Ciara Treacy

Objective: The inhibition deficit hypothesis postulates that inhibitory functioning declines with age, which negatively impacts other cognitive abilities. Yet still, the impact of healthy aging on inhibitory functioning remains unclear, with the multifaceted nature of inhibition often an overlooked factor. Moreover, no prior study has empirically tested whether inhibitory subcomponents explain differential age effects in sustained attention—an open question that this work aimed to address. Method: We cross-sectionally investigated the inhibition deficit hypothesis in 80 healthy older adults (Mage = 67.78 years, 44 female). We utilized the PsyToolkit platform to administer three inhibition tasks (i.e., flanker, Stroop, and go/no-go), each targeting a distinct subcomponent process, along with the Sustained Attention to Response Task. Results: The flanker task had low internal consistency and was deemed unreliable. Semipartial correlations of the remaining inhibition measures with age resulted in significant positive relationships with task performance on the Stroop (errors: ρ = 0.337, p = .014; reaction time: ρ = 0.313, p = .028) and a negative association with the go/no-go (balanced integrated score: ρ = −0.471, p < .001), such that older individuals had more pronounced Stroop effects and worse overall go/no-go performance. Finally, go/no-go performance completely mediated the relationship between aging and sustained attention performance (t = −2.30, 95% CI [−0.05, −0.01]), while Stroop effects partially mediated this association (t = −2.16, 95% CI [−0.03, −0.002]). Conclusions: Age-related declines were observed across reliable inhibition tasks, lending support for the inhibition deficit hypothesis. The mediation findings demonstrate that inhibitory subcomponents account for age-related declines in sustained attention, over and beyond aging itself via an indirect path, representing an important cognitive domain to maintain throughout aging.

Inhibition represents a core executive function which underlies the ability to suppress interfering or distracting stimuli, thereby building resistance against task-irrelevant information. However, the impact of ageing on inhibitory functioning and the role of neuroplasticity - largely driven by predominant excitatory (glutamatergic) and inhibitory (GABAergic) neurochemicals – remains poorly understood. This study investigated age relationships with neurochemical concentrations (GABA + and Glx) and their associations with inhibitory sub-components in healthy ageing. Participants completed three inhibition tasks (flanker, Stroop, go/no-go), each measuring a different sub-component process, via the PsyToolkit platform. MRS data were acquired in the sensorimotor (SM1; n = 71, mean age (SD) = 68.3 (± 9.7) years, 39 females) and prefrontal (PFC; n = 58, mean age (SD) = 67.6 (± 9.6) years, 30 females) regions using a HERMES sequence and analysed using OSPREY’s pipeline. After correcting for gender and education, semi-partial correlations revealed no significant relationships between age and GABA + or Glx concentrations in either the SM1 or PFC. Furthermore, after correcting for age, gender and education, partial correlations identified a significant negative relationship between SM1 Glx concentrations and go/no-go error rates, such that greater concentrations of SM1 Glx were associated with greater go/no-go accuracy. The null age-neurochemical results suggest that GABA + and Glx may not uniformly decline during healthy ageing, indicating a more nuanced relationship than previously reported. In addition, our neurochemical-behavioural findings provide neurochemically-and-spatially specific evidence that SM1 Glx concentrations may be important for response inhibition. This result indicates a role for the glutamatergic system in supporting inhibition, independent of age.

The 2024 Lancet Commission on Dementia estimates that up to 45% of dementia cases could be prevented by addressing modifiable risk factors, emphasizing both prevention opportunities and the need to understand the biological mechanisms. This study investigated neurophysiological mechanisms underlying modifiable dementia risk factors in cognitively unimpaired older adults. Seventy-nine cognitively unimpaired older adults underwent magnetic resonance imaging brain scans, with spectroscopy measurements taken from the sensorimotor cortex (SMC) and prefrontal cortex (PFC), using a Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy sequence, optimized for measuring GABA+. Modifiable dementia risk scores were calculated using the Assessment for Cognitive Health and Dementia Risk (CogDrisk). Hierarchical linear regression analyses revealed a significant negative relationship within the SMC, with lower GABA+ (β = −0.249, P = 0.009) associated with higher risk scores. In the PFC, lower tNAA and tCho concentrations significantly predicted higher risk scores (β = −0.168 and −0.170, respectively). These findings suggest that GABAergic system alterations may underlie the pathophysiology of modifiable dementia risk in healthy aging, while changes in tNAA and tCho may reflect early alterations in neuronal integrity. These region-specific neurochemical findings may help identify potential early biomarkers for dementia risk and suggest new therapeutic pathways for preventive interventions.

The aim of this study was to advance post-traumatic stress disorder (PTSD) understanding in older adults (48–77 years) by determining if circulating cytokines (IL-1β, IL-2, IL-4, IL-6, IL-12p70, IL17A and TNFα), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF-A) and neuroanatomical brain volumes (grey and white matter, hippocampus, and amygdala) significantly differed in those with versus without PTSD. While none of the tested cytokines showed a significant difference, serum BDNF and VEGF-A levels were found to be significantly higher in the PTSD cohort. The assay used for BDNF quantification was important, with differences in general BDNF detected, but not when pro- and mature BDNF were measured specifically. Additionally, BDNF genotyping revealed a significant difference in Val66Met genotype distribution by PTSD diagnosis, with Val66Met carriers generally having lower circulating levels of BDNF compared to their Val66Val counterparts, regardless of PTSD diagnosis. Neuroanatomically, an all-female subset was examined to find total grey and white matter volumes and left and right hippocampal volumes were significantly smaller in those with PTSD. Collectively, these results show that both novel (VEGF-A) and established targets (BDNF and neuroimaging) may serve as useful biomarkers for older adults with PTSD.

Background
The rising prevalence of dementia necessitates identifying early neurobiological markers of dementia risk. Reduced cerebral white matter volume and flattening of the slope of the electrophysiological 1/f spectral power distribution provide neurobiological markers of brain ageing alongside cognitive decline. However, their association with modifiable dementia risk remains to be understood.

Methods
A cross-sectional sample of 98 healthy older adults (79 females, mean age = 65.44) underwent structural magnetic resonance imaging (sMRI), resting-state electroencephalography (EEG), cognitive assessments and dementia risk scoring using the CogDrisk framework. Univariate and multivariate linear regression models were conducted to investigate the relationships between modifiable dementia risk and sMRI brain volumes, the exponent of EEG 1/f spectral power, and cognition, whilst controlling for non-modifiable factors.

Results
Smaller global white matter volume (F(1,87) = 6.884, R2 = 0.073, P = .010), and not grey (F(1,87) = 0.540, R2 = 0.006, P = .468) or ventricle volume (F(1,87) = 0.087, R2 = 0.001, P = .769), was associated with higher modifiable dementia risk. A lower exponent, reflecting a flatter 1/f spectral power distribution, was associated with higher dementia risk at frontal (F(1,92) = 4.096, R2 = 0.043, P = .046) but not temporal regions. No significant associations were found between cognitive performance and dementia risk. In multivariate analyses, both white matter volume and the exponent of the 1/f spectral power distribution independently associated with dementia risk.

Conclusions
Structural and functional neurobiological markers of early brain ageing, but not cognitive function, are independently associated with modifiable dementia risk in healthy older adults.

Sustained attention is important for maintaining cognitive function and autonomy during ageing, yet older people often show reductions in this domain. The role of the underlying neurobiology is not yet well understood, with most neuroimaging studies primarily focused on fMRI. Here, we utilise sMRI to investigate the relationships between age, structural brain volumes and sustained attention performance. Eighty-nine healthy older adults (50–84 years, Mage 65.5 (SD=8.4) years, 74 f) underwent MRI brain scanning and completed two sustained attention tasks: a rapid visual information processing (RVP) task and sustained attention to response task (SART). Independent hierarchical linear regressions demonstrated that greater volumes of white matter hyperintensities (WMH) were associated with worse RVP_A’ performance, whereas greater grey matter volumes were associated with better RVP_A’ performance. Further, greater cerebral white matter volumes were associated with better SART_d’ performance. Importantly, mediation analyses revealed that both grey and white matter volumes completely mediated the relationship between ageing and sustained attention. These results explain disparate attentional findings in older adults, highlighting the intervening role of brain structure.

While structural and biochemical brain changes are well-documented in ageing, functional neuronal network differences, as indicated by electrophysiological markers, are less clear. Moreover, age-related changes in sustained attention and their associated electrophysiological correlates are still poorly understood. To address this, we analysed cross-sectional baseline electroencephalography (EEG) and cognitive data from the Lifestyle Intervention Study for Dementia Risk Reduction (LEISURE). Participants were 96 healthy older adults, aged 50-84. We examined resting-state EEG periodic (individual alpha frequency [IAF], aperiodic-adjusted individual alpha power [aIAP]) and aperiodic (exponent and offset) activity, and their associations with age and sustained attention. Results showed associations between older age and slower IAF, but not aIAP or global aperiodic exponent and offset. Additionally, hierarchical linear regression revealed that after controlling for demographic variables, faster IAF was associated with better Sustained Attention to Response Task performance, and mediation analysis confirmed IAF as a mediator between age and sustained attention performance. These findings indicate that IAF may be an important marker of ageing, and a slower IAF may signal diminished cognitive processing capacity for sustained attention in older adults.

Dementia is understood to arise from a mixed etiology, enveloping chronic inflammatory and vascular impacts on the brain, driven by a constellation of modifiable risk factors which are largely mediated by lifestyle-related behaviors. These risk factors manifest over a prolonged preclinical period and account for up to 40% of the population attributable risk for dementia, representing viable targets for early interventions aimed at abating disease onset and progression. Here we outline the protocol for a 12-week randomized control trial (RCT) of a multimodal Lifestyle Intervention Study for Dementia Risk Reduction (LEISURE), with longitudinal follow-up at 6-months and 24-months post-intervention. This trial integrates exercise, diet, sleep, and mindfulness to simultaneously target multiple different etiopathogenetic mechanisms and their interplay in a healthy older adult population (aged 50-85 years), and assesses dementia risk reduction as the primary endpoint. The LEISURE study is located in the Sunshine Coast region of Australia, which has one of the nation's highest proportions of adults aged over 50 years (36.4%), and corresponding dementia prevalence. This trial is novel in its inclusion of mindfulness and sleep as multidomain lifestyle targets, and in its comprehensive suite of secondary outcomes (based on psychological, physical health, sleep activity, and cognitive data) as well as exploratory neuroimaging (magnetic resonance imaging and electroencephalography) and molecular biology measures. These measures will provide greater insights into the brain-behavioral underpinnings of dementia prevention, as well as the predictors and impacts of the proposed lifestyle intervention. The LEISURE study was prospectively registered (ACTRN12620000054910) on 19 January 2020.