Machine learning nominates the inositol pathway and novel genes in Parkinson ’s disease
AbstractThere are 78 loci associated with Parkinson ’s disease in the most recent genome-wide association study (GWAS), yet the specific genes driving these associations are mostly unknown. Herein, we aimed to nominate the top candidate gene from each Parkinson’s disease locus and identify variants and pathways potentially involved in Parkinson’ s disease. We trained a machine learning model to predict Parkinson’s disease-associated genes from GWAS loci using genomic, transcriptomic and epigenomic data from brain tissues and dopaminergic neurons. We nominated candidate genes in each locus and identified novel pathw...
Source: Brain - October 6, 2023 Category: Neurology Source Type: research

On the origin of F-wave: involvement of central synaptic mechanisms
In this study, we developed anex vivo mouse sciatic nerve-attached spinal cord preparation with sensory axons severed.In this preparation, stimulation of the whole sciatic nerve or its tibial branch evoked responses with the electrophysiological signatures of F-waves. Manipulations of synaptic transmission by either removal of extracellular calcium or block of post-synaptic glutamate receptors abolished these responses.These results suggest that F-waves are mediated by spinal microcircuits activated by recurrent motor axon collaterals via glutamatergic synapses. (Source: Brain)
Source: Brain - October 5, 2023 Category: Neurology Source Type: research

Closed-loop stimulation in periods with less epileptiform activity drives improved epilepsy outcomes
AbstractIn patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore he...
Source: Brain - October 5, 2023 Category: Neurology Source Type: research

Longitudinal associations of serum biomarkers with early cognitive, amyloid and grey matter changes
In conclusion, serum GFAP, NfL and A β1-42/A β1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner. (Source: Brain)
Source: Brain - October 3, 2023 Category: Neurology Source Type: research

Role of pattern recognition receptors in chemotherapy-induced neuropathic pain
AbstractProgress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment.CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in r...
Source: Brain - October 3, 2023 Category: Neurology Source Type: research

Extracellular glutamate and GABA transients at the transition from interictal spiking to seizures
AbstractFocal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transient...
Source: Brain - October 3, 2023 Category: Neurology Source Type: research

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson ’s disease
AbstractPostoperative apathy is a frequent symptom in Parkinson ’s disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimula tion of the subthalamic nucleus.The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson’s disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to ide...
Source: Brain - October 3, 2023 Category: Neurology Source Type: research

Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria
AbstractCerebral malaria is the deadliest complication that can arise fromPlasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria.To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and c...
Source: Brain - September 30, 2023 Category: Neurology Source Type: research

Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias
AbstractThe spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic t...
Source: Brain - September 30, 2023 Category: Neurology Source Type: research

Extracellular vesicles set the stage for brain plasticity and recovery by multimodal signalling
AbstractExtracellular vesicles (EVs) are extremely versatile naturally occurring membrane particles that convey complex signals between cells. EVs of different cellular sources are capable of inducing striking therapeutic responses in neurological disease models. Differently from pharmacological compounds that act by modulating defined signalling pathways, EV-based therapeutics possess multiple abilities via a variety of effectors, thus allowing the modulation of complex disease processes that may have very potent effects on brain tissue recovery. When appliedin vivo in experimental models of neurological diseases, EV-base...
Source: Brain - September 28, 2023 Category: Neurology Source Type: research

Neural basis of speech and grammar symptoms in non-fluent variant primary progressive aphasia spectrum
AbstractThe non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. ‘Splitting’ views propose separate clinical entities: ‘primary progressiv...
Source: Brain - September 28, 2023 Category: Neurology Source Type: research

Neuroinflammation is linked to dementia risk in Parkinson ’s disease
In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies. (Source: Brain)
Source: Brain - September 27, 2023 Category: Neurology Source Type: research

Clinical severity in Parkinson ’s disease is determined by decline in cortical compensation
AbstractDopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson ’s disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased m otor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual diffe...
Source: Brain - September 27, 2023 Category: Neurology Source Type: research

Cholinergic innervation topography in GBA-associated de novo Parkinson ’s disease patients
AbstractThe most common genetic risk factors for Parkinson ’s disease areGBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients withGBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD.The study in...
Source: Brain - September 25, 2023 Category: Neurology Source Type: research

Grey matter heterotopia subtypes show specific morpho-electric signatures and network dynamics
AbstractGrey matter heterotopia (GMH) are neurodevelopmental disorders associated with abnormal cortical function and epilepsy. Subcortical band heterotopia (SBH) and periventricular nodular heterotopia (PVNH) are two well-recognized GMH subtypes in which neurons are misplaced, either forming nodules lining the ventricles in PVNH, or forming bands in the white matter in SBH. Although both PVNH and SBH are commonly associated with epilepsy, it is unclear whether these two GMH subtypes differ in terms of pathological consequences or, on the contrary, share common altered mechanisms.Here, we studied two robust preclinical mod...
Source: Brain - September 19, 2023 Category: Neurology Source Type: research