Vento, Stephanie

ImportancePlasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)–associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.ObjectiveTo validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.Design, Setting, and ParticipantsThis multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.Main Outcome and MeasuresPlasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.ResultsOf 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005).Conclusions and RelevanceIn this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

AbstractBackgroundThere is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [18F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA).Method38 participants underwent amyloid and [18F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [18F]PI‐2620 was administered. [18F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS.ResultPatients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p < 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, rs < 0.44, p > 0.05 uncorrected).Conclusion[18F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.

AbstractBackgroundIn preparation for treatment trials in frontotemporal dementia (FTD), sensitive assessments to detect early clinical deficits and track longitudinal changes are needed. Remote digital data collection using smartphones may improve sensitivity to detect and follow abnormalities by allowing novel methods of data capture and more frequent assessments. Furthermore, remote evaluations can reduce patient and staff burden. Despite these benefits, little is known about the reliability and validity of self‐administered cognitive testing completed on smartphones.MethodWe investigated self‐administered smartphone cognitive tests from the ALLFTD Mobile App in a mixed sample of 45 participants, including 10 functionally intact older adults, 24 participants from families harboring pathogenic FTD mutations (asymptomatic n=14; mildly symptomatic n=10;), and 11 symptomatic FTD‐spectrum participants. A subset (n=15) was missing CDR®+NACC‐FTLD data but consensus diagnoses were available. Participants were asked to complete five tests that were repeated three times over eight days. Tests included versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive spatial working memory test. Reliability was assessed using split‐half reliability (first testing session, 100 simulations) and intraclass correlations (ICC) across the three testing sessions. Linear models were fitted to evaluate the association of test performance with age and disease severity (CDR®+NACC‐FTLD Global and Box Scores), covarying for sex and education level. Models evaluating age associations excluded symptomatic participants.ResultParticipants completed 72.4% of available instruments. Split‐half reliability (range: 0.76 to 0.97) and ICCs (0.70 to 0.92) suggested adequate‐to‐excellent internal consistency and test‐retest reliability. Across the five tests, negative associations were observed with CDR®+NACC‐FTLD Box Scores (ßs = ‐0.24 to ‐0.77), and in clinically asymptomatic individuals, negative associations were observed with age (ßs = ‐0.43 to ‐0.88). Performance on all measures was worse in symptomatic participants compared to asymptomatic (p‐values<.05). Mildly symptomatic cases (CDR®+NACC‐FTLD=0.5) performed worse on Stroop, Flanker, and spatial working memory than asymptomatic participants (p‐values<.03). Flanker and Stroop tasks consistently showed the strongest reliability and validity findings.ConclusionSmartphone adaptations of common neuropsychological tests produced promising preliminary results. Strong associations with disease severity and age suggest these metrics may be valid for detecting clinically relevant cognitive changes, even in mildly symptomatic FTD.