An Introduction to the Society of Toxicologic Pathology’s 44th Annual Symposium on Toxicologic Neuropathology: Basics and Beyond

We had the pleasure to serve as co-chairs of the Society of Toxicologic Pathology (STP) Scientific Program Planning Committee for the 2025 STP symposium on “Toxicologic Neuropathology: Basics and Beyond.” The symposium was held from June 22 to 25 in Chicago, IL, USA, and had an attendance of approximately 400 colleagues.

The main objective of this meeting was to address the use of animal studies in the development of neurotherapeutics in humans, especially for Alzheimer’s disease (AD) and other devastating cognitive disorders (“dementias”). Currently, about 11% of individuals who are 65 years of age or older in the United States live with Alzheimer’s dementia, and it is estimated that Alzheimer’s disease will affect nearly 13 million people in the United States by 2050 (https://www.alz.org/getmedia/ef8f48f9-ad36-48ea-87f9-b74034635c1e/alzheimers-facts-and-figures.pdf). The economic and familial burdens of caring for the afflicted will greatly affect society around the world.

We had the most rewarding experience working with a group of distinguished neuropathologists who helped us organize the scientific program as session co-chairs, Drs Deepa B. Rao, Greenfield Pathology Services, Inc.; James P. Morrison, Charles River; Diethilde Theil, Roche Laboratories; Xavier Palazzi, AstraZeneca; Félix Goulet, Charles River Laboratories; Madhu Sirivelu, Novartis; Dinesh Bangari, Sanofi; Elizabeth L. Buza, Gemma Biotherapeutics Inc.; Alok K. Sharma, Labcorp; Alys Bradley, Charles River Laboratories; Lisa Lanigan, Charles River Laboratories; and Elizabeth Galbreath, EPL, Inc. In addition, we had an influential liaison from the STP Executive Committee, Dr Deepa B. Rao. Her contribution and hard work were impactful.

This symposium was opened by the first keynote speaker, Rudolph J. Castellani, MD, Professor of Pathology and Program Director, Neuropathology Fellowship Training Program at Northwestern University, Feinberg School of Medicine. He discussed the toxicity findings by non-invasive imaging and/or histopathology observed in patients treated with amyloid-β immunotherapy and the benefits of such innovative approaches in treating AD. Amyloid-β Immunotherapy is considered as an alternative and advanced therapy for AD despite the recently recognized risk to patients for developing amyloid-related imaging abnormalities (ARIA) including perivascular microhemorrhages, edema, and death. Similar topics were covered by Anita Hutter, MD, Yale University and Drs. Reina N. Fuji, Session 2 and Oded Foreman in Session 4 from Genentech. Collectively, these speakers presented the challenges of AD and related dementias, lessons learned with Alzheimer’s biologic therapeutics, and the use of a spatial transcriptomic atlas of Alzheimer’s disease to identify potential new therapeutic targets.

The second Keynote speaker was Jeffrey A. Loeb, MD, PhD, John S. Garvin Chair, Professor & Head Department of Neurology and Rehabilitation, University of Illinois College of Medicine. He delivered a very uplifting and enthusiastic lecture titled “Translating Neuropathology into Animal Models and Novel Therapeutics.” During his presentation, he shared information on new alternatives to treat amyotrophic lateral sclerosis (ALS) and the association between traumatic brain injury and ALS.

In addition to the keynote lectures, the remainder of the symposium was divided into five themed sessions. The themes began with a consideration of fundamental principles for toxicologic neuropathology investigations, proceeded by considering specialty topics such as animal models and biomarkers, and ended with a consideration of current “hot topics.”

Session 1: Five lectures covered “Fundamentals of Neuropathology.” The first lecture by Dr Rao discussed core concepts in neuropathology evaluation in toxicologic pathology, emphasizing the need to improve sampling of the brain in nonclinical species for test articles being developed for nervous system indications, especially those being administered directly into the central nervous system (CNS). In particular, current STP “best practice” recommendations appropriate for general toxicology studies^2,3 are not suitable for neurotoxicity studies where a more detailed assessment of multiple targets^1,3 is necessary. Dr Jeffrey T. Joseph, University of Calgary and Smitha PS Pillai, Pfizer, Inc. delivered interesting lectures, respectively, on functional neuroanatomy of the cerebellum including neuroanatomic connections of the cerebellum with the cerebrum and spinal cord and drug-induced toxicity related to the special sense of gustation (taste). Drs Debra A. Tokarz, Experimental Pathology Laboratories (EPL), Inc. and Ricardo de Miguel, AnaPath Services GmbH covered the differences among neuronal necrosis, degeneration and tissue artifacts and postmortem changes in the CNS in rats after different times of post fixation, respectively. Information covered during this session provided the foundation for the following sessions.

Session 2: Five talks covered the topic “Neurodegenerative Diseases—Translation” Apart from the two lectures about AD covered by Drs Huttner and Fuji, Session 2 included two more lectures on preclinical development of TM-CD20 (a “brain shuttle” to facilitate entry of biomolecules across the blood-brain barrier [BBB]) to advance CD20-targeted immunotherapies for multiple sclerosis and the preclinical development of Risdiplam (Evrysdi^®) for spinal muscular atrophy, presented by Drs Vanessa Schumacher and Lutz Müller, PhD, Roche, respectively. An excellent student presentation on “Severe Cerebellar Dysplasia and Congenital Hydrocephalus Associated with Mice Lacking Hsd17b7 in Wnt1 Cell Lineages” was presented by Dr Bayla Bessemer.

Session 3: The session on “Neurobiomarkers” highlighted the opportunities and challenges of different non-invasive neural biomarkers and endpoints in nonclinical studies for early detection and monitoring of nervous system pathology and/or injury caused by test articles. Inclusion of endpoints such as electrophysiology by Ms Nataliya Sadekova, Charles River Laboratories, molecular pathology tools to characterize pathology lesions in the visual pathways by Dr Typhaine Lejeune, Charles River Laboratories, fluid-based biomarkers by Dr Madhu Sirivelu, Novartis, the use of magnetic resonance imaging (MRI) to deliver test articles to the CNS by Dr Christen Simon-Anderson, Northern Biomedical Research, and quantifying dorsal root ganglion (DRG) changes using techniques like stereology, micro-computed tomography (CT), and nano-CT by Dr Klaus Weber, AnaPath Services GmbH in conjunction with an adequate histological evaluation showed how including special biomarkers (when warranted) may substantially facilitate detecting and derisking neurotoxicity in nonclinical studies compared to reliance on conventional pathology endpoints alone. An excellent student presentation on “Immunohistochemical Evaluation of Ketamine-Induced Neurotoxicity in Neonatal Sprague Dawley Rats as a Model for Pediatric Anesthesia” was presented by Mr Simone Canesi.

Session 4: The session on “Neuro-Omics” explored the applications of spatial transcriptomics, mass spectrometry imaging, spatial lipidomics, and other molecular pathology techniques for investigating different neurologic indications. The basis for current and future neurologic disease research and therapeutics is rooted in the integrated understanding of genetic, transcriptional, and molecular expression profiles of cells and spatial relationships in an anatomical context. Neuro-omics aim to analyze all conceivable molecular and morphological variations within the nervous system using specific methods such as genomics, transcriptomics, proteomics, metabolomics, and pathomics (i.e., radiology and histology). Drs Saravanan Kaliyaperumal, and Mathieu Marella, Johnson & Johnson Innovative Medicine presented a multimodal application of spatial molecular pathology techniques for mechanistic studies in neuroscience. Dr Kerstin Hahn, Roche presented on unveiling CNS drug responses through spatial transcriptomics, discussing the spatial mapping of molecules to assess CNS drug response. Dr LaTasha Crawford, University of Wisconsin-Madison presented transcriptomics to inform the understanding of sensory pathology and pain.

Session 5: The session on “Hot Topics, Challenges, Future Directions” included cutting–edge updates on several miscellaneous topics. Talks covered “Challenges and Opportunities of Digital Pathology in the Nervous System” Dr Aleksandra Zuraw, Charles River Laboratories and “Brain Barriers and CNS Immunity, Comparison of Microscopic Findings and Efficacy of an AAV Gene Therapy Candidate Administered Either Directly Intraparenchymal or via the CSF, Parts 1 and 2,” delivered by Drs Jimmy Tran, Biogen and Elizabeth Galbreath, EPL, Inc respectively. This session ended with an illustrative presentation about the comparative anatomy of the cervical 1 (C1) segment DRG by Dr Felix Goulet, Charles River Laboratory, where this DRG has been shown to be absent in most nonclinical species and humans despite the presence of a C1 dorsal spinal nerve root.

A mystery slide session sponsored by INNOTIV and organized and moderated by Drs. Caroline J. Zeiss, Yale University, Jerrold M. Ward, Global VetPathology and Brad Bolon, GEMpath, was well attended and included six interesting cases across multiple species, including human. Peripheral nerve pathology was well represented across three cases presented by Drs Debra Tokarz, EPL Inc. (cranial nerve hypertrophic neuropathy in a rat, incidental finding), Ricardo de Miguel, AnaPath Services GmbH (experimental surgical sciatic nerve injury and repair in a rat) Charles Halsey, Pfizer, CT (test article induced facial nerve injury in a cynomolgus macaque). Experimental spinal cord and dorsal root pathology following test article injection was described in a cynomolgus macaque by Dr Cathy Ruff, Genentech and a beagle by Dr Lisa Berman-Booty, Ionis, CA. Finally, Dr Anita Huttner, Yale University presented patient material demonstrating multiple neuropathologic co-morbidities that may accompany clinical dementia and Alzheimer’s disease. Scanned slides are available for viewing through June 2026 at https://inotiv.proscia.com/imageSets/4898.

There were two Pre-Symposium events offering additional continuing education opportunities. The “Satellite Symposium: Pathology Potpourri” was chaired by Dr Michelle C. Cora, from the Division of Translational Toxicology, National Institute of Environmental Health Sciences, NIH. This symposium provided seven case presentations of presenters from industry, government, and academic institutions on the interpretation of histopathology and clinical pathology data, with topics ranging from experimental silicosis associated with artificial stone in rats and increased cerebellar spheroids in beagles to hematologic vignettes in mice and vertebral deformations and gas gland adenomas in killifish. Each case generated lively discussions between the speaker and approximately 80 audience members. The presentations included sequential images of lesions or hematology data, followed by multiple-choice questions. Audience members voted on their answer selections electronically, with real-time voting results guiding the subsequent case presentation and discussions. The half-day format allowed for the coverage of diverse histopathology and clinical pathology findings while maintaining audience engagement. The Continuing Education course on “Multi-Modality Investigative Pathology: Levering the Full Potential of Spatial Pathobiology in Pharmaceutical Therapeutic Discovery and Development” was co-chaired by Drs Elizabeth Clark, Boehringer Ingelheim; S, Vinicius S. Carreira, Johnson & Johnson Innovative Medicine; Ingrid Cornax, Altos LLabs; Saravanan Kaliyaperumal, Johnson & Johnson Innovative Medicine; and Anoop M. Kavirayani, St. Jude Children’s Research Hospital. This course presented the current state of the practice of molecular pathology and artificial intelligence (AI) in industry and academia, highlighted current innovations, and forward-thinking proposals for discussion. Topics included the “Past, present, and future in tissue-based molecular pathology,” “Integrating Spatial Morphology and Omics Data with AI and Foundation Models: The Big Data Challenge,” “Molecular Pathology—A Navigator in Drug discovery for Multiple Therapeutic Modalities,” and concluded with “Transformative Potential of Spatial ‘Omics’ in Investigative Pathology.” The panel discussion focused on fit-for-purpose technology selection, reagent and technology limitations for non-clinical species, and whether the implementation of, and data generated from “omics” workflows are practical for toxicologic pathology assessment. Final discussions centered on the current and future use of AI in our field.

In conclusion, the various topics in these sessions were designed to promote a fundamental understanding of key therapeutic opportunities and challenges underlying prominent human neurologic diseases and the roles that toxicologic pathologists may play in developing such therapies. While routine practices were reviewed, considerable time was dedicated to the use of animal models and employment of cutting-edge technologies to effectively support preclinical to clinical translation in human risk assessment. Neurologic diseases and the roles that toxicologic pathologists may play in developing such therapies. While routine practices were reviewed, considerable time was dedicated to the use of animal models and employment of cutting-edge technologies to effectively support preclinical to clinical translation in human risk assessment.

Ingrid D. PardoBiogen, Cambridge, Massachusetts, USA Caroline J. ZeissYale University, New Haven, Connecticut, USA LuAnn McKinneySilver Spring, Maryland, USA