Faculty Bibliography

INTRODUCTION/BACKGROUND:Underlying causes of Alzheimer's disease (AD) remain unknown, making it imperative to identify molecular mechanisms driving the pathobiology of AD onset and progression. METHODS:Laser capture microdissection was used to isolate layer III pyramidal neurons from post mortem human prefrontal cortex (Brodmann area 9). Single population RNA sequencing was conducted using tissue from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. Differentially expressed genes (DEGs) were compared across groups. RESULTS:DEGs increased from prodromal (MCI vs. NCI) to progression (AD vs. MCI) to frank AD (AD vs. NCI). The majority of DEGs and pathways shared between prodromal and progression exhibited a change in the direction of dysregulation unlike pathways between progression and frank AD. DISCUSSION/CONCLUSIONS:Candidate genes and pathways were identified that demarcate early-stage AD onset from AD progression, providing a roadmap to study cortical cellular vulnerability and key targets for intervention at early stages of AD. HIGHLIGHTS/CONCLUSIONS:Pyramidal neuron differentially expressed genes (DEGs) are directionally divergent between prodromal, progression, and frank Alzheimer's disease (AD). Pyramidal neuron DEGs are directionally convergent between progression and frank AD. Dysfunctional bioenergetic pathways increased dysregulation as the AD spectrum progressed. Immune response pathways were more dysregulated in frank AD than prodromal stages. DEGs, = biological pathways, and interactomes demarcate specific stages across the AD spectrum.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally^1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic^3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype^7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable¹⁰, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

Astrocytes, the bushy, star-shaped glial cells of the brain and spinal cord, support the proper development and function of many cells in the central nervous system. In response to disease or injury they transform, adopting varied morphologies, molecular signatures, and functions-this state of transformation is known as reactivity. For over a century, the reactivity of astrocytes has been recognized, but it is the recent surge in technological innovation that has shed light on the diverse nature of this reactivity. It is this developing understanding of the heterogeneity of reactive astrocytes across disease-specific contexts and a spatiotemporal gradient that now excites the astrocyte field. In this review, we discuss the current understanding of reactive astrocyte heterogeneity, highlight the biological implications of this heterogeneity, and propose future approaches to aid in fully understanding the heterogeneity of reactive astrocytes.

Social behaviors, including parental care, mating, and fighting, all depend on the hormonal milieu of an organism. Decades of work highlighted estrogen as a key hormonal controller of social behaviors, exerting its influence primarily through binding to estrogen receptor alpha (ERα). Recent technological advances in chemogenetics, optogenetics, gene editing, and transgenic model organisms have allowed for a detailed understanding of the neuronal subpopulations and circuits for estrogen action across Esr1-expressing interconnected brain regions. Focusing on rodent studies, in this review we examine classical and contemporary research demonstrating the multifaceted role of estrogen and ERα in regulating social behaviors in a sex-specific and context-dependent manner. We highlight gaps in knowledge, particularly a missing link in the molecular cascade that allows estrogen to exert such a diverse behavioral repertoire through the coordination of gene expression changes. Understanding the molecular and cellular basis of ERα's action in social behaviors provides insights into the broader mechanisms of hormone-driven behavior modulation across the lifespan.

BACKGROUND:Complex Regional Pain Syndrome (CRPS) is a challenging and often disabling condition marked by persistent pain, most commonly in a limb following injury or surgery. It presents with a wide array of symptoms, including intense pain, swelling, alterations in skin color and temperature, motor dysfunction, and trophic changes such as skin and tissue atrophy. While the precise cause of CRPS is not fully understood, it is thought to stem from abnormal nervous system activity, leading to heightened pain sensitivity and inflammatory responses. A thorough understanding of CRPS is essential for accurate diagnosis, effective treatment, and enhancing patients' quality of life.Although attempts have been made to distinguish between acute and chronic CRPS, there are currently no established diagnostic criteria specific to chronic CRPS in medical literature. OBJECTIVE:This ASIPP guidance document offers updated, evidence-based recommendations for the diagnosis and management of Chronic Complex Regional Pain Syndrome (CRPS), with a primary focus on introducing novel, time-based diagnostic criteria specific to the chronic phase. These proposed criteria address significant gaps in the current literature, where existing standards, such as the Budapest Criteria, do not sufficiently differentiate between the acute and chronic stages of the condition. METHODS:An expert panel convened by the American Society of Interventional Pain Physicians (ASIPP) conducted a comprehensive literature review and employed a structured consensus process to develop recommendations. Acknowledging that the clinical and pathological characteristics of CRPS change significantly beyond 12 months, the panel proposed chronic-specific diagnostic criteria based on disease duration, clinical history, physical examination findings, and optional diagnostic tests. These draft criteria were refined through multidisciplinary input and expert consensus. RESULTS:The diagnostic framework for chronic CRPS consists of four key components:General Criteria - Require fulfillment of the Budapest Criteria for at least 12 months, continued recognition of CRPS as a diagnosis of exclusion, and differentiation from generalized nociplastic pain syndromes.History-Based Criteria - Mandate the presence of at least three out of five specific historical features.Physical Examination Criteria - Include asymmetric limb findings, sensory disturbances, and musculoskeletal changes.Optional Diagnostic Testing - May involve assessments such as intraepidermal nerve fiber density (IENFD) and imaging evidence of regional bone demineralization.This framework builds upon the Budapest Criteria by incorporating time-dependent features of chronic CRPS, including musculoskeletal dystrophy, neurogenic inflammation, and sympathetic dysfunction. Emerging objective tools-such as quantitative sensory testing (QST), skin biopsy for IENFD, functional MRI, and serum biomarkers of neuroinflammation-may further support diagnosis in complex or uncertain cases.Treatment recommendations highlight a multimodal strategy that integrates physical rehabilitation, pharmacologic management of neuropathic pain, sympathetic nerve blocks, and advanced neuromodulation. Emphasis is placed on individualized care pathways tailored to disease stage and patient-specific characteristics. CONCLUSIONS:This article presents the first structured, time-sensitive diagnostic criteria for chronic CRPS, aimed at improving diagnostic accuracy and informing treatment strategies. Adoption of these criteria may enhance clinical outcomes and promote further research into the natural history and pathophysiology of CRPS progression.

Many chemotherapeutic agents impair cancer growth by inducing DNA damage. The impact of these agents on mutagenesis in normal cells, including sperm, is largely unknown. Here, we applied high-fidelity duplex sequencing to 94 samples from 36 individuals exposed to diverse chemotherapies and 32 controls. We found that many of the sperm samples from men exposed to chemotherapy, the mutation burden was elevated as compared to controls and the expected burden based on trio studies, with one subject having >10-fold increase over expected for age. Saliva from this same individual also had a markedly higher mutation burden. We then validated this finding using other tissues, also finding an increased mutation burden in the blood and liver of many subjects exposed to chemotherapy as compared to unexposed controls. Similarly, mice treated with three cycles of cisplatin had an increased mutation burden in sperm but also in the liver, and hematopoietic progenitor cells. These results suggest an association between cancer therapies and mutation burden, with implications for counseling cancer patients considering banking sperm prior to therapy and for cancer survivors considering the tradeoffs of using banked sperm as compared to conceiving naturally.

Alston's singing mice (Scotinomys teguina) are highly vocal Central American rodents that produce structured "songs" (duration: 5-10 s),¹

OBJECTIVE:To validate the carotid web (CW) risk stratification assessment described in previous works within a larger cohort of patients with symptomatic and incidentally found asymptomatic CWs. METHODS:A retrospective analysis of our institution's electronic medical records identified all patients with a diagnosis of CW from 2017 to 2024. We included symptomatic patients and those with asymptomatic CWs, that is, incidentally found webs without history of stroke or transient ischemic attack. Patient charts were reviewed for demographics, imaging, comorbidities, and a diagnosis of stroke after diagnosis of asymptomatic CW. All angles were measured as described in previous work on a sagittal reconstruction of neck CT angiography in which the common carotid artery (CCA), external carotid artery, and internal carotid artery (ICA) were well visualized, together with the CW itself. Principal component analysis and logistic regression were performed to evaluate the association between high-risk angles and stroke risk.  RESULTS: Twenty-six symptomatic and 26 asymptomatic patients were identified. Of note, the number of patients with hypertension, hyperlipidemia, and smoking history was 17 (65.0%), 16 (62.0%), and 8 (31.0%) for symptomatic patients and 18 (69.0%), 17 (65.0%), and 15 (58.0%) for asymptomatic patients. All angular measurements showed statistically significant associations with stroke status. The CCA-web-pouch angle showed the strongest association (p=2.07×10⁻⁴), followed by the CCA-pouch-tip angle (p=3.23×10⁻⁴), ICA-web-pouch angle (p=0.004), and ICA-pouch-tip angle (p=0.005). Each additional high-risk angle increased the odds of stroke by 9.47-fold (p<0.0001). The associated probability of stroke increased from 6.3% with no high-risk angles to 39.1% with one high-risk angle and further to 85.9% with two high-risk angles. The model demonstrated high sensitivity, correctly identifying 84.6% of positive cases, and high specificity, correctly identifying 88.5% of negative cases. The F1 score was 0.863, indicating good overall model performance.  CONCLUSION: Given this successful stratification of CWs into high- and low-risk groups, the utilization of geometric CW parameters may play a role in improving patient selection for intervention in the setting of incidentally diagnosed CW. .

Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.

This collective eulogy by colleagues, co-authors and friends is a tribute to the work and life of Rudolf Nieuwenhuys. 'Neurofascination' is an apt label for his scholarly life in the sciences from the start in 1955 until his last days in 2024. In addition, he had a broad interest in Roman and Gothic architecture, the history and politics of the twentieth century, religion and the music of Johann Sebastian Bach. Extensive discussions on one or more of these topics often led to long-lasting friendships, some of which inform the following pages. Rudolf is remembered for his highly didactical and remarkably illustrated presentations and publications, including the three-volume The Central Nervous System of Vertebrates and the four editions of The Human Central Nervous System. His research interests addressed an impressively wide range of topics concerning development and evolutionary neurobiology and a systematic approach to comparative brain structures in vertebrates. His almost endless fascination for neuromorphology included the invertebrates as well. But unfortunately, even his long life was not enough to write the book on the comparative neuroanatomy of invertebrates which he long had in mind. The many years of his career spanned the remarkable histology of the gigantocerebellum of mormyrids to an exploratory synthesis of subdivisions of the human cortex, as originally mapped by the Vogt-Vogt school of cortical architectonics.