Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression.

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, 'wild-type like' (WTL) and 'metal binding region' (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlighted key differences in the dynamic behaviour between WTL and MBR SOD1 variants, and between variants and wild-type SOD1 at an atomic and molecular level, that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression.

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course-a joint PhD student course at University College London and University of Gothenburg.

Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases.In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid ß (Aß) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays.As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring.

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta-analyses.

Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta-analyses of studies comparing plasma amyloid beta (Aß) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aß plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta-analyses. Meta-analyses showed higher plasma Aß40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aß42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aß40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aß42 /Aß40 ratios (SMD = -0.33, 95% CI [-0.63, -0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aß40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra-sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.

Stress Effects on Multiple Memory System Interactions.

Extensive behavioural, pharmacological, and neurological research reports stress effects on mammalian memory processes. While stress effects on memory quantity have been known for decades, the influence of stress on multiple memory systems and their distinct contributions to the learning process have only recently been described. In this paper, after summarizing the fundamental biological aspects of stress/emotional arousal and recapitulating functionally and anatomically distinct memory systems, we review recent animal and human studies exploring the effects of stress on multiple memory systems. Apart from discussing the interaction between distinct memory systems in stressful situations, we will also outline the fundamental role of the amygdala in mediating such stress effects. Additionally, based on the methods applied in the herein discussed studies, we will discuss how memory translates into behaviour.