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Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke
Purpose Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP. Methods: 215 consecutive acute stroke patients with HAP (2003–2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions. Results: The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP. Conclusions: HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression
Characterizing Subtypes and Neural Correlates of Receptive Aprosodia in Acute Right Hemisphere Stroke
Introduction: Speakers naturally produce prosodic variations depending on their emotional state. Receptive prosody has several processing stages. We aimed to conduct lesion-symptom mapping to determine whether damage (core infarct or hypoperfusion) to specific brain areas was associated with receptive aprosodia or with impairment at different processing stages in individuals with acute right hemisphere stroke. We also aimed to determine whether different subtypes of receptive aprosodia exist that are characterized by distinctive behavioral performance patterns.
Methods: Twenty patients with receptive aprosodia following right hemisphere ischemic stroke were enrolled within five days of stroke; clinical imaging was acquired. Participants completed tests of receptive emotional prosody, and tests of each stage of prosodic processing (Stage 1: acoustic analysis; Stage 2: analyzing abstract representations of acoustic characteristics that convey emotion; Stage 3: semantic processing). Emotional facial recognition was also assessed. LASSO regression was used to identify predictors of performance on each behavioral task. Predictors entered into each model included 14 right hemisphere regions, hypoperfusion in four vascular territories as measured using FLAIR hyperintense vessel ratings, lesion volume, age, and education. A k-medoid cluster analysis was used to identify different subtypes of receptive aprosodia based on performance on the behavioral tasks.
Results: Impaired receptive emotional prosody and impaired emotional facial expression recognition were both predicted by greater percent damage to the caudate. The k-medoid cluster analysis identified three different subtypes of aprosodia. One group was primarily impaired on Stage 1 processing and primarily had frontotemporal lesions. The second group had a domain-general emotion recognition impairment and maximal lesion overlap in subcortical areas. Finally, the third group was characterized by a Stage 2 processing deficit and had lesion overlap in posterior regions.
Conclusions: Subcortical structures, particularly the caudate, play an important role in emotional prosody comprehension. Receptive aprosodia can result from impairments at different processing stages
Measurement of cortical thickness asymmetry in carotid occlusive disease
Despite being considered an important anatomical parameter directly related to neuronal density, cortical thickness is not routinely assessed in studies of the human brain in vivo. This paucity has been largely due to the size and convoluted shape of the human cortex, which has made it difficult to develop automated algorithms that can measure cortical thickness efficiently and reliably. Since the development of such an algorithm by Fischl and Dale in 2000, the number of studies investigating the relationship between cortical thickness and other physiological parameters in the brain has been on the rise. There have been no studies however that have validated cortical asymmetry against known vascular anatomy. To this aim, using high-resolution MRI, we measured cortical thickness and volume in the primary motor (M1) and primary visual (V1) cortex in patients with unilateral, high-grade carotid occlusive disease (n = 29, age = 74 ± 10 years). These regions were selected based on the hypothesis that there will be thinning of the cortical thickness of M1 in the territory supplied by the occluded carotid artery, whereas V1 will show no asymmetry since its blood supply is provided by unaffected posterior arteries. To test for an effect of handedness, cortical thickness and volume were also measured in healthy volunteers (n = 8, age = 37 ± 13 years). In patients, we found thinner cortex in M1 on the occluded side (mean = 2.07 ± 0.19 mm vs 2.15 ± 0.20 mm, p = 0.0008) but no hemispheric difference in V1 (1.80 ± 0.17 mm in occluded vs 1.78 ± 0.16 mm in unoccluded, p = 0.31). Although the mean cortical volume of M1 in the occluded hemisphere was also lower, the difference did not reach statistical significance (p = 0.09). Similarly, in healthy controls, the results showed no hemispheric asymmetry in either cortical thickness or volume in either region (p \u3e 0.1). To test for an orientation bias in the method, the analysis was repeated with images flipped from neurological to radiological orientation. While the algorithm did not yield identical results for the two orientations, the effect did not alter the findings of the study. These results provide a method for within-subject validation of a pathophysiological effect of carotid occlusive disease on the human cortex and warrant further investigation for underlying mechanisms
An insight into the brain of patients with type-2 diabetes mellitus and impaired glucose tolerance using multi-modal magnetic resonance image processing
The purpose of this thesis was to investigate brain anatomy and physiology of subjects with impaired glucose tolerance (IGT - 12 subjects), type-2 diabetes (T2DM - 17 subjects) and normoglycemia (16 subjects) using multi-modal magnetic resonance imaging (MRI) at 3T.
Perfusion imaging using quantitative STAR labeling of arterial regions (QUASAR) arterial spin labeling (ASL) was the core dataset. Optimization of the post-processing methodology for this sequence was performed and the outcome was used for hemodynamic analysis of the cohort. Typical perfusion-related parameters, along with novel hemodynamic features were quantified. High-resolution structural, angiographic and carotid flow scans were also acquired and processed. Functional acquisitions were repeated following a vasodilating stimulus. Differences between the groups were examined using statistical analysis and a machine-learning framework.
Hemodynamic parameters differing between the groups emerged from both baseline and post-stimulus scans for T2DM and mainly from the post-stimulus scan for IGT. It was demonstrated that quantification of not-typically determined hemodynamic features could lead to optimal group-separation. Such features captured the pattern of delayed delivery of the blood to the arterial and tissue compartments of the hyperglycemic groups. Alterations in gray and white matter, cerebral vasculature and carotid blood flow were detected for the T2DM group. The IGT cohort was structurally similar to the healthy cohort but demonstrated functional similarities to T2DM. When combining all extracted MRI metrics, features driving optimal separation between different glycemic conditions emerged mainly from the QUASAR scan. The only highly discriminant non-QUASAR feature, when comparing T2DM to healthy subjects, emerged from the cerebral angiogram.
In this thesis, it was demonstrated that MRI-derived features could lead to potentially optimal differentiation between normoglycemia and hyperglycemia. More importantly, it was shown that an impaired cerebral hemodynamic pattern exists in both IGT and T2DM and that the IGT group exhibits functional alterations similar to the T2DM group
Physiological underpinnings of healthy brain ageing
Changes in cerebral perfusion or metabolism can occur as a result of healthy ageing, and in conditions of impaired ageing such as mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Overarchingly, this thesis
aimed to explore physiological magnetic resonance imaging (MRI) measures to study both cerebral perfusion and metabolism in the healthy ageing brain. Specifically, arterial spin labelling (ASL) and functional magnetic resonance spectroscopy (1H-fMRS) were employed in the elucidation of healthy ageing.
Investigation of cerebral functionality is clinically important, enabling understanding of healthy ageing and disease pathology beyond that provided by structural measures. Given the necessity for tightly-regulated tissue
perfusion in the delivery of oxygen to the brain, assessment of brain perfusion can enable elucidation of related brain health. Firstly, this thesis focused on changes in brain perfusion within a cross-sectional retrospective cohort of
healthy subjects. This study aimed to assess the utility of univariate and multivariate pattern analysis (MVPA) techniques, and determine whether spatial coefficient of variation (sCoV) measures – which provide a method for
inferring spatial heterogeneity of blood flow from single post-label delay (PLD) ASL data – are more significantly associated with age than standard perfusion metrics (ml/100g/min values). The impact of data processing steps on
quantification of perfusion was initially assessed. Particularly, the influence of partial volume effect (PVE) correction and how this affected quantification of cerebral perfusion was of interest. The relationship between measures of cerebral perfusion – in regions of interest, vascular territories, and grey matter – and age were assessed, before grey matter (GM) spatial covariance patterns were identified, with MVPA hypothesised to elucidate more subtle
age-related change than univariate, voxel-wise methodology. The executive control network (ECN) was the only network exhibiting a significant decline in perfusion with age, after controlling for relevant covariates. Interestingly, whilst the PCA approach resulted in a pattern of both positive and negative associations with age across cerebral GM, the surviving clusters in voxel-wise approaches were deemed spurious. Five-fold cross validation of PCA findings
was used to assess whether the resultant spatial covariance patterns were able to predict subject age. This prediction was successful, with related r2 values of between 0.5316 and 0.7297 (p < 0.001 for all), however validation of these findings in an unseen dataset is required. The utility of the sCoV metric was also compared with standard tissue perfusion values, finding that sCoV may be more closely associated with ageing than ml/100g/min in certain
regions. Particularly, a significant increase in whole GM sCoV with age was notable, given the absence of significant changes in perfusion with age in the same region.
Additionally, a MVPA approach was used to establish the complex unknown relationship between cerebral perfusion and the Montreal Cognitive Assessment (MoCA), before graph visualisation was used to further understand the regional relatedness of the spatial covariance pattern. PCA resulted in a model which provided a moderate explanation of the
aforementioned relationship, but this may be improved by inclusion of additional covariates in subsequent work, such as those pertaining to genetic status, such as apolipoprotein E (APOE). This study also replicates an FDG
PET cognitive resilience signature in an ASL cohort for the first time, with a trend towards declining perfusion with age found (p = .08).
Lastly, as ageing is associated with metabolic failure in the brain, which is often investigated using methodology which employs ionising radiation, the final study was motivated to investigate possible metabolic markers of brain
ageing which can be measured using MRI. Metabolic-functional coupling can be studied using functional stimulation, and functional magnetic resonance spectroscopy (fMRS) is perfectly poised to elucidate certain metabolic
behaviour. Given the close relationship between glucose (Glc) – the key fuel for cerebral functionality – and lactate (Lac) metabolism, an optimised long echo time (TE) semi-localized by adiabatic selective refocusing (semi-LASER) sequence (TE=144ms) with optimised J-modulation selection at 7T was employed to assess the effects of age on the dynamic behaviour of Lac, and determine its absolute concentrations throughout the time course, whilst a
visual stimulation paradigm was viewed. Successful quantification of metabolite concentrations – including Lac, tCr and tNAA – was achieved in both the young and old cohorts, and their Lac peaks clearly visually identifiable throughout the time course. A significant increase in Lac
concentration was observed between rest and stimulation, but not stimulation and recovery, in the young cohort. No significant Lac time course changes were identified in the full old cohort.
This thesis concluded by summarising and contextualising the key findings herein, and discussion of possible directions for further associated research. The findings of this thesis broaden the field of knowledge around healthy ageing, and therefore may contribute to subsequent translation efforts for both clinical diagnostics and treatment approaches
Role of Cerebrovascular Abnormality in Neurodegenerative Disease and Subcortical Ischemic Disease: CT Perfusion and PET Imaging
Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical ischemic lesions.
Chapter 2 investigates the early hemodynamic disturbances within the first month after transient CI insult in the presence of Aβ toxicity in the comorbid rat model. CT perfusion revealed significantly lower cerebral blood flow (CBF) and blood volume (CBV) at acute phase due to the transient ischemia, and increased CBF and CBV in the ipsilateral striatum of CI+Aβ and CI groups at the first week post ischemia. These results suggest that CI is the primary driving factor of cerebrovascular abnormalities at early stage, and prolonged hyperperfusion and hypervolemia may imply reperfusion-related injury and downstream inflammation. Chapter 3 further addresses these questions with CT Perfusion-PET imaging.
Chapter 3 describes the temporal profiles of blood-brain barrier (BBB) disruption and neuroinflammation over 3 months after CI with and without concurrent Aβ toxicity in the comorbid rat model. CT perfusion showed significantly higher BBB permeability surface product (BBB-PS) in the ipsilateral striatum of CI+Aβ group at day 7, month 2 and 3, as compared to CI and sham group. PET imaging revealed the highest level of neuroinflammation as reflected by the significantly increased 18F-FEPPA uptake due to microglial activation in the striatal lesion of CI+Aβ group at day 7 and 14. The temporal features of these cererbrovascular and cellular changes may serve as early imaging biomarkers for development of cognitive impairment in high-risk patients post ischemic insult.
Chapter 4 investigates the temporal changes in BBB-PS and cerebral perfusion using CT perfusion over the first 3 months after small lacunar/subcortical stroke in patients. This longitudinal investigation suggests the chronic BBB leakage detected by CT perfusion may contribute to cognitive impairment and associated pathology in lacunar/subcortical stroke.
Overall, the imaging results presented in this thesis have demonstrated that BBB-PS, CBF, CBV and activated microglia can be used as imaging biomarkers for delineating the early pathogenic pattern and underlying contribution of cerebral ischemia to the disease development in the animal comorbid model and subcortical stroke patients
White Matter Integrity as a Biomarker for Stroke Recovery: Implications for TMS Treatment
White matter consists of myelinated axons which integrate information across remote brain regions. Following stroke white matter integrity is often compromised leading to functional impairment and disability. Despite its prevalence among stroke patients the role of white matter in development of post-stroke rehabilitation has been largely ignored. Rehabilitation interventions like repetitive transcranial magnetic stimulation (rTMS) are promising but reports on its efficacy have been conflicting. By understanding the role of white matter integrity in post-stroke motor recovery, brain reorganization and TMS efficacy we may be able to improve the development of future interventions. In this dissertation we set out answer these questions by investigating the relationship between white matter integrity and 1) bimanual motor performance following stroke, 2) cortical laterality following stroke and 3) TMS signal propagation (in a group of cocaine users without stroke). We identified white matter integrity of the corpus callosum as a key structure influencing bimanual performance using kinematic measures of hand symmetry (Chapter 2). Second, we found that reduced white matter integrity of corpus callosum was correlated with loss of functional laterality of the primary motor cortex during movement of the affected hand (Chapter 3). Lastly, we found that reduced white matter tract integrity from the site of stimulation to a downstream subcortical target, was correlated to the ability to modulate that target (Chapter 4). Taken together these studies support white matter integrity as a valuable biomarker for future rTMS trials in stroke. To emphasize the implications of these findings, we provide an example of how to incorporate white matter integrity at multiple levels of rTMS study design
A four-dimensional probabilistic atlas of the human brain
The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on structure and function of the human brain in persons between the ages of 18 and 90 years. Given the presumed large but previously unquantified degree of structural and functional variance among normal persons in the human population, the basis for this atlas and reference system is probabilistic. Through the efforts of the International Consortium for Brain Mapping (ICBM), 7,000 subjects will be included in the initial phase of database and atlas development. For each subject, detailed demographic, clinical, behavioral, and imaging information is being collected. In addition, 5,800 subjects will contribute DNA for the purpose of determining genotype-phenotype-behavioral correlations. The process of developing the strategies, algorithms, data collection methods, validation approaches, database structures, and distribution of results is described in this report. Examples of applications of the approach are described for the normal brain in both adults and children as well as in patients with schizophrenia. This project should provide new insights into the relationship between microscopic and macroscopic structure and function in the human brain and should have important implications in basic neuroscience, clinical diagnostics, and cerebral disorders
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