Paroxysmal Kinesigenic Dyskinesia

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition associated with heterozygous mutations in the PRRT2 gene. Phenomenology shown: In this letter we illustrate the phenomenology of PKD in a man previously misdiagnosed as Tourette’s syndrome. Educational value: Regardless of underlying phenotype, PKD is highly responsive to some antiepileptic drugs

Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid.

BackgroundClinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem.ObjectiveSince impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that profiles of select lysosomal network proteins in cerebrospinal fluid could be differentially expressed in these parkinsonian syndromes.MethodsCerebrospinal fluid samples were collected from PD patients (n = 18), clinically diagnosed 4-repeat tauopathy patients; corticobasal syndrome (CBS) (n = 3) and PSP (n = 8); and pathologically diagnosed PSP (n = 8) and CBD patients (n = 7). Each patient set was compared to its appropriate control group consisting of age and gender matched individuals. Select lysosomal network protein levels were detected via Western blotting. Factor analysis was used to test the diagnostic sensitivity, specificity and accuracy of the select lysosomal network protein expression profiles.ResultsPD, CBD and PSP were markedly different in their cerebrospinal fluid lysosomal network protein profiles. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in PD; early endosomal antigen 1 was decreased and lysozyme increased in PSP; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in CBD. A panel of lysosomal-associated membrane protein 2, lysozyme and microtubule-associated protein 1 light chain discriminated between controls, PD and 4-repeat tauopathies.ConclusionsThis study offers proof of concept that select lysosomal network proteins are differentially expressed in cerebrospinal fluid of Parkinson's disease, corticobasal syndrome and progressive supranuclear palsy. Lysosomal network protein analysis could be further developed as a diagnostic fluid biomarker in parkinsonian syndromes

Progressive Ataxia with Elevated Alpha-Fetoprotein: Diagnostic Issues and Review of the Literature

Background: Ataxias represent a challenging group of disorders due to significant clinical overlap. Here, we present a patient with early-onset progressive ataxia, polyneuropathy and discuss how elevation of alpha fetoprotein (AFP) narrows the differential diagnosis. Case report: Ataxia, polyneuropathy, and mild elevation of AFP are features compatible with ataxia with oculomotor apraxia type 2 (AOA2) but also with ataxia with oculomotor apraxia type 4 (AOA4). A genetic analysis demonstrated biallelic mutations in senataxin (SETX), confirming the diagnosis of AOA2. Discussion: Mild elevation of AFP is found in patients with AOA2 and AOA4, and higher levels are commonly seen in ataxia-telangiectasia. AFP is a useful diagnostic tool but not a biomarker for disease progression in AOA2

Deep Learning for Time Series Classification of Parkinson's Disease Eye Tracking Data

Eye-tracking is an accessible and non-invasive technology that provides information about a subject's motor and cognitive abilities. As such, it has proven to be a valuable resource in the study of neurodegenerative diseases such as Parkinson's disease. Saccade experiments, in particular, have proven useful in the diagnosis and staging of Parkinson's disease. However, to date, no single eye-movement biomarker has been found to conclusively differentiate patients from healthy controls. In the present work, we investigate the use of state-of-the-art deep learning algorithms to perform Parkinson's disease classification using eye-tracking data from saccade experiments. In contrast to previous work, instead of using hand-crafted features from the saccades, we use raw $\sim1.5\,s$ long fixation intervals recorded during the preparatory phase before each trial. Using these short time series as input we implement two different classification models, InceptionTime and ROCKET. We find that the models are able to learn the classification task and generalize to unseen subjects. InceptionTime achieves $78\%$ accuracy, while ROCKET achieves $88\%$ accuracy. We also employ a novel method for pruning the ROCKET model to improve interpretability and generalizability, achieving an accuracy of $96\%$. Our results suggest that fixation data has low inter-subject variability and potentially carries useful information about brain cognitive and motor conditions, making it suitable for use with machine learning in the discovery of disease-relevant biomarkers.Comment: Extended Abstract presented at Machine Learning for Health (ML4H) symposium 2023, December 10th, 2023, New Orleans, United States, 12 page

α-Synuclein induced toxicity in brain stem serotonin neurons mediated by an AAV vector driven by the tryptophan hydroxylase promoter

We studied the impact of α-synuclein overexpression in brainstem serotonin neurons using a novel vector construct where the expression of human wildtype α-synuclein is driven by the tryptophan hydroxylase promoter, allowing expression of α-synuclein at elevated levels, and with high selectivity, in serotonergic neurons. α-Synuclein induced degenerative changes in axons and dendrites, displaying a distorted appearance, suggesting accumulation and aggregation of α-synuclein as a result of impaired axonal transport, accompanied by a 40% loss of terminals, as assessed in the hippocampus. Tissue levels of serotonin and its major metabolite 5-HIAA remained largely unaltered, and the performance of the α-synuclein overexpressing rats in tests of spatial learning (water maze), anxiety related behavior (elevated plus maze) and depressive-like behavior (forced swim test) was not different from control, suggesting that the impact of the developing axonal pathology on serotonin neurotransmission was relatively mild. Overexpression of α-synuclein in the raphe nuclei, combined with overexpression in basal forebrain cholinergic neurons, resulted in more pronounced axonal pathology and significant impairment in the elevated plus maze. We conclude that α-synuclein pathology in serotonergic or cholinergic neurons alone is not sufficient to impair non-motor behaviors, but that it is their simultaneous involvement that determines severity of such symptoms

Predominant Spastic Paraparesis Associated With the D178N Mutation in PRNP

Here we report on a 70-year-old female presenting with an unusual progressive syndrome with fatal outcome. The predominant features in this case were spastic paraparesis, cognitive decline and respiratory failure. Relatives affected with a similar syndrome were previously diagnosed with lipofuscinosis. However, whole-genome sequencing (WGS) in our case did not reveal any pathogenic variants in genes associated with lipofuscinosis, but instead detected the known D178 variant in PRNP. The course of disease was rapid despite the presence of methione at codon 129 in the mutated and valine in the healthy allele of PRNP. Typical neuropathological abnormalities for familial fatal insomnia (FFI) were found, Western blot analysis suggested a type 2B prion protein isoform. The serendipitous diagnosis obtained with WGS illustrates a role for the method in elusive cases

Arylpiperazine agonists of the serotonin 5-HT1A receptor preferentially activate cAMP signaling versus recruitment of β-arrestin-2

G protein-coupled receptors (GPCRs) mediate biological signal transduction through complex molecular pathways. Therapeutic effects of GPCR-directed drugs are typically accompanied by unwanted side effects, owing in part to the parallel engagement of multiple signaling mechanisms. The discovery of drugs that are ‘functionally selective’ towards therapeutic effects, based on their selective control of cellular responses through a given GPCR, is thus a major goal in pharmacology today. In the present study, we show that several arylpiperazine ligands of the serotonin 5-HT1A receptor (5-HT1AR) preferentially activate 3',5'-cyclic adenosine monophosphate (cAMP) signaling versus b-arrestin-2 recruitment. The pharmacology of these compounds is thus qualitatively different from the endogenous agonist serotonin, indicating functional selectivity of 5-HT1AR-mediated response pathways. Preliminary evidence suggests that phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) downstream of 5-HT1AR is a substrate of functionally selective signaling by partial agonists. We propose that the compounds described in the present study are useful starting points for the development of signaling pathway-selective drugs targeting 5-HT1AR

Concomitant Medication Usage with Levodopa-Carbidopa Intestinal Gel : Results from the COSMOS Study

Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels.The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD.The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter.Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment.LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease:A dose-finding study

In advanced stages of Parkinson's disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias