Creutzfeldt-Jakob Disease with Initial Typical Parkinsonism Precipitated by COVID-19? A Case Report (preprint)

Background Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by the accumulation of PrPSc. While COVID-19-induced sporadic CJD (sCJD) with parkinsonism as the initial symptom is extremely uncommon, this report aims to raise awareness of sCJD cases that present with parkinsonism that are not associated with genetic mutations or pathological α-synuclein (α-Syn) accumulation. Case presentation This report presents the case of a 72-year-old man with probable sporadic Creutzfeldt-Jakob disease (sCJD) who initially showed symptoms of parkinsonism, which worsened rapidly after contracting COVID-19. Despite a history of responsive tremor and bradykinesia, his condition deteriorated following the viral infection, leading to rapid consciousness decline and diffuse myoclonus. Diagnostic tests, including brain MRI, cerebrospinal fluid analysis, and EEG, pointed towards prion disease. PrPSc, a marker for CJD, was detected in both the cerebrospinal fluid and skin samples using RT-QuIC, further confirming the diagnosis. Notably, skin analysis revealed PrPSc but no pathological α-synuclein deposits, ruling out typical Parkinson's disease.  Conclussion This case underscores the importance of considering sCJD in patients with parkinsonism, especially if they experience sudden neuropsychiatric symptoms, especially if they do not exhibit pathological α-Syn accumulation or have genetic mutations.

SARS-CoV-2 Spike amyloid fibrils specifically and selectively accelerates amyloid fibril formation of human prion protein and the amyloid β peptide (preprint)

An increasing number of reports suggest an association between COVID-19 infection and initiation or acceleration of neurodegenerative diseases including Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Both these diseases and several other neurodegenerative diseases are caused by conversion of human proteins into a misfolded, aggregated amyloid fibril state. The fibril formation process is self-perpetuating by seeded conversion from preformed fibril seeds. We recently described a plausible mechanism for amyloid fibril formation of SARS-CoV-2 spike protein. Spike-protein formed amyloid fibrils upon cleavage by neutrophil elastase, abundant in the inflammatory response to COVID-19 infection. We here provide evidence of significant Spike-amyloid fibril seeded acceleration of amyloid formation of CJD associated human prion protein (HuPrP) using an in vitro conversion assay. By seeding the HuPrP conversion assay with other in vitro generated disease associated amyloid fibrils we demonstrate that this is not a general effect but a specific feature of spike-amyloid fibrils. We also showed that the amyloid fibril formation of AD associated A{beta}1-42 was accelerated by Spike-amyloid fibril seeds. Of seven different 20-amino acid long peptides, Spike532 (532NLVKNKCVNFNFNGLTGTGV551) was most efficient in seeding HuPrP and Spike601 (601GTNTSNQVAVLYQDVNCTEV620) was most effective in seeding A{beta}1-42, suggesting substrate dependent selectivity of the cross-seeding activity. Albeit purely in vitro, our data suggest that cross-seeding by Spike-amyloid fibrils can be implicated in the increasing number of reports of CJD, AD, and possibly other neurodegenerative diseases in the wake of COVID-19.

Application of real-time quaking-induced conversion in Creutzfeldt-Jakob disease surveillance.

BACKGROUND: Evaluation of the application of CSF real-time quaking-induced conversion in Creutzfeldt-Jakob disease surveillance to investigate test accuracy, influencing factors, and associations with disease incidence. METHODS: In a prospective surveillance study, CSF real-time quaking-induced conversion was performed in patients with clinical suspicion of prion disease (2014-2022). Clinically or histochemically characterized patients with sporadic Creutzfeldt-Jakob disease (n = 888) and patients with final diagnosis of non-prion disease (n = 371) were included for accuracy and association studies. RESULTS: The overall test sensitivity for sporadic Creutzfeldt-Jakob disease was 90% and the specificity 99%. Lower sensitivity was associated with early disease stage (p = 0.029) and longer survival (p < 0.001). The frequency of false positives was significantly higher in patients with inflammatory CNS diseases (3.7%) than in other diagnoses (0.4%, p = 0.027). The incidence increased from 1.7 per million person-years (2006-2017) to 2.0 after the test was added to diagnostic the criteria (2018-2021). CONCLUSION: We validated high diagnostic accuracy of CSF real-time quaking-induced conversion but identified inflammatory brain disease as a potential source of (rare) false-positive results, indicating thorough consideration of this condition in the differential diagnosis of Creutzfeldt-Jakob disease. The surveillance improved after amendment of the diagnostic criteria, whereas the incidence showed no suggestive alterations during the COVID-19 pandemic.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2021.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2021. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2021, a total of 548 domestic CSF specimens were referred for 14-3-3 protein testing; 73 persons with suspected human prion disease were formally added to the national register. As of 31 December 2021, just over half of the 73 suspect case notifications (37/73) remain classified as 'incomplete'; 17 cases were classified as 'definite' and 13 as 'probable' prion disease; six cases were excluded through either detailed clinical follow-up (two cases) or neuropathological examination (four cases). For 2021, sixty-four percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia.

Creutzfeldt-Jakob disease after COVID-19: infection-induced prion protein misfolding? A case report.

Creutzfeldt-Jakob disease (CJD) is a rare, fatal disease presenting with rapidly progressive neurological deficits caused by the accumulation of a misfolded form (PrPSc) of prion protein (PrPc). Coronavirus disease 2019 (COVID-19) is a primarily respiratory syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); many diverse neurological complications have been observed after COVID-19. We describe a young patient developing CJD two months after mild COVID-19. Presenting symptoms were visuospatial deficits and ataxia, evolving into a bedridden state with preserved consciousness and diffuse myoclonus. Diagnostic work-up was suggestive of CJD. The early age of onset and the short interval between respiratory and neurological symptoms might suggest a causal relationship: a COVID-19-related neuroinflammatory state may have induced the misfolding and subsequent aggregation of PrPSc. The present case emphasizes the link between neuroinflammation and protein misfolding. Further studies are needed to establish the role of SARS-CoV-2 as an initiator of neurodegeneration.

Creutzfeldt-Jakob Disease complicated by Covid-19 : A Case Report and Differential Diagnoses (preprint)

Although sporadic Creutzfeldt Jakob disease is always fatal and no accepted treatment is currently available. Moreover, prevalence of COVID-19 in the same patient makes management protocol difficult and prognosis worse.

Impact of the COVID-19 pandemic on Creutzfeldt-Jakob disease surveillance and patient care in the United Kingdom.

BACKGROUND AND PURPOSE: Creutzfeldt-Jakob disease (CJD) is lethal and transmissible. We assessed the impact of the COVID-19 pandemic on UK CJD surveillance. We hypothesized that (i) disruptions prolonged diagnostic latency; (ii) autopsy rates declined; and (iii) COVID-19 infection negatively affected diagnosis, care, and survival. METHODS: We retrospectively investigated the first year of the pandemic, using the preceding year as a comparator, quantifying numbers of individuals assessed by the UK National CJD Research & Surveillance Unit for suspected CJD, time to diagnosis, disease duration, and autopsy rates. We evaluated the impact of COVID-19 status on diagnosis, care, and survival in CJD. RESULTS: A total of 148 individuals were diagnosed with CJD in the pandemic (from a total of 166 individuals assessed) compared to 141 in the comparator (from 145 assessed). No differences were identified in disease duration or time to diagnosis. Autopsy rates were unchanged. Twenty individuals had COVID-19; 60% were symptomatic, and 10% had severe disease. Disruptions in diagnosis and care were frequently identified. Forty percent of COVID-19-positive individuals died; however, COVID-19 status did not significantly alter survival duration in CJD. CONCLUSIONS: The COVID-19 pandemic has not impacted UK CJD case ascertainment or survival, but diagnostic evaluation and clinical care of individuals have been affected.

COVID-19-associated encephalitis or Creutzfeldt-Jakob disease: a case report.

Background: Accurate diagnosis and management of patients with rapidly progressive dementia may be challenging during the COVID-19 pandemic, which has negatively influenced the diagnostic performances, medical resource allocation and routine care for all non-COVID-19 diseases. Case presentation: We herein present a case of a 57-year-old male with rapidly progressive cognitive decline, headache, diplopia, myalgia, unsteady gait, aggression, depression, insomnia, hallucinations and delusions of persecution. COVID-19-associated encephalitis was briefly considered as a differential diagnosis. However, this hypothesis was rejected upon further investigation. A final diagnosis of sporadic Creutzfeldt-Jakob disease was made. Conclusion: A timely and accurate diagnosis of Creutzfeldt-Jakob disease gives patients and their families the chance to receive a good standard of healthcare and avoid extensive evaluations for other conditions.

COVID-19-associated immune-mediated encephalitis mimicking acute-onset Creutzfeldt-Jakob disease.

We report a subtype of immune-mediated encephalitis associated with COVID-19, which closely mimics acute-onset sporadic Creutzfeldt-Jakob disease. A 64-year-old man presented with confusion, aphasia, myoclonus, and a silent interstitial pneumonia. He tested positive for SARS-CoV-2. Cognition and myoclonus rapidly deteriorated, EEG evolved to generalized periodic discharges and brain MRI showed multiple cortical DWI hyperintensities. CSF analysis was normal, except for a positive 14-3-3 protein. RT-QuIC analysis was negative. High levels of pro-inflammatory cytokines were present in the CSF and serum. Treatment with steroids and intravenous immunoglobulins produced EEG and clinical improvement, with a good neurological outcome at a 6-month follow-up.

Creutzfeldt-Jakob disease as a cause of dementia.

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder belonging to the family of transmissible spongiform encephalopathies. The disease is believed to be caused by an abnormal isoform of a cellular glycoprotein known as the prion protein. Our patient is an 84-year-old Caucasian man who presented to the geriatric clinic for evaluation of short-term memory loss and decreased concentration which started 3 months prior to initial evaluation. Rapid progression of dementia demonstrated by severe impairment in tasks with a predominantly visual component, including visual scanning, perceptual reasoning and visual spatial processing. Diagnosis of CJD was determined by characteristic ribboning on brain MRI as well as notable real-time quaking-induced conversion on cerebrospinal fluid.

Application of telehealth for comprehensive Creutzfeldt-Jakob disease surveillance in the United Kingdom.

Creutzfeldt-Jakob disease (CJD) is a fatal human prion disease. Surveillance systems operate globally with the goals of accurate in-life case ascertainment, appropriate public health interventions to minimise secondary transmission, and monitoring trends in disease epidemiology. The UK experienced the highest incidence of variant CJD (vCJD) in the world following widespread population exposure to bovine spongiform encephalopathy (BSE). 178 cases of vCJD have been identified in the UK by the National CJD Research & Surveillance Unit (NCJDRSU), including three cases of secondary transmission via blood transfusion. The NCJDRSU performs high-fidelity surveillance, assessing all cases of suspected CJD referred to the unit. COVID-19 has caused widespread disruption to healthcare and poses a threat to services. The NCJDRSU converted to telehealth-based surveillance in March 2020. We report the results of the application of telehealth for comprehensive CJD surveillance during the first four months of the pandemic. 59 cases were assessed for suspected CJD. In 52 cases the relatives were interviewed for an informant history, by video conference or telephone call. 34 patients underwent video examination; 1 case was examined in-person. MRI images were assessed in all cases and 46 underwent CSF testing. Feedback was obtained from interviewees and the NCJDRSU team on their experiences. 50 cases were diagnosed with sporadic CJD; 5 received an alternative diagnosis, and the remaining 4 remained unresolved, with further investigations underway. Telehealth significantly reduced time taken to assessment compared to in-person assessments in 2019. Telehealth is an effective way to provide comprehensive CJD surveillance at a national level.

Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.