Many disorders are associated with regional brain volumes. The analysis of these volumes from MR images often requires sequential processing steps such as localization and delineation. It is common to perform volumetric normalization using intracranial volume (ICV, the total volume inside the cranial cavity) when comparing regional brain volumes, since head size varies considerably between individuals. Multiple methods for estimating ICV and procedures for volume normalization exist. A method for interhemispheric surface localization and extraction, using both intensity and symmetry information and without time consuming pre-processing, was developed. Evaluations of hemisphere division accuracy as well as suitability as a pre-processing step for interhemispheric structure localization were made. The performance of the method was comparable to that of methods focusing on either of these tasks, making it suited for use in many different studies. Automated ICV estimations from Freesurfer and SPM were evaluated using 399 reference segmentations. Both methods overestimated ICV and estimations using Freesurfer contained errors associated with skull-size. Estimations from SPM contained errors associated with gender and atrophy. An experiment showed that the choice of method can affect study results. Manual ICV estimation is very time consuming, but can be performed using only a subset of voxels in an image to increase speed and decrease manual labor. Segmenting every nth slice and stereology were evaluated in terms of required manual labor and estimation error, using the previously created ICV references. An illustration showing how much manual labor is required for a given estimation error using different combinations of n and stereology grid spacing was presented. Finally, different procedures for ICV normalization of regional brain volumes when investigating gender related volume differences were theoretically explained and evaluated using both simulated and real data. Resulting volume differences were seen to depend on the procedure used. A suggested workflow for procedure selection was presented. Methodological contributions that can aid the analysis of the human brain have been presented. The performed studies also contribute to the understanding of important methodological considerations for regional brain volume analysis.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24797号 / 医博第4989号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 髙橋 良輔, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Understanding the ageing process is of increasing importance to an ageing society and one aspect of this is investigating what role the brain has in this process. Cognitive ability declines as we age and it is one of the most distressing aspects of getting older. Brain tissue deterioration is a significant contributor to lower cognitive ability in late life but the underlying biological mechanisms in the brain are not yet fully understood. One reason for this is the difficulty in obtaining accurate measures of potential ageing-related brain biomarkers. The chapters in this thesis explore the difficulties of quantifying brain changes in the ageing brain from Magnetic Resonance Imaging (MRI), and how the changes identified are related to cognition in later life. The data was acquired as part of the second wave of the longitudinal Lothian Birth Cohort 1936 study in which 866 people aged 73 years, returned for cognitive and medical assessment. At this stage of the study 702 underwent MR imaging resulting in 627 complete datasets across all testing. The entire data, a randomly chosen subset of 150 and 416 freely available data were used to investigate global and regional measurement methods in older brains and how the resultant measurements related to cognitive performance. Furthermore the presence of early life cognitive data in the form of a general intelligence test sat at age 11, served as an indicator of cognitive ability prior to the potential influence of the ageing process. The chapters concerning global measures at first establish, that a measure of intracranial volume (ICV) serves as both a way of correcting for individual differences in brain size between participants and as a proxy premorbid measure of brain size. The analysis, utilising freely available cross-sectional MRI data (http://www.oasis-brains.org) revealed that ICV differed very little between 18-28 year olds and 84-96 year olds where as total brain tissue volume (TBV) differed by 14.1% between the two groups, which was more than twice the standard deviation across the entire age range (18-96 years). Second a validated, reliable method for measuring ICV was investigated using 150 people randomly chosen from the LBC1936 study. Automated and semi-automated methods were validated against reference measurements the results of which showed that common ageing features make automated and semi-automated methods that do not have an additional manual editing step, ineffective at producing accurate ICV measurements. This analysis also highlighted the need to employ additional spatial overlap assessment to volumetric comparison of measurement methods to reduce the effect of false-positives and false-negatives skewing apparent discrepancies between methods. Using the information gained here ICV and TBV from the entire LBC1936 cohort were analysed in a structural equation model, alongside cognitive ability measures at both age 11 and age 73. We found that TBV was a stronger predictor of later life cognitive ability, after accounting for early life ability, but that a modest association remained between ICV and late life cognition. This suggests that early life factors pay a role in how well we age, though the relationship is complex. The regional measures chapters look at two brain regions commonly associated with ageing, the hippocampus and the frontal lobes. Measuring either of these brain regions in large samples of healthy older adults is challenging for many reasons. The hippocampus is small and as with all brain regions shows greater variation in older age, this makes employing automated methods that have the advantage of being fast and reproducible difficult. Following the results of our systematic review of automated methods for measuring the hippocampus, the two most commonly used and available automated methods were validated against reference standard measurements. The results indicated that although automated methods present an attractive alternative to laborious manual measurements they still require manual editing to produce accurate measurements in older adults. The modified strategy employed across the LBC1936 was to use an automated method and then manually edit the output; these segmentations were used to investigate the potential of multimodal image analysis in clarifying associations between the hippocampus and cognitive ability in old age. The analysis focused on associations between longitudinal relaxation time (T1), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus and general factors of fluid intelligence, cognitive processing speed and memory. The findings show that multi-modal MRI assessments were more sensitive than volumetric measurements at detecting associations with cognitive measures. The difficulty with producing a relevant frontal lobe measure was made apparent when the result of a large systematic review looking at the manual protocols used revealed 19 methods and 15 different landmarks had been employed. This resulted in an analysis that took the 5 most common boundaries reported and applied them to 10 randomly selected participants from the LBC1936. The results showed significant differences between the resultant volumes, with the smallest measurement when using the genu as the posterior marker representing only 35% of the measurement acquired using the central sulcus. The results from the studies presented in this thesis strongly highlight the need to develop age specific methods when using brain MRI to study ageing. Furthermore the implications of using unstandardised protocols, making assumptions about a methods performance based on validation in younger samples and the need to account for early life factors in this area of research have been made clearer. Studies building on these findings will be beneficial in elucidating the role of the brain in ageing.

Abstract This work evaluated the safety and effectiveness of operative techniques used in cranioplastic surgery and outcomes of these surgical methods. In study I the feasibility of endocranial fixation in frontal remodeling surgery for metopic and coronal synostosis was established. Good to excellent aesthetic results were seen in 96% of cases evaluated by a surgeon at the time of follow-up. Three patients out of 27 had complications requiring revisions. No mortality or permanent morbidity, nor complications related to endocranial placement of the plates were seen. Thus it was verified that placing resorbable material intracranially reduces the aesthetic impact without hindering the final result. Study II found that posterior cranial vault distraction procedures produced a mean increase of 25% in intracranial volume. This proved to be an effective technique for treating a variety of craniosynostosis with significant shortage of intracranial volume. 3D photogrammetric imaging was found to be a suitable non-ionizing method for evaluation of cranial volume increase following distraction. In study III a new tool was developed and successfully used for the intraoperative guidance of distractor device placement to ensure congruent vectors and thus reduced complications of these surgical procedures. In study IV long-term functional and aesthetic outcomes of the surgical treatment for sagittal synostoses in patients reaching adulthood was examined. The mean follow-up time was 26.5 years and the patients were 18 to 41 years old at the time of follow-up. The patients treated for sagittal synostosis were equally satisfied with their facial appearance as were their age and gender matched controls. Independent panels found patients’ appearance to be slightly less attractive, but the difference was less than 10 mm on a 100 mm Visual Analogue Scale, representing a low clinical significance. Patients’ socioeconomic situation such as education, housing, employment and marital status equaled controls with similar frequencies of headaches, mental problems or health issues as the controls. / Tiivistelmä Tässä tutkimuksessa selvitettiin kallon saumojen ennenaikaisen luutumisen (kraniosynostoosi) leikkausmenetelmien tehokkuutta ja turvallisuutta sekä pitkäaikaisia tuloksia. Leikkausmenetelmä, jossa epämuotoinen kallo uudelleenmuotoillaan ja luiset osat kiinnitetään toisiinsa kallon sisäpuolelle asennettavilla ja kudokseen hajoavilla levyillä oli tehokas ja luotettava (N=27). Jälkitarkastuksessa tulos arvioitiin erinomaiseksi tai hyväksi 96 %:lla tapauksista. Leikkaushoitoa vaativia ongelmia tai komplikaatioita esiintyi kolmella, mutta pysyvää haittaa ei jäänyt. Komplikaatiot eivät johtuneet levyjen sijainnista kallon sisällä. Saumojen ennenaikaisesta luutumisesta johtuvaa kallon tilavuuden alenemaa hoidettiin venytyshoidolla (N=30). Menetelmällä saavutettiin keskimäärin 25 %:n lisääntyminen tilavuudessa, ja se soveltuukin erityisen hyvin potilaille, joilla tarvitaan suuri tilavuuden lisääntyminen. Leikkaustekniikkaan ei liittynyt isoja komplikaatioita. Tulosta arvioitiin osalla potilaista kolmiulotteisella valokuvauksella, joka perinteisistä seurantamenetelmistä poiketen ei altista ionisoivalle säteilylle, ja se osoittautui käyttökelpoiseksi seurantamenetelmäksi. Venytyshoitoa varten kallon pintaan kiinnitettävät pidennyslaitteet tulee asettaa yhdensuuntaisesti, ja se on teknisesti haasteellista. Työssä kehitettiin kirurginen instrumentti, jolla venyttimet voidaan luotettavammin asetella samansuuntaisiksi. Uusi tekniikka ehkäisee mekaanisia ongelmia, joita muuten voisi ilmetä erisuuntaisten venyttimien välillä pidennyksen edetessä. Lapsuudessa venekallon johdosta leikattujen potilaiden (N=40) pitkäaikaiset hoitotulokset sekä selviytyminen elämässä 26.5 vuoden seuranta-ajan jälkeen olivat hyviä. Heidän taloudellinen ja sosiaalinen tilanne (koulutus, asumismuoto, työllistyminen, siviilisääty ym.) ei eronnut ikä- ja sukupuolivakioitujen vertailuhenkilöiden (N=40) tilanteesta. Yleisessä terveydentilassa, päänsärkyjen esiintymisessä ja mielenterveysongelmissa ei ollut eroa. Potilaiden tyytyväisyys omaan ulkonäköönsä oli samankaltainen kuin vertailuhenkilöillä. Ulkopuolisen asiantuntijapaneelin tekemän arvion perusteella potilaiden kasvojen ulkonäkö oli vähemmän miellyttävä kuin vertailuhenkilöillä, mutta ero oli vähäinen (<10 % ero visual analogue scale, VAS, asteikolla). Asiantuntijapaneeli teki arvionsa tietämättä onko arvioitava henkilö potilas vai vertailuhenkilö.

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