Prion最新文献

Fatal familial insomnia (FFI) is a rare autosomal dominant genetic neurodegenerative disease. Generally, FFI patients will develop rapidly progressive dementia, sleep disturbance, autonomic dysfunction, and so on. Cerebrospinal fluid examination of FFI patients normally shows no obvious abnormalities. Here, we report a young male patient who was diagnosed with FFI during the COVID-19 epidemic. Clinical symptoms include psychobehavioral abnormality, cognitive decline, sleep disturbance, and autonomic dysfunction. No abnormalities were found in routine examinations after admission. However, the number of white blood cells in the cerebrospinal fluid increased. Though the patient was treated with anti-infection and immunotherapy, the symptoms were not relieved. A lumbar puncture was performed again, and it was found that the total Tau protein in the cerebrospinal fluid was elevated, and PET results showed that brain metabolism decreased. Finally, a genetic test was used to confirm the diagnosis of FFI. This case suggests that patients with FFI may also have elevated white blood cells in cerebrospinal fluid and timely detection of Tau protein in cerebrospinal fluid is helpful for early identification of FFI. And precise diagnosis relies on genetic testing.

Prion diseases are fatal neurologic disorders that can be transmitted by blood transfusion. The route for neuroinvasion following exposure to infected blood is not known. Carotid bodies (CBs) are specialized chemosensitive structures that detect the concentration of blood gasses and provide feedback for the neural control of respiration. Sensory cells of the CB are highly perfused and densely innervated by nerves that are synaptically connected to the brainstem and thoracic spinal cord, known to be areas of early prion deposition following oral infection. Given their direct exposure to blood and neural connections to central nervous system (CNS) areas involved in prion neuroinvasion, we sought to determine if there were cells in the human CB that express the cellular prion protein (PrP^C), a characteristic that would support CBs serving as a route for prion neuroinvasion. We collected CBs from cadaver donor bodies and determined that mast cells located in the carotid bodies express PrP^C and that these cells are in close proximity to blood vessels, nerves, and nerve terminals that are synaptically connected to the brainstem and spinal cord.

Worldwide, 10-15% human prion disease are genetic and inherited, due to the special mutations or insertions in PRNP gene. Herein, we reported two Chinese patients with rapidly progressive dementia who were referred to the national Creutzfeldt-Jacob disease (CJD) surveillance as suspected CJD. Those two patients displayed sporadic CJD (sCJD)-like clinical phenotype, e.g. rapidly progressive dementia, visional and mental problems, sCJD-associated abnormalities in MRI. A missense mutation was identified in one PRNP allele of these two patients, resulting in a change from serine to asparagine at codon 97 (S97N). RT-QuIC of the cerebrospinal fluid samples from those two cases were positive. It indicates that they are very likely to be prion disease.

Genetic Creutzfeldt-Jakob disease (gCJD) is a prion disease caused by mutations in the prion protein gene (PRNP). It has an autosomal dominant inheritance, so gCJD with homozygous mutations is extremely rare, and the influence of homozygous mutations on the gCJD phenotype is unknown. We describe the clinical and laboratory features of a patient with a PRNP T188K homozygous mutation and perform a literature review of gCJD cases with PRNP homozygous mutations. The patient was presented with cerebellum symptoms, cognitive decline and visual disturbances. Auxiliary examinations revealed restricted diffusion in magnetic resonance imaging and glucose hypometabolism on ¹⁸Fluorodeoxyglucose-positron emission tomography. No periodic sharp wave complexes were detected in electroencephalography, and the cerebrospinal fluid 14-3-3 protein was negative. PRNP sequencing revealed the presence of a homozygous T188K variant. The patient died 15 months after disease onset. A literature review revealed PRNP V203I, E200K and E200D as the only three mutations reported as homozygous in gCJD. To the best of our knowledge, this is the first report of a gCJD patient with a PRNP T188K homozygous mutation. Although the clinical manifestations of our patient were similar to those with PRNP T188K heterozygous mutations, she presented with a slightly earlier onset and had a longer survival time. This is consistent with previous observations from patients with PRNP V203I and E200K homozygous mutations. Further studies are essential to clarify the influence of homozygous mutations on the gCJD phenotype.

We aimed to identify targets for neuropalliative care interventions in sporadic Creutzfeldt-Jakob disease by examining characteristics of patients and sources of distress and support among former caregivers. We identified caregivers of decedents with sporadic Creutzfeldt-Jakob disease from the University of California San Francisco Rapidly Progressive Dementia research database. We purposively recruited 12 caregivers for in-depth interviews and extracted associated patient data. We analysed interviews using the constant comparison method and chart data using descriptive statistics. Patients had a median age of 70 (range: 60-86) years and disease duration of 14.5 months (range 4-41 months). Caregivers were interviewed a median of 22  (range 11-39) months after patient death and had a median age of 59 (range 45-73) years. Three major sources of distress included (1) the unique nature of sporadic Creutzfeldt-Jakob disease; (2) clinical care issues such as difficult diagnostic process, lack of expertise in sporadic Creutzfeldt-Jakob disease, gaps in clinical systems, and difficulties with end-of-life care; and (3) caregiving issues, including escalating responsibilities, intensifying stress, declining caregiver well-being, and care needs surpassing resources. Two sources of support were (1) clinical care, including guidance from providers about what to expect and supportive relationships; and (2) caregiving supports, including connection to persons with experience managing Creutzfeldt-Jakob disease, instrumental support, and social/emotional support. The challenges and supports described by caregivers align with neuropalliative approaches and can be used to develop interventions to address needs of persons with sporadic Creutzfeldt-Jakob disease and their caregivers.

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.

Human prion diseases (PrDs) are a group of transmissible neurodegenerative diseases that can be clarified as sporadic, genetic and iatrogenic forms. In this study, we have analysed the time and geographic distributions of 2011 PrD cases diagnosed by China National Surveillance for Creutzfeldt-Jakob disease (CNS-CJD) since 2006, including 1792 sporadic CJD (sCJD) cases and 219 gPrD cases. Apparently, the cases numbers of both sCJD and gPrD increased along with the surveillance years, showing a stepping up every five years. The geographic distributions of the PrDs cases based on the permanent residences were wide, distributing in 30 out of 31 provincial-level administrative divisions in Chinese mainland. However, the case numbers in the provincial level varied largely. The provinces in the eastern part of China had much more cases than those in the western part. Normalized the case numbers with the total population each province revealed higher incidences in six provinces. Further, the resident and referring places of all PrD cases were analysed, illustrating a clear concentrating pattern of referring in the large metropolises. Five provincial-level administrative divisions reported more PrD cases from other provinces than the local ones. Particularly, BJ reported not only more than one-fourth of all PrDs cases in Chinese mainland but also 3.64-fold more PrDs cases from other provinces than its local ones. We believed that good medical resources, well-trained programmes and knowledge of PrDs in the clinicians and the CDC staffs contributed to well-referring PrD cases in those large cities.

Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP^C) into scrapie isoform (PrP^Sc) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP^C to PrP^Sc conversion, increasing PrP^Sc removal, and PrP^C stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro, only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.

Prion diseases are fatal and irreversible neurodegenerative diseases induced by the pathogenic form of the prion protein (PrP^Sc), which is converted from the benign form of the prion protein (PrP^C). These diseases are characterized by an extended asymptomatic incubation period accompanied by continuous conversion of PrP^C to PrP^Sc. However, to date, the mechanism governing the conversion to PrP^Sc in the initial stages of prion disease has not been fully elucidated. We collected transcriptome data from the hippocampus of wild-type mice and prion-infected mice at 8 weeks post injection from the Gene Expression Omnibus and analysed differentially expressed genes and related signalling biological process using bioinformatic tools. We identified a total of 36 differentially expressed genes, including 22 upregulated genes and 14 downregulated genes. In addition, we identified that the cilium-related biological process was enriched in the early stages of prion disease. Furthermore, up- and down-regulated genes were associated with cilium-related cellular components and synapse-related cellular components, respectively. To the best of our knowledge, our study was the first to observe the upregulation of cilium-related genes in the early stages of prion disease.