Abnormal tau in amyloid PET negative individuals.

We examined the characteristics of individuals with biomarker evidence of tauopathy but without ß-amyloid (Aß) (A-T+) in relation to individuals with (A+T+) and without (A-T-) evidence of Alzheimer's disease (AD). We included 561 participants with Aß and tau PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We compared A-T- (n = 316), A-T+ (n = 63), and A+T+ (n = 182) individuals on demographics, amyloid, tau, hippocampal volumes, and cognition. A-T+ individuals were low on apolipoprotein E ɛ4 prevalence (17%) and had no evidence of subtly elevated brain Aß within the negative range. The severity of tau deposition, hippocampal atrophy, and cognitive dysfunction in the A-T+ group was intermediate between A-T- and A+T+ (all p < 0.001). Tau uptake patterns in A-T+ individuals were heterogeneous, but approximately 29% showed tau deposition in the medial temporal lobe only, consistent with primary age-related tauopathy and an additional 32% showed a pattern consistent with AD. A-T+ individuals also share other features that are characteristic of AD such as cognitive impairment and neurodegeneration, but this group is heterogeneous and likely reflects more than one disorder.

Longitudinal Cognitive and Biomarker Measurements Support a Unidirectional Pathway in Alzheimer's Disease Pathophysiology.

BACKGROUND: Amyloid-ß (Aß) likely plays a primary role in Alzheimer's disease pathogenesis, but longitudinal Aß, tau, and neurodegeneration (A/T/N) measurements in the same individuals have rarely been examined to verify the temporal dynamics of these biomarkers. METHODS: In this study, we investigated the temporal ordering of Aß, tau, and neurodegeneration using longitudinal biomarkers in nondemented elderly individuals. A total of 395 cognitively unimpaired individuals and 204 individuals with mild cognitive impairment (320 [53%] were female) were classified into 8 A±/T±/N± categories according to the abnormal (+)/normal (-) status of Aß (18F-florbetapir or 18F-florbetaben) positron emission tomography (PET), 18F-flortaucipir PET, and adjusted hippocampal volume (aHCV). Follow-up Aß PET, tau PET, and aHCV measurements at 0.6 to 4.1 years were available for 35% to 63% of the sample. Baseline Aß, tau, and aHCV were compared between different A/T/N profiles. We investigated the associations of baseline and longitudinal Aß, tau, and neurodegeneration in relation to one another continuously. RESULTS: Among T- participants, tau was higher for A+/T-/N- individuals compared with the A-/T-/N- group (p = .02). Among N- participants, neurodegeneration was worse among A+/T+/N- individuals compared with the A-/T-/N- group (p = .001). High baseline Aß was associated (p < .001) with subsequent tau increase and high baseline tau was associated (p = .002) with subsequent aHCV decrease, whereas high tau and low aHCV at baseline were not associated with subsequent Aß increase. CONCLUSIONS: These findings define a sequence of pathological events in Alzheimer's disease that support a current model of Alzheimer's disease pathogenesis in which Aß appears early, followed by deposition of abnormal tau aggregates and subsequent neurodegeneration.

Evaluation of a visual interpretation method for tau-PET with 18F-flortaucipir.

INTRODUCTION: Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed. METHODS: We developed a visual interpretation method for 18F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MCI], AD dementia, and non-AD diagnoses). Two readers interpreted 18F-flortaucipir PET using two complementary indices: a global visual score and a visual distribution pattern. RESULTS: Global visual scores were reliable, correlated with global cortical 18F-flortaucipir standardized uptake value ratio (SUVR) and were associated with clinical diagnosis and amyloid status. The AD-like 18F-flortaucipir pattern had good sensitivity and specificity to identify amyloid-positive patients with AD dementia or MCI. DISCUSSION: This 18F-flortaucipir visual rating scheme is associated with SUVR quantification, clinical diagnosis, and amyloid status, and constitutes a promising approach to tau measurement in clinical settings.

Conscientiousness is associated with less amyloid deposition in cognitively normal aging.

Little is known about the association between personality and Alzheimer's disease (AD) biomarkers, and existing results are inconsistent. We aimed to determine whether personality was associated with ß-amyloid (Aß) accumulation in cognitively normal aging. One hundred twenty-nine participants were included in this cross-sectional study. Personality was measured with the Big Five Inventory (BFI) and brain Aß deposition was assessed with [11C] Pittsburgh compound B (PiB)-positron emission tomography (PET) imaging. Conscientiousness scores had a negative association with global PiB distribution volume ratio (DVR) in all participants after adjusting for age, sex, education, and vascular risk factors (ß[SE] = -0.19[0.09], 95% confidence interval [CI: -0.35, -0.02], p = .031), while agreeableness, extraversion, neuroticism, and openness had no association with global PiB DVR. Assuming the relative stability of personality traits, these findings suggest that conscientiousness may protect against Aß accumulation in cognitively normal aging through mechanisms that are as yet unknown. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Normalization of CSF pTau measurement by Aß40 improves its performance as a biomarker of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD)-related tauopathy can be measured with CSF phosphorylated tau (pTau) and tau PET. We aim to investigate the associations between these measurements and their relative ability to predict subsequent disease progression. METHODS: In 219 cognitively unimpaired and 122 impaired Alzheimer's Disease Neuroimaging Initiative participants with concurrent amyloid-ß (Aß) PET (18F-florbetapir or 18F-florbetaben), 18F-flortaucipir (FTP) PET, CSF measurements, structural MRI, and cognition, we examined inter-relationships between these biomarkers and their predictions of subsequent FTP and cognition changes. RESULTS: The use of a CSF pTau/Aß40 ratio eliminated positive associations we observed between CSF pTau alone and CSF Aß42 in the normal Aß range likely reflecting individual differences in CSF production rather than pathology. Use of the CSF pTau/Aß40 ratio also increased expected associations with Aß PET, FTP PET, hippocampal volume, and cognitive decline compared to pTau alone. In Aß+ individuals, abnormal CSF pTau/Aß40 only individuals (26.7%) were 4 times more prevalent (p <  0.001) than abnormal FTP only individuals (6.8%). Furthermore, among individuals on the AD pathway, CSF pTau/Aß40 mediates the association between Aß PET and FTP PET accumulation, but FTP PET is more closely linked to subsequent cognitive decline than CSF pTau/Aß40. CONCLUSIONS: Together, these findings suggest that CSF pTau/Aß40 may be a superior measure of tauopathy compared to CSF pTau alone, and CSF pTau/Aß40 enables detection of tau accumulation at an earlier stage than FTP among Aß+ individuals.