Faculty Bibliography

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.

Coronavirus disease 2019 (COVID-19) is an acute infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in its multiple variants that classically presents with cough, fatigue, fever, headache, myalgias, and diarrhea. As vaccination becomes widely available and infection rates facilitate herd immunity across the globe, more attention has been given to long-term symptoms that may persist after the index infection, which include impairments in concentration, executive dysfunction, sensory disturbances, depression, anxiety, fatigue, and cough, among other symptoms classified under the umbrella term of postacute sequelae of SARS-CoV-2 infection (PASC).Functional neurologic disorder (FND), also known as conversion disorder and functional neurologic symptom disorder, refers to the presence of one or more symptoms of altered voluntary motor or sensory function that are incompatible with and not better explained by a known neurological or medical condition that causes significant distress and functional impairment. Although the diagnosis of FND may not require the identification of an underlying psychological stressor, being diagnosed with an FND can worsen stigma and shift attention and resources away from other medical concerns that should be concomitantly addressed.This review summarizes the literature on the overlapping nature and discrimination of PASC from FND in COVID-19 survivors. Based on this, we develop a treatment framework that targets unique domains of these complex overlapping presentations, following a multidisciplinary approach with an individualized treatment plan inclusive of physical and psychological interventions focused on functional rehabilitation.

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons.

Mild traumatic brain injury (TBI) and concussion can have serious consequences that develop over time with unpredictable levels of recovery. Millions of concussions occur yearly, and a substantial number result in lingering symptoms, loss of productivity, and lower quality of life. The diagnosis may not be made for multiple reasons, including due to patient hesitancy to undergo neuroimaging and inability of imaging to detect minimal damage. Biomarkers could fill this gap, but the time needed to send blood to a laboratory for analysis made this impractical until point-of-care measurement became available. A handheld blood test is now on the market for diagnosis of concussion based on the specific blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl terminal hydrolase L1 (UCH-L1). This paper discusses rapid blood biomarker assessment for mild TBI and its implications in improving prediction of TBI course, avoiding repeated head trauma, and its potential role in assessing new therapeutic options. Although we focus on the Abbott i-STAT TBI plasma test because it is the first to be FDA-cleared, our discussion applies to any comparable test systems that may become available in the future. The difficulties in changing emergency department protocols to include new technology are addressed.

As the search for modalities to cure Alzheimer's disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration. Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile. Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy. Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health. As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression.

Background: While those with COPD are twice as likely to develop depression, it is under-diagnosed and under-treated due to symptom overlap (i.e. low energy) and broad treatment guidelines (Yohannes, 2014; Kroenke, 2002). Specifically, moderate depression management (PHQ=10-14) may range from follow-up to psychotherapy or pharmacotherapy (Kroenke, 2002). This leaves patients with COPD vulnerable as clinicians may misconstrue depression symptoms to be a consequence of COPD and opt to treat more conservatively. Hence, it is crucial to understand how the presentation of depression is affected by COPD. Though von Siemens et al. (2019, Germany) found single symptom homogeneity among those with varying degrees of COPD, the generalizability of their findings to the more heterogeneous American population remains unclear. Therefore, we aim to study if moderate depression is captured similarly by the PHQ-9 in patients with and without co-morbid COPD, in an effort to highlight the importance of depression treatment in both groups.
Method(s): A retrospective review of nationally representative NHANES data from 2017 to March 2020 was conducted (CDC, 2021). To illustrate the limited role COPD symptomatology plays in how moderate depression presents (PHQ=10-14), individual question responses were compared between participants with and without COPD, using Pearson Chi-Square test for independence (Kroenke, 2002).
Result(s): Among the 8306 participants evaluated, 503 screened positive for moderate depression and, of those, 91 were told they had co-morbid COPD. In participants who screened positive for moderate depression, the number of responses to how frequently one was bothered by anhedonia, feeling down/depressed/hopeless, trouble sleeping (too much), poor appetite/overeating, feeling bad about oneself, moving/speaking too slowly/quickly, and thoughts of self harm, over the last two weeks, did not statistically differ between those with and those without COPD (p > 0.05). Meanwhile, the frequency with which those with and those without COPD reported being bothered by feeling tired/fatigued and/or trouble concentrating did significantly differ (p > 0.05).
Discussion(s): These results suggest the PHQ-9 similarly captures moderate depression in American population, regardless of co-morbid COPD. Therefore, clinicians should not attribute patient symptoms to a consequence of COPD and opt for conservative management. Conclusion/Implications: Understanding that depression symptomatology depression is largely unchanged by COPD should result in its increased diagnosis and treatment. References: Centers for Disease Control and Prevention. National Center for Health Statistics. National Health and Nutrition Examination Survey Data, 2017-2020. Kroenke K, Spitzer R. The PHQ-9: A New Depression Diagnostic and Severity Measure. Psychiatric Annals. 09/01 2002;32:509-521. von Siemens SM, et al. Effect of COPD severity and comorbidities on the result of the PHQ-9 tool for the diagnosis of depression: results from the COSYCONET cohort study. Respir Res. Feb 11 2019;20(1):30. Yohannes AM, Alexopoulos GS. Depression and anxiety in patients with COPD. Eur Respir Rev. Sep 2014;23(133):345-9.
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Background and aim/UNASSIGNED:Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Prior work showed that resveratrol's anti-atherogenic properties are mediated in part through the adenosine A2A receptor. The present study explores the potential contribution of adenosine A2A receptor activation to neuroprotective action of resveratrol on cognitive deficits in a model of atherosclerosis-prone systemic lupus erythematosus. Experimental procedure/UNASSIGNED:Using behavioral analysis (open field, static rod, novel object recognition) and QRT-PCR, this study measured working memory, anxiety, motor coordination, and expression of mRNA in the brain. Results and conclusion/UNASSIGNED:Data indicate that resveratrol increases working memory, on average but not statistically, and shows a trend towards improved motor coordination (p = 0.07) in atherosclerosis-prone lupus mice. Additionally, resveratrol tends to increase mRNA levels of SIRT1, decrease vascular endothelial growth factor and CX3CL1 mRNA in the hippocampus. Istradefylline, an adenosine A2A receptor antagonist, antagonizes the effects of resveratrol on working memory (p = 0.04) and the expression of SIRT1 (p = 0.03), vascular endothelial growth factor (p = 0.04), and CX3CL1 (p = 0.03) in the hippocampus.This study demonstrates that resveratrol could potentially be a therapeutic candidate in the modulation of cognitive dysfunction in neuropsychiatric lupus, especially motor incoordination. Further human studies, as well as optimization of resveratrol administration, could confirm whether resveratrol may be an additional resource available to reduce the burden of cognitive impairment associated with lupus. Additionally, further studies need to address the role of A2A blockade in cognitive function among the autoimmune population. Section/UNASSIGNED:3. Dietary therapy/nutrients supplements. Taxonomy classification by EVISE/UNASSIGNED:autoimmunity, inflammation, neurology.