Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer's Disease.

Astrocytes with their specialised morphology are essential for brain homeostasis as metabolic mediators between blood vessels and neurons. In neurodegenerative diseases such as Alzheimer's disease (AD), astrocytes adopt reactive profiles with molecular and morphological changes that could lead to the impairment of their metabolic support and impact disease progression. However, the underlying mechanisms of how the metabolic function of human astrocytes is impaired by their morphological changes in AD are still elusive. To address this challenge, we developed and applied a metabolic multiscale modelling approach integrating the dynamics of metabolic energy pathways and physiological astrocyte morphologies acquired in human AD and age-matched control brain samples. The results demonstrate that the complex cell shape and intracellular organisation of energetic pathways determine the metabolic profile and support capacity of astrocytes in health and AD conditions. Thus, our mechanistic approach indicates the importance of spatial orchestration in metabolism and allows for the identification of protective mechanisms against disease-associated metabolic impairments.

Who to escalate during a pandemic? A retrospective observational study about decision-making during the COVID-19 pandemic in the UK.

BACKGROUND: Optimal decision-making regarding who to admit to critical care in pandemic situations remains unclear. We compared age, Clinical Frailty Score (CFS), 4C Mortality Score and hospital mortality in two separate COVID-19 surges based on the escalation decision made by the treating physician. METHODS: A retrospective analysis of all referrals to critical care during the first COVID-19 surge (cohort 1, March/April 2020) and a late surge (cohort 2, October/November 2021) was undertaken. Patients with confirmed or high clinical suspicion of COVID-19 infection were included. A senior critical care physician assessed all patients regarding their suitability for potential intensive care unit admission. Demographics, CFS, 4C Mortality Score and hospital mortality were compared depending on the escalation decision made by the attending physician. RESULTS: 203 patients were included in the study, 139 in cohort 1 and 64 in cohort 2. There were no significant differences in age, CFS and 4C scores between the two cohorts. Patients deemed suitable for escalation by clinicians were significantly younger with significantly lower CFS and 4C scores compared with patients who were not deemed to benefit from escalation. This pattern was observed in both cohorts. Mortality in patients not deemed suitable for escalation was 61.8% in cohort 1 and 47.4% in cohort 2 (p<0.001). CONCLUSIONS: Decisions who to escalate to critical care in settings with limited resources pose moral distress on clinicians. 4C score, age and CFS did not change significantly between the two surges but differed significantly between patients deemed suitable for escalation and those deemed unsuitable by clinicians. Risk prediction tools may be useful in a pandemic to supplement clinical decision-making, even though escalation thresholds require adjustments to reflect changes in risk profile and outcomes between different pandemic surges.

Facial tremors in patients with and without parkinsonism.

Facial (lip and jaw) tremors can be an early sign of Parkinson's disease (PD), essential tremor and other parkinsonisms. Its response to acute dopaminergic therapy and further predictive clinical diagnosis has not been previously addressed. The aim of this study was to evaluate facial tremors response to acute dopaminergic therapy and further predictive value for clinical diagnosis. A retrospective review of medical records from patients with recent onset of facial tremor, with or without parkinsonism, submitted to acute levodopa challenge for clinical prediction of sustained long-term dopaminergic response was conducted. Twenty-eight out of 559 patients (5 %) had facial tremors, which responded to levodopa in 46 % of patients. Facial tremors response to acute levodopa challenge showed 92 % sensitivity and 93 % specificity to predict a final PD diagnosis. In PD patients, facial tremor magnitude of response to levodopa was not different from that of hand rest tremor (p = 0.8). Facial tremors, although infrequent, can be an early sign of PD. Positive response to acute levodopa challenge predicts long-term PD diagnosis.

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene.

Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter- and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA.

A multifactorial study on nutritional status, binge eating and physical activity as main factors directly influencing body weight in Parkinson's disease.

Weight lossisa multifactorial disorder commonly affecting Parkinson's disease patients. The aim of this study was to investigate the relationship between body weight, nutritional status, physical activity, and Parkinson's disease-related factors. A total of 114 consecutive Parkinson's disease patients without dietary restrictions were evaluated prospectively with respect to: nutritional status (Mini Nutritional Assessment), physical activity level (Yale Physical Activity Survey), MDS-UPDRS score, olfactory function, depression, cognitive functionand impulse-control disorders, among other variables. Structural equation modeling was used to build multivariate models and to calculate standardized regression weights (srw) for pairs of variables, which are homologous to correlation coefficients, taking into account the effects of all other variables in the model. Sixty (53%) patients were males. Mean age was 66.1 ± 9.8 years and mean disease duration was 8.3 ± 5.6 years. Longer disease duration was negatively related to nutritional status (srw = -0.25; p = 0.01). UPDRS II + III score was associated with reduced cognitive function (srw = -0.39; p = 0.01), which was positivelyrelated to nutritional status (srw = 0.23; p = 0.01). Finally, nutritional status was positively related to body weight (srw = 0.22, p < 0.01). Binge eating and physical activity were also directly and positively related to body weight (srw = 0.32; p = 0.001 and srw = 0.23; p = 0.001). Nutritional status, binge eating and physical activity were directly and independently related to body weight in our sample of Parkinson's disease patients. Therefore, physicians should actively explore nutritional status and binge eating in Parkinson's disease patients to avoid alterations in body weight regulation. Effects of physical activity should be further explored.