In-vivo imaging of grey and white matter neuroinflammation in Alzheimer's disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA

Abstract

Our primary aim was to compare neuroinflammation in cognitively intact control subjects and patients with Alzheimer's disease (AD) by using positron emission tomography (PET) with translocator protein 18 kDa (TSPO)-specific radioligand [(18)F]-FEPPA. [(18)F]-FEPPA PET scans were acquired on a high-resolution research tomograph in 21 patients with AD (47- 81 years) and 21 control subjects (49-82 years). They were analyzed by using a 2-tissue compartment model with arterial plasma input function. Differences in neuroinflammation, indexed as [(18)F]-FEPPA binding were compared, adjusting for differences in binding affinity class as determined by a single polymorphism in the TSPO gene (rs6971). In grey matter areas, [(18)F]-FEPPA was significantly higher in AD compared with healthy control subjects. Large increases were seen in the hippocampus, prefrontal, temporal, parietal and occipital cortex (average Cohen's d= 0.89). Voxel-based analyses confirmed significant clusters of neuroinflammation in the frontal, temporal and parietal cortex in patients with AD. In white matter, [(18)F]-FEPPA binding was elevated in the posterior limb of the internal capsule, and the cingulum bundle. Higher neuroinflammation in the parietal cortex (r= -0.7, P= 0.005), and posterior limb of the internal capsule (r= -0.8, P=0.001) was associated with poorer visuospatial function. In addition, a higher [(18)F]-FEPPA binding in the posterior limb of the internal capsule was associated with a greater impairment in language ability (r= -0.7, P=0.004). Elevated neuroinflammation can be detected in AD patients throughout the brain grey and white matter by using [(18)F]-FEPPA PET. Our results also suggest that neuroinflammation is associated with some cognitive deficits.

Figure 1.

[¹⁸F]-FEPPA total distribution volume (V_T) with partial volume error correction in participants with Alzheimer’s disease (n = 18) and cognitively intact healthy subjects (n = 21) in grey matter regions of interest, shown separately for high-affinity binders and mixed-affinity binders. (a) Across regions of interest [¹⁸F]-FEPPA V_T was 38% higher in high-affinity binders participants with Alzheimer’s disease than high-affinity binders healthy control subjects. (b) Similarly, [¹⁸F]-FEPPA V_T was 33% higher in mixed-affinity binders participants with Alzheimer’s disease than mixed-affinity binders controls. The effect sizes were large for both high-affinity binders and mixed-affinity binders (the average Cohen’s d across regions was 0.96 for high-affinity binders and 0.69 for mixed-affinity binders, Supplementary Material, Supplementary Table S1). *P ⩽ 0.05, **P ⩽ 0.01 ***P ⩽ 0.001.

Figure 2.

[¹⁸F]-FEPPA total distribution volume (V_T) in participants with Alzheimer’s disease (n = 17) and cognitively intact healthy subjects (n = 20) in the white matter regions, shown separately for high-affinity binders and mixed-affinity binders. (a) Across regions of interest, [¹⁸F]-FEPPA V_T was 37% higher in high-affinity binders participants with Alzheimer’s disease than high-affinity binders healthy control subjects. (b) [¹⁸F]-FEPPA V_T was 17% higher in mixed-affinity binders participants with Alzheimer’s disease than in mixed-affinity binders control subjects. The effect sizes were moderate to large for high-affinity binders (average Cohen’s d: 0.72), and lower for mixed-affinity binders (average Cohen’s d: 0.4) (Supplementary Material, Supplementary Table S1).

Figure 3.

Relationships between [¹⁸F]-FEPPA total distribution volume (V_T) and neuropsychological scores in participants with Alzheimer’s disease, shown separately for high-affinity binders and mixed-affinity binders. In the grey matter regions of interest, strong negative associations were seen between [¹⁸F]-FEPPA V_T in the parietal cortex and repeatable battery for the assessment of neuropsychological status visuospatial score (a), prefrontal cortex and repeatable battery for the assessment of neuropsychological status visusopatial score (b). In the white matter regions of interest, strong negative associations were seen between [¹⁸F]-FEPPA V_T in the posterior limb of internal capsule and repeatable battery for the assessment of neuropsychological status language scores (c), posterior limb of internal capsule and repeatable battery for the assessment of neuropsychological status visuospatial score (d). Repeatable battery for the assessment of neuropsychological status scores were standardized for age and gender. Data were partial volume error corrected.