Examining the Relationship between Autobiographical Episodic Memory and Theory of Mind in Developmental Amnesia and with fMRI: The Role of Personal Familiarity

The purpose of this dissertation was to examine if, and under what conditions, autobiographical memory (AM) supported by the hippocampus benefits theory of mind (ToM). To this end, I attempted to address two main questions: (a) Are AM difficulties caused by early-onset hippocampal damage associated with impaired performance on standard measures of ToM (Experiment 1)? (b) Is AM and the brain regions that support it involved to a greater extent in imagining the experiences of personally known others compared to unknown others (Experiments 2, 3, and 4)? In Experiment 1, ToM abilities were examined in H.C., a young woman with impaired AM development due to early hippocampal damage. H.C. performed at the same level as controls on a wide range of ToM tests. These findings suggest that normal AM development is not critical for the development or expression of ToM, at least as measured by standard tests. In Experiment 2, healthy individuals were scanned with fMRI to test whether different neural and cognitive mechanisms support imagining the experiences of personally known others (pToM) versus unknown others (ToM). There was greater neural overlap between AM and pToM compared to pToM and ToM. Furthermore, a direct comparison between pToM and ToM revealed that midline regions associated with AM predominated during pToM, whereas more lateral regions associated with semantic memory predominated during ToM. These findings suggest that there are multiple routes to ToM and the extent to which AM is recruited depends, at least in part, on whether the target person is personally known. Experiment 3 corroborated the neuroimaging results reported in Experiment 2 by showing that H.C. was impaired at producing detailed descriptions of events relating to her own past as well as events relating to personally known others. In contrast, she was intact at describing events relating to unknown others. Experiment 4 explored the neural basis of H.C.’s performance on AM, pToM, and ToM. fMRI analyses revealed that measures of percent signal change and functional connectivity were equivalent between H.C. and controls across all conditions. These finding suggest that BOLD fMRI cannot necessarily distinguish between preserved and impaired behavioural performance in developmental amnesia. Overall, these results contribute substantially to our current understanding of the functional and neural relationship between AM and ToM, and add to the literature suggesting that the hippocampus plays a broader role in cognition beyond that of recalling past events

Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.

Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome-pathology correlation identified casein kinase 1ε (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome-pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Stage I Non-Small Cell Lung Cancer

Published data suggests that wedge resection for stage I non-small cell lung cancer (NSCLC) is associated with improved overall survival compared to stereotactic body radiation therapy. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs) were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV). Treatment plans were designed using a mean of 156 pencil beams. Doses delivered to the PTV ranged from 42 to 60 Gy in three fractions. The 30 Gy isodose contour extended at least 1 cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3 month follow-up intervals. Forty patients (median age 76) with a median maximum tumor diameter of 2.6 cm (range, 1.4–5.0 cm) and a mean post-bronchodilator percent predicted forced expiratory volume in 1 s (FEV1) of 57% (range, 21–111%) were treated. A median dose of 48 Gy was delivered to the PTV over 3–13 days (median, 7 days). The 30 Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12–72 months) follow-up, the 3 year Kaplan–Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91 and 75%, respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1–2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Single Peripheral Lung Metastases

Standard treatment for operable patients with single peripheral lung metastases is metastasectomy. We report mature CyberKnife outcomes for high-risk surgical patients with biopsy proven single peripheral lung metastases. Twenty-four patients (median age 73 years) with a mean maximum tumor diameter of 2.5 cm (range, 0.8–4.5 cm) were treated over a 6-year period extending from September 2004 to September 2010 and followed for a minimum of 1 year or until death. A mean dose of 52 Gy (range, 45–60 Gy) was delivered to the prescription isodose line in three fractions over a 3–11 day period (mean, 7 days). At a median follow-up of 20 months, the 2-year Kaplan–Meier local control and overall survival rates were 87 and 50%, respectively. CyberKnife with fiducial tracking is an effective treatment for high-risk surgical patients with single small peripheral lung metastases. Trials comparing CyberKnife with metastasectomy for operable patients are necessary to confirm equivalence

State, trait, and accumulated features of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) in mild Alzheimer's disease

Background The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD). Methods A latent state–trait model with autoregressive effects was used to determine how much of the ADAS-Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next). Results Participants with mild AD (n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS-Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion-specific information, but they varied between items in the relative amounts of trait versus accumulated effects. Conclusions Although the ADAS-Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion-specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS-Cog item measures

A pragmatic randomized trial of mailed fecal immunochemical testing to increase colorectal cancer screening among low‐income and minoritized populations

BackgroundColorectal cancer (CRC) screening is underused, particularly among low-income and minoritized populations, for whom the coronavirus disease 2019 (COVID-19) pandemic has challenged progress in achieving equity.MethodsA hub-and-spoke model was used. The hub was a nonacademic organization and the spokes were three community health center (CHC) systems overseeing numerous clinic sites. Via a cluster-randomized trial design, nine clinic sites were randomized to intervention and 16 clinic sites were randomized to usual care. Patient-level interventions included invitation letters, mailed fecal immunochemical tests (FITs), and call/text-based reminders. Year 1 intervention impact, which took place during the COVID-19 pandemic, was assessed as the proportion completing screening among individuals not up to date at baseline, which compared intervention and nonintervention clinics accounting for intraclinic cluster variation; confidence intervals (CIs) around differences not including 0 were interpreted as statistically significant.ResultsAmong 26,736 patients who met eligibility criteria, approximately 58% were female, 55% were Hispanic individuals, and 44% were Spanish speaking. The proportion completing screening was 11.5 percentage points (ppts) (95% CI, 6.1-16.9 ppts) higher in intervention versus usual care clinics. Variation in differences between intervention and usual care clinics was observed by sex (12.6 ppts [95% CI, 7.2-18.0 ppts] for females; 8.8 ppts [95% CI, 4.7-13.9 ppts] for males) and by racial and ethnic group (13.8 ppts [95% CI, 7.0-20.6 ppts] for Hispanic individuals; 13.0 ppts [95% CI, 3.6-22.4 ppts] for Asian individuals; 11.3 ppts [95% CI, 5.8-16.8 ppts] for non-Hispanic White individuals; 6.1 ppts [95% CI, 0.8-10.4 ppts] for Black individuals).ConclusionsA regional mailed FIT intervention was effective for increasing CRC screening rates across CHC systems serving diverse, low-income populations

Occupational color vision standards: new prospects

Occupational color vision standards in transport have been implemented for 100 years. A review of these standards has taken place early this century prompted by antidiscrimination laws in the workplace and several transport accidents. The Australian and Canadian Railways have developed new lanterns to address their occupational medical requirements. The Civil Aviation Authority in the UK has adopted the Color Assessment and Diagnosis (CAD) test as the standard for assessing color vision for professional flight crews. The methodology employed using the CAD test ensures that color deficient pilot applicants able to complete the most safety-critical task with the same accuracy as normal trichromats can be accepted for pilot training. This methodology can be extended for setting new color vision standards in other work environments