Additional Safety and Exploratory Efficacy Data at 48 and 60 Months from Open-HART, an Open-Label Extension Study of Pridopidine in Huntington Disease.

BACKGROUND: Open-HART was an open-label extension of HART, a randomized, double-blind, placebo-controlled study of pridopidine in Huntington disease (HD). Previously, we reported safety and exploratory efficacy data after 36 months of treatment with pridopidine 45 mg twice daily. In the interim, emerging data suggests pridopidine may have neuroprotective effects mediated by sigma-1 receptor agonism. OBJECTIVE: To report additional safety and exploratory efficacy data for continued open-label use of 45 mg BID pridopidine at 48 and 60 months. METHODS: Patients in Open-HART were followed up to or greater than 60 months. Adverse events, concomitant medications, vital signs, laboratory values, and ECG data were monitored. Rates of decline in total functional capacity (TFC) and total motor score (TMS) over 60 months were evaluated in an exploratory analysis and compared between Open-HART and placebo recipients from the 2CARE trial. To account for missing data, sensitivity analyses were performed. RESULTS: Of the original Open-HART baseline cohort (N = 118), 40 remained in the study at 48 months and 33 at 60 months. Pridopidine remained safe and well tolerated over the 60-month interval. TFC and TMS at 48 and 60 months remained stable, showing less decline at these timepoints compared to historical placebo controls from the 2CARE trial. TFC differences at 48 and 60 months observed remained nominally significant after sensitivity analysis. CONCLUSION: The 45 mg BID pridopidine dosage remained safe and tolerable over 60 months. Exploratory analyses show TFC and TMS stability at 48 and 60 months, in contrast to placebo historical controls from the 2CARE trial. Results are consistent with data reported from the recent Phase 2 PRIDE-HD trial showing less functional decline in the pridopidine 45 mg BID treated group at 52 weeks.

Abnormalities on structural MRI associate with faster disease progression in multiple system atrophy.

BACKGROUND: The rate of clinical progression in patients with multiple system atrophy (MSA) varies between individuals and predictors for disease progression remain undefined. While the MSA-rasagiline study found no difference in the rates of clinical progression for patients treated with rasagiline versus placebo, it included a large, prospective magnetic resonance imaging (MRI) substudy that can provide new information on the underlying disease progression in patients with early MSA. METHODS: This post-hoc analysis compared the rate of clinical progression in patients with MSA-specific structural changes at baseline (MRI-positive group) versus the rate of progression in patients without evidence of such changes at baseline (MRI-negative group) using a repeated measures ANCOVA. Clinical progression was assessed using the Unified MSA Rating Scale (UMSARS) and Clinical Global Impression of Improvement (CGI-I). RESULTS: Twenty-eight patients with early MSA of the parkinsonian subtype (MRI-positive n = 13; MRI-negative n = 15) who had complete baseline and follow-up UMSARS data were included in this analysis. Patients in the MRI-positive group had faster clinical progression from baseline to the end of the 48-week study compared with those in the MR-negative group as assessed by the UMSARS total (p = 0.028) and UMSARS motor (p = 0.008) scales. At week 48, MRI-positive patients also had a significantly worse health status vs. MRI-negative patients (p = 0.015). CONCLUSIONS: This is the first study to demonstrate that MSA-specific abnormalities on structural MRI might represent a variant of MSA-P that is associated with more rapid progression and an overall worse prognosis.

Safety and Exploratory Efficacy at 36 Months in Open-HART, an Open-Label Extension Study of Pridopidine in Huntington's Disease.

BACKGROUND: Open-HART is an open-label extension of HART, a randomized, placebo-controlled, dose-ranging, parallel-group study. OBJECTIVE: To evaluate safety and exploratory efficacy of open-label pridopidine over 36 months in subjects with Huntington's disease (HD). METHODS: Open-HART subjects were treated with pridopidine 45 mg twice daily (BID). After initial evaluation by telephone (Week 1) and in person (Month 1), in-person visits occurred every 3 months, alternating between safety and clinical visits (safety plus Unified Huntington's Disease Rating Scale [UHDRS] assessment). The UHDRS was performed for pre-specified analysis as a secondary outcome measure. Adverse events (AEs), laboratory values, and electrocardiography were monitored throughout. RESULTS: Most subjects (89%) reported at least one AE, with 30% experiencing treatment-related AEs. The most common AEs during the first year were falls (12.7%), anxiety (9.3%), insomnia (8.5%), irritability (6.8%), and depression (5.9%). Ninety-nine percent of subjects took concomitant medications. Two seizures were reported as AEs. No arrhythmias or suicide attempts were reported. Five deaths occurred, all considered treatment unrelated. Secondary exploratory analyses of subjects on pridopidine demonstrated motor deterioration (as measured by the UHDRS total motor score) consistent with HD's natural history, as shown in large observational studies. A post-hoc, exploratory analysis of TFC performance compared to placebo groups from other long-term HD studies demonstrated no significant effect for pridopidine on TFC progression after correction for multiple comparisons. CONCLUSIONS: Pridopidine 45 mg BID was generally safe and tolerable in HD subjects over 36 months. TMS declined in a manner consistent with the known natural history of HD.

Tablet-Based Application for Objective Measurement of Motor Fluctuations in Parkinson Disease.

BACKGROUND: The motor subscale of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) has limited applicability for the assessment of motor fluctuations in the home setting. METHODS: To assess whether a self-administered, tablet-based application can reliably quantify differences in motor performance using two-target finger tapping and forearm pronation-supination tasks in the ON (maximal dopaminergic medication efficacy) and OFF (reemergence of parkinsonian deficits) medication states, we recruited 11 Parkinson disease (PD) patients (age, 60.6 ± 9.0 years; disease duration, 12.8 ± 4.1 years) and 11 healthy age-matched controls (age, 62.5 ± 10.5 years). The total number of taps, tap interval, tap duration, and tap accuracy were algorithmically calculated by the application, using the more affected side in patients and the dominant hand in healthy controls. RESULTS: Compared to the OFF state, PD patients showed a higher number of taps (84.2 ± 20.3 vs. 54.9 ± 26.9 taps; p = 0.0036) and a shorter tap interval (375.3 ± 97.2 vs. 708.2 ± 412.8 ms; p = 0.0146) but poorer tap accuracy (2,008.4 ± 995.7 vs. 1,111.8 ± 901.3 pixels; p = 0.0055) for the two-target task in the ON state, unaffected by the magnitude of coexistent dyskinesia. Overall, test-retest reliability was high (r >0.75) and the discriminatory ability between OFF and ON states was good (0.60 ≤ AUC ≤ 0.82). The correlations between tapping data and MDS-UPDRS-III scores were only moderate (-0.55 to 0.55). CONCLUSIONS: A self-administered, tablet-based application can reliably distinguish between OFF and ON states in fluctuating PD patients and may be sensitive to additional motor phenomena, such as accuracy, not captured by the MDS-UPDRS-III.

Minimally clinically important decline in the parkinsonian variant of multiple system atrophy.

INTRODUCTION: We provide the first characterization of the minimally clinically important difference on the Unified Multiple System Atrophy Rating Scale in patients with the parkinsonian variant of early MSA. METHODS: Data from a randomized controlled trial of rasagiline were analyzed using clinical global impression as an anchor. Because too few patients improved with treatment, analyses were limited to defining scale cutoffs that discriminated between minimal worsening and no change. RESULTS: Based on receiver operating characteristic curves, minimally clinically important differences were 1.5 points on the activities of daily living scale, 1.5 points on the motor scale, and 3.5 points on the total scale. CONCLUSIONS: Appreciation of the minimally clinically important difference is important when deciding if statistically significant effects should influence practice. For the Unified Multiple System Atrophy Rating Scale, further work is required to establish cutoffs for improvement, extend relevance to cerebellar-predominant disease, and characterize progression rates at different disease stages. © 2016 International Parkinson and Movement Disorder Society.

The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease.

IMPORTANCE: In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE: To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS: A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS: Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington's Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, -48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, -47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE: As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.

Descriptive epidemiology of cervical dystonia.

BACKGROUND: Cervical dystonia (CD), the most common form of adult-onset focal dystonia, has a heterogeneous clinical presentation with variable clinical features, leading to difficulties and delays in diagnosis. Owing to the lack of reviews specifically focusing on the frequency of primary CD in the general population, we performed a systematic literature search to examine its prevalence/incidence and analyze methodological differences among studies. METHODS: We performed a systematic literature search to examine the prevalence data of primary focal CD. Sixteen articles met our methodological criteria. Because the reported prevalence estimates were found to vary widely across studies, we analyzed methodological differences and other factors to determine whether true differences exist in prevalence rates among geographic areas (and by gender and age distributions), as well as to facilitate recommendations for future studies. RESULTS: Prevalence estimates ranged from 20-4,100 cases/million. Generally, studies that relied on service-based and record-linkage system data likely underestimated the prevalence of CD, whereas population-based studies suffered from over-ascertainment. The more methodologically robust studies yielded a range of estimates of 28-183 cases/million. Despite the varying prevalence estimates, an approximate 2:1 female:male ratio was consistent among many studies. Three studies estimated incidence, ranging from 8-12 cases/million person-years. DISCUSSION: Although several studies have attempted to estimate the prevalence and incidence of CD, there is a need for additional well-designed epidemiological studies on primary CD that include large populations; use defined CD diagnostic criteria; and stratify for factors such as age, gender, and ethnicity.

OnabotulinumtoxinA muscle injection patterns in adult spasticity: a systematic literature review.

BACKGROUND: OnabotulinumtoxinA has demonstrated significant benefit in adult focal spasticity. This study reviews the injection patterns (i.e., muscle distribution, dosing) of onabotulinumtoxinA for treatment of adult spasticity, as reported in published studies. METHODS: A systematic review of clinical trials and observational studies published between 1990 and 2011 reporting data on muscles injected with onabotulinumtoxinA in adult patients treated for any cause of spasticity. RESULTS: 28 randomized, 5 nonrandomized, and 37 single-arm studies evaluating 2,163 adult patients were included. The most frequently injected upper-limb muscles were flexor carpi radialis (64.0% of patients), flexor carpi ulnaris (59.1%), flexor digitorum superficialis (57.2%), flexor digitorum profundus (52.5%), and biceps brachii (38.8%). The most frequently injected lower-limb muscles were the gastrocnemius (66.1% of patients), soleus (54.7%), and tibialis posterior (50.5%). The overall dose range reported was 5-200 U for upper-limb muscles and 10-400 U for lower-limb muscles. CONCLUSIONS: The reviewed evidence indicates that the muscles most frequently injected with onabotulinumtoxinA in adults with spasticity were the wrist, elbow, and finger flexors and the ankle plantar flexors. OnabotulinumtoxinA was injected over a broad range of doses per muscle among the studies included in this review, but individual practitioners should be mindful of local regulatory approvals and regulations.

Gastric stasis in migraineurs: etiology, characteristics, and clinical and therapeutic implications.

BACKGROUND: Migraine is a disabling neurological disorder often complicated by gastrointestinal conditions such as gastric stasis. The association between migraine and gastric stasis has received very little attention in the literature, but the existing evidence suggests that they may share a common etiology. RESULTS: Patients with migraine and those with gastric stasis exhibit abnormal autonomic nervous system function. Furthermore, empirical studies demonstrate that migraineurs experience significant delays in gastric emptying, both during and outside of attacks, when compared to non-migrainous controls. CONCLUSION: More research is needed to establish the relationship between gastric stasis and migraine burden and to determine the impact of gastric stasis on migraine treatment.

Patient diaries as a clinical endpoint in Parkinson's disease clinical trials.

Parkinson's disease (PD) is the second most common neurodegenerative disorder with an estimated 4 million patients worldwide. L-dopa is standard, and often initial, therapy for patients with this condition; however, with continued dopaminergic treatment and as the disease progresses, the majority of patients experience complications such as "wearing-off" symptoms, dyskinesias, and other motor complications. These complications may become disabling and profoundly affect quality of life. Treatment modification and combination therapies with L-dopa, dopamine agonists, monoamine oxidase type B inhibitors, and catechol-O-methyltransferase inhibitors are commonly used to manage complications. In recent years regulatory agencies, clinical researchers, and sponsors have widely accepted and utilized changes in "ON" and "OFF" time measured by Patient Hauser Diaries as endpoints for measuring efficacy of therapeutics seeking approval for symptomatic treatment of PD. Successful antiparkinsonian medications have been associated with treatment effects of more than 1 h in either reduction of "OFF" time of increase in "ON" time. Accurate "ON" and "OFF" time registration during clinical studies requires rigorous patient training. Reduced compliance, recall bias and diary fatigue are common problems seen with patient diary reported measures. Electronic diaries may help reducing some of these problems but may be associated with other challenges in large, multicenter studies.

Rationale and design of a prospective study: Cervical Dystonia Patient Registry for Observation of OnaBotulinumtoxinA Efficacy (CD PROBE).

BACKGROUND: A registry of patients with cervical dystonia (Cervical Dystonia Patient Registry for Observation of onaBotulinumtoxinA Efficacy [CD PROBE]) was initiated to capture data regarding physician practices and patient outcomes with onabotulinumtoxinA (BOTOX®, Allergan, Inc., Irvine, CA, USA). Methods and baseline demographics from an interim analysis are provided. METHODS/DESIGN: This is a prospective, multicenter, clinical registry in the United States enrolling subjects with cervical dystonia (CD) who are toxin naïve and/or new to the physicians' practices, or who had been in a clinical trial but received their last injection ≥ 16 weeks prior to enrollment. Subjects are followed over 3 injection cycles of onabotulinumtoxinA, with assessments at time of injection and 4-6 weeks later. Information on physician's practice, patient demographics, CD disease history, duration of treatment intervals and neurotoxin dose, dilution, use of electromyography, and muscles injected are collected. Outcomes are assessed by physicians and subjects using various questionnaires. DISCUSSION: This ongoing registry includes 609 subjects with the following baseline data: 75.9% female, 93.6% Caucasian, mean age 57.6 ± 14.3, age at symptom onset 48.3 ± 16.2, and time to diagnosis 5.4 ± 8.6 years, with an additional 1.0 ± 3.5 years before treatment. Of those employed at the time of diagnosis, 36.6% stopped working as a result of CD. CD PROBE, the largest clinical registry of CD treatment, will provide useful data on current treatment practices with onabotulinumtoxinA, potentially leading to refinements for optimization of outcomes. TRIAL REGISTRATION: NCT00836017.

Objective quantification of neuromotor symptoms in Parkinson's disease: implementation of a portable, computerized measurement tool.

Quantification of neuromotor symptoms with device-based measures provides a useful supplement to clinical evaluation. Research using the CATSYS has established its utility as a computerized measurement system to quantify neuromotor function. The primary objective of this study is to provide technical guidance on the use of the CATSYS in Parkinson's disease (PD). Forty-four patients with idiopathic PD and 28 healthy controls were prospectively recruited and evaluated with CATSYS, a portable, Windows-based system consisting of a data logger and four different sensors (tremor pen, touch recording plate, reaction time handle, and force plate for balance recording) for quantification of neuromotor functions. CATSYS discriminated between PD and controls on measurements of rest/postural tremor, pronation/supination, finger tapping, simple reaction time, and postural sway intensity and velocity. CATSYS measurements using the proposed test battery were associated with relevant clinician-rated Unified Parkinson's disease rating scale (UPDRS) items assessing tremor and bradykinesia. More work is warranted to establish CATSYS as a diagnostic/monitoring instrument in movement disorders using the proposed technical approaches.

PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.

Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.

An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers.

OBJECTIVE: Adenosine A2A receptor antagonists are potential new treatments for Parkinson disease. We used positron emission tomography (PET) of the A2A receptor radiotracer, [C]SCH442416, to assess binding of the novel A2A antagonist, vipadenant (previously known as BIIB014), to human brain A2A receptors and to investigate the relationship among dose, steady-state plasma levels, and receptor occupancy. METHODS: We used PET to compare [C]SCH442416 uptake before and after blockade with daily oral vipadenant (2.5-100 mg/d for 10 or 11 days) in healthy volunteers (n = 15). We estimated receptor occupancy in brain regions of interest, particularly the putamen, by kinetic modeling of PET data. We estimated the dose, minimal plasma concentration at steady state (Cmin), and area under the plasma concentration curve (AUC0-tau) at the steady state required for saturation (> or =90% receptor occupancy) using Bayesian Emax and logistic regression models. RESULTS: The estimated receptor occupancy of vipadenant in the brain regions of interest varied from 74% to 94% at the lowest daily dose (2.5 mg) and reached saturation in all regions at 100 mg. In the putamen, the estimated minimal daily dose, steady-state Cmin, and steady-state AUC0-tau required for receptor saturation were 10.2 mg (interquartile range, 28%), 0.097 microg/mL (27%), and 6 microg h/mL (21%), respectively. CONCLUSIONS: This study provides the first evidence that vipadenant occupies A2A receptors in the human brain. Receptor occupancy was related to both dose and plasma levels of vipadenant. These results, coupled with previous efficacy results in animals, justify continued development of vipadenant as a potential treatment for Parkinson disease.

SRRM2, a potential blood biomarker revealing high alternative splicing in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms. METHODOLOGY/PRINCIPAL FINDINGS: We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5') exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls. CONCLUSIONS/SIGNIFICANCE: The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.

Melatonin MT1 and MT2 receptor expression in Parkinson's disease.

BACKGROUND: Idiopathic Parkinson disease (PD) is a multi-system disorder with a multifactorial etiology and diverse clinical phenotype. Selective, regional dopaminergic neuronal degeneration in the substantia nigra and other CNS areas including the amygdala are observed in all patients. Apoptotic mechanisms resulting from oxidative stress and mitochondrial dysfunction have been implicated in the pathogenesis of the disease. Although the role of melatonin, a potent endogenous antioxidant, has been highlighted in PD there is no data on the expression of melatonin receptors in affected CNS regions. MATERIAL/METHODS: We conducted an RT-PCR-based study to determine the MT1 and MT2 receptors expression in whole brain post-mortem tissue from the amygdala and substantia nigra of well-characterized PD and control subjects. RESULTS: PD cases showed a statistically significant decrease of MT1 receptor expression in both substantia nigra (FC=5.11; p<0.05) and the amygdala (FC=3.11; p<0.001) versus normal controls. The expression of MT2 receptor expression was also decreased in both substantia nigra (FC=3.90; p<0.0001) and the amygdala (FC=1.91; p<0.001) versus normal controls. CONCLUSIONS: The results demonstrate a down-regulation of melatonin receptors in regions affected by PD, suggesting their possible involvement in the disease process. Future studies are needed to elucidate the role of melatonin and its receptors in the treatment/pathogenesis of PD.

ß-N-methylamino-L-alanine induces neurological deficits and shortened life span in Drosophila.

The neurotoxic non-protein amino acid, ß-N-methylamino-L-alanine (BMAA), was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam. Recently, BMAA has been implicated as a fierce environmental factor that contributes to the etiology of Alzheimer's and Parkinson's diseases, in addition to ALS. However, the toxicity of BMAA in vivo has not been clearly demonstrated. Here we report our investigation of the neurotoxicity of BMAA in Drosophila. We found that dietary intake of BMAA reduced life span, locomotor functions, and learning and memory abilities in flies. The severity of the alterations in phenotype is correlated with the concentration of BMAA detected in flies. Interestingly, developmental exposure to BMAA had limited impact on survival rate, but reduced fertility in females, and caused delayed neurological impairment in aged adults. Our studies indicate that BMAA exposure causes chronic neurotoxicity, and that Drosophila serves as a useful model in dissecting the pathogenesis of ALS/PDC.

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset.

Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens.