•COVID-19 is caused by a highly pathogenic coronavirus named “SARS-CoV-2”.•COVID-19 pathophysiology is primarily defined by acute respiratory illness.•Several studies have revealed a possible ...neurological component to COVID-19.•Various neurological manifestations have also been reported for SARS and MERS.•Further research into the importance of neurological manifestations in COVID-19 is needed.
Central to COVID-19 pathophysiology is an acute respiratory infection primarily manifesting as pneumonia. Two months into the COVID-19 outbreak, however, a retrospective study in China involving more than 200 participants revealed a neurological component to COVID-19 in a subset of patients. The observed symptoms, the cause of which remains unclear, included impaired consciousness, skeletal muscle injury and acute cerebrovascular disease, and appeared more frequently in severe disease. Since then, findings from several studies have hinted at various possible neurological outcomes in COVID-19 patients. Here, we review the historical association between neurological complications and highly pathological coronaviruses including SARS-CoV, MERS-CoV and SARS-CoV-2. We draw from evidence derived from past coronavirus outbreaks, noting the similarities and differences between SARS and MERS, and the current COVID-19 pandemic. We end by briefly discussing possible mechanisms by which the coronavirus impacts on the human nervous system, as well as neurology-specific considerations that arise from the repercussions of COVID-19.
The retina as a window into the brain Frith, Peggy; Mehta, Arpan R
Lancet neurology,
November 2021, 2021-11-00, 20211101, Letnik:
20, Številka:
11
Journal Article
Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon ...extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation,
C9orf72
. Using paired mutant and isogenic expansion-corrected controls, we show that
C9orf72
MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of
C9orf72
-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in
C9orf72
MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in
C9orf72-
ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.
Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non‐cell autonomous contributors to ALS ...pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72‐mediated ALS. Here, we use a human iPSC‐based model to study the cell autonomous and non‐autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72‐related ALS pathology and, upon co‐culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage‐activated Na+ and K+ currents. Importantly, CRISPR/Cas‐9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell‐autonomous astrocyte pathology and non‐cell autonomous motor neuron pathophysiology.
Main points
Human iPSC‐derived astrocytes harboring C9orf72 mutations recapitulate key aspects of ALS pathology and cause non‐cell autonomous pathophysiology in human iPSC‐derived motor neurons.
The pathophysiology induced in motor neurons by ALS astrocytes is characterised by a progressive loss of action potential output due to a decrease in voltage‐gated sodium and potassium currents.
CRISPR/Cas9 mediated excision of C9orf72 repeat expansions reverses the pathophysiological effects of astrocytes on motor neurons.
In the history of neuroscience, Cajal stands tall. Many figures in the late 19th and early 20th centuries made major contributions to neuroscience-Sherrington, Ferrier, Jackson, Holmes, Adrian, and ...Békésy, to name a few. But in the public mind, Cajal is unique. His application of the Golgi method, with an array of histologic stains, unlocked a wealth of new knowledge on the structure and function of the brain. Here we argue that Cajal's success should not only be attributed to the importance of his scientific contributions but also to the artistic visual language that he created and to his pioneering self-branding, which exploited methods of the artist, including classical drawing and the new invention of photography. We argue that Cajal created his distinctive visual language and self-branding strategy by interweaving an ostensibly objective research product with an intimately subjective narrative about the brain and himself. His approach is evident in the use of photography, notably self-portraits, which furthered broad engagement initially inspired by his scientific drawings. Through his visual language, Cajal made an impact in art and culture far beyond the bounds of science, which has sustained his scientific legacy.
Background
Up to 50% of people with amyotrophic lateral sclerosis (ALS) experience cognitive dysfunction, whilst depression and anxiety are reported in up to 44% and 33%, respectively. These symptoms ...impact on quality of life, and are associated with a poorer prognosis. Historically, outcomes in clinical trials have focused on the effect of candidate drugs on physical functioning.
Methods
We reviewed the past 25 years of clinical trials of investigative medicinal products in people with ALS, since the licensing of riluzole, and extracted data on frequency and type of assessment for neuropsychiatric symptoms and cognitive impairment. Trial registry databases, including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed, were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 31/10/2019. No language restrictions were applied. Outcome measures, exclusion criteria and assessment tool used were extracted.
Results
216 trials, investigating 26,326 people with ALS, were reviewed. 35% assessed neuropsychiatric symptoms, and 22% assessed cognition, as Exclusion Criteria or Outcome Measures. 3% (
n
= 6) of trials assessed neuropsychiatric symptoms as a Secondary Outcome Measure, and 4% (
n
= 8) assessed cognition as Outcome Measures; only one trial included assessments for both cognition and neuropsychiatric symptoms as Outcome Measures. Three ALS-specific assessments were used in six trials.
Conclusions
Trials for people with ALS have neglected the importance of neuropsychiatric symptoms and cognitive impairment. Evaluation of these extra-motor features is essential to understanding the impact of candidate drugs on all symptoms of ALS.
PROPSERO registration
CRD42020175612.
The aim is to review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICDs) in Parkinson's disease.
Large cross-sectional and case-control multicentre studies ...show that ICDs in Parkinson's disease are common, with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity, suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data point towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possible inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation.
Recent large-scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in Parkinson's disease, which can guide prevention of these behaviours and optimize therapeutic approaches.
Purkinje cells and their trees Zoghbi, Huda Y; Mehta, Arpan R
Lancet neurology,
September 2021, 2021-Sep, 2021-09-00, 20210901, Letnik:
20, Številka:
9
Journal Article
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