Sporadic Creutzfeldt-Jakob disease.

Being considered among the most fatal neurological conditions, Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by its unknown etiology and rapidly progressive neurodegenerative symptoms that often lead to a mean survival of 6 to 12 months. The accumulation of the prionic protein causes brain matter degeneration, which leads to a set of clinical findings that include rapidly progressive dementia, myoclonus, tremors, cerebellar ataxia, and extrapyramidal signs. This clinical presentation is non-specific, which makes CJD a very difficult condition to diagnose, due to the low level of clinical suspicion. However, combining this clinical presentation with neuroimaging, a lumbar puncture and an encephalogram will help us make the correct diagnosis. We present the case of a 57-year-old male presenting to the Emergency department with complaint of personality change and intermittent memory loss. The patient's physical exam was significant for resting pill roll tremor, bilateral cogwheel rigidity, dysmetria, and shuffling gait. Magnetic resonance imaging of his brain showed symmetric bilateral diffusion signal abnormality involving the cortex, bilateral caudate heads and putamina. Continuous electroencephalogram revealed multiple bifrontal delta discharges with triphasic morphology. Lumbar puncture was significant for presence of 14-3-3 protein in cerebrospinal fluid. The multiple examinations performed in conjunction with the previous findings supported the diagnosis of acute encephalopathy secondary to sporadic CJD.

Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases.

The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNPE200K, trisomy 21 (T21), and LRRK2G2019S, which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson's disease. We utilized no known disease/healthy COs (HC) as normal function controls. At 3-4 and 6-10 months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6-10 months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the HC, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na-K-Cl cotransport 1 (NKCC1) in Cl- homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the T21 COs only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations PRNPE200K, T21, and LRRK2G2019S significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance.

Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion.

Genetic prion disease accounts for 10-15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt-Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt-Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt-Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt-Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.

Stimulus-Induced Rhythmic or Periodic Intermittent Discharges (SIRPIDs) in patients with triphasic waves and Creutzfeldt-Jakob disease.

Since the term Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs) was introduced into the vocabulary of electrophysiologists/neurologists, there has been an ongoing debate about its significance, as well as its correlation with outcomes. SIRPIDs are frequently seen in patients who are critically ill from various causes. The literature reflects the findings of triphasic morphology, with the generalized periodic discharge (GPD) classification in many patients with SIRPIDs: toxic/metabolic encephalopathies, septic, and hypoxemic/hypercapnic encephalopathies, but also sharp periodic complexes in Creutzfeldt-Jakob disease and advanced Alzheimer's disease. In these settings, GPDs disappear when patients fall asleep and reappear when patients spontaneously wake up, or are awoken by an external stimulus, or sometimes because of a respiratory event, with the possibility of the appearance of GPDs with a cyclic alternating pattern. SIRPIDs may be seen as a transitional pattern between sleep and waking states, corresponding to a postarousal/awakening phenomenon. As SIRPIDs are a transient phenomenon and can usually be recorded repeatedly with each stimulation, the word "Ictal" could be replaced by "Intermittent": Stimulus-Induced Rhythmic or Periodic Intermittent Discharges. However, considering that SIRPIDs may be "potentially ictal" or on an "ictal-interictal continuum" in some situations, the "plus" modifier may be added: SIRPIDs-plus.

Case report of homozygous E200D mutation of PRNP in apparently sporadic Creutzfeldt-Jakob disease.

BACKGROUND: Inherited prion diseases are rare autosomal dominant disorders associated with diverse clinical presentations. All are associated with mutation of the gene that encodes prion protein (PRNP). Homozygous mutations with atypical clinical phenotypes have been described but are extremely rare. CASE PRESENTATION: A Chinese patient presented with a rapidly progressive cognitive and motor disorder in the clinical spectrum of sCJD. Investigations strongly suggested a diagnosis of CJD. He was found to carry a homozygous mutation at PRNP codon 200 (E200D), but there was no known family history of the disorder. The estimated allele frequency of E200D in East Asian populations is incompatible with it being a highly penetrant mutation in the heterozygous state. CONCLUSION: In our view the homozygous PRNP E200D genotype is likely to be causal of CJD in this patient. Homotypic PrP interactions are well known to favour the development of prion disease. The case is compatible with recessively inherited prion disease.

Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. METHODS: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. RESULTS: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. INTERPRETATION: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer's disease (Aß and tau), Parkinson's disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aß and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aß pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

A meta-analysis on RT-QuIC for the diagnosis of sporadic CJD.

Creutzfeld-Jakob disease (CJD) is a fatal neurodegenerative disease which belongs to the family of transmissible spongiform encephalopathies (TSEs), or prion diseases. Historically, CJD diagnosis has been based on the combination of clinical features and in vivo markers, including CSF protein assays, MRI and EEG changes. Brain-derived CSF proteins, such as 14-3-3, t-tau and p-tau have been largely used to support the diagnosis of probable CJD, although with certain limitations concerning sensitivity and specificity of these tests. More recently, a new method for the pre-mortem diagnosis of sporadic CJD has been developed, based on the ability of PrPsc to induce the polymerization of protease-sensitive recombinant PrP (PrPsen) into amyloid fibrils, and is known as Real-Time Quaking- Induced Conversion (RT-QuIC) assay allows the detection of > 1 fg of PrPsc in diluted CJD brain homogenate and a variety of biological tissues and fluids. In the present study, we did a meta-analysis on the liability of RT-QuIC method in the diagnosis of sporadic CJD, in comparison to 14-3-3 and Tau protein. Twelve studies were finally included in the statistical analysis which showed that RT-QuIC has a very high specificity and comparable sensitivity to 14-3-3 protein and Tau protein in the CSF, and hence can be used as a reliable biomarker for the diagnosis of sporadic CJD.

How common are seizures in the heidenhain variant of creutzfeldt-jakob disease? A case report and systematic review.

The Heidenhain variant of Creutzfeld-Jakob disease (HvCJD) is a relentlessly progressive and fatal neurodegenerative disorder characterised by prominent visual features early in its clinical course. However, seizures are uncommonly reported in HvCJD. The case history of a patient admitted to our institution with HvCJD and seizures is described followed by a systematic review of the association between HvCJD and seizures. A systematic search of the databases Medline, PubMed, and PsycInfo was conducted, from inception to November 2019, using keywords relating to 'Creutzfeldt-Jakob disease' and 'Heidenhain variant', to ascertain the frequency of seizures in HvCJD, as well as, seizure semiology and electrographic features. The Preferred Items Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in the construction of this systematic review. All studies, including case reports of patients who met the diagnostic criteria for HvCJD where details pertaining to clinical presentation, imaging, biochemical and EEG findings were available were included. There were 46 articles reporting on a total of 73 patients. Seizures occurred in only four out of 73 cases (5.5%). The semiology of these seizures were focal motor seizures with or without secondary generalisation and occipital lobe seizures. Imaging and electrographic findings were most commonly abnormal in the posterior cerebral cortices (in particular the occipital and occipito-parietal regions). This systematic review suggests that seizures are uncommon in HvCJD despite the frequency of imaging and electrographic abnormalities in the posterior cerebral regions. A key limitation of this systematic review is the variability of publications in terms of incomplete reporting of clinical data, in particular potential under-reporting of seizures, as well as follow up, which may have contributed to the lower frequency of seizures reported in patients with HvCJD.

Modelling neurodegenerative disease using brain organoids.

Neurodegenerative Diseases such as Alzheimer's Disease represent a major public health challenge, with no disease modifying therapies available. The availability of induced pluripotent stem cells from patients with phenotypes and genotypes of interest, that can be subsequently differentiated in vitro into disease-affected cell types, has revolutionised our ability to generate physiologically relevant disease models. The recent availability of brain organoids - self-organising in vitro tissue models - as enabled the generation of complex, multicellular systems to study brain development and disease. Although widely used for modelling neurodevelopment, early studies have demonstrated great promise in the use of organoids as models of neurodegenerative disease. Here, I will review recent progress to model neurodegenerative diseases using organoids and comment on future directions and challenges.

Atypical and early symptoms of sporadic Creutzfeldt - Jakob disease: case series and review of the literature.

BACKGROUND: Prion diseases are rapidly progressive fatal conditions caused by abnormally shaped proteins. Sporadic Creutzfeldt - Jakob disease (sCJD) is the most common human prion disorder accounting for 85-90 % of cases. Clinical manifestations include rapidly evolving dementia in conjunction with neurological symptoms such as ataxia, myoclonus, pyramidal and extrapyramidal signs. However, the early symptoms of the disease are often non-specific and mental disorder is delayed, making the diagnostic process difficult and challenging. PATIENTS AND METHODS: We present 3 cases with atypical early symptoms and late onset of cognitive decline. The first case presented with isolated visual symptoms (Heidenhain variant), the second patient had isolated anomic aphasia and the third one non-convulsive status epilepticus. A review of the past literature concerning the atypical and rare early clinical features of the sCJD was conducted. RESULTS: The following manifestations were found: psychiatric and visual symptoms, which are relatively common, epileptic seizures, otologic symptoms and presentation of sCJD as an acute vascular event. Moreover, language, communication and writing impairments, movement disorders, symptoms from the peripheral nervous system and bulbar signs were reported as well. CONCLUSION: Increased clinical suspicion, along with the aid of existing diagnostic methods and the development of novel techniques could contribute to a better understanding of the disease's pathophysiology, early and accurate diagnosis and improvement of patient management.

Status epiléptico refractario en enfermedad de Creutzfeldt-Jakob genética por mutación E200K / Refractory status epilepticus in genetic Creutzfeldt-Jakob disease with E200K mutation

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MM2-type sporadic Creutzfeldt-Jakob disease: new diagnostic criteria for MM2-cortical type.

OBJECTIVE: To clinically diagnose MM2-cortical (MM2C) and MM2-thalamic (MM2T)-type sporadic Creutzfeldt-Jakob disease (sCJD) at early stage with high sensitivity and specificity. METHODS: We reviewed the results of Creutzfeldt-Jakob disease Surveillance Study in Japan between April 1999 and September 2019, which included 254 patients with pathologically confirmed prion diseases, including 9 with MM2C-type sCJD (MM2C-sCJD) and 10 with MM2T-type sCJD (MM2T-sCJD), and 607 with non-prion diseases. RESULTS: According to the conventional criteria of sCJD, 4 of 9 patients with MM2C- and 7 of 10 patients with MM2T-sCJD could not be diagnosed with probable sCJD until their death. Compared with other types of sCJD, patients with MM2C-sCJD showed slower progression of the disease and cortical distribution of hyperintensity lesions on diffusion-weighted images of brain MRI. Patients with MM2T-sCJD also showed relatively slow progression and negative results for most of currently established investigations for diagnosis of sCJD. To clinically diagnose MM2C-sCJD, we propose the new criteria; diagnostic sensitivity and specificity to distinguish 'probable' MM2C-sCJD from other subtypes of sCJD, genetic or acquired prion diseases and non-prion disease controls were 77.8% and 98.5%, respectively. As for MM2T-sCJD, clinical and laboratory features are not characterised enough to develop its diagnostic criteria. CONCLUSIONS: MM2C-sCJD can be diagnosed at earlier stage using the new criteria with high sensitivity and specificity, although it is still difficult to diagnose MM2T-sCJD clinically.

Dressing Apraxia as Initial Manifestation of Creutzfeldt-Jakob Disease.

Background: Creutzfeldt-Jakob disease (CJD) is a rare prion disease characterized by rapidly progressive dementia. Case Report: A 76-year-old woman exhibited pronounced signs and symptoms of dressing apraxia for about seven weeks before the disease progressed and probable CJD was diagnosed supported by imaging and CSF findings. Discussion: Dressing apraxia as the initial manifestation of CJD has been sparsely reported. This remarkably focal syndrome should be considered with view on movement and neuropsychological disorders in early CJD.

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.

Serial evaluation of swallowing function in a long-term survivor of V180I genetic Creutzfeldt-Jakob disease.

Swallowing function in long-term survivors with Creutzfeldt-Jakob disease (CJD) remains unknown. Herein, we demonstrated serial evaluation of swallowing function in a case with V180I genetic CJD (gCJD) using videofluoroscopic examination of swallowing (VF). A 69-year-old woman was admitted to our hospital because of bradykinesia and memory disturbances 4 months after the onset of symptoms. Neurological examination revealed dementia, bradykinesia and frontal signs. Diffusion-weighted MRI revealed bilateral cortical hyperintensity in the frontal, temporal, and parietal cortices, and PRNP gene analysis indicated a V180I mutation. Her dysphagia gradually progressed, and she received percutaneous gastrostomy 42 months after the onset. VF was performed at 27, 31, 39, and 79 months after the onset. Although bolus transport from oral cavity to pharynx gradually worsened and initiation of the pharyngeal swallow was gradually delayed, the pharyngeal swallowing function was preserved even at 72 months after onset. MRI revealed no apparent atrophy of brainstem, and single photon emission computed tomography showed preserved regional cerebral blood flow in the brainstem. These findings suggest that the pathophysiology of dysphagia in a long-term survivor of V180I gCJD is that of pseudobulbar palsy, likely owing to preserved brainstem function even in the akinetic mutism state.

Sporadic Creutzfeldt-Jakob Disease: A Retrospective Analysis of 104 Cases.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD) is an extremely rare fatal and infectious neurodegenerative brain disorder characterized by rapidly progressive dementia, cerebellar ataxia, and visual disturbances. This article summarizes the retrospective analysis of 104 sCJD patients in the First Medical Center of Chinese PLA General Hospital from 2003 to 2019. METHODS: A retrospective analysis of the medical records of the 104 patients diagnosed with sCJD was performed from the aspects of demographic data, clinical manifestations, laboratory examinations, cerebrospinal fluid analysis, electroencephalograms (EEGs), diffusion-weighted imaging (DWI) scans, positron emission tomography (PET) scans, and prion protein gene mutations. RESULTS: In the 104 sCJD patients, pathological evidence of a spongiform change was found in 11 patients, while the remaining 93 patients were probable sCJD. The 104 patients included 57 males and 47 females, with the age of onset ranging from 29 to 82 (mean: 58, median: 60) years. The time from disease onset to death ranged from 1 to 36 months. Most of the patients died 7-12 months after the onset of sCJD. In most patients, rapidly progressive dementia appeared as the initial symptom, followed by cerebellar ataxia, visual disturbances, and neurobehavioral disorders. Most patients' DWI images showed symmetric or asymmetric hyperintensity in the cortex. In terms of EEGs, 38.2% of the patients had periodic sharp wave complexes. The sensitivity of 14-3-3 protein detection was 34.1%. The brain PET scans of 50 patients with sCJD presented 96% sensitivity for the diagnosis of sCJD. CONCLUSIONS: This study indicated that sCJD occurred at an early age in patients in China. The sensitivity of 14-3-3 protein detection was significantly low, but brain PET was highly sensitive in the diagnosis of sCJD.