Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals.

INTRODUCTION: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-ß (Aß) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aß and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODS: We assessed 138 CU and 87 CI with available plasma p-tau231, 217+ , and 181, Aß42/40, GFAP and Aß- and tau-PET. RESULTS: In CU, only plasma p-tau231 and p-tau217+ significantly improved the performance of the demographics in detecting Aß-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217+ and GFAP significantly contributed to demographics to identify both Aß-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity. DISCUSSION: Our results support plasma p-tau231 and p-tau217+ as state markers of early Aß deposition, but in later disease stages they inform on tau tangle accumulation. HIGHLIGHTS: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex). Plasma p-tau231 and p-tau217+ contribute to demographic information to identify brain Aß pathology in preclinical AD. In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217+ and GFAP inform on both Aß deposition and tau pathology.

Blood-brain barrier integrity impacts the use of plasma amyloid-ß as a proxy of brain amyloid-ß pathology.

INTRODUCTION: Amyloid-ß (Aß) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers. METHODS: We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography Aß, p-tau, and albumin measures. RESULTS: Plasma Aß42/40 better identified CSF Aß42/40 and Aß-PET positivity in individuals with high BBB permeability. An interaction between plasma Aß42/40 and BBB permeability on CSF Aß42/40 was observed. Voxel-wise models estimated that the association of positron emission tomography (PET), with plasma Aß was most affected by BBB permeability in AD-related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p-tau levels. DISCUSSION: These findings suggest that BBB integrity may influence the performance of plasma Aß, but not p-tau, biomarkers in research and clinical settings. HIGHLIGHTS: BBB permeability affects the association between brain and plasma Aß levels. BBB integrity does not affect the association between brain and plasma p-tau levels. Plasma Aß was most affected by BBB permeability in AD-related brain regions. BBB permeability increases with age but not according to cognitive status.

Psychological functioning and quality of life in patients with mastocytosis: A cross-sectional study.

BACKGROUND: Psychological symptoms appear to be frequent among patients with mastocytosis and can significantly affect patient quality of life. However, it remains unclear whether and to which extent this may be the case. OBJECTIVE: To investigate he presence and type of psychological symptoms and quality of life in patients with mastocytosis. METHODS: In this cross-sectional cohort study of adult patients with mastocytosis, all patients completed the 36-item Short Form Health Survey (SF-36) and the 90-item Symptom Checklist (SCL-90). Results were compared with those of a healthy groups of patients with other diseases (chronic pain and cancer) and healthy populations. RESULTS: Fifty patients were included in the study. Seventy percent had indolent systemic mastocytosis. Patients with mastocytosis scored significantly worse than a healthy norm group on the total SCL-90 and more specifically on the dimensions of depression, somatization, sleeping problems, and inadequacy of acting and thinking. Strikingly, patients with mastocytosis scored similarly to patients with cancer on the SF-36 subdomains of general health perception and vitality. However, no significant difference in the mental health subdomain of the SF-36 was found when compared with a healthy group. CONCLUSION: In addition to the presence of psychological symptoms, the physical symptoms that are associated with mastocytosis also have a significant impact on the quality of life of patients with this disease. Therefore, correct treatment through symptom control and psychological counseling is necessary. TRIAL REGISTRATION: EudraCT Identifier 2015-004604-37.

Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-ß load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-ß+ mild cognitive impairment and 54 amyloid-ß+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (ß = 0.43, P = 0.03) and V-VI (ß = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (ß = 0.43, P = 0.02) and V-VI (ß = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (ß = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (ß = 1.69, P < 0.0001), the Everyday Cognition (ß = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (ß = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.

Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET.

Introduction: [18F]AZD4694 is an amyloid beta (Aß) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aß accumulation measured with [18F]AZD4694. Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups. Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aß positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aß positive mild cognitive impairment (MCI) and dementia was modest across the neocortex. Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aß levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies.

The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework.

Amyloid-ß plaques and neurofibrillary tangles (NFTs) are the 2 histopathologic hallmarks of Alzheimer disease (AD). On the basis of the pattern of NFT distribution in the brain, Braak and Braak proposed a histopathologic staging system for AD. Braak staging provides a compelling framework for staging and monitoring of NFT progression in vivo using PET imaging. Because AD staging remains based on clinical features, there is an unmet need to translate neuropathologic staging to a biologic clinical staging system. Such a biomarker staging system might play a role in staging preclinical AD or in improving recruitment strategies for clinical trials. Here, we review the literature regarding AD staging with the Braak framework using tau PET imaging, here called PET-based Braak staging. Our aim is to summarize the efforts of implementing Braak staging using PET and assess correspondence with the Braak histopathologic descriptions and with AD biomarkers. Methods: We conducted a systematic literature search in May 2022 on PubMed and Scopus combining the terms "Alzheimer" AND "Braak" AND ("positron emission tomography" OR "PET"). Results: The database search returned 262 results, and after assessment for eligibility, 21 studies were selected. Overall, most studies indicate that PET-based Braak staging may be an efficient method to stage AD since it presents an adequate ability to discriminate between phases of the AD continuum and correlates with clinical, fluid, and imaging biomarkers of AD. However, the translation of the original Braak descriptions to tau PET was done taking into account the limitations of this imaging technique. This led to important interstudy variability in the anatomic definitions of Braak stage regions of interest. Conclusion: Refinements in this staging system are necessary to incorporate atypical variants and Braak-nonconformant cases. Further studies are needed to understand the possible applications of PET-based Braak staging to clinical practice and research. Furthermore, there is a need for standardization in the topographic definitions of Braak stage regions of interest to guarantee reproducibility and methodologic homogeneity across studies.

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography.

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-ß plaques and tau neurofibrillary tangles. Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral ß-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). Design, Setting, and Participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. Main Outcomes and Measures: Associations between p-tau biomarkers with amyloid PET and tau PET. Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts. Conclusions and Relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-ß accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

APOEε4 potentiates amyloid ß effects on longitudinal tau pathology.

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-ß (Aß) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aß ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aß effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aß effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217+) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aß downstream effects on the aggregation of phosphorylated tau in the living human brain.