Biology subjects

Harding, I. H.

Publications and source records attributed to Harding, I. H..

7 recordsLinked to original sources

bioRxiv2025

Factor Analysis of Multimodal MRI, Biofluid and Vascular Health Biomarkers Reveals Latent Constructs of Brain Health

Individual imaging and fluid biomarkers provide insights into specific components of brain health, but integrated multimodal approaches are necessary to capture the complex, interrelated biological systems that contribute to brain homeostasis and neurodegenerative disease. Using data from the Brain and Cognitive Health (BACH) cohort study (N=127; mean age=67 years, 68% women), we performed an exploratory factor analysis to identify latent constructs of brain health. We included multimodal neurovascular imaging markers, brain atrophy metrics, plasma Alzheimers disease (AD) biomarkers and cardiovascular risk factors. Five constructs emerged: "Brain & Vascular Health" (greater hippocampal volume, basal ganglia enlarged perivascular spaces [ePVS], cerebral blood flow and HDL cholesterol; lower ventricle volume and BMI); "Structural Integrity" (greater cortical thickness, fractional anisotropy and basal ganglia ePVS); "Fluid Transport" (greater white matter ePVS and Free Water); "AD Biomarkers" (higher phosphorylated tau [pTau]181 and pTau217; lower amyloid-beta 42/40 ratio); and "Neuronal Injury" (higher glial fibrillary acidic protein and neurofilament light chain). All constructs were associated with age ({beta}=-0.70-0.39, p[≤].014), except for Fluid Transport (p>.05). Brain & Vascular Health and Structural Integrity (partial r=.305, p<.001), and AD Biomarkers and Neuronal Injury (partial r=.248, p=.005) were positively correlated. Only Brain & Vascular Health was associated with global cognition ({beta}=0.27, SE=0.13, p=.043). These findings provide a data-driven framework for examining distinct constructs underlying vascular health, fluid regulation and neurodegenerative pathology. We demonstrate the utility of using multiple biomarkers to probe these biological systems, paving the way for future research to explore how these systems change across diverse neurodegenerative conditions.

neuroscience↗

bioRxiv2025

Plasma pTau-217 Correlates with Brain Atrophy, Cognition, and CSF Biomarkers in a Cognitively Healthy Community Cohort

Plasma biomarkers are promising for detecting Alzheimers disease (AD) pathology, but their role in cognitively healthy individuals remains unclear. Plasma pTau-217 has high diagnostic accuracy for clinical and prodromal AD, yet its relevance in preclinical stages is underexplored. We examined if plasma biomarkers of AD, neurodegeneration, and neuroinflammation were associated with cognition, brain structure, and their cerebrospinal fluid (CSF) counterparts in dementia-free older adults. We studied community-based, dementia-free older adults from the Brain and Cognitive Health (BACH) cohort. Neuropsychological testing assessed global cognition (MMSE), memory (Logical Memory II), visual processing (Hooper Visual Organization Test), processing speed (Trail Making Test-A), and reasoning (Similarities). Paired plasma and CSF biomarkers (pTau-217, pTau-181, GFAP, NfL, A{beta}42/40) were measured using SIMOA. MRI-derived cortical thickness was used as a neurodegeneration marker. Multivariable linear regression assessed associations between log10-transformed plasma biomarker levels, cognition (adjusted for age, sex, education, hypertension, hyperlipidemia, diabetes), and cortical thickness (adjusted for age, sex, education, and intracranial volume). Pearsons correlations and Bland-Altman plots evaluated plasma-CSF agreement. There were 147 dementia-free participants (mean age{+/-}SD: 66.7{+/-}7.7 years; 56 % women). Higher plasma pTau-217 levels associated with lower global cognition scores ({beta} -0.80, 95% C.I. -1.56, -0.03, p=0.041) and abstract reasoning ({beta} -0.86, 95% confidence interval [C.I.] -1.62, -0.09, p=0.028). Greater plasma pTau-217 also associated with lower global cortical thickness ({beta}eta [{beta}] -0.21, 95% confidence interval [C.I]. -0.37, -0.06, per log unit change; p=0.006). No associations were found between the plasma biomarkers and processing speed or visual processing (p>0.05 for all). Among 47 participants with paired plasma-CSF biomarkers, plasma pTau-217 showed the strongest correlation with its CSF counterpart (R=0.76, p<0.0001), outperforming pTau-181 (R=0.61, p<0.0001), GFAP (R=0.66, p<0.0001), NfL (R=0.56, p<0.0001), and A{beta}42/40 (R=0.53, p=0.0001). In conclusion, plasma pTau-217 levels were associated with both cognition and cortical thickness in dementia-free older adults. All plasma biomarkers correlated significantly with their CSF counterpart. These findings reinforce the utility of plasma biomarkers, particularly pTau-217, as indicators of neurodegenerative processes, even in asymptomatic individuals.

neuroscience↗

bioRxiv2024

Relationships between measures of neurovascular integrity and fluid transport in aging: a multi-modal neuroimaging study

Fluid transport in the neurovascular unit (NVU) is essential for maintaining brain health through nutrient delivery and waste clearance. NVU integrity and fluid regulation can be assessed through MRI measures, including water exchange rate through the NVU (BBB kw), enlarged perivascular spaces (ePVS), cerebral blood flow (CBF), free water (FW), and white matter hyperintensities (WMH). This study investigated relationships between these MRI measures using Bayesian mixed models, and their variation with chronological age or biological brain age (brainageR) using linear regression in 132 non-clinical older adults (mean age=67 years; 68% female). BBB kw positively associated with CBF ({beta}^=0.08, 95% credible interval (CI)=[0.02,0.15]). FW positively associated with both ePVS ({beta}^=0.44, CI=[0.30,0.63]) and WMH ({beta}^=0.13, CI=[0.04,0.21]). BBB kw, CBF and ePVS decreased with age, while FW and WMH increased (all p<.05). There were no associations with brain age (all p>.05). Relationships between FW, ePVS and WMH likely reflect interconnectivity of fluid regulation within different compartments, while the relationship between BBB kw and CBF indicates a link between NVU fluid flow and vessel function. While individual metrics of NVU integrity are associated with age, their inter-relationships appear stable, providing a baseline for future research in fluid transport and vascular health in neurodegenerative disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/622194v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@df1273org.highwire.dtl.DTLVardef@1343e84org.highwire.dtl.DTLVardef@f475c2org.highwire.dtl.DTLVardef@15f32d1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Neurovascular function and the fluid transport system. The brains fluid transport system comprises the neurovascular unit, interstitial fluid exchange in the parenchyma and venous outflow. a. The flow of water molecules from the vessel to the perivascular space through the blood-brain barrier, and subsequently into the brain (facilitated by aquaporin-4 (AQP4) channels) in quantified by BBB kw. b. Greater cerebral blood flow rate (CBF) is associated with greater BBB kw, possibly due to vessel pulsations increasing osmotic pressure. c. Enlarged perivascular spaces (ePVS) may indicate reduced fluid flow within the NVU and are associated with (d.) increased extracellular free water (FW) in the parenchyma, suggesting a link between fluid regulation within the vasculature and the surrounding brain tissue. Greater white matter hyperintensity (WMH) volume also occurs alongside increase FW, in line with WMH reflecting more severe fluid flow stagnation occurring in concert with neuroinflammation and/or neuronal demyelination. C_FIG

neuroscience↗

bioRxiv2024

The Pattern and Staging of Brain Atrophy in Spinocerebellar Ataxia Type 2 (SCA2): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterised by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2, however the evolution and pattern of whole-brain atrophy in SCA2 remain unclear. We undertook a multi-site, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2. MethodsVoxel-based morphometry analyses of 110 participants with SCA2 and 128 controls were undertaken to assess groupwise differences in whole-brain volume. Correlations with clinical severity and genotype, and cross-sectional profiling of atrophy patterns at different disease stages, were also performed. ResultsAtrophy in SCA2 relative to controls was greatest (Cohens d>2.5) in the cerebellar white matter (WM), middle cerebellar peduncle, pons, and corticospinal tract. Very large effects (d>1.5) were also evident in the superior cerebellar, inferior cerebellar, and cerebral peduncles. In cerebellar grey matter (GM), large effects (d>0.8) mapped to areas related to both motor coordination and cognitive tasks. Strong correlations (|r|>0.4) between volume and disease severity largely mirrored these groupwise outcomes. Stratification by disease severity showed a degeneration pattern beginning in cerebellar and pontine WM in pre-clinical subjects; spreading to the cerebellar GM and cerebro-cerebellar/corticospinal WM tracts; then finally involving the thalamus, striatum, and cortex in severe stages. InterpretationThe magnitude and pattern of brain atrophy evolves over the course of SCA2, with widespread, non-uniform involvement across the brainstem, cerebellar tracts, and cerebellar cortex; and late involvement of the cerebral cortex and striatum.

neuroscience↗

bioRxiv2021

Hypothalamic effective connectivity at rest is associated with body weight and energy homeostasis

Hunger and satiety states drive eating behaviours via changes in brain function. The hypothalamus is a central component of the brain networks that regulate food intake. Animal research parsed the roles of the lateral hypothalamus (LH) and the medial hypothalamus (MH) in hunger and satiety respectively. Here, we examined how hunger and satiety change information flow between human LH and MH brain networks, and how these interactions are influenced by body mass index. Forty participants (15 overweight/obese) underwent two resting-state functional MRI scans: after overnight fasting (fasted state) and following a standardised meal (sated state). The direction and valence (excitatory/inhibitory influence) of information flow between the MH and LH was modelled using spectral dynamic causal modelling. Our results revealed two core networks interacting across homeostatic state and weight status: subcortical bidirectional connections between the LH, MH and the substantia nigra pars compacta (prSN), and cortical top-down inhibition from frontoparietal and temporal areas. During fasting relative to satiety, we found higher inhibition between the LH and prSN, whereas the prSN received greater top-down inhibition from across the cortex. Individuals with higher BMI showed that these network dynamics occur irrespective of fasted or satiety states. Our findings reveal fasting affects brain dynamics over a distributed hypothalamic-midbrain-cortical network. This network is less sensitive to state-related fluctuations among people with obesity.

neuroscience↗

bioRxiv2020

Neural network modelling reveals changes in directional connectivity between cortical and hypothalamic regions in obesity

Obesity has been ascribed to corticostriatal regions taking control over homeostatic areas. To test this assumption, we applied an effective connectivity approach to reveal the direction of information flow between brain regions and the valence of connections (excitatory versus inhibitory) as a function of adiposity and homeostatic state. Forty-one participants (21 overweight/obese) underwent two resting-state fMRI scans: after overnight fasting (hunger) and following a standardised meal (satiety). We used spectral dynamic causal modelling to unravel hunger and adiposity related changes in directed connectivity between cortical, insular, striatal and hypothalamic regions. During hunger, as compared to satiety, we found increased excitation of the ventromedial prefrontal cortex over the ventral striatum and hypothalamus, suggesting enhanced top-down modulation compensating energy depletion. Adiposity was associated with increased excitation of the anterior insula over the hypothalamus across the hunger and satiety conditions. The interaction of hunger and adiposity yielded decreased intra-cortical excitation from the dorsolateral to the ventromedial prefrontal cortex. Our findings suggest that obesity is associated with persistent top-down excitation of the hypothalamus, regardless of homeostatic state, and hunger-related reductions of dorsolateral to ventromedial prefrontal inputs. These findings are compatible with eating without hunger and reduced self-regulation views of obesity. Significance StatementObesity is a leading contributor to morbidity and mortality. Neurobiological theories propose that, in obese people, corticostriatal regions take over homeostatic areas. Neuroimaging-based functional connectivity is well-poised to unravel such abnormalities by examining between-regions communication, but existing studies have only measured signal covariance, not direction and valence of connectivity. We applied computational modelling to reveal the direction of information flow between brain regions and excitatory/inhibitory valence of connections in obese versus healthy-weight participants. Obesity associated with heightened top-down excitation from the insula to hypothalamus, and reduced excitation within prefrontal regions. Findings have two advantages relative to current knowledge: demonstrate theory-based directional abnormalities, i.e. cortical regions taking over homeostatic areas; and inform brain stimulation therapies targeting cortical input to lower-level regions.

neuroscience↗

bioRxiv2018

Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA

BackgroundFriedreich ataxia is a recessively inherited, progressive neurological disease characterised by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of pathology in these structures.\n\nMethodsUsing in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n=20) and healthy controls (n=18) over a two-year period.\n\nResultsThe longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Moreover, atrophy was maximal in individuals early in the disease course, while the rate of iron concentration increased with disease progression.\n\nConclusionsProgressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

neuroscience↗