Faculty Bibliography

In the COMET trial of patients with late-onset Pompe disease, greater improvement in upright forced vital capacity (FVC) % predicted was observed with avalglucosidase alfa (AVA) vs alglucosidase alfa (ALGLU) (estimated treatment difference: 2.43%). The pre-specified mixed model repeated measures (MMRM) analysis demonstrated non-inferiority of AVA (P = 0.0074) and narrowly missed superiority (P = 0.063; 95% CI: -0.13-4.99). We report superiority of AVA in two post-hoc analyses that account for an extreme outlier participant with low FVC and severe chronic obstructive pulmonary disease at baseline: MMRM excluding the outlier (P = 0.013) and non-parametric analysis of all data with repeated measures analysis of covariance (P = 0.019).

Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC.

BACKGROUND/UNASSIGNED:Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer's disease (AD) pathology during midlife, particularly in the hippocampal component of the medial temporal lobe memory circuit. However, molecular and cellular mechanisms underlying selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during DS/AD onset. This is compounded by evidence showing spatial (e.g., deep versus superficial) localization of pyramidal neurons (PNs) has profound effects on activity and innervation within the CA1 region. OBJECTIVE/UNASSIGNED:We investigated whether there is a spatial profiling difference in CA1 PNs in an aged female DS/AD mouse model. We posit dysfunction may be dependent on spatial localization and innervation patterns within discrete CA1 subfields. METHODS/UNASSIGNED:Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region. RESULTS/UNASSIGNED:RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. The entire CA1 region displayed the most differentially expressed genes (DEGs) in trisomic mice reflecting innate DS vulnerability, while trisomic CA1a deep PNs exhibited fewer but more physiologically relevant DEGs, as evidenced by bioinformatic inquiry. CONCLUSIONS/UNASSIGNED:CA1a deep neurons displayed numerous DEGs linked to cognitive functions whereas CA1a superficial neurons, with approximately equal numbers of DEGs, were not linked to pathways of dysregulation, suggesting the spatial location of vulnerable CA1 PNs plays an important role in circuit dissolution.

 The tau protein undergoes pathological changes in Alzheimer's disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of some antibodies targeting amyloid-β in Alzheimer's disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer's disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

AIM/UNASSIGNED:Oral cancer patients suffer pain at the site of the cancer, which degrades quality of life (QoL). The University of California San Francisco Oral Cancer Pain Questionnaire (UCSFOCPQ), the only validated instrument specifically designed for measuring oral cancer pain, measures the intensity and nature of pain and the level of functional restriction due to pain. PURPOSE/UNASSIGNED:The aim of this study was to compare pain reported by untreated oral cancer patients on the UCSFOCPQ with pain they reported on the Brief Pain Inventory (BPI), an instrument widely used to evaluate cancer and non-cancer pain. PATIENTS AND METHODS/UNASSIGNED:The correlation between pain measured by the two instruments and clinical characteristics were analyzed. Thirty newly diagnosed oral cancer patients completed the UCSFOCPQ and the BPI. RESULTS/UNASSIGNED:Pain severity measurements made by the UCSFOCPQ and BPI were concordant; however, the widely used BPI average pain over 24 hours score appeared less sensitive to detect association of oral cancer pain with clinical characteristics of patients prior to treatment (nodal status, depth of invasion, DOI). A BPI average score that includes responses to questions that measure both pain severity and interference with function performs similarly to the UCSFOCPQ in detection of associations with nodal status, pathologic T stage (pT stage), stage and depth of invasion (DOI). CONCLUSION/UNASSIGNED:Pain assessment instruments that measure sensory and interference dimensions of oral cancer pain correlate with biologic features and clinical behavior.

OBJECTIVE/UNASSIGNED:The process of resident recruitment is costly, and our surgical residency program expends significant time on the resident selection process while balancing general duties and responsibilities. The aim of our study was to explore the relationship between otolaryngology-head and surgery (OHNS) residents' National Residency Matching Program (NRMP) rank-list position at our institution and their subsequent residency performance. STUDY DESIGN/UNASSIGNED:Retrospective cohort study. SETTING/UNASSIGNED:Single site institution. METHODS/UNASSIGNED:). RESULTS/UNASSIGNED: > .05). CONCLUSION/UNASSIGNED:Our results showed that there were no significant correlations between OHNS rank order and various measures of success in residency training, which aligns with existing literature. Further investigation of this relationship should be conducted to ensure the applicability of our findings.

The cerebellum takes in a great deal of sensory information from the periphery and descending signals from the cerebral cortices. It has been debated whether the paramedian lobule (PML) in the rat and its paravermal regions that project to the interpositus nucleus (IPN) are primarily involved in motor execution or motor planning. Studies that have relied on single spike recordings in behaving animals have led to conflicting conclusions regarding this issue. In this study, we tried a different approach and investigated the correlation of field potentials and multi-unit signals recorded with multi-electrode arrays from the PML cortex along with the forelimb electromyography (EMG) signals in rats during behavior. Linear regression was performed to predict the EMG signal envelopes using the PML activity for various time shifts (±25, ±50, ±100, and ± 400 ms) between the two signals to determine a causal relation. The highest correlations (~0.5 on average) between the neural and EMG envelopes were observed for zero and small (±25 ms) time shifts and decreased with larger time shifts in both directions, suggesting that paravermal PML is involved both in processing of sensory signals and motor execution in the context of forelimb reaching behavior. EMG envelopes were predicted with higher success rates when neural signals from multiple phases of the behavior were utilized for regression. The forelimb extension phase was the most difficult to predict while the releasing of the bar phase prediction was the most successful. The high frequency (>300 Hz) components of the neural signal, reflecting multi-unit activity, had a higher contribution to the EMG prediction than did the lower frequency components, corresponding to local field potentials. The results of this study suggest that the paravermal PML in the rat cerebellum is primarily involved in the execution of forelimb movements rather than the planning aspect and that the PML is more active at the initiation and termination of the behavior, rather than the progression.

BACKGROUND/UNASSIGNED:Chinese and Korean Americans are among the fastest-growing minority groups in the US but face disparities in income and limited English proficiency, leading to health inequities in Alzheimer's disease and related dementias (ADRD) care. OBJECTIVE/UNASSIGNED:This study aims to understand cultural influences in ADRD care from the perspectives of Chinese and Korean American caregivers to inform culturally sensitive support for caregivers in Asian immigrant populations. METHODS/UNASSIGNED:We conducted a study that was part of a broader project aimed at informing the cultural adaptation of the NYU Caregiver Intervention-Enhanced Support (NYUCI-ES) program specifically for Chinese and Korean American caregivers managing multiple chronic conditions. In our interviews with 14 Chinese American and 11 Korean American caregivers, we focused on how their roles as primary caregivers were influenced by cultural and family expectations, the impact of caregiving on their personal and emotional well-being, and the specific barriers they face in accessing healthcare for themselves and their relatives with dementia. RESULTS/UNASSIGNED:Cultural beliefs and values significantly influenced the perceptions and utilization of support systems among Chinese and Korean American caregivers. Family stigma and adherence to cultural norms impacted their caregiving experiences. The study also highlighted the added burden during the pandemic and the potential benefits of telehealth and information technology in ADRD care. CONCLUSIONS/UNASSIGNED:Developing culturally tailored, person-centered programs is crucial to meeting the unique needs of Chinese and Korean American caregivers. This research contributes to understanding and supporting this vulnerable population, promoting healthcare equity for ADRD patients and caregivers.