Abstract
PurposeStudies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau181p) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [18F]THK5317 (tau) and [18F]FDG PET (glucose metabolism).MethodsFourteen Alzheimer’s disease (AD) patients (seven prodromal, seven dementia) underwent [18F]THK5317 and [18F]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included.ResultsWhile the levels of all forms of CSF tau were found to be inversely associated with baseline [18F]FDG uptake, associations with baseline [18F]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([18F]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau181p and T-tau levels, and improved concordance with dichotomized regional [18F]THK5317 measures.ConclusionOur findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau181p and T-tau, tau-368 and tau N-Mid may better capture tau pathology and synaptic impairment.
Highlights
Many details surrounding the pathogenesis of Alzheimer’s disease (AD) remain unclear, a dominant viewpoint is that the dysmetabolism of amyloid-β (Aβ) initiates tau pathology that results in neurodegeneration and cognitive decline
Baseline Mini-Mental State Examination (MMSE) scores were significantly lower in AD dementia patients than in prodromal AD patients (p < 0.01)
Data are presented as median [quartile 1, quartile 3] unless otherwise specified a Two patients had progressed to AD dementia at clinical follow-up b Significantly lower, relative to prodromal AD (p < 0.01) c Significantly lower, relative to baseline (p < 0.01)
Summary
Many details surrounding the pathogenesis of Alzheimer’s disease (AD) remain unclear, a dominant viewpoint is that the dysmetabolism of amyloid-β (Aβ) initiates tau pathology that results in neurodegeneration and cognitive decline. Positron emission tomography (PET) ligands selective for AD-related paired helical filament (PHF) tau present in NFTs have been introduced into the field One such ligand is [18F]flortaucipir (formerly known as [18F]T-807 and [18F]AV1451) [2, 3], and studies examining the relationship between [18F]flortaucipir uptake and CSF tau levels have shown modest positive correlations in cognitively unimpaired older adults and in patients with AD and non-AD neurodegenerative disorders [4,5,6,7]. Increasing evidence, indicates the presence of tau fragments spanning both the mid-domain and various terminal regions [10], suggesting that assays targeting specific variants of tau may be required to more fully characterize the relationship between CSF and PET tau biomarkers These studies did not examine the link between CSF tau levels and [18F]FDG PET, an important measure given evidence indicating that synaptic integrity mediates the impact of tau on cognition [11]
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