Introduction:

Neuroinflammation is increasingly recognized as a hallmark in neurodegenerative diseases like Alzheimer’s disease (AD), complementing the staging of cognitive decline, functional impairment and pathological aggregation of β-amyloid and tau. This study investigates the spatiotemporal dynamics of reactive astrogliosis, captured by the novel MAO-B specific radiotracer [¹⁸F]Fluorodeprenyl-D2 ([¹⁸F]F-DED), across clinical AD stages and in relation to β-amyloid and tau pathology.

 

Methods:

AD n=70 CTRL n=15

Clinical assessments (MMSE, CSF: Aβ42/40 Ratio, pTau-181) + PET imaging (Radiochemistry, Acquisition, Reconstruction, Pre-Processing, Analysis): 

[¹⁸F]F-DED 0-60 min p.i., [¹⁸F]Flutemetamol 0-10 min p.i. + 90-110 min p.i., [¹⁸F]PI-2620 30-60 min p.i. + T1w MRI

-> Statistics: Voxel-wise comparison (Multi-regional analysis), Linear regression model [1] (Multi-tracer analysis (I x ATN))

Astrogliosis ([18F]F-DED), Aβ ([18F]Flutemetamol), Tau ([18F]PI-2620), eAMY -> Spatial normalization and brain parcellation (150 brain regions) -> Standardized differences (z-scores) vs. age-matched controls -> I A T N

I = β0x0+ βAxA + βTxT+ βNxN

Results:

I) [18F]F-DED PET

Compared with controls, individuals of the AD continuum showed significant [¹⁸F]F-DED binding in cortical regions including frontal, temporal, parietal and occipital areas, pronounced in the white matter in contrast to the grey matter [2]

II) [18F]F-DED PET vs MMSE

No significant association was observed between regional [¹⁸F]F-DED binding and cognitive performance measured by the MMSE, although highest tracer uptake was frequently present in the early-stage individuals

III) ATNI Regression

Multivariable regression analyses revealed a positive association between astrocyte activation and regional amyloid burden, while negative associations with regional tau burden were more prominent in later disease stages

Astrocyte PET signals showed a consistent positive relationship with regional perfusion, suggesting a potential link between reactive astrogliosis and neuronal hyperactivity

Conclusions:

[¹⁸F]F-DED PET demonstrates:

▪ significantly higher binding in patients of the AD continuum

▪ increased VT values as early as initial stages

▪ subcortical white matter prevalence in binding differences

Astrocyte activation closely relates to regional perfusion and amyloid pathology, while its association with tau deposition appears stage-dependent

These findings support [¹⁸F]F-DED PET as a promising biomarker of reactive astrogliosis and highlight a potential role of astrocytes in early pathophysiological mechanisms of AD

References:

1 Finze A, et al., Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies. Mol Psychiatry. 2023. 28(10): 4438-4450.

2 Jaisa-Aad M, et al., Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer's disease and related dementias. Acta Neuropathol. 2024. 147(1):66.