Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

Abstract

Objective: To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).

Methods: Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.

Results: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10).

Conclusions: PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

Figure 1. Pittsburgh compound B (PiB), fluorodeoxyglucose (FDG), and histopathology in selected patients

Images are displayed in neurologic orientation and in NIH color scale as viewed by the visual raters. Patient 1 (clinical Alzheimer disease [AD]) showed diffuse cortical and striatal PiB binding (PiB-positive by consensus) and temporoparietal-predominant hypometabolism on FDG (FDG-AD by consensus). Autopsy was consistent with high-likelihood AD: amyloid plaques in temporal cortex are illustrated on staining with thioflavin-S, a dye that is structurally related to PiB. Patient 2 (clinical frontotemporal lobar degeneration [FTLD]–amyotrophic lateral sclerosis [ALS]) was PiB-negative by consensus, with FDG demonstrating frontal-predominant hypometabolism (consensus FDG-FTLD). Pathologic diagnosis was FTLD-TDP with motor neuron disease: characteristic TDP-43 cytoplasmic inclusions are demonstrated in anterior cingulate neurons by immunohistochemistry (arrows). Early Aβ pathology in the form of diffuse plaques was also found (insert: Aβ immunohistochemistry in occipital cortex). Patient 3 (clinical AD) was PiB-positive by consensus, but FDG showed frontal hypometabolism suggestive of FTLD (FDG-FTLD by consensus). Autopsy revealed Consortium to Establish a Registry for Alzheimer's Disease frequent neuritic plaques (shown: Aβ immunohistochemistry in middle frontal gyrus) and Braak stage 6 neurofibrillary pathology (insert: tau immunohistochemistry in posterior cingulate cortex) consistent with high-likelihood AD.

Figure 2. Pittsburgh compound B (PiB) and fluorodeoxyglucose (FDG) scatterplots by clinical diagnosis

PiB index (measure of cortical PiB binding) is displayed by (A) visual read or (B) FDG majority classification (best of 3 between 2 visual ratings and quantitative classification). FDG Z difference (difference in Z scores between lowest frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) regions of interest) is displayed by (C) visual read or (D) majority PiB classification (best of 3 between 2 visual ratings and quantitative classification). Horizontal solid lines represent quantitative thresholds for PiB positivity (PiB index ≥ 1.20) or FDG-AD classification (FDG Z difference >0); hatched lines represent group median values.