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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.

BackgroundReduced dopamine transporter (DAT) binding in the striatum has been reported in patients with progressive supranuclear palsy (PSP). However, the relationship between striatal dopaminergic lesions and the disease severity of PSP remains to be explored.ObjectiveTo investigate the contributions of striatal dopaminergic lesions to the disease severity of PSP.MethodsOne hundred patients with clinically diagnosed PSP were consecutively enrolled in this study. The disease severity was systemically assessed using the PSP rating scale (PSPrs), and the dopaminergic lesions were assessed using the 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane positron emission tomography (11C-CFT PET) imaging. To explore the correlations between striatal DAT bindings and the disease severity, both the region-wise and voxel-wise analysis were adopted. Partial correlations and multiple linear regressions were performed to investigate the contribution of striatal dopaminergic lesions to the disease severity in PSP.ResultsSixty-three patients of PSP with Richardson’s syndrome (PSP-RS) and 37 patients with PSP-non-RS were finally included. The disease severity in PSP-RS was much heavier than that in the PSP-non-RS. The DAT bindings in the caudate and anterior putamen correlated significantly with the PSPrs total scores, mainly in the domains of history, mentation, bulbar, and ocular motor symptoms. The striatal DAT bindings (caudate) contributed significantly to the disease severity of PSP, independent of the motor, cognition, emotion and behavioral dysfunctions.ConclusionOur study highlighted the independent contribution of striatal dopaminergic lesions to the disease severity in PSP.

BackgroundObjective motor ratings and subjective motor complaints are both widely used in Parkinson’s disease (PD). However, the objective basis to the self-perceived mobility quality is still not well elucidated.PurposesWe aimed to figure out the relevancy between the UPDRS motor scores and PDQ39 mobility sub-scores, and further explore whether physician-assessed motor dysfunctions and patients-reported mobility deficits have some shared mechanisms.Methods49 patients with PD who completed the PDQ39 scale were retrospectively included. The relevancy between mobility quality and UPDRS scores was assessed, as well as the related presynaptic dopaminergic binding (11C-CFT) and glucose metabolism (18F-FDG) in this dual-tracer PET imaging study.ResultsModest correlation was found between UPDRS motor score and the PDQ39 mobility sub-score (r = 0.440, p = 0.002). No correlation was found between PDQ39 mobility SI and the dopaminergic lesions in putamen; however, the strict correlation was found with the UPDRS motor scores. In terms of global PD related pattern (PDRP) scores, the two motor scores both correlated strictly. In the further regional metabolism exploration, cerebellum correlated positively with PDQ39 mobility sub-scores, and the frontal and parietal regions mainly correlated negatively with the motor quality scores.ConclusionUPDRS motor scores and PDQ39 mobility scores were only modestly correlated. The mechanisms involved under mobility quality were beyond dopaminergic deficiency, including motor related cerebellum hyper-metabolism and non-motor related frontal hypo-metabolism. Conclusively, the self-reported mobility experience may have the neurophysiological basis related to both motor and non-motor manifestations in PD.