Cognitive outcomes in patients with essential tremor treated with deep brain stimulation: a systematic review.

Introduction: Essential tremor (ET) is a common neurological disease. Deep brain stimulation (DBS) to the thalamic ventral intermediate nucleus (VIM) or the adjacent structures, such as caudal zona incerta/ posterior subthalamic area (cZi/PSA), can be effective in treating medication refractory tremor. However, it is not clear whether DBS can cause cognitive changes, in which domain, and to what extent if so. Methods: We systematically searched PubMed and the Web of Science for available publications reporting on cognitive outcomes in patients with ET who underwent DBS following the PICO (population, intervention, comparators, and outcomes) concept. The PRISMA guideline for systematic reviews was applied. Results: Twenty relevant articles were finally identified and included for review, thirteen of which were prospective (one also randomized) studies and seven were retrospective. Cognitive outcomes included attention, memory, executive function, language, visuospatial function, and mood-related variables. VIM and cZi/PSA DBS were generally well tolerated, although verbal fluency and language production were affected in some patients. Additionally, left-sided VIM DBS was associated with negative effects on verbal abstraction, word recall, and verbal memory performance in some patients. Conclusion: Significant cognitive decline after VIM or cZi/PSA DBS in ET patients appears to be rare. Future prospective randomized controlled trials are needed to meticulously study the effect of the location, laterality, and stimulation parameters of the active contacts on cognitive outcomes while considering possible medication change post-DBS, timing, standard neuropsychological battery, practice effects, the timing of assessment, and effect size as potential confounders.

A case report of a patient with primary familial brain calcification with a PDGFRB genetic variant.

Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr's disease include PDGFB, PDGFRB, SLC20A2, XPR1, MYORG, and JAM2. We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient's serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the PDGFRB gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the PDGFRB gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.

Tracking human neurologic disease status in mouse brain/plasma using reporter-tagged, EV-associated biomarkers.

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a retrotransposon insertion in intron 32 of the TAF1 gene. This insertion causes mis-splicing of intron 32 (TAF1-32i) and reduced TAF1 levels. TAF1-32i transcript is unique to XDP patient cells and can be detected in their extracellular vesicles (EVs). We engrafted patient and control iPSC-derived neural progenitor cells (hNPCs) into the striatum of mice. To track TAF1-32i transcript spread by EVs, we transduced the brain-implanted hNPCs with a lentiviral construct called ENoMi, which consists of a re-engineered tetraspanin scaffold tagged with bioluminescent and fluorescent reporter proteins under an EF-1α promoter. Alongside this improved detection in ENoMi-hNPCs-derived EVs, their surface allows specific immunocapture purification, thereby facilitating TAF1-32i analysis. Using this ENoMi-labeling method, TAF1-32i was demonstrated in EVs released from XDP hNPCs implanted in mouse brains. Post-implantation of ENoMi-XDP hNPCs, TAF1-32i transcript was retrieved in EVs isolated from mouse brain and blood, and levels increased over time in plasma. We compared and combined our EV isolation technique to analyze XDP-derived TAF1-32i with other techniques, including size exclusion chromatography and Exodisc. Overall, our study demonstrates the successful engraftment of XDP patient-derived hNPCs in mice as a tool for monitoring disease markers with EVs.

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X-linked Dystonia-Parkinsonism.

BACKGROUND: X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript. OBJECTIVES: The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism. METHODS: RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array. RESULTS: In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79. CONCLUSIONS: TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Exogenous Galactosylceramide as Potential Treatment for CLN3 Disease.

OBJECTIVE: CLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long-term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 Δex7/8 knock-in mice. Additionally, the impact of galactosylceramide on ceramide synthesis enzymes is documented. METHODS: A group of 72 mice received galactosylceramide or vehicle for 40 weeks. The effect of galactosylceramide supplementation on Cln3 Δex7/8 mice was determined by performing behavioral tests, measuring ceramide in brains and serum, and assessing impact on longevity, subunit C storage, astrogliosis, and neuronal cell counts. RESULTS: Galactosylceramide resulted in enhanced grip strength of forelimbs in male and female mice, better balance on the accelerating rotarod in females, and improved motor coordination during pole climbing in male mice. Brain and serum ceramide levels as well as apoptosis rates were lower in galactosylceramide-treated Cln3 Δex7/8 mice. Galactosylceramide also increased neuronal cell counts significantly in male and female mice and tended to decrease subunit C storage in specific brain regions. Astrogliosis dropped in females compared to a slight increase in males after galactosylceramide. Galactosylceramide increased the lifespan of affected mice. INTERPRETATION: Galactosylceramide improved behavioral, neuropathological, and biochemical parameters in Cln3 Δex7/8 mice, paving the way for effective therapy for CLN3 disease and use of serum ceramide as a potential biomarker to track impact of therapies. ANN NEUROL 2019;86:729-742.

Developmental Comparison of Ceramide in Wild-Type and Cln3 Δex7/8 Mouse Brains and Sera.

CLN3 disease is a neurodevelopmental disease leading to early visual failure, motor decline, and death. CLN3 pathogenesis has been linked to dysregulation of ceramide, a key intracellular messenger impacting various biological functions. Ceramide is upregulated in brains of CLN3 patients and activates apoptosis. Ceramide levels over the lifespan of WT and Cln3 Δex7/8 mice were measured using the DGK assay. Ceramide subspecies were determined by LC-MS. Ceramide synthesis enzymes and pre- and post-synaptic mRNA expression was measured in Cln3 Δex7/8 and normal mouse brains. Neuronal cell death was established by PARP cleavage and Caspases 3/6/9 and cytochrome C mRNA expression in Cln3 Δex7/8 and normal mouse brains. In WT mouse, a ceramide peak was noted at 3 weeks of age. The absence of this peak in Cln3 Δex7/8 mice might be related to early disease pathogenesis. Increase of ceramide in Cln3 Δex7/8 mouse brain at 24 weeks of age precedes neuronal apoptosis. The correlation between serum and brain ceramide in WT mice, and dysregulation of ceramide in serum and brain of Cln3 Δex7/8 mice, and the significant increase in ceramide in Cln3 Δex7/8 mouse brains and sera argue for use of easily accessible serum ceramide levels to track response to novel therapies in human CLN3 disease.

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses.

OBJECTIVE: Neuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease-modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro. METHODS: Aromatic carbamate derivatives were tested by establishing growth curves under pro-apoptotic conditions and activity evaluated by trypan blue and JC-1 staining, as well as a drop in pro-apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the CLN3 gene, and CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts. Ceramide levels were determined in CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts before and after treatment. Expression of BCL-2, ceramide synthesis enzymes (CERS2/CERS6/SMPD1/DEGS2) and Caspases 3/8/9 levels were compared in treated versus untreated CLN3-deficient PC12 cells by qRT-PCR. RESULTS: Retigabine, the benzyl-derivatized carbamate and an allyl carbamate derivative were neuroprotective in CLN3-defective PC12 cells and rescued CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts from diminished growth and accelerated apoptosis. All drugs decreased ceramide in CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts. Increased BCL-2 and decreased ceramide synthesis enzyme expression were established in CLN3-derived PC12 cells treated with the benzyl and allyl carbamate derivatives. They down-regulated Caspase 3/Caspase 8 expression. Caspase 9 expression was reduced by the benzyl-derivatized carbamate. INTERPRETATION: These findings establish that compounds analogous to flupirtine demonstrate anti-apoptotic activity with potential for treatment of NCL disease and use of ceramide as a marker for these diseases.