Interpretable simultaneous localization of MRI corpus callosum and classification of atypical Parkinsonian disorders using YOLOv5

Structural MRI(S-MRI) is one of the most versatile imaging modality that revolutionized the anatomical study of brain in past decades. The corpus callosum (CC) is the principal white matter fibre tract, enabling all kinds of inter-hemispheric communication. Thus, subtle changes in CC might be associated with various neurological disorders. The present work proposes the potential of YOLOv5-based CC detection framework to differentiate atypical Parkinsonian disorders (PD) from healthy controls (HC). With 3 rounds of hold-out validation, mean classification accuracy of 92% is obtained using the proposed method on a proprietary dataset consisting of 20 healthy subjects and 20 cases of APDs, with an improvement of 5% over SOTA methods (CC morphometry and visual texture analysis) that used the same dataset. Subsequently, in order to incorporate the explainability of YOLO predictions, Eigen CAM based heatmap is generated for identifying the most important sub-region in CC that leads to the classification. The result of Eigen CAM showed CC mid-body as the most distinguishable sub-region in classifying APDs and HC, which is in-line with SOTA methodologies and the current prevalent understanding in medicine

Neuroimaging in Dementia: More than Typical Alzheimer Disease

Alzheimer disease (AD) is the most common cause of dementia. The prevailing theory of the underlying pathology assumes amyloid accumulation followed by tau protein aggregation and neurodegeneration. However, the current antiamyloid and antitau treatments show only variable clinical efficacy. Three relevant points are important for the radiologic assessment of dementia. First, besides various dementing disorders (including AD, frontotemporal dementia, and dementia with Lewy bodies), clinical variants and imaging subtypes of AD include both typical and atypical AD. Second, atypical AD has overlapping radiologic and clinical findings with other disorders. Third, the diagnostic process should consider mixed pathologies in neurodegeneration, especially concurrent cerebrovascular disease, which is frequent in older age. Neuronal loss is often present at, or even before, the onset of cognitive decline. Thus, for effective emerging treatments, early diagnosis before the onset of clinical symptoms is essential to slow down or stop subsequent neuronal loss, requiring molecular imaging or plasma biomarkers. Neuroimaging, particularly MRI, provides multiple imaging parameters for neurodegenerative and cerebrovascular disease. With emerging treatments for AD, it is increasingly important to recognize AD variants and other disorders that mimic AD. Describing the individual composition of neurodegenerative and cerebrovascular disease markers while considering overlapping and mixed diseases is necessary to better understand AD and develop efficient individualized therapies

Multiple system atrophy - a clinicopathological update

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: the forgotten partner

Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following different insults to the central nervous system including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinating diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with abnormal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein deposits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus signaling their involvement in the disease. Emerging evidence suggests that such deposits in oligodendrocytes are not mere bystanders but rather are associated with functional alterations. Moreover, operative modifications in oligodendrocytes are also detected in the absence of oligodendroglial inclusions in certain diseases. The present review focuses first on general aspects of oligodendrocytes and precursors, and their development and functions, and then introduces and updates alterations and dysfunction of oligodendrocytes in selected neurodegenerative diseases with abnormal protein aggregates such as multiple system atrophy, Lewy body diseases, tauopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration with TDP-43 inclusions (TDP-43 proteinopathies), and Creutzfeldt-Jakob´s disease as a prototypical human prionopathy

Magnetic resonance imaging techniques for diagnostics in Parkinson’s disease and atypical parkinsonism

Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized by rigidity, hypokinesia, tremor and postural instability. PD is a clinical diagnosis based on neurological examination, patient history and treatment response. Similar symptoms can be caused by other movement disorders such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), making it difficult to clinically separate them in early stages. However, these diseases differ in underlying pathology, treatment and prognosis. PSP and MSA have more rapid deterioration and develop additional symptoms such as impaired eye movements or autonomic dysfunction. Magnetic resonance imaging (MRI) is commonly performed as part of the clinical work-up in patients presenting with parkinsonism. There are no overt changes on structural MRI in PD. In atypical parkinsonian syndromes there are typically no visible changes until later disease stages. Purpose: The aim of this thesis is to evaluate novel MRI techniques for diagnostics and for investigation of disease processes in Parkinson’s disease, PSP and MSA. Paper I: A retrospective cohort from Karolinska University Hospital (102 participants; 62 PD, 15 PSP, 11 MSA, 14 controls) was assessed using susceptibility mapping processed from susceptibility weighted imaging. We show that there is elevated susceptibility in the red nucleus and the globus pallidus in PSP compared to PD, MSA and controls. Higher susceptibility levels were also seen in MSA compared to PD in the putamen, and in PD compared to controls in the substantia nigra. Using the red nucleus susceptibility as a diagnostic biomarker, PSP could be separated from PD with an accuracy of 97% (based on the area under the receiver operating characteristic curve, AUC), from MSA with AUC 75% and from controls with AUC 98%. We concluded that susceptibility changes, particularly in the red nucleus in PSP, could be potential biomarkers for differential diagnostics in parkinsonism. Paper II: A prospective cohort from Lund, the BioFINDER study (199 participants; 134 PD, 11 PSP, 10 MSA, 44 controls), was investigated using the susceptibility mapping pipeline developed for Paper I. The finding from Paper I with elevated susceptibility in the red nucleus was validated for PSP compared to PD, MSA and controls. The elevated putaminal susceptibility was also confirmed in MSA compared to PD. The potential role of red nucleus susceptibility as a biomarker for separating PSP from PD and MSA was also similar to the results in Paper I, with AUC 98% for separating PSP from PD and AUC 96% for separating PSP from MSA. We concluded that we could confirm our previous findings from Paper I, with the red nucleus susceptibility being a potential biomarker for separating PSP from PD and MSA. Paper III: A retrospective cohort from Karolinska University Hospital (196 participants; 140 PD, 29 PSP, 27 MSA) was evaluated to employ automated volumetric brainstem segmentation using FreeSurfer. The volumetric approach was compared to manual planimetric measurements: midbrain-pons ratio, magnetic resonance parkinsonism index 1.0 and 2.0. Intra- and inter-scanner as well as intra- and inter-rater reliability were calculated. We found good repeatability in both automated volumetric and manual planimetric measurements. Normalized midbrain volume performed better than the planimetric measurements for separating PSP from PD. We concluded that, if further developed and incorporated in a radiology workflow, automated brainstem volumetry could increase availability of brainstem metrics and possibly save time for radiologists conducting manual measurements. Paper IV: Two cohorts, a retrospective from Karolinska University Hospital (184 participants; 129 PD, 28 PSP, 27 MSA) and a prospective from Lund (185 participants; 125 PD, 11 PSP, 8 MSA, 41 controls), were studied to investigate a new method of creating T1-/T2-weighted ratio images and its diagnostic capabilities in differentiating parkinsonian disorders. In the explorative retrospective cohort, differences in white matter normalized T1-/T2- weighted ratios were seen in the caudate nucleus, putamen, thalamus, subthalamic nucleus and red nucleus in PSP compared to PD; in the caudate nucleus and putamen in MSA compared to PD and in the subthalamic nucleus and the red nucleus in PSP compared to MSA. These differences were validated externally in the prospective cohort, where the changes could be confirmed in the subthalamic nucleus and the red nucleus in PSP compared to PD and MSA. We concluded that there are different patterns of white matter normalized T1-/T2-weighted ratio between the disorders and that this reflects differences in underlying pathophysiology. The T1-/T2-weighted ratio should be further investigated for better understanding of pathological processes in parkinsonian disorders and could possibly be utilized for diagnostic purposes if further developed

Quantifying structural changes in the ageing brain from magnetic resonance imaging

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

Pathophysiological mechanisms in Parkinson`s Disease and Dystonia – converging aetiologies

In this thesis I used a range of experimental approaches including genetics, enzyme activity measurements, histology and imaging to explore converging pathophysiological mechanisms of Parkinson`s disease and dystonia, two conditions with frequent clinical overlap. First, based on a combined retro- and prospective cohort of patients, using a combination of lysosomal enzyme activity measurements in peripheral blood and brain samples, as well as a target gene approach, I provide first evidence of reduced levels of enzyme activity in Glucocerebrosidase and the presence of GBA mutations, indicating lysosomal abnormality, in a relevant proportion of patients with dystonia of previously unknown origin. Second, based on a retrospective cohort of patients, I detail that a relevant proportion of genetically confirmed mitochondrial disease patients present with a movement disorder phenotype - predominantly dystonia and parkinsonism. Analysing volumetric MRI data, I describe a patterned cerebellar atrophy in these particular patients. This also includes the first cases of isolated dystonia due to mitochondrial disease, adding the latter as a potential aetiology for dystonia of unknown origin. Third, I used a combination of post-GWAS population genetic approaches and tissue-based experiments to explore in how far the strong association between advancing age and Parkinson ́s disease is mediated via telomere length. Although the initial finding of an association between genetically determined telomere length and PD risk did not replicate in independent cohorts, I provide evidence that telomere length in human putamen physiologically shortens with advancing age and 3 is regulated differently than in other brain regions. This is unique in the human brain, implying a particular age-related vulnerability of the striatum, part of the nigro-striatal network, crucially involved in PD pathophysiology. I conclude by discussing the above findings in light of the current literature, expand on their relevance and possible direction of future experiments