Staging tau pathology with tau PET in Alzheimer’s disease: a longitudinal study

Abstract

A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer’s Disease Neuropathology

“…However, NFT pathology also occurs in normal aging, as described in the previous section. For this reason, it could be questioned if Braak staging provides a valid prediction for AD, and also for NDAN [ 75, 76 ]. Especially during the slow-developing pathology of AD, morphological changes in the brain do not always directly translate into behavioral differences.…”

Recent Updates on PET Imaging in Neurodegenerative Diseases

“…사후뇌조직에서 평가한 알츠하이머병의 타우병리 Braak stage ( 48 )는 타우 PET 영상으로 인체에서 재현되었다( 49 50 51 52 ). 질병 초기 타우병리는 내측 측두엽(transentorhinal/entorhinal region)에 국한되어 있으며(Braak stage I, II), 이후 외측 측두엽으로 타우병리가 확장되면서 대부분의 내측 측두엽에 타우병리가 분포하며(Braak stage III), 외측 측두엽과 쐐기소엽에서도 타우의 집적이 관찰된다(Braak stage IV), 진행된 알츠하이머병 환자에서는 대부분의 대뇌신피질에서(Braak stage V, VI), 타우병리에 의한 방사능 집적을 관찰할 수 있다.…”

“…한편, 진단 시 타우 PET 영상에서 타우집적의 정도는 환자의 예후와 관련성을 보이고 있어 예후 예측 바이오 마커로 사용될 수 있다( 58 59 ). 경도인지장애 환자를 대상으로 한 추적연구에서 진단 시 타우 PET 영상에서 Braak stage IV 이상의 진행된 타우병리를 보인 환자군의 경우, 그보다 낮은 정도의 타우병리를 보이는 환자군과 비교하여 인지저하와 기능감소가 더 빠르게 진행되는 것을 관찰하였고, 이 결과를 바탕으로 타우 PET 환자의 예후추적에 유용한 바이오마커임을 제시하였다( 51 ). 또한, 여러 연구에서 인지적 정상 노인 또는 아밀로이드 PET 음성 소견을 보이는 경도인지장애 환자의 추적검사에서도 아밀로이드병리의 유무와 함께 타우병리의 유무가 환자의 예후와 연관성을 보고하고 있다( 51 54 55 58 ).…”

Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET

“…The ROIs vulnerable to AD, in this sense, include the entorhinal, amygdala, parahippocampal, fusiform, inferior temporal, and middle temporal regions [23,24]. Likewise, some studies combined AD-vulnerable ROIs for the quantification and classified tau in multi-stages rather than merely rating it as positive/negative [9,25,26]. However, with accumulated evidence of the various spatiotemporal tau patterns and trajectories, a simple region-specific quantification of tau PET can be considered to be less effective [11][12][13][14][15][16][17][18][19][20].…”