The role of insulin resistance and APOE genotype on blood–brain barrier integrity in Alzheimer's disease

INTRODUCTION: Growing evidence suggests a connection between insulin resistance and apolipoprotein E (APOE) genotype in Alzheimer's disease (AD) pathogenesis, but the mechanisms are unclear. We examined effects of insulin resistance and APOE genotype on blood–brain barrier (BBB) integrity in AD. METHODS: BBB integrity was measured in 196 biologically-confirmed non-diabetic patients with AD evaluating CSF/serum albumin ratio, kappa and lambda free light chains (FLCs). Insulin resistance was assessed using triglyceride–glucose index (TyG). The impact of TyG on BBB integrity, and its interaction with APOE genotypes, was analyzed using multivariate models. RESULTS: Sixty-four percent of patients with AD showed altered TyG, with the 21.8% classified as high TyG. TyG subgroups were associated with BBB abnormalities, with similar AD clinical and biomarkers profile. A significant interaction between TyG and APOE ε4/ε4 genotype on BBB permeability was found in multivariate analyses. DISCUSSION: Insulin resistance is a common feature in non-diabetic AD and correlates with altered BBB permeability, interacting synergistically with APOE genotype. Highlights: Insulin resistance and apolipoprotein E (APOE) genotype are well-recognized risk factors for Alzheimer's disease (AD). Insulin resistance shows high prevalence in patients with AD. Insulin resistance is related to damage in blood–brain barrier (BBB) integrity. The association between the triglyceride–glucose (TyG) index and BBB permeability varies in relation to APOE genotype; patients with the APOE ε4/ε4 displayed higher BBB permeability

Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison

Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer's disease, 70 with other neurodegenerative diseases with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate Alzheimer's disease from other neurodegenerative diseases and controls was investigated using receiver operating characteristic analyses. The p-tau217 levels measured by the two techniques demonstrated a strong correlation, showing a consistent relationship with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating Alzheimer's disease from other neurodegenerative diseases [area under the curve (AUC) 0.952, 95% confidence interval (CI) 0.927-0.978 versus 0.955, 95% CI 0.928-0.982, respectively] and healthy controls (AUC 0.938, 95% CI 0.910-0.966 and 0.937, 95% CI 0.907-0.967 for both assays). This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using fully automated or semi-automated techniques

Increased Cerebrospinal Fluid Angiotensin-Converting Enzyme 2 Fragments as a Read-Out of Brain Infection in Patients with COVID-19 Encephalopathy

Background This study assesses the cerebrospinal fluid (CSF) levels of the viral receptor angiotensin-converting enzyme 2 (ACE2) and of the serine protease TMPRSS2 fragments in patients with SARS-CoV-2 infection presenting encephalitis (CoV-Enceph). Methods The study included biobanked CSF from 18 CoV-Enceph, 4 subjects with COVID-19 without encephalitis (CoV), 21 with non-COVID-19-related encephalitis (Enceph), and 21 neurologically healthy controls. Participants underwent a standardized assessment for encephalitis. A large subset of samples underwent analysis for an extended panel of CSF neuronal, glial, and inflammatory biomarkers. ACE2 and TMPRSS2 species were determined in the CSF by western blotting. Results ACE2 was present in CSF as several species, full-length forms and 2 cleaved fragments of 80 and 85kDa. CoV-Enceph patients displayed increased CSF levels of full-length species, as well as the 80kDa fragment, but not the alternative 85kDa fragment, compared with controls and Enceph patients, characterized by increases of both fragments. Furthermore, TMPRSS2 was increased in the CSF of Enceph patients compared with controls, but not in CoV-Enceph patients. The CoV patients without encephalitis displayed unaltered CSF levels of ACE2 and TMPRSS2 species. Conclusions Patients with encephalitis displayed an overall increase in CSF ACE2, probably as a consequence of brain inflammation. The increase of the shortest ACE2 fragment only in CoV-Enceph patients may reflect the enhanced cleavage of the receptor triggered by SARS-CoV-2, thus serving to monitor brain penetrance of the virus associated with the rare encephalitis complication. TMPRSS2 changes in the CSF appeared related to inflammation, but not with SARS-CoV-2 infection

Plasma levels of glial fibrillary acidic protein and neurofilament light chain in patients with chronic migraine: a multicenter case-control study

Objective: Plasma glial fibrillary acidic protein (pGFAP) and plasma neurofilament light chain (pNfL) levels reflect astrocyte activation and neuronal damage, respectively. Whether these phenomena play a role in migraine is unknown. This study aimed to compare pGFAP and pNfL levels in patients with chronic migraine (CM) and age-matched controls and to analyze their relation with clinical features. Methods: The study evaluated two independent cohorts of patients, including in total 58 CM and 69 controls. pGFAP and pNfL were quantified with single molecule array (Simoa) technology. Demographic and clinical data were collected for each subject; differences in NfL/GFAP levels between CM and controls were evaluated in analyses adjusted for the effect of age and sex; clinical characteristics associated with NfL/GFAP levels were separately evaluated in the two cohorts. Results: In both cohorts, we did not find a significant difference in pGFAP or pNFL levels between CM and matched controls. The study did not find any correlation between pGFAP or pNfL levels and any migraine characteristics (namely presence of migraine aura, attack frequency, migraine intensity, years of disease). Conclusions: Our negative results support the assumption that migraine represents a benign condition, characterized by transient functional brain alterations and not by the accumulation over time of neuroaxonal damage and/or associated astrocyte activation detectable by neurodegeneration marker proteins

Biomarker discovery in Alzheimer's and neurodegenerative diseases using Nucleic Acid Linked Immuno-Sandwich Assay

INTRODUCTION: Recent advancements in immunological methods accurately quantify biofluid biomarkers for Alzheimer's disease (AD) pathology. Despite progress, more biomarkers, ideally in blood, are needed for effective disease monitoring for AD and other neurodegenerative proteinopathies. METHODS: We used the Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) central nervous system panel for biomarker quantification in plasma, serum, and cerebrospinal fluid of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers. RESULTS: NULISA identified phosphorylated tau217 and neurofilament light chain as the most deregulated biomarkers in the AD continuum and GRN mutation carriers, respectively. Importantly, numerous novel proteomic changes were observed in each disease endophenotype, which included synaptic processing, inflammation, microglial reactivity, TAR DNA-binding protein 43, and α-synuclein pathology. DISCUSSION: We underline the potential of next-generation biomarker identification tools to detect novel proteomic features that also incorporate established biomarkers. These findings highlight the importance of continued biomarker discovery to improve treatment decisions and help us better understand the complexities of neurodegenerative disorders. Highlights: The, direct, or indirect, measures in blood that complement phosphorylated tau (p-tau)217 for other proteinopathies or disease progression are urgently needed. Significant novel proteomic changes were observed in each disease endophenotype in plasma, serum, and cerebrospinal fluid, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TAR DNA-binding protein 43, and α-synuclein pathology. Nucleic Acid Linked Immuno-Sandwich Assay continued to unbiasely highlight p-tau217 and neurofilament light chain as the most significantly deregulated blood biomarkers in the Alzheimer's disease continuum and progranulin mutation carriers, respectively

Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform

Global implementation of blood tests for Alzheimer’s disease (AD) would be facilitated by easily scalable, cost-effective and accurate tests. In the present study, we evaluated plasma phospho-tau217 (p-tau217) using predefined biomarker cutoffs. The study included 1,767 participants with cognitive symptoms from 4 independent secondary care cohorts in Malmö (Sweden, n = 337), Gothenburg (Sweden, n = 165), Barcelona (Spain, n = 487) and Brescia (Italy, n = 230), and a primary care cohort in Sweden (n = 548). Plasma p-tau217 was primarily measured using the fully automated, commercially available, Lumipulse immunoassay. The primary outcome was AD pathology defined as abnormal cerebrospinal fluid Aβ42:p-tau181. Plasma p-tau217 detected AD pathology with areas under the receiver operating characteristic curves of 0.93–0.96. In secondary care, the accuracies were 89–91%, the positive predictive values 89–95% and the negative predictive values 77–90%. In primary care, the accuracy was 85%, the positive predictive values 82% and the negative predictive values 88%. Accuracy was lower in participants aged ≥80 years (83%), but was unaffected by chronic kidney disease, diabetes, sex, APOE genotype or cognitive stage. Using a two-cutoff approach, accuracies increased to 92–94% in secondary and primary care, excluding 12–17% with intermediate results. Using the plasma p-tau217:Aβ42 ratio did not improve accuracy but reduced intermediate test results (≤10%). Compared with a high-performing mass-spectrometry-based assay for percentage p-tau217, accuracies were comparable in secondary care. However, percentage p-tau217 had higher accuracy in primary care and was unaffected by age. In conclusion, this fully automated p-tau217 test demonstrates high accuracy for identifying AD pathology. A two-cutoff approach might be necessary to optimize performance across diverse settings and subpopulations