Dementia Risk Scores are significantly associated with GABA+, but not Glx, or Impulse Control

1130 

Abstract Submission 

Jacob Levenstein¹, Ciara Treacy¹, Sophie Andrews¹

¹Thompson Institute, University of the Sunshine Coast, Birtinya, QLD

Jacob Levenstein, DPhil, MSc.  
Thompson Institute, University of the Sunshine Coast
Birtinya, QLD

Ciara Treacy, BBiomedSc  
Thompson Institute, University of the Sunshine Coast
Birtinya, QLD

Sophie Andrews, PhD  
Thompson Institute, University of the Sunshine Coast
Birtinya, QLD

Dementia is a neurodegenerative disease with a terminal trajectory, characterized by a complex symptomatology, including impaired memory, behavioral changes, and progressive functional decline. A Dementia risk score (DRS) quantifies an individual's risk of developing dementia, based on protective and detrimental risk-factors. Further, DRSs can be utilized to examine the neurophysiological pathogenesis of dementia risk. Recent review articles have highlighted the potential role of glutamatergic and GABAergic systems underpinning dementia etiology [1,2]. Here, we investigate whether neurochemical concentrations are associated with DRSs in an aging population without a dementia diagnosis. We aim to measure neurochemical concentrations in relation to modifiable risk factors, which have been shown to account for ~40% of dementias world-wide [3]. We hypothesize that individuals with greater DRSs will have lower GABA+ and Glx (after controlling for age and education). A secondary question explores whether behavioral measures of response inhibition relate to dementia risk and or neurochemicals. We hypothesize that individuals with worse inhibitory control will have greater DRSs, greater Glx and lower GABA+.

This study was approved by UniSC's Human Research Ethics Committee (S211620) and all participants provided informed consent. To date, 78 healthy older adults aged 50-85 completed this study. After reviewing quality metrics and model fits of the MRS data, 62 participants were included in the final cohort (31f, 67.7M-age,+/-10.01). DRSs were computed using the CogDrisk assessment [4], based on 17 modifiable and non-modifiable risk factors. All participants completed an MRI brain scan at the Thompson Institute, via a 3T Skyra (Siemens, Erlangen Germany). In brief, a T1-weighted structural scan (MPRAGE) was acquired and used for placement of the MRS volume of interest (VOI). Two single-voxel MR spectroscopy (MRS) scans were acquired using a Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy sequence (HERMES,[5]; VOI=3cm³, TR=2000ms, TE=80ms, flip angle=90°, averages=320, TA=10:48). MRS was acquired in the left sensorimotor cortex (M1) and left prefrontal cortex. MRS data was analyzed using OSPREY's standard processing and fitting pipeline (v.2.4.0, [6]). Only the M1 GABA+ and Glx results are presented here, with each expressed as a ratio of creatine and phosphocreatine (tCr). A suite of behavioral tasks were collected to probe inhibitory control, attention, and cognition. Presented here are the error rate results from the Go-NoGo task administered using PsyToolKit[7] and analyzed with in-house scripts. Hierarchical linear regression was performed using SPSS (v.29.0,[8]). For all models, age and education were entered in step 1, with step 2 containing the regressor of interest.

Hierarchical linear regression revealed that dementia risk scores were significantly associated with age, education and M1 GABA+ (F(3,58)=20.41,p<0.001,R²=0.514). After controlling for age and education, GABA+ remained a significant predictor of dementia risk (ß=-0.258,t=-2.80,p=0.007,R²=0.119). Age nor education were significantly correlated with GABA+ concentrations (ps. ≥ 0.31). For both Glx and Error Rate, neither were significantly associated with dementia risk, with or without controlling for age and education (ps. ≥ 0.49). Finally, Glx, but not GABA+, was significantly associated with Error Rate from the Go NoGo task (β=-0.349,t=-2.76,p=0.008,R²=0.118).

These results demonstrate that M1 GABA+ concentrations were significantly associated with dementia risk scores. No relationship was identified between Glx and dementia risk, suggesting that the GABAergic system at M1 may provide unique insight into the pathophysiology of modifiable dementia risk in healthy aging. To determine the mechanism(s) underpinning this relationship, further analysis of MRS VOIs, metabolites, and an evaluation of unique measures of modifiable risk factors are required.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s)

Executive Function, Cognitive Control and Decision Making

Aging ¹

MR Spectroscopy ²

Physiology, Metabolism and Neurotransmission Other

Aging

Cognition

Degenerative Disease

GABA

Glutamate

Magnetic Resonance Spectroscopy (MRS)

MR SPECTROSCOPY

Neurotransmitter

Somatosensory

Other - Dementia Risk Factors