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A recent research article suggested that psychiatric and behavioral symptoms are not currently part of the diagnostic criteria for sporadic CJD and argued that they should be added. In this letter, the authors clarify that this statement is incorrect.

In fact, current diagnostic guidelines used in the United States and internationally already include neuropsychiatric symptoms as part of the criteria for diagnosing probable sporadic CJD. Since 2018, the Centers for Disease Control and Prevention has recognized that a neuropsychiatric syndrome, when combined with a positive specialized laboratory test called RT-QuIC, is sufficient for diagnosis. These updated criteria were developed to reflect real-world clinical experience and have been shown to improve diagnostic accuracy and early detection.

The reason specific psychiatric symptoms are not listed individually in the criteria is that CJD can cause a wide range of mental and behavioral changes. The term “neuropsychiatric syndrome” is meant to broadly include problems with thinking, behavior, mood, and perception.

We explain that studies relying on older diagnostic frameworks, developed before modern laboratory testing was available, may underestimate how common and how early psychiatric symptoms appear in CJD. Using current criteria helps clinicians recognize the disease sooner and avoid misdiagnosis.
We conclude by encouraging the journal to clarify this issue so clinicians are not misled and so that psychiatric and behavioral symptoms continue to be recognized as an important part of identifying CJD early, as is already reflected in modern diagnostic guidelines.  This project was partially funded by work through the CDC.

Although many people think of CJD as a rapidly progressive illness with dramatic neurological symptoms, not all forms of the disease behave the same way. This study focuses on a less common subtype known as the cortical subtype of sporadic CJD, which affects about 5% of all CJD cases.
The researchers studied 56 people from multiple countries whose diagnosis was confirmed by brain examination after death. They found that this subtype often looks very different from “classic” CJD, especially early in the disease.

Most patients with this cortical subtype first developed slowly progressive cognitive problems, such as memory loss, difficulty finding words, or problems with thinking and attention. Early in the illness, many patients did not have obvious movement problems, muscle jerks, or coordination issues, which are often expected in CJD. Because of this, the disease can easily be mistaken for Alzheimer’s disease, frontotemporal dementia, or other neurodegenerative conditions.

The study also showed that this subtype tends to progress more slowly, with an average disease duration of about 16 months, which is longer than typical CJD. In some patients, additional prion protein types were present in the brain. These “mixed” cases progressed more quickly and developed movement and balance problems earlier than those with the pure cortical form.

Importantly, the researchers evaluated how well different medical tests identify this subtype during life. Brain MRI scans were the most reliable test, showing characteristic changes in nearly all patients. A specialized spinal fluid test called RT-QuIC, which detects abnormal prion proteins, was also helpful but slightly less sensitive than in other forms of CJD. Other commonly used tests were less reliable.
The key message of this study is that CJD can sometimes present as a slowly progressive dementia without early prominent neurological signs, making it difficult to recognize. Greater awareness of this subtype, along with careful use of MRI and modern spinal fluid testing, can help doctors diagnose the disease earlier and more accurately.

Recognizing this form of CJD is important not only for patients and families, but also for clinical trials, infection control, and public health surveillance, since delayed diagnosis can have significant consequences.  This project was partially funded by work through the CDC.

Prion diseases, including Creutzfeldt-Jakob disease (CJD), are rare but devastating brain disorders that progress rapidly and place enormous strain on family caregivers. While much attention has focused on diagnosing and treating patients, far less research has examined the experiences and well-being of the people caring for them.

In this study, we followed 30 patients with prion disease and their caregivers over time using a telemedicine program called Teleneurology Assessment Program for CJD (TAPCJD). Caregivers regularly completed questionnaires that measured stress, emotional distress, mental health, physical health, and overall caregiver burden. The goal was to better understand how caregiver burden changes during the illness and what factors might predict higher levels of distress. 

The study found that caregiver burden in prion disease is very high, even compared with other types of dementia such as Alzheimer’s disease and frontotemporal dementia. At the start of the study, most caregivers already reported distress levels well above thresholds considered clinically significant.
One important finding was that caregivers experienced greater burden when the disease began at a younger age. This likely reflects added pressures such as financial strain, work disruption, and caring for dependent children. In contrast, caregiver burden was not strongly linked to disease subtype, disease duration, motor disability, or the caregiver’s relationship to the patient.

We also observed that neuropsychiatric symptoms tended to increase early in the illness, peak around the midpoint of the disease, and then decline later on. This pattern may reflect the course of prion disease, where generally early stages are marked by severe behavioral and psychiatric symptoms, followed by later stages when patients become less interactive and physically debilitated.

Interestingly, participation in support groups was not clearly associated with lower caregiver burden in this small sample, although individual experiences varied. The authors suggest that simply receiving a clear diagnosis and being connected with experienced clinicians may temporarily reduce distress by reducing uncertainty and confusion.

Overall, this study confirms that caregiver burden in prion disease is profound and persistent, especially early in the illness and in younger-onset cases. The findings highlight the urgent need for better caregiver education, psychosocial support, and targeted interventions throughout the disease course. Larger studies are needed, but this work provides an important foundation for improving care not only for patients, but also for the families who support them.  This work was partially funded by the CJD Foundation and the Stivison Fund for CJD Research.

Creutzfeldt-Jakob disease (CJD) is a rare and fatal brain disease caused by abnormal proteins called prions. About 10 to 15 percent of people with prion disease inherit a genetic change that causes the illness. The most common of these inherited forms is linked to a specific genetic mutation known as E200K.

This study examined 177 people with genetic CJD caused by the E200K mutation, making it the largest and most detailed study of this condition to date. By analyzing clinical symptoms, brain scans, spinal fluid tests, and brain tissue after death, the researchers found that E200K-related CJD does not have a single presentation, but instead includes several distinct subtypes.

A key finding is that a common genetic variation at another location in the prion protein gene, called codon 129, strongly influences how the disease looks and progresses. Depending on whether this position contains methionine (M) or valine (V), patients can develop very different patterns of symptoms, brain damage, and disease duration.

Some people with E200K develop a rapidly progressive dementia similar to classic CJD, often lasting only a few months. Others have a much longer disease course, sometimes more than a year, and may initially resemble Alzheimer’s disease, frontotemporal dementia, or even fatal insomnia. A small group showed prominent sleep disturbances and thalamic brain involvement, closely mimicking fatal insomnia despite having a different genetic cause.

The study identified five main disease subtypes, each with characteristic clinical features and patterns of brain damage. Importantly, modern diagnostic tests such as MRI brain scans and a specialized spinal fluid test called RT-QuIC were highly effective across nearly all subtypes.

Another important discovery was that although some subtypes show very little visible abnormal prion protein using standard laboratory techniques, they still demonstrate strong prion “seeding” activity when tested with RT-QuIC. This suggests that disease severity is not determined simply by how much abnormal protein is seen, but by more subtle molecular properties of the prions themselves.

Overall, this research shows that genetic CJD due to the E200K mutation is highly diverse, and that genetic background plays a major role in determining symptoms, progression, and diagnostic findings. Recognizing these differences can help doctors diagnose the disease earlier, avoid misdiagnosis as other dementias, improve counseling for families, and better prepare for future clinical trials and therapies.  This project was partially funded by work through the CDC.

Prion diseases (PrD) are a group of rapid, fatal neurodegenerative conditions where patients experience a quick functional decline, often reaching akinetic mutism within months. To track this progression, the MRC Prion Disease Rating Scale was developed as a 20-point tool covering 11 functional domains, ranging from basic physical tasks like feeding and mobility to cognitive functions like judgment and memory.

While the scale is a validated and pragmatic outcome measure, research identified that ambiguities in domain wording and scoring levels could lead to inconsistent results between different raters. To address this, a team of researchers developed a standardized User Guide through a multi-stage process:

• Expert and Caregiver Input: The project began with qualitative interviews with 12 former caregivers and international clinical experts to identify specific scoring challenges.
• Consensus Building: A draft guide was refined through an online survey and a 90-minute consensus meeting with an Advisory Committee of experts from Australia, France, Germany, Israel, and the United States.
• Standardized Clarifications: The final guide provides clear definitions for subjective terms (such as "help" or "occasional"), establishes a 24-hour recall period for most domains, and instructs raters to record the level of function regardless of whether the impairment is caused by motor or cognitive symptoms.

The User Guide is designed to complement the original scale without changing its structure. As global research into disease-modifying treatments for prion diseases accelerates, this tool ensures that patient assessments remain robust, reproducible, and standardized across different clinical and research settings.

Prion diseases are universally fatal neurodegenerative disorders characterized by a rapid decline in health and function. Because there are currently no cures, clinical care focuses heavily on managing symptoms and supporting caregivers. A study of 172 patients across the Mayo Clinic healthcare system examined how palliative care resources—services specifically designed to improve quality of life through symptom management and advance care planning—are utilized in this population.

Key findings from the study include:

• Significant Underutilization: While 95.9% of patients experienced symptoms that could be helped by supportive care (such as gait disturbances, sleep disruption, and myoclonus), more than one-third (34.3%) did not access specialty palliative care during their illness.
• Reactive Referral Patterns: Referrals to palliative care were often triggered by acute events or specific distressing symptoms. Patients were significantly more likely to be referred following emergency department visits or hospital admissions. Specific symptoms independently associated with higher referral rates included behavioral changes (agitation or combativeness) and constipation.
• Delayed Access: When palliative care was utilized, it was typically accessed late—often in the final months or weeks of life—and delivered primarily through hospice care.
• Barriers to Outpatient Care: The study found a significant disparity in wait times; while inpatient and hospice services were accessed within a median of one day, outpatient consultations had a median wait time of 19 days.
• Gaps in Planning: Goals of care, such as nutritional and hospitalization plans, were clarified and documented for less than half of the patients (47.1%).

The researchers conclude that there is a vital opportunity to improve patient outcomes by promoting early access to palliative care. Integrating these services sooner can better support symptom management, provide essential training for caregivers, and ensure that patient autonomy is protected through timely advance care planning.

Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical, and fatal subtype of prion disease currently classified as sporadic. Because approximately 42% of VPSPr patients have a positive family history of dementia—a rate higher than that seen in sporadic Creutzfeldt-Jakob disease (sCJD)—researchers investigated whether a hidden genetic variant might be the cause.

The study utilized exome sequencing and deep targeted sequencing of the PRNP locus (including non-coding regions) on 67 autopsy-confirmed VPSPr cases to search for causal mutations. Key findings from this research include:

• No Causal Variants Identified: The search found no potentially causal protein-coding or non-coding variants for VPSPr in any single gene, including PRNP.
• M129V as the Primary Risk Factor: The common PRNP polymorphism M129V was confirmed as the largest genetic risk factor for the disease, with an odds ratio of 7.0. Specifically, the 129V allele is significantly overrepresented in these patients.
• Linkage to 129V: Other variants near PRNP that appeared to be associated with VPSPr risk were determined to be in linkage disequilibrium with M129V, meaning they do not confer independent risk.
• No Association with Other Dementias: The researchers ruled out associations with known Mendelian genes for other neurodegenerative conditions, such as Alzheimer’s or Parkinson’s disease.

The researchers concluded that their data supports the classification of VPSPr as a genuinely sporadic disease, suggesting that the risk is not typically transmitted through families. The high rate of reported family history may be due to chance, the older age of onset allowing for more complete family histories, or the misattribution of more common dementias in relatives to the patient's condition. While the study cannot entirely rule out causal variants in unsearched genomic regions, it indicates that VPSPr does not have a high-penetrance genetic cause.

A real-world study of 215 U.S. patients revealed that the diagnostic journey for Creutzfeldt-Jakob disease (CJD) typically consumes roughly two-thirds of the total disease course. On average, patients experienced symptoms for 5 months before receiving a correct diagnosis, with 80% presenting with three or more symptoms, most commonly altered mental status (82%), gait disturbances (60%), and malaise (44%). During this period, 63% of patients received at least one alternative diagnosis—such as cerebrovascular disease, vertigo, or Alzheimer's—often requiring multiple diagnostic procedures, including MRIs (97%), EEGs (87%), and lumbar punctures (74%) before CJD was identified.

Due to these delays, the window for care after a CJD diagnosis is remarkably brief, with a median survival of only 1.1 months. This rapid decline is accompanied by a significant economic burden; total healthcare expenditures averaged $93,601 per patient, peaking sharply at nearly $49,000 during the month of initial diagnosis. These costs were driven primarily by acute-care hospitalizations, which accounted for 92% of expenditures in the month following diagnosis. Researchers emphasize that CJD must be considered earlier in differential diagnoses for rapidly progressing dementia to improve patient management and facilitate future enrollment in clinical trials for emerging disease-modifying treatments.

A 58-year-old woman in the United States developed iatrogenic Creutzfeldt-Jakob disease (iCJD) following an exceptionally long incubation period after treatment with cadaveric human growth hormone (chGH). Prion diseases like CJD are fatal neurodegenerative conditions caused by pathogenic misfolded proteins (PrPSc) that trigger a cascade resulting in widespread neuronal death. Between the 1960s and 1980s, roughly 7,700 U.S. patients received chGH through the National Hormone Pituitary Program (NHPP) before it was replaced with recombinant hormone due to the risk of prion contamination.

The patient's clinical course was characterized by a rapid decline:

• Initial Presentation and Misdiagnosis: After receiving chGH for 9.3 years starting in 1971, the patient presented nearly five decades later with tremors and gait imbalance. An initial neurologic exam and brain MRI were unremarkable, leading physicians to favor a diagnosis of a functional neurologic disorder.
• Rapid Progression: Within four weeks, her condition worsened significantly, including urinary incontinence, decreased speech, and appendicular rigidity. She eventually fell into a coma and required intubation.
• Confirmation: A follow-up MRI two months later revealed classic CJD markers, such as diffusion restriction in the caudate heads and insulae. Her diagnosis was confirmed by positive RT-QuIC prion testing and subsequent autopsy.

Using the midpoint of her pre-1978 treatment to the onset of symptoms, researchers determined the patient had a latency period of 48.3 years. This is the 36th identified iCJD case among U.S. NHPP recipients and represents a significant outlier in incubation length. Several factors likely contributed to this extended timeline, including the patient's heterozygous (M/V) genotype at codon 129 of the PRNP gene, which is associated with longer incubation periods in acquired prion diseases. Additionally, a new purification step introduced in 1977 greatly reduced, but did not eliminate, prion contamination in hormone lots.

The researchers conclude that although the U.S. iCJD outbreak has slowed, clinicians must remain vigilant and include iCJD in the differential diagnosis for any patient with progressive neurologic signs who has a history of cadaveric human growth hormone treatment.

This study provides a rigorous psychometric validation of the Medical Research Council-Prion Disease Rating Scale (MRC-PDRS) using data from 101 participants. While the 20-point scale was already in use, this research established definitive statistical evidence of its reliability, validity, and responsiveness, confirming it as a robust tool for tracking the rapid functional decline characteristic of prion disease.

Key findings from the analysis include:

• High Reliability and Validity: The scale demonstrated excellent internal consistency, with reliability scores exceeding 0.90. It showed strong convergent validity with cognitive assessments (TICS), while simultaneously maintaining clear divergent validity by showing little association with neuropsychiatric symptoms (NPI-Q). This confirms that the scale specifically measures functional disability and disease progression rather than behavioral changes.
• Sensitivity to Change: The tool proved highly responsive over time; as patients’ cognitive scores dropped, their MRC-PDRS functional scores declined concordantly.
• Meaningful Change Threshold: Researchers identified a minimally important change (MIC) threshold of 1 to 3 points. This provides clinicians and researchers with a clear statistical baseline to determine when a patient has experienced a clinically significant decline.

The researchers conclude that the MRC-PDRS is a reliable primary endpoint for clinical trials, offering a more consistent measure of functional ability than survival time alone. In clinical practice, it serves as a valuable tool for prognostication and for helping families understand the disease trajectory and the rationale behind management strategies.

Researchers identified two novel, rare subtypes of sporadic Creutzfeldt–Jakob disease (sCJD) in patients with the 129MM genotype who exhibit PrP plaques. These variants, termed pGM-CJD (gray matter) and pWM-CJD (white matter), account for about 0.6% of all sporadic cases. While pGM-CJD features large plaques (~20 µm) primarily in the cerebellar gray matter, pWM-CJD is characterized by smaller plaques (~10 µm) distributed throughout the brain's white matter.

Molecular and transmission studies confirm these subtypes represent distinct prion strains, with pWM-CJD possessing a unique protein signature known as a T1²¹⁻²⁰ doublet. Clinically, these patients often present with cognitive and psychiatric symptoms rather than typical cerebellar signs. Notably, the CSF 14-3-3 protein test was only 50% sensitive in these cases, compared to 94% in typical sCJD, highlighting a potential diagnostic challenge for these atypical variants.

This study introduces a novel diagnostic algorithm designed to identify the specific subtype of sporadic Creutzfeldt-Jakob disease (sCJD) in living patients. Currently, these seven subtypes, which differ significantly in symptoms and disease duration, can only be definitively diagnosed through a brain autopsy.

Methodology and Technology
Researchers utilized a discriminative event-based model (DEBM), a data-driven approach that analyzes diffusion-weighted imaging (DWI) from brain MRIs. By studying 488 autopsy-confirmed cases, the model estimated the spatiotemporal cascades of lesions across 12 brain regions to identify subtype-specific patterns of disease progression.

Key Findings

• Subtype-Specific Propagation: The study confirmed that lesion cascades are unique to each molecular subtype. For instance, subtypes like MM1, MM2, and VV1 typically begin in the parietal cortex before spreading to subcortical regions. In contrast, VV2 and MV2K cascades begin in the striatum and propagate toward the cortex.
• High Diagnostic Accuracy: When combined with the patient's PRNP codon 129 genotype, the algorithm achieved a 76.5% balanced accuracy and an 87.0% weighted accuracy (accounting for subtype prevalence in the general population).
• Reliability: The method showed low rater dependency, performing consistently regardless of the specific neuroradiologist's level of expertise.

Clinical Significance
The ability to identify sCJD subtypes ante mortem is a significant advancement for patient prognostication and clinical management. Furthermore, this model allows for better patient stratification in clinical trials, ensuring that future therapeutics are tested effectively against specific prion strains.

Human prion diseases are fatal neurodegenerative conditions driven by the misfolding of the native prion protein (PrP^C) into a disease-causing isoform (PrP^D). While most cases are sporadic, the prion protein gene (PRNP) plays a critical role across all etiologies—sporadic, genetic, and acquired—by influencing disease susceptibility, age of onset, and clinical phenotype.

The codon 129 polymorphism is the most significant genetic modifier across all forms of prion disease. For example, methionine homozygosity (MM) at this codon is a major risk factor for sporadic CJD (sCJD) and typically leads to a faster functional decline compared to heterozygotes. Conversely, the codon 219 polymorphism found in some Asian populations is strongly protective against sCJD.

Accounting for 10–15% of cases, genetic prion diseases result from more than 60 different pathogenic PRNP mutations. These are generally classified into three major clinico-pathologic phenotypes:

• Genetic CJD (gCJD): The most common form (most frequently the E200K mutation), which closely resembles the symptoms and progression of sporadic CJD.
• Fatal Familial Insomnia (FFI): Characterized by early sleep and autonomic disturbances; it is typically linked to the D178N mutation when it occurs alongside methionine at codon 129.
• Gerstmann-Sträussler-Scheinker syndrome (GSS): Often involves early cerebellar ataxia or Parkinsonism and generally has a much longer disease duration than CJD.

A critical aspect of these diseases is variable penetrance; some mutations are nearly 100% penetrant, while others (like V180I) have a much lower risk of causing disease. This makes specialized genetic counseling and adherence to established protocols, such as the Huntington disease protocol, essential for predictive testing.

Because PrP^C is required for disease transmission and neurotoxicity, current research focuses on reducing the production of the host prion protein. Antisense oligonucleotides (ASOs) are a leading experimental approach designed to degrade PrP mRNA, effectively lowering PrPC levels. In animal models, ASOs have successfully prolonged survival even when administered to symptomatic subjects, offering hope for future disease-modifying treatments for both patients and asymptomatic mutation carriers.

The diagnostic landscape for human prion diseases has been transformed by the development of highly specific, non-invasive testing. The second-generation RT-QuIC assay is considered a "game-changer," offering 90.3–97.2% sensitivity and 98.5–100% specificity across most prion diseases. While exceptionally accurate for common sporadic CJD (sCJD) subtypes, RT-QuIC has reduced sensitivity in atypical variants such as Fatal Familial Insomnia (FFI), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Variably Protease-Sensitive Prionopathy (VPSPr).

In addition to laboratory tests, brain MRI remains a primary diagnostic tool, showing up to 98% sensitivity for identifying characteristic signal abnormalities in the basal ganglia and cortex. Traditional fluid biomarkers like 14-3-3 and Tau are useful but non-specific indicators of neuronal death, whereas newer markers like alpha-synuclein demonstrate higher diagnostic accuracy. For cases where standard tests fail, PRNP gene sequencing is the definitive method for identifying genetic mutations. These advancements have largely eliminated the clinical need for invasive pre-mortem brain biopsies. Finally, researchers emphasize continued surveillance of Chronic Wasting Disease (CWD) to monitor its potential for zoonotic transmission to humans.

The authors review the evolving diagnostic landscape for sporadic Creutzfeldt-Jakob disease (sCJD), a fatal neurodegenerative condition characterized by the accumulation of misfolded prion proteins. Traditional diagnostic frameworks have long relied on a combination of clinical symptoms, EEG periodic sharp-wave complexes, and the detection of CSF surrogate biomarkers like 14-3-3 and total-tau. While these markers are valuable, they often lack disease-specificity and can yield false positives in the presence of "CJD mimics," such as autoimmune encephalitis or stroke. Brain MRI remains a critical tool, offering high sensitivity (up to 98%) by identifying typical restricted diffusion patterns in the cortex and basal ganglia, which helps distinguish sCJD from other rapidly progressive dementias.

The development of real-time quaking-induced conversion (RT-QuIC) represents a major breakthrough, providing a highly specific (99–100%) and sensitive (up to 97%) method for detecting pathogenic prion protein seeding activity in cerebrospinal fluid. Because of its exceptional accuracy, RT-QuIC has been integrated into updated diagnostic criteria, allowing for earlier clinical confirmation and improved surveillance. Current research is now shifting toward blood-based biomarkers, such as plasma total-tau and neurofilament light (NfL), which may serve as accessible triage tools or longitudinal measures for monitoring disease progression in future clinical trials. While challenges remain regarding the availability of these tests and their sensitivity in rare disease subtypes, these advancements are moving the field toward more robust and non-invasive diagnostic models.

The authors investigated the clinical and molecular characteristics of the 2-octapeptide repeat insertion (2-OPRI) genetic variant in the prion protein gene (PRNP), a mutation whose pathogenicity has historically been unclear compared to larger insertions. By analyzing eight cases from surveillance centers in the United States, United Kingdom, and Australia, the researchers found that 2-OPRI cases were clinically and histopathologically indistinguishable from sporadic Creutzfeldt–Jakob disease (sCJD) of the same molecular subtype. While the patients presented with typical CJD features like dementia and ataxia, Western blot analysis revealed that 2-OPRI and sCJD have distinct prion protein profiles when examined without enzymatic digestion, although they become virtually identical following proteinase K treatment.

To assess the risk for asymptomatic carriers, the study interrogated three large-scale population genetic databases, identifying sixteen 2-OPRI alleles in individuals not known to have the disease. The researchers calculated an extremely low penetrance of 0.3% or below, suggesting that 2-OPRI is not a high-penetrance mutation but rather a low-risk genetic variant that increases the lifetime risk of CJD to approximately 1 in 500. Because the risk is so minimal, the authors conclude that predictive genetic testing for asymptomatic relatives is likely not justified, though they noted that the codon 129 genotype still appears to influence the age of onset in those who do develop the disease.