Interplay of plasma phosphorylated tau with GFAP, sex on hippocampal connectivity in preclinical AD
Poster No:
240
Submission Type:
Abstract Submission
Authors:
Noah Schweitzer1, Rebecca Thurston2, Brian Lopresti3, William Klunk2, Beth Snitz4, Dana Tudorascu2, Ann Cohen2, M. Ilyas Kamboh5, Edythe Eddy-Halligan2, Thomas Karikari2, Bistra Iordanova1, Victor Villemagne2, Howard Aizenstein2, Minjie Wu2
Institutions:
1Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 2Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 3Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 4Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 5Department of Human Genetics, School of Public Health,University of Pittsburgh, Pittsburgh, PA
First Author:
Co-Author(s):
M. Ilyas Kamboh
Department of Human Genetics, School of Public Health,University of Pittsburgh
Pittsburgh, PA
Department of Human Genetics, School of Public Health,University of Pittsburgh
Pittsburgh, PA
Introduction:
Mounting evidence suggests that blood plasma phosphorylated tau (p-tau) may be a useful biomarker of Alzheimer's Disease (AD). Functional MRI (fMRI) studies have associated impaired memory networks with AD pathology. There have been few fMRI studies which examine the relationship between p-tau measures and the memory network. We aim to test how functional hippocampal connectivity alterations associated with p-tau measures differ based on plasma GFAP levels and sex.
Methods:
This study included cognitively unimpaired (CU) elders who had their blood drawn within two years prior to their MRI scan. 23 subjects had plasma measures of Aβ42/40, GFAP and p-tau217 (n=17 female, mean age 72.4 +- 5.3 years) and 25 subjects had measures of p-tau231, p-tau181, GFAP and Aβ42/40 (n=13 female, mean age 71.7 +- 5.2 years). All subjects underwent PET imaging using [11C]PiB to assess Aβ load via PiB SUVR. A median split of GFAP was performed for each group of p-tau measures, where each subject was classified as either "high GFAP" or "low GFAP". Task fMRI was collected while participants performed a face-name associative memory task. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and other regions in the brain. To extract regions of interest (ROI), second level analyses included two separate linear regression models testing for each p-tau measure: one model testing for the interaction between GFAP, p-tau and another model testing for the interaction between p-tau, sex. Both models controlled for age and PiB SUVR or Aβ42/40. To control for multiple comparisons, joint height and extent thresholds were determined via Monte Carlo simulations with an a priori medial temporal and frontal lobe mask (AlphaSim, AFNI).
Results:
Two ROIs presented significant p-tau217 by GFAP interactions: left-right hippocampus and left-left hippocampus (between hippocampus and parahippocampus). In both ROIs, hippocampal connectivity increased with higher p-tau217 levels for high GFAP subjects, but decreased connectivity with higher p-tau217 levels for low GFAP subjects (Fig. 1A). Both ROIs were significant when controlling for PiB SUVR or Aβ42/40. For p-tau181 by sex interaction, three ROI's survived multiple comparisons when controlling for PiB SUVR but not Aβ42/40: left hippocampus-anterior cingulate cortex (Fig 1B), left hippocampus-right medial frontal gyrus (MFG), and left hippocampus-left MFG. In all three ROIs, hippocampal connectivity increased for males but not females. There were no significant ROIs observed for the interaction between p-tau181 and GFAP nor p-tau217 and sex. There were no significant ROIs observed for effects of p-tau231 on hippocampal connectivity.
Conclusions:
In a cohort of CU elders, we observed unique hippocampal connectivity alterations based on p-tau measures with GFAP, sex, and soluble and insoluble Aβ levels. Astrocyte reactivity has been shown to predict whether CU Aβ-positive individuals will develop tau pathology[1]. Astrocytes also play a critical role in maintaining neuronal circuit homeostasis[2]. Taken together, our observation of increased local hippocampal hyperconnectivity associated with high GFAP and increasing p-tau217 may reflect a critical point in the disease stage. P-tau217 appears earlier and has a stronger association with Aβ compared to p-tau181 in preclinical AD[3]. This may partially explain why local hippocampal hyperconnectivity is only associated with p-tau217. The ROIs observed between p-tau181, sex interaction mirrors the ROIs observed by our study examining hippocampal connectivity changes based on sex and PiB SUVR[4]. GFAP and p-tau181 have also been shown to be associated with insoluble Aβ levels measured via PET. This may partially explain why the p-tau181, sex interaction is only significant when controlling for PiB SUVR but not Aβ42/40. In conclusion, our findings may reflect the disease progression in the hippocampus during pre-clinical AD based on different p-tau measurements.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Learning and Memory:
Learning and Memory Other
Lifespan Development:
Aging
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
fMRI Connectivity and Network Modeling 2
Keywords:
Aging
Degenerative Disease
FUNCTIONAL MRI
Memory
MRI
1|2Indicates the priority used for review
Provide references using author date format
2. Khakh, B.S. & Deneen, B. The Emerging Nature of Astrocyte Diversity. Annu Rev Neurosci 42, 187-207 (2019).
3. Gonzalez-Ortiz, F. et al. Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications. Molecular Neurodegeneration 18, 18 (2023).
4. Wu, M. et al. Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women. Neurobiology of Aging 76, 141-150 (2019).