Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed.
We assessed the diagnostic performance of p-tau
, p-tau
, ...and p-tau
in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity.
Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau
(AUC = 76%) and p-tau
(AUC = 82%) assessments performed inferior to CSF p-tau
(AUC = 87%) and p-tau
(AUC = 95%) for amyloid-PET positivity. However, plasma p-tau
(AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity.
Plasma and CSF p-tau
had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau
may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD.
p-tau
in plasma performed equivalent to p-tau
in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau
is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau
and plasma p-tau
performed worse than p-tau
and p-tau
in CSF for AD diagnosis.
Gold-standard diagnosis of Alzheimer's disease (AD) relies on histopathological staging systems. Using the topographical information from
FMK6240 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 (pTau
, pTau
, pTau
and pTau
) and plasma (pTau
and pTau
), 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.
Abstract
Introduction
18FAZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ ...accumulation measured with 18FAZD4694.
Methods
We assessed 146 individuals who were evaluated with 18FAZD4694 at baseline and 2‐year follow‐up. We calculated annual rates of 18FAZD4694 change for clinically defined and biomarker‐defined groups
Results
Cognitively unimpaired (CU) older adults displayed subtle 18FAZD4694 standardized uptake value ratio (SUVR) accumulation over the follow‐up period. In contrast, Aβ positive CU older adults displayed higher annual 18FAZD4694 SUVR increases. 18FAZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex
Discussion
Larger increases in 18FAZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. 18FAZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti‐amyloid therapies.
Abstract
A classical early sign of typical Alzheimer’s disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and ...recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer’s disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-β+ individuals with mild cognitive impairment and 29 amyloid-β+ Alzheimer’s disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent 18FMK6240 tau and 18FAZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions.
Fernández-Arias et al. report early delayed recall deficits concomitant with tau accumulation in the anterior medial temporal lobe, and recognition dysfunction with further tau buildup in neocortical regions in the Alzheimer’s disease spectrum. The study underscores the advantage of using PET-Braak staging to characterize memory-related deficits in Alzheimer’s disease.
Graphical Abstract
Graphical abstract
Abstract Alzheimer’s disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in ...facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns (“gradient contraction”) are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.
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 18FMK6240 tau-PET, plasma pTau181 and pTau231.
We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with 18FMK6240, plasma pTau181, pTau 231, 18FAZD4694 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, 18FAZD4694 global SUVR, hippocampal volume and CSF pTau181.
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 18FAZD4694 global SUVR, hippocampal atrophy and CSF pTau181.
Plasma pTau181, pTau231 and 18FMK6240 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.
Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec.
Abstract
Alzheimer’s disease biomarkers are primarily evaluated through MRI, PET and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based ...biomarkers have shown promise for simple, inexpensive, accessible and minimally invasive tools with diagnostic and prognostic value for Alzheimer’s disease. Most recently, plasma phosphorylated tau181 has shown excellent performance. The relationship between plasma phosphorylated tau181 and cerebral metabolic dysfunction assessed by 18Ffluorodeoxyglucose PET in Alzheimer’s disease is still unknown. This study was performed on 892 older individuals (297 cognitively unimpaired; 595 cognitively impaired) from the Alzheimer’s Disease Neuroimaging Initiative cohort. Plasma phosphorylated tau181 was assessed using single molecular array technology and metabolic dysfunction was indexed by 18Ffluorodeoxyglucose PET. Cross-sectional associations between plasma and CSF phosphorylated tau181 and 18Ffluorodeoxyglucose were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by β-amyloid status. Associations between baseline plasma phosphorylated tau181 and longitudinal (24 months) rate of brain metabolic decline were also assessed in 389 individuals with available data using correlations and voxelwise regression models. Plasma phosphorylated tau181 was elevated in β-amyloid positive and cognitively impaired individuals as well as in apolipoprotein E ε4 carriers and was significantly associated with age, worse cognitive performance and CSF phosphorylated tau181. Cross-sectional analyses showed strong associations between plasma phosphorylated tau181 and 18Ffluorodeoxyglucose PET in cognitively impaired and β-amyloid positive individuals. Voxelwise longitudinal analyses showed that baseline plasma phosphorylated tau181 concentrations were significantly associated with annual rates of metabolic decline in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes. The associations between plasma phosphorylated tau181 and reduced brain metabolism, primarily in cognitively impaired and in β-amyloid positive individuals, supports the use of plasma phosphorylated tau181 as a simple, low-cost, minimally invasive and accessible tool to both assess current and predict future metabolic dysfunction associated with Alzheimer’s disease, comparatively to PET, MRI and CSF methods.
Lussier et al. report that plasma phosphorylated tau181 is associated cross-sectionally with CSF phosphorylated tau181 and 18Ffluorodeoxyglucose PET in 823 individuals from the Alzheimer’s Disease Neuroimaging Initiative cohort. The authors also report a significant association between baseline plasma p-tau181 and longitudinal change in brain glucose metabolism indexed by 18Ffluorodeoxyglucose PET.
Graphical Abstract
Graphical Abstract
To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and ...Alzheimer's disease.
Observational data was obtained from the Alzheimer's Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry.
We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months.
Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer's disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.
The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with ...whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant’s real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau’s synergistic impact on neuronal activity ( q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.
Background
By obtaining a better grasp on the impact of the COVID‐19 pandemic on individuals with cognitive impairment, this knowledge could be used to improve the delivery of information to this ...particular group. We aimed to assess the relationship between tau deposition and the change in anxiety levels, before and during the pandemic. We hypothesized that since the pandemic, higher tau loads would lower the change in anxiety. Furthermore, we expected these anxiety levels not to be associated with COVID‐19 related stress in participants with cognitive decline.
Methods
63 participants of the Translational Biomarker of Aging and Dementia (TRIAD) cohort (cognitively healthy, N=38; cognitively impaired, N=25, of which 7 had dementia due to Alzheimer’s disease), were assessed to evaluate their individual change in anxiety levels (GAD‐7). This was done at three different timepoints, of which the latest fell during the COVID‐19 lockdown period. Two rates of change, one before and one during the pandemic, were determined using the following definition: (next timepoint – current timepoint)/time difference. In addition, at the latest timepoint, subjective stress due to COVID‐19 was measured using the Montreal Assessment of Stress related to COVID‐19 (MASC). To assess the levels of tau, standard uptake value ratios (SUVR) from previously obtained 18FMK‐6240 PET‐scans were used.
Results
18FMK‐6240 tracer binding in the lingual gyrus was negatively associated with the rate of change in GAD‐7 scores after correcting for age, sex, years of education and the presence of APOE ε4, but only in cognitively impaired individuals during the pandemic (fig 1A). In addition, the GAD‐7 score at the latest timepoint was associated with stress related to COVID‐19, but only in cognitively healthy individuals (fig 1B and 1C).
Conclusions
The presence of tau in the lingual gyrus negatively affected the rate of change in GAD‐7 scores during the COVID‐19 pandemic in individuals with cognitive impairment. This could indicate that information pertaining to the pandemic does not reach these individuals in an efficient manner. The missing association between COVID‐19 induced stress and the latest GAD‐7 scores in these individuals is a further indication of this.
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