ADVANCEMENTS IN QUANTITATIVE PERFUSION MAGNETIC RESONANCE IMAGING (MRI) OF DEMENTIA

Alzheimer's disease (AD) affects a considerable, and increasing, part of the population. Early diagnosis of AD is very important to permit effective therapy, and minimize AD's social and economic burden. The goal of our research is to evaluate the changes of cerebral perfusion (i.e., blood flow) in the early stages of AD and the effects from hypertension.We studied volunteers with Mild Cognitive Impairment (MCI) and early AD from the Pittsburgh cohort of the Cardiovascular Health Study (CHS) Cognitive Study during a four-year follow-up. Previously, studies used referral patients who typically have more advanced AD. No perfusion data concerning the early and transitional disease stages are currently available from population studies (i.e., subjects who have been monitored longitudinally in time). There are no common techniques for perfusion quantification and image analysis so that inconsistencies are observed between/within studies, modalities, and researchers. Several advancements were achieved in preparation for the cohort study. First, we improved the accuracy and speed of brain perfusion quantification. Second, we improved the accuracy of image registration to a reference brain using quantitative validation of a registration method and performance comparison with a popular registration method. Third, we improved the method of statistical analysis for evaluating the changes of perfusion between groups. Fourth, we evaluated the changes of cerebral perfusion between cognitive groups (controls, MCIs, ADs), and hypertension and normo-tensive subgroups.Individual perfusion maps were improved by measuring and incorporating individual arrival time, saturation effects, and individual inversion efficiency. A fully deformable registration technique was shown to be more accurate than standard techniques like statistical parametric mapping to detect local perfusion changes. All of the published literature for perfusion up-to-date reported decreased perfusion in AD, but we found hyperperfusion in some regions. The regional findings imply that a hemodynamic process, at the capillary level, accompanied the neurodegenerative process. Hypertensive normal cognitive controls demonstrated hypoperfusion in regions usually involved in AD pathology. However, the effect of hypertension was attenuated after the onset of the pathological cognitive process

Asymmetric Cerebral Blood Flow in Patients with Mild Cognitive Impairment: Possible Relationship to Further Cognitive Deterioration

To explore patterns of cerebral blood flow in patients with mild cognitive impairment (MCI), who (1) eventually deteriorate into overt dementia, with no particular focus on the type of dementia, or (2) do not appear to further deteriorate in their cognitive functions

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

Technical note: development of a 3D printed subresolution sandwich phantom for validation of brain SPECT analysis

Purpose: To make an adaptable, head shaped radionuclide phantom to simulate molecular imaging of the brain using clinical acquisition and reconstruction protocols. This will allow the characterization and correction of scanner characteristics, and improve the accuracy of clinical image analysis, including the application of databases of normal subjects. Methods: A fused deposition modeling 3D printer was used to create a head shaped phantom made up of transaxial slabs, derived from a simulated MRI dataset. The attenuation of the printed polylactide (PLA), measured by means of the Hounsfield unit on CT scanning, was set to match that of the brain by adjusting the proportion of plastic filament and air (fill ratio). Transmission measurements were made to verify the attenuation of the printed slabs. The radionuclide distribution within the phantom was created by adding 99mTc pertechnetate to the ink cartridge of a paper printer and printing images of gray and white matter anatomy, segmented from the same MRI data. The complete subresolution sandwich phantom was assembled from alternate 3D printed slabs and radioactive paper sheets, and then imaged on a dual headed gamma camera to simulate an HMPAO SPECT scan. Results: Reconstructions of phantom scans successfully used automated ellipse fitting to apply attenuation correction. This removed the variability inherent in manual application of attenuation correction and registration inherent in existing cylindrical phantom designs. The resulting images were assessed visually and by count profiles and found to be similar to those from an existing elliptical PMMA phantom. Conclusions: The authors have demonstrated the ability to create physically realistic HMPAO SPECT simulations using a novel head-shaped 3D printed subresolution sandwich method phantom. The phantom can be used to validate all neurological SPECT imaging applications. A simple modification of the phantom design to use thinner slabs would make it suitable for use in PET

Cognitive impairment in patients with symptomatic carotid artery occlusion

Background Although transient ischemic attacks (TIAs) by definition do not cause neurologic deficits, cognitive impairment has been suggested in patients with carotid artery disease (CAD) and ipsilateral TIAs. The cause of this impairment has not been elucidated yet. Thrombo-embolism, but also chronic cerebral hypoperfusion have been suggested to play a role. In this light, surgical interventions that improve the blood flow towards the brain have been promoted to halt or even reverse cognitive deterioration in patients with symptomatic CAD. However, studies on the effect of revascularization surgery on cognition have yielded conflicting results. Before conclusions can be drawn, knowledge is required on the natural history of cognitive impairment in these patients. Methods Between September 1995 and July 1998, 113 patients with TIAs or moderately disabling stroke attributable to an angiographically proved carotid artery occlusion were recruited from consecutive patients referred to the departments of Neurology or Vascular Surgery of the University Medical Center Utrecht. Neuropsychological assessment, MR investigations (MRI, 1H-MRS, MRA), TCD ultrasonography (CO2 reactivity) and investigations of health-related quality of life (SF-36) and depressive mood took place at three points in time: after inclusion in the study, and 6 and 12 months thereafter. Spouses of the patients were asked to cooperate with the neuropsychological assessment, thus providing a healthy control group. Results At baseline, 40% of patients with TIAs, and 70% of patients with minor stroke were cognitively impaired. Cognitive ipairment was non-specific in nature, and mild to moderate in severity. Impairment was not restricted to patients with MRI-detected lesions. Mean flow and mean CO2 reactivity ipsilateral to the carotid occlusion were decreased, as well as the median NAA/creatine ratio in non-infarcted white matter. Lactate in non-infarcted white matter was present in 27% of the patients with TIAs, and 47% of the patients with minor stroke. In patients with TIAs, the presence of lactate was a better indicator of cognitive impairment than MRI-detected lesions. In both patients with TIAs as those with stroke, cognitive functioning did not correlate with CO2 reactivity. At follow-up, cognitive functioning improved, but only in patients without lactate in white matter, and without recurrent TIAs at follow-up. A minority of patients underwent carotid endarterectomy (CEA) for stenosis of the contralateral carotid artery. Although CEA led to improved CO2 reactivity and MCA flow on the side of the carotid occlusion, it had no impact on cognitive functioning. Self-perceived quality of life (QoL) was affected, both in patients with TIAs and in those with minor stroke. Depressive mood was associated with impaired QoL on all the subscales of the SF-36, disability according to the modified Rankin scale correlated only with self-perceived physical functioning, whereas cognitive impairment had no impact on QoL. Conclusions A substantial portion of patients with symptomatic carotid artery occlusion is cognitively impaired. Cognitive functioning may improve in the 1.5 years after the occurrence of ischemia, if symptoms do not recur. Severity and course of cognitive impairment correlate with measures of metabolism, but not with quantitative flow and CO2 reactivity. CEA for contralateral carotid stenosis results not in improvement of cognitive functioning within one year

Dynamics of proteinopathies in Alzheimer’s disease as measured by PET and CSF biomarkers

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the extracellular aggregation of the amyloid-β (Aβ; amyloid) peptide and the intraneuronal accumulation of the protein tau. Independently, and in concert, these protein opathies lead to the loss of synapses and neurons (neurodegeneration). These processes can be measured in living individuals using positron emission tomography (PET) and cerebrospinal fluid (CSF) based measurements (biomarkers). Biomarkers for AD include the retention in the brain of varied PET ligands (e.g. [11C]PIB and [18F]flutemetamol, Aβ; [18F]THK5317, tau; and [18F]FDG, glucose metabolism, a proxy for synaptic integrity), as well as CSF levels of Aβ1-42, and tau phosphorylated at threonine 181 (p-tau181p), and total-tau (t-tau), reflecting Aβ, the formation tau tangle pathology, and axonal damage, respectively. The aim of this thesis, which comprises five studies, was to obtain new insight into how these biomarkers interrelate in AD, and to examine their potential utility from a clinical standpoint. In study I, agreement between dichotomised (i.e. normal/abnormal) [11C]PIB PET and CSF Aβ1-42 in AD and related disorders was found to persist after controlling for potential methodological confounds tied to CSF, suggesting biological underpinnings to biomarker mismatches. Concordance, however, was substantially improved across patient groups when using Aβ1-42 in ratio with Aβ1-40. In study II, the impact of amyloid imaging with [18F]flutemetamol PET was examined in a cohort of diagnostically unclear patients, drawn from a tertiary memory clinic. [18F]Flutemetamol investigations resulted in substantial changes to pre-amyloid PET diagnoses and an incease in the use of cholinesterase inhibitors, with the greatest impact seen among patients with a pre-[18F]flutemetamol diagnosis of MCI. In study III, the relationship between [18F]THK5317 tau PET and CSF tau, including measures derived from assays capturing novel fragments, was shown to vary by isocortical hypometabolism, suggesting that the relationship between tau biomarkers may vary by disease stage. Novel CSF markers better tracked longitudinal PET, as compared to p-tau181p and t-tau, and improved concordance with [18F]THK5317. Moreover, comparison of cross-sectional and rate of change findings suggest a temporal delay between tau pathology and synaptic impairment. In studies IV and V, perfusion information derived from [18F]THK5317 tau PET scans was shown to strongly correlate with [18F]FDG PET metabolic imaging; though our cross-sectional data support the use of perfusion parameters as a substitute for [18F]FDG, longitudinal findings suggest that the coupling between perfusion and metabolism may vary as a function of disease stage, warranting further studies

VALUTAZIONE CON SPECT-CT DI SOGGETTI CON MCI E AD. UNO STUDIO CONTROLLATO

2004/2005XVII Ciclo1949Versione digitalizzata della tesi di dottorato cartacea