Influence of common reference regions on regional tau patterns in cross-sectional and longitudinal [18F]-AV-1451 PET data

Abstract

Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer’s disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions ( e.g ., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A +) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A +) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A +, and MCI A + groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

APOE effects on regional tau in preclinical Alzheimer’s disease

“…One difference between the A4/LEARN and ADNI results was that the overall magnitude of the total e4 effect on regional tau in MTL and neocortical regions was 2–3 times stronger in ADNI (increase of 0.039–0.152 SUVR per allele) than A4/LEARN (increase in 0.019–0.073 SUVR per allele). The stronger total effects in ADNI can be explained by the inclusion of Aβ+ MCI in the ADNI analyses, who are known to have a greater range of tau PET values than Aβ+ CU [ 27 , 50 ]. Despite differing magnitudes, the fact that the proportion of e4 direct and indirect effects remained consistent in both cohorts provides further support for an association between e4 on tau during the pre-dementia stages of disease.…”

Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi‐site cohort

“…The MTL is crucial for encoding new information into long‐term memory, 39 a necessary process for improved performance on repeated task exposure, and tau deposition in this region is associated with poorer memory performance even among CU 40,41 . In addition to the initial manifestation of tau in the MTL, IT and IP also show early tau accumulation 42 and are regions with relatively high rates of annual tau accumulation among A+ CU and A+ mild cognitive impairment 43 . The association between practice effects and tau burden was also observed when examining practice effects on individual tests of BPSO and FNAME, but not OCL.…”

What’s the cut-point?: a systematic investigation of tau PET thresholding methods

“…For example, use of PVC, intensity normalization method, and acquisition parameters such as spatial resolution and timing of acquisition likely also influences outcomes [ 45 – 48 ]. These were not investigated in our study in order for parsimony in comparisons, but their effect on cut-points should be systematically assessed in future studies given prior research demonstrating the importance of these factors [ 49 – 51 ]. Additionally, non-flortaucipir tau PET tracers were not investigated; comparison of these tracers and use of a centiloid-based analytic approach may improve standardization across studies with different tau PET tracers.…”