The Black and African American Connections to Parkinson's Disease (BLAAC PD) study protocol.

Determining the genetic contributions to Parkinson's disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson's Disease (BLAAC PD) study is part of the Global Parkinson's Genetics Program, supported by the Aligning Science Across Parkinson's initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population.

Simplification of Mobility Tests and Data Processing to Increase Applicability of Wearable Sensors as Diagnostic Tools for Parkinson's Disease.

Quantitative mobility analysis using wearable sensors, while promising as a diagnostic tool for Parkinson's disease (PD), is not commonly applied in clinical settings. Major obstacles include uncertainty regarding the best protocol for instrumented mobility testing and subsequent data processing, as well as the added workload and complexity of this multi-step process. To simplify sensor-based mobility testing in diagnosing PD, we analyzed data from 262 PD participants and 50 controls performing several motor tasks wearing a sensor on their lower back containing a triaxial accelerometer and a triaxial gyroscope. Using ensembles of heterogeneous machine learning models incorporating a range of classifiers trained on a set of sensor features, we show that our models effectively differentiate between participants with PD and controls, both for mixed-stage PD (92.6% accuracy) and a group selected for mild PD only (89.4% accuracy). Omitting algorithmic segmentation of complex mobility tasks decreased the diagnostic accuracy of our models, as did the inclusion of kinesiological features. Feature importance analysis revealed that Timed Up and Go (TUG) tasks to contribute the highest-yield predictive features, with only minor decreases in accuracy for models based on cognitive TUG as a single mobility task. Our machine learning approach facilitates major simplification of instrumented mobility testing without compromising predictive performance.

Spirituality in Parkinson's Disease within a Sample from the USA.

Spirituality and religious beliefs are important for coping with medical conditions. The dopaminergic system is involved in reward behavior, and its dysfunction in Parkinson Disease (PD) raises questions about religiosity and spirituality in people with PD. This study examines the association between levels of spirituality and religiosity and the severity of PD motor and non-motor symptoms. The secondary aim investigates the perceived impact of PD diagnosis on spirituality and religiosity. This was a cross-sectional analysis of demographic, physical, mental, and spirituality and religiosity status in patients with PD recruited for the Health Outcomes Measurement (HOME) Study at the University of Maryland Parkinson Disease and Movement Disorders Center, Baltimore, USA. Spirituality and religiosity were assessed using the Spiritual Well-being Scale, and the World Health Organization Quality of Life Spiritual Religious and Personal Belief field-test instrument. The sample size was 85 PD patients. The mean age (standard deviation) was 65.5 (9.4) years and 67.1% were male. Higher levels of spirituality and religiosity were associated with younger age, sex (female), less education, religious affiliation (Christian), and mental health status. After adjusting for age, education, gender, race, marital status, religion, physical health, mental health, and comorbidity, only anxiety was associated with all of the spirituality/religiosity assessments. The majority of patients reported no change in their religious or spiritual beliefs following diagnosis. Greater spirituality and religiosity were associated with less anxiety. Also, younger women with PD showed higher levels of spirituality and religiosity. Longitudinal studies on more diverse populations are needed.

Genome Sequencing in the Parkinson Disease Clinic.

Background and Objectives: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. Methods: In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD (LRRK2); (2) risk of PD dementia (GBA); (3) PD genetic risk score; and (4) secondary, medically actionable variants (BRCA1). Results: Genome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion: Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.

Confirming Parkinson Disease Diagnosis: Patterns of Diagnostic Changes by Movement Disorder Specialists.

Background: The American Academy of Neurology Parkinson Disease (PD) quality measures include an annual diagnostic review. Objective: To investigate the frequency and pattern of changes in diagnoses between PD and other causes of parkinsonism. Methods: This prospective longitudinal cohort study included consented patients diagnosed with PD at least once and a minimum of two times at the Movement Disorders Center between 2002 and 2017. Movement disorder specialists confirmed and documented diagnoses at every visit. Longitudinal changes in diagnoses were identified across visits. Results: Of 1567 patients with parkinsonism, 174 had non-PD parkinsonism with no change over time. Of 1393 patients diagnosed with PD at least once, 94% (N = 1308) had no change of diagnosis over time and 6% (N = 85) had a change of diagnosis including PD ⟷ drug-induced parkinsonism (DIP) (27.1%), PD ⟷ multiple system atrophy (MSA) (20.0%), PD ⟷ progressive supranuclear palsy (PSP) (18.8%), PD ⟷ Lewy body dementia (DLB) (16.5%), PD⟷ vascular parkinsonism (9.4%), more than two diagnoses (4.7%), and PD ⟷ corticobasal syndrome (CBS) (3.5%). The direction of diagnostic switches was as follows: PD ⟶ other parkinsonism diseases (36.5%), other parkinsonism diseases ⟶ PD (31.8%), and 31.8% of multiple switches. There were no significant differences in duration of follow-up, age at first visit, gender, race, marital status, education, income, cognition, or employment between the stable and unstable groups. Diagnostic change was associated with greater PD severity and greater medical comorbidity. Conclusion: Over a 15-year period, movement disorder specialists changed their clinical diagnosis of PD in 6% of patients. The most common diagnostic switches, to or from PD, were DIP, MSA, PSP, and DLB. This study describes routine clinical diagnostic patterns in the absence of pathologic confirmation. The presence of diverse diagnostic changes over time underscores the value of confirming PD diagnosis.

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes.

OBJECTIVE: To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms. METHODS: In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. RESULTS: Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, p subtype = 0.01, p ratio = 0.03), SH3GL2 (rs10756907, p subtype = 0.02, p ratio = 0.01), HIP1R (rs10847864, p subtype = 0.02), RIT2 (rs12456492, p subtype = 0.02), and FBRSL1 (rs11610045, p subtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p ratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor. CONCLUSIONS: Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

INTRODUCTION: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS). METHODS: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS. RESULTS: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. CONCLUSION: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.

Weight loss and weight gain in Parkinson disease.

INTRODUCTION: Parkinson disease (PD) has been associated with both weight loss and gain in different stages of the disease. Our study aimed to determine the prevalence and associations with weight change over two years based on 3% and 5% weight change. METHODS: In this longitudinal analysis, weight at baseline and follow-up was used to classify patients into groups of weight loss, stable, and weight gain. Differences between these groups at baseline and then with change over time were tested. RESULTS: The sample was 668 patients with mean(SD) age 66.1(10) and disease duration 5.3(5.4) years. Using 3% weight change criteria: 32.6% lost, 23.1% gained, and 55.7% had stable weight. Using 5% criteria: 22.6% lost, 15.7% gained, and 61.7% had stable weight. Age was associated with both 3% and 5% change in weight. Other associations with 5% weight change were disease duration, Total and Motor Unified Parkinson's Disease Rating Scale, Older Americans Resource and Services disability, and Hoehn & Yahr staging. The effects of 3% weight loss on Motor UPDRS, IADLs, and depression, and the effects of 5% weight loss on IADLs remained statistically significant when controlling for baseline differences in age, levodopa use, and Total UPDRS. CONCLUSION: PD patients are more likely to experience 3% than 5% weight change and this lower threshold of weight change was associated with greater disease severity and disability over time. Attention to more subtle weight change may help identify those at greater risk of disability.

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. METHODS: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. FINDINGS: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7). INTERPRETATION: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. FUNDING: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

Quantitative mobility metrics from a wearable sensor predict incident parkinsonism in older adults.

INTRODUCTION: Mobility metrics derived from wearable sensor recordings are associated with parkinsonism in older adults. We examined if these metrics predict incident parkinsonism. METHODS: Parkinsonism was assessed annually in 683 ambulatory, community-dwelling older adults without parkinsonism at baseline. Four parkinsonian signs were derived from a modified Unified Parkinson's Disease Rating Scale (UPDRS). Parkinsonism was based on the presence of 2 or more signs. Participants wore a sensor on their back while performing a 32 foot walk, standing posture, and Timed Up and Go (TUG) tasks. 12 mobility scores were extracted. Cox proportional hazards models with backward elimination were used to identify combinations of mobility scores independently associated with incident parkinsonism. RESULTS: During follow-up of 2.5 years (SD = 1.28), 139 individuals developed parkinsonism (20.4%). In separate models, 6 of 12 mobility scores were individually associated with incident parkinsonism, including: Speed and Regularity (from 32 ft walk), Sway (from standing posture), and 3 scores from TUG subtasks (Posterior sit to stand transition, Range stand to sit transition, and Yaw, a measure of turning efficiency). When all mobility scores were analyzed together in a single model, 2 TUG subtask scores, Range from stand to sit transition (HR, 1.42, 95%CI, 1.09, 1.82) and Yaw from turning (HR, 0.56, 95%CI, 0.42, 0.73) were independently associated with incident parkinsonism. These results were unchanged when controlling for chronic health covariates. CONCLUSION: Mobility metrics derived from a wearable sensor complement conventional gait testing and have potential to enhance risk stratification of older adults who may develop parkinsonism.

Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms.

BACKGROUND: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. OBJECTIVES: To identify the genetic determinants of PD age at onset. METHODS: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. RESULTS: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. CONCLUSIONS: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

Parkinson's Disease: Patients' Knowledge, Attitudes, and Interest in Genetic Counseling.

The objective of this study was to assess the genetics knowledge of patients with Parkinson's disease (PD), and to explore their attitudes on genetic testing and interest in genetic counseling. We surveyed 158 patients from the University of Maryland Parkinson's Disease and Movement Disorders Center. Patients averaged a score of 63% on general genetics knowledge and 73% on PD genetics knowledge. Participants had an overall positive attitude toward genetic testing: 80% believed that the use of genetic tests among people should be promoted, and 83% would undertake genetic test for PD if it was available. Patients reported a high interest to discuss the benefits, risks, and impacts of genetic testing for PD (mean sum score = 26, range = 9-35), and 43% patients expressed interest in meeting with a genetic counselor. Multivariate regression analysis showed that patients who had more positive attitudes toward genetic testing for PD were more interested in meeting with a genetic counselor (ß = 0.6, p < 0.001). This study is the first to demonstrate an interest in genetic counseling among patients with PD. Our findings demonstrate a new niche for genetic counselors to support patients in clarifying gaps or misconceptions in knowledge about PD genetics as well as the possible risks, benefits, and limitations of genetic testing.

Response shift - The experience of disease progression in Parkinson disease.

OBJECTIVE: To investigate response shift, the recalibration of perceived quality of life (QoL) relative to symptomatic changes in Parkinson disease (PD). BACKGROUND: Health-related QoL in PD is influenced by improvement vs. decline in disease severity. However, it is unclear how disease course changes internal standards of QoL over time. METHODS: 124 PD patients were subdivided based on Total UPDRS change over 1 year (stable, improved, declined). The EuroQol Visual Analog Scale assessed QoL at baseline (T1) and 1 year later (T2). At T2, patients rated current QoL (T2-current) and reappraised their T1 QoL (T2-retrospective). Recalibration response shifts were represented by the difference between T1 and T2-retrospective QoL ratings. RESULTS: At follow-up (T2), the total patient sample reported no difference between current (T2 current mean (M) = 76.3) and retrospective (T2-R M = 77.8) QoL ratings. While there was no significant difference between T1 (M = 79.2) and T2-R ratings 1 year later (M = 77.8) for the total sample, there was a change by group interaction (p < 0.005) which showed that retrospectively, decliners reduced ratings (M Δ = -9.0) and improvers increased ratings (M Δ = +6.4) while stable patients did not change. CONCLUSIONS: When PD patients consider their health status one year ago, decliners recalibrate and downgrade last year's health assessment, while improvers upgrade last year's assessment. Changes in internal calibrations cushion periods of decline or improvement in PD such that patients tend to "stabilize" their general disease course when recalling symptom trajectory, providing insight into the process of adaptation to the effects of disease progression and treatment over time.

Migratory stroke-like lesions in a case of adult-onset mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and a review of imaging findings.

Imaging findings of adult-onset mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is poorly documented. The authors present a 48-year-old woman with subacute onset of word-finding difficulties and right arm stiffness. Magnetic resonance imaging performed 2 weeks prior revealed left temporal lobe diffusion and fluid-attenuated inversion recovery hyperintensity predominantly involving the cortex. The apparent diffusion coefficient map showed preserved signal in the temporal cortex. Subsequent magnetic resonance imagings demonstrated a new diffusion signal abnormality extending to the left parietal cortex and occipital cortex with resolving diffusion hyperintensity in the temporal lobe. MR spectroscopy showed scattered areas of lactate deposition. Diagnosis of MELAS syndrome was confirmed by genetic analysis. Fluctuating, migratory stroke-like lesions with a predilection for the parietal, temporal, and occipital cortex that do not conform to a vascular territory and a lactate spike at 1.3 ppm on MR spectroscopy are characteristic of MELAS syndrome. Preserved signal intensity on apparent diffusion coefficient is useful to distinguish MELAS syndrome from ischemic infarction where the signal is typically reduced.

Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease.

PURPOSE OF REVIEW: Recent studies on clinical, genetic and pathological heterogeneity of Parkinson disease have renewed the old debate whether we should think of Parkinson disease as one disease with variations, or as a group of independent diseases that happen to present with similar phenotypes. Here, we provide an overview of where the debate is coming from, and how recent findings in clinical subtyping, genetics and clinico-pathological correlation have shaped this controversy over the last few years. RECENT FINDINGS: New and innovative clinical diagnostic criteria for Parkinson disease have been proposed and await validation. Studies using functional imaging or wearable biosensors, as well as biomarker studies, provide new support for the validity of the traditional clinical subtypes of Parkinson disease (tremor-dominant versus akinetic-rigid or postural instability/gait difficulty). A recent cluster analysis (as unbiased data-driven approach to subtyping) included a wide spectrum of nonmotor variables, and showed correlation of the proposed subtypes with disease progression in a longitudinal analysis. New genetic factors contributing to Parkinson disease susceptibility continue to be identified, including rare mutations causing monogenetic disease, common variants with small effect size and risk factors (like mutations in the gene for glucocerebrosidase) that fall in between the two other categories. Recent studies show some limited correlation between genetic factors and clinical heterogeneity. Despite some variations in patterns of pathology, Lewy bodies are still the hallmark of Parkinson disease, including the vast majority of genetic subgroups. SUMMARY: Evidence of clinical, genetic and pathological heterogeneity of Parkinson disease continues to emerge, but clearly defined subtypes that hold up in more than one of these domains remain elusive. For research to identify such subtypes, splitting is likely the way forward; until then, for clinical practice, lumping remains the more pragmatic approach.

Reverse sensory geste in cervical dystonia.

Sensory gestes (SG) are a pathognomonic sign of dystonia, which can be detected in up to two thirds of patients with cervical dystonia (CD). They reduce dystonia severity markedly but transiently. We report a patient whose CD substantially worsened with sensory input to the back of the head and neck in different body postures, a phenomomen recently termed "reverse" sensory geste (rSG) in craniocervical dystonia. In a cohort of CD outpatients, screening for "reverse" effects of SG on dystonia yielded a prevalence of 12.8% (n = 6/47). The most frequent rSG pattern was increased dystonic activity in a supine, resting position while trying to fall asleep. The response to rSG persisted throughout the course of the disease arguing for an impairment of central integration of neck proprioception. Assessment of rSG should be included in the routine examination of CD patients, since BTX treatment may have to beadjusted accordingly to be efficacious.

Ultrasound-guided injection of the iliopsoas muscle with botulinum toxin in camptocormia.

Camptocormia is characterized by an abnormal posture of the trunk with pronounced flexion of the thoraco-lumbar spine during standing and walking, which abates in a supine position. Treatment options for camptocormia are limited and mostly futile. Here, we report on the ultrasound-guided ventral injection of botulinum toxin A (BTX) into deep portions of the iliopsoas muscle in four parkinsonian patients with camptocormia as chief complaint. Using this novel and safe application technique, all patients received 500-1,500 MU of BTX per side in 4-6 month intervals. Treatment was generally well tolerated. At the highest dose, all patients complained of mild weakness of hip flexion. Standardized physical exam at follow-up visits, as well as self-assessment of patients, failed to show a relevant and lasting improvement of posture. In conclusion, injection of BTX into the iliopsoas does not appear to be a promising approach for the treatment of parkinsonism-associated camptocormia.

MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity.

Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.

Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy.

Mutations in the genes coding for alpha-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. Alpha-synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of alpha-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T alpha-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T alpha-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T alpha-synuclein-overexpressing mice are not altered in parkin null alpha-synuclein-overexpressing double-mutant mice. Our results demonstrate that mutant alpha-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by alpha-synuclein and parkin mutations may occur via independent mechanisms.

Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death.

Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-alpha treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.