Characterising the structural brain changes in Huntington’s disease using translational neuroimaging

This thesis examined the macro-structural and micro-structural changes in Huntington’s disease (HD) in order to improve understanding of the temporal and spatial patterns of neurodegeneration, and the functional relevance of these changes. Translational techniques were employed using genetic mouse models of HD in combination with a patient cohort to examine grey and white matter changes with a particular focus on white matter microstructure. In the patient cohort, the cognitive profile was examined using a cognitive battery not before applied in HD. Specific deficits were found in set-shifting and flexibility, verbal reasoning, working memory and paired associate learning, along with subtle differences in response inhibition that were sensitive to disease burden. A composite cognitive score was produced to examine the relationship between cognitive function and brain structure. A multi-modal examination of white matter tract-specific microstructural measurements revealed abnormalities in the corpus callosum and cingulum bundle that were sensitive to disease burden (chapter 4). In chapter 5, multiple analysis techniques converged to reveal tissue macrostructure abnormalities that were also sensitive to disease burden in HD. Cortical changes were less consistent, and unlike the microstructure findings, white matter macrostructural abnormalities were not related to disease burden. In chapters 6 and 7, genetic mouse models of HD were used to examine changes across the disease course, and to pilot an interventional design. In vivo diffusion MRI and T2-weighted MRI sequences were acquired at 2 different time points in the HdhQ150 knock-in model of HD and imaging data is presented alongside behavioural results and immunohistochemistry. In chapter 7, an environmental modification regime was tested in the YAC128 mouse model using in vivo MRI. Environmental intervention reduced the degree of disease-related atrophy, altered tissue microstructure and improve motor but not cognitive performance in YAC128 mice

Assessment of the effects of aerobic fitness on cerebrovascular function in young adults using multiple inversion time arterial spin labelling MRI

The cross-sectional study investigated the effects of aerobic fitness on cerebrovascular function in the healthy brain. We quantified grey matter (GM) cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), in a sample of young adults within a normal fitness range. Based on existing TCD and fMRI evidence, we predicted a positive relationship between fitness and resting GM CBF, and CVR. Exploratory hypotheses that highe

Hypertension, antihypertensive use and the delayed onset of Huntington's Disease

Background: Hypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease. Methods: Using longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length. Results: Huntington's disease patients had a lower prevalence of hypertension compared with age‐matched gene‐negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease. Conclusions: We report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease‐modifying potential of antihypertensives in neurodegenerative diseases are warranted

Assessment of the effects of aerobic fitness on cerebrovascular function in young adults using multiple inversion time arterial spin labeling MRI

This cross-sectional study investigated the effects of aerobic fitness on cerebrovascular function in the healthy brain. Gray matter cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) were quantified in a sample of young adults within a normal fitness range. Based on existing Transcranial Doppler ultrasound and fMRI evidence, we predicted a positive relationship between fitness and resting gray matter CBF and CVR. Exploratory hypotheses that higher V.O2peak would be associated with higher GM volume and cognitive performance were also investigated. 20 adults underwent a V.O2peak test and a battery of cognitive tests. All subjects also underwent an MRI scan where multiple inversion time (MTI) pulsed arterial spin labeling (PASL) was used to quantify resting CBF and CVR to 5% CO2. Region of interest analysis showed a non-significant inverse correlation between whole-brain gray matter CBF and V.O2peak; r = −0.4, p = 0.08, corrected p (p′) = 0.16 and a significant positive correlation between V.O2peak and whole-brain averaged gray matter CVR; r = 0.62, p = 0.003, p′ = 0.006. Voxel-wise analysis revealed a significant inverse association between V.O2peak and resting CBF in the left and right thalamus, brainstem, right lateral occipital cortex, left intra-calcarine cortex and cerebellum. The results of this study suggest that aerobic fitness is associated with lower baseline CBF and greater CVR in young adults

Robust MR-based approaches to quantifying white matter structure and structure/function alterations in Huntington's disease

Background: Huge advances have been made in understanding and addressing confounds in diffusion MRI data to quantify white matter microstructure. However, there has been a lag in applying these advances in clinical research. Some confounds are more pronounced in HD which impedes data quality and interpretability of patient-control differences. This study presents an optimised analysis pipeline and addresses specific confounds in a HD patient cohort. Method: 15 HD gene-positive and 13 matched control participants were scanned on a 3T MRI system with two diffusion MRI sequences. An optimised post processing pipeline included motion, eddy current and EPI correction, rotation of the B matrix, free water elimination ( FWE ) and tractography analysis using an algorithm capable of reconstructing crossing fibres. The corpus callosum was examined using both a region-of-interest and a deterministic tractography approach, using both conventional diffusion tensor imaging ( DTI )-based and spherical deconvolution analyses. Results: Correcting for CSF contamination significantly altered microstructural metrics and the detection of group differences. Reconstructing the corpus callosum using spherical deconvolution produced a more complete reconstruction with greater sensitivity to group differences, compared to DTI-based tractography. Tissue volume fraction ( TVF ) was reduced in HD participants and was more sensitive to disease burden compared to DTI metrics. Conclusion: Addressing confounds in diffusion MR data results in more valid, anatomically faithful white matter tract reconstructions with reduced within-group variance. TVF is recommended as a complementary metric, providing insight into the relationship with clinical symptoms in HD not fully captured by conventional DTI metrics

Cerebral metabolic changes during visuomotor adaptation assessed using quantitative fMRI

The brain retains a lifelong ability to adapt through learning and in response to injury or disease-related damage, a process known as functional neuroplasticity. The neural energetics underlying functional brain plasticity have not been thoroughly investigated experimentally in the healthy human brain. A better understanding of the blood flow and metabolic changes that accompany motor skill acquisition, and which facilitate plasticity, is needed before subsequent translation to treatment interventions for recovery of function in disease. The aim of the current study was to characterize cerebral blood flow (CBF) and oxygen consumption (relative CMRO2) responses, using calibrated fMRI conducted in 20 healthy participants, during performance of a serial reaction time task which induces rapid motor adaptation. Regions of interest (ROIs) were defined from areas showing task-induced BOLD and CBF responses that decreased over time. BOLD, CBF and relative CMRO2 responses were calculated for each block of the task. Motor and somatosensory cortices and the cerebellum showed statistically significant positive responses to the task compared to baseline, but with decreasing amplitudes of BOLD, CBF, and CMRO2 response as the task progressed. In the cerebellum, there was a sustained positive BOLD response in the absence of a significant CMRO2 increase from baseline, for all but the first task blocks. This suggests that the brain may continue to elevate the supply energy even after CMRO2 has returned to near baseline levels. Relying on BOLD fMRI data alone in studies of plasticity may not reveal the nature of underlying metabolic responses and their changes over time. Calibrated fMRI approaches may offer a more complete picture of the energetic changes supporting plasticity and learning

The spatiotemporal dynamics of cerebral autoregulation in functional magnetic resonance imaging

The thigh-cuff release (TCR) maneuver is a physiological challenge that is widely used to assess dynamic cerebral autoregulation (dCA). It is often applied in conjunction with Transcranial Doppler ultrasound (TCD), which provides temporal information of the global flow response in the brain. This established method can only yield very limited insights into the regional variability of dCA, whereas functional MRI (fMRI) has the ability to reveal the spatial distribution of flow responses in the brain with high spatial resolution. The aim of this study was to use whole-brain blood-oxygenation-level-dependent (BOLD) fMRI to characterize the spatiotemporal dynamics of the flow response to the TCR challenge, and thus pave the way toward mapping dCA in the brain. We used a data driven approach to derive a novel basis set that was then used to provide a voxel-wise estimate of the TCR associated haemodynamic response function (HRFTCR). We found that the HRFTCR evolves with a specific spatiotemporal pattern, with gray and white matter showing an asynchronous response, which likely reflects the anatomical structure of cerebral blood supply. Thus, we propose that TCR challenge fMRI is a promising method for mapping spatial variability in dCA, which will likely prove to be clinically advantageous

Cerebrovascular Function in the Large Arteries Is Maintained Following Moderate Intensity Exercise

Exercise has been shown to induce cerebrovascular adaptations. However, the underlying temporal dynamics are poorly understood, and regional variation in the vascular response to exercise has been observed in the large cerebral arteries. Here, we sought to measure the cerebrovascular effects of a single 20-min session of moderate-intensity exercise in the one hour period immediately following exercise cessation. We employed transcranial Doppler (TCD) ultrasonography to measure cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) before, during, and following exercise. Additionally, we simultaneously measured cerebral blood flow (CBF) in the internal carotid artery (ICA) and vertebral artery (VA) before and up to one hour following exercise cessation using Duplex ultrasound. A hypercapnia challenge was used before and after exercise to examine exercise-induced changes in cerebrovascular reactivity (CVR). We found that MCAv and PCAv were significantly elevated during exercise (p = 4.81 × 10-5 and 2.40 × 10-4, respectively). A general linear model revealed that these changes were largely explained by the partial pressure of end-tidal CO2 and not a direct vascular effect of exercise. After exercise cessation, there was no effect of exercise on CBFV or CVR in the intracranial or extracranial arteries (all p > 0.05). Taken together, these data confirm that CBF is rapidly and uniformly regulated following exercise cessation in healthy young males

Dual-calibrated fMRI measurement of absolute cerebral metabolic rate of oxygen consumption and effective oxygen diffusivity

Dual-calibrated fMRI is a multi-parametric technique that allows for the quantification of the resting oxygen extraction fraction (OEF), the absolute rate of cerebral metabolic oxygen consumption (CMRO2), cerebral vascular reactivity (CVR) and baseline perfusion (CBF). It combines measurements of arterial spin labelling (ASL) and blood oxygenation level dependent (BOLD) signal changes during hypercapnic and hyperoxic gas challenges. Here we propose an extension to this methodology that permits the simultaneous quantification of the effective oxygen diffusivity of the capillary network (DC). The effective oxygen diffusivity has the scope to be an informative biomarker and useful adjunct to CMRO2, potentially providing a non-invasive metric of microvascular health, which is known to be disturbed in a range of neurological diseases. We demonstrate the new method in a cohort of healthy volunteers (n = 19) both at rest and during visual stimulation. The effective oxygen diffusivity was found to be highly correlated with CMRO2 during rest and activation, consistent with previous PET observations of a strong correlation between metabolic oxygen demand and effective diffusivity. The increase in effective diffusivity during functional activation was found to be consistent with previously reported increases in capillary blood volume, supporting the notion that measured oxygen diffusivity is sensitive to microvascular physiology