Objective To investigate the safety and tolerability of convection‐enhanced delivery of an adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor into the bilateral putamina of PD patients. Methods Thirteen adult patients with advanced PD underwent adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18F]FDOPA‐PET scanning preoperatively and 6 and 18 months postoperatively. Results Adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5–274% and 8–130%; median, 36% and 54%), respectively. Ki differences between baseline and 6‐ and 18‐month follow‐up were statistically significant (P < 0.0002). Conclusion Adeno‐associated virus, serotype‐2 vector carrying glial cell line‐derived neurotrophic factor infusion was safe and well tolerated. Increased [18F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Objective This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinson disease. Methods Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS‐), and noncarriers with or without DBS (GBA‐DBS+, GBA‐DBS‐). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS‐, 98 GBA‐DBS+, and 128 GBA‐DBS‐ subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA‐DBS‐ subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS‐ subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA‐DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN‐DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision‐making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN‐DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435

PMCA2, a major calcium pump, is expressed at particularly high levels in Purkinje neurons. Accordingly, PMCA2-null mice exhibit ataxia suggesting cerebellar pathology. It is not yet known how changes in PMCA2 expression or activity affect molecular pathways in Purkinje neurons. We now report that the levels of metabotropic glutamate receptor 1 (mGluR1), which plays essential roles in motor coordination, synaptic plasticity, and associative learning, are reduced in the cerebellum of PMCA2-null mice as compared to wild type littermates. The levels of inositol 1,4,5-triphosphate receptor type 1 (IP3R1), an effector downstream to mGluR1, which mediates intracellular calcium signaling, and the expression of Homer 1b/c and Homer 3, scaffold proteins that couple mGluR1 to IP3R1, are also reduced in somata and dendrites of some Purkinje cell subpopulations. In contrast, no alterations occur in the levels of mGluR1 and its downstream effectors in the hippocampus, indicating that the effects are region specific. The reduction in cerebellar mGluR1, IP3R1 and Homer 3 levels are neither due to a generic decrease in Purkinje proteins nor extensive dendritic loss as immunoreactivity to total and non-phosphorylated neurofilament H (NFH) is increased in Purkinje dendrites and microtubule associated protein 2 (MAP2) staining reveals a dense dendritic network in the molecular layer of the PMCA2-null mouse cerebellum. PMCA2 coimmunoprecipitates with mGluR1, Homer 3 and IP3R1, suggesting that the calcium pump is a constituent of the mGluR1 signaling complex. Our results suggest that the decrease in the expression of mGluR1 and its downstream effectors and perturbations in the mGluR1 signaling complex in the absence of PMCA2 may cumulatively result in aberrant metabotropic glutamate receptor signaling in Purkinje neurons leading to cerebellar deficits in the PMCA2-null mouse.

Chorea is a hyperkinetic movement disorder consisting of involuntary irregular, flowing movements of the trunk, neck or face. Although Huntington’s disease is the most common cause of chorea in adults, chorea can also result from many other neurodegenerative, metabolic, and autoimmune conditions. While the pathophysiology of these different conditions is quite variable, recent advances in functional imaging have enabled the development of new methods for analysis of brain activity and neuronal dysfunction. In this paper we review the growing body of functional imaging data that has been performed in chorea syndromes and identify particular trends, which can be used to better understand the underlying network changes within the basal ganglia. While it can be challenging to identify whether changes are primary, secondary, or compensatory, identification of these trends can ultimately be useful in diagnostic testing and treatment in many of the conditions that cause chorea.

PRKN mutations are the most common recessive cause of Parkinson’s disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson’s disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson’s disease [odds ratio = 0.91 (0.58–1.38), P-value 0.76] or a parent with Parkinson’s disease [odds ratio = 1.12 (0.94–1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson’s disease [odds ratio = 1.29 (0.74–2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson’s disease.

BackgroundMost patients with small cell lung cancer (SCLC) or neuroblastoma (NB) already show clinically detectable metastases at diagnosis and have an extremely poor prognosis even when treated with combined modalities. The HuD-antigen is a neuronal RNA-binding protein that is expressed in 100% of SCLC tumor cells and over 50% of neuroblastoma cells. The correlation between high titers of circulating anti-HuD antibodies in patients and spontaneous tumor remission suggests that the HuD-antigen might be a potential molecular target for immunotherapy.MethodsWe have constructed a new antibody-toxin compound (called BW-2) by assembling a mouse anti-human-HuD monoclonal antibody onto streptavidin/saporin complexes.ResultsWe found that the immunotoxin BW-2 specifically killed HuD-positive human SCLC and NB cancer cells at very low concentrations in vitro. Moreover, intratumoral immunotoxin therapy in a nude mouse model of human SCLC (n = 6) significantly reduced local tumor progression without causing toxicity. When the same intratumoral immunotoxin protocol was applied to an immunocompetent A/J mouse model of NB, significant inhibition of local tumor growth was also observed. In neuroblastoma allografted A/J mice (n = 5) treated twice with intratumoral immunotoxin, significant tumor regression occurred in over 80% of the animals and their duration of tumor response was significantly prolonged.ConclusionsOur study suggests that anti-HuD based immunotoxin therapy may prove to be an effective alternative treatment for patients with SCLC and NB.

Background Focal dystonia is the most common type of adult-onset dystonia; however, it infrequently affects truncal musculature. Although commonly attributed to secondary etiologies such as a neurodegenerative illness or tardive syndromes, the entity of idiopathic adult-onset truncal dystonia has only been previously described in a few case reports and small case series. Here we characterize seven cases of adult-onset primary truncal dystonia and present them within the scope of the existing literature. Methods Retrospective chart review of medical records and patient videos of seven adult patients with idiopathic truncal dystonia evaluated by the senior movement disorder neurologists in an urban outpatient clinic. Results The mean age of onset of idiopathic truncal dystonia was 47.6 years old and the majority of patients were male. Truncal flexion was the most common direction of dystonic movement and the dystonia was most frequently induced by action and could be improved by use of a sensory trick. The majority of patients were refractory to 3 or more oral treatments and only two patients exhibited significant functional improvement with botulinum toxin injections. One patient enjoyed significant benefit with bilateral internal globus pallidus deep brain stimulation. Conclusions Although a relatively rare presentation, patients with idiopathic adult-onset truncal dystonia can be identified by a common phenomenology. Diagnosis of this highly disabling condition is important because these patients are frequently refractory to multiple oral treatments and may benefit from early treatment with botulinum toxin or deep brain stimulation. Electronic supplementary material The online version of this article (doi:10.1186/s40734-016-0044-9) contains supplementary material, which is available to authorized users.