In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease

Abstract

Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.

Keywords: Alzheimer’s disease; mild cognitive impairment; neuroinflammation; positron emission tomography.

Figure 1

Alzheimer’s disease (AD) patients (filled circle) had greater uptake of ¹¹C-PBR28 than healthy controls (open circle) in target, but not background, brain regions. Concentration of radioactivity after injection of ¹¹C-PBR28, given as standardized uptake value (SUV) and corrected for partial volume effect, for inferior parietal lobule (A) and cerebellum (B) are shown. SUV = (concentration of activity per g tissue / injected activity) × g body weight. Data not adjusted for TSPO genotype. Data given as mean ± SD.

Figure 2

¹¹C-PBR28 binding was related to early age of onset in Alzheimer’s disease (AD). (A) Early-onset (EOAD) patients had greater binding than late-onset patients (LOAD). Bar graphs show values for ¹¹C-PBR28 binding (V_T / f_P) in inferior parietal lobule, corrected for partial volume effect. ¹¹C-PBR28 binding values were adjusted for TSPO genotype, Mini-Mental State Examination score, and duration of symptoms. Error bars denote SD. (B) ¹¹C-PBR28 binding negatively correlated with age of symptom onset in patients with Alzheimer’s disease and MCI. ¹¹C-PBR28 binding values from inferior parietal lobule, corrected for partial volume effect, and age of onset were adjusted for TSPO genotype, Mini-Mental State Examination score, and duration of symptoms before correlative analysis. Standardized adjusted values are shown. Correlation coefficient (r) = −0.438, P = 0.017.