Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders

Abstract

The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known. OBJECTIVE To examine the novel tau PET tracer RO948 F 18 ([ 18 F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders. DESIGN, SETTING, AND PARTICIPANTS In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer [ 18 F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [ 18 F]RO948 and flortaucipir F 18 ([ 18 F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA). EXPOSURES [ 18 F]RO948 (all patients) and [ 18 F]flortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratio [Aβ42/Aβ40], and Aβ42/p-tau181 ratio). MAIN OUTCOMES AND MEASURES Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between [ 18 F]RO948 and [ 18 F]flortaucipir. RESULTS Diagnostic groups among the 613 participants included cognitively unimpaired (mean [SD] age, 65.8 [12.1] years; 117 men [46%]), mild cognitive impairment (age, 70.8 [8.3] years; 82 men [53%]), AD dementia (age, 73.5 [6.7] years; 57 men [57%]), and non-AD disorders (age, 70.5 [8.6] years; 41 men [40%]). Retention of [ 18 F]RO948 was higher in AD dementia compared with all other diagnostic groups. [ 18 F]RO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using [ 18 F]RO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of [ 18 F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temp...

Plasma Neurofilament Light: A Marker of Neurodegeneration in Mild Behavioral Impairment

“…Use of the MBI-C would also allow appropriate examination in pre-dementia populations of MBI domain specific associations with NfL. The MBI-C is being incorporated into some cohorts (COMPASS-ND Canada [51], PROTECT-UK [12], CatchCog -Netherlands [52], BHR -USA [53], CobTek -France [54], Czech Brain Aging Study-Czech Republic [55], Swedish BioFINDER2 [56]), although data will only emerge slowly. In the meantime, our best approach to explore the association of pre-dementia NPS and dementia biomarkers is to use existing datasets to determine if there are signals, which can be explored further.…”

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

“…According to the NIA-AA diagnostic criteria [24,25] and a research framework [26], we only included Aβ+ AD dementia (n = 430) and MCI (n = 381) patients (determined using PET and/or CSF, see previous work for details [5,6]). A total of 370 participants were diagnosed with a non-AD neurodegenerative disorder according to formal diagnostic criteria [5,6], including Parkinson's disease (n = 123), progressive supranuclear palsy (n = 58), dementia with Lewy bodies (n = 51), behavioral variant frontotemporal dementia (n = 50), corticobasal syndrome (n = 27), the semantic (n = 19) and non-fluent (n = 17) variants of primary progressive aphasia, multiple system atrophy (n = 12), and dementia not otherwise specified (n = 14). CU individuals (n = 1157) performed within normal limits on neuropsychological testing and had no significant neurological or psychiatric illnesses.…”

“…However, several hurdles need to be overcome in order to accelerate the transition of tau PET from an investigational technique to a diagnostic biomarker. One of these challenges is the observation of negative tau PET scans in individuals suspected of having symptomatic AD [4][5][6][7] or, conversely, positive tau PET scans in individuals suspected for a non-AD neurodegenerative disorder like frontotemporal lobar degeneration (behavioral or language phenotype) or Parkinsonian disorders [5,6,8,9]. This can potentially hamper the interpretation of the tau PET result or lead to suboptimal patient selection for a clinical tau PET scan.…”

Advancing medicine for Alzheimer’s disease: A plasma neural exosome platform

“…5 The risk of progression to AD can be accurately determined during the preclinical period by bioimaging methods and quantification of specific proteins in blood and cerebrospinal fluid. 6,7 Despite this diagnostically and prognostically actionable base of knowledge as well as a long preclinical period perfectly suited to preventative medicine, no effective means of prevention or therapy have emerged. Notably, many attempts at suppressing production of primary neuropathic proteins or their deposition on and in neurons all have failed.…”