Biomarker modeling of Alzheimer’s disease using PET-based Braak staging

Gold-standard diagnosis of Alzheimer’s disease (AD) relies on histopathological staging systems. Using the topographical information from [18F]MK6240 tau positron-emission tomography (PET), we applied the Braak tau staging system to 324 living individuals. We used PET-based Braak stage to model the trajectories of amyloid-β, phosphorylated tau (pTau) in cerebrospinal fluid (pTau181, pTau217, pTau231 and pTau235) and plasma (pTau181 and pTau231), neurodegeneration and cognitive symptoms. We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau-PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III–IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, whereas Braak stages V–VI were incompatible with normal cognition. In 159 individuals with follow-up tau-PET, progression beyond stage III took place uniquely in the presence of amyloid-β positivity. Our findings support PET-based Braak staging as a framework to model the natural history of AD and monitor AD severity in living humans

Comparing tau status determined via plasma pTau181, pTau231 and [¹⁸F]MK6240 tau-PET

Background: Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [18F]MK6240 tau-PET, plasma pTau181 and pTau231. / Methods: We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [18F]MK6240, plasma pTau181, pTau 231, [18F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment. We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aβ status, APOEε4 status, [18F]AZD4694 global SUVR, hippocampal volume and CSF pTau181. / Findings: The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aβ positivity, APOEε4 carriership, higher levels of [18F]AZD4694 global SUVR, hippocampal atrophy and CSF pTau181. / Interpretation: Plasma pTau181, pTau231 and [18F]MK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity. / Funding: Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec

Seven-day overfeeding enhances adipose tissue dietary fatty acid storage and decreases myocardial and muscle dietary fatty acid partitioning in healthy subjects

International audienceBACKGROUND: Increased myocardial partitioning of dietary fatty acids (DFA) and decreased left-ventricular (LV) function is associated with insulin resistance in prediabetes. OBJECTIVE: We hypothesized that enhanced myocardial DFA partitioning and reduced LV function may be induced concomitantly with reduced insulin sensitivity upon a 7-day hypercaloric (+50% in caloric intake), high saturated fat (~11% of energy) and simple carbohydrates (~54% of energy) diet (HIGHCAL) vs. an isocaloric diet (ISOCAL) with a moderate amount of saturated fat (~8% of energy) and carbohydrates (~50% of energy). DESIGN: Thirteen healthy subjects (7 men/6 women) underwent HIGHCAL vs. ISOCAL in a randomized crossover design, with organ-specific DFA partitioning and LV function measured using the oral 14(R,S)-[(18)F]-fluoro-6-thia-heptadecanoic acid and [(11)C]-acetate positron emission tomography methods at the end of both interventions. RESULTS: HIGHCAL induced a decrease in insulin sensitivity indexes with no significant change in body composition. HIGHCAL led to increased subcutaneous abdominal (+4.2+/-1.6 %, P\textless0.04) and thigh (+2.4+/-1.2 %, P\textless0.08) adipose tissue storage and reduced cardiac (-0.31+/-0.11 mean standard uptake value [SUV], P\textless0.03) and skeletal muscle (-0.17+/-0.08 SUV, P\textless0.05) DFA partitioning without change in LV function. CONCLUSIONS: We conclude that early increase in adipose tissue DFA storage protects the heart and skeletal muscles from potential deleterious effects of DFA

Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples

Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer's disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples