Distinct associations between tau PET and cognitive impairment across brain regions and cognitive domains in Alzheimer’s disease
Authors: Rathore Saima , Tronchin Giulia , Higgins Ixavier A. , Wessels Alette M , Iaccarino Leonardo , Sims John R. , Mintun Mark A. , Shcherbinin Sergey 
Published: December 2023

Background

Compared with biofluid‐biomarkers, tau‐PET shows stronger association with cognitive impairment (Ossenkoppele,R‐2021) and decline, and better detects Alzheimer’s disease (AD) pathology (Coomans,EM‐2022; Smith,R‐2022). Conventionally, tau‐cognition relationship has been evaluated between global cortical tau‐PET and composite cognitive scores. However, tau‐PET binding patterns are heterogenous, with regional binding showing strong correlations with domain‐specific cognitive performance and decline. The goal of this study was to evaluate domain‐specific patterns of tau‐PET at baseline and in change‐from‐baseline (CFB) in symptomatic AD patients.

Method

Amyloid‐positive participants (n = 172) with a clinical diagnosis of mild‐cognitive‐impairment (n = 97) or dementia due to AD (n = 76) and amyloid‐negative healthy‐controls (n = 68) underwent a 18Flortaucipir tau‐PET and neuropsychological testing (AV1451‐A05:NCT02016560) at baseline and 18months. Observed cognitive scores in impaired patients were normalized to age‐adjusted outcomes in healthy‐controls at baseline and 18months (Ossenkoppele,R‐2015). These scores were subsequently averaged within the episodic‐memory, semantic‐memory, language, visuospatial, and executive function cognitive domains (Malpetti,M‐2022). Standardized uptake value ratio (SUVr) in automated‐anatomical‐labelling regions (Tzourio‐Mazoyer,M‐2002) and AD‐specific region (MUBADA; Devous,M‐2017) was calculated in reference to cerebellum‐crus. The CFB (18months‐baseline) in SUVr and domain‐specific sub‐scores were calculated for all participants. Correlations between global SUVr versus composite cognitive score and regional SUVr versus domain‐specific scores at baseline and CFB were calculated.

Result

Differential cross‐sectional tau‐PET patterns showed significant negative associations with domain‐specific cognitive performance (Fig.1A). When evaluated longitudinally, higher global CFB in tau‐PET SUVr showed no‐to‐modest correlation with cognitive decline (Fig.2: ADAS‐Cog11 = 0.012, FAQ = ‐0.015, MMSE = ‐0.210, CDR‐SB = 0.014), however, heterogeneous associations were observed at the regional‐ and voxel‐level (Fig.1B,Fig.3), ranging from maximum of r = ‐0.45 (p<0.001; frontal‐inferior and visuospatial) to minimum of r = ‐0.002 (p<0.1; lingual and episodic). Increase in tau‐PET signal was associated with greater cognitive decline (i.e. visuospatial function: predominantly frontal; executive function: parietal and prefrontal; semantic‐memory: superior temporal region). An extensive and asymmetric tau‐PET pattern (L>R) in frontal and occipital regions was related to language.

Conclusion

We found associations between patterns of tau accumulation and domain‐specific cognitive decline in MCI and AD dementia. After validations using larger datasets, these relationships can supplement widely used associations between global tau‐PET and composite cognitive scores and, therefore, enhance tau PET‐guided and patient‐centered staging, prognosis, and response assessment.