Neuroimmunology Faculty Spotlight: Holly Appleberry, DO, MBA. Comprehensive Care for Neuroimmunology Conditions and a Focus on Patient Advocacy and Health Care Policy

Holly Appleberry, DO, MBA, is assistant professor of neurology in the Department of Neurology at the University of Pittsburgh School of Medicine and an attending physician in the Neuroimmunology/MS Division at UPMC.

Dr. Appleberry joined UPMC in August 2022. She earned her medical degree from the Kansas City University College of Medicine and Biosciences, followed by her residency in neurology at Penn State University. She completed a fellowship in neuroimmunology/MS at Georgetown University immediately before joining UPMC and the University of Pittsburgh. Dr. Appleberry also earned a Master of Business Administration degree from Rockhurst University Helzberg School of Management in conjunction with her medical degree in a dual-degree program.

Dr. Appleberry’s clinical practice covers the full spectrum of neuroimmunology conditions. In addition to seeing patients at the UPMC MS Center, she runs a specialized clinic for patients with genetic demyelinating diseases.

Complementing her clinical practice and research interests, Dr. Appleberry also focuses on patient advocacy and influencing health care policy at the legislative level—regionally and nationally—to improve treatment options and long-term outcomes for patients with rare neurological conditions.

Dr. Appleberry also has an interest in clinical trials for rare diseases and in precision medicine approaches for patients living with complex neuroimmunology conditions.

Getting Into Medicine

Dr. Appleberry’s interest in medicine began early and was shaped by observing family members’ health care challenges, including a relative’s experience with a ruptured brain aneurysm.

“I remember asking questions and being curious about how and why disease develops,” says Dr. Appleberry. “These early experiences, combined with my lifelong interest in the sciences, had a pull on me, and my coursework and job experiences solidified my interest in becoming a neurologist.”

After earning an undergraduate degree in chemistry, Dr. Appleberry worked in a rheumatology research laboratory before enrolling in medical school, where she developed an interest in autoimmune processes. She later worked at a biotech company conducting immunoassays for pharmaceutical clients.

“I grew to appreciate the complexity of the immune system during my lab experiences before medical school,” Dr. Appleberry says. “That interest holds today as someone who treats patients with neuroimmunology conditions, like MS.”

A Clinical Gap in Identifying and Treating Atypical White Matter Diseases

During residency training at Penn State and fellowship at Georgetown, Dr. Appleberry began to encounter patients with white matter abnormalities on brain MRI that did not fit established diagnostic categories. These cases exhibited demyelinating features but lacked the clinical characteristics of multiple sclerosis (MS) and did not align with vascular, infectious, or neoplastic etiologies that could explain the findings and symptoms.

Without definitive diagnostic frameworks, these patients often experience a diagnostic odyssey through multiple subspecialty clinics without a clear path forward. Many are treated empirically with immunosuppression under the assumption of an atypical autoimmune disease, even without definitive markers.

“There was no one who really specialized in these undiagnosed white matter disorders during my training,” Dr. Appleberry says. “You would naturally try to refer complex cases to someone with deeper expertise, but for these patients, that infrastructure just did not exist.”

Through continued evaluation and research, Dr. Appleberry and others in the field have recognized that a subset of these patients likely has rare forms of adult leukodystrophies or other white matter disorders with a genetic basis. In such cases, immunosuppression often lacks clinical utility and can introduce unnecessary risk. While some genetic disorders may lead to inflammatory processes over time, they do not respond to immunomodulatory therapies in the same way MS does.

“We are learning that certain genetic white matter diseases may eventually develop inflammation and, in some cases, may benefit from targeted immunosuppression,” Dr. Appleberry says. “But this is not the same as treating MS, and applying MS-style therapies empirically can be harmful in some cases.”

Dr. Appleberry also has seen the emotional toll diagnostic uncertainty takes on patients. Even when a genetic diagnosis is achieved, some patients are told that if no treatment exists, they may be discharged from a neurology practice due to limited understanding of their condition.

“These patients are often left in limbo, and primary care physicians are sometimes left to manage highly complex neurologic cases without adequate support,” Dr. Appleberry says. “There is a clear need for neurology to own this clinical space.”

To address this gap at UPMC, Dr. Appleberry established a dedicated White Matter Disease Clinic to serve this patient population. The clinic provides a framework for comprehensive evaluation, symptom management, and genetic testing. It also serves as a platform for natural history studies and phenotype–genotype correlation in cases where patients present with variants of uncertain significance or phenotypes that differ from what has been reported in the literature.

“I am seeing patients with milder or atypical presentations of known mutations,” Dr. Appleberry says. “By following them over time, we can begin to develop a clearer understanding of prognosis, variation, and therapeutic needs.”

Even in cases without a confirmed diagnosis, symptom-directed management is essential. Many patients with these conditions experience spasticity, bladder dysfunction, or mobility challenges—symptoms that overlap with MS, even when the underlying condition is not autoimmune or inflammatory.

“These are white matter disorders of the brain, and even if they are not autoimmune, they can present with very similar functional impairments,” Dr. Appleberry says. “We can leverage our existing infrastructure in our division to provide supportive care while also advancing our understanding through longitudinal observation.”

ADLD: An Underrecognized Adult Leukodystrophy

One condition Dr. Appleberry has begun to see with increasing frequency is Adult-Onset Autosomal Dominant Leukodystrophy (ADLD), a rare but underdiagnosed mimicker of primary progressive MS. It is caused by mutations in the LMNB1 gene and is characterized by autonomic dysfunction followed by weakness, spasticity, and gait disturbance. The condition is progressive and ultimately fatal, with an average disease duration of about 15 to 20 years.

Because ADLD presents between ages 40 and 60, many patients are diagnosed after they have already had children, adding distress and urgency for families seeking treatment options. In one family Dr. Appleberry follows, all five siblings were diagnosed with the disease.

“There is a real opportunity to advance care here,” Dr. Appleberry says. “This is a single-gene disorder with complete penetrance and a relatively homogeneous presentation. For a rare disorder, we have a good understanding of disease progression, which can inform future clinical trials for disease-modifying therapy.”

Expanding Patient and Provider Resources

Dr. Appleberry is currently developing a dedicated web resource focused on autosomal dominant leukodystrophy (ADLD). The goal is to provide accurate, accessible information for patients, families, and referring physicians, including guidance on diagnostic workup, genetic testing, symptom management, and opportunities for research participation.

The site will also serve as a centralized access point for providers who encounter patients with unexplained adult-onset white matter changes and are unsure how to proceed. By providing a clearly defined referral pathway, the initiative aims to reduce diagnostic delays and avoid mismanagement.

This effort is part of a broader strategy to formalize care delivery for patients with rare white matter diseases and to build infrastructure for observational studies and future clinical trials. Increasing visibility is critical, as too often patients go years without a diagnosis or are told that nothing can be done.

“Just knowing there is a dedicated clinic, and a place to turn to for evaluation and follow-up, can change the entire trajectory of care,” Dr. Appleberry says.

Advancing Biomarker and Therapeutic Research

Dr. Appleberry is leading an observational study to evaluate a blood-based biomarker of central nervous system demyelination in patients with MS. Currently, there are no blood-based biomarkers specific for demyelination. This protein, Semaphorin 4A, is toxic to myelin precursors and has been shown to be elevated in a small number of MS patients. If validated in a large MS population, it may have future applications in genetically mediated demyelinating diseases such as ADLD.

She also plans to develop a study to repurpose existing MS therapies for symptomatic use in ADLD. One candidate is dalfampridine, an oral potassium channel blocker currently approved to improve walking speed and control spasticity in people with MS.

“This pilot study is still in the early planning stages, but it’s something that I’m devoting time to this year as part of the work I’m doing as a NeuroNEXT fellow,” Dr. Appleberry says.

Neuroscience Clinical Trials Infrastructure and the NeuroNEXT Fellowship

To expand her capacity for investigator-initiated trials and formalize research infrastructure for rare neurological diseases, Dr. Appleberry is participating in the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Fellowship, which she began in mid-2025. NeuroNEXT is a national consortium established by the National Institutes of Health to accelerate early-phase clinical trial readiness across the neurological disease spectrum. The University of Pittsburgh is one of 25 institutions currently participating in the NeuroNEXT network.

The one-year fellowship provides structured training in clinical trial design, regulatory requirements, operational execution, and biostatistics, while offering access to a collaborative network of trial sites with streamlined activation protocols. The program is designed to support studies in conditions that lack standard treatments or have significant unmet needs.

“The fellowship is giving me protected time and additional training to expand and formalize my research projects,” Dr. Appleberry says.

Advocacy for Access and Systems-Level Reform

In addition to her clinical neurology and research work, Dr. Appleberry is engaged in health policy and patient advocacy for people with chronic neurologic disease, including rare diseases. Her work in this area began during her residency training through participation in Neurology on the Hill, an annual initiative of the American Academy of Neurology that brings neurologists to Washington, D.C., to meet with lawmakers. She has also served as a delegate to the Allegheny County Medical Society and the Pennsylvania Medical Society.

A central concern of her advocacy has been insurance denials for MS medications, which can result in severe relapses.

“I have had MS patients who were stable on their medication, only to relapse after an insurer suddenly cut off access to therapy or denied IV infusions because of location,” Dr. Appleberry says. “If the spinal cord is involved, that could mean paralysis. It’s something that shouldn’t happen but unfortunately does.”

Dr. Appleberry is equally committed to advocacy for rare disease patients, regardless of their underlying condition.

“For many of these conditions, the first challenge is simply awareness,” Dr. Appleberry says. “Early detection can lead to a better quality of life and the opportunity to enroll in clinical trials earlier. It also means these patient populations can have a voice at the table when health care policies are being developed.”

Patient Referrals

For patient referrals or consultations, contact the UPMC Multiple Sclerosis Center at 412-641-6600.