Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer's disease ...(AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ-). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the AD-vulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials.
The link between brain amyloid-β (Aβ), metabolism, and dementia symptoms remains a pressing question in Alzheimer's disease. Here, using positron emission tomography (
Fflorbetapir tracer for Aβ and
...FFDG tracer for glucose metabolism) with a novel analytical framework, we found that Aβ aggregation within the brain's default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aβ aggregation is associated with subsequent cognitive decline. These results were also observed in transgenic Aβ rats that do not form neurofibrillary tangles, which support these findings as an independent mechanism of cognitive deterioration. These results suggest a model in which distant Aβ induces regional metabolic vulnerability, whereas the interaction between local Aβ with a vulnerable environment drives the clinical progression of dementia.
The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer's disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive ...MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with
FMK6240 and
FAZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of
FMK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t
= -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.
APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer's disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the ...other major proteinopathy of Alzheimer's disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer's disease subjects: (1) 211 participants who underwent tau-PET with
FMK6240 and amyloid-PET with
FAZD4694, (2) 264 individuals who underwent tau-PET with
FFlortaucipir and amyloid-PET with
FFlorbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with
FFlorbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer's disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.
Tracking longitudinal tau tangles accumulation across the Alzheimer's disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the ...available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-β-negative, 22 cognitively unimpaired elderly amyloid-β-positive, 21 mild cognitive impairment amyloid-β-positive and 17 Alzheimer's disease dementia amyloid-β-positive individuals) with baseline amyloid-β 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90-110 min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer's disease dementia who died after the PET scans. We found that the cognitively unimpaired amyloid-β-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-β-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer's dementia amyloid-β-positive exhibited tau accumulation in Braak regions III-VI but not I-II. Cognitively impaired amyloid-β-positive individuals that were Braak II-IV at baseline displayed a 4.6-7.5% annual increase in tau accumulation in the Braak III-IV regions, whereas those who were cognitively impaired amyloid-β-positive Braak V-VI at baseline showed an 8.3-10.7% annual increase in the Braak regions V-VI. Neuropathological assessments confirmed PET-based Braak stages V-VI in the two brain donors. Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer's disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual's baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer's disease.
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.
Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in ...preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase
We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ (18FAZD4694) and tau (18FMK6240) position emission tomography (PET) and clinical assessment
All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached
We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application
Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec.
Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as ...well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent
FMK-6240.
In vitro properties of
FMK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of
FMK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for
FMK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging.
In vitro
FMK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo,
FMK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time-activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates.
This evaluation shows an
FMK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection.
FMK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions.
Abstract
Alzheimer’s disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the ...interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.
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