Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome

Abstract

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.

Evaluating the Effect of Alzheimer's Disease‐Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy

“…We combined CSF, plasma, and PiB PET imaging to divide the groups into AD positive and negative. Both CSF and plasma biomarkers have good sensitivity and specificity to detect AD pathology, 29,32,53 and plasma p-tau217 performs similar to CSF AD biomarkers and PiB PET imaging. 53 We acknowledge that we are introducing a new source of variability by using different types of biomarkers, but this approach allowed us to increase the sample size and potentiate the statistical power.…”

“…Abeta1-42, phosphorylated tau (p-tau181) and total tau (t-tau) in cerebrospinal fluid (CSF), plasma phosphorylated tau 217 (p-tau217), and PET scans with 11-labeled Pittsburgh Compound B ( 11 C-PiB) have been suggested as reliable biomarkers of AD pathology. [29][30][31][32] The aim of this study was to evaluate the effect of AD-related biomarker changes on clinical features, brain atrophy, and functional connectivity of patients with clinical diagnosis of CBS and PSP. We expected an AD-like phenotype in patients with CBS/PSP that are positive for AD-related biomarker change (ie, cognitive impairment and relatively spared motor functions, atrophy in AD signature areas, and alteration in the DMN connectivity) compared to CBS/PSP without AD.…”

Differential Synaptic Loss in β‐Amyloid Positive Versus β‐Amyloid Negative Corticobasal Syndrome

“…52 Another explanation for the differential patterns of synaptic loss could be the likely heterogeneous distribution and progression patterns of tau pathology in CBS-AD versus CBS-CBD/PSP. Although current blood biomarkers such as pTau217 levels or glial fibrillary acidic protein provide high specificity in differentiating between AD and non-AD dementias, 8,53 they do not reveal changes in specific pathological pathways or regions, but rather complement and enrich PET insights.…”

Relationships between PET and blood plasma biomarkers in corticobasal syndrome

“…A few studies have reported abnormal levels of GFAP and NfL in plasma or CSF in CBS, 45 , 46 , 47 , 48 , 49 and one study has shown that a plasma p‐tau measure can identify Aβ positivity within CBS. 50 However, it is unknown whether GFAP, NfL, or Aβ42/40 differ according to Aβ status in CBS.…”