Clinical heterogeneity of neuro-inflammatory PET profiles in early Alzheimer's disease

Abstract

The relationship between neuroinflammation and cognition remains uncertain in early Alzheimer's disease (AD). We performed a cross-sectional study to assess how neuroinflammation is related to cognition using TSPO PET imaging and a multi-domain neuropsychological assessment. A standard uptake value ratio (SUVR) analysis was performed to measure [¹⁸F]-DPA-714 binding using the cerebellar cortex or the whole brain as a (pseudo)reference region. Among 29 patients with early AD, the pattern of neuroinflammation was heterogeneous and exhibited no correlation with cognition at voxel-wise, regional or whole-brain level. The distribution of the SUVR values was independent of sex, APOE phenotype, early and late onset of symptoms and the presence of cerebral amyloid angiopathy. However, we were able to demonstrate a complex dissociation as some patients with similar PET pattern had opposed neuropsychological profiles while other patients with opposite PET profiles had similar neuropsychological presentation. Further studies are needed to explore how this heterogeneity impacts disease progression.

Keywords: Alzheimer; PET scan; TSPO; neuroinflammation; neuropsychology.

Figure 1

Inter-individual heterogeneity of the relationship between cognitive performances and SUVR values. (Panel A) represents the relationship between the MMS score and the whole brain SUVR. (Panel B) shows the relationship between the 7-day total recall on the FCSRT and the temporal meta-ROI SUVR. To facilitate comparisons between the distribution of cognitive scores and SUVR values, we calculated z-scores based on the present population (i.e., a null z-value corresponds to the mean of the study cohort). Each line represents one AD patient (MAB or HAB). The reference region was the CC for the whole brain SUVR (panel A) and the WB for the temporal meta-ROI (panel B). CC: cerebellar cortex; FCSRT: free and cued selective reminding test; MMS: mini-mental state examination; ROI: region of interest; SUVR: standard uptake value ratio; WB: whole brain.

Figure 2

Clinical and neuropsychological features are unrelated to neuroinflammation in early AD. Panels show the relationship between the whole brain SUVR relative to the cerebellar cortex, and sex (A), age at onset (B), APOE genotype (C), cerebrovascular co-pathology (D) and MMS score (E). In addition, panels show the relationship between the temporal meta-ROI SUVR using the whole brain as a reference and the FCSRT 20-minutes total recall (F) and FCSRT 7-day total recall (G). (Panel H) represents the relationship between the SUVR of the frontal area relative to the WB and the FAB score. HAB are represented in green circles and MAB in pink triangles. Age at diagnosis was used as proxy to classify patients as early (<65 years) or late (≥65 years) onset AD (EOAD or LOAD respectively). APOE: apolipoprotein; EOAD: early onset Alzheimer’s disease; FCSRT: free and cued selective reminding test; CAA: cerebral amyloid angiopathy; FAB: frontal assessment battery; HAB: high affinity binder; LOAD: late onset Alzheimer’s disease; MAB: mixed affinity binder; MMS: mini-mental state examination; ROI: region of interest; SUVR: standard uptake value ratio.