title: 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 Mini-Mental 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom; and.
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pasqualetti
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom; and.
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Campus, London, United Kingdom Department of Nuclear Medicine, Aarhus University, Denmark.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Campus, London, United Kingdom MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom; and paul.edison@imperial.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Edison
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D011485:Protein Binding; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: Alzheimer’s disease; MCI; PET study; TSPO; cognitive function