Intracavitary Magnetic Resonance Elastography for Prostate Cancer Imaging

Prostate cancer is currently the most prevalent cancer and third leading cause of cancer related deaths amongst Canadian men. Highly sensitive, but non-specific, diagnostic techniques have made it challenging for clinicians to balance treatment efficacy with associated side-effects. Prostate imaging techniques are being investigated to assist in diagnosis, staging, monitoring, and localizing prostate cancer within the gland itself. Measuring changes in tissue biomechanics could provide important functional and morphological information about prostate cancer. Magnetic resonance elastography (MRE) is a potential candidate for imaging tissue mechanical properties, in vivo. MRE gives quantitative stiffness measurements by transmitting micrometer amplitude shear waves into tissues. Previous reports of performing MRE in prostate cancer patients have used an external source to generate shear waves inside the prostate, which has imposes limitations on the spatial resolution of the stiffness maps (elastograms). An alternative approach is to use an internal or intra-cavitary actuator to generate shear waves in closer proximity to the prostate in order to produce higher resolution elastograms. Since clinically significant prostate cancers can have diameters on the order of 1 cm, high resolution elastograms are essential in order to evaluate MRE as a potential tool for assisting in disease prognosis. This thesis demonstrates the technical feasibility of intra-cavitary (transurethral, endorectal) MRE for the purposes of evaluating localized regions of stiffness within the prostate gland. First, a combination of gel and canine experiments were performed to help outline the imaging characteristics of intra-cavitary MRE. Secondly, the feasibility of performing endorectal MRE by connecting a piezoceramic actuator to an endorectal radiofrequency receive coil while simultaneously preserving the signal to noise ratio of the acquired images wave demonstrated. Thirdly, the feasibility and tolerability of endorectal MRE in conjunction with current clinical endorectal RF coil designs was successfully demonstrated in human volunteers. This represented the first evaluation of endorectal MRE in humans. Lastly, a compliant mechanical amplifier was designed in order to develop a reliable high amplitude piezoceramic actuator for performing intracavitary MRE. Taken together, this work demonstrates the feasibility of intracavitary MRE and provides a method for locally probing the biomechanical properties of the prostate gland.Ph.D

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences

Genetic associations with dementia‐related proteinopathy: Application of item response theory

IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.ResultsFinal included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors