It is essential to characterize and quantify naturally occurring morphometric changes in the human brain when investigating the onset or progression of neurodegenerative disorders. The aim of this thesis is to characterize the properties and measure the performance of several popular automated magnetic resonance image analysis tools dedicated to brain morphometry. The thesis begins with an overview of morphometric analysis methods, followed by a literature review focusing on cortical parcellation protocols. Our work identified unanimous protocol weaknesses across all packages in particular issues when addressing cortical variability. The next chapters present a ground truth dataset and a dedicated software to analyse manually parcellated data. The dataset (https://datashare.is.ed.ac.uk/handle/10283/2936) includes 10 healthy middle-aged subjects, whose metrics we used as reference against automated tools. To develop the ground truth dataset, we also present a manual parcellation protocol (https://datashare.is.ed.ac.uk/handle/10283/3148) providing step-by-step instructions for outlining three cortical gyri known to vary with ageing and dementia: the superior frontal gyrus, the cingulate gyrus and the supramarginal gyrus. The software, Masks2Metrics (https://datashare.is.ed.ac.uk/handle/10283/3018), was built in Matlab to calculate cortical thickness, white matter surface area, and grey matter volume from 3D binary masks. Characterizing these metrics allowed further understanding of the assumptions made by software when creating and measuring anatomical parcels. Next, we present results from processing the raw T1-weighted volumes in the latest versions of several automated image analysis tools-FreeSurfer (versions 5.1 and 6.0), BrainGyrusMapping, and BrainSuite (version 13a)- against our ground truth. Tool repeatability for the same system was confirmed as multiple runs yielded identical results. Compared to our ground truth, the closest results were generated by BrainGyrusMapping for volume metrics and by FreeSurfer 6.0 for thickness and surface area metrics. In conclusion, our work sheds light on the significance of clearly detailed parcellation protocols and accurate morphometric tools due to the implications that they both will have. We therefore recommend extra caution when selecting image analysis tools for a study, and the use of independent publicly available ground truth datasets and metrics tools to assist with the selection process.

The logistical complexities of performing multi-site longitudinal diffusion-weighted imaging (DWI) studies requires careful construction of analysis tools and procedures. Proposed clinical trials for therapies in neurodegenerative disease are known to re- quire several hundred subjects, thus mandating multiple site participation to obtain sufficient sample sizes. DWI is an important tool for monitoring diffusivity properties of white matter (WM) in disease progression. The multi-site nature of clinical trials requires new strategies in DWI processing and analysis to reliably measure longitudi- nal WM changes. This work describes the process of developing and validating robust analysis methodologies to process multi-site DWI data in a rare, neurodegenerative disease. Key processing components to accomplish a robust DWI processing system include: DICOM conversion, automated quality control, unbiased atlas construction, fiber tracking, and statistical analysis. Extensive validation studies were performed to characterize methodological results within and across the common confounds inherent in multi-site clinical trials. The conversion and automated quality control tools optimized for this work both enhanced the ability to reliably obtain repeat diffusion tensor image (DTI) scalar measurements in a reliability analysis of healthy controls scanned at multiple sites using multiple scanner vendors. A DTI scalar analysis performed on focused WM regions showed it was possible to detect significant mean differences of DTI scalars among separate groups of a neurodegenerative disease population. The DTI scalar analysis paved the way for an atlas-based cross-sectional fiber tracking analysis. In the cross-sectional fiber tracking analysis, multi-site data was brought into the same space, making major fiber tracts terminating in the focused WM regions of the scalar analysis from all participants comparable. Significant differences in diffusivity were found throughout each tract among separate groups of the neurodegenerative disease population. In addition, multiple neuropsychological cognitive variables that have a documented ability to track disease progression of the neurodegenerative disease, strongly correlated with many of the DTI scalars in each tract. The findings of the cross-sectional fiber tracking analysis were reinforced by similar findings produced by a longitudinal fiber tracking analysis. Collectively, these findings suggest that cogni- tive deficits seen in the neurodegenerative disease population could be explained by changes in diffusivity of the tracts explored in this work. In addition to the longi- tudinal fiber tracking analysis examining diffusivity, methods for a WM morphology analysis using parallel transport to apply longitudinal volume changes to a template was explored.

<p>Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions.</p><p>The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF).</p><p>The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin.</p><p>A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role.</p><p>In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF.</p><p>In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks > 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.</p>

The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.

The purpose of this study was to investigate the relationship between word reading and white matter (WM) integrity in the reading system and test a theory-based moderated mediation model such that relationship of WM integrity with word reading is mediated by processing speed and indirect effect is moderated by group. Thirty-seven adult survivors of childhood brain tumor and typically developing adults participated (mean age=24.19(4.51) years, 62% female). Tractography identified the WM tract for three reading system connections. Fractional anisotropy of the IFOF and PT-OT tracts were significantly correlated with word reading in survivors (r=.55, .46, respectively; p

In two separate studies, we used diffusion tensor imaging (DTI)to examine white matter changes secondary to traumatic brain injury (TBI) and spinal cord injury (SCI). The first study examined the utility of DTI for a single case diagnosis of mild TBI (mTBI) and demonstrated that the anterior limb of the internal capsule and the genu of the corpus callosum were sensitive and specific to mTBI. The second study examined the sub-acute effects of SCI on white matter tissue in the brain and demonstrated that SCI patients have a significantly greater degree of FA asymmetry than control subjects in the superior and posterior corona radiata. The first study has provided preliminary proof of principal evidence that DTI can be used to diagnose mTBI in individual cases. The second study suggests that the degree of asymmetry may be a useful biomarker for detecting subtle white matter changes.

In two separate studies, we used diffusion tensor imaging (DTI)to examine white matter changes secondary to traumatic brain injury (TBI) and spinal cord injury (SCI). The first study examined the utility of DTI for a single case diagnosis of mild TBI (mTBI) and demonstrated that the anterior limb of the internal capsule and the genu of the corpus callosum were sensitive and specific to mTBI. The second study examined the sub-acute effects of SCI on white matter tissue in the brain and demonstrated that SCI patients have a significantly greater degree of FA asymmetry than control subjects in the superior and posterior corona radiata. The first study has provided preliminary proof of principal evidence that DTI can be used to diagnose mTBI in individual cases. The second study suggests that the degree of asymmetry may be a useful biomarker for detecting subtle white matter changes.

A complete scientific understanding of human nature requires delineation of the neurobiological characteristics underlying the unique features of the human mind. This effort can be facilitated by comparing the human brain with the brains of other living primate species. Humans are more susceptible to neurodegenerative diseases than other primate species, including our closest living primate relatives, the chimpanzees. Comparing age-related changes in brain structure between humans and non-human primates could, therefore, potentially shed light on the neurological basis of this human vulnerability. Further, human brains are lateralized with specialized cognitive and behavioral functions. Comparing the magnitude of hemispheric asymmetries in brain structure between humans and non-human primates can probe insights into this human specific capability and learn more about human evolution. Diffusion weighted MRI protocols were developed for different species, taking into account their neuroanatomical differences. For Chimpanzees, a multi-shot DWI sequence was developed and compared with a single-shot DWI sequence to determine which provided a better quality diffusion data free of acquisition related artifacts. Different simulation techniques were used to evaluate the effect of segmentation-related motion artifact (ghosting) on the multi-shot DTI data. Although both protocols generated high-resolution diffusion MRI data with correctable susceptibility-induced distortions, the single-shot protocol enables the acquisition of the high-resolution diffusion MRI data freed of ghosting and with twice the signal-to-noise ratio (SNR), for the same scan duration. The acquired chimpanzee and macaque diffusion data were used to compare the magnitude of microstructural asymmetries and age-related decline of brain white matter with those in humans. Hemispheric asymmetry results show a pattern of strong leftward asymmetry in human DTI indices that differs markedly from the chimpanzee (multi-shot data) and the rhesus macaque patterns involving both rightward and leftward asymmetries. The magnitude of leftward asymmetry increased for chimpanzees scanned with single-shot DTI sequence. Region of interest analyses within the corpus callosum revealed a significant age-related increase in fractional anisotropy (FA) in the genu for chimpanzees (multi-shot data) and no significant change in any region for macaques. Additionally, voxel-wise analysis using Tract Based Spatial Statistics (TBSS) revealed widespread age-related FA increases for chimpanzees (multi-shot data) and weak age-related decreases in FA for macaques across most white matter tracts. Overall, results from these multi-shot data analyses suggest that rhesus monkeys show age-related decreases in white matter integrity that parallel changes found in humans, whereas chimpanzees show age-related increases in white matter integrity. On the contrary, the single-shot data results for chimpanzees revealed no significant relationship between age and the different DTI indices. These noteworthy species differences may help to explain the unique features of the human mind and why humans are more susceptible to neurodegenerative diseases. Furthermore, these studies demonstrate the need for complementary histological studies of white matter microstructure in humans, chimpanzees and macaques to clarify the cellular and molecular basis of these findings.

<p>The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.</p>

Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions. The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF). The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin. A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role. In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF. In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks &gt; 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.