Audiovisual Processing is Abnormal in Parkinson\u27s Disease and Correlates with Freezing of Gait and Disease Duration

Background: Sensory and perceptual disturbances progress with disease duration in Parkinson’s disease (PD) and probably contribute to motor deficits such as bradykinesia and gait disturbances, including freezing of gait (FOG). Simple reaction time tests are ideal to explore sensory processing, as they require little cognitive processing. Multisensory integration is the ability of the brain to integrate sensory information from multiple modalities into a single coherent percept, which is crucial for complex motor tasks such as gait. 9 10 11 12 13 Objectives: The aims of this study were to: 1. Assess differences in unisensory (auditory and visual) and multisensory processing speed in people with PD and age-matched healthy controls. 2. Compare relative differences in unisensory processing in people with PD with disease duration and freezing of gait status taking into account the motor delays, which are invariably present in PD. 3. Compare relative differences in multisensory (audiovisual) processing between the PD cohort and age-matched controls. 14 15 16 17 Methods: 39 people with PD (23 with FOG) and 17 age-matched healthy controls performed a reaction time task in response to unisensory (auditory-alone, visual-alone) and multisensory (audiovisual) stimuli. 18 19 Results: The PD group were significantly slower than controls for all conditions compared with healthy controls but auditory reaction times were significantly faster than visual for the PD group only. These relative unisensory differences are correlated with disease duration and divide the PD group by FOG status, but these factors are co-dependent. Although multisensory facilitation occurs in PD, it is significantly less enhanced than in healthy controls. 20 21 22 23 Conclusion: There are significant unisensory and multisensory processing abnormalities in PD. The relative differences in unisensory processing are specific to PD progression, providing a link between these sensory abnormalities and a motor feature of PD. Sensory disturbances have previously been postulated to be central to FOG but this is the first study to predict audiovisual processing abnormalities using FOG status. The multisensory processing abnormalities are independent of disease duration and FOG status and may be a potential biomarker for the disease

Loss of visual feedback revealing motor impairment – an early symptom of Parkinson’s disease in two Irish farmers

BACKGROUND: In the absence of visual feedback, humans depend upon proprioceptive information for reaching movements and coordination. Use of sensory information in order to assist movement is impaired in patients with early Parkinson’s disease (PD). It has been postulated that patients with PD compensate for this kinaesthetic deficit by relying on visual information. CASE PRESENTATION: We report two farmers who first noticed symptoms of PD when working on the farm in situations requiring processing of the proprioceptive/kinaesthetic information in order to execute motor output in the absence of visual cues. A 68-year-old right-handed farmer had a 5-year history of left hand awkwardness. He first noticed the problem while performing artificial insemination in cattle using the recto-vaginal technique. He was diagnosed with PD 15 months after his initial symptoms and responded well to a combination of carbidopa-levodopa and ropinirole but has not returned to performing artificial insemination since. Clinical examination revealed asymmetric parkinsonism with normal sensation on gross neurological examination (including proprioception). A 60-year-old right-handed farmer had a 6-year history of difficulty manoeuvring his right hand whilst turning the calf during calving only when he did not have direct sight of his hand. 18 months later he developed right hand tremor and bradykinesia. He was diagnosed with PD 2 years following these initial symptoms. He had a good response to a combination of carbidopa-levodopa, rasagiline and ropinirole. He switched to using his left hand during calf delivery but is not as dextrous as previously. Clinical examination revealed parkinsonism, more marked in the right hand and normal sensation in all modalities. CONCLUSIONS: Although task-specific motor impairment could explain the symptoms of these patients, it is noteworthy that loss of visual feedback was central to both of these presentations. Given that early kinaesthetic deficits are known to be present in patients with PD, we postulate that removing visual feedback can expose such deficits in early PD, even when not detectable on routine examination. These two patients suggest that sensorimotor control can be impaired early in PD and may be the first symptom. Once the visual compensatory mechanism is not available, it becomes difficult or impossible to perform complex hand movements

Novel gene (TMEM230) linked to Parkinson’s disease

Mutations in six genes are known to cause Parkinson’s disease (PD) (autosomal dominant: alpha-synuclein, LRRK2, VPS35 and autosomal recessive: Parkin, PINK1 and DJ1) and number of other genes are implicated. In a recent article Deng and colleagues studied a large four generation American family of European descent and linked mutations in a novel gene, transmembrane-protein 230 gene (TMEM230) with lewy body confirmed PD. The authors demonstrated that pathogenic TMEM230 variants in primary mouse neurons affected movement of synaptic vesicles suggesting that TMEM230 may slow vesicular transport. Further experiments in HEK293 cells (carrying the pathogenic TMEM230 variants) showed increased alpha-synuclein levels. This study indicated that the impaired vesicular trafficking may contribute to the pathogenesis of PD. Understanding the various cellular mechanisms leading to PD may lead to the development of novel, much needed therapeutic options. These mechanisms could include: enhanced clearance of damaged mitochondria, development of kinase inhibitors, VPS35/retromer function enhancers or now the possibility of vesicular transport modification

Medical management of myoclonus-dystonia and implications for underlying pathophysiology

Myoclonus-dystonia is an early onset genetic disorder characterised by subcortical myoclonus and less prominent dystonia. Its primary causative gene is the epsilonsarcoglycan gene but the syndrome of “myoclonic dystonia” has been shown to be a heterogeneous group of genetic disorders. The underlying pathophysiology of myoclonus-dystonia is incompletely understood, although it may relate to dysfunction of striatal monoamine neurotransmission or disruption of cerebellothalamic networks (possibly via a GABAergic deficit of Purkinje cells). A broad range of oral medical therapies have been used in the treatment of myoclonus-dystonia with a varying response, and limited data relating to efficacy and tolerability, yet this condition responds dramatically to alcohol. Few well conducted randomized controlled trials have been undertaken leading to an empirical ad hoc approach for many patients. We review the current evidence for pharmacological therapies in myoclonus-dystonia, discuss implications for underlying pathogenesis of the condition and propose a treatment algorithm for these patients

MicroRNA inhibition using antimiRs in acute human brain tissue sections

Antisense inhibition of microRNAs is an emerging preclinical approach to pharmacoresistant epilepsy. A leading candidate is an "antimiR" targeting microRNA-134 (ant-134), but testing to date has used rodent models. Here, we develop an antimiR testing platform in human brain tissue sections. Brain specimens were obtained from patients undergoing resective surgery to treat pharmacoresistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF) and dissected for clinical neuropathological examination, and unused material was transferred for sectioning. Individual sections were incubated in oxygenated ACSF, containing either ant-134 or a nontargeting control antimiR, for 24 h at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels were measured using quantitative reverse transcriptase polymerase chain reaction. Specimens transported in ACSF could be used for neuropathological diagnosis and had good RNA integrity. Ant-134 mediated a dose-dependent knockdown of miR-134, with approximately 75% reduction of miR-134 at 1 μmol L-1 and 90% reduction at 3 μmol L-1 . These doses did not have off-target effects on expression of a selection of three other miRNAs. This is the first demonstration of ant-134 effects in live human brain tissues. The findings lend further support to the preclinical development of a therapy that targets miR-134 and offer a flexible platform for the preclinical testing of antimiRs, and other antisense oligonucleotide therapeutics, in human brain

Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property–free knowledge base for future anticoronavirus drug discovery

Obesity in adults: a 2022 adapted clinical practice guideline for Ireland

This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients' lived experiences; move beyond simplistic approaches of "eat less, move more" and address the root drivers of obesity. People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay