Research News

Climbing stairs is associated with a longer life, according to research presented today at ESC Preventive Cardiology 2024, a scientific congress of the European Society of Cardiology (ESC).1

https://www.sciencedaily.com/releases/2024/04/240426110051.htm

Abstract:

Dopamine’s role as the principal neurotransmitter in motor functions has long been accepted. We broaden this conventional perspective by demonstrating the involvement of non-dopaminergic mechanisms. In mouse models of Parkinson’s disease, we observed that L-DOPA elicited a substantial motor response even when its conversion to dopamine was blocked by inhibiting the enzyme aromatic amino acid decarboxylase (AADC). Remarkably, the motor activity response to L-DOPA in the presence of an AADC inhibitor (NSD1015) showed a delayed onset, yet greater intensity and longer duration, peaking at 7 h, compared to when L-DOPA was administered alone. This suggests an alternative pathway or mechanism, independent of dopamine signalling, mediating the motor functions. We sought to determine the metabolites associated with the pronounced hyperactivity observed, using comprehensive metabolomics analysis.

Our results revealed that the peak in motor activity induced by NSD1015/L-DOPA in Parkinson’s disease mice is associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (also known as ophthalmate in its anionic form). Interestingly, we found that administering ophthalmate directly to the brain rescued motor deficits in Parkinson’s disease mice in a dose-dependent manner. We investigated the molecular mechanisms underlying ophthalmate’s action and discovered, through radioligand binding and cAMP-luminescence assays, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR).

Additionally, our findings demonstrated that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate, further solidifying the evidence that ophthalmate modulates motor functions through the activation of the CaSR. The discovery of ophthalmate as a novel regulator of motor function presents significant potential to transform our understanding of brain mechanisms of movement control and the therapeutic management of related disorders.

Sammy Alhassen, Derk Hogenkamp, Hung Anh Nguyen, Saeed Al Masri, Geoffrey W Abbott, Olivier Civelli, Amal Alachkar, Ophthalmate is a new regulator of motor functions via CaSR: implications for movement disorders, Brain, Volume 147, Issue 10, October 2024, Pages 3379–3394, https://doi.org/10.1093/brain/awae097

https://academic.oup.com/brain/article/147/10/3379/7636309

Abstract: 

Background: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies.

Methods: In this analysis, we use the Institute for Health Metrics and Evaluation’s Future Health Scenarios platform to forecast the effects of three smoking prevalence scenarios on all-cause and cause-specific YLLs and life expectancy at birth until 2050. YLLs were computed for each scenario using the Global Burden of Disease Study 2021 reference life table and forecasts of cause-specific mortality under each scenario. The reference scenario forecasts what could occur if past smoking prevalence and other risk factor trends continue, the Tobacco Smoking Elimination as of 2023 (Elimination-2023) scenario quantifies the maximum potential future health benefits from assuming zero percent smoking prevalence from 2023 onwards, whereas the Tobacco Smoking Elimination by 2050 (Elimination-2050) scenario provides estimates for countries considering policies to steadily reduce smoking prevalence to 5%. Together, these scenarios underscore the magnitude of health benefits that could be reached by 2050 if countries take decisive action to eliminate smoking. The 95% uncertainty interval (UI) of estimates is based on the 2·5th and 97·5th percentile of draws that were carried through the multistage computational framework.

Findings: Global age-standardised smoking prevalence was estimated to be 28·5% (95% UI 27·9-29·1) among males and 5·96% (5·76-6·21) among females in 2022. In the reference scenario, smoking prevalence declined by 25·9% (25·2-26·6) among males, and 30·0% (26·1-32·1) among females from 2022 to 2050. Under this scenario, we forecast a cumulative 29·3 billion (95% UI 26·8-32·4) overall YLLs among males and 22·2 billion (20·1-24·6) YLLs among females over this period. Life expectancy at birth under this scenario would increase from 73·6 years (95% UI 72·8-74·4) in 2022 to 78·3 years (75·9-80·3) in 2050. Under our Elimination-2023 scenario, we forecast 2·04 billion (95% UI 1·90-2·21) fewer cumulative YLLs by 2050 compared with the reference scenario, and life expectancy at birth would increase to 77·6 years (95% UI 75·1-79·6) among males and 81·0 years (78·5-83·1) among females. Under our Elimination-2050 scenario, we forecast 735 million (675-808) and 141 million (131-154) cumulative YLLs would be avoided among males and females, respectively. Life expectancy in 2050 would increase to 77·1 years (95% UI 74·6-79·0) among males and 80·8 years (78·3-82·9) among females.

Interpretation: Existing tobacco policies must be maintained if smoking prevalence is to continue to decline as forecast by the reference scenario. In addition, substantial smoking-attributable burden can be avoided by accelerating the pace of smoking elimination. Implementation of new tobacco control policies are crucial in avoiding additional smoking-attributable burden in the coming decades and to ensure that the gains won over the past three decades are not lost.

GBD 2021 Tobacco Forecasting Collaborators. Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Public Health. 2024 Oct;9(10):e729-e744. doi: 10.1016/S2468-2667(24)00166-X. PMID: 39366729.

https://pubmed.ncbi.nlm.nih.gov/39366729/

Highlights

Beatriz Muñoz Ospina, Natalia Cadavid-Ruiz, The effect of aerobic exercise on serum brain-derived neurotrophic factor (BDNF) and executive function in college students, Mental Health and Physical Activity, Volume 26,2024,100578, https://doi.org/10.1016/j.mhpa.2024.100578.

https://www.sciencedirect.com/science/article/pii/S1755296624000036

See also:

Tang SW, Chu E, Hui T, Helmeste D, Law C. Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects. Neurosci Lett. 2008 Jan 24;431(1):62-5. doi: 10.1016/j.neulet.2007.11.019. Epub 2007 Nov 17. PMID: 18068900.

https://pubmed.ncbi.nlm.nih.gov/18068900/

Abstract: Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8⁺ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8⁺ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8⁺ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8⁺ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.

Kavaka V., et al., Twin study identifies early immunological and metabolic dysregulation of CD8⁺ T cells in multiple sclerosis.  Science Immunology 9(99), 27 Sept.2024:    DOI: 10.1126/sciimmunol.adj8094

https://www.science.org/doi/10.1126/sciimmunol.adj8094

Abstract:

Comi, G., Dalla Costa, G., Stankoff, B. et al. Assessing disease progression and treatment response in progressive multiple sclerosis. Nat Rev Neurol 20, 573–586 (2024). https://doi.org/10.1038/s41582-024-01006-1

https://www.nature.com/articles/s41582-024-01006-1

Abstract:  Exercise training represents a health behavior for the treatment and management of the multi-faceted manifestations of multiple sclerosis (MS). This paper provides a comprehensive overview of evidence from randomized controlled trials (RCTs) regarding benefits, safety, participation, and guidelines for exercise training in MS, based on systematic reviews and meta-analyses. The paper then provides our opinions based on extensive experience regarding challenges for improving and expanding future RCTs that will advance our understanding of exercise training in MS. The comprehensive review of evidence from RCTs indicates that exercise training yields substantial improvements in aerobic and muscle fitness, mobility, fatigue and depression, quality of life, and participation outcomes. There is a non-significant increase in the risk of adverse events or serious adverse events with exercise training compared with control conditions or healthy populations. Rates of adherence and compliance with exercise training (i.e., participation) approximate 80% and 70%, respectively. The current prescriptive guidelines suggest 2-3 days per week of aerobic and resistance exercise training as the minimal dose for safely benefiting from exercise training in MS. We propose 10 important topics as avenues for expanding the body of research and improving its scope for evidence-based practice in MS. Overall, the research on exercise training in MS is strong, but it can get stronger. The expansion and advancement of evidence are critical for moving exercise training into the clinical armamentarium of MS disease treatment and management.

Motl RW, Pilutti LA. Advancements and Challenges in Exercise Training for Multiple Sclerosis: Comprehensive Review and Future Directions for Randomized Controlled Trials. Neurol Ther. 2024 Sep 13. doi: 10.1007/s40120-024-00656-z. Epub ahead of print. PMID: 39271645.

https://pubmed.ncbi.nlm.nih.gov/39271645/

Abstract: Kawasaki disease is an acute, self-limiting, systemic vasculitis of small and medium-sized arteries. It predominantly occurs in children under 4 years of age, though rarely older children can also be affected. This disease is the leading cause of acquired heart disease in children, with coronary aneurysms being a hallmark finding. The risk of coronary complications necessitates regular monitoring and possible preventative treatment with thromboprophylaxis. Here we discuss a rare case of a 10-year-old boy who exhibited typical symptoms of Kawasaki disease and was found to have multiple coronary artery aneurysms through diagnostic imaging.

Wagle G, Khatiwada A, Bastakoti S, K C S. Late onset Kawasaki disease with multiple coronary arterial aneurysms: A case report. Radiol Case Rep. 2024 Aug 10;19(11):4762-4765. doi: 10.1016/j.radcr.2024.07.066. PMID: 39228940; PMCID: PMC11366877.

https://pubmed.ncbi.nlm.nih.gov/39228940/

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1469614/pdf

Abstract:  “With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual’s risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.“

Tandon R, Nasrallah H, Akbarian S, Carpenter WT Jr, DeLisi LE, Gaebel W, Green MF, Gur RE, Heckers S, Kane JM, Malaspina D, Meyer-Lindenberg A, Murray R, Owen M, Smoller JW, Yassin W, Keshavan M. The schizophrenia syndrome, circa 2024: What we know and how that informs its nature. Schizophr Res. 2024 Feb;264:1-28. doi: 10.1016/j.schres.2023.11.015. Epub 2023 Dec 12. PMID: 38086109.

https://pubmed.ncbi.nlm.nih.gov/38086109/