Creutzfeldt-Jakob Research Articles

A Retrospective Cohort Study of a Newly Proposed Criteria for Sporadic Creutzfeldt–Jakob Disease

Background/Objectives: Sporadic Creutzfeldt–Jakob disease (sCJD) is a fatal neurodegenerative disorder traditionally diagnosed based on the World Health Organization (WHO) criteria in 1998. Recently, Hermann et al. proposed updated diagnostic criteria incorporating advanced biomarkers to enhance early detection of sCJD. This study aimed to evaluate the sensitivity and specificity of Hermann’s criteria compared with those of the WHO criteria in a large cohort of patients suspected of prion disease in Japan. Methods: In this retrospective cohort study, we examined the new criteria using data of 2004 patients with suspected prion disease registered with the Japanese Prion Disease Surveillance (JPDS) between January 2009 and May 2023. Patients with genetic or acquired prion diseases or incomplete data necessary for the diagnostic criteria were excluded, resulting in 786 eligible cases. The sensitivity and specificity of the WHO and Hermann’s criteria were calculated by comparing diagnoses with those made by the JPDS Committee. Results: Of the 786 included cases, Hermann’s criteria helped identify 572 probable cases compared with 448 by the WHO criteria. The sensitivity and specificity of the WHO criteria were 96.4% and 96.6%, respectively. Hermann’s criteria demonstrated a sensitivity of 99.3% and a specificity of 95.2%, indicating higher sensitivity but slightly lower specificity. Fifty-five cases were classified as “definite” by both criteria. Conclusions: The findings suggest that Hermann’s criteria could offer improved sensitivity for detecting sCJD, potentially reducing diagnostic oversight. However, caution is advised in clinical practice to avoid misdiagnosis, particularly in treatable neurological diseases, by ensuring thorough exclusion of other potential conditions.

Neuronal Intranuclear Inclusion Disease Presenting with Acute-Onset Dementia and Cortical Edema: A Case Report

BackgroundNeuronal Intranuclear Inclusion Disease (NIID) is a neurodegenerative disorder characterized by the formation of eosinophilic inclusions in the neurons, visceral and skin cells. The cause is associated with the GGC nucleotide repeat expansion in the NOTCH2NLC gene. The imaging hallmark of NIID is hyperintensities on diffusion-weighted imaging (DWI) at the corticomedullary junction. Clinical manifestations of NIID are highly heterogeneous. Here, we report a case of NIID presenting with acute-onset dementia and cortical edema.Case presentationWe describe an elderly male patient who presented with sudden dementia within a day. Considering the abrupt onset and the stroke history, we initially diagnosed vascular disease. However, further imaging revealed cortical edema in the temporo-parieto-occipital lobes. Blood and cerebrospinal fluid tests ruled out immunological, metabolic, infectious, or neoplastic etiologies. Genetic testing ultimately confirmed the diagnosis of NIID. Intravenous immunoglobulin (IVIG) therapy did not improve the patient’s symptoms; However, about 1 month after treatment, spontaneous improvement was observed. It is noteworthy that 22 months before the onset of cognitive impairment, the patient’s MRI for headaches already exhibited the typical imaging lesions of this disease in the cerebellum paravermal region.ConclusionPatients with encephalopathy syndrome exhibiting imaging features resembling mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome or Creutzfeldt-Jakob disease should consider the NIID as differential diagnosis. Chronic headaches and symmetric lesions in the cerebellar paravermal region on MRI may be noteworthy indicators of NIID during non-episodic phases.

Multisite Skin Biopsies vs Cerebrospinal Fluid for Prion Seeding Activity in the Diagnosis of Prion Diseases

Recent studies have revealed that autopsy skin samples from cadavers with prion diseases (PRDs) exhibited a positive prion seeding activity similar to cerebrospinal fluid (CSF). It is worthwhile to validate the findings with a large number of biopsy skin samples and compare the clinical value of prion seeding activity between skin biopsies and concurrent CSF specimens. To compare the prion seeding activity of skin biopsies and CSF samples and to determine the effectiveness of combination of the skin biopsies from multiple sites and numerous dilutions on the diagnosis for various types of PRDs. In the exploratory cohort, patients were enrolled from September 15, 2021, to December 15, 2023, and were followed up every 3 months until April 2024. The confirmatory cohort enrolled patients from December 16, 2023, to June 31, 2024. The exploratory cohort was conducted at a single center, the neurology department at Xuanwu Hospital. The confirmatory cohort was a multicenter study involving 4 hospitals in China. Participants included those diagnosed with probable sporadic Creutzfeldt-Jakob disease or genetically confirmed PRDs. Patients with uncertain diagnoses or those lost to follow-up were excluded. All patients with PRDs underwent skin sampling at 3 sites (the near-ear area, upper arm, lower back, and inner thigh), and a portion of them had CSF samples taken simultaneously. In the confirmatory cohort, a single skin biopsy site and CSF samples were simultaneously collected from a portion of patients with PRDs. The skin and CSF prion seeding activity was assessed using the real-time quaking-induced conversion (RT-QUIC) assay, with rHaPrP90-231, a Syrian hamster recombinant prion protein, as the substrate. In the exploratory cohort, skin samples were tested at dilutions of 10-2 through 10-4. In the confirmatory cohort, skin samples were tested at a dilution of 10-2. A total of four 15-μL wells of CSF were used in the RT-QUIC assay. Correlations between RT-QUIC results from the skin and CSF and the final diagnosis of enrolled patients. In the exploratory cohort, the study included 101 patients (mean [SD] age, 60.9 [10.2] years; 63 female [62.4%]) with PRD and 23 patients (mean [SD] age, 63.4 [9.1] years; 13 female [56.5%]) without PRD. A total of 94 patients had CSF samples taken simultaneously with the skin biopsy samples. In the confirmatory cohort, a single skin biopsy site and CSF sample were taken simultaneously in 43 patients with PRDs. Using an experimental condition of 10-2 dilution, the RT-QUIC positive rates of skin samples from different sites were comparable with those of the CSF (skin: 18 of 26 [69.2%] to 74 of 93 [79.6%] vs CSF: 71 of 94 [75.5%]). When tested at 3 different dilutions, all skin sample positivity rates increased to over 80.0% (79 of 93 for the near-ear area, 21 of 26 for the upper arm, 77 of 92 for the lower back, and 78 of 92 for the inner thigh). Combining samples from skin sites near the ear, inner thigh, and lower back in pairs yielded positivity rates exceeding 92.1% (93 of 101), significantly higher than CSF alone (71 of 94 [75.5%]; P =.002). When all skin sample sites were combined and tested at 3 dilution concentrations for RT-QUIC, the sensitivity reached 95.0% (96 of 101). In the confirmatory cohort, the RT-QUIC positive rate of a single skin biopsy sample was slightly higher than that of the CSF (34 of 43 [79.1%] vs 31 of 43 [72.1%]; P = .45). Results of this diagnostic study suggest that the sensitivity of an RT-QUIC analysis of a combination of 2 or more skin sites was superior to that of CSF in diagnosing PRDs.

Sporadic Creutzfeldt Jakob disease: Case series in Peru.

A series of 6 cases with a probable diagnosis of sporadic CJD, treated in a Peruvian national reference hospital, are presented. The relevant clinical signs were rapidly progressive dementia and myoclonus, followed by akinetic mutism and pyramidal signs. Of the cases presented, 80% were men, with an average age of presentation of 65 years and duration from diagnosis to death of 6.5 months. Laboratory tests, images (Brain Resonance) and protein dosage 14.3.3 were performed to support the clinical suspicion. There is no effective treatment at the moment for said pathology. Creutzfeldt-Jakob disease (CJD) is a progressive, fatal, neurodegenerative disease of low prevalence and incidence. Great clinical suspicion and the exclusion of other etiologies are required. Currently there is no treatment for this entity and there is a high probability of death before one year.

C9orf72 Gene-Associated Frontotemporal Dementia Mimicking Autoimmune Pathology.

The C9orf72 mutation can manifest in diverse clinical ways, including rapid cognitive decline, parkinsonism, or late-life neuropsychiatric symptoms, sometimes mimicking autoimmune encephalitis. A 64-year-old female presented to the autoimmune neurology clinic with rapidly progressive dementia (RPD) associated with episodes of headache, confusion, auditory hallucinations, and abnormal electroencephalogram. She was treated empirically at an outside hospital for possible autoimmune encephalitis with intravenous methylprednisolone, but there was no improvement, and rapid cognitive decline continued. Family history was notable for RPD with akinetic mutism in her sister, sudden severe depression followed by parkinsonism with progressive dementia in her father in his 60s, and late-life gradually progressive dementia in her mother. Additional testing revealed a low titer positive contactin-associated protein-like 2 (CASPR2) immunoglobulin G (IgG) in the serum and elevated CSF 14-3-3 protein. CSF CASPR2 IgG and real-time quaking-induced conversion for Creutzfeldt-Jakob disease were negative. Brain MRI showed normal parenchymal volume. Genetic testing was conducted, which identified a heterozygous pathogenic hexanucleotide tandem repeat expansion in the C9orf72 gene. This case underscores the phenotypic variability of C9orf72 mutation and the importance of a detailed family history exploring young or atypical deaths and neuropsychiatric symptoms or behavioral changes. Genetic etiologies are crucial to consider in those with a family history concerning autosomal dominant inheritance patterns of early-onset dementia, parkinsonism, or late-onset psychiatric disease. Emphasis is placed on considering alternative etiologies early, particularly when there is no response to first-line immunomodulation for suspected autoimmune dementia.

Impact of Social Determinants of Health in Diagnosing Creutzfeldt-Jakob Disease

Impact of Social Determinants of Health in Diagnosing Creutzfeldt-Jakob Disease

A Novel Approach to Preventing the PrPSc Induced Neurotoxicity Which Characterizes Creutzfeldt-Jakob Disease Through the Inhibition of Glypican-1

A Novel Approach to Preventing the PrPSc Induced Neurotoxicity Which Characterizes Creutzfeldt-Jakob Disease Through the Inhibition of Glypican-1

Unusual Presentation of Creutzfeldt-Jakob Disease: A Case Report of Progressive Bulbar Symptoms with Unique Imaging Findings

Unusual Presentation of Creutzfeldt-Jakob Disease: A Case Report of Progressive Bulbar Symptoms with Unique Imaging Findings

Reactive microglia partially envelop viable neurons in prion diseases.

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrated that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occured in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrPSc in the brain. Microglia that enveloped neurons exhibited hypertrophic, cathepsin D-positive lysosomal compartments. However, most neurons undergoing envelopment were only partially encircled by microglia. Despite up to 40% of cortical neurons being partially enveloped at clinical stages, only a small percentage of envelopment proceeded to full engulfment. Partially enveloped neurons lacked apoptotic markers but showed signs of functional decline. Neuronal envelopment was independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. This phenomenon of partial envelopment was consistently observed across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.

Creutzfeldt-Jakob disease: From presentation to palliative care.

Creutzfeldt-Jakob disease: From presentation to palliative care.

S891 A Novel Protocol for Endoscope Handling and Disposal in the Setting of Creutzfeldt-Jakob and Other Prion Disease

S891 A Novel Protocol for Endoscope Handling and Disposal in the Setting of Creutzfeldt-Jakob and Other Prion Disease

Regulated Proteolysis Induces Aberrant Phase Transition of Biomolecular Condensates into Aggregates; A Protective Role for the Chaperone Clusterin

Several proteins associated with neurodegenerative diseases, such as the mammalian prion protein (PrP), undergo liquid–liquid phase separation (LLPS), which led to the hypothesis that condensates represent precursors in the formation of neurotoxic protein aggregates. However, the mechanisms that trigger aberrant phase separation are incompletely understood. In prion diseases, protease-resistant and infectious amyloid fibrils are composed of N-terminally truncated PrP, termed C2-PrP. C2-PrP is generated by regulated proteolysis (β-cleavage) of the cellular prion protein (PrPC) specifically upon prion infection, suggesting that C2-PrP is a misfolding-prone substrate for the propagation of prions. Here we developed a novel assay to investigate the role of both LLPS and β-cleavage in the formation of C2-PrP aggregates. We show that β-cleavage induces the formation of C2-PrP aggregates, but only when full-length PrP had formed biomolecular condensates via LLPS before proteolysis. In contrast, C2-PrP remains soluble after β-cleavage of non-phase-separated PrP. To investigate whether extracellular molecular chaperones modulate LLPS of PrP and/or misfolding of C2-PrP, we focused on Clusterin. Clusterin does not inhibit LLPS of full-length PrP, however, it prevents aggregation of C2-PrP after β-cleavage of phase-separated PrP. Furthermore, Clusterin interferes with the in vitro amplification of infectious human prions isolated from Creutzfeldt-Jakob disease patients. Our study revealed that regulated proteolysis triggers aberrant phase transition of biomolecular condensates into aggregates and identified Clusterin as a component of the extracellular quality control pathway to prevent the formation and propagation of pathogenic PrP conformers.

Role of MRI in Diagnosis of Rapidly Progressive Cognitive Impairment- A Case Of Sporadic Creutzfeldt Jakob Disease (sCJD)

Abstract Background The role of neuroimaging in dementia extends beyond its traditional role of excluding neurosurgical lesions. Radiological findings may support the diagnosis of specific neurodegenerative disorders and aid differentiation from other neurodegenerative conditions e.g. CJD1. sCJD is a fatal neurodegenerative disease, which typically presents with neuropsychiatric symptoms, myoclonus, cerebellar and pyramidal/extrapyramidal symptoms. The diagnosis often is quite difficult, requiring high degree of suspicion, advanced neuroimaging and biochemical markers. Confirmation is only possible via brain biopsy. The condition can result in rapidly progressive dementia/neurocognitive decline and death, usually within a year from onset. Methods We report a case of a rapidly progressive dementia in a 79-year-old male who was diagnosed with probable sCJD, after having an MRI which picked up suspicious characteristic findings leading to the eventual diagnosis confirmation via further workup. The patient presented with acute rapid progressive forgetfulness and functional decline of 2 weeks with initial workup unyielding. Results A contrast MRI Brain eventually showed focal increased T2 and flair signals in the right parafalcine and parietal cortex demonstrating mild fluid restriction without any focal contrast enhancement, a pattern highly suspicious for sCJD. A CSF sample subsequently revealed RT-QulC positivity confirming the diagnosis. The patient eventually passed away despite ward-based care after 4 weeks of admission due to rapid neurological decline. A brain biopsy was not deemed feasible given patient’s condition. Conclusion The case highlights a relatively atypical symptomology of sCJD and, highlights the role of MRI imaging in assessment and diagnosis of dementias and specifically in sCJD. Increasing use of advanced neuroimaging may aid in diagnosis of specific/rare causes of rapidly progressive dementias. Reference Vitali, P., Maccagnano, E., Caverzasi, E., Henry, R.G., Haman, A., Torres-Chae, C., Johnson, D.Y., Miller, B.L. and Geschwind, M.D., 2011. Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias. Neurology, 76(20), pp. 1711-1719.

Characterization of Laboratory-Confirmed Creutzfeldt-Jakob Disease From 3 Ontario Tertiary Care Centers Between 2012 and 2022: A Retrospective Cohort Study.

Globally, Creutzfeldt-Jakob disease (CJD) affects one in one million people annually, but there is a paucity of recent Canadian data. This study summarizes epidemiology trends and diagnostic timelines of laboratory-confirmed CJD cases in three tertiary Ontario hospitals. Using laboratory information systems, we identified 30 patients with a laboratory-confirmed CJD diagnosis between 2012 and 2022 at three major tertiary hospitals in Ontario. Retrospective chart reviews were then completed. Patients had a mean of 2.2 hospital visits (SD, 1.2) prior to being admitted for testing. The most common symptom presentations included loss of coordination (63.3%), behavioral changes (60%), progressive mobility loss (53.4%), memory loss (50.0%), and involuntary movements (50.0%). Magnetic resonance imaging findings showed potential CJD in 76.7% of cases, and 56.7% exhibited periodic sharp wave complexes characteristic of CJD on electroencephalogram. The mean duration from symptom onset to microbiologic testing was 91 days (SD, 90.7). End-point quaking-induced conversion (EP-QuIC) testing of cerebrospinal fluid was positive in 90.0% of patients, while 83.3% tested positive for 14-3-3 on enzyme-linked immunosorbent assay. Elevated cerebrospinal fluid 14-3-3 levels significantly correlated with shorter duration from symptom onset to death (R 2 = 0.71, F = 19.55, P = .0022). Post-diagnosis, 46.7% of patients were discharged home, 16.6% were transferred to external palliative care or hospice facilities, and 36.7% died during admission. The mean time from symptom onset to death was 121 days (SD, 120.7), and from diagnosis to death 35 days (SD, 83.9). This study highlights the importance of early CJD consideration and laboratory testing when appropriate neurologic symptoms are present.

Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrPC). Why these mutations are pathogenic, and how they alter the properties of PrPC are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrPC may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics.

Dopaminergic neurodegeneration in Gerstmann-Sträussler-Scheinker (P102L) disease: insights from imaging and pathological examination.

Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease characterized by dementia, cerebellar ataxia, and painful sensory disturbances. GSS is pathologically defined by the presence of amyloid plaques comprised of prion protein predominantly localized in the cerebral cortex, cerebellar cortex, and basal ganglia, resulting from mutations in the prion protein gene. This study investigated five cases of GSS P102L [GSS caused by a leucine (L) substitution of proline (P) at position 102 of the prion protein gene] with L-dopa-resistant extrapyramidal symptoms and reduced dopamine transporter single-photon emission computed tomography (DAT-SPECT) uptake. Clinical findings revealed diverse manifestations, with all cases exhibiting parkinsonism, and four patients had a vertical gaze palsy. Notably, all patients showed reduced striatal DAT-SPECT uptake, indicating neurodegeneration of the nigrostriatal system. Autopsy findings in one case confirmed prion protein plaques and dopaminergic neuron loss in the substantia nigra of a patient with GSS P102L. Additionally, reduced DAT immunostaining was observed in the putamen compared with a control. While previous studies have identified reduced DAT-SPECT and positron emission tomography uptake in Creutzfeldt-Jakob disease and fatal familial insomnia owing to nigrostriatal neurodegeneration induced by abnormal prion protein deposition, similar phenomena in GSS P102L have not been reported. This study provides support for a correlation between abnormal prion protein deposition and nigrostriatal system degeneration in GSS P102L. Our results reveal the importance of considering GSS P102L in cases of atypical Parkinsonism and abnormal DAT-SPECT results, which would serve as a valuable indicator for subsequent prion genetic testing.

Exploring the effects of 4-chloro-o-phenylenediamine on human fibrinogen: A comprehensive investigation via biochemical, biophysical and computational approaches

Fibrinogen (Fg), an essential plasma glycoprotein involved in the coagulation cascade, undergoes structural alterations upon exposure to various chemicals, impacting its functionality and contributing to pathological conditions. This research article explored the effects of 4-Chloro-o-phenylenediamine (4-Cl-o-PD), a common hair dye component (IUPAC = 1-Chloro-3,4-diaminobenzene), on human fibrinogen through comprehensive computational, biophysical, and biochemical approaches. The formation of a stable ligand-protein complex is confirmed through molecular docking and molecular dynamics simulations, revealing possible interaction having a favorable −4.8 kcal/mol binding energy. Biophysical results, including UV–vis and fluorescence spectroscopies, corroborated with the computational findings, whereas Fourier transform infrared spectroscopy (FT-IR) and circular dichroism spectroscopy (CD) provide insights into the alterations of secondary structures upon interaction with 4-Cl-o-PD. Anilinonaphthalene-sulfonic acid (ANS) fluorescence showed a partially unfolded protein, with enhanced α to β-sheet transition as evidenced by thioflavin T (ThT) spectroscopy and microscopy. Moreover, biochemical assays confirmed the formation of carbonyl compounds that may be responsible for the oxidation of methionine residues in fibrinogen. Electrophoresis and electron microscopy confirmed the formation of aggregates. Our findings elucidate the interaction pattern of 4-Cl-o-PD with Fg, leading to structural perturbation, which may have potential implications for fibrinogen misfolding or its aggregation. Protein aggregation or its misfolded products affect peripheral tissues and the central nervous system. Many chronic progressive diseases, like type II diabetes mellitus, Alzheimer's disease, Parkison's disease, and Creutzfeldt-Jakob disease are associated with intrinsically aberrant disordered proteins. Understanding these interactions may offer new perspectives on the safety and biocompatibility of dye compounds, which may contribute to developing improved strategies for acquired amyloidogenesis.

Optimizing Corneal Transplant Safety: The Impact of Mandatory Prion Protein Testing on Iatrogenic Creutzfeldt-Jakob Disease Prevention in the Czech Republic.

The purpose of this study was to assess the effectiveness of legally mandated testing for pathogenic prion proteins in corneal tissue donors in the Czech Republic, considering its impact on safety, financial, and temporal costs. Between January 2007 and December 2023, standardized brain regions were collected from all corneal tissue donors in the Czech Republic. Tissue samples were tested for the presence of pathogenic prion proteins by the Czech Reference Laboratory for Human Prion Diseases. The testing used a Western blot analysis, using 2 distinct monoclonal anti-PrP antibodies. A total of 8030 donors were tested. Four tested samples were initially weakly positive. Subsequent testing conclusively determined these samples to be negative. The remaining 8026 tests yielded negative results confirming the safety of donor screening. We did not observe any cases of proven transmissible spongiform encephalopathies (TSEs). TSE testing has consistently confirmed that no patients with TSE have been selected into the corneal donor pool, solidifying the effectiveness of the active surveillance program and exclusion criteria. We propose that these mechanisms effectively prevent patients with TSEs from being included in the corneal tissue donor pool. However, the substantial financial costs and a 2-day delay in processing pose challenges, contributing to graft nonutilization and potential negative impacts on patients in acute need. Moreover, the unique requirement for pathogenic prion testing in the Czech Republic also makes importing any corneal grafts from other countries impossible, as those tissues do not fulfill Czech legal requirements.

Revision and update of the position paper on the management of notifications of donors with Creutzfeldt-Jakob disease in Italy.

Revision and update of the position paper on the management of notifications of donors with Creutzfeldt-Jakob disease in Italy.

An autopsy case of MM1‐type sporadic Creutzfeldt–Jakob disease with long survival of 7 years

An autopsy case of MM1‐type sporadic Creutzfeldt–Jakob disease with long survival of 7 years