Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

Abstract

Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects. To translate the findings of neuroinflammation studies to the entire population, it is crucial to establish the influence of TSPO genotypes on AD. Here, we investigated whether different TSPO genotypes influence cognitive function, amyloid load, and disease progression over time. Methods: We evaluated 798 subjects (225 control, 388 with mild cognitive impairment [MCI], and 185 with AD) from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during follow-up. All subjects were screened for TSPO genotype and underwent detailed clinical and neuropsychologic assessments yearly for 4 y. Of the 798 subjects, 255 also had T1-and T2-weighted MR imaging and amyloid PET with 11 C-Pittsburgh compound B or 18 F-florbetapir. Results: We demonstrated that all TSPO binding groups (HAB, MAB, and LAB) have same level of amyloid load in AD and MCI subjects. We also demonstrated that the prevalence is 50.3% for HAB, 41.2% for MAB, and 8.5% for LAB, without a statistical difference among the AD, MCI, and control groups. During longitudinal follow-up, the mean change in neuropsychometric test scores on the MiniMental State Examination, the cognitive and modified Alzheimer Disease Assessment Scales (ADASs), and the Geriatric Depression Scale over time were similar in AD and MCI subjects among the 3 TSPO binding groups. Analysis of the covariates showed that diagnostic group (control, MCI, AD), apolipoprotein E4 status, and sex had a significant effect on decline on the modified Alzheimer Disease Assessment Scale (.3 points of the scale), but age and TSPO genotype did not. Conclusion: This study suggests that information obtained from evaluating a subgroup of AD or MCI subject using second-generation TSPO tracers can be translated to the entire AD and MCI population. Thus, we can study fewer AD subjects in evaluating new antineuroinflammatory and antimicroglial agents in intervention studies and in observational studies evaluating the role of neuroinflammation.

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…To date, the significance of the rs6971 polymorphism is undetermined (58). Knowledge of the binding phenotype is critical for studies comparing baseline TSPO levels between patients and healthy controls as previously demonstrated (35,59). As expected in our healthy control cohort, baseline V T values were 50% higher in HABs than MABs, but interestingly, the TSPO response to LPS (%Δ V T ) was independent of the subjects' binding affinity.…”

Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease

“…In the latter study, patients had a comparable MMSE as the AD subjects in the present study (25 ± 3). However, as in all these in these studies rs6971 TSPO polymorphism TSPO genotyping was not performed Although it was discussed whether results with secondgeneration TSPO tracers, which depends on the TSPO genotype coded by the rs6971 singlenucleotide polymorphism, would be responsible for the lack of TSPO expression difference between controls and the AD population [33],, the high variance induced by this grouping of low-, medium and high-binders may which can explain the negative results obtained in these results. our study adds further data that activated microglia may not be present to a significant amount in early AD patients in vivo.…”

The impact of the rs6971 polymorphism in TSPO for quantification and study design

“…A recent study in mild cognitive impairment patients and Alzheimer's disease also found no difference between genotypes in amyloid load or disease progression [24]. Under the assumption, therefore, the rs6971 genotype does not affect the underlying disease process, this allows for one of the following approaches:…”