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Special Course Presentations

Special Course Introduction - Neuropathology: Past, Present & Future
Edward Lee, MD, PhD
University of Pennsylvania, Philadelphia, PA

Biography
Edward B. Lee, M.D., Ph.D., graduated Phi Beta Kappa and with honors from Stanford in 1997 and obtained his M.D. and Ph.D. degrees from the University of Pennsylvania in 2005 where he studied the pathophysiology of beta-amyloid in various Alzheimer’s disease experimental models under the mentorship of Virginia M.-Y. Lee, PhD. After clinical training in Anatomic Pathology and Neuropathology at the Hospital of the University of Pennsylvania, Edward was appointed Assistant Professor and then promoted to Associate Professor with tenure in the Department of Pathology and Laboratory Medicine. Edward is Director of the Center for Neurodegenerative Disease Research Brain Bank, Co-Director of the Institute on Aging, Associate Director of the Penn Alzheimer’s Disease Research Center, and principal investigator of the Translational Neuropathology Research Laboratory (TNRL). TNRL supports studies on the molecular neuropathology of Alzheimer’s disease, trauma related neurodegeneration, amyotrophic lateral sclerosis, and frontotemporal degeneration. He has contributed to our fundamental understanding of numerous aging-related neurodegenerative diseases with over 225 publications including the recent discovery of a novel form of dementia called vacuolar tauopathy linked to mutations in VCP. He is also dedicated to training the next-generation of academic neuropathologists, currently serving as the course director for the R13 funded AANP Scholars’ Workshop at AANP.

Learning Objectives

1. Summarize how key areas of neuropathology have evolved over the last century.
2. Cite 2-3 advances across key areas of neuropathology, including new research, approaches, and tools and techniques.

Special Course 1
Jason Huse, MD, PhD
University of Texas MD Anderson Cancer Center, Houston, TX

Biography
Dr. Huse is a Professor and Section Chief of Neuropathology at the University of Texas MD Anderson Cancer Center. He specializes in the diagnosis and molecular characterization of malignant primary and secondary brain tumors. His research lab focuses on the molecular pathogenesis of malignant glioma and brain metastasis with an emphasis on the role of epigenetic dysregulation and downstream impacts on complex cellular phenotypes.

Learning Objectives
1. Describe clinically relevant morphological features designating brain tumor entities and subclasses
2. Describe several disease classifying molecular biomarkers and their associations with tumor entities
3. Provide examples of specific tumor-classifying biomarkers that have become effective targets for therapeutic intervention

Abstract
History has accelerated for brain tumor classification and diagnosis over the past generation. This lecture will explore the transition from histomorphology-based diagnosis to one fundamentally grounded in highly recurrent molecular biomarkers, examining illustrative case studies along the way. The impact of recent developments in molecular classification on the prospect of improved treatment strategies will also be considered.

References
PMIDS: 26061751, 24120142, 23079654, 25965575, 32289278, 22134537, 26919435

Special Course 2
Sriram Venneti, MD, PhD
University of Michigan, Ann Arbor, MI

Biography
Sriram Venneti is a neuropathologist and physician-scientist whose work focuses on understanding the biology of brain tumors. He is the Al and Robert Glick Family Research Professor of Pediatrics and the Scientific Director of the Chad Tough Pediatric Brain Center at the University of Michigan. He oversees a collaborative scientific research program focusing on the biology of pediatric brain tumors including genomics, metabolomics, immunology, and pre-clinical trials. His laboratory explores the intersection of epigenetics and cancer metabolism in pediatric brain tumors including ependymomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas. His body of work has led to establishment of biomarkers to enable the diagnosis and prognostication of ependymomas that have been universally adopted including by the World Health Organization (WHO) classification Of Central Nervous System Tumors. His studies on metabolic and epigenetic reprogramming have been successfully translated to clinical trials that have shown benefit in diffuse midline gliomas and diffuse intrinsic pontine gliomas. He is recognized as a leader in the field of pediatric neuro oncology and is the recipient of several awards including the Sidney Kimmel foundation award, Doris Duke Clinical Scientist Development Award, and the Sontag Foundation Distinguished Scientist Award, and is an elected member to the American Society for Clinical Investigation.

Learning Objectives
1. Review key advances in neuro-oncology
2. Define how single-cell analyses can reveal tumor heterogeneity, glioma tumor cell differentiation states in relation to potential tumor cells-of-origin
3. Define how therapeutics can influence tumor heterogeneity, treatment resistance, and tumor recurrence.

Abstract
We have made several critical breakthroughs in neuro-oncology. Recent advancements have focused on defining the intricate interplay between tumor heterogeneity, therapeutic strategies, and treatment outcomes. Single-cell analyses in brain tumors have uncovered the complex landscape of tumor heterogeneity enabling delineating glioma tumor cell differentiation states, shedding light on potential tumor cells-of-origin. Therapeutic interventions can also impact on tumor heterogeneity, treatment resistance mechanisms, and the propensity for tumor recurrence. These advances provide insights into the evolving landscape of neuro-oncology research and its implications for personalized therapeutic and diagnostic approaches.

References
1.Spitzer A, Gritsch S, Nomura M, Jucht A, Fortin J, Raviram R, Weisman HR, Gonzalez Castro LN, Druck N, Chanoch-Myers R, Lee JJY, Mylvaganam R, Lee Servis R, Fung JM, Lee CK, Nagashima H, Miller JJ, Arrillaga-Romany I, Louis DN, Wakimoto H, Pisano W, Wen PY, Mak TW, Sanson M, Touat M, Landau DA, Ligon KL, Cahill DP, Suvà ML, Tirosh I. Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma. Cancer Cell. 2024 May 13;42(5):904-914.e9. doi: 10.1016/j.ccell.2024.03.008. Epub 2024 Apr 4. PMID: 38579724; PMCID: PMC11096020.
2.Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, Richman AR, Silverbush D, Shaw ML, Hebert CM, Dewitt J, Gritsch S, Perez EM, Gonzalez Castro LN, Lan X, Druck N, Rodman C, Dionne D, Kaplan A, Bertalan MS, Small J, Pelton K, Becker S, Bonal D, Nguyen QD, Servis RL, Fung JM, Mylvaganam R, Mayr L, Gojo J, Haberler C, Geyeregger R, Czech T, Slavc I, Nahed BV, Curry WT, Carter BS, Wakimoto H, Brastianos PK, Batchelor TT, Stemmer-Rachamimov A, Martinez-Lage M, Frosch MP, Stamenkovic I, Riggi N, Rheinbay E, Monje M, Rozenblatt-Rosen O, Cahill DP, Patel AP, Hunter T, Verma IM, Ligon KL, Louis DN, Regev A, Bernstein BE, Tirosh I, Suvà ML. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell. 2019 Aug 8;178(4):835-849.e21. doi: 10.1016/j.cell.2019.06.024. Epub 2019 Jul 18. PMID: 31327527; PMCID: PMC6703186.
3.Filbin MG, Tirosh I, Hovestadt V, Shaw ML, Escalante LE, Mathewson ND, Neftel C, Frank N, Pelton K, Hebert CM, Haberler C, Yizhak K, Gojo J, Egervari K, Mount C, van Galen P, Bonal DM, Nguyen QD, Beck A, Sinai C, Czech T, Dorfer C, Goumnerova L, Lavarino C, Carcaboso AM, Mora J, Mylvaganam R, Luo CC, Peyrl A, Popović M, Azizi A, Batchelor TT, Frosch MP, Martinez-Lage M, Kieran MW, Bandopadhayay P, Beroukhim R, Fritsch G, Getz G, Rozenblatt-Rosen O, Wucherpfennig KW, Louis DN, Monje M, Slavc I, Ligon KL, Golub TR, Regev A, Bernstein BE, Suvà ML. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science. 2018 Apr 20;360(6386):331-335. doi: 10.1126/science.aao4750. PMID: 29674595; PMCID: PMC5949869.
4.Venneti S, Kawakibi AR, Ji S, Waszak SM, Sweha SR, Mota M, Pun M, Deogharkar A, Chung C, Tarapore RS, Ramage S, Chi A, Wen PY, Arrillaga-Romany I, Batchelor TT, Butowski NA, Sumrall A, Shonka N, Harrison RA, de Groot J, Mehta M, Hall MD, Daghistani D, Cloughesy TF, Ellingson BM, Beccaria K, Varlet P, Kim MM, Umemura Y, Garton H, Franson A, Schwartz J, Jain R, Kachman M, Baum H, Burant CF, Mottl SL, Cartaxo RT, John V, Messinger D, Qin T, Peterson E, Sajjakulnukit P, Ravi K, Waugh A, Walling D, Ding Y, Xia Z, Schwendeman A, Hawes D, Yang F, Judkins AR, Wahl D, Lyssiotis CA, de la Nava D, Alonso MM, Eze A, Spitzer J, Schmidt SV, Duchatel RJ, Dun MD, Cain JE, Jiang L, Stopka SA, Baquer G, Regan MS, Filbin MG, Agar NYR, Zhao L, Kumar-Sinha C, Mody R, Chinnaiyan A, Kurokawa R, Pratt D, Yadav VN, Grill J, Kline C, Mueller S, Resnick A, Nazarian J, Allen JE, Odia Y, Gardner SL, Koschmann C. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways. Cancer Discov. 2023 Nov 1;13(11):2370-2393. doi: 10.1158/2159-8290.CD-23-0131. PMID: 37584601; PMCID: PMC10618742.
5.Chen CCL, Deshmukh S, Jessa S, Hadjadj D, Lisi V, Andrade AF, Faury D, Jawhar W, Dali R, Suzuki H, Pathania M, A D, Dubois F, Woodward E, Hébert S, Coutelier M, Karamchandani J, Albrecht S, Brandner S, De Jay N, Gayden T, Bajic A, Harutyunyan AS, Marchione DM, Mikael LG, Juretic N, Zeinieh M, Russo C, Maestro N, Bassenden AV, Hauser P, Virga J, Bognar L, Klekner A, Zapotocky M, Vicha A, Krskova L, Vanova K, Zamecnik J, Sumerauer D, Ekert PG, Ziegler DS, Ellezam B, Filbin MG, Blanchette M, Hansford JR, Khuong-Quang DA, Berghuis AM, Weil AG, Garcia BA, Garzia L, Mack SC, Beroukhim R, Ligon KL, Taylor MD, Bandopadhayay P, Kramm C, Pfister SM, Korshunov A, Sturm D, Jones DTW, Salomoni P, Kleinman CL, Jabado N. Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell. 2020 Dec 10;183(6):1617-1633.e22. doi: 10.1016/j.cell.2020.11.012. Epub 2020 Nov 30. PMID: 33259802; PMCID: PMC7791404.

Special Course 3
Marta Margeta, MD, PhD
University of California San Francisco, San Francisco, CA

Biography
Dr. Marta Margeta is Professor of Pathology, Vice-Chair of Education, and Associate Director of Neuropathology at UCSF, where she directs Neuromuscular Pathology Service and serves as the Medical Director of the Neuromuscular Pathology Lab. Dr. Margeta’s clinical and research interests center on neuromuscular pathology, and she writes annual neuromuscular disease updates for Free Neuropathology. In addition. she serves as the Neuroscience Section Editor for Autophagy and an Associate Editor for Acta Neuropathological Communications

Learning Objectives
1. Outline the critical milestones in muscle pathology diagnostics since the 1950s
2. Define which myopathologic changes can only be observed in cryosections
3 .Explain how the inclusion of serologic data changed the classification of idiopathic inflammatory disorders in the 2010s
4. Describe how clinical indications for muscle biopsy have changed over time

Abstract
Muscle biopsy is an important diagnostic tool in the workup of neuromuscular disorders, but its utility was very limited until the mid-1970s when the introduction of enzyme histochemistry and other stains performed on the sections of rapidly frozen muscle tissue revolutionized the field of myopathology. The subsequent development of an ever-growing repertoire of immunohistochemical stains, which can be performed on either frozen or FFPE muscle tissue, has enabled myopathologists to refine their interpretations further and to discontinue the use of technically challenging stains such as ATPase, which is highly pH-sensitive and requires use of restricted chemicals that need careful monitoring and bookkeeping. Recent clinical developments, such as easy access to DNA genetic testing and the integration of serologic testing into the classification of idiopathic inflammatory myopathies, have led to further changes in the myopathology landscape, with shifts from genetic to acquired myopathies and from straightforward to complex cases, which can be appropriately worked up only in highly specialized neuromuscular pathology laboratories. The next myopathology frontier will be the inclusion of molecular genetic techniques (such as mtDNA and RNA sequencing) and computational pathology approaches into routine muscle biopsy interpretation, with a potential to re-establish the muscle biopsy as a critical diagnostic tool in the workup of genetic myopathies, almost 50% of which remain without a definitive molecular diagnosis using the standard genetic testing assays.

References

1. Greenfield JG, Shy MG, Alvord EC Jr, Berg L. An atlas of muscle pathology in neuromuscular diseases. Edinburgh: E & S Livingstone; 1957.
2. Dubowitz V, Brooke MH. Muscle biopsy: A modern approach. London: WB Saunders; 1973.
3. Carpenter S, Carpati G. Pathology of skeletal muscle. 2^nd edition. Oxford University Press, 2001.
4. Goebel HH, Sewry CA, Weller RO (eds): Muscle disease: Pathology and genetics. Wiley Blackwell, 2013.
5. Dubowitz V, Sewry CA, Oldfors A. Muscle biopsy: A practical approach. 5th edition. Elsevier; 2021.
6. Walters J, Baborie A. Muscle biopsy: What and why and when? Pract Neurol. 2020;20(5):385-395. doi:10.1136/practneurol-2019-002465
7. Cotta A, Carvalho E, da-Cunha-Júnior AL, et al. Muscle biopsy essential diagnostic advice for pathologists. Surg Exp Pathol 2021; 4:3. doi.org/10.1186/s42047-020-00085-w
8. Allenbach Y, Benveniste O, Goebel HH, Stenzel W. Integrated classification of inflammatory myopathies. Neuropathol Appl Neurobiol. 2017;43:62-81. doi: 10.1111/nan.12380. PMID: 28075491.
9. Cummings BB, Marshall JL, Tukiainen T, et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017;9(386):eaal5209. doi:10.1126/scitranslmed.aal5209
10. Marchant RG, Bryen SJ, Bahlo M, et al. Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone. Ann Clin Transl Neurol. 2024;11:1250-1266. doi:10.1002/acn3.52041

Special Course 4
Cheng-Ying Ho, MD, PhD
Johns Hopkins Hospital, Baltimore, MD

Biography
Dr. Cheng-Ying Ho is an Associate Professor of Pathology & Medicine and Deputy Director of Neuropathology Fellowship at Johns Hopkins University School of Medicine.
She received her medical degree from National Taiwan University and her PhD in Pathobiology from Columbia University. She completed Anatomic Pathology & Neuropathology Combined Residency/Fellowship Program at the Johns Hopkins Hospital. Dr. Ho has specialized expertise in neuromuscular and pediatric pathology. She has published more than 50 peer-reviewed articles including several in high-impact journals such as New England Journal of Medicine and JAMA Neurology. Her main research interest is peripheral neuropathy and sensory neuroscience. Her research focuses on the impact of the skin microenvironment on the development of peripheral neuropathy, particularly diabetic neuropathy.

Learning Objectives
1. Use the updated approaches for diagnosis of neuromuscular disorders
2. Describe novel and emerging therapies for neuromuscular disorders
3. Recognize new/emerging neuromuscular disorders
4. Describe research advances in neuromuscular disorders

Abstract
In the last decade, the evolution of diagnostic technologies, such as next-generation sequencing (NGS), has drastically improved the diagnostic yield and changed how physicians approach and manage neuromuscular disorders. In addition, the breakthrough in targeted therapies, including exon skipping and gene replacement therapy, has held promise to cure several inherited neuromuscular disorders. This lecture aims to provide an update in diagnostic advancement and an overview of the current landscape of gene therapy for neuromuscular disorders. Furthermore, I will discuss a few newly recognized diagnostic entities as well as research advances in the field of neuromuscular medicine. I hope that a better understanding of the novel diagnostic tools, entities and therapeutics can help neuropathoogists and neuromuscular specialists improve the diagnostic yield and maximize the treatment benefit for patients with neuromuscular disorders.

References
1. Advances in the diagnosis of inherited neuromuscular diseases and implications for therapy development. Thompson R, et al. Lancet Neurol. 2020; 19: 522-532.
2. Major advances in neuromuscular disorders in the past two decades. Wadman RI, et al. Lancet Neurol. 2022; 21: 585-587.
3. Using gene panels in the diagnosis of neuromuscular disorders: A mini-review. Ng KWP, et al. Front Neurol. 2022; 13: 997551.

Special Course 5
Colin Smith, MD
University of Edinburgh, Edinburgh, United Kingdom

Biography
I graduated MBChB from Glasgow 1992, PhD 1998 and FRCPath 2000. I was appointed Professor of Neuropathology at Edinburgh University in 2014, and Director of the University’s Centre for Clinical Brain Sciences in 2022. I have both a diagnostic and research component, and my main research interests lie around neurotrauma and neurovascular disease, and particularly assessment of human tissue in these disorders. I run the Edinburgh Brain Bank and lead the UK Brain Bank Network. I was President of the British Neuropathological Society (BNS) 2015-2018.

Learning Objectives
1. Contrast the neuropathology of traumatic brain injury from 100 years ago to what we now know.
2. Compare the key pathologic changes associated with impact and rotational head injuries.
3. Appraise the evidence base for the links between traumatic brain injury and neurodegeneration.

Abstract
The understanding of the neuropathologic basis of traumatic brain injury (TBI) has evolved significantly over the past century. Courville (1937) describes craniocerebral injuries, differentiating direct impacts from penetrating head injuries. Contusions are well described but white matter and brain stem hemorrhages, although described, are poorly understood. By 1947 Dr Scheinker was describing “post traumatic vasoparalysis” in an unconscious patient who died within 5-hours of an accident, with white matter hemorrhages, and in the 1950’s Dr Richard Lindenberg continued to add knowledge through detailed autopsy cohorts. A major breakthrough came in 1956 when Sabine Stritch described shearing injury which, in time, would become diffuse traumatic injury (TAI). The pioneering work from Glasgow, in collaboration with Philadelphia, from the 1960’s-1990s, both clinical and pathologic, transformed our understanding of axonal injury produced by rotational forces, and their clinical impact. More recent studies have focused on cellular and molecular changes associated with acute TBI, although to date novel therapies remain elusive.
Although known since 1928 (Martland- Punch drunk syndrome) the effects of TBI on cognitive function remained poorly studied at the cellular level until the late 1990’s and the term chronic traumatic encephalopathy (CTE) was first used in 1949 (Critchley) but gained widespread use in the mid-2000’s and has been the subject of intensive research since. The next 100 years will lead to many exciting breakthroughs and novel therapies, both for the acute effects of TBI and the long-term

References
1. Strich SJ. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry. 1956 Aug;19(3):163-85. doi: 10.1136/jnnp.19.3.163.PMID: 13357957
2. Adams JH, Graham DI, Gennarelli TA, Maxwell WL Diffuse axonal injury in non-missile head injury. J Neurol Neurosurg Psychiatry. 1991 Jun;54(6):481-3. doi: 10.1136/jnnp.54.6.481.PMID: 1880506
3. Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982 Dec;12(6):564-74. doi: 10.1002/ana.410120611.PMID: 7159060
4. Ommaya AK, Gennarelli TA. Cerebral concussion and traumatic unconsciousness. Correlation of experimental and clinical observations of blunt head injuries Brain. 1974 Dec;97(4):633-54. doi: 10.1093/brain/97.1.633.PMID: 4215541
5. Sherriff FE, Bridges LR, Gentleman SM, Sivaloganathan S, Wilson S. Markers of axonal injury in post mortem human brain Acta Neuropathol. 1994;88(5):433-9. doi: 10.1007/BF00389495.PMID: 7847072
6. Geddes JF, Vowles GH, Nicoll JA, Révész T. Neuronal cytoskeletal changes are an early consequence of repetitive head injury Acta Neuropathol. 1999 Aug;98(2):171-8. doi: 10.1007/s004010051066.PMID: 10442557
7. Bieniek KF, Cairns NJ, Crary JF, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Dams-O'Connor K, Gordon WA, Tripodis Y, Alvarez VE, Mez J, Alosco ML, McKee AC; TBI/CTE Research Group. The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy J Neuropathol Exp Neurol. 2021 Feb 22;80(3):210-219. doi: 10.1093/jnen/nlab001.PMID: 33611507

Special Course 6
Amber Nolan, MD, PhD
University of Washington, Seattle, WA

Biography
Dr. Amber Nolan is a board-certified neuropathologist. She received her medical and doctorate training at the University of Chicago (MD and PhD in Computational Neuroscience) and then performed her post graduate training at the University of California San Francisco in both Anatomic Pathology in Neuropathology. Her research program at the University of Washington focuses on traumatic brain injury, with the goal of understanding circuit-based mechanisms that lead to cognitive dysfunction and neurodegeneration through analysis of animal models and human tissue.

Learning Objectives
1. Describe how our understanding of the markers of diffuse axonal injury is changing. 2. Describe what neuroinflammatory response is most prominent after chronic community traumatic brain injury.
3. Describe how satellite microglia might interact with neuronal circuits to modify activity.

Abstract
Our knowledge of the neuropathology of acute and chronic traumatic brain injury is evolving. This lecture will discuss new findings in both acute and chronic traumatic brain injury by focusing on research into the association between microhemorrhage and axonal injury at the acute stage and the neuroinflammatory response at the chronic stage. Mechanistic studies derived from human neuropathology observations will be presented that further elucidate our understanding of how microglia might interact with neuronal circuits to induce hyperexcitability. Understanding the evolving landscape of traumatic brain injury will be vital for targeted future therapeutic development.

References
1. Griffin AD, Turtzo LC, Parikh GY, Tolpygo A, Lodato Z, Moses AD, Nair G, Perl DP, Edwards NA, Dardzinski BJ, Armstrong RC, Ray-Chaudhury A, Mitra PP, Latour LL. Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury. Brain. 2019 Nov 1;142(11):3550-3564. doi: 10.1093/brain/awz290. PMID: 31608359; PMCID: PMC6821371.
2. Jolly AE, Bălăeţ M, Azor A, Friedland D, Sandrone S, Graham NSN, Zimmerman K, Sharp DJ. Detecting axonal injury in individual patients after traumatic brain injury. Brain. 2021 Feb 12;144(1):92-113. doi: 10.1093/brain/awaa372. PMID: 33257929; PMCID: PMC7880666.
3. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain. 2013 Jan;136(Pt 1):28-42. doi: 10.1093/brain/aws322. PMID: 23365092; PMCID: PMC3562078.
4. Krukowski K, Nolan A, Becker M, Picard K, Vernoux N, Frias ES, Feng X, Tremblay ME, Rosi S. Novel microglia-mediated mechanisms underlying synaptic loss and cognitive impairment after traumatic brain injury. Brain Behav Immun. 2021 Nov;98:122-135. doi: 10.1016/j.bbi.2021.08.210. Epub 2021 Aug 14. PMID: 34403733; PMCID: PMC9119574.
5. Wan Y, Feng B, You Y, Yu J, Xu C, Dai H, Trapp BD, Shi P, Chen Z, Hu W. Microglial Displacement of GABAergic Synapses Is a Protective Event during Complex Febrile Seizures. Cell Rep. 2020 Nov 3;33(5):108346. doi: 10.1016/j.celrep.2020.108346. PMID: 33147450.

Special Course 7
Marco Hefti, MD
University of Iowa, Iowa City, IA

Learning Objectives
1. Describe neuropathological developments in the 19th century
2. Summarize the role of developmental neuropathology in Nazi Germany
3. Describe the beginnings of developmental neuropathology in the United States

Abstract
Forthcoming

References
1. Banker, B. Q., and J. C. Larroche. “Periventricular Leukomalacia of Infancy. A Form of Neonatal Anoxic Encephalopathy.” Archives of Neurology 7 (November 1962): 386–410. https://doi.org/10.1001/archneur.1962.04210050022004.
2. Boles, Russell S. “Verlag von Leuschner u. Lubensky.” In Transactions and Studies of The College of Physicians of Philadelphia., Vol. 37. Baltimore: Waverly Press, Inc., 1970.
3. Hallervorden, Julius. “Entwicklungsstörungen und frühkindliche Erkrankungen des Zentralnervensystems.” In Neurologie, 905–1002. Berlin: Springer Verlag, 1953.
4. Kundrat, Hanns. Typische Art von Missbildung. Graz: Verlag von Leuschner u. Lubensky, 1882.
5. Peiffer, J. “Assessing Neuropathological Research Carried out on Victims of the ‘euthanasia’ Programme. With Two Lists of Publications from Institutes in Berlin, Munich and Hamburg.” Medizinhistorisches Journal 34, no. 3–4 (1999): 339–55.
6. Rosales, R. K., and H. E. Riggs. “Symmetrical Thalamic Degeneration in Infants.” Journal of Neuropathology and Experimental Neurology 21 (July 1962): 372–76. https://doi.org/10.1097/00005072-196207000-00004.
7. Schwartz, Philip, and Fink, Lotte. “Morphologie Und Entstehung Der Gehurtsiraumatischen Blutungen in Gehirn Und Schaedel Des Neugeborenen.” Zeitrschrift Fuer Kinderheilkunde, no. XL (n.d.).

Special Course 8
Angela Viaene, MD, PhD
Children’s Hospital of Philadelphia, Philadelphia, PA

Biography
Angela N Viaene, MD, PhD is an Assistant Professor of Pathology and Laboratory Medicine at the Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, PA. She holds the Lucy Balian Rorke-Adams Endowed Chair in Neuropathology and is the Associate Director of Neuropathology at the Children's Hospital of Philadelphia. She received both her PhD in Computational Neuroscience and MD from the University of Chicago, Chicago, IL. Following this, Angela completed a combined Anatomic Pathology residency and Neuropathology fellowship at the Hospital of the University of Pennsylvania, graduating in 2018. She is board-certified in both Anatomic Pathology and Neuropathology and is a practicing pediatric neuropathologist at the Children's Hospital of Philadelphia. Her neuroscience research experience began over twenty years ago as an undergraduate studying reaching movements following cerebrovascular insults in humans and non-human primates. Since then, Angela has investigated a wide range of topics from the synaptic properties and anatomical features of thalamocortical projections to a number of human neurologic diseases including perinatal hypoxic/ischemic brain injury, nervous system tumors, and neurogenetic disorders. She is also very involved in medical education and is the Director of the Brain and Behavior Neuropathology unit at the Perelman School of Medicine and a member of the Perelman School of Medicine Program Evaluation Committee.

Learning Objectives
1. Summarize the complex etiologies of central nervous system malformations.
2. Describe an example of how alterations in one gene may result in different phenotypes/malformations.
3. Identify diagnostic and therapeutic challenges in perinatal brain injury.

Abstract
Pediatric neuropathology is a diverse field encompassing a wide variety of genetic, neoplastic, and acquired disorders. This lecture will focus on primary disruptions of central nervous system (CNS) development (malformations) and acquired lesions of the perinatal period. The complex etiologies of CNS malformations will be discussed along with challenges for developing treatments for these disorders. The second portion of the lecture centers around perinatal brain injury with a focus on techniques to better identify and classify injury on post-mortem examination, how advances in clinical practice affect CNS pathologies, and the role of animal models in understanding acquired lesions and developing future therapies.

References
1. Edwards TJ, Sherr EH, Barkovich AJ, Richards LJ. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain. 2014 Jun;137(Pt 6):1579-613. PMID: 24477430; PMCID: PMC4032094.
2. Pang T, Atefy R, Sheen V. Malformations of cortical development. Neurologist. 2008 May;14(3):181-91. PMID: 18469675; PMCID: PMC3547618.
3. Najm I, Lal D, Alonso Vanegas M, Cendes F, Lopes-Cendes I, Palmini A, Paglioli E, Sarnat HB, Walsh CA, Wiebe S, Aronica E, Baulac S, Coras R, Kobow K, Cross JH, Garbelli R, Holthausen H, Rössler K, Thom M, El-Osta A, Lee JH, Miyata H, Guerrini R, Piao YS, Zhou D, Blümcke I. The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission. Epilepsia. 2022 Aug;63(8):1899-1919. PMID: 35706131; PMCID: PMC9545778.
4. Viaene AN. A role for immunohistochemical stains in perinatal brain autopsies. J Neuropathol Exp Neurol. 2024 Mar 4:nlae019. doi: 10.1093/jnen/nlae019. Epub ahead of print. PMID: 38441171.
5. Rettenmaier LA, Kirby PA, Reinking BE, Viaene AN, Hefti MM. Neuropathology of Congenital Heart Disease in an Inpatient Autopsy Cohort 2000-2017. J Am Heart Assoc. 2020 Apr 7;9(7):e013575. PMID: 32200729; PMCID: PMC7428607.
6. Cristancho AG, Gadra EC, Samba IM, Zhao C, Ouyang M, Magnitsky S, Huang H, Viaene AN, Anderson SA, Marsh ED. Deficits in Seizure Threshold and Other Behaviors in Adult Mice without Gross Neuroanatomic Injury after Late Gestation Transient Prenatal Hypoxia. Dev Neurosci. 2022;44(4-5):246-265. PMID: 35279653; PMCID: PMC9464267.
7. Partridge EA, Davey MG, Hornick MA, McGovern PE, Mejaddam AY, Vrecenak JD, Mesas-Burgos C, Olive A, Caskey RC, Weiland TR, Han J, Schupper AJ, Connelly JT, Dysart KC, Rychik J, Hedrick HL, Peranteau WH, Flake AW. An extra-uterine system to physiologically support the extreme premature lamb. Nat Commun. 2017 Apr 25;8:15112. PMID: 28440792; PMCID: PMC5414058.
8. Adle-Biassette H, Harding BN, and Golden J. Developmental Neuropathology, Second Edition. John Wiley & Sons, Ltd. 2018. p55-132.

Special Course 9
Mark Cohen, MD
Case Western Reserve University, Cleveland, OH

Biography
I am of Eastern European extraction, was educated in New York, and have been working at Case Western Reserve University for the last 40 years.

Learning Objectives
1. Name 5 AANP presidents who made seminal contributions to the understanding of prion diseases
2. Describe the relationships among host genotype, prion strains, and the species barrier in the pathogenesis of transmissible spongiform encephalopathies.
3. Discuss the strengths and limitations of seed amplification assays in the diagnosis of prion diseases.

Abstract
We will begin this look back at prion diseases by first recognizing that beside every Nobel Prize winner there is a great neuropathologist. We will then trace the evolution of our understanding of these protein pathogens beginning with what the kuru epidemic taught us regarding host susceptibility to infection. Mad cows and variant CJD will serve as fodder for the consideration of prion strains, strain adaptation, and the species barrier. Finally, we will consider how the prion paradigm of autocatalytic templating has informed both diagnosis and possible treatment of prion disease.

References
1. Elias E. Manuelidis, Creutzfeldt-Jakob Disease, J Neuropathol Exp Neurol. 1985;44:1-17
2. Piccardo P, Dlouhy SR, Lievens PM, et al. Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol. 1998;57(10):979-988.
3. Liberski PP, Sikorska B, Lindenbaum S, et al. Kuru: genes, cannibals and neuropathology. J Neuropathol Exp Neurol. 2012;71(2):92-103.
4. Stephen J. DeArmond, Autobiography Series: From Sleep-Wake Mechanisms to Prion Diseases, J Neuropathol Exp Neurol. 2017;76:631–642
5. Mead S, Lloyd S, Collinge J. Genetic Factors in Mammalian Prion Diseases. Annu Rev Genet. 2019;53:117-147.
6. Asher DM, Belay E, Bigio E, et al. Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns. J Neuropathol Exp Neurol. 2020;79(11):1141-1146.
7. Pierluigi Gambetti, Autobiography Series: A Life of Anecdotes, J Neuropathol Exp Neurol. 2021;80:608–623
8. Hermann P, Schmitz M, Cramm M, et al. Application of real-time quaking-induced conversion in Creutzfeldt-Jakob disease surveillance. J Neurol. 2023;270(4):2149-2161. 9. Vallabh SM, Zou D, Pitstick R, et al. Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease. J Virol. 2023;97(2):e0167222.
10. Bartz JC, Benavente R, Caughey B, et al. Chronic Wasting Disease: State of the Science. Pathogens. 2024;13(2):138

Special Course 10
Stephanie Bissel, PhD
Indiana University, Indianapolis, IN

Biography
The primary focus of my laboratory is to study the immunology of neurodegenerative diseases, including Alzheimer’s disease (AD).
The accrued expertise required to guide the execution of the proposed studies began during my tenure as a Ph.D. student at the University of Pittsburgh under the mentorship of Clayton Wiley. The primary focus of my work was to investigate the contribution of microglia and macrophage biology during lentiviral infections in the brain.
During my postdoctoral training at UCLA, I gained expertise in immunology studying signal transduction pathways in T cells under the guidance of M. Carrie Miceli.
I returned to the University of Pittsburgh where I was appointed Research Assistant Professor in the Neuropathology Division in the Department of Pathology. My scientific interests concentrated on the involvement of immune responses in the pathogenesis of neurodegenerative diseases associated with CNS viral infection and aging, regulation of astrocyte and microglia immune responses, acute respiratory infection with orthomyxovirus, and the role of YKL-40 (CHI3L1) during neuroinflammation.
In 2018, I joined the faculty at Indiana University School of Medicine as an Assistant Research Professor in Medical and Molecular Genetics. It has been exciting to expand my research interests and bring my expertise to the biology of AD. At the Stark Neuroscience Institute at Indiana University, my research focuses on microglia-mediated inflammatory response during the pathogenesis of AD. The recent discoveries of microglia-related gene variants TREM2 and PLCG2 conferring either elevated risk or protection for AD has opened exciting avenues to understand the role microglial responses play in neurodegeneration. My expertise in immunology and neuropathology complements my goal of translating basic biology of microglia processes into novel therapies for treating neurodegeneration.
I am a co-investigator with the TREAT-AD center that aims to define the efficacy of small molecule activators of PLCG2.
I was presently promoted to Associate Research Professor.

Learning Objectives
1. Describe evidence indicating that innate immune signaling is a key component of Alzheimer’s disease pathogenesis.
2. Discuss the functional impact that different genetic variants of innate immune proteins found in microglia have on neuroinflammation and disease pathogenesis.
3. Explain how to dissect transcriptional programs that identify protective or detrimental microglial signatures in response to pathology.

Abstract
Neuroinflammation contributes to the onset and progression of several neurological disorders. This is underscored by recent findings that genes for innate immune receptors and pathways are associated with Alzheimer’s disease (AD). Microglia, the resident myeloid cells of the brain, specifically express several of these AD risk genes. In this presentation, we will describe how genetic risk variants in microglia affect the signaling pathways governing the microglial response to AD pathology. Specifically, we will explore innate immune signaling pathways that are necessary to mount a protective microglial response while, conversely, dissecting the pathways that trigger detrimental microglial responses to brain pathology. We will discuss how genetic risk factors alter downstream functions of microglia and how this contributes to neuroinflammation.

References
1. Tsai AP, Dong C, Lin PB, Oblak AL, Viana Di Prisco G, Wang N, Hajicek N, Carr AJ, Lendy EK, Hahn O, Atkins M, Foltz AG, Patel J, Xu G, Moutinho M, Sondek J, Zhang Q, Mesecar AD, Liu Y, Atwood BK, Wyss-Coray T, Nho K, Bissel SJ, Lamb BT, Landreth GE. Genetic variants of phospholipase C-g2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease. Immunity (2023) 56(9):2121-2136.e6
2. Tsai AP, Dong C, Lin PB, Messenger EJ, Casali BT, Moutinho M, Liu Y, Oblak AL, Lamb BT, Landreth GE, Bissel SJ, Nho K. PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease. Genome Med (2022) 14:17.
3. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen C, Cummings J, van der Flier WM. Alzheimer’s disease. Lancet (2021) 397:1577-1590.
4. Podlesny-Drabiniok A, Marcora E, Goate AM. Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics. Trends Neurosci (2020) 43(12):965-979.
5. Sims R, van der Lee SJ, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet (2017) 49(9):1373-1384.
6. Vecchiarelli HA, Tremblay M. Microglial Transcriptional Signatures in the Central Nervous System: Toward a Future of Unraveling Their Function in Health and Disease. Annu Rev Genet (2023) 57:65-86.
7. Chen Z, Zhong D, Li G. The role of microglia in viral encephalitis: a review. J Neuroinflamm (2019) 16:76.

Special Course 11
Charles L. White, III, MD
University of Texas Southwestern Medical School, Dallas, TX

Biography
Charles L. White, III, M.D., is Professor of Pathology and holds the Nancy R. McCune Distinguished Chair in Alzheimer Disease Research at the University of Texas Southwestern Medical School in Dallas. Dr. White earned his medical degree at the University of Arizona College of Medicine. He completed 5 years of residency and fellowship training in anatomic pathology and neuropathology at Johns Hopkins. He took his first faculty position as Director of Neuropathology at UT Southwestern in 1983 and has remained on the faculty there for 40 years. Dr. White’s clinical and research interests focus on neurodegenerative brain disorders. He has been generously funded by the NIH, the Michael J. Fox Foundation, the Chan-Zuckerberg Neurodegeneration Challenge Network, and the Texas Alzheimer’s Research and Care Consortium, and has published over 200 peer-reviewed papers. Dr. White is also the Program Director of the ACGME-accredited Neuropathology Fellowship at UT Southwestern, which has proudly graduated 27 trainees to date. Dr. White has been active in AANP since 1982. He served as its president from 2012-2013 and is currently the AANP Archivist and Senior Associate Editor of the Journal of Neuropathology and Experimental Neurology. He is most grateful to have received AANP’s Award from Meritorious Contributions to Neuropathology in 2020.

Learning Objectives
1. Discuss the evolution in technology that has facilitated advances in neurodegenerative disease neuropathology
2. Cite 2 or 3 examples that illustrate how the development of immunohistochemical analyses has altered our approach to neurodegenerative disease diagnosis
3. Discuss the evolution of the concept of comorbidity as it relates to neurodegenerative disease neuropathology

Abstract
The central role of neuropathology in advancing knowledge about nervous system disorders is, in the broadest sense, the identification of the key structural alterations that characterize each entity. Our understanding of the clinical features and pathogenesis of neurodegenerative disorders has benefited tremendously from such knowledge gained over the past century. A logical and stepwise approach to neuropathologic phenotyping of each of these disorders has emerged, and can be summarized as follows: 1) initial discovery of the diagnostic lesion(s); 2) careful and detailed histologic analysis of the diagnostic changes, with special attention to their distribution among cell types and anatomic regions; 3) further characterization of the lesions, e.g. by immunohistochemistry, biochemistry, quantitative analysis, etc.; and 4) establishment and refinement of consensus criteria that codify the key diagnostic features and optimal diagnostic methods. The last 2 steps are typically an iterative process as new technologies for characterizing lesions are introduced. This presentation will review this paradigm as it has unfolded for Alzheimer disease, Lewy body diseases, and frontotemporal lobar degenerations. Both the evolving methods and some of the key investigators who have spearheaded some of the major advances will be highlighted. The ultimate goal is to stimulate the creativity of our junior colleagues to apply the newest technologies available to them to continue to push the limits of our knowledge of these tragic, but hopefully eventually treatable or preventable, diseases.

References
1. Terry, R.D., The Fine Structure of Neurofibrillary Tangles in Alzheimer's Disease. Journal of Neuropathology & Experimental Neurology, 1963. 22(4): p. 629-642.
2. Tomlinson, B.E., G. Blessed, and M. Roth, Observations on the brains of non-demented old people. Journal of the neurological sciences, 1968. 7: p. 331 - 356.
3. Tomlinson, B.E., G. Blessed, and M. Roth, Observations on the brains of demented old people. Journal of the neurological sciences, 1970. 11: p. 205 - 242.
4. Burns, A., B.E. Tomlinson, and D.M. Mann, Observations on the brains of demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of the Neurological Sciences (1970) 11, 205-242 and Observations on the brains of non-demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of Neurological Sciences (1968) 7, 331-356. International Journal of Geriatric Psychiatry, 1997. 12(8): p. 785 - 790.
5. Khachaturian, Z.S., Diagnosis of Alzheimer's Disease. Archives of Neurology, 1985. 42(11): p. 1097-1105.
6. Mirra, S.S., et al., The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology, 1991. 41(4): p. 479-86.
7. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiology of aging, 1997. 18(4 Suppl): p. S1-2.
8. McKeith, I.G., et al., Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology, 2017. 89(1): p. 88-100.
9. Montine, T.J., et al., National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathologica, 2011. 123(1): p. 1-11.
10. Crary, J.F., et al., Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathologica, 2014. 128(6): p. 755-766.
11. Mackenzie, I.R.A., et al., A harmonized classification system for FTLD-TDP pathology. Acta Neuropathologica, 2011. 122(1): p. 111-113.
12. Nelson, P.T., et al., Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain, 2019. 142(6): p. 1503-1527.

Special Course 12
Annie Hiniker, MD, PhD
University of California, San Diego, La Jolla, CA

Biography
Annie Hiniker, M.D., Ph.D., is Associate Professor of Pathology at the Keck School of Medicine, University of Southern California (USC) and Director of the USC Alzheimer’s Disease Research Center (ADRC) Neuropathology Core. Dr. Hiniker was AOA at University of Michigan where she completed her MD and PhD; she did residency and fellowship in Anatomic Pathology and Neuropathology at UCSF. Prior to her recruitment to USC in 2024, she was Assistant Professor and Co-Director of the ADRC Neuropathology Core at UCSD. Dr. Hiniker’s research leverages classical neuropathology combined with cell biology, omics, and seeding assays to define the molecular mechanisms of Parkinson’s Disease and other neurodegenerative diseases, with particular emphasis on LRRK2-mediated neurodegeneration. Current and past funding sources include NINDS (R01, K08), the Epstein Family Foundation, AFAR Paul B. Beeson Award, Congressionally Directed Medical Research Program Parkinson’s Disease Early Investigator Award, the Alzheimer’s Association, and the American Parkinson’s Disease Association. She has been a member of AANP since her first year of residency in 2010, is a co-director of the AANP Neurodegenerative Scholars R13 program, serves on the AANP Education Committee, and is a member of the Editorial Board of Free Neuropathology.

Learning Objectives


Abstract


References