Faculty Bibliography

BACKGROUND:Nephrolithiasis recurs after an initial episode within 5 years for 30-50% of stone formers without dietary and/or pharmacological therapy to prevent or reduce stone recurrence. Preventive interventions target increasing urine volume or altering urinary concentration of key risk factors: high calcium, oxalate or uric acid and low urinary citrate. Two strategies for achieving stone prevention involve an untailored generalized approach (empiric therapy) and an approach tailored to results from 24 h urine testing (selective therapy). METHODS:Adults with recurrent kidney stone disease were randomly assigned to empiric (Emp) or selective (Sel) therapy upon completing 24 h urine testing. Participants in the Emp group received standard guideline-based diet and medication therapy. Participants in the Sel group received therapy tailored to their 3 most severe urine abnormalities. Within-group differences in dietary and urinary variables were assessed via the Wilcoxon test and difference between groups in changes from baseline to 8 weeks via general linear modeling. RESULTS:The Emp group had a 33% reduction in dietary oxalic acid intake (p = 0.02), but no significant changes in intakes of water, sodium, animal-based protein, or servings of fruits and vegetables. There were also no significant changes in urine volume or urinary sodium excretion. Overall, Sel participants increased daily intake of water by 17% (p = 0.02), doubled their number of daily fruit/vegetable servings (p = 0.04), and reduced their oxalate (p = 0.04) and sodium (p = 0.05) intakes. Sel participants in the urinary citrate and calcium subgroups showed greater reductions in urinary calcium oxalate supersaturation (-38%) compared to the Emp group (-30%). CONCLUSIONS:The findings suggest that a more personalized approach with a limited number of dietary targets supports improvements that are less likely to occur with empiric therapy which reflects a "one size fits all" method. However, even with tailored therapy, the inter-individual variability in dietary intake and response to treatment must be considered as adherence to dietary recommendations is particularly challenging in a condition that is lifelong. This trial was registered at clinicaltrials. gov NCT05365477.

What is a 'natural' behavior? I argue that the study of natural behaviors is often the study of the spontaneous behaviors of animals placed in quantifiably different environments. For behavioral generalists such as rodents, humans, and many other species, there may be no such definable construct as a native habitat or 'natural behavior', due to their successful abilities and needs to rapidly adapt to a wide range of different ecosystems. Instead of prioritizing naturalness, it may be more essential to determine objective outcome measures related to specific behaviors; i.e., which sequences of behaviors and adaptive mechanisms allow animals to survive and reproduce, across a range of dynamic or hazardous physical and social environments.

Neurons accumulate somatic mutations with age, but how mutation processes vary among neuronal types remains unclear. Characterizing this variability may elucidate the role of genome integrity in brain function and disease and reveal determinants of mutation rates and patterns. Using high-fidelity duplex DNA sequencing, we profiled somatic mutations across the lifespan in human cerebellar Purkinje and granule neurons, which differ markedly in size and physiology. Surprisingly, they exhibited similar substitution rates, including rates of SBS5, the body's predominant mutational signature, whose mechanism is unknown. However, their substitution patterns and insertion/deletion rates and patterns differed, with transcription associated with these differences. In surviving granule neurons from five cerebellar ataxias, we detected only a small disease effect on mutation profiles. Our work indicates that neuronal types can differ in aging-related mutagenesis and that key features distinguishing Purkinje and granule neurons are unlikely, in these neurons, to be major determinants of SBS5 activity.

Applying advanced measurement technologies proactively in asymptomatic populations predictably yields false positives, as a consequence of Bayes’ Theorem. Yet the same Bayesian arithmetic suggests a remedy: adding context. Serial and multimodal measurements, integrated using context-aware AI that prioritizes within-person change over population norms, can reduce false positive rates while preserving sensitivity. We describe early illustrations from imaging and molecular diagnostics and discuss challenges including cost, anxiety, liability, and equity.

INTRODUCTION/BACKGROUND:We assessed plasma biomarkers for the diagnosis of early Alzheimer's disease (AD). METHODS: = 45). Plasma assays for amyloid beta (Aβ) 40, Aβ42, neurofilament light chain protein, glial fibrillary acidic protein, and phosphorylated tau181 levels were measured using single molecule array (Simoa) technology. Neuroinflammation and blood-brain barrier (BBB) biomarkers were measured using the Corplex cytokine 10-Plex kit and the angiogenesis 6-Plex kit, respectively. RESULTS:Biomarker levels were regressed by cognitive group, age, sex, race, and apolipoprotein E apoE ε4 status, yielded significant positive associations between age and numerous AD, neuroinflammation, cytokine, and BBB plasma markers. DISCUSSION/CONCLUSIONS:Linear regression analysis, adjusted for age, sex, race, and ApoE status, revealed significant differences between cognitive groups in levels of several plasma biomarkers and associations with age and sex. Neuroinflammation and BBB dysfunction showed significant positive associations with age across different stages of AD.

INTRODUCTION/BACKGROUND:Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown. METHODS:CU older adults underwent clinical evaluation and cerebrospinal fluid (CSF) assessment of fibrinogen, Aβ42, total tau (tTau), phosphorylated tau 181 (pTau181), and YKL-40. Linear regression tested baseline associations. Linear mixed-effects models tested whether baseline fibrinogen predicted longitudinal pTau181 change. RESULTS:Among 169 CU participants with baseline fibrinogen, 87 had longitudinal pTau181 measurements (mean follow-up 2.5-years). Higher fibrinogen was associated with elevated YKL-40 (β = 0.28, 95% confidence interval [CI] [0.11, 0.45]) but not Aβ42, tTau, or pTau181 at baseline. Baseline fibrinogen modified longitudinal pTau181 trajectories (interaction β = 0.11, 95% CI [0.04, 0.19]), with only participants above the median showing significant pTau181 increases (β = 0.13, 95% CI [0.08, 0.18]). DISCUSSION/CONCLUSIONS:CSF fibrinogen associates cross-sectionally with glial inflammation and predicts accelerated tau accumulation in preclinical AD.

Pain is a pervasive and multifaceted condition that imposes a significant medical and economic burden worldwide. This burden is underscored by the urgent need for transformative, non-addictive opioid alternatives. Nanomedicine offers a promising avenue for addressing the many limitations associated with conventional pain treatments, such as off-target effects, poor bioavailability, and rapid clearance, while enabling advanced therapeutic approaches such as precise spatiotemporal control and robust delivery of biologics. In this review, we explore the convergence of nanomedicine and pain management. We examine current literature on pain and chronic pain physiology and provide collated pharmacological data on current therapeutic approaches as a reference for formulation development. Recent advancements in lipid-based, polymeric, and inorganic nanoscale drug delivery systems (NDDS) for pain are surveyed, along with their progress toward clinical translation. Strategies for enhancing the efficacy of NDDS for pain are discussed, including supramolecular depot localization methods, active and passive targeting, controlled release kinetics, and the incorporation of stimuli-responsive elements for triggered release. We identify knowledge and technical gaps limiting progression beyond sustained-release formulations toward designs exploiting pain-specific biology. Overall, this review provides a comprehensive overview of the state-of-the-art in nanomedicine-based approaches for pain management and provides a roadmap for future innovations.

Astrocyte loss occurs in various neurological conditions and can disrupt local tissue homeostasis. While astrocytes surrounding border-forming lesions adopt reactive states without restoring astrocyte networks, how astrocytes respond to spatially confined astrocyte loss remains poorly understood. Here we used longitudinal in vivo two-photon microscopy, combined with spatiotemporal transcriptional profiling, to examine astrocyte responses following focal aquaporin-4 antibody-mediated ablation in the somatosensory cortex of adult mouse brain, a model of astrocytopathy relevant to neuromyelitis optica spectrum disorder. Here we show that perilesional astrocytes undergo pronounced structural remodeling during lesion repopulation, characterized by cell proliferation, prolonged multinucleated astrocyte states, polarized process extension into the depleted area and gradual displacement of nuclei into previously unoccupied astrocyte territories. Spatial transcriptomics reveal an injury-associated molecular response that resolves as the astrocyte network is restored. Together, our findings delineate the spatiotemporal dynamics of astrocyte regeneration after astrocyte loss, extending current understanding of astroglial plasticity in the adult brain.

Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.