Chuantao Zuo

Background: Tau pathology in Alzheimer’s disease (AD) is heterogeneous, but the significance of hemispheric tau asymmetry remains unclear. We aimed to identify tau laterality subtypes and assess associations with cognitive decline, tau accumulation, amyloid-β (Aβ), and cortical thickness. Methods: We included 393 Aβ-positive and tau-positive participants from the Shanghai Memory Study (SMS; discovery, n=212) and Alzheimer’s Disease Neuroimaging Initiative (ADNI; validation, n=181). Participants underwent Aβ PET, tau PET, T1-weighted MRI, and neuropsychological assessment. Laterality indices for tau, Aβ, and cortical thickness were calculated across 40 paired regions. Tau subtypes were identified using unsupervised k-means consensus clustering. Linear mixed-effects models assessed cognitive trajectories adjusted for age, sex, education, and baseline tau burden. Follow-up tau PET in SMS assessed longitudinal tau accumulation. Propensity score matching further accounted for baseline tau burden. Findings: In SMS, clustering identified tau-symmetric (72.2%) and tau-asymmetric (27.8%) subtypes. The asymmetric subtype showed faster MoCA decline (β=-1.30, p<0.001), with greater deterioration in executive, language, and visuospatial domains. In the follow-up PET subset, this subtype showed faster tau accumulation (β=0.091, p<0.001), whereas tau laterality remained stable. Global tau laterality was positively associated with Aβ laterality (β=0.676, p<0.001) and inversely associated with cortical thickness laterality (β=-2.020, p<0.001). Findings were replicated in ADNI and remained robust after matching. Interpretation: Hemispheric tau asymmetry is a common and relatively stable feature of AD heterogeneity, associated with faster tau accumulation and accelerated cognitive decline beyond baseline tau burden. Asymmetric tau distribution may have potential value for prognostic stratification and individualized management.

The 2024 revised criteria introduced an integrated framework for staging Alzheimer disease (AD) across biological and clinical dimensions. However, how this criterion characterizes clinical and biological features in populations outside the original development setting, particularly in non-Western and specialized clinic settings, remains insufficiently described. We consecutively enrolled 1,214 memory clinic participants who underwent both amyloid-PET and tau-PET imaging. Among amyloid-positive (A+) individuals, clinical stages (0-6) and biological stages (A-D) were assigned according to the 2024 criteria. Participants were classified as typical (concordant stages), susceptible (clinical > biological), or resilient (clinical < biological). Plasma p-tau217 was measured in 379 A+ participants. Associations were examined using generalized linear models adjusted for relevant covariates, with false discovery rate correction for multiple comparisons. Among the 1,214 participants, 818 were amyloid positive, comprising 412 (50.4%) typical, 330 (40.3%) susceptible, and 76 (9.3%) resilient individuals. Plasma p-tau217 increased progressively across advancing tau PET stages (p for trend q = 0.029) and stage C (0.95 pg/mL, q = 0.013). Compared with the typical group, resilient individuals demonstrated superior cognitive performance (e.g., Mini-Mental State Examination [MMSE]: β = 8.56, q < 0.001), higher educational attainment (>9 years: 74.1% vs 45.1%, q = 0.020), and greater AD-signature regional cortical thickness (t = 3.033, q = 0.005) and volume (t = 3.209, q = 0.003). Conversely, susceptible individuals exhibited inferior cognitive scores (e.g., MMSE: β = -8.29, q < 0.001), reduced cortical thickness (t = -2.872, q = 0.005), and volume (t = -2.751, q = 0.007) in AD-signature regions and a numerically higher burden of vascular risk factors. In a large cohort from a specialized tertiary memory clinic, clinical-biological stage discordance under the 2024 AD criteria was common among amyloid-positive individuals. Distinct cognitive, educational, biomarker, and neuroanatomic profiles characterized susceptible, typical, and resilient subgroups. In addition, plasma p-tau217 showed a stepwise increase across tau PET stages, supporting its utility as a blood-based marker of tau pathology severity. These findings support the clinical relevance of the revised staging framework and may inform future refinements of AD diagnostic guidelines. This study provides Class II evidence that the 2024 revised biological and clinical criteria for AD demonstrate clinical utility in a Chinese cohort from a specialized tertiary memory clinic.

Background: Behavioral variant of frontotemporal dementia (bvFTD) often presents with parkinsonism. Our study aimed to characterize the dopaminergic deficit pattern in bvFTD-parkinsonism (bvFTD-P) using dopamine transporter (DAT) positron emission tomography (PET) and to assess its potential value in differentiating bvFTD-P from progressive supranuclear palsy (PSP), multiple system atrophy–parkinsonism (MSA-P), and Parkinson disease (PD). Methods: A total of 30 bvFTD-P patients underwent ¹¹ C-CFT or ¹⁸ F-FP-CIT PET and were compared with 71 patients with PSP, 41 with MSA-P, 61 with PD, and 43 healthy controls (HC). DAT binding values in the caudate, anterior putamen, and posterior putamen, as well as caudate/anterior putamen (C/AP) and caudate/posterior putamen (C/PP) ratios, were analyzed with generalized linear models. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic accuracy of DAT binding values and ratios. Results: BvFTD-P patients exhibited significantly reduced DAT binding in the caudate, anterior putamen, and posterior putamen compared with HC (all P 18 F-FP-CIT cohort. ROC analysis demonstrated that the C/PP ratio provided superior discriminatory performance between bvFTD-P and HC or other parkinsonian syndromes than absolute binding values. Furthermore, lateralization of striatal DAT reduction corresponded to the side of predominant motor symptoms. Conclusions: The caudate-predominant pattern of striatal dopaminergic deficit in bvFTD-P may serve as a useful imaging biomarker for differentiating it from PSP, MSA-P, and PD.

Parkinson’s disease (PD) exhibits a characteristic posterior-to-anterior gradient of striatal dopamine loss, yet the underlying upstream mechanisms remain unclear. We combined in vivo ¹⁸F-FPCIT dopamine transporter (DaT) PET/MRI, quantitative susceptibility mapping, and diffusion MRI tractography in 48 PD patients and 10 healthy controls to test whether substantia nigra pars compacta (SNc) iron and microstructural disruption mediate posterior putaminal vulnerability. PD patients showed marked posterior putamen (pPut) DaT reduction (~60%) and elevated SNc iron. SNc iron negatively correlated with striatal DaT availability, and nigrostriatal pathways to the pPut exhibited higher axial diffusivity. Serial mediation analyses demonstrated that SNc iron indirectly impaired striatal DaT function via reduced SNc DaT binding. Putaminal DaT-SBR robustly discriminated PD from controls (AUC 0.93–0.96), exceeding caudate performance. Transgenic and α-synuclein preformed fibril mouse models provided qualitative anatomical support. These findings identify SNc iron–related degeneration as a key driver of posterior striatal vulnerability in PD.

The proposed body-first and brain-first Parkinson's disease (PD) subtypes are classified based on the initial localization of α-synuclein inclusions. Emerging evidence indicates the copathology of α-synuclein and tau in PD. However, the topographical pattern of tau deposition and its difference between these two phenotypes remain unclear. This study aimed to describe the tau deposits via ¹⁸F-Florzolotau PET/CT imaging in PD patients with the putative body-first and brain-first subtypes. A total of ten PD patients with presumed body-first subtypes (PDpRBD+), sixteen PD patients with presumed brain-first subtypes (PDpRBD-), and seventeen healthy controls (HCs) were enrolled. Clinical assessments and ¹⁸F-Florzolotau PET imaging were conducted. ¹⁸F-Florzolotau uptake was higher in the right precuneus and left posterior cingulate regions in the PDpRBD+ group than in the PDpRBD- group. Additionally, ¹⁸F-Florzolotau uptake in the right limbic and paralimbic structures was inversely correlated with Mini-Mental State Examination (MMSE) scores in PD patients with the putative body-first subtype. Our preliminary findings demonstrated distinct ¹⁸F-Florzolotau uptake patterns between the hypothesized PD subtypes. These results provide in vivo evidence of subtype-related differences in tau PET signals, suggesting potential heterogeneity beyond classical α-synuclein pathology, though further validation is warranted.

Background: Corticobasal syndrome (CBS) may arise from heterogeneous neuropathological substrates, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD), and biomarker‐based stratification has therefore become central to its characterization in vivo . In a large CBS cohort, we examined whether ¹⁸ F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) metabolic patterns reflect underlying amyloid‐ β deposition and tau topography, and how these patterns relate to the clinical phenotype. Methods: We conducted a cross‐sectional study of consecutive patients with CBS and were enrolled at Huashan Hospital, Fudan University, between December 2019 and February 2025. Each patient underwent ¹⁸ F‐FDG PET for cerebral glucose metabolism, amyloid status assessment using amyloid PET or cerebrospinal fluid biomarkers, and florzolotau( ¹⁸ F) PET for tau topography. Results: Among 113 patients, ¹⁸ F‐FDG PET identified five distinct metabolic subgroups: AD type (n = 20), CBD type I (n = 45), CBD type II (n = 18), PSP type (n = 26), and frontotemporal dementia type (n = 4). The AD metabolic pattern showed high specificity for amyloid‐ β positivity (98.5%) and for combined AD pathology (amyloid‐ β plus tau, 98.6%), with correspondingly lower sensitivity (54.2% and 72.2%). ¹⁸ F‐FDG PET patterns further showed high specificity for the PSP tau profile (96.2%) and high sensitivity for the CBD tau profile (97.7%). On spatial analysis, amyloid‐ β deposition significantly mediated the regional coupling between tau accumulation and cerebral glucose hypometabolism. Conclusions: ¹⁸ F‐FDG PET identifies metabolic patterns that correspond to specific proteinopathies underlying CBS with high specificity but requires integration within multimodal biomarker frameworks for comprehensive patient stratification. © 2026 International Parkinson and Movement Disorder Society.

Background: Progressive supranuclear palsy (PSP) is a rare tauopathy with multiple clinical phenotypes. The PSP‐related metabolic pattern (PSPRP) has proved useful for differentiating PSP from other parkinsonian syndromes, but type‐specific metabolic patterns remain incompletely characterized. Objective: This study aimed to identify type‐specific metabolic patterns in PSP and evaluate their ability to monitor progression and predict conversion of variant PSP (vPSP) to PSP with Richardson's syndrome (PSP‐RS). Methods: PSP‐RS, PSP with predominant parkinsonism (PSP‐P), PSP with predominant gait freezing (PSP‐PGF), and PSP with predominant postural instability (PSP‐PI) underwent baseline and follow‐up positron emission tomography with ¹⁸ F‐fluorodeoxyglucose ( ¹⁸ F‐FDG PET) imaging. First, the PSP‐RS–related pattern, PSP‐P–related pattern, PSP‐PGF–related pattern (PGFRP), and PSP‐PI–related pattern (PIRP) were identified by scaled subprofile modeling/principal‐component analysis. Furthermore, we evaluated the similarity of these patterns to previously reported PSPRP and tested their ability to classify clinical phenotypes. Finally, we evaluated these patterns longitudinally for monitoring disease progression and predicting conversion of vPSP to PSP‐RS. Results: All type‐specific patterns showed significant topographic similarity and association with PSPRP. The PGFRP exhibited more extensive involvement in the striatum than other type‐specific patterns. In general, both type‐specific patterns and PSPRP demonstrated similar performance in distinguishing PSP‐RS from vPSP. Pattern expressions increased at follow‐up and correlated with clinical progression. Higher baseline pattern expressions significantly predicted conversion from vPSP to PSP‐RS. Conclusions: PSP phenotypes exhibit type‐specific metabolic covariance patterns that largely overlap with PSPRP but show phenotype‐relevant differences. These patterns hold promise for longitudinal monitoring of disease progression and prediction of vPSP conversion to PSP‐RS. © 2026 International Parkinson and Movement Disorder Society.

White matter (WM) signal on ¹⁸F-florbetapir positron emission tomography (PET) is often regarded as nonspecific, yet its biological significance

Motor impairment in Parkinson's disease (PD) is classically attributed to striatal dopaminergic degeneration, yet dopamine loss alone does not fully explain symptom severity, suggesting a key role for circuit-level mechanisms. The cortico-basal ganglia-thalamo-cortical (CBGTC) system is central to dopaminergic motor modulation, but whether dysfunction within individualized CBGTC circuits mediates motor severity across disease stages remains unclear. Here, we studied 76 PD patients (40 mild, 36 moderate-to-severe) who underwent ¹⁸F-FP-CIT PET and multimodal MRI. Individualized long and short CBGTC loops were reconstructed using connectivity profile-based segmentation and probabilistic tractography, with functional connectivity (FC) quantified alongside striatal dopaminergic integrity. Compared with mild PD, moderate-to-severe PD showed a global reduction in striatal dopamine binding, most pronounced in the bilateral caudate. Critically, FC between the caudate and premotor cortex in the more-affected hemisphere was selectively reduced with increasing disease severity in both CBGTC loops (p-FDR = 0.027). The cross-sectional mediation models demonstrated that caudate-premotor FC statistically accounted for the association between caudate dopaminergic loss and motor symptom severity. These findings position individualized cortico-basal ganglia circuit connectivity as a potential mechanistically grounded biomarker linking molecular pathology to motor impairment in PD, with potential relevance for future circuit-guided therapeutic strategies.