Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial.

BACKGROUND: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. OBJECTIVES: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. METHODS: OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. RESULTS: Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). CONCLUSIONS: The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Diagnosis and Outcomes of Late-Onset Wilson's Disease: A National Registry-Based Study.

BACKGROUND: Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms. OBJECTIVE: The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD. METHODS: Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up. RESULTS: Forty-five patients were identified (median age: 49, range: 40-64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser-Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis. CONCLUSIONS: In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ambulatory blood pressure and drug treatment for orthostatic hypotension as predictors of mortality in patients with multiple system atrophy.

OBJECTIVES: Multiple system atrophy (MSA) is a rare fatal neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. This study was aimed at investigating possible associations between mortality, 24-h blood pressure (BP) level and variability, and drug treatments for orthostatic hypotension (OH) in MSA patients. METHODS: A total of 129 patients followed at the French Reference Center for MSA who underwent routine 24-h ambulatory BP monitoring were included. Unified MSA Rating Scale (UMSARS) scores, drug treatments and the occurrence and cause of death were recorded. RESULTS: Seventy patients died during follow-up (2.9 ± 1.8 years), mainly from terminal illness, pulmonary or sudden death. Multivariate Cox regression analysis, after adjustment for gender, disease duration and severity (UMSARS I+II score), showed that increased daytime systolic BP variability, OH severity and OH drug treatment were independently correlated with mortality. OH treatment was associated with the risk of cardiac causes and/or sudden death (p = 0.01). In a fully adjusted model, male gender [(female vs. male) hazard ratio (HR) 0.56, 95% CI 0.34-0.94, p = 0.03], UMSARS I+II score (HR 1.04, 95% CI 1.02-1.06, p < 0.01), systolic BP daytime variability (HR 3.66, 95% CI 1.46-9.17, p < 0.01) and OH treatment (HR: 2.13, 95% CI 1.15-3.94, p = 0.02) predicted mortality. CONCLUSIONS: Increased daytime BP variability and OH treatment were predictive of mortality in patients with MSA, independently from disease severity. Further studies are required to assess if these associations are explained by more severe autonomic dysfunction or if OH treatment exposes per se to a specific risk in this population.

Natural History of Adult Patients with GM2 Gangliosidosis.

OBJECTIVE: GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. METHODS: We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS: We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION: Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.

Repetitive transcranial magnetic stimulation for functional tremor: A randomized, double-blind, controlled study.

OBJECTIVES: The objective of this study was to compare the effect on functional tremor of active versus sham repetitive transcranial magnetic stimulation and investigate whether the addition of hypnosis might help to prolong any repetitive transcranial magnetic stimulation-induced therapeutic effect. METHODS: We compared the effect of 5 consecutive daily sessions of active/sham repetitive transcranial magnetic stimulation on functional tremor, at 1 and 2 months, in a randomized, double-blind, 2-arm, parallel-controlled study. In a second open-label phase, all patients underwent 3 weekly sessions of hypnosis combined with single sessions of real repetitive transcranial magnetic stimulation. The primary outcome was a change in the Psychogenic Movement Disorder Rating Scale at month 1 when compared with baseline. Secondary outcomes were changes in the Psychogenic Movement Disorder Rating Scale and Tremor subscores, the 36-item Short Form Health Survey, the Self-Report Hospital Anxiety and Depression Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impression Scale assessed at months 1, 2, 6, and 12. RESULTS: A total of 33 outpatients affected by functional tremor were screened, and 18 outpatients fulfilling the inclusion criteria (8 men, 10 women) were randomized. One month after the intervention, the mean Psychogenic Movement Disorder Rating Scale score had decreased in both groups, but the differences from baseline were only significant in the active repetitive transcranial magnetic stimulation group (P < .001). This remained significant at month 2 (P < .001). The significant decrease of the Psychogenic Movement Disorder Rating Scale and Tremor subscores were maintained at months 6 and 12 for the active repetitive transcranial magnetic stimulation group. For the control group, the Psychogenic Movement Disorder Rating Scale score had returned almost to its baseline value by month 2 and remained unchanged at months 6 and 12. CONCLUSION: Repetitive transcranial magnetic stimulation could represent a valuable therapeutic option in the management of functional tremor. © 2019 International Parkinson and Movement Disorder Society.

Examining the Reserve Hypothesis in Parkinson's Disease: A Longitudinal Study.

BACKGROUND: Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function. OBJECTIVE: To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression. METHODS: We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models. RESULTS: Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P < 0.001), but not with the rate of motor decline (P > 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms. CONCLUSIONS: Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society.

Dopaminergic denervation using [123I]-FPCIT and pain in Parkinson's disease: a correlation study.

In patients with Parkinson's disease (PD), abnormal activations of nociceptive brain areas and lowered pain thresholds were reported, probably reflecting a central modification of pain processing. The aim of this study was to investigate the possible correlation between the striatal and extrastriatal dopaminergic system and pain threshold in PD patients. We included 25 PD patients with various intensities of central pain (visual analog scale). Subjective pain threshold (thermotest) and a motor examination (UPDRS III) were performed. Patients underwent SPECT imaging with [123I]-FP-CIT. We analyzed the correlation between [123I]-FP-CIT binding and subjective pain threshold, using a simple linear regression model for striatal uptake and a voxel-based approach for extrastriatal uptake. The covariables were age, sex, duration of PD, and UPDRS motor score. A pain matrix mask was also used to identify clusters in relation with pain matrix. Striatal analysis revealed that [123I]-FP-CIT binding was negatively correlated with age (p = 0.02), duration of PD (p = 0.0002) and UPDRS motor score (p = 0.006), but no correlation with pain threshold was observed. The extrastriatal analysis showed a positive correlation between [123I]-FP-CIT binding and subjective heat pain threshold for the left posterior cingulate cortex (PCC) (p < 0.001) and negative correlations for the right secondary visual cortex (p < 0.001) and left insula (p < 0.001). When applying the pain matrix mask, correlations remained significant only in the left PCC and the left insula. We suggest that pain perception abnormalities in PD are not directly related to striatal dopaminergic dysfunction. Painful sensations may be related to extrastriatal monoaminergic systems.

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.

Neurological presentations revealing acquired copper deficiency: diagnosis features, aetiologies and evolution in seven patients.

BACKGROUND: Acquired copper deficiency (ACD) is a rare condition usually diagnosed from haematological changes. AIMS: To characterise the diagnosis features and the evolution of patients with ACD revealed by neurological symptoms. METHODS: Clinical, biological and magnetic resonance imaging (MRI) data were prospectively analysed at diagnosis and during follow up under copper supplementation. RESULTS: Seven patients were studied over a 5-year period. Time to diagnosis ranged from 2.5 to 15 months. Subacute ascending paraesthesias and gait disorder were the first symptoms. All patients had a posterior cord syndrome (PCS) with sensory ataxic gait associated with superficial hypoesthesia of the feet; 50% had also lateral cord signs. Electrodiagnostic tests diagnosed a lower limb sensory neuropathy in four patients. Spinal cord MRI was normal in three of seven patients. Anaemia and lymphopenia were diagnosed in six of seven patients. Serum copper was always low, and urinary copper was low or normal. Serum and urinary zinc were high in four patients. Decreased copper intake (stoma/parenteral nutrition, malnutrition, malabsorption with lack of vitamin supplementation after bariatric or other digestive surgeries) was found in four patients, and the chronic use of denture adhesive paste containing zinc was discovered in four patients. One patient had both the causes recorded. After copper supplementation, copper balance and then haematological disturbances were the first features to normalise gradually in 2 months. Radiological myelitis disappeared in 10 months, whereas neurological symptoms improved in six of seven patients after a mean follow up of 2 years. CONCLUSIONS: Progressive PCS with anaemia and lymphopenia must raise the possibility of an ACD. Early copper supplementation could increase the neurological prognosis.

Case report of Lewy body disease mimicking Creutzfeldt-Jakob disease in a 44-year-old man.

BACKGROUND: Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. CASE PRESENTATION: We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14-3-3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on (18)F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. CONCLUSIONS: This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed.

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.

After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

International validation of a behavioral scale in Parkinson's disease without dementia.

The "Ardouin Scale of Behavior in Parkinson's Disease" is a new instrument specifically designed for assessing mood and behavior with a view to quantifying changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This study was aimed at analyzing the psychometric attributes of this scale in patients with Parkinson's disease without dementia. In addition to this scale, the following measures were applied: the Unified Parkinson's Disease Rating Scale, the Montgomery and Asberg Depression Rating Scale, the Lille Apathy Rating Scale, the Bech and Rafaelsen Mania Scale, the Positive and Negative Syndrome Scale, the MacElroy Criteria, the Patrick Carnes criteria, the Hospital Anxiety and Depression Scale, and the Mini-International Neuropsychiatric Interview. Patients (n=260) were recruited at 13 centers across four countries (France, Spain, United Kingdom, and United States). Cronbach's alpha coefficient for domains ranged from 0.69 to 0.78. Regarding test-retest reliability, the kappa coefficient for items was higher than 0.4. For inter-rater reliability, the kappa values were 0.29 to 0.81. Furthermore, most of the items from the Ardouin Scale of Behavior in Parkinson's Disease correlated with the corresponding items of the other scales, depressed mood with the Montgomery and Asberg Depression Rating Scale (ρ=0.82); anxiety with the Hospital Anxiety and Depression Scale-anxiety (ρ=0.56); apathy with the Lille Apathy Rating Scale (ρ=0.60). The Ardouin Scale of Behavior in Parkinson's disease is an acceptable, reproducible, valid, and precise assessment for evaluating changes in behavior in patients with Parkinson's disease without dementia.

Personality and quality-of-life improvement after apomorphine infusion in Parkinson's disease.

People with Parkinson's disease with motor fluctuations can be treated by continuous subcutaneous apomorphine infusion (CSAI) to reduce their symptoms. Nonetheless, factors are lacking to predict patients' quality-of-life amelioration after CSAI. This pilot study aimed to evaluate associations between personality dimensions and quality-of-life improvement after 6 months of CSAI. Thirty-nine people with Parkinson's disease awaiting CSAI were included. Linear regression models between 'Temperament and Character Inventory' personality dimensions at baseline and percentage of change in Parkinson's Disease Questionnaire-39 scores after 6 months of CSAI were realized (n = 35). The Temperament and Character Inventory was also compared between patients awaiting CSAI and patients awaiting deep brain stimulation of the sub-thalamic nucleus (n = 39 from the PREDI-STIM study). Higher reward dependence scores were associated with a better quality-of-life outcome after 6 months of CSAI, while self-directedness scores were associated with a better quality of life before CSAI (as opposed to harm avoidance, reward dependence and self-transcendence scores associated with a worse quality of life). Moreover, people with Parkinson's disease awaiting deep brain stimulation of the sub-thalamic nucleus had similar Temperament and Character Inventory dimensions compared to patients awaiting CSAI. People with Parkinson's disease with higher reward dependence scores at baseline had the best quality-of-life improvement after 6 months of CSAI. This finding could be used to better prepare and accompany people with Parkinson's disease during CSAI establishment. Moreover, this result could serve as an orientation factor to second-line treatments.

Prognosis of impulse control disorders in Parkinson's disease: a prospective controlled study.

BACKGROUND: The long-term prognosis of impulsive compulsive disorders (ICD) remains poorly studied in Parkinson's disease (PD). OBJECTIVE: Evaluating the natural history of ICD and its impact on PD symptoms including cognition and treatment adjustments. MATERIALS AND METHODS: We assessed PD patients at baseline (BL) with (BL-ICD+) or without (BL-ICD-) ICD despite dopamine agonist (DA) exposure of > 300 mg levodopa-equivalent daily dose for > 12 months at baseline and after more than two years of follow-up. ICD were assessed using the Ardouin's Scale of Behaviors in PD (ASBPD), cognition using the Mattis scale, and PD symptoms using the UPDRS score. Treatment adjustments, DA withdrawal-associated symptoms, and ICDs social consequences were recorded. RESULTS: 149 patients were included (78 cases and 71 controls), mean duration of follow-up was 4.4 ± 1 years. At baseline, psychiatric disorders were more common among BL-ICD + (42.3 vs 12.3% among BL-ICD-, p < 0.01). At follow-up, 53.8% of BL-ICD + were not ICD-free while 21.1% of BL-ICD- had developed ICD. BL-ICD + more frequently experienced akinesia (21.8 vs 8.5%, p = 0.043) and rigidity worsening (11.5 vs 1.4%, p = 0.019) following therapeutic modifications. Decision to decrease > 50% DA doses (12.8 vs 1.4%, p = 0.019) or to withdraw DA (19.2 vs 5.6%, p = 0.025) was more frequently considered among BL-ICD+ . At follow-up, the prevalence of cognitive decline was lower among BL-ICD + (19.2 vs 37.1%, p = 0.025). CONCLUSION: ICDs were associated with increased psychiatric burden at baseline and better cognitive prognosis. Most patients were still showing ICDs at the follow-up visit, suggesting ICD to be considered as a chronic, neuropsychiatric disorder.

The impact of subthalamic deep-brain stimulation in restoring motor symmetry in Parkinson's disease patients: a prospective study.

BACKGROUND AND OBJECTIVES: The impact of subthalamic deep-brain stimulation (STN-DBS) on motor asymmetry and its influence on both motor and non-motor outcomes remain unclear. The present study aims at assessing the role of STN-DBS on motor asymmetry and how its modulation translates into benefits in motor function, activities of daily living (ADLs) and quality of life (QoL). METHODS: Postoperative motor asymmetry has been assessed on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. Asymmetry was evaluated at both baseline (pre-DBS) and 1 year after STN-DBS. A patient was considered asymmetric when the right-to-left MDS-UPDRS part III difference was ≥ 5. In parallel, analyses have been carried out using the absolute right-to-left difference. The proportion of asymmetric patients at baseline was compared to that in the post-surgery evaluation across different medication/stimulation conditions. RESULTS: 537 PD patients have been included. The proportion of asymmetric patients was significantly reduced after both STN-DBS and medication administration (asymmetric patients: 50% in pre-DBS MedOFF, 35% in MedOFF/StimON, 26% in MedON/StimOFF, and 12% in MedON/StimON state). Older patients at surgery and with higher baseline UPDRS II scores were significantly less likely to benefit from STN-DBS at the level of motor asymmetry. No significant correlation between motor asymmetry and ADLs (UPDRS II) or overall QoL (PDQ-39) score was observed. Asymmetric patients had significantly higher mobility, communication, and daily living PDQ-39 sub-scores. CONCLUSIONS: Both STN-DBS and levodopa lead to a reduction in motor asymmetry. Motor symmetry is associated with improvements in certain QoL sub-scores.