Plasma GFAP and p-tau-181 Association with Synaptic Density at 18F-SynVest-1 PET Imaging

Neurology Medicine Medical Imaging
Alzheimer's disease synaptic density PET imaging plasma biomarkers neuroinflammation

Association of Plasma GFAP and p-tau-181 with Synaptic Density in Alzheimer’s Disease

Academic Background

Alzheimer’s Disease (AD) is a multifactorial neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and tau protein aggregates in the brain. Recent research has shown that multiple factors are involved in the development and progression of AD, including neuroinflammation, synaptic loss, and vascular risk factors. Synaptic loss is a prominent pathology in AD and is closely tied to cognitive impairment. Neuropathologic studies have consistently shown that synaptic loss is more closely associated with cognitive decline than Aβ plaque load. The hippocampus is often the site with the earliest and most substantial synaptic loss, likely due to the degeneration of entorhinal cortical cells that project to the hippocampus via the perforant path.

Synaptic vesicle glycoprotein 2a (SV2a) is widely expressed in synapses and located in synaptic vesicles at presynaptic terminals, making it a promising tool for assessing synaptic integrity and function in neurodegeneration. The advent of PET imaging targeting SV2a, such as 18F-SynVest-1 (a fluorine-18 labeled radiotracer), has enabled the in vivo evaluation of synaptic loss and its neuropathologic correlates.

Although synaptic loss plays a crucial role in AD, there is currently a lack of blood assays that conveniently and rapidly reflect changes in synaptic density. Therefore, this study aims to explore the associations between multiple potential synaptic blood markers and synaptic density using 18F-SynVest-1 PET imaging and to further investigate the independent relationships between these markers and synaptic density.

Study Source

This study was conducted by researchers from the Department of Nuclear Medicine and PET Center at Huashan Hospital, Fudan University, including Junhao Wu and Binyin Li, and was published in Radiology in 2024. The study was supported by multiple research projects, including the National Natural Science Foundation of China and the Shanghai Municipal Science and Technology Major Project.

Study Process

This prospective study included 120 participants from the Memory Clinic of Ruijin Hospital, Shanghai Jiao Tong University, and local communities in Shanghai, of whom 50 were cognitively unimpaired and 70 had cognitive impairment. The primary objective was to evaluate the associations between synaptic density and multiple blood markers using 18F-SynVest-1 PET imaging.

  1. Participant Recruitment and Grouping
    Participants were voluntarily recruited through public advertisements or reports of memory decline by family members. The cognitive impairment group included individuals with mild cognitive impairment and dementia. All participants underwent high-resolution 3D MRI, plasma assays, Aβ PET/CT, and SV2a PET/MRI.

  2. Blood Biomarker Measurement
    Plasma Aβ42, Aβ40, GFAP, and neurofilament light (NfL) were measured using the Neurology 4-plex E Advantage Kit (Quanterix). Plasma p-tau-181 was measured using the P-tau-181 V2 Simoa Advantage Assay (Quanterix).

  3. Image Acquisition and Analysis
    All participants underwent high-resolution 3D MRI and 18F-SynVest-1 PET imaging. PET images were analyzed using SPM12 software, and partial volume correction was performed using the Müller-Gärtner method.

  4. Statistical Analysis
    SPSS and SPM12 were used for statistical analysis. Pearson correlation analysis was used to assess the relationships between plasma markers and synaptic density, and multiple linear regression models and mediation analysis were used to explore the effects of other AD-related pathologies on these relationships.

Key Results

  1. Association of Plasma p-tau-181 and GFAP with Synaptic Density
    In all participants, plasma p-tau-181 and GFAP were negatively correlated with synaptic density in the global cortex (rp-tau-181 = -0.352, rgfap = -0.386; p < 0.001) and hippocampus (rp-tau-181 = -0.361, rgfap = -0.369; p < 0.001). These associations persisted after controlling for plasma Aβ42/40 ratio, Aβ PET, or cortical thickness but disappeared after controlling for tau PET.

  2. Influence of Tau Accumulation on Synaptic Density
    Multiple linear regression models showed that the associations of plasma p-tau-181 and GFAP with synaptic density were primarily influenced by tau accumulation rather than Aβ deposition or cortical thickness. Mediation analysis further confirmed that tau accumulation completely mediated the relationships between plasma p-tau-181 and GFAP with synaptic density.

Conclusion

This study demonstrates that plasma p-tau-181 and GFAP are closely associated with synaptic density measured using 18F-SynVest-1 PET/MRI, and this relationship is primarily influenced by tau accumulation rather than Aβ deposition or cortical thickness. These findings provide potential biomarkers for the early diagnosis and monitoring of synaptic protection therapies in AD.

Highlights

  1. Key Findings
    The associations of plasma p-tau-181 and GFAP with synaptic density offer new blood biomarkers for the early diagnosis of AD.

  2. Methodological Innovation
    This study is the first to use 18F-SynVest-1 PET imaging in combination with multiple blood markers to systematically evaluate the relationship between synaptic density and AD pathology.

  3. Application Value
    Detecting synaptic loss through blood biomarkers can provide important insights for early screening and personalized treatment of AD, promoting the development and application of novel drugs.

Additional Valuable Information

The limitations of this study include its cross-sectional design, which does not provide detailed insights into the specific trajectory of AD pathology. Additionally, not all participants underwent tau PET, which may affect the accurate determination of tau positivity. Future research should include a larger cohort of participants, incorporate additional AD-related indicators, and use improved follow-up assessments to further validate these relationships.

Plasma p-tau-181 and GFAP, as potential biomarkers, hold promise for early screening and synaptic protection therapies in AD.