Imaging in-vivo tau pathology in Alzheimer’s disease with THK5317 PET in a multimodal paradigm

Abstract

PurposeThe aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [18F]THK5317 (also known as (S)-[18F]THK5117) retention in different stages of Alzheimer’s disease; and study any associations with markers of hypometabolism and amyloid-beta deposition.MethodsThirty-three individuals were enrolled, including nine patients with Alzheimer’s disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer’s disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [18F]THK5317, [11C] Pittsburgh compound B ([11C]PIB), and [18F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [11C]PIB-positive (n = 11) and MCI [11C]PIB-negative (n = 2) groups.ResultsTest-retest variability for [18F]THK5317-PET was very low (1.17–3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [11C]PIB-positive) and dementia-stage Alzheimer’s disease had significantly higher [18F]THK5317 retention than healthy controls (p = 0.002 and p = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [18F]THK5317 retention and [18F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [18F]THK5317 and [11C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [11C]PIB but high [18F]THK5317 retentions with a different regional distribution from that in Alzheimer’s disease patients.ConclusionsThe tau-specific PET tracer [18F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3363-z) contains supplementary material, which is available to authorized users.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia

“…In brief, binary tau pathology maps were created for every patient at baseline and follow-up, based on the 90% confidence interval of tau distribution in healthy controls. 12 The subtraction of the baseline map from the follow-up map for each patient generated individual 'tau spreading indices'. Positive indices would illustrate that tau pathology in the cortex was overall spreading/ expanding in an individual patient, and negative indices would illustrate an overall decrease of tau pathology distribution.…”

“…The procedures for clinical assessment and patient recruitment are detailed elsewhere. 12 At baseline, six patients were diagnosed with AD dementia (that is, probable AD and a positive [ 11 C]PIB PET scan 19,20 ), and 10 with prodromal AD (that is, amnestic multi-domain mild cognitive impairment and a positive [ 11 C]PIB PET scan 20,21 During the follow-up interval, four of the patients with prodromal AD developed AD dementia.…”

“…12 Our choice of ROIs was based on previously published crosssectional data on tau PET imaging-12,25 parahippocampal gyrus, fusiform gyrus, middle and inferior temporal gyrus, posterior cingulate cortex and orbitofrontal cortex for patients with AD, and putamen for patients with CBS. A composite isocortical ROI was created for quantifying [ 11 C]PIB retention.…”

“…THK5317 [(S)-THK5117], a well characterised tau-specific tracer, [9][10][11] showed high retention in patients with AD with a regional pattern matching that of the distribution of tau pathology described by post-mortem studies. 12 Cross-sectionally, high load of tau pathology, as measured with THK5317 PET, was associated with hypometabolism in restricted brain regions, 12 while more extensive associations were reported in patients with substantially greater cognitive impairment, as measured with another tau tracer. [13][14][15] Studies with a longitudinal, multimodal design will shed light on the spreading of tau pathology in AD, and allow investigating whether the temporal trajectories of tau aggregation and hypometabolism are closely associated, or whether this association becomes closer with disease progression.…”

“…Case series have revealed high regional retention of the tau tracers in patients with clinical diagnoses of corticobasal syndrome (CBS), but the regional distribution in these cases was different from that in patients with AD. 12,[16][17][18] The understanding of the in vivo propagation of the pathology in the different degenerative tauopathies, however, remains elusive.…”