Novel method for classification of prion diseases by detecting PrPres signal patterns from formalin-fixed paraffin-embedded samples.

Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.

[Clinical characteristics and diagnostics of human spongiform encephalopathies: an update]. / Klinik und Diagnostik humaner spongiformer Enzephalopathien: ein Update.

Human spongiform encephalopathies are rare transmissible neurodegenerative diseases of the brain and the nervous system that are caused by misfolding of the physiological prion protein into a pathological form and its deposition in the central nervous system (CNS). Prion diseases include Creutzfeldt-Jakob disease (CJD, sporadic or familial), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Prion diseases can be differentiated into three etiological categories: spontaneous (sporadic CJD), inherited (familial CJD, FFI, and GSS) and acquired (variant CJD and iatrogenic CJD). Most cases occur sporadically. Prion diseases can lead to a variety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play a crucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. A causal treatment or specific therapeutic agents are not yet available. In general, a palliative therapeutic concept is indicated.

Development of statistical auto-segmentation method for diffusion restriction gray matter lesions in patients with newly diagnosed sporadic Creutzfeldt-Jakob disease.

Quantification of diffusion restriction lesions in sporadic Creutzfeldt-Jakob disease (sCJD) may provide information of the disease burden. We aim to develop an automatic segmentation model for sCJD and to evaluate the volume of disease extent as a prognostic marker for overall survival. Fifty-six patients (mean age ± SD, 61.2 ± 9.9 years) were included from February 2000 to July 2020. A threshold-based segmentation was used to obtain abnormal signal intensity masks. Segmented volumes were compared with the visual grade. The Dice similarity coefficient was calculated to measure the similarity between the automatic vs. manual segmentation. Cox proportional hazards regression analysis was performed to evaluate the volume of disease extent as a prognostic marker. The automatic segmentation showed good correlation with the visual grading. The cortical lesion volumes significantly increased as the visual grade aggravated (extensive: 112.9 ± 73.2; moderate: 45.4 ± 30.4; minimal involvement: 29.6 ± 18.1 mm3) (P < 0.001). The deep gray matter lesion volumes were significantly higher for positive than for negative involvement of the deep gray matter (5.6 ± 4.6 mm3 vs. 1.0 ± 1.3 mm3, P < 0.001). The mean Dice similarity coefficients were 0.90 and 0.94 for cortical and deep gray matter lesions, respectively. However, the volume of disease extent was not associated with worse overall survival (cortical extent: P = 0.07; deep gray matter extent: P = 0.12).

The Role of PET Imaging in Patients with Prion Disease: A Literature Review.

Prion diseases are rare, rapidly progressive, and fatal incurable degenerative brain disorders caused by the misfolding of a normal protein called PrPC into an abnormal protein called PrPSc. Their highly variable clinical presentation mimics various degenerative and non-degenerative brain disorders, making diagnosis a significant challenge for neurologists. Currently, definitive diagnosis relies on post-mortem examination of nervous tissue to detect the pathogenic prion protein. The current diagnostic criteria are limited. While structural magnetic resonance imaging (MRI) remains the gold standard imaging modality for Creutzfeldt-Jakob disease (CJD) diagnosis, positron emission tomography (PET) using 18fluorine-fluorodeoxyglucose (18F-FDG) and other radiotracers have demonstrated promising potential in the diagnostic assessment of prion disease. In this context, a comprehensive and updated review exclusively focused on PET imaging in prion diseases is still lacking. We review the current value of PET imaging with 18F-FDG and non-FDG tracers in the diagnostic management of prion diseases. From the collected data, 18F-FDG PET mainly reveals cortical and subcortical hypometabolic areas in prion disease, although fails to identify typical pattern or laterality abnormalities to differentiate between genetic and sporadic prion diseases. Although the rarity of prion diseases limits the establishment of a definitive hypometabolism pattern, this review reveals some more prevalent 18F-FDG patterns associated with each disease subtype. Interestingly, in both sporadic and genetic prion diseases, the hippocampus does not show significant glucose metabolism alterations, appearing as a useful sign in the differential diagnosis with other neurodegenerative disease. In genetic prion disease forms, PET abnormality precedes clinical manifestation. Discordant diagnostic value for amyloid tracers among different prion disease subtypes was observed, needing further investigation. PET has emerged as a potential valuable tool in the diagnostic armamentarium for CJD. Its ability to visualize functional and metabolic brain changes provides complementary information to structural MRI, aiding in the early detection and confirmation of CJD.

Creutzfeldt-Jakob disease and other prion diseases.

Prion diseases share common clinical and pathological characteristics such as spongiform neuronal degeneration and deposition of an abnormal form of a host-derived protein, termed prion protein. The characteristic features of prion diseases are long incubation times, short clinical courses, extreme resistance of the transmissible agent to degradation and lack of nucleic acid involvement. Sporadic and genetic forms of prion diseases occur worldwide, of which genetic forms are associated with mutations in PRNP. Human to human transmission of these diseases has occurred due to iatrogenic exposure, and zoonotic forms of prion diseases are linked to bovine disease. Significant progress has been made in the diagnosis of these disorders. Clinical tools for diagnosis comprise brain imaging and cerebrospinal fluid tests. Aggregation assays for detection of the abnormally folded prion protein have a clear potential to diagnose the disease in peripherally accessible biofluids. After decades of therapeutic nihilism, new treatment strategies and clinical trials are on the horizon. Although prion diseases are relatively rare disorders, understanding their pathogenesis and mechanisms of prion protein misfolding has significantly enhanced the field in research of neurodegenerative diseases.

Variably protease-sensitive prionopathy with methionine homozygosity at codon 129 in the prion protein gene.

Variably protease-sensitive prionopathy (VPSPr) is a recently characterised rare subtype of sporadic prion disease, mainly affecting individuals with valine homozygosity at codon 129 in the prion protein gene, with only seven methionine homozygote cases reported to date. This case presents clinical, neuropathological and biochemical features of the eighth VPSPr case worldwide with methionine homozygosity at codon 129 and compares the features with the formerly presented cases.The patient, a woman in her 70s, presented with cognitive decline, impaired balance and frequent falls. Medical history and clinical presentation were suggestive of a rapidly progressive dementia disorder. MRI showed bilateral thalamic hyperintensity. Cerebrospinal fluid real-time quaking-induced conversion was negative, and the electroencephalogram was unremarkable. The diagnosis was established through post-mortem pathological examinations. VPSPr should be suspected in rapidly progressive dementia lacking typical features or paraclinical results of protein misfolding diseases.

Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone.

Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aß) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aß as the root cause of AD. We previously reported human transmission of Aß pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt-Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aß seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aß can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aß assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.

Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden.

The development of in vitro seed amplification assays (SAA) detecting misfolded alpha-synuclein (αSyn) in cerebrospinal fluid (CSF) and other tissues has provided a pathology-specific biomarker for Lewy body disease (LBD). However, αSyn SAA diagnostic performance in early pathological stages or low Lewy body (LB) pathology load has only been assessed in small cohorts. Moreover, the relationship between SAA kinetic parameters, the number of αSyn brain seeds and the LB pathology burden assessed by immunohistochemistry has never been systematically investigated. We tested 269 antemortem CSF samples and 138 serially diluted brain homogenates from patients with and without neuropathological evidence of LBD in different stages by the αSyn Real-Time Quaking-Induced Conversion (RT-QuIC) SAA. Moreover, we looked for LB pathology by αSyn immunohistochemistry in a consecutive series of 604 Creutzfeldt-Jakob disease (CJD)-affected brains. αSyn CSF RT-QuIC showed 100% sensitivity in detecting LBD in limbic and neocortical stages. The assay sensitivity was significantly lower in patients in early stages (37.5% in Braak 1 and 2, 73.3% in Braak 3) or with focal pathology (50% in amygdala-predominant). The average number of CSF RT-QuIC positive replicates significantly correlated with LBD stage. Brain homogenate RT-QuIC showed higher sensitivity than immunohistochemistry for the detection of misfolded αSyn. In the latter, the kinetic parameter lag phase (time to reach the positive threshold) strongly correlated with the αSyn seed concentration in serial dilution experiments. Finally, incidental LBD prevalence was 8% in the CJD cohort. The present results indicate that (a) CSF RT-QuIC has high specificity and sufficient sensitivity to detect all patients with LB pathology at Braak stages > 3 and most of those at stage 3; (b) brain deposition of misfolded αSyn precedes the formation of LB and Lewy neurites; (c) αSyn SAA provides "quantitative" information regarding the LB pathology burden, with the lag phase and the number of positive replicates being the most promising variables to be used in the clinical setting.

Personalized brain MRI revealed distinct functional and anatomical disruptions in Creutzfeldt-Jakob disease and Alzheimer's disease.

AIMS: Creutzfeldt-Jakob disease (CJD) is a lethal neurodegenerative disorder, which leads to a rapidly progressive dementia. This study aimed to examine the cortical alterations in CJD, changes in these brain characteristics over time, and the differences between CJD and Alzheimer's disease (AD) that show similar clinical manifestations. METHODS: To obtain reliable, subject-specific functional measures, we acquired 24 min of resting-state fMRI data from each subject. We applied an individual-based approach to characterize the functional brain organization of 10 patients with CJD, 8 matched patients with AD, and 8 normal controls. We measured cortical atrophy as well as disruption in resting-state functional connectivity (rsFC) and then investigated longitudinal brain changes in a subset of CJD patients. RESULTS: CJD was associated with widespread cortical thinning and weakened rsFC. Compared with AD, CJD showed distinct atrophy patterns and greater disruptions in rsFC. Moreover, the longitudinal data demonstrated that the progressive cortical thinning and disruption in rsFC mainly affected the association rather than the primary cortex in CJD. CONCLUSIONS: CJD shows unique anatomical and functional disruptions in the cerebral cortex, distinct from AD. Rapid progression of CJD affects both the cortical thickness and rsFC in the association cortex.

Pathological findings in autoimmune encephalitis autopsy specimens from cases of suspected prion disease.

OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.

Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

[Sporadic Creutzfeldt-Jakob Disease With Slow Progression:Report of One Case].

Sporadic Creutzfeldt-Jakob disease(sCJD)is a prion-caused degenerative disease of the central nervous system,with the typical clinical manifestation of rapidly progressive dementia.The course of disease is less than 1 year in most patients and more than 2 years in only 2% to 3% patients.We reported a case of sCJD with expressive language disorder and slow progression in this paper.By summarizing the clinical manifestations and the electroencephalograhpy,MRI,and pathological features,we aimed to enrich the knowledge about the sCJD with slow progression.

Misdiagnosis of rarest subtype of sporadic Creutzfeldt Jakob Disease: a case report.

BACKGROUND: Creutzfeldt-Jakob disease (CJD), is a deadly degenerative condition of the central nervous system marked by rapidly progressive dementia. Magnetic resonance imaging (MRI) abnormalities in the cerebral cortex, basal ganglia, thalamus, and cerebellum could indicate severe acute diseases caused by a variety of factors. Although their MRI patterns may resemble those of CJD, clinical history, additional MRI findings, and laboratory testing are all necessary to provide a reliable difference. Here, we report a misdiagnosed case of probable VV1 subtype of sporadic CJD (sCJD) in which follow-up MRI supported the diagnosis. CASE PRESENTATION: A 41-year-old male patient attended the Neuropsychiatry Department with rapidly progressive dementia, akinetic mutism, and difficulty walking and speaking. His problem began with forgetfulness, disorganized behavior, and disorganized speech 7 months earlier which progressed rapidly and was accompanied by aphasia, apraxia, agnosia, and akinetic mutism in the last 2 months. On neurologic examination, hypertonia, hyperreflexia, frontal ataxia, bradykinesia, gait apraxia, and aphasia were noted. Based on clinical features and rapid symptoms progression the likely diagnosis of CJD was suspected. MRI and electroencephalography (EEG) were advised. MRI revealed features of diffuse cortical injury of both cerebral hemispheres also involving bilateral corpus striatum with evidence of cerebral volume loss. EEG showed lateralized periodic theta slow waves on the right side. According to the CDC's diagnostic criteria for CJD, the diagnosis of probable sCJD was established. Supportive care and symptomatic treatment are provided for the patient. After a 1-month follow up the patient's condition deteriorated significantly. The time-lapse from the first reported symptom to death was about 13 months. CONCLUSION: The need of addressing CJD in patients presenting with rapidly progressive dementia is highlighted in this case report. In the early stages of the disease, interpretation of MRI results might cause diagnostic difficulties; therefore, follow-up MRI is critical in obtaining the correct diagnosis.

Human prion disease: molecular pathogenesis, and possible therapeutic targets and strategies.

INTRODUCTION: Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP) aggregation and self-propagation. Despite their rarity, prion diseases comprise a broad spectrum of phenotypic variants determined at the molecular level by different conformers of misfolded PrP and host genotype variability. Moreover, they uniquely occur in idiopathic, genetically determined, and acquired forms with distinct etiologies. AREA COVERED: This review provides an up-to-date overview of potential therapeutic targets in prion diseases and the main results obtained in cell and animal models and human trials. The open issues and challenges associated with developing effective therapies and informative clinical trials are also discussed. EXPERT OPINION: Currently tested therapeutic strategies target the cellular PrP to prevent the formation of misfolded PrP or to favor its elimination. Among them, passive immunization and gene therapy with antisense oligonucleotides against prion protein mRNA are the most promising. However, the disease's rarity, heterogeneity, and rapid progression profoundly frustrate the successful undertaking of well-powered therapeutic trials and patient identification in the asymptomatic or early stage before the development of significant brain damage. Thus, the most promising therapeutic goal to date is preventing or delaying phenoconversion in carriers of pathogenic mutations by lowering prion protein expression.

Real-time quaking-induced conversion assay using a small-scale substrate production workflow for the diagnosis of Creutzfeldt-Jakob disease.

The lack of a dedicated surveillance program for prion disease, particularly in low- and middle-income countries (LMICs), has hindered the global effort to address this public health threat. Although cerebrospinal fluid (CSF) Real-time quaking-induced conversion (RT-QuIC) is considered the most reliable test for sporadic Creutzfeldt-Jakob disease (sCJD), its availability in LMICs is limited because of its cost and technical difficulty in generating the recombinant prion protein substrate (recPrP). This study aimed to evaluate the performance of RT-QuIC with recPrP produced in-house through a small-scale method-that is, the application of reusable prepacked chromatography columns and subsequent dialysis. Here, CSF specimens from patients suspected of having prion disease were consecutively collected and stored between October 2015 and January 2023. Electronic medical record data were reviewed to clinically classify participants as probable sCJD or non-sCJD. CSF RT-QuIC was performed using in-house recPrP. Its specificity and sensitivity for diagnosing probable sCJD were reported, along with details of other clinical data and investigations. We found that among 39 eligible participants, with a median (interquartile range) age of 64 (56-70) years and 16 (41%) female, 13 had probable sCJD and the remaining 26 unequivocally suffered from nonprion disorders. Magnetic resonance imaging and electroencephalogram were suggestive of sCJD in 100% (13/13) and 46.2% (6/13) of sCJD participants, respectively. RT-QuIC was positive in 12/13 sCJD participants (sensitivity 0.92, 95% confidence interval [CI] 0.67-0.99) and negative in all non-sCJD participants (specificity 1.00, 95% CI 0.87-1.00). CSF tau/p-tau ratio showed sensitivity and specificity of 0.62-1.0 and 0.85-1.0, respectively. In summary, RT-QuIC using recPrP generated through a small-scale workflow demonstrated great performance in detecting sCJD. Given its performance results along with its low cost, this technique could feasibly be implemented in LMICs and potentially be the first step toward establishing local prion disease surveillance programs.

A novel subtype of sporadic Creutzfeldt-Jakob disease with PRNP codon 129MM genotype and PrP plaques.

The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt-Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrPD type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrPD T1 mimic those of sCJDMM1, the most common human prion disease. Here, we describe the clinical features, histopathology, and molecular properties of two distinct PrP plaque phenotypes affecting the gray matter (pGM) or the white matter (pWM) of sCJD cases with the PrP 129MM genotype (sCJDMM). Prevalence of pGM- and pWM-CJD proved comparable and was estimated to be ~ 0.6% among sporadic prion diseases and ~ 1.1% among the sCJDMM group. Mean age at onset (61 and 68 years) and disease duration (~ 7 months) of pWM- and pGM-CJD did not differ significantly. PrP plaques were mostly confined to the cerebellar cortex in pGM-CJD, but were ubiquitous in pWM-CJD. Typing of resPrPD T1 showed an unglycosylated fragment of ~ 20 kDa (T120) in pGM-CJD and sCJDMM1 patients, while a doublet of ~ 21-20 kDa (T121-20) was a molecular signature of pWM-CJD in subcortical regions. In addition, conformational characteristics of pWM-CJD resPrPD T1 differed from those of pGM-CJD and sCJDMM1. Inoculation of pWM-CJD and sCJDMM1 brain extracts to transgenic mice expressing human PrP reproduced the histotype with PrP plaques only in mice challenged with pWM-CJD. Furthermore, T120 of pWM-CJD, but not T121, was propagated in mice. These data suggest that T121 and T120 of pWM-CJD, and T120 of sCJDMM1 are distinct prion strains. Further studies are required to shed light on the etiology of p-CJD cases, particularly those of T120 of the novel pGM-CJD subtype.

V180I genetic Creutzfeldt-Jakob disease: Severe degeneration of the inferior olivary nucleus in an autopsied patient with identification of the M2T prion strain.

Genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation (V180I gCJD) is the most common type of gCJD in Japan, characterized by an older age at onset, slower progression, and moderate to severe cortical degeneration with spongiform changes and sparing of the brainstem and cerebellum. Degeneration of the inferior olivary nucleus (IO) is rarely observed in patients with CJD but is known to occur in fatal familial insomnia (FFI) and MM2-thalamic-type sporadic CJD (sCJD-MM2T) involving type 2 prion protein (M2T prion). Here we report on an 81-year-old Japanese woman who initially developed depressive symptoms followed by progressive cognitive impairment, myoclonus, and hallucinations and died after a clinical course of 23 months. Insomnia was not evident. Genetic analysis of the prion protein (PrP) identified a V180I mutation with methionine/valine heterozygosity at codon 129. Pathologic analysis demonstrated extensive spongiform degeneration, neuronal loss in the cortices, and weak synaptic-type PrP deposition. Except for IO degeneration, the clinicopathologic features and Western blotting PrP band pattern were compatible with those of previously reported V180I gCJD cases. Quantitative analysis revealed that the neuronal density of the IO, especially in the dorsal area, was considerably reduced to the same extent as that of a patient with sCJD-MM2T but preserved in other patients with V180I gCJD and sCJD-MM1 (this patient, 2.3 ± 0.53/mm2 ; a patient with sCJD-MM2T, 4.2 ± 2; a patient with V180I gCJD, 60.5 ± 9.3; and a patient with sCJD-MM1, 84.5 ± 17.9). Use of the protein misfolding cyclic amplification (PMCA) method confirmed the presence of the M2T prion strain, suggesting that the latter might be associated with IO degeneration in V180I gCJD. Autopsy studies are necessary to better understand the nature of CJD, since even if patients present with the common clinical picture, pathologic analysis might provide new insights, as was the case here.

An autopsy case of variably protease-sensitive prionopathy with Met/Met homogeneity at codon 129.

The typical clinical manifestations of sporadic Creutzfeldt-Jakob disease (sCJD) are rapid-progressive dementia and myoclonus. However, the diagnosis of atypical sCJD can be challenging due to its wide phenotypic variations. We report an autopsy case of variably protease-sensitive prionopathy (VPSPr) with Met/Met homogeneity at codon 129. An 81-year-old woman presented with memory loss without motor symptoms. Seventeen months after the onset, her spontaneous language production almost disappeared. Diffusion-weighted images (DWI) showed hyperintensity in the cerebral cortex while electroencephalogram (EEG) showed nonspecific change. 14-3-3 protein and real-time qualing-induced conversion (RT-QuIC) of cerebrospinal fluid were negative. She died at age 85, 3.5 years after the onset. Pathological investigation revealed spongiform change, severe neuronal loss, and gliosis in the cerebral cortex. Mild to moderate neuronal loss and gliosis were observed in the basal ganglia. PrP immunostaining revealed plaque-like, dotlike, and synaptic structures in the cerebral cortex and small plaque-like structures in the molecular layer of the cerebellum. Analysis of PRNP showed no pathogenic mutations, and Western blot examination revealed the lack of a diglycosylated band consistent with VPSPr. The present case, which is the first report on a VPSPr case in Japan, supports previously published evidence that VPSPr cases can present variable and nonspecific clinical presentations. Because a small number of VPSPr cases can show typical magnetic resonance imaging (MRI) change in sCJD. We should investigate the possibility of VPSPr in a differential diagnosis with atypical dementia that presented DWIs of high intensity in the cortex, even though 14-3-3 proteins and RT-QuIC are both negative. In addition, VPSPr cases can take a longer clinical course compared to that of sCJD, and long-term follow-up is important.

Cerebral cortex swelling in V180I genetic Creutzfeldt-Jakob disease: comparative imaging study between sporadic and V180I genetic Creutzfeldt-Jakob disease in the early stage.

The most common genetic Creutzfeldt-Jakob disease (gCJD) in Japan is caused by a point mutation in which isoleucine replaces valine at codon 180 of the prion protein (PrP) gene (V180I gCJD). Evidence suggests that cerebral cortex swelling, which appears as abnormal hyperintensities on diffusion-weighted imaging (DWI), is a characteristic magnetic resonance imaging (MRI) finding of V180I gCJD. However, no study has directly compared the MRI findings between V180I gCJD and sporadic CJD (sCJD). The current study, therefore, aims to clarify the imaging features of V180I gCJD, which would lead to prompt genetic counselling and analysis of the PrP gene, particularly focusing on cerebral cortex swelling. We included 35 patients with sCJD (n = 23) or V180I gCJD (n = 12). Cerebral cortex swelling on T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) wherein abnormal cortical hyperintensities were observed on DWI, and the distribution of grey matter hyperintensities on DWI were visually evaluated. V180I gCJD patients had significantly more cerebral cortex swelling (100% vs. 13.0%, p < 0.001), an overall correct classification of 91.4%, and parahippocampal gyrus hyperintensities on DWI (100% vs. 39.1%, q = 0.019) than sCJD patients. Cerebral cortical hyperintensities on DWI with swelling on T2WI or FLAIR are characteristic imaging findings of V180I gCJD and are useful for differentiating it from sCJD.

The natural history study of preclinical genetic Creutzfeldt-Jakob Disease (CJD): a prospective longitudinal study protocol.

BACKGROUND: Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrPsc), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion. METHODS: The study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an "in-depth" visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a "brief" visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one "in-depth" visit, similar to the baseline visit of healthy relatives. DISCUSSION: This continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions. TRIAL REGISTRATION: The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.