Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism

Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection

OBJECTIVE: To investigate the role of homocysteine in neuronal injury in HIV infection. METHODS: Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. RESULTS: A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = –0.41, p < 0.001) and folate (r = –0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). CONCLUSION: A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causa

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

BACKGROUND: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions. OBJECTIVE: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients (n = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001–2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization. RESULTS: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499–2744] ng/L) than those without relapse (264 [125–537] ng/L, p < 0.001) and patients with gadolinium-enhancing lesions had 3.3 times higher median NFL (1414 [606.8–3210] ng/L) than those without (426 [IQR 221–851] ng/L, p < 0.001). The sensitivity and specificity of cNFL to detect disease activity was 75% and 98.5%, respectively. High cNFL at MS onset predicted progression to Expanded Disability Status Scale (EDSS) ⩾ 3 (p < 0.001, hazard ratios (HR) = 1.89, 95% CI = 1.44–2.65) and conversion to secondary progressive MS (SPMS, p = 0.001, HR = 2.5, 95% CI = 1.4–4.2). CONCLUSIONS: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset

EU Peatlands: Current Carbon Stocks and Trace Gas Fluxes

Peatlands in Europe has formed a significant sink for atmospheric CO2 since the last glacial maximum. Currently they are estimated to hold ca. 42 Gt carbon in the form of peat and are therefore a considerable component in the European carbon budget. Due to the generally wet soil conditions in peatlands they are also significant emitters of the strong greenhouse gas (GHG) methane (CH4) and in some cases also of nitrous oxide (N2O). The EU funded CarboEurope-GHG Concerted Action attempts to develop a reliable and complete greenhouse gas budget for Europe and this report aims to provide a review and synthesis of the available information about GHG exchanges in European peatlands and their underlying processes. A best estimate for all the European countries shows that some are currently sinks for atmospheric CO2 while others are sources. In contrast, for CH4 and N2O, only the sources are relevant. Whilst some countries are CO2 sinks, all countries are net GHG emitters from peatlands. The results presented, however, carry large uncertainties, which cannot be adequately quantified yet. One outstanding uncertainty is the distribution of land use types, particular in Russia, the largest European peat nation. The synthesis of GHG exchange, nevertheless, indicates some interesting features. Russia hosts an estimated 41% of European peatlands and contributes most to all GHG exchanges (CO2: 25%, CH4: 52%, N2O: 26%, Total: 37%). Germany is the second-largest emitter (12% of European total) although it contains only 3.2% of European peatlands. The reason is the use of most of the peatland area for intensive cropland and grassland. The largest CO2 emitters are countries with large agricultural peatland areas (Russia, Germany, Belarus, Poland), the largest N2O emitters are those with large agricultural fen areas (Russia, Germany, Finland). In contrast, the largest CH4 emitters are concentrated in regions with large areas of intact mires, namely Russia and Scandinavia. High average emission densities above 3.5 t C-equiv. ha-1 are found in the Southeast Mediterranean, Germany and the Netherlands where agricultural use of peatlands is intense. Low average emission densities below 0.3 t C-equiv. ha-1 occur where mires and peatland forests dominate, e.g. Finland and the UK. This report concludes by pointing at key gaps in our knowledge about peatland carbon stocks and GHG exchanges which include insufficient basic information on areal distribution of peatlands, measurements of peat depth and also a lack of flux datasets providing full annual budgets of GHG exchanges

Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer's disease

INTRODUCTION: Several blood‐based biomarkers are associated with neuronal injury, but their utility in interventional clinical trials is unclear. This study retrospectively evaluated the utility of plasma neurofilament light (NfL) and total tau (t‐tau) in an 18‐month trial in mild Alzheimer's disease (AD). METHODS: Correlation and conditional independence analyses and Gaussian graphical models were used to investigate cross‐sectional and longitudinal relations between NfL, t‐tau, and clinical scales. RESULTS: NfL had a stronger association than t‐tau with clinical scales; t‐tau did not hold additional information to that given by NfL (P > 0.05 at all time points). NfL held independent information about shorter‐term (3‐ to 6‐month) progression beyond patient age and clinical scores. However, no meaningful gain in power was found when adjusting a longitudinal analysis of cognitive scores for baseline NfL. DISCUSSION: Plasma NfL is superior to t‐tau in mild AD. The ability of NfL to detect changes before clinical manifestations makes it a promising biomarker of drug response in trials of disease‐modifying drugs

Label-free quantitative comparison of cerebrospinal fluid glycoproteins and endogenous peptides in subjects with Alzheimer's disease, mild cognitive impairment, and healthy individuals

PURPOSE: The goal of this study is to investigate putative molecular dynamic changes in cerebrospinal fluids (CSFs) collected from individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) as compared to healthy controls. EXPERIMENTAL DESIGN: The CSF samples from 12 subjects comprised of four cognitively normal individuals and eight patients with MCI and AD, respectively. Two aliquots of each CSF samples (total 1 mL) of each participant are used for this study. Endogenous peptide separations are performed using 10 000 molecular weight cut-off filters followed by LC-MS/MS identification and quantitation while lectin-enrichment chromatography is used to enrich glycoproteins in CSF followed by trypsin digestion and subsequent LC-MS/MS for shotgun identification and label-free quantitation. RESULTS: Using an optimized submicrogram peptide separation with molecular weight cut-off filtration and an in house-constructed database, 645 peptides are identified. Glycoproteins are enriched by lectin affinity chromatography, resulting in 795 identified proteins. The discovery and alterations of proSAAS-derived peptides and transthyretin are described and their roles in AD are discussed. CONCLUSIONS AND CLINICAL RELEVANCE: Comprehensive identification of endogenous CSF peptidome is achieved. Fifteen proteins are found to be differentially expressed among the three groups. The dynamic changes of transthyretin are reported for the first time

Kappa free light chain index as a diagnostic biomarker in multiple sclerosis: a real-world investigation

Kappa free light chain (KFLC)-index, a measure for intrathecal production of free kappa chains, has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal-bands (OCBs). Our objective was to investigate the sensitivity, specificity, and overall diagnostic accuracy of KFLC-index in MS. KFLC-index was prospectively determined as part of the diagnostic workup in patients with suspected MS (n=327) between May 2013 and February 2020. Patients with clinically isolated syndrome (CIS), radiologically isolated syndrome (RIS), and MS had markedly higher KFLC-index (44.6, IQR 16-128) compared with subjects with other neuro-inflammatory disorders (ONID) and symptomatic controls (SC) (2.19, IQR 1.68-2.98, pIF and better than for IgG-index. We show that KFLC-index was influenced neither by DMT, nor by demographic factors or other inflammatory or degenerative processes in MS as determined by biomarkers in CSF

No neurochemical evidence of neuronal injury or glial activation in children with Pediatric Acute-onset Neuropsychiatric Syndrome: An explorative pilot study

OBJECTIVE: Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterised by an acute onset of obsessive compulsive disorder, combined with at least two other neuropsychiatric symptoms with acute onset. Diagnostic criteria also require that no specific medical aetiology is identified. Although there are no verified aetiological biomarkers, PANS is assumed to be a neuroinflammatory disorder with a possible autoimmune aetiology. Neurochemical markers such as neurofilament light (NfL, a neuronal injury marker) and glial fibrillary acidic protein (GFAP, an astrocytic activation marker) have not been published for this patient group. METHOD: Blood samples from 17 children meeting diagnostic criteria for PANS, after assessment at a child neuropsychiatry clinic were analysed for serum concentrations of NfL and GFAP. Ten age-matched children without any neurological or psychiatric disorder served as a comparison group. RESULTS: No difference was found in mean NfL and mean GFAP serum concentrations between children with PANS and controls. CONCLUSION: Neuronal injury and astrocyte activation do not seem to be a major event in PANS. The study group was small, and even if findings may be reassuring for parents and patients, they should be interpreted with caution and verified in larger cohorts and possibly with other markers in both serum and CSF

Hallmarks of neurodegenerative diseases

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs