Partial Volume Correction in Quantitative Amyloid Imaging.

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition

BRAIN AGE AS A MEASURE OF BRAIN RESERVE IN NEUROPSYCHIATRIC DISORDERS

Aging represents a highly heterogeneous process with highly variable clinical outcomes. Differential expression of risk and resilience factors may provide explanations for this variability. Gaining a better understanding of resilience in aging is critical as it will allow for improved individualized outcome prediction, as well as providing insight for targeted interventions that may improve the process of aging. Currently, the prevailing models of neurocognitive resilience are cognitive reserve and brain reserve. The theory of cognitive reserve suggests that those with greater cognitive reserve may better cope with loss of brain integrity through presence of more adaptable and efficient neural systems. Most studies utilize education level to assess cognitive reserve; however, many proxy measures are subjective and susceptible to hindsight bias. The concept of brain reserve overlaps with that of cognitive reserve but focuses instead on the biological characteristics that allow the brain to be resilient to the effects of aging and pathological insults. It is generally thought that with sufficient brain substrate (e.g., larger grey matter volumes, greater synaptic density, more elaborate network complexity), the brain is more capable of preserving normal functioning and maintaining homeostasis despite the presence of factors of neurodegeneration or trauma. Overall, the main goals of this dissertation are to demonstrate the impact of cognitive and brain reserve on neuropsychological outcomes and brain activation patterns (Aim 1, Chapters 2 and 3), to utilize machine learning brain age prediction as a novel proxy of brain reserve (Aim 2, Chapter 4), and to utilize brain age prediction in several iv neuropsychiatric disorders to predict outcome or gain a better understanding on the disease process (Aim 3, Chapters 5, 6, 7)

Inflammation and Preclinical AD: Associations between Peripheral Inflammatory Biomarkers, Cognition, and Amyloid-B deposition in Non-demented Older Adults

The central role of inflammatory processes in the development of beta-amyloid (Aβ) pathology has been widely shown in rodent models, but has yet to be elucidated in humans, particularly prior to the onset of clinical symptoms. We examined associations between peripheral inflammatory mediators, cognition, and two neuroimaging Alzheimer’s disease (AD) biomarkers, Aβ plaques and hippocampal atrophy, in non-demented older adults. Cross-sectional and longitudinal data were used to assess associations between peripheral inflammatory biomarkers (soluble CD14, TNF-α receptor concentrations, and IL-6) and memory performance on the California Verbal Learning Test (CVLT) and Rey-Osterrieth Complex Figure Test in 173 non-demented older adults. Of these 173 participants, 134 were cognitively normal (CN) and 34 had MCI. Ninety of these participants underwent repeated assessments at 24 months. Structural MRI and Pittsburgh compound B-PET imaging were used to quantify hippocampal volume and Aβ plaque deposition. After adjusting for demographics, linear regression analysis revealed that higher levels of TNF-α and IL-6 predicted poorer global and verbal memory performance in the full sample, and the CN subsample. Elevated concentrations of pro-inflammatory markers were also associated with higher global Aβ deposition, specifically among those that also exhibited greater hippocampal atrophy. Secondary analysis using template-derived regions of interest showed that these moderation effects were specific to PiB uptake in the anterior cingulate gyrus, frontal cortex, and precuneus. These associations remained after adjusting for hypertension, diabetes, heart disease and white matter lesions (all p<0.05). Furthermore, higher levels of circulating IL-6 predicted subsequent conversion to MCI and increased longitudinal accumulation of Aβ pathology in regions susceptible to early amyloid deposition. Hippocampal volume moderated the association between inflammatory markers and Aβ deposition, suggesting potential disease-state-dependent differences in peripheral inflammatory profiles during the preclinical phase of AD. These findings highlight potential protein signatures that may vary depending on the prodromal phase of disease progression, and could help identify those in specific preclinical stages. from CN to MCI. Moreover, chronic, low-level systemic inflammation may accelerate the deposition of Aβ pathology and, consequently, place individuals at a higher risk of developing clinically significant cognitive impairment

Applied Clinical Neuroimaging in Cerebral Amyloid Angiopathy and Spontaneous Intracerebral Haemorrhage

Sporadic cerebral amyloid angiopathy is a common small vessel disease that preferentially involves small cortical and leptomeningeal arteries due to progressive amyloid-β deposition in their walls. Cerebral amyloid angiopathy occurs frequently in elderly people, and is a common and important cause of symptomatic lobar intracerebral haemorrhage and cognitive impairment. There is currently a growing interest in cerebral amyloid angiopathy, at least partly thanks neuroimaging, which now allows an unprecedented ability to investigate the disease dynamics in vivo using MRI to reveal complex patterns of cerebral bleeding and ischaemia. The detection of CAA during life is becoming an increasingly important challenge, since approaches of prevention or treatment (disease-modification) are now emerging as realistic possibilities. Determining the most promising treatments requires development of reliable biomarkers, the goal of my research. The main objective of this PhD thesis is to provide new insights into potential clinical and applied clinical neuroimaging biomarkers in patients with cerebral amyloid angiopathy. This is accomplished by a portfolio of research studies investigating: (a) the clinical and radiological spectrum of transient focal neurological episodes as a potential clinical clue for cerebral amyloid angiopathy; (b) cortical superficial siderosis, a distinct pattern on bleeding in the brain, as both a diagnostic and a prognostic marker of cerebral amyloid angiopathy; (c) MRI-visible perivascular spaces topography, as a new marker of small vessel disease and cerebral amyloid angiopathy; (d) potential pathological, neuroimaging and genetic differences in patients with pathology-proven CAA with and without intracerebral haemorrhage and presents evidence for different disease phenotypes; (e) the evidence whether the presence and burden of cerebral microbleeds on MRI scans is associated with an increased risk of recurrent spontaneous ICH, and if this risk is different according to MRI-defined microangiopathy subtype, in a meta-analysis