Focused Ultrasound Stimulation as a Neuromodulatory Tool for Parkinson’s Disease::A Scoping Review

Non-invasive focused ultrasound stimulation (FUS) is a non-ionising neuromodulatory technique that employs acoustic energy to acutely and reversibly modulate brain activity of deep-brain structures. It is currently being investigated as a potential novel treatment for Parkinson’s disease (PD). This scoping review was carried out to map available evidence pertaining to the provision of FUS as a PD neuromodulatory tool. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews, a search was applied to Ovid MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials on 13 January 2022, with no limits applied. In total, 11 studies were included: 8 were from China and 1 each from Belgium, South Korea and Taiwan. All 11 studies were preclinical (6 in vivo, 2 in vitro, 2 mix of in vivo and in vitro and 1 in silico). The preclinical evidence indicates that FUS is safe and has beneficial neuromodulatory effects on motor behaviour in PD. FUS appears to have a therapeutic role in influencing the disease processes of PD, and therefore holds great promise as an attractive and powerful neuromodulatory tool for PD. Though these initial studies are encouraging, further study to understand the underlying cellular and molecular mechanisms is required before FUS can be routinely used in PD

Lifetime body size and reproductive factors: comparisons of data recorded prospectively with self reports in middle age

<p>Abstract</p> <p>Background</p> <p>Data on lifetime exposures are often self-reported in epidemiologic studies, sometimes many years after the relevant age. Validity of self-reported data is usually inferred from their agreement with measured values, but few studies directly quantify the likely effects of reporting errors in body size and reproductive history variables on estimates of disease-exposure associations.</p> <p>Methods</p> <p>The MRC National Survey of Health and Development (NSHD) and the Million Women Study (MWS) are UK population-based prospective cohorts. The NSHD recruited participants at birth in 1946 and has followed them at regular intervals since then, whereas the MWS recruited women in middle age. For 541 women who were participants in both studies, we used statistical measures of association and agreement to compare self-reported MWS data on body size throughout life and reproductive history, obtained in middle age, to NSHD data measured or reported close to the relevant ages. Likely attenuation of estimates of linear disease-exposure associations due to the combined effects of random and systematic errors was quantified using regression dilution ratios (RDRs).</p> <p>Results</p> <p>Data from the two studies were very strongly correlated for current height, weight and body mass index, and age at menopause (Pearson r = 0.91-0.95), strongly correlated for birth weight, parental heights, current waist and hip circumferences and waist-to-height ratio (r = 0.67-0.80), and moderately correlated for age at menarche and waist-to-hip ratio (r = 0.52-0.57). Self-reported categorical body size and clothes size data for various ages were moderately to strongly associated with anthropometry collected at the relevant times (Spearman correlations 0.51-0.79). Overall agreement between the studies was also good for most quantitative variables, although all exhibited both random and systematic reporting error. RDRs ranged from 0.66 to 0.86 for most variables (slight to moderate attenuation), except weight and body mass index (1.02 and 1.04, respectively; little or no attenuation), and age at menarche, birth weight and waist-to-hip ratio (0.44, 0.59 and 0.50, respectively; substantial attenuation).</p> <p>Conclusions</p> <p>This study provides some evidence that self-reported data on certain anthropometric and reproductive factors may be adequate for describing disease-exposure associations in large epidemiological studies, provided that the effects of reporting errors are quantified and the results are interpreted with caution.</p

AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins

Abstract We previously reported that kenpaullone, which inhibits GSK-3a/b and CDKs inhibited CCCP mediated mitochondrial depolarisation and augments the mitochondrial network. To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Furthermore, treatment with AZD5438 alone increased the complexity of the mitochondrial network. We also found that AZD5438 prevented the rotenone induced decrease in PGC-1alpha and TOM20 levels and that it mediated powerful anti-apoptotic effects and promoted glycolytic respiration. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential