Ventricular dilatation in aging and dementia

The general objective of this thesis was to study the causes and consequences of ventricular dilatation in aging and dementia. For this purpose, we used ventricular shape analysis to study potential new MRI markers of cognitive decline in aging, subjective memory complaints, mild cognitive impairment and Alzheimer's Disease. In addition, we designed a volumetric measure that may objectively quantify the disproportionate ventricular dilatation that is characteristic of Normal Pressure Hydrocephalus (NPH). We investigated the value of this measure for the selection of candidates with NPH for ventricular shunting, studied its association with NPH-like symptoms in the general population and used the measure to explore a possible cardiovascular origin of cerebral ventricular dilatation.UBL - phd migration 201

Neuroanatomical correlates of cognitive dysfunction in obstructive sleep apnoea

Obstructive sleep apnoea (OSA) has been reported to be associated with brain hypotrophy and cognitive dysfunction; however, whether these normalise after treatment is unclear. The overall aim of this thesis is to investigate the relationship between OSA and brain structure using FreeSurfer (a new automated technique that reliably measures brain structures). I have investigated changes in brain morphology and the newly described phenomenon in OSA of ischaemic preconditioning. Chapters 4 and 5 will also assess brain structural response to CPAP, and investigate the association between brain structure and cognitive function in OSA. Chapter 3 reports an observational study investigating brain structure. FreeSurfer analysis of magnetic resonance imaging (MRI) found OSA patients had hypertrophy in the right hippocampus (p=0.03) and right choroid plexus (p=0.02) but hypotrophy of the corpus callosum (p=0.04) compared to healthy controls. Chapter 4 reports a randomised controlled trial of CPAP in OSA. At baseline hypotrophy was seen in the corpus callosum (p=0.03) and pallidum (p=0.03) of OSA patients compared to healthy controls. Hypertrophic changes in the right thalamus were seen in the CPAP group after 1 month (p=0.06), associated with improvement in verbal memory (p=0.04). Chapter 5 reports a randomised controlled trial of CPAP in older patients with OSA. A significant decrease in left fimbria volume was seen in the CPAP group (p=0.01). A significant increase in the left presubiculum volume was seen in the best supportive care group (p=0.03). No hippocampal hypertrophy was seen in the CPAP group. In summary, young and middle-aged OSA patients had evidence of brain hypotrophy, but also areas of hypertrophy that may signify dendritic sprouting and increased connectivity as a result of ischaemic preconditioning. This allows recovery of brain hypotrophy after CPAP treatment. This was not seen in older OSA patients suggesting an age-related difference which may have implications for OSA treatment in older people.Open Acces

Do informal caregivers of people with dementia mirror the cognitive deficits of their demented patients?:A pilot study

Recent research suggests that informal caregivers of people with dementia (ICs) experience more cognitive deficits than noncaregivers. The reason for this is not yet clear. Objective: to test the hypothesis that ICs ‘mirror' the cognitive deficits of the demented people they care for. Participants and methods: 105 adult ICs were asked to complete three neuropsychological tests: letter fluency, category fluency, and the logical memory test from the WMS-III. The ICs were grouped according to the diagnosis of their demented patients. One-sample ttests were conducted to investigate if the standardized mean scores (t-scores) of the ICs were different from normative data. A Bonferroni correction was used to correct for multiple comparisons. Results: 82 ICs cared for people with Alzheimer's dementia and 23 ICs cared for people with vascular dementia. Mean letter fluency score of the ICs of people with Alzheimer's dementia was significantly lower than the normative mean letter fluency score, p = .002. The other tests yielded no significant results. Conclusion: our data shows that ICs of Alzheimer patients have cognitive deficits on the letter fluency test. This test primarily measures executive functioning and it has been found to be sensitive to mild cognitive impairment in recent research. Our data tentatively suggests that ICs who care for Alzheimer patients also show signs of cognitive impairment but that it is too early to tell if this is cause for concern or not

Clinical and genetic heterogeneity in young onset sporadic Alzheimer’s disease

Alzheimer’s disease, the commonest neurodegenerative condition, is characterised by accumulation of amyloid plaques and neurofibrillary tangles, neuronal loss, brain atrophy and cognitive impairment. Sporadic young onset Alzheimer’s disease shows marked clinical heterogeneity, with non-memory presentations including the syndromes of posterior cortical atrophy, logopenic aphasia and frontal Alzheimer’s disease, seen in around a third of individuals. This variability presents challenges for diagnosis and may confound clinical trial outcomes, but provides an opportunity to explore factors influencing differential selective vulnerability within neural networks which in turn may provide important clues to Alzheimer’s disease pathogenesis. This thesis describes the recruitment of a cohort of a deeply phenotyped patients with sporadic young onset Alzheimer’s disease (n=45) and healthy controls (n=24), and a series of genetic, clinical, neuropsychological, and structural, diffusion and functional magnetic resonance imaging experiments to explore disease heterogeneity and its associations. There are a number of key findings. APOE ε4 genotype contributes to, but does not fully explain clinical heterogeneity, with the youngest ages of onset and most atypical presentations seen in ε4-ve individuals. Heterozygosity of the rare TREM2 genetic variant for late-onset Alzheimer’s disease, p.R47H, is shown to confer risk for young onset Alzheimer’s disease, driving younger age of onset rather than clinical phenotype. Regional brain atrophy profiles in APOE ε4 genotypes are shown to broadly align with the associated neuropsychological deficits. Microstructural damage studied using diffusion tensor imaging, and – applied for the first time to Alzheimer’s disease – Neurite Orientation Dispersion and Density Imaging – provides a fine-grained profile of white matter network breakdown, revealing regional differences based on APOE ε4 genotype, and correlations with focal neuropsychological deficits. Finally, activation fMRI using a music paradigm to probe relationships between cognitive performance and brain function is shown to delineate different patterns of brain activation during memory tasks in different Alzheimer’s disease phenotypes

Diffusion Tensor Imaging in Pediatric Brain Tumor Patients

In this dissertation, we outline our efforts to introduce an advanced MRI imaging technique called Diffusion Tensor Imaging (DTI) to the pediatric brain tumor population. We discuss the theory and application of DTI as it was performed in a series of translational investigations at St. Jude Children’s Research Hospital. We present evidence of how the introduction of this technique impacted diagnosis, and treatment. And finally, we demonstrate how DTI was used to investigate cognitive morbidities associated with cancer treatment and how this research provided insight into the underlying pathophysiology involved in the development of these treatment sequela. This research has generated important insights into the fundamental causes of neuroanatomical and cognitive deficits associated with cancer and cancer therapy. The use of DTI has permitted us to identify potential targets for improved radiological and surgical techniques as well as targets for pharmacological and behavioral interventions that might improve cognitive function in cancer survivors. The discoveries here afford us an opportunity to reduce the negative effects of cancer therapy on patients treated in the future while maintaining successful survival rates

When I show the Beatles then you say: "Ramones!" : imaging semantic memory in Alzheimer's disease and semantic dementia

Elderly people contacting the health care system because of suspected dementia very often report word forgetfulness, a clinical condition referred as anomia, often one of the first signs of cognitive decline. Considering the complexity of human language it is no wonder that dementia disorders can affect language processing, which in its turn relies heavily on the intactness of the semantic memory system. In an attempt to study language impairment in dementia, this thesis aimed to investigate semantic memory, from its normal degradation in healthy ageing, to its disruption in dementia, and from controlled to unconscious semantic processing. Moreover we chased the anatomical locus of semantic memory with the combination of several neurophysiological and neuroimaging techniques. In Study I we investigated controlled semantic retrieval together with pattern of blood perfusion through the performance of verb fluency (VF) and animal fluency (AF), combined with Single-Photon Emission Computed Tomography (SPECT) in patients suffering from Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Impairment (SCI). In Study II we enquired automatic semantic retrieval in healthy young and healthy elderly, combining a novel semantic priming paradigm to Event Related Potential (ERP) Electroencephalography (EEG). In Study III we used the same semantic paradigm and ERP EEG measurement as in Study II to investigate automatic semantic retrieval in AD, Semantic Dementia (SD), and an healthy elderly population. The result was then correlated to measure of blood perfusion by means of Pulsed Continuous Arterial Spin Labelling (PCALS) Magnetic Resonance Imaging (MRI). In Study IV we chased the anatomical locus of semantic memory through the study of grey (GM) and white matter (WM) pathology in AD, SD, and healthy ageing, combining Voxel-Based Morphometry (VBM) MRI and Diffusion Tensor Imaging (DTI) MRI. We could show that controlled semantic retrieval, and in particular VF is impaired in dementia and that this correlates to hypoperfusion in particular anatomical regions. Moreover, we could prove the automatic semantic retrieval remains stable under the span of healthy adulthood while controlled retrieval is not, and that this processes activates neurophysiologically comparable neural networks for healthy young as well as for healthy elderly. In addition we could show that automatic spread of activation is spared in mild dementia despite the deviant result in measures of controlled semantic processes and we found a possible early marker differentiating SD from AD and healthy ageing. We could even associate patterns of hypoperfusion to impairment in controlled semantic memory processing, this indicating that the altered electrophysiology of dementia patients is closely related to their structural and baseline blood degeneration. Finally we could detect different patterns of GM and WM loss in the AD compared to the SD group. In particular we could detect a specific area of WM disruption significantly separating AD from SD

Automated morphometric analysis and phenotyping of mouse brains from structural µMR images

In light of the utility and increasing ubiquity of mouse models of genetic and neurological disease, I describefully automated pipelines for the investigation of structural microscopic magnetic resonance images of mouse brains – for both high-throughput phenotyping, and monitoring disease. Mouse models offer unparalleled insight into genetic function and brain plasticity, in phenotyping studies; and neurodegenerative disease onset and progression, in therapeutic trials. I developed two cohesive, automatic software tools, for Voxel- and Tensor-Based Morphometry (V/TBM) and the Boundary Shift Integral (BSI), in the mouse brain. V/TBM are advantageous for their ability to highlight morphological differences between groups, without laboriously delineating regions of interest. The BSI is a powerful and sensitive imaging biomarker for the detection of atrophy. The resulting pipelines are described in detail. I show the translation and application of open-source software developed for clinical MRI analysis to mouse brain data: for tissue segmentation into high-quality, subject-specific maps, using contemporary multi-atlas techniques; and for symmetric, inverse-consistent registration. I describe atlases and parameters suitable for the preclinical paradigm, and illustrate and discuss image processing challenges encountered and overcome during development. As proof of principle and to illustrate robustness, I used both pipelines with in and ex vivo mouse brain datasets to identify differences between groups, representing the morphological influence of genes, and subtle, longitudinal changes over time, in particular relation to Down syndrome and Alzheimer’s disease. I also discuss the merits of transitioning preclinical analysis from predominately ex vivo MRI to in vivo, where morphometry is still viable and fewer mice are necessary. This thesis conveys the cross-disciplinary translation of up-to-date image analysis techniques to the preclinical paradigm; the development of novel methods and adaptations to robustly process large cohorts of data; and the sensitive detection of phenotypic differences and neurodegenerative changes in the mouse brai

Deep learning of brain asymmetry digital biomarkers to support early diagnosis of cognitive decline and dementia

Early identification of degenerative processes in the human brain is essential for proper care and treatment. This may involve different instrumental diagnostic methods, including the most popular computer tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These technologies provide detailed information about the shape, size, and function of the human brain. Structural and functional cerebral changes can be detected by computational algorithms and used to diagnose dementia and its stages (amnestic early mild cognitive impairment - EMCI, Alzheimer’s Disease - AD). They can help monitor the progress of the disease. Transformation shifts in the degree of asymmetry between the left and right hemispheres illustrate the initialization or development of a pathological process in the brain. In this vein, this study proposes a new digital biomarker for the diagnosis of early dementia based on the detection of image asymmetries and crosssectional comparison of NC (normal cognitively), EMCI and AD subjects. Features of brain asymmetries extracted from MRI of the ADNI and OASIS databases are used to analyze structural brain changes and machine learning classification of the pathology. The experimental part of the study includes results of supervised machine learning algorithms and transfer learning architectures of convolutional neural networks for distinguishing between cognitively normal subjects and patients with early or progressive dementia. The proposed pipeline offers a low-cost imaging biomarker for the classification of dementia. It can be potentially helpful to other brain degenerative disorders accompanied by changes in brain asymmetries