Unveiling paths to Alzheimer’s disease: excitation-inhibition ratio shapes hierarchical dynamics
Poster No:
192
Submission Type:
Abstract Submission
Authors:
Francesca Saviola1, Asia Ferrari2, Daniele Corbo2, Michela Pievani3, Silvia Saglia4, Giulia Quattrini5, Valentina Cantoni6, Enrico Premi7, Barbara Borroni2, Roberto Gasparotti6
Institutions:
1EPFL, Geneva, Geneva, 2University of Brescia, Brescia, Italy, 3IRCSS Fatebenefratelli, Brescia, Italy, 4University of Verona, Verona, Verona, 5IRCSS Fatebenefratelli, Brescia, Brescia, 6University of Brescia, Brescia, Brescia, 7ASST Spedali Civili, Brescia, Brescia
First Author:
Co-Author(s):
Introduction:
Alzheimer's disease (AD) manifests as cognitive decline and memory loss, with early disruptions in excitation-inhibition (E/I) balance closely tied to brain changes1,2. The posterior-to-anterior hypothesis of the disease posits that neurodegeneration begins from key hubs of the Default Mode Network (DMN), such as the hippocampus and posterior cingulate cortex (PCC), and progressively spreads to anterior regions. This research aims to (i) assess the clinical validity of functional connectivity (FC) proxies of E/I and (ii) investigate the interplay between E/I and functional temporality in the continuum from cognitively unimpaired at-risk subjects to symptomatic AD.
Methods:
This study analyzed a total of 97 subjects classified into three subgroups: 28 AD patients (of whom 20 Apolipoprotein E allele carriers (ɛ4+)), 35 cognitively unimpaired (CU) ɛ4+ (at-risk subjects) and 34 CU ɛ4-. For all subjects, resting-state fMRI and T1-weighted image were acquired, with an additional GABA-edited MRS located in PCC for a subsample of AD group. Intrinsic Neural Timescale (INT) was derived from single-subject parcellated rs-fMRI data3 and then applied to inform FC matrices. MRS data were preprocessed to target GABA+ and Glx estimation in the differential spectrum, to later compute in-vivo E/I estimation4. Multivariate statistical analysis along with functional connectome identifiability5,6 of subjects based on INT were performed to investigate the functional fingerprints of genetic risk for AD.
Results:
We probed that in-vivo E/I ratio (4.0 ± 0.7; Glx/GABA+; Figure 1A) in PCC is associated with cognitive deficits (ADAS-Cog13: β = -0.25, pFDR<0.05) in AD subjects, where lower values (less GABAergic content, non-significant trend: (β=-0.29, p<0.05) are associated to worse cognitive performance (Figure 1B). Voxel-wise association between E/I in PCC and whole-brain INT demonstrated a positive association in DMN regions (t= 11.9; TFCE pFWE<0.02; Figure 1C-D). Moreover, INT fluctuations within DMN demonstrated a significant association with cognitive performance: (i) reduced INT values were linked to lower MMSE scores (β = 0.01, pFDR=0.01; Figure 1E); (ii) multivariate analysis (p< 0.02; 95% variance explained; Figure 1F) uncovered a brain-cognition relationship involving attention, executive function, and memory scores, particularly in individuals at genetic risk (i.e. CU ɛ4+ and AD-ɛ4+, Figure 1G). Within DMN INT enables the distinction of group differences based between the interaction of genetic risk and AD presence (χ² = 221.4, p<0.05, all significant post-hoc pairwise comparison, Figure 2B-C). Lastly, while looking at individual FC profile informed with INT (Figure 2E) we found a significant effect of group (χ²=14.6, p<0.01) showing reduced subject identifiability in AD-ɛ4- (Idiff: 0.3±0.1) respect to CU ɛ4+ (Idiff: 0.4±0.1), but preserved unique and highly heterogeneous profiles in AD-ɛ4+ (Idiff: 0.4±0.1). Spatial specificity of brain fingerprinting informed by INT (Figure 2F), contrasted to the healthy reference (CU ɛ4-), revealed a peculiar pattern:(i) CU ɛ4+ and AD-ɛ4- showed fingerprinting increase for most between-networks FC, (ii) while AD-ɛ4+ exhibit fingerprinting increase for both between- and within-networks FC.
Conclusions:
This study provides compelling evidence for the clinical validity of FC proxies of E/I balance in AD, particularly highlighting a significant role of the DMN7. Our findings demonstrate that in-vivo E/I ratio of posterior regions is largely associated with INT patterns in the DMN. Additionally, we reveal that these fluctuations are significantly associated with cognitive function, particularly in individuals at genetic risk for AD. The distinct functional fingerprints identified through INT analysis underscore the nuanced interplay between genetic risk and disease presence, suggesting that E/I proxies could serve as valuable biomarkers for early detection and monitoring of AD shifting or progression.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Lifespan Development:
Aging
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 2
Multivariate Approaches
Physiology, Metabolism and Neurotransmission:
Physiology, Metabolism and Neurotransmission Other
Keywords:
Degenerative Disease
FUNCTIONAL MRI
GABA
Glutamate
Magnetic Resonance Spectroscopy (MRS)
MRI
1|2Indicates the priority used for review
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2. Fortel, I., Zhan, L., Ajilore, O., Wu, Y., Mackin, S., & Leow, A. (2023). Disrupted Excitation-Inhibition balance in cognitively normal individuals at risk of alzheimer’s disease. Journal of Alzheimer's Disease, (Preprint), 1-19.
3. Raut, R. V., Snyder, A. Z., & Raichle, M. E. (2020). Hierarchical dynamics as a macroscopic organizing principle of the human brain. Proceedings of the National Academy of Sciences, 117(34), 20890-20897.
4. Edden, R. A., Puts, N. A., Harris, A. D., Barker, P. B., & Evans, C. J. (2014). Gannet: A batch‐processing tool for the quantitative analysis of gamma‐aminobutyric acid–edited MR spectroscopy spectra. Journal of magnetic resonance imaging, 40(6), 1445-1452.
5. Krishnan, A., Williams, L. J., McIntosh, A. R., & Abdi, H. (2011). Partial Least Squares (PLS) methods for neuroimaging: a tutorial and review. Neuroimage, 56(2), 455-475.
6. Finn, E. S., Shen, X., Scheinost, D., Rosenberg, M. D., Huang, J., Chun, M. M., ... & Constable, R. T. (2015). Functional connectome fingerprinting: identifying individuals using patterns of brain connectivity. Nature neuroscience, 18(11), 1664-1671.
7. Maestú, F., de Haan, W., Busche, M. A., & DeFelipe, J. (2021). Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology. Ageing Research Reviews, 69, 101372.