Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI.

Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.

Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions.

As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) plays a crucial role in shaping the frequency and amplitude of oscillations, which suggests a role for GABA in shaping the topography of functional connectivity and activity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) using the GABA transporter 1 (GAT1) blocker, tiagabine (15 mg). In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo. We quantified whole brain activity and functional connectivity in discrete frequency bands. Drug-by-session (2 × 4) analysis of variance in connectivity revealed interaction and main effects. Post-hoc permutation testing of each post-drug recording vs. respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, across 1- 3- and 5- hour recordings following tiagabine only. The same analysis applied to activity revealed significant increases across frontal regions, coupled with reductions in posterior regions, across delta, theta, alpha and beta frequencies. Crucially, the spatial distribution of tiagabine-induced changes overlap with group-averaged maps of the distribution of GABAA receptors, from flumazenil (FMZ-VT) PET, demonstrating a link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. Our results indicate that the relationship between PET receptor distributions and MEG effects warrants further exploration, since elucidating the nature of this relationship may uncover electrophysiologically-derived maps of oscillatory activity as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging.

Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease.

Preclinical models of Alzheimer's disease (AD) suggest that volumetric reductions in medial temporal lobe (MTL) structures manifest before clinical onset. AD polygenic risk scores (PRSs) are further linked to reduced MTL volumes (the hippocampus/amygdala); however, the relationship between the PRS and specific subregions remains unclear. We determine the relationship between the AD-PRSs and MTL subregions in a large sample of young participants (N = 730, aged 22-35 years) using a multimodal (T1w/T2w) approach. We first demonstrate that the PRSs for the hippocampus/amygdala predict their respective volumes and specific hippocampal subregions (pFDR < 0.05). We further observe negative relationships between the AD-PRSs and whole hippocampal/amygdala volumes. Critically, we demonstrate novel associations between the AD-PRSs and specific hippocampal subfields such as CA1 (ß = -0.096, pFDR = 0.045) and the fissure (ß = -0.101, pFDR = 0.041). We provide evidence that the AD-PRS is linked to specific MTL subfields decades before AD onset. This may help inform preclinical models of AD risk, providing additional specificity for intervention and further insight into mechanisms by which common AD variants confer susceptibility.

Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity.

Preclinical models of Alzheimer's disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.

Polygenic impact of common genetic risk loci for Alzheimer's disease on cerebral blood flow in young individuals.

Genome-wide association studies (GWAS) show that many common alleles confer risk for developing Alzheimer's disease (AD). These risk loci may contribute to MRI alterations in young individuals, preceding the clinical manifestations of AD. Prior evidence identifies vascular dysregulation as the earliest marker of disease progression. However, it remains unclear whether cerebrovascular function (measured via grey-matter cerebral blood flow (gmCBF)) is altered in young individuals with increased AD genetic risk. We establish relationships between gmCBF with APOE and AD polygenic risk score in a young cohort (N = 75; aged: 19-32). Genetic risk was assessed via a) possessing at least one copy of the APOE ɛ4 allele and b) a polygenic risk score (AD-PRS) estimated from AD-GWAS. We observed a reduction in gmCBF in APOE ɛ4 carriers and a negative relationship between AD-PRS and gmCBF. We further found regional reductions in gmCBF in individuals with higher AD-PRS across the frontal cortex (PFWE < 0.05). Our findings suggest that a larger burden of AD common genetic risk alleles is associated with attenuated cerebrovascular function, during young adulthood. These results suggest that cerebral vasculature is a mechanism by which AD risk alleles confer susceptibility.