Thesis (Ph. D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed Mar. 31, 2010). Additional advisors: N. Shastry Akella, James E. Cox, Gitendra Uswatte, Victor W. Mark. Includes bibliographical references (p. 50-60).

Basic science and early clinical trial evidence suggest the safe diuretic drug amiloride, may exert a neuroprotective effect in multiple sclerosis (MS) through blockade of the acid sensing ion channel. Neuroprotective treatments are a key unmet need in multiple sclerosis. Optic neuritis (ON) is a discrete CNS inflammatory event leading to neuro-axonal injury in the optic nerve and retina. The optic nerve is part of the visual system, one of the most functionally and structurally eloquent systems in the central nervous system, which affords a number of unique modalities to assess neurodegeneration and neuroprotection. The visual system can be classified into two parts, the anterior and posterior visual systems, which are defined by the lateral geniculate nucleus, where the two components synapse. The extent of neurodegeneration following ON in the anterior visual system can be imaged in vivo through scanning laser polarimetry (GDx) and optical coherence tomography (OCT). The posterior visual system can be imaged by quantitative and functional magnetic resonance imaging (MRI) of the brain, giving insights into white matter structural integrity and cortical plasticity over time. Combining these modalities in a longitudinal study, allows assessment of the impact of neurodegeneration in the anterior visual system on neurodegeneration downstream in the posterior visual system and on changes in functional connectivity over time in the visual cortex. Furthermore, in the clinical trial setting the neuroprotective effect of any intervention both on direct anterior neurodegeneration and downstream processes can be assessed. The functional relevance of changes in all of these biomarkers can be tested through a number of visual measures, including low contrast visual acuity. In MS, the contribution of transsynaptic neurodegeneration to the global neuronal loss experienced by patients is an area of incomplete understanding. In addition, the role of the visual cortex, through neuroplasticity, in aiding visual recovery from optic neuritis, is unclear. To address these issues, this thesis reports the results of the first clinical trial of amiloride in ON, and shows that despite the pre- and early clinical evidence of neuroprotection of amiloride, no neuroprotective benefit was found. It goes on to explore reasons for this lack of effect including the finding of early retinal neurodegeneration in ON, and the need for early recruitment windows in the future. From there, it makes a detailed assessment of the longitudinal changes in retinal OCT for 12 months following ON, including a novel finding of the temporal evolution of inner nuclear layer swelling, previously reported only cross-sectionally. Next, for the first time macular retinal neurodegeneration is shown to influence diffusion tensor MRI derived measures of white matter integrity in the optic radiations, indicating transsynaptic neurodegeneration. Finally, longitudinal changes in resting state functional connectivity following ON are found in the visual system for the first time. The interaction between this cortical functional, retinal neurodegeneration and visual recovery is probed.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder that causes distinct motor impairments (i.e., resting tremor, bradykinesia, rigidity, postural instability) and affects approximately one percent of the global population over the age of 60 years. Currently, there is no cure and diagnosis remain challenging due to the lack of well validated biomarkers. Prodromal PD is a phase that predates the onset of motor symptoms but includes brain changes and nonmotor symptoms, such as rapid eye movement sleep behaviour disorder (RBD) and hyposmia. Diffusion tensor imaging (DTI) provides non-invasively acquired metrics of microstructural changes in white matter and subcortical tissue and has potential as a biomarker for PD. To date, most DTI studies have focused on the clinical phase of PD. Investigating potential biomarkers in the prodromal phase of the disease is key for early diagnosis and treatment. This study had two primary objectives: (1) to investigate how white matter microstructure changes in different phases of PD progression, and (2) to investigate how sleep and motor symptoms relate to white matter microstructure in different phases of PD. Methods: All study data were downloaded from the Parkinson’s Progression Markers Initiative database. Subjects included 21 heathy controls (mean age=68.17±4.69; 6 female), 20 individuals with prodromal PD (14 with RBD and 6 with hyposmia) (mean age=67.95±5.90; 6 female), and 17 individuals with clinical PD (mean age=67.69±5.97; 6 female) (at baseline and one-year later). Tract based spatial statistics were used to determine between group differences in fractional anisotropy (FA) and mean diffusivity (MD) at the whole brain level and in a region of interest (ROI), the substantia nigra. The relationship between sleep or motor symptoms and DTI metrics were investigated within each group. Results: There were no differences between the groups in age, education level, or cognitive scores. Clinical PD had significantly higher motor symptoms than healthy controls or prodromal PD, and this significantly increased from baseline to one-year later. Between group comparisons showed increased MD (reflecting increased neurodegeneration) in prodromal PD relative to clinical PD (both at baseline and one-year later), while there were no group differences between either prodromal or clinical PD and healthy controls at the whole brain level or within the ROI. Increased motor symptoms were associated with neurodegeneration (i.e., decreased FA and increased MD) for healthy controls, while increased sleep symptoms were associated with decreased MD for clinical PD. Conclusion: This was the first to study of white matter microstructure differences in a mixed prodromal PD group relative to clinical PD. The detected early brain changes may support an RBD subtype of PD with overall different pattern of neurodegeneration. However, these results are preliminary and future studies must be conducted to clarify and expand upon the microstructural differences between prodromal and clinical PD, ideally with longitudinal follow-up. / Graduate / 2019-07-27

Thesis (M.Sc (Radiography))--Cape Peninsula University of Technology, 2016. / Multiple sclerosis (MS) affects the central nervous system (CNS) and is characterized by multiple demyelinating lesions. It is in this context that a need arises for reliable biomarkers such as Magnetic Resonance Imaging (MRI), which could lead to the early diagnosis and therapeutic intervention when maximum potential impact is possible. This study examines the impact of MRI as a marker and the sequences that give the best images to aid in evaluation of disease progression (which can indirectly be seen as disability) and the early diagnosis of MS which will, in turn, lead to more effective management of the disease. METHOD: Sixteen subjects underwent a neurological examination, the Expanded Disability Status Scale (EDSS), blood tests for iron parameters and a 3Tesla Magnetic Resonance Imaging (MRI) scan. In a study of MS, 11 had MRI data that could be analysed by using tract-based spatial statistics (TBSS). Subjects were divided according to the EDSS score (8 of the subjects had an EDSS score of ≤ 3 while 3 subjects had scores of ≥ 6). Diffusion tensor imaging (DTI), the fused Proton Density and Fluid Attenuation Recovery (FLAIR) was utilised to compute the lesion numbers and standard laboratory procedures were used to measure other biochemical markers (serum iron, % transferrin saturation, ferritin, haemoglobin) in subjects with disability and simultaneously assess the disease process. RESULTS: The FA of white matter tracts (WMTs) as a parameter of myelin integrity was lower in subjects with MS only in those who had high EDSS scores. An association between FA and iron parameters, especially percentage transferrin saturation (% Tf) sat were observed, which suggests that iron availability to the WM may be a requirement for optimal myelin functionality. CONCLUSION: The FA of WMTs as a parameter of myelin integrity was lower only in those MS subjects who had high EDSS scores. Subjects who had EDSS scores < 3 (i.e. who had a “benign” disease outcome) had FA values similar to control values and this finding was not related to their age or disease duration. The association found between FA and iron parameters, especially % Tf sat, suggests that iron availability to the WM may be a requirement for optimal myelin functionality. Results also suggest that serum iron concentration, ferritin and % Tf sat had an effect on myelination. The lack of association between FA and Hb suggests that the iron in this protein is not available for WM function.

Esclerose Múltipla (MS) é uma doença neurodegenerativa que tem ganhado grande atenção nas últimas décadas, sendo o diagnóstico por imagens de ressonância magnética (MRI) um grande aliado para a avaliação da doença.Porém, um dos principais desafios é garantir uma maior sensibilidade e especificidade para detecção de diferentes lesões no sistema nervoso central (CNS) e assim classificar as diferentes variantes da MS, auxiliando na tomada de decisão para o tratamento farmacológico. Nas últimas décadas, a técnica de imagens ponderadas por difusão (DWI), em especial a técnica de imagem por tensor de difusão (DTI), têm sido evidenciada com grande potencial para o estudo da MS, apresentando uma melhora significativa para a detecção de lesões sutis, ainda em estágios iniciais da MS. Desta forma, as técnicas de processamento de imagens estão em constante aprimoramento para que sejam adaptados às novas modalidades de aquisição de imagens. Neste estudo focamos o desenvolvimento de uma técnica de processamento digital de imagens multimodais a fim de proporcionar uma solução viável para a rotina de diagnóstico por imagem em MS. Um conjunto de 25 pacientes de uma variante de MS foi selecionado aleatoriamente do banco de imagens do HCFMRP. Três modalidades de imagens foram coletadas para a avaliação da segmentação automatica (T1, T2-FLAIR e DTI), assim como a segmentação manual do especialista para cada paciente. Três métodos de segmentação multimodal automática de lesões foram analisados (Bayesiano, Frequentista e Agrupamento) afim de analisar a sensibilidade e especificidade de detecção de lesões na substância branca aparentemente normal (NAWM). Os resultados sugerem que o método de segmentação Bayesiano apresenta maior robustes e precisão na definição tanto de lesões visivelmente contrastantes em T1 e T2-FLAIR (i.e. lesões hipo e hiperintensas) assim como lesões da NAWM evidentes nos mapas quantitativos de DTI (FA e ADC). O erro associado à técninca automática de segmentação ficou em torno de 1.51 +- 0.51 % do volume total de lesões marcadas pelo especialista. Concluímos que o uso de ferramentas multimodais de segmentação de imagens MRI alcançou patamares razoáveis de detecção de lesões de MS, tornando assim uma ferramenta computacional hábil para uso no diagnóstico clínico. / Multiple sclerosis (MS) is a neurodegenerative disease that has gained great attention in the last decades, which magnetic resonance imaging (MRI) have shown as an important tool for the disease evaluation. However, one of the main challenges is guaranteeing greater lesion detection sensitivity and specificity in the whole central nervous system (CNS) and thus classify the different variants of MS, which aids in decision making for pharmacological treatment. In the last decades, the diffusion-weighted imaging (DWI) technique, especially the diffusion tensor imaging approach (DTI), has been evidenced with great potential for the study of MS, presenting a significant improvement for the detection of lesions even in early stages of MS. Hence, the techniques of image processing are constantly improving in order to be adapted on a multimodal image evaluation. In this study, the development of a multimodal digital image processing technique to provide a viable solution to the MS imaging routine was focused. A set of 25 patients from a MS variant was randomly selected from the HCFMRP imaging database. Three MR imaging modalities were collected for the evaluation of our automatic segmentation (T1, T2-FLAIR and DTI), as well as manual segmentation of the specialist for each patient. Three methods of automatic multimodal segmentation of MS lesions were analyzed (Bayesian, Frequentist and Clustering) in order to analyze the sensitivity and specificity of lesion detection in the apparently normal white matter (NAWM). The results suggest that the Bayesian segmentation method presented greater robustness and precision in the definition of visibly contrasting lesions in T1 and T2-FLAIR (i.e. hypo and hyperintense lesions) as well as NAWM lesions that are evident in quantitative DTI (FA and ADC). The error associated with the automatic segmentation technique was around 1.51 +- 0.51 % of the total lesion volume being evaluated by the a specialist. We conclude that the use of multimodal MRI images can be used in an automatic segmentation tools, reaching reasonable levels of MS lesion detection, thus making it a useful tool for clinical diagnosis.

Diffusion-weighted magnetic resonance imaging (dMRI) has been used to non-invasively investigate the integrity of white matter and the connectivity of the brain. In this work, high angular resolution diffusion imaging (HARDI), an advanced dMRI methodology was developed and employed in bonnet macaque monkeys to study the connectivity of the orbitofrontal cortex (OFC) and amygdala, two gray matter regions involved in making reward-guided decisions. With age, it is believed that there is a decline in the white matter connectivity between these two regions, also known as uncinate fasciculus (UF), and that this affects reward-value assignment and feedback learning in older adults. The analysis pipeline involved correction for distortions due to eddy currents and field inhomogeneity, noise reduction using a local principal component analysis based technique and subsequent registration to the high-resolution T1-weighted images. Gray matter regions corresponding to OFC and amygdala were identified on the T1-weighted images and probabilistic tractography was carried out to delineate the tracts belonging to UF. The output connectivity map from tractography was used to extract imaging parameters of interest such as fractional anisotropy, axial and radial diffusivity along the UF. A significant reduction in the fractional anisotropy index and the axial diffusivity index along the UF tract was observed with increased age of monkeys. Compared to the left hemisphere, stronger trends were observed in the right hemisphere of the monkeys, indicating possible laterality.

The default mode network (DMN) consists of a set of interconnected brain regions supporting autobiographical memory, our concept of the self, and the internal monologue. These processes must be maintained at all times and consume the highest amount of the brain’s energy during its baseline state. However, when faced with an active, externally-directed cognitive task, the DMN shows a small, but significant, decrease in activity. The reduction in DMN activity during the performance of an active, externally-directed task compared to a baseline state is termed task-induced deactivation (TID), which is thought to ‘free-up’ resources required to respond to external demands. However, older adults show a reduced level of TID in the DMN. Recently, it has begun to be appreciated that this decrease in TID may be associated with poorer cognitive performance, especially during tasks placing high demands on executive function (EF). Diminished DMN TID has not only been associated with increasing age but also with multiple age-related neurobiological correlates such as accumulating Alzheimer’s disease (AD) pathology and reductions in white matter (WM) connectivity. However, these biological factors—age, WM connectivity reductions and increasing AD pathology—are themselves related. Based on the literature, we hypothesized that declining WM connectivity may represent a common pathway by which both age and AD pathology contribute to diminished DMN TID. Further, we hypothesized that declines in DMN function and WM connectivity would predict poorer in EF. Three experiments were carried out to test these hypotheses. Experiment 1 tested whether WM connectivity predicted the level of DMN TID during a task requiring a high level of EF. Results from 117 adults (ages 25-83) showed that WM connectivity declined with increasing age, and that this decline in WM connectivity was directly associated with reduced DMN TID during the task. Experiment 2 tested whether declines in WM connectivity explained both age-related and AD pathology-related declines in DMN TID. Results from 29 younger adults and 35 older adults showed that declining WM connectivity was associated with increasing age and AD pathology, and that this decline in WM connectivity was a common pathway for diminished DMN TID associated with either aging or AD pathology. Experiment 3 investigated whether measures of WM connectivity and DMN TID at baseline could predict EF measured using clinically-used tests. Results from 29 older adults from Experiment 2 showed that less DMN TID predicted poorer EF at baseline and diminished WM connectivity at baseline predicted a greater decline in EF after 3 years. Further, WM connectivity explained reductions in EF predicted by baseline AD pathology, as well as further reductions in EF not predicted by baseline AD pathology. Together the results of these studies suggest that WM connectivity is a key pathway for age-related and AD pathology-related patterns of diminished DMN TID associated with poorer EF. Further, WM connectivity may represent a potential therapeutic target for interventions attempting to prevent future declines in EF occurring in aging and AD.

Visuomotor behaviour – from handling simple objects to operating complex devices – is of fundamental importance in our everyday lives, yet there is relatively little evidence as to how healthy ageing affects these processes. A central role is played by the human capacity for reaching and grasping. Grasping an object requires complex visuomotor transformations, including processing of the object’s extrinsic features (it’s spatial location) and intrinsic features (such as size and shape). It has been documented that action relevant intrinsic object properties automatically facilitate specific motor actions despite being task-irrelevant, the so-called object affordance effect. These effects have been demonstrated for (1) grasp type (precision and power grips being facilitated by small and large objects) and (2) object-orientation (whereby right and left handed grasps are facilitated by object-orientation), and might underlie the effortlessness with which humans can interact with objects. Yet, these paradigms have not previously been employed in the study of healthy ageing, and little is known concerning how these processes change over the life span. Elucidating these changes is of particular importance as age-related degeneration of white matter integrity is well documented. Consequently, if successful visuomotor behaviour relies on white matter integrity, age-related reductions in affordance effects should be observed. This prediction was tested in a series of experiments. Experiment 1 investigated age-differences in object-size compatibility effects, and results corroborated our prediction of age-related reductions in object-size effects. Experiment 2 investigated age-differences in (1) spatial compatibility effects versus object-orientation effects, and (2) the locus of the effects (facilitation versus interference effects). Results revealed (1) some evidence of larger affordance than spatial effects in both age-groups, and (2) interference effects in the younger group and both facilitation and interference effects in the older group, showing a potential change in processing modes or strategies. Experiments 3 and 4 addressed the main competing account, the attention-directing hypothesis (according to which attentional shifts are responsible for the generation of automatic response codes, rather than the affects arising from afforded actions), by using a novel stimulus set in which such attentional differences can be ruled out. Results provided strong evidence in favour of the object-size affordance hypothesis. A final neuroimaging experiment investigated age-differences in the object-size effect and its neural correlates by combining behavioural, functional MRI and diffusion tensor imaging (DTI) data. Results revealed evidence of age-differences, both on the behavioural and functional level. For the DTI data, we investigated all four diffusion metrics (something which is not frequently reported in the healthy ageing literature), and found widespread age-related differences in white matter integrity. The empirical findings presented in this thesis offer a significant contribution to ageing research, by further elucidating the relationship between age-related neurophysiological changes and visuomotor behaviour. The overall picture which emerged from this series of experiments was consistent with our prediction of age-related reductions in affordance effects. Furthermore, it is likely that these age-differences may have, at least in part, a neurophysiological basis.

Non-cognitive features including personality changes are increasingly recognized in the three PPA variants (semantic-svPPA, non fluent-nfvPPA, and logopenic-lvPPA). However, differences in emotion processing among the PPA variants and its association with white matter tracts are unknown. We compared emotion detection across the three PPA variants and healthy controls (HC), and related them to white matter tract integrity and cortical degeneration. Personality traits in the PPA group were also examined in relation to white matter tracts. Thirty-three patients with svPPA, nfvPPA, lvPPA, and 32 HC underwent neuropsychological assessment, emotion evaluation task (EET), and MRI scan. Patients' study partners were interviewed on the Clinical Dementia Rating Scale (CDR) and completed an interpersonal traits assessment, the Interpersonal Adjective Scale (IAS). Diffusion tensor imaging of uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), and voxel-based morphometry to derive gray matter volumes for orbitofrontal cortex (OFC), anterior temporal lobe (ATL) regions were performed. In addition, gray matter volumes of white matter tract-associated regions were also calculated: inferior frontal gyrus (IFG), posterior temporal lobe (PTL), inferior parietal lobe (IPL) and occipital lobe (OL). ANCOVA was used to compare EET performance. Partial correlation and multivariate linear regression were conducted to examine association between EET and neuroanatomical regions affected in PPA. All three variants of PPA performed significantly worse than HC on EET, and the svPPA group was least accurate at recognizing emotions. Performance on EET was related to the right UF, SLF, and ILF integrity. Regression analysis revealed EET performance primarily relates to the right UF integrity. The IAS subdomain, cold-hearted, was also associated with right UF integrity. Disease-specific emotion recognition and personality changes occur in the three PPA variants and are likely associated with disease-specific neuroanatomical changes. Loss of white matter integrity contributes as significantly as focal atrophy in behavioral changes in PPA.

Mild traumatic brain injury (mTBI) is a common and often inconspicuous wound that is frequently associated with chronic low-grade symptoms and cognitive dysfunction. Previous evidence suggests that daily blue wavelength light therapy may be effective at reducing fatigue and improving sleep in patients recovering from mTBI. However, the effects of light therapy on recovering brain structure remain unexplored. In this study, we analyzed white matter diffusion properties, including generalized fractional anisotropy, and the quantity of water diffusion in isotropic (i.e., isotropic diffusion) and anisotropic fashion (i.e., quantitative anisotropy, QA) for fibers crossing 11 brain areas known to be significantly affected following mTBI. Specifically, we investigated how 6 weeks of daily morning blue light exposure therapy (compared to an amber-light placebo condition) impacted changes in white matter diffusion in individuals with mTBI. We observed a significant impact of the blue light treatment (relative to the placebo) on the amount of water diffusion (QA) for multiple brain areas, including the corpus callosum, anterior corona radiata, and thalamus. Moreover, many of these changes were associated with improvements in sleep latency and delayed memory. These findings suggest that blue wavelength light exposure may serve as one of the potential non-pharmacological treatments for facilitating structural and functional recovery following mTBI; they also support the use of QA as a reliable neuro-biomarker for mTBI therapies.