Alzheimer’s disease can present clinically with either the typical amnestic phenotype or with atypical phenotypes, such as logopenic progressive aphasia and posterior cortical atrophy. We have recently described longitudinal patterns of flortaucipir PET uptake and grey matter atrophy in the atypical phenotypes, demonstrating a longitudinal regional disconnect between flortaucipir accumulation and brain atrophy. However, it is unclear how these longitudinal patterns differ from typical Alzheimer’s disease, to what degree flortaucipir and atrophy mirror clinical phenotype in Alzheimer’s disease, and whether optimal longitudinal neuroimaging biomarkers would also differ across phenotypes. We aimed to address these unknowns using a cohort of 57 participants diagnosed with Alzheimer’s disease (18 with typical amnestic Alzheimer’s disease, 17 with posterior cortical atrophy and 22 with logopenic progressive aphasia) that had undergone baseline and 1-year follow-up MRI and flortaucipir PET. Typical Alzheimer’s disease participants were selected to be over 65 years old at baseline scan, while no age criterion was used for atypical Alzheimer’s disease participants. Region and voxel-level rates of tau accumulation and atrophy were assessed relative to 49 cognitively unimpaired individuals and among phenotypes. Principal component analysis was implemented to describe variability in baseline tau uptake and rates of accumulation and baseline grey matter volumes and rates of atrophy across phenotypes. The capability of the principal components to discriminate between phenotypes was assessed with logistic regression. The topography of longitudinal tau accumulation and atrophy differed across phenotypes, with key regions of tau accumulation in the frontal and temporal lobes for all phenotypes and key regions of atrophy in the occipitotemporal regions for posterior cortical atrophy, left temporal lobe for logopenic progressive aphasia and medial and lateral temporal lobe for typical Alzheimer’s disease. Principal component analysis identified patterns of variation in baseline and longitudinal measures of tau uptake and volume that were significantly different across phenotypes. Baseline tau uptake mapped better onto clinical phenotype than longitudinal tau and MRI measures. Our study suggests that optimal longitudinal neuroimaging biomarkers for future clinical treatment trials in Alzheimer’s disease are different for MRI and tau-PET and may differ across phenotypes, particularly for MRI. Baseline tau tracer retention showed the highest fidelity to clinical phenotype, supporting the important causal role of tau as a driver of clinical dysfunction in Alzheimer’s disease.

中文翻译：

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纵向神经影像生物标志物因阿尔茨海默病表型而异。

阿尔茨海默病在临床上可表现为典型的遗忘表型或非典型表型，例如 logopenic 进行性失语症和后皮质萎缩。我们最近描述了非典型表型中 flortaucipir PET 摄取和灰质萎缩的纵向模式，表明 flortaucipir 积累和脑萎缩之间存在纵向区域脱节。然而，尚不清楚这些纵向模式与典型的阿尔茨海默病有何不同，氟托西吡和萎缩在多大程度上反映了阿尔茨海默病的临床表型，以及最佳纵向神经影像生物标志物是否也会因表型而异。我们旨在通过 57 名被诊断患有阿尔茨海默病的参与者（18 名患有典型的遗忘性阿尔茨海默病，17 名患有后皮质萎缩，22 名患有 logopenic 进行性失语症），这些患者接受了基线和 1 年随访 MRI 和 flortaucipir PET。典型的阿尔茨海默病参与者在基线扫描时被选为 65 岁以上，而没有年龄标准用于非典型阿尔茨海默病参与者。相对于 49 名认知未受损的个体和表型，评估了 tau 积累和萎缩的区域和体素水平率。实施主成分分析来描述基线 tau 摄取和积累率以及基线灰质体积和不同表型的萎缩率的可变性。用逻辑回归评估主要成分区分表型的能力。纵向 tau 积累和萎缩的地形因表型而异，所有表型的额叶和颞叶的 tau 积累的关键区域和后皮质萎缩的枕颞区的萎缩的关键区域，左颞叶的 logopenic 进行性失语症和内侧和外侧颞叶用于典型的阿尔茨海默病。主成分分析确定了 tau 摄取和体积的基线和纵向测量的变化模式，这些模式在不同表型之间存在显着差异。与纵向 tau 和 MRI 测量相比，基线 tau 摄取能更好地映射到临床表型。我们的研究表明，用于阿尔茨海默病未来临床治疗试验的最佳纵向神经影像生物标志物对于 MRI 和 tau-PET 是不同的，并且可能因表型而异，尤其是对于 MRI。基线 tau 示踪剂保留显示出对临床表型的最高保真度，支持 tau 作为阿尔茨海默病临床功能障碍的驱动因素的重要因果作用。