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The ketone body -hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0 –1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson’s r 0.99), BHBv (r 0.91), and BHBc (r 0.91), all P 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64 – 0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions. [ABSTRACT FROM AUTHOR]

Background: Cortisol, one of the most important mediators of stress in humans, is often found increased in Alzheimer's disease (AD) patients and correlates with disease severity. Stress response and inflammation are two systems that are tightly associated to one another. Several lines of evidence suggest that cortisol can promote inflammation. However, less is known on the interaction of cortisol with neuroinflammation in the context of AD, and to the best of our knowledge there are no human studies that have systematically explored the association of these two systems in AD patients so far. The aim of this study was to investigate levels of cerebrospinal fluid (CSF) biomarkers of neuroinflammation and their relationship to salivary cortisol in a memory clinic cohort. Method: A total of 108 memory clinic patients with subjective cognitive decline (SCI, n = 40), mild cognitive impairment (MCI, n = 39) and AD (n = 29), from the Karolinska University Hospital in Stockholm, Sweden, were included in this study. Salivary cortisol was collected at six timepoints during the day on two days, to quantify awakening cortisol, cortisol awakening response (CAR), bedtime cortisol and total cortisol. CSF levels of 37 neuroinflammation and cerebrovascular dysfunction biomarkers were determined by a multiplex immunoassay. Associations among cortisol and neuroinflammation markers were assessed by linear regression models adjusting for age and diagnosis. ANCOVA tests were used to compare biomarker levels between the diagnostic groups. Result: Awakening cortisol was significantly elevated in the AD group compared to the SCI and MCI participants. Higher IP‐10 and placental growth factor (PlGF) levels were associated with decreased CAR independent of age and diagnosis. Thymus and activation‐regulated chemokine (TARC), CRP, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) levels were upregulated in MCI participants compared to SCI and AD. Conclusion: We provide evidence that the HPA axis is altered in AD. Moreover, salivary cortisol is associated to neuroinflammation in an age and diagnosis independent manner. Finally, neuroinflammatory and vascular dysfunction regulators are increased in CSF during MCI stages followed by a drop in their levels in AD participants, presumably reflecting a more active role of neuroinflammation at an early state. [ABSTRACT FROM AUTHOR]

Background: Synaptic dysfunction plays a key role in cognitive decline during progression of Alzheimer's disease (AD). Higher levels of several synaptic proteins including the presynaptic protein ß‐synuclein have been measured in cerebrospinal fluid (CSF) of individuals with AD. Recently a quantitative assay using mass spectrometry allowed detection of ß‐synuclein in plasma. The aim of this study was to investigate the relationship between plasma ß‐synuclein levels and brain amyloid‐β (Aβ) plaque load in a cohort of memory clinic patients who underwent [18F]flutemetamol PET. Method: A clinical cohort of 118 patients (age = 65.6±8.3, 65F/53M), who despite extensive clinical assessment (including neuropsychological testing, CT/MRI, CSF biomarker analysis) at the Karolinska University Hospital, Sweden had an uncertain diagnosis and were referred to [18F]flutemetamol PET, was included in this work. The diagnostic groups were as follows: mild cognitive impairment (MCI, n = 16 Aβ+, and n = 24 Aβ‐), AD (n = 53), non‐AD dementia (n = 20),no dementia (n = 5). Plasma and CSF ß‐synuclein were measured using targeted mass spectrometry and ELISA. Result: We found a significant correlation between β‐synuclein values in plasma and CSF (p<0.001), with higher plasma β‐synuclein levels in AD (11.53±3.25pg/mL,p<0.001) compared to MCI Aβ‐ (7.74±2.63pg/mL) and non‐AD (8.18±3.00 pg/mL), and also between MCI Aβ+ (10.85±2.75pg/mL,p<0.01) in comparison to MCI Aβ‐. No significant difference was observed in plasma/CSF β‐synuclein levels between AD and MCI Aβ+. 18F‐Flutemetamol uptake positively correlated with plasma ß‐synuclein levels in the whole sample (R2 = 0.29,p<0.001) and in the MCI group (R2 = 0.26,p<0.01) (after controlling for sex and age). Individuals with comparable [18F]flutemetamol uptake values showed great variability in plasma ß‐synuclein levels. No correlation was observed between plasma ß‐synuclein and MMSE, brain atrophy, or white matter changes. Conclusion: In a clinical cohort of patients with [18F]flutemetamol‐PET, significantly elevated ß‐synuclein in plasma mirrored the higher levels of ß‐synuclein in CSF of Aß+ individuals. In the AD continuum, plasma ß‐synuclein seemed to capture pathological processes which were more closely associated with amyloid‐pathology rather than neuronal loss or clinical stage of the disease. The variability in plasma ß‐synuclein levels of Aß+ subjects warrants further exploration of factors that might contribute to increased plasma ß‐synuclein. [ABSTRACT FROM AUTHOR]

Background: Isolation of brain‐secreted extracellular vesicles (BEVs) from blood, provides a novel, minimally invasive way to sample brain tissue in individuals along the Alzheimer's disease (AD) continuum. BEVs in blood demonstrate enormous potential to serve as a novel AD biomarker discovery platform and treatment tool. However, at present, BEV isolation and validation protocols vary from center to center. Given the growing popularity of immunoprecipitation (IP)‐based BEV isolation methods, we assessed the brain‐specificity of reported cell‐surface and cargo proteins associated with this category of methods. Method: We performed a systematic evaluation of BEV isolation and validation protocols from 34 published articles investigating biomarker potential of blood‐isolated BEVs in AD. Proteins used for polyethylene glycol‐based precipitation followed by IP‐capture BEV isolation, or as BEV biomarker candidates, were compiled. The proteins were categorized by brain specificity, abundance, extracellular accessibility and extracellular vesicles presence by examining their expression from publicly available datasets in over 60 human tissue types, including 13 central nervous system (CNS) regions and 48 peripheral tissues. Result: We compiled 68 unique IP or biomarker protein candidates. Analyses demonstrated that of these, 22 had extracellular domains (that could be used for BEV isolation), 7 were membrane proteins lacking extracellular domains, and the remaining were intracellular proteins. Moreover, >50% of the compiled proteins were present in extracellular vesicle datasets, >20% were considered highly CNS specific, and ∼60% demonstrated moderate‐to‐high CNS abundance (Fig.1). Furthermore, in addition to confirming that some proteins widely used for IP‐based BEV isolation are CNS‐enriched (e.g., L1CAM, Fig. 1B), we also identified, at least, 5 additional proteins with higher CNS abundance and specificity, extracellular domains, and known to be present in extracellular vesicles. Conclusion: Consensus harmonization of BEV isolation and validation protocols are essential steps in blood‐isolated BEV biomarker work in AD, and is advocated by the Alzheimer's Association BBB‐PIA. This harmonization of BEV protocols is crucial, given the growing interest in developing minimally‐invasive AD biomarker discovery tools, and the increasing number of researchers worldwide conducting BEV biomarker work. Moreover, the additional proteins identified by the EWG‐BBB‐PIA will lead to better IP‐based BEV isolation from blood. [ABSTRACT FROM AUTHOR]

Background: The heterogeneity of a multifactorial disease like Alzheimer's disease (AD) cannot be captured solely with ATN biomarkers. Previous research has identified mixed neuropathologies as well as subtypes discovered by brain scans and cerebrospinal fluid (CSF) proteomics in AD cohorts. Still, we need a better understanding of how clinical characteristics distribute between subgroups of AD. Additionally, various approaches determining subgroups need to be evaluated. AD, which falls under the umbrella term dementia, could in fact also be considered an umbrella itself with distinct subgroups. Method: Altogether 288 CSF samples from patients from the Karolinska University Hospital memory clinic in Solna, Sweden, were analysed. Patients in the cohort were diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and different dementias, mainly AD. Using an antibody‐based suspension bead array, levels of 75 proteins were measured. Clustering analysis methods were used to identify subgroups. Result: The assessed panel reveals differences in patterns of protein levels within diagnostic groups and by applying clustering analyses subgroups across the dementia spectrum can be identified. Furthermore, Gene Ontology search implies differences in plausible underlying disease mechanisms between the distinct subgroups. It is of interest to explore to what extent, e.g., cardiovascular conditions or psychological burden are represented in the subgroups. Conclusion: Identifying subgroups within different diagnostic groups may prove to be crucial for finding the most suitable prevention and treatment options, particularly when disease modifying drugs are developed and tested. [ABSTRACT FROM AUTHOR]

The ketone body β-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r  = 0.99), BHBv ( r  = 0.91), and BHBc ( r  = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.