Increased CSF GAP-43 leads to accelerated tau accumulation and spread in Alzheimer’s disease
Poster No:
289
Submission Type:
Abstract Submission
Authors:
Nicolai Franzmeier1, Amir Dehsarvi1, Anna Steward1, Davina Biel1, Anna Dewenter1, Sebastian Niclas Roemer1, Fabian Wagner1, Matthias Brendel2, Michael Ewers3, Kaj Blennow4, Henrik Zetterberg5, Michael Schöll6
Institutions:
1University Hospital LMU Munich, Munich, Bavaria, 2Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany, Munich, Germany, 3Institute for Stroke and Dementia Research, Munich, Bavaria, 4Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Västergötland, 5University College London, London, United Kingdom, 6University of Gothenburg, Gothenburg, Sweden
First Author:
Co-Author(s):
Matthias Brendel
Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
Munich, Germany
Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
Munich, Germany
Kaj Blennow
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
Gothenburg, Västergötland
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
Gothenburg, Västergötland
Introduction:
Preclinical studies found that tau spreads trans-synaptically in an activity-dependent manner, suggesting that synapses route tau spread in Alzheimer's disease (AD). Importantly, amyloid-beta (Aβ) induces aberrant synaptic activity, which may accelerate trans-synaptic tau spread. In AD patients, we found previously that tau spreads from epicenters across functionally connected regions but it is unclear whether Aβ-related synaptic changes accelerate tau spreading. The presynaptic growth-associated protein 43 (GAP-43) is implicated in synaptic plasticity and is increased in cerebrospinal fluid (CSF) in AD, suggesting that GAP-43 captures synaptic integrity deviations such as aberrant synaptic activity. We therefore tested whether higher GAP-43 is associated with faster Aβ-related tau spread.
Methods:
We included longitudinal [18F]Flortaucipir tau-PET, baseline [18F]Florbetapir amyloid-PET and CSF GAP-43 from 93 subjects (controls Aβ-, n=54; cognitively normal/Mild Cognitive Impairment Aβ+, n=33/21). To model connectivity-associated tau spread, we determined a connectivity template across 200 cortical regions (i.e., Schaefer atlas) using 3T resting-state fMRI in an independent control sample. Statistical models were controlled for age, sex and diagnosis.
Results:
Higher CSF GAP-43 was associated with faster Aβ-related tau-PET increase in pre-defined ROIs (centiloid x GAP-43 interaction, global/temporal-meta-ROI: b=0.0019/0.0028; p=0.009/0.007, Fig.1) as well as in the personalized Q1 ROI (b=0.0024; p=0.004) that summarizes regions most closely connected to tau epicenters with highest baseline tau-PET (Fig.2A). Importantly, the centiloid x GAP-43 interaction decreased across regions less strongly connected to tau epicenters (Q2/Q3/Q4: b=0.0017/0.0008/0.0002; p=0.009/0.080/0.344, Fig.2B-D). Further, we quantified subject-specific connectivity-associated tau spread (i.e., the regression-derived association between epicenter connectivity and tau-PET increase in remaining brain regions). Here, higher CSF GAP-43 was associated with a stronger association between Aβ and connectivity-associated tau spread (centiloid x GAP-43 interaction, b=-0.0031; p=0.037).
Conclusions:
Higher CSF GAP-43 is associated with faster Aβ-related tau spread across interconnected brain regions, rendering synaptic changes a potential target to attenuate tau spreading.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural) 2
Keywords:
FUNCTIONAL MRI
Neurological
Positron Emission Tomography (PET)
1|2Indicates the priority used for review
·Figure 1
·Figure 2