Proteomic correlates of cortical thickness in cognitively normal individuals with normal and abnormal cerebrospinal fluid beta-amyloid1-42

Cortical atrophy is an early feature of Alzheimer´s disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (≤192 ng/L, n = 32) CSF beta-amyloid1-42 (Aβ42). Interactions for Aβ42 status were tested. Panther GeneOntology and Cytoscape ClueGO analyses were used to evaluate biological processes associated with regional cortical thickness. 170 (77.3 %) proteins related with cortical thickness in at least 1 brain region across the total group, and 171 (77.7 %) proteins showed Aβ42 specific associations. Higher levels of proteins related to axonal and synaptic integrity, amyloid accumulation, and inflammation were associated with thinner cortex in lateral temporal regions, the rostral anterior cingulum, the lateral occipital cortex and the pars opercularis only in the abnormal Aβ42 group. Alterations in CSF proteomics are associated with a regional cortical atrophy in the earliest stages of AD.</p

Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([F-18]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer's disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes-two diseases characterized by systemic insulin resistance-are associated with an increased risk for AD. Along with the well-defined patterns of fasting [F-18]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [F-18]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders

Insuliiniresistenssi, aivot ja muistisairausriski

Tyypin 2 diabetes ja siihen liittyvä insuliiniresistenssi ovat muistisairauden riskitekijöitä. Insuliiniresistenssi ennustaa tiedonkäsittelytoimintojen heikentymistä jo henkilöillä, joille ei vielä ole kehittynyt diabetesta. Insuliinilla on useita tärkeitä säätelytehtäviä keskushermostossa. Se vaikuttaa esimerkiksi synapsien toimintaan ja niiden pitkäkestoiseen vahvistumiseen. Insuliiniresistenssiin liittyvään hyperinsulinemiaan on puolestaan yhdistetty paradoksaalisesti keskushermoston pienentynyt insuliinipitoisuus. Alzheimerin tautia sairastavilla insuliinin vaste keskushermostossa on heikentynyt. Insuliinilla ja Alzheimerin taudille tyypillisellä beeta-amyloidilla on aivoissa yhteinen hajottajaentsyymi. Muutokset tämän entsyymin toiminnassa ja määrässä voivat vaikuttaa beeta-amyloidin kertymään aivoissa. Insuliiniresistenssi voi altistaa kognition heikentymiselle myös aivojen pienten suonten muutosten kautta. Insuliiniresistenssi voi siis vaikuttaa tiedonkäsittelytoimintoihin ja Alzheimerin taudin neuropatologiaan useita eri reittejä.</p

Head-to-head comparison of plasma p-tau181, p-tau231 and glial fibrillary acidic protein in clinically unimpaired elderly with three levels of APOE4-related risk for Alzheimer's disease

Plasma phosphorylated tau (p-tau) and glial fibrillary acidic protein (GFAP) both reflect early changes in Alzheimer's disease (AD) pathology. Here, we compared the biomarker levels and their association with regional β-amyloid (Aβ) pathology and cognitive performance head-to-head in clinically unimpaired elderly (n = 88) at three levels of APOE4-related genetic risk for sporadic AD (APOE4/4 n = 19, APOE3/4 n = 32 or non-carriers n = 37). Concentrations of plasma p-tau181, p-tau231 and GFAP were measured using Single molecule array (Simoa), regional Aβ deposition with 11C-PiB positron emission tomography (PET), and cognitive performance with a preclinical composite. Significant differences in plasma p-tau181 and p-tau231, but not plasma GFAP concentrations were present between the APOE4 gene doses, explained solely by brain Aβ load. All plasma biomarkers correlated positively with Aβ PET in the total study population. This correlation was driven by APOE3/3 carriers for plasma p-tau markers and APOE4/4 carriers for plasma GFAP. Voxel-wise associations with amyloid-PET revealed different spatial patterns for plasma p-tau markers and plasma GFAP. Only higher plasma GFAP correlated with lower cognitive scores. Our observations suggest that plasma p-tau and plasma GFAP are both early AD markers reflecting different Aβ-related processes

The production and turnover of extramatrical mycelium of ectomycorrhizal fungi in forest soils : role in carbon cycling

Peer reviewedPublisher PD

Characterisation of CART-containing neurons and cells in the porcine pancreas, gastro-intestinal tract, adrenal and thyroid glands

<p>Abstract</p> <p>Background</p> <p>The peptide CART is widely expressed in central and peripheral neurons, as well as in endocrine cells. Known peripheral sites of expression include the gastrointestinal (GI) tract, the pancreas, and the adrenal glands. In rodent pancreas CART is expressed both in islet endocrine cells and in nerve fibers, some of which innervate the islets. Recent data show that CART is a regulator of islet hormone secretion, and that CART null mutant mice have islet dysfunction. CART also effects GI motility, mainly via central routes. In addition, CART participates in the regulation of the hypothalamus-pituitary-adrenal-axis. We investigated CART expression in porcine pancreas, GI-tract, adrenal glands, and thyroid gland using immunocytochemistry.</p> <p>Results</p> <p>CART immunoreactive (IR) nerve cell bodies and fibers were numerous in pancreatic and enteric ganglia. The majority of these were also VIP IR. The finding of intrinsic CART containing neurons indicates that pancreatic and GI CART IR nerve fibers have an intrinsic origin. No CART IR endocrine cells were detected in the pancreas or in the GI tract. The adrenal medulla harboured numerous CART IR endocrine cells, most of which were adrenaline producing. In addition CART IR fibers were frequently seen in the adrenal cortex and capsule. The capsule also contained CART IR nerve cell bodies. The majority of the adrenal CART IR neuronal elements were also VIP IR. CART IR was also seen in a substantial proportion of the C-cells in the thyroid gland. The majority of these cells were also somatostatin IR, and/or 5-HT IR, and/or VIP IR.</p> <p>Conclusion</p> <p>CART is a major neuropeptide in intrinsic neurons of the porcine GI-tract and pancreas, a major constituent of adrenaline producing adrenomedullary cells, and a novel peptide of the thyroid C-cells. CART is suggested to be a regulatory peptide in the porcine pancreas, GI-tract, adrenal gland and thyroid.</p

Phosphorus regulates ectomycorrhizal fungi biomass production in a Norway spruce forest

Ectomycorrhizal fungi (EMF) are important components of soil microbial communities, and EMF biomass can potentially increase carbon (C) stocks by accumulating in the soils as necromass and producing recalcitrant structures. EMF growth depends on the C allocated belowground by the host trees, and the nutrient limitation on tree growth is expected to influence this allocation. Therefore, studying EMF production and understanding the factors that regulates it in natural soils are important to understand C cycling in forests. Fungal mycelium collected from ingrowth mesh bags is commonly used to estimate EMF biomass, but these measurements might not reflect the total EMF production since turnover rates of the hyphae are not considered. Here we estimated EMF production and turnover in response to P fertilization (applied as superphosphate) in a Norway spruce forest where nitrogen (N) deposition has resulted in phosphorus (P) limitation of plant production by using a combination of mesh bags with different incubation periods and with Bayesian inferences. To test how localized patches of N and P influence EMF production and turnover we amended some bags with a nitrogen source (methylene urea) or P source (apatite). Additionally, the Bayesian model tested the effect of seasonality (time of mesh-bag harvesting) on EMF production and turnover. We found that turnover of EMF was not affected by P fertilization or mesh-bag amendment. P fertilization had a negative effect on EMF production in all the mesh-bag amendments, suggesting a reduced belowground C allocation to the EMF when P limitation is alleviated. Apatite amendment significantly increased EMF biomass production in comparison with the pure quartz bags in the control plots but not in the P-fertilized plots. This indicates that P-rich patches enhance EMF production in P-limited forests, but not when P is not limiting. Urea amendment had a generally positive effect on EMF production, but this was significantly reduced by P fertilization, suggesting that a decrease in EMF production due to the alleviated P limitation will affect N foraging. Seasonality had a significant effect on EMF production, and the differences registered between the treatments were higher during the warmer months and disappeared at the end of the growing season. Many studies highlight the importance of N for regulating belowground C allocation to EMF in northern coniferous forests, but here we show that the P status of the forest can be equally important for belowground carbon allocation to EMF production in areas with high N deposition.</p

The remote monad design pattern

Remote Procedure Calls are expensive. This paper demonstrates how to reduce the cost of calling remote procedures from Haskell by using the remote monad design pattern, which amortizes the cost of remote calls. This gives the Haskell community access to remote capabilities that are not directly supported, at a surprisingly inexpensive cost. We explore the remote monad design pattern through six models of remote execution patterns, using a simulated Internet of Things toaster as a running example. We consider the expressiveness and optimizations enabled by each remote execution model, and assess the feasibility of our approach. We then present a full-scale case study: a Haskell library that provides a Foreign Function Interface to the JavaScript Canvas API. Finally, we discuss existing instances of the remote monad design pattern found in Haskell libraries

ASIC-E4: Interplay of Beta-Amyloid, Synaptic Density and Neuroinflammation in Cognitively Normal Volunteers With Three Levels of Genetic Risk for Late-Onset Alzheimer's Disease – Study Protocol and Baseline Characteristics

Background: Detailed characterization of early pathophysiological changes in preclinical Alzheimer's disease (AD) is necessary to enable development of correctly targeted and timed disease-modifying treatments. ASIC-E4 study (“Beta-Amyloid, Synaptic loss, Inflammation and Cognition in healthy APOE ε4 carriers”) combines state-of-the-art neuroimaging and fluid-based biomarker measurements to study the early interplay of three key pathological features of AD, i.e., beta-amyloid (Aβ) deposition, neuroinflammation and synaptic dysfunction and loss in cognitively normal volunteers with three different levels of genetic (APOE-related) risk for late-onset AD. Objective: Here, our objective is to describe the study design, used protocols and baseline demographics of the ASIC-E4 study. Methods/Design: ASIC-E4 is a prospective observational multimodal imaging study performed in Turku PET Centre in collaboration with University of Gothenburg. Cognitively normal 60–75-year-old-individuals with known APOE ε4/ε4 genotype were recruited via local Auria Biobank (Turku, Finland). Recruitment of the project has been completed in July 2020 and 63 individuals were enrolled to three study groups (Group 1: APOE ε4/ε4, N = 19; Group 2: APOE ε4/ε3, N = 22; Group 3: APOE ε3/ε3, N = 22). At baseline, all participants will undergo positron emission tomography imaging with tracers targeted against Aβ deposition (11C-PIB), activated glia (11C-PK11195) and synaptic vesicle glycoprotein 2A (11C-UCB-J), two brain magnetic resonance imaging scans, and extensive cognitive testing. In addition, blood samples are collected for various laboratory measurements and blood biomarker analysis and cerebrospinal fluid samples are collected from a subset of participants based on additional voluntary informed consent. To evaluate the predictive value of the early neuroimaging findings, neuropsychological evaluation and blood biomarker measurements will be repeated after a 4-year follow-up period. Discussion: Results of the ASIC-E4 project will bridge the gap related to limited knowledge of the synaptic and inflammatory changes and their association with each other and Aβ in “at-risk” individuals. Thorough in vivo characterization of the biomarker profiles in this population will produce valuable information for diagnostic purposes and future drug development, where the field has already started to look beyond Aβ