Comparative Analysis of Different Definitions of Amyloid-beta Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer

Amyloid-β (Aβ) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aβ pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer’s continuum is critical. Here, we compare different Aβ classification approaches and we show their performance in detecting pathophysiological changes downstream Aβ pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer’s continuum. Participants underwent Aβ PET and CSF biomarkers assessment. We classified participants as Aβ -positive using five approaches: (1) CSF Aβ42 12; (4) Aβ PET Centiloid > 30 or (5) Aβ PET Positive visual read. We assessed the correlations between Aβ biomarkers and compared the prevalence of Aβ positivity. We determined which approach significantly detected associations between Aβ pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aβ-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aβ-positive but PET Aβ-negative than CSF Aβ-negative but PET Aβ-positive. The CSF Aβ 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aβ-positive group. Altogether, we highlight the need for sensitive Aβ -classifications to study the preclinical Alzheimer’s continuum. Approaches that define Aβ positivity based on optimal discrimination of symptomatic Alzheimer’s disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease

BACKGROUND: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. METHODS: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. RESULTS: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. CONCLUSIONS: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. TRIAL REGISTRATION: NCT01835717 , NCT02485730 , NCT02685969

To be, or not to be, a non-native freshwater fish?

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Habitat quality affects the condition of Luciobarbus sclateri in the Guadiamar River (SW Iberian Peninsula): Effects of disturbances by the toxic spill of the Aznalcóllar mine

This study analyzes the somatic condition of southern Iberian barbel Luciobarbus sclateri (Günther, 1868) in the Guadiamar River (SW Iberian Peninsula). This river was seriously affected by a toxic spill of about 4 million cubic meters of acidic water and 2 million cubic meters of mud rich in heavy metals. Once the spill removal works concluded, sites affected and unaffected by the accident were sampled to study its effects on the fish fauna. The ecological variables registered were related to water quality, physical state of reaches, ecological quality, resources exploited by fish, and potential intra-specific interactions. From an initial 15 ecological variables, seasonal water flow and pH explained most of the variation in barbel condition. This study shows that the Guadiamar River, 56 months after the accident, is still undergoing a recovery process where, beyond ecological variables, proximity to the affected area is the most influential factor for fish condition. © 2012 Springer Science+Business Media B.V

Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer’s disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer’s continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer’s continuum

A review and meta-analysis of the environmental biology of bleak Alburnus alburnus in its native and introduced ranges, with reflections on its invasiveness

The bleak Alburnus alburnus is a medium body-size leuciscid fish that is naturally distributed across central European and western Asian fresh waters. However, during the last two decades A. alburnus has been widely introduced elsewhere in Europe and in northern Africa, mostly as a forage species for game fishes. Given its relatively recent history of invasion in non-native Eurasian waters, where it can become highly abundant, A. alburnus poses a serious risk to native communities where introduced. This study provides a review and meta-analysis of the biological traits of A. alburnus coupled with insights into its invasiveness. In its native range, A. alburnus has a moderate lifespan, inhabiting lakes or still waters in medium-to-large rivers, where it feeds mainly on zooplankton. However, non-native A. alburnus populations display high phenotypic plasticity in their biological attributes. Thus, growth, reproductive and/or dietary traits have adapted to local environmental conditions, with the species also invading lotic (stream) ecosystems. Feeding changes to benthic invertebrates, plant material and detritus when zooplankton is scarce. Such plasticity, including broad physiological tolerance, is likely to facilitate the species' adaptation and invasion of new habitats in the near future

APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer’s disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field