p = 0.0001; CTRL-PD p = 0.003), suggesting an increased risk-taking behavior. Interestingly, we found that ICD-PD patients estimated the value of decks differently from CTRL-PD patients, taking into account mainly the positive reinforced value of the decks (Mann-Whitney test, p = 0.04). This study showed that executive pattern and risk-taking behavior are similar between ICD-PD and CTRL-PD patients. However, ICD-PD patients showed a specific deficit of the subjective estimation of the reward. Links between this deficit and metacognitive skills are discussed.

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.

OBJECTIVE: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. METHODS: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). RESULTS: We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. CONCLUSIONS: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease.

OBJECTIVE: To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS: Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS: Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION: In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial.

OBJECTIVE: The AMANDYSK trial was designed to assess long-term efficacy of chronic treatment with amantadine in patients with Parkinson disease (PD) and levodopa-induced dyskinesia (LID). METHODS: This was a 3-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group, wash-out study conducted in 57 amantadine-treated (≥200 mg/d for ≥6 months) dyskinetic patients with PD. The primary outcome measure was the change from baseline in a Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia subscore (items 32 [duration] + 33 [severity]). Secondary outcomes included other LID measurements ("responders" analysis, premature dropout for LID, Abnormal Involuntary Movement Scale). Exploratory outcomes included time with troublesome dyskinesia as measured by diaries, UPDRS Motor Examination (part III) for motor symptoms of PD, and fatigue and apathy scores for nonmotor symptoms. RESULTS: UPDRS items 32 + 33 deteriorated more in patients switched to placebo ("discontinuing" group) (+1.7 ± 2.0 units; 95% confidence interval 0.9, 2.4) as compared with those maintained on amantadine ("continuing" group) (+0.2 ± 1.5 units; 95% confidence interval -0.4, 0.8; p = 0.003). Secondary outcomes confirmed this difference because there were significantly more responders, more dropouts for LID, greater increase in "ON" time with troublesome dyskinesia, and greater worsening of Abnormal Involuntary Movement Scale score in the discontinuing group. There were no between-group differences in the UPDRS Motor Examination, whereas apathy (as measured by caregivers) and fatigue scores tended to worsen more in patients randomized to placebo. CONCLUSION: Wash-out of amantadine in dyskinetic patients with PD significantly worsened LID. No significant effect was observed on motor parkinsonian symptoms, while exploratory outcomes suggested that amantadine might improve apathy and fatigue in such patients. CLASSIFICATION OF EVIDENCE: This article provides Class II evidence that in patients with PD, withdrawing amantadine significantly aggravates LID in a median time of 7 days.

DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.

IMPORTANCE: Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified. OBJECTIVE: To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype). DESIGN, SETTING, AND PARTICIPANTS: Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated. MAIN OUTCOMES AND MEASURES: Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers. RESULTS: We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia. CONCLUSIONS AND RELEVANCE: Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.

Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), the response to L-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase (AAAD, encoded by the DDC gene). OBJECTIVE: To determine the motor response to L-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC(T/C)) and rs3837091 AGAG del (DDC(AGAG/-))). METHODS: Thirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following L-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of L-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. RESULTS: When adjusted for the L-dopa dose, the AUCΔUPDRS was significantly lower in DDC(CC/CT) patients (n = 14) than in DDC(TT) patients (n = 19) and significantly lower in DDC(-/- or AGAG/-) patients (n = 8) than in DDC(AGAG/AGAG) patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for L-dopa and dopamine. DISCUSSION: The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.

[Non-motor symptoms in Parkinson's disease: cognition and behavior]. / Les symptômes non moteurs dans la maladie de Parkinson : cognition et comportement.

Although the diagnosis of Parkinson disease is based on motor symptoms, it is now well known that non-motor symptoms are an integral part of this pathology, involving in fact multiple systems. These non-motor symptoms affect large population of patients and can appear sometimes before the motor disorders. The non-motor symptoms include mainly neuropsychological difficulties, neuropsychiatric symptoms, and autonomic disorders, but involve also pain and sleep disturbances for example. Depression may occur at any stage of the disease, and consists in major depressive disorder, minor depressive disorder, and dysthymia. During the course of the disease, 50% of patients experience anxiety. Apathy is present in up to 30-40% of patients, due to loss of motivation, appearing in emotional, intellectual and behavioral domains. Dopamine dysregulation syndrome and impulse control disorders are not rare, and in relation with dopaminergic therapies. Impulse control disorders include pathological gambling, hyper sexuality, compulsive shopping, and eating disorder. Visual hallucinations can occur in 30% of patients, mostly induced by dopaminergic therapies. Often, they have deeper impact on the quality of life than the motor symptoms themselves, which stay the focus of attention during consulting. Identifying those can help in providing better care with a positive impact on the quality of life of the patients.

Nonmotor symptoms in Parkinson's disease in 2012: relevant clinical aspects.

Nonmotor symptoms (NMSs) of Parkinson's disease (PD) are common, but they are often underrecognized in clinical practice, because of the lack of spontaneous complaints by the patients, and partly because of the absence of systematic questioning by the consulting physician. However, valid specific instruments for identification and assessment of these symptoms are available in 2012. The administration of the self-completed screening tool, NMSQuest, associated with questioning during the consultation, improves the diagnosis of NMSs. NMSs play a large role in degradation of quality of life. More relevant NMSs are described in this review, mood disorders, impulse control disorders, cognitive deficits, hallucinations, pain, sleep disorders, and dysautonomia.

EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

Mutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene, encoding a component of the eIF4F translation initiation complex, were recently reported as a possible cause for the autosomal dominant form of Parkinson's disease (PD). Here, we describe the screening of all 31 EIF4G1 coding exons in a series of 251 index cases with autosomal dominant PD, mostly of French origin and in 236 European control subjects. We identified 12 rare coding variants (either nonsynonymous amino acid substitutions or in frame deletions/insertions), including 6 variants present only in cases and 3 in controls. Segregation was possible only for 1 variant (p.E462delInsGK) that was found in 2 affected siblings. In addition, we found 2 previously reported pathogenic variants in 2 isolated patients (p.G686C) and in a control subject (p.R1197W). These data do not support the pathogenicity of several EIF4G1 variants in PD, at least in the French population.

Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale.

BACKGROUND: The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. METHODS AND FINDINGS: Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. CONCLUSIONS: The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00211224.

Understanding facial emotion perception in Parkinson's disease: the role of configural processing.

Parkinson's disease (PD) has been frequently associated with facial emotion recognition impairments, which could adversely affect the social functioning of those patients. Facial emotion recognition requires processing of the spatial relations between facial features, known as the facial configuration. Few studies, however, have investigated this ability in people with PD. We hypothesized that facial emotion recognition impairments in patients with PD could be accounted for by a deficit in configural processing. To assess this hypothesis, three tasks were proposed to 10 patients with PD and 10 healthy controls (HC): (i) a facial emotion recognition task with upright faces, (ii) a similar task with upside-down faces, to explore the face inversion effect, and (iii) a configural task to assess participants' abilities to detect configural modifications made on a horizontal or vertical axis. The results showed that when compared with the HC group, the PD group had impaired facial emotion recognition, in particular for faces expressing anger and fear, and exhibited reduced face inversion effect for these emotions. More importantly, the PD group's performance on the configural task to detect vertical modifications was lower than the HC group's. Taken together, these results suggest the presence of a configural processing alteration in patients with PD, especially for vertical, second-order information. Furthermore, configural performance was positively correlated with emotion recognition for anger, disgust, and fear, suggesting that facial emotion recognition could be related, at least partially, to configural processing.

The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial.

OBJECTIVE: In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMT(HH) ), intermediate (Val/Met, COMT(HL) ), or low (Met/Met, COMT(LL) ). The objective of this study was to determine the response to entacapone in COMT(HH) and COMT(LL) PD patients. METHODS: Thirty-three PD patients, homozygous for the COMT alleles COMT(HH) (n = 17) and COMT(LL) (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. RESULTS: The gain in the best ON time was higher in COMT(HH) than in COMT(LL) patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMT(HH) than in COMT(LL) patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT(HH) than in COMT(LL) patients (-0.54 ± 0.07 vs -0.31 ± 0.06 pmol/min/mg protein, p = 0.02). INTERPRETATION: The COMT(HH) genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined.

Urodynamic analysis in multiple system atrophy: characterisation of detrusor-sphincter dyssynergia.

In multiple system atrophy (MSA), parkinsonism and a cerebellar syndrome are associated with autonomic dysfunction. Both bladder neck dysfunction and external sphincter denervation have been implicated in detrusor-sphincter dyssynergia. However, urethral dysfunction may not be adequately reflected by a single global measurement of urethral pressure. Pressure assessment at several levels of the urethra is needed to unravel the mechanisms of bladder-urethra dysfunction. Here, we evaluated the use of multiple sensor pressure transducers to assess bladder-sphincter function in 52 patients with MSA in comparison to patients with Parkinson's disease (PD) who were matched for age and severity in the "off" condition. Urinary dysfunction appeared significantly earlier in MSA (<2 years) than in PD (>5 years). Detrusor under-activity with dysuria was observed in 58% of MSA patients within 4 years and in 76% of patients thereafter. Detrusor-urethral dyssynergia in MSA patients was always better characterized by multiple sensor pressure transducer measurement of bladder and urethral pressure than by a single global measurement. This new approach may prove useful for differential diagnosis of parkinsonian syndromes, and especially MSA.

Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study.

S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate.

A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death.

Lewy bodies in Parkinson disease could be innocent bystanders or active agents responsible for neuronal death. Eighteen elderly patients with a Parkinson syndrome were studied prospectively and selected postmortem on the presence of Lewy bodies (14 cases with Parkinson disease, four with dementia with Lewy bodies). Information on disease duration was available in 17 cases. While akinesia and rigidity were linked with the neuronal loss, the percentages of Lewy body bearing neurons and of alpha-synuclein immunoreactive neurons in the substantia nigra were not correlated with the symptoms or the disease duration, and appeared stable, involving 3.6% of the neurons on average. Such stability indicated that, during the whole course of the disease, the destruction of the Lewy bodies was equal to their production. In the model that is proposed here, the Lewy bodies are eliminated when the neurons that bear them die. With the hypothesis that neuronal death is directly related to Lewy bodies, it is possible to estimate their life span, which was calculated to be 6.2 months (15.9 months for any type of alpha-synuclein inclusion).

Long-term effects of pallidal or subthalamic deep brain stimulation on quality of life in Parkinson's disease.

We assessed the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) or internal pallidum (GPi-DBS) on health-related quality of life (HrQoL) in patients with advanced Parkinson's disease participating in a previously reported multicenter trial. Sickness Impact Profile (SIP) questionnaires were available for analysis in a subgroup of n = 20/20 patients with GPi-DBS and n = 45/49 patients with STN-DBS at baseline, 6 and 36 months. The SIP provides a physical dimension and a psychosocial dimension sum score and 12 category scores: Alertness/Intellectual Behavior (AIB), Ambulation (A), Body Care and Movement (BCM), Communication (C), Eating (E), Emotional Behavior (EB), Home Management (HM), Mobility (M), Recreation and Pastimes (RP), Sleep and Rest (SR), Social Interaction (SI), and Work (W). Motor functioning was assessed by means of the Unified Parkinson's Disease Rating Scale and diaries. At 6 months significant improvements in off-period motor symptoms and activities of daily living were paralleled by significant reductions in the total, physical, and psychosocial SIP score in both treatment groups. At 3 years, sustained improvements were observed in the physical dimension score, BCM, E, M, RP after STN-DBS and M, SI after GPi-DBS. All other SIP subscores approached baseline values, but were still the same or better (except C) whereas motor functioning remained stable after 36 months. STN-DBS and GPi-DBS led to significant early improvements in HrQoL. Despite sustained motor improvements many of these initial benefits were lost after 3 years. This may reflect either progression of the disease or adaptive changes in the subjective perception of health-related wellbeing over time.

Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.

OBJECTIVE: Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism. DESIGN: Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California). SUBJECTS: Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened. RESULTS: Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement. CONCLUSIONS: Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.