Numerous studies have demonstrated the rise in neurological and psychiatric issues linked to post-COVID-19 infections. The most prevalent symptoms include encephalopathy, seizures, depression, anxiety, and ischemic or hemorrhagic stroke. The occurrence of Creutzfeldt-Jakob disease (CJD) after COVID-19 was unusual, but recent studies have shown a connection between COVID-19 and prion disease. Most cases of CJD present within weeks or a few months after the onset of COVID-19. The late onset of Creutzfeldt-Jakob disease following the COVID-19 infection raises questions about the potential pathophysiological mechanisms underlying this association. Although the exact link remains elusive, this case adds to the growing body of evidence suggesting a possible relationship between COVID-19 and neurodegenerative diseases. Further research is warranted to elucidate the underlying mechanisms and optimize management strategies for post-COVID-19 neurological complications. We present to you an 83-year-old man with a history of COVID-19 infection who presents with memory impairment, mood instability, and declining cognitive function. Despite initial improvement, his condition rapidly deteriorated, ultimately leading to a diagnosis of probable Creutzfeldt-Jakob disease.

BACKGROUND: MRI is an important tool for disease diagnosis of Creutzfeldt-Jakob disease (CJD), yet its role in identifying preclinical stages of disease remains unclear. Here, we explored subtle white matter (WM) alterations in genetic CJD (gCJD) patients and in asymptomatic E200K mutation carriers using MRI, depending on total tau protein (t-tau) levels in CSF.
METHODS: Six symptomatic gCJD patients and N=60 healthy relatives of gCJD patients were included. Participants underwent genetic testing for the E200K mutation, MRI scans at 3T and a lumbar puncture (LP) for t-tau. Diffusion tensor imaging (DTI) metrics were calculated along WM tracts.
RESULTS: gCJD patients demonstrated higher mean diffusivity (MD), radial diffusivity (RD) and lower fractional anisotropy (FA) values compared with healthy relatives in several WM tracts (p<0.05). Out of the healthy relatives, 50% (N=30) were found to be carriers of the E200K mutation. T-tau levels in cerebrospinal fluid (CSF) were above the normal range (>290 pg/mL) in N=8 out of 23 carriers who underwent an LP. No significant differences in FA, MD, axial diffusivity (AD) and RD were detected between healthy mutation carriers (HMC) and healthy non-carriers within the WM tracts. Finally, significantly higher FA and lower MD, RD and AD along several WM tracts were found in HMC with elevated t-tau compared with HMC with normal t-tau (p<0.05).
CONCLUSIONS: DTI abnormalities along WM tracts were found in healthy E200K mutation carriers with elevated t-tau in CSF. Longer follow-up is required to determine whether these subtle WM alterations are predictive of future conversion to symptomatic gCJD.
BACKGROUND: NCT05746715.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal degenerative brain disease characterized by rapidly progressive dementia. Sporadic CJD (sCJD) is the best-known and most common subtype. Because the disease is uncommon and has highly diverse presenting symptoms, early diagnosis is challenging. We herein report a case of probable sCJD diagnosed at a very early stage.
METHODS: A 61-year-old female patient had mild attention and memory problems for a few months that were noticed by her husband but did not bother her and did not affect her daily life activities. The first brain magnetic resonance imaging (MRI) at another hospital was normal, lacking diffusion-weighted imaging (DWI). Although the newly taken brain MRI without DWI was normal, the patient\'s husband brought his patient to our outpatient clinic because he continued to think that there was a difference in his wife\'s attention and memory. A neurological examination of the patient revealed almost normal findings. The neuropsychiatric evaluation of the patient was consistent with mild cognitive impairment. The patient\'s electroencephalography taken upon admission had no characteristic findings for CJD but showed generalized epileptiform activity. Therefore, the patient was hospitalized, and a second brain MRI, including DWI sequences, was performed. DWI displayed bilateral asymmetrical typical patterns of restricted diffusion. Cerebrospinal fluid 14-3-3 was positive, and total-tau was highly elevated. She had a diagnosis of probable sCJD at an early stage. Later, the patient developed progressive dementia, ataxia, seizures, and extrapyramidal symptoms, followed by mutism, and died.
CONCLUSIONS: Although there is no cure for CJD today, early diagnosis is essential, mainly because of its potential infectivity and for future planning. Diagnosing sCJD in its early stages is difficult. However, taking into account the observations of not only the patient\'s history but also their longterm partners in cognitive evaluations will be helpful in making an early and accurate diagnosis.

Prion diseases are caused by prions, which are proteinaceous infectious particles that have been identified as causative factors of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). Prion diseases are devastating neurodegenerative disorders in humans and many animals, including sheep, cows, deer, cats, and camels. Prion diseases are classified into sporadic and genetic forms. Additionally, a third, environmentally acquired category exists. This type includes kuru, iatrogenic CJD caused by human dura mater grafts or human pituitary-derived hormones, and variant CJD transmitted through food contaminated with bovine spongiform encephalopathy prions. Bovine spongiform encephalopathy and variant CJD have nearly been controlled, but chronic wasting disease, a prion disease affecting deer, is spreading widely in North America and South Korea and recently in Northern Europe. Recently, amyloid-beta, alpha-synuclein, and other proteins related to Alzheimer\'s disease, Parkinson\'s disease, and other neurodegenerative diseases were reported to have prion features such as transmission to animals. Amyloid-beta transmission to humans has been suggested in iatrogenic CJD cases and in cerebral amyloid angiopathy cases with cerebral bleeding occurring long after childhood neurosurgery with or without cadaveric dura mater transplantation. These findings indicate that diseases caused by various prions, namely various transmissible proteins, appear to be a threat, particularly in the current longevity society. Prion disease represented by CJD has obvious transmissibility and is considered to be an \"archetype of various neurodegenerative diseases\". Overcoming prion diseases is a top priority currently in our society, and this strategy will certainly contribute to elucidating pathomechanism of other neurodegenerative diseases and developing new therapies for them.

Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative spongiform encephalopathy that causes neuronal derangement secondary to prion protein. Its initial diagnosis is often complex and challenging due to non-specific clinical presentation, lack of awareness, and low clinical suspicion. This disease is invariably fatal, and most patients die within 12 months of presentation. Definite diagnosis of prion disease requires neuropathological analysis, usually done at autopsy. Here, we present the autopsy findings of a 57-year-old male patient, illustrating the complexity of diagnosing this disease early in the clinical course and the need for a broad differential diagnosis at the onset.

OBJECTIVE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data.
METHODS: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets.
RESULTS: Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD.
CONCLUSIONS: Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, ~1% were transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate focal initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of >5,000X across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a focal presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

Although the development of aggregation assays has noticeably improved the accuracy of the clinical diagnosis of prion diseases, research on biomarkers remains vital. The major challenges to overcome are non-invasive sampling and the exploration of new biomarkers that may predict the onset or reflect disease progression. This will become extremely important in the near future, when new therapeutics are clinically evaluated and eventually become available for treatment. This article aims to provide an overview of the achievements of biomarker research in human prion diseases, addresses unmet needs in the field, and points out future perspectives.

Authors are commenting on the evolving geographical incidence trends observed with the genetic form of Creutzfeldt-Jakob disease and discussing the diverse array of factors contributing to the heightened incidence rates observed in specific geographical regions.

OBJECTIVE: To systematically review the reported cases of Creutzfeldt-Jakob disease (CJD) in Iran.
METHODS: A comprehensive literature review of CJD cases in Iran was undertaken using the PubMed®, Scopus® and Google Scholar databases. In addition, the Iranian database MagIran was searched for Persian language reports. Case selection used the following criteria: (i) patients of Iranian origin; (ii) publication in peer-reviewed journals or reputable medical databases; (iii) a definitive diagnosis of CJD based on established diagnostic criteria.
RESULTS: Thirteen cases from twelve reports were included in this systematic review. The majority of the cases were female (11 of 13; 84.6%). The mean ± SD age of patients at hospital admission was 59.38 ± 7.44 years. The findings of the case review suggested that the prevalence of CJD in Iran is not fully established. CJD may be misdiagnosed alongside other clinical signs. The most prevalent early indications of the disease were psychiatric and neurological in nature. A considerable delay in diagnosis was observed in some cases and there was a shortage of brain autopsy records.
CONCLUSIONS: Efforts to improve diagnostic capabilities, promote awareness and establish monitoring systems are necessary for managing the challenges of providing an early diagnosis of CJD in Iran.