CGPR: You’re a geriatric psychiatrist with experience in neurotherapeutics. What led you to focus on prion diseases, and what is important for clinicians to know about them?
Dr. Uflacker: Prion diseases are important to me both professionally and personally. I’ve cared for families affected by these illnesses, and my own family has been touched by prion disease. Clinically, they matter because they are not as rare as many of us were taught in medical school. They present as rapidly progressive dementias, often with psychiatric or behavioral changes early on, so psychiatrists and geriatric clinicians may be the first to evaluate these patients. Early recognition can prevent prolonged diagnostic odysseys, reduce fragmented care, and allow timely connection to palliative resources and research opportunities. Even though we do not yet have disease-modifying treatments, making the diagnosis promptly has significant implications for patient counseling, caregiver support, and infection-control considerations in medical settings.

CGPR: How common are prion diseases in the United States?
Dr. Uflacker: They are uncommon but not vanishingly rare. Recent CDC data indicate that approximately 1 in 6,000 deaths in 2022 were attributed to Creutzfeldt-Jakob disease (www.tinyurl.com/mscw469e). Incidence increases with age. In adults 65 and older, rates rise to over 6 per million, compared to an age-adjusted incidence of roughly 1 to 2 per million in the general population. Reported cases have increased over the past two decades, likely reflecting improved recognition and better diagnostic tools, particularly advanced MRI techniques and RT-QuIC testing. For geriatric psychiatrists and neurologists, this means that prion disease should be included in the differential diagnosis of rapidly progressive or atypical dementias.

CGPR: What causes prion diseases?
Dr. Uflacker: Prion diseases are caused by misfolding of the prion protein, a normal protein found primarily on the surface of neurons. In its healthy form, the protein contains three alpha-helices and two beta-pleated sheets and is known to play a role in myelin integrity. When the protein misfolds into an abnormal beta-pleated-rich form, it becomes insoluble and causes other prion proteins to misfold as well. This creates a chain reaction that spreads through the brain. Over time, the abnormal proteins accumulate and damage neurons, producing the characteristic “spongiform” or sponge-like appearance seen on brain pathology.

CGPR: How do prion diseases typically progress?
Dr. Uflacker: Prion diseases progress much faster than most other neurodegenerative disorders. Conditions like Alzheimer’s disease (AD) or Lewy body dementia (LBD) usually develop gradually over many years. In contrast, prion diseases often worsen over weeks to months. Average survival is about four months, although some patients live one to two years. This unusually rapid course is one of the most important clinical clues. When dementia progresses over weeks to months rather than years, clinicians should keep prion diseases on the differential.

CGPR: What are the main types of prion disease?
Dr. Uflacker: The most common form is sporadic Creutzfeldt-Jakob disease, which accounts for roughly 85% of cases and typically presents in the sixth or seventh decade of life (Staffaroni AM et al, JAMA Neurol 2019;76(8):969–977). There are also genetic forms, inherited in an autosomal dominant fashion, caused by mutations in the prion protein gene. These may present earlier, sometimes in the fourth or fifth decade, depending on the mutation. Variant Creutzfeldt-Jakob disease, linked historically to bovine spongiform encephalopathy exposure, is transmitted through ingestion of infected tissue and is very rare, accounting for less than 1% of cases. There are also rarer phenotypes such as sporadic fatal insomnia and variably protease-sensitive prionopathy. Each subtype can differ in clinical presentation and tempo, which complicates diagnosis.

“Behavioral and psychiatric symptoms occur in up to 90% of cases during the disease course. If you see an atypical presentation that is deteriorating over weeks, especially with new motor signs, neurology consultation and further workup are warranted.”
Alice B. Uflacker, MD

CGPR: Early symptoms can resemble other conditions. What are the initial clinical signs that should raise suspicion?
Dr. Uflacker: Early symptoms are often nonspecific. Patients may report foggy thinking, difficulty concentrating, anxiety, sleep disturbance, weight loss, or subtle personality changes. Some present with new-onset paranoia or depression. Because these features overlap with primary psychiatric disorders or more common dementias, prion disease is rarely suspected initially. The key red flag is rapid progression. If cognitive decline accelerates over weeks to a few months, especially with emerging neurologic signs such as myoclonus, ataxia, visual disturbances, or focal weakness, suspicion should increase. Myoclonus is particularly classic. A timeline that shows stepwise deterioration within months rather than years is one of the most important diagnostic clues.

CGPR: When psychiatric symptoms predominate, what should prompt a neurology referral?
Dr. Uflacker: I become concerned when psychiatric symptoms are accompanied by neurologic findings or when there is failure to respond to appropriate psychiatric treatment combined with rapid functional decline. The emergence of myoclonus, ataxia, visual hallucinations, worsening executive dysfunction, or unexplained weight loss should prompt referral. Behavioral and psychiatric symptoms occur in up to 90% of cases during the disease course (Krasnianski A et al, J Clin Psychiatry 2015;76(9):1209–1215). If you see an atypical presentation that is deteriorating over weeks, especially with new motor signs, neurology consultation and further workup are warranted. The trajectory is often more informative than any single symptom.

CGPR: What is typically included in your differential diagnosis?
Dr. Uflacker: The differential can be broad. Rapidly progressive AD, LBD, and frontotemporal dementia can all resemble prion disease in early stages. Autoimmune encephalitis should always be considered, as it can also present with psychiatric symptoms and rapid decline. Paraneoplastic syndromes, metabolic disorders, toxic exposures, and severe mood disorders with psychotic features may enter the differential depending on presentation. Weight loss with cognitive changes may prompt an oncologic evaluation. Visual symptoms might lead to a Lewy body diagnosis. The distinguishing feature again is the pace of progression. Including prion disease in the differential when evaluating autoimmune encephalitis is a particularly important clinical pearl.

CGPR: How has the diagnostic workup evolved?
Dr. Uflacker: Historically, doctors sometimes performed brain biopsies, but biopsy has fallen out of routine use due to its invasive nature and infection-control risks. EEG and CSF markers such as 14-3-3 protein and total tau were once the mainstays. EEG may show periodic sharp wave complexes, and 14-3-3 can be elevated, but these are sensitive rather than specific markers. Total tau levels are typically markedly elevated. The field has shifted toward MRI and RT-QuIC testing as the central tools. These allow earlier and more accurate detection without the risks associated with biopsy. Autopsy remains the definitive confirmation, but in life we can reach a high-probability diagnosis using modern methods.

CGPR: What MRI findings are characteristic?
Dr. Uflacker: Diffusion-weighted MRI is especially useful. You may see cortical ribboning or hyperintensity in the striatum and thalamus. In variant Creutzfeldt-Jakob disease, the pulvinar sign, which is brightening of the posterior thalamus, is a classic sign (Hermann P et al, Lancet Neurol 2021;20(3):235–246). These diffusion-weighted abnormalities can appear relatively early in the disease course and are both sensitive and specific when interpreted in the right clinical context. MRI is noninvasive and widely available, so it should be obtained early if prion disease is suspected. It complements CSF testing and may raise suspicion even before other markers become positive.

CGPR: What is real-time quaking-induced conversion (RT-QuIC)?
Dr. Uflacker: RT-QuIC is performed through specialized centers, including the National Prion Disease Pathology Surveillance Center (NPDPSC) and the Mayo Clinic. The test amplifies misfolded prion protein “seeds” in a sample, typically CSF, and detects them using a fluorescence marker. Unlike 14-3-3 or tau, which are indirect markers of neuronal injury, RT-QuIC detects the abnormal prion protein itself. It has very high specificity, approaching 100%, and high sensitivity, particularly for sporadic Creutzfeldt-Jakob disease (Hermann et al, 2021). In practice, the lab processing is relatively quick (one to two days) and results typically come back in less than a week. Because of that combination of accuracy and turnaround, RT-QuIC has become a cornerstone of the modern workup. We’re also starting to see it expand beyond prion disease, with emerging use in detecting abnormal proteins in synucleinopathies and tauopathies.

CGPR: How do you sequence MRI, EEG, CSF studies, and RT-QuIC in practice?
Dr. Uflacker: Psychiatrists may be the first few clinicians to encounter these patients because early symptoms can be behavioral or psychiatric, but once prion disease is suspected, neurology referral is important. If suspicion is meaningful, I would obtain an MRI and involve neurology early. Most of the formal diagnostic workup, including lumbar puncture for RT-QuIC, is typically coordinated by neurology rather than psychiatry. MRI and RT-QuIC are usually prioritized. EEG and traditional CSF markers such as 14-3-3 and total tau remain useful adjuncts. They can help characterize disease stage and add supportive evidence. However, I would not rely solely on older markers when MRI and RT-QuIC are available. Because the disease progresses quickly, delaying definitive testing can cost valuable time for counseling and planning. Ideally, these studies complement one another rather than replace each other. The goal is to reach a high-confidence diagnosis as efficiently as possible.

CGPR: Do biomarkers or clinical features predict survival?
Dr. Uflacker: Certain features correlate with shorter survival. Markedly elevated CSF total tau has been associated with more aggressive disease and shorter survival (Shir D et al, JAMA Netw Open 2022;5(8):e2225098). Elevated CSF 14-3-3 may also be associated with shorter disease duration, though its prognostic value is less well established than that of tau. Clinically, the presence of myoclonus, visual symptoms, and cerebellar findings has also been linked with shorter survival (Shir et al, 2022). MRI and RT-QuIC provide high diagnostic accuracy but are less clearly predictive of exact survival duration. Ultimately, though, variability remains. Even with biomarkers, precise prognostication is difficult. What we can say is that most cases progress rapidly, and planning should assume a limited time frame.

CGPR: How do you approach psychiatric symptom management?
Dr. Uflacker: The principles mirror those used in other major neurocognitive disorders. Nonpharmacologic strategies are first line whenever possible (Thompson A et al, Am J Psychiatry 2014;171(3):265–274). Environmental modifications, caregiver education, and behavioral approaches can reduce agitation and distress. When medications are necessary, we use them judiciously. Benzodiazepines, such as lorazepam, may help with acute agitation or myoclonus but carry significant risks of sedation, falls, and delirium. For severe psychosis or agitation, antipsychotics are an option, but I’m cautious. Patients with prion disease are especially sensitive to extrapyramidal side effects, so I tend to avoid higher-risk agents and favor options like quetiapine or low-dose olanzapine when needed, with close monitoring. Antidepressants may help with anxiety or agitation in earlier phases. Ongoing reassessment is essential because the clinical picture changes rapidly.

CGPR: What about treating insomnia, especially in fatal familial insomnia?
Dr. Uflacker: In fatal familial insomnia, sleep disruption is central to the disease. Management is largely symptomatic. Sedating agents such as quetiapine are sometimes used because they can address multiple symptoms and have relatively lower extrapyramidal risk. However, there is no specific therapy that halts the underlying process. As with other aspects of prion disease, the goal is comfort and quality of life rather than cure. Any medication must be weighed against risks of oversedation or worsening confusion.

CGPR: How do you counsel families once the diagnosis is suspected or confirmed?
Dr. Uflacker: Counseling focuses on clarity, compassion, and practical planning. I explain that this is a rapidly progressive neurodegenerative disease for which we do not yet have disease-modifying therapy. I emphasize that time is precious and that early integration of palliative care and hospice can improve quality of life. I connect families with reputable resources, including the CJD Foundation, the NPDPSC, and the CDC. The NPDPSC can provide diagnostic testing and expert consultation, while the CJD Foundation offers support and care resources. The CJD International Support Alliance is also useful for identifying referral centers and support organizations worldwide. Families often experience fragmented care before diagnosis, seeing multiple providers without answers. A clear diagnosis can bring a measure of relief and allow them to focus on support, comfort, and meaningful time together.

CGPR: Are there ongoing research efforts patients should know about?
Dr. Uflacker: Yes. Because prion disease is fundamentally a single-protein misfolding disorder, it is an attractive target for disease-modifying approaches. Researchers such as Drs. Sonia Vallabh and Eric Vallabh Minikel have dedicated their life’s work to developing therapies for prion disease. Some drug companies are actively pursuing approaches such as gene-targeting and small-molecule therapies, with some already undergoing clinical trials for symptomatic patients. I encourage families to connect with national organizations to learn about research participation if they are interested. Even in the absence of approved treatments, contributing to research can be meaningful for some patients and caregivers.

CGPR: Are there any clinical pearls you would emphasize for psychiatrists?
Dr. Uflacker: The most important pearl is to consider prion disease in cases of rapidly progressive cognitive or psychiatric decline. If a patient deteriorates over weeks to months rather than years, especially with emerging neurologic signs, include prion disease in your differential and initiate appropriate workup. Early MRI and RT-QuIC testing can shorten the diagnostic journey. Even without curative therapy, timely diagnosis allows for better counseling, coordinated care, and meaningful time for patients and families. As psychiatrists, we are often on the front lines when behavioral symptoms appear first. Recognizing the pattern can make a profound difference in the care trajectory.

CGPR: Thank you for your time, Dr. Uflacker.