18F-MK-6240 PET for early and late detection of neurofibrillary tangles

Abstract

Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer’s disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I–II), in contrast to ∼80–90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer’s disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90–110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer’s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85–100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV–VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V–VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer’s disease in the near future.

Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease

“…Additional pre-processing corrections were performed as described elsewhere 35 . PET images were meninges and skull stripped, linearly and non-linearly registered to the ADNI template space and then spatially smoothed to achieve a nal resolution of 8 mm FWHM 36 . The inferior cerebellum and whole cerebellum gray matter were used as the reference regions for [ 18 F]MK6240 and [ 18 F]AZD4694, respectively.…”

The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

“…In contrast, tau pathology in AD is characterized by a more readily apparent pattern of spread, originating in the entorhinal cortex with additional involvement of neocortical regions in the temporal lobe, association cortices, and finally the primary sensory cortices [35]. Despite inter-individual variations, this well-defined anatomical progression has been systematized in neuropathological staging schemes such as those proposed by Braak [36] or Delacourte [37], and recapitulated in PET imaging studies with recently developed tau PET tracers [38][39][40]. While there is a general trend for more advanced clinical disease to be associated with higher tau stages, a range of tau stages is generally observed at each clinical stage, possibly reflecting a role of co-pathologies and/or cognitive reserve [7].…”

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

“…The pathological findings of extracellular deposits of amyloid-β plaques and intraneuronal neurofibrillary tangles containing aggregated tau protein are observed as diagnostic markers in the brains of patients with Alzheimer's disease [162,163]. PET imaging with radioligands for amyloid-β or tau protein, such as 11 C-PiB and 18 F-MK-6240, respectively, is already being used to diagnose Alzheimer's disease in living patients [164][165][166], replacing pathological diagnosis.…”