Creutzfeldt-Jakob Research Articles

"By the Time We Knew …": Poetic Analysis of End-of-Life Caregiving Experiences for Rapidly Progressive and Slower-Duration Dementia Syndromes.

One in three older adults in the United States dies with or from dementia. Little is known about whether end-of-life caregiving experiences differ by dementia diagnosis. We conducted a secondary analysis of two qualitative studies. Participants included caregivers of decedents with "rapid-type" sporadic Creutzfeldt-Jakob Disease (sCJD, survival prognosis of < 1 year) or "slow-type" Alzheimer's disease and related dementias (survival prognosis of 5-20 years). We used reflexive thematic analysis and a novel method, poetic analysis, to compare end-of-life caregiving experiences. "Rapid-type" caregivers (n = 12) had a median age of 59 (range 45-73) years; 6 were female, and 9 were spouses. "Slow-type" caregivers (n = 15) had a median age of 69 (45-82) years; 9 were female, and 11 were spouses. We identified three main areas of differential experience that were influenced by syndrome rarity and participation in research yet hinged on time. Time enables preparation: Due to the rarity of sCJD, "rapid-type" caregivers struggled to obtain accurate diagnoses, which prevented preparation for end-of-life care. Weeks or months before death, specialists simultaneously disclosed sCJD diagnoses and recommended hospice. In contrast, for "slow-type" dementia, preparation began years before death. Time complicates conflict: Most "rapid-type" caregivers described conflicts, rarely resolved before death, about code status, treatment, or care location decisions. Fewer "slow-type" caregivers experienced such conflicts, and these were typically resolved before death; instead, they experienced conflict between needs and what the care system provides. Postmortem experience contrasts with perimortem: For "rapid-type" dementia, short perimortem periods contrasted with elongated and often intense postmortem logistics and grief. For "slow-type" caregivers, preparation and perimortem grieving typically led to shorter duration and minimally intrusive postmortem logistics and grief. End-of-life care for dementia should attend to and support axes of differential experience based on diagnosis and rarity, time since symptom onset (affecting preparation and conflict resolution), and participation in research studies.

Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.

Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study (GWAS) summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies (TWAS & PWAS) and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline on the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself and beyond the previously highlighted sCJD risk loci through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis.

Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.

The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.

Association of Glymphatic Function With Clinical Characteristics in Patients With Clinical and Asymptomatic Creutzfeldt-Jakob Disease.

Abnormal glymphatic system-related proteins have been identified in a small-scale pathologic study of patients with Creutzfeldt-Jakob disease (CJD). However, it remains unclear whether glymphatic dysfunction occurs in vivo in patients with CJD and whether this decline begins during the preclinical stage. This study aimed to investigate the relationship between glymphatic dysfunction and clinical characteristics in patients with CJD, as well as potential glymphatic impairment in preclinical CJD. This prospective cohort study recruited patients with CJD and healthy controls (HCs) from the Department of Neurology at Xuanwu Hospital, Capital Medical University, Beijing, China, from 2018 to 2022. In addition, a family with preclinical genetic CJD carrying the G114V pathogenic variant was followed over 6 years with 3 evaluations. All participants underwent diffusion tensor imaging along the perivascular space (DTI-ALPS) to measure glymphatic function in vivo and 18F-fludeoxyglucose-PET to identify CJD-related metabolic patterns. Associations between the DTI-ALPS index and Medical Research Council Prion Disease Rating Scale (MRC-PDRS) score were evaluated using multiple linear regression. We enrolled 35 patients with CJD (mean age 59.6 ± 10.7 years, 40% female, with the time from onset to glymphatic dysfunction assessment averaging 39% of the total disease course), 28 age-matched and sex-matched HCs, and a family with preclinical genetic CJD consisting of 7 carriers and 7 noncarriers. Patients with CJD exhibited lower DTI-ALPS values compared with HCs (p < 0.001). Partial correlation analyses revealed significant correlations between the DTI-ALPS index and MRC-PDRS score (r = 0.346, p = 0.049) and disease progression (r = -0.468, p = 0.006), but not with disease duration or cognitive severity after adjusting for age and sex. Multivariate linear analysis demonstrated that poorer MRC-PDRS scores (β = 0.702, p = 0.014) were associated with a lower DTI-ALPS index. The DTI-ALPS index of asymptomatic G114V carriers showed no significant difference compared with noncarriers. However, a preclinical CJD case exhibited an 8.2% decrease in the DTI-ALPS index 3.3 years before onset. No significant correlation was found between regional metabolic standardized uptake value ratios and DTI-ALPS index. Our study indicates that glymphatic dysfunction is associated with CJD severity and disease progression. Glymphatic dysfunction may occur in the preclinical stage, but these findings should be interpreted with caution because they are based on individual findings.

Demyelinating neuropathy as the initial presentation of familial E200K Creutzfeldt-Jakob disease in two patients.

To describe peripheral neuropathy associated with familial Creutzfeldt-Jakob disease. We report two unrelated patients with genetic Creutzfeldt-Jakob disease with demyelinating peripheral neuropathy as initial presentation, with a comprehensive clinical, electrophysiological and neuropathological description. Both patients exhibited gait disturbance and paresthesia. Electrodiagnostic studies revealed demyelinating abnormalities with motor conduction blocks suggestive of chronic inflammatory demyelinating polyradiculoneuropathy, with abnormal plexus MRI and elevated CSF protein levels. One of them had pes cavus and a late-onset Charcot-Marie-Tooth (CMT) disease was also initially hypothesized. Central nervous system involvement manifested 1-2 years after the onset of peripheral symptoms. Both patients had a heterozygous E200K mutation in the PRNP gene. Postmortem neuropathological examinations showed PrPSc deposits in the peripheral nervous system, particularly in Schwann cells. Peripheral neuropathy in E200K genetic forms of Creutzfeldt-Jakob disease can be inaugural and mimic chronic inflammatory demyelinating polyradiculoneuropathy.

Evidence Suggesting That Alzheimer's Disease May Be a Transmissible Disorder.

Alzheimer's disease (AD) is characterised by progressive neurodegeneration with the formation of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain parenchyma. The causes of AD have been attributed to a combination of age-related changes within the brain as well as genetic, environmental and lifestyle factors. However, a recent study by Banerjee et al. highlights the possibility that AD may be a transmissible disease and that iatrogenic AD could be environmentally acquired, similar to iatrogenic Creutzfeldt-Jakob disease (iCJD). The study reports that contaminated Aβ in cadaver-derived pituitary growth hormone (c-hGH) therapy, which patients received during childhood inoculation, may accidentally transmit into their brains, triggering neurodegeneration and AD onset in older age. Furthermore, corroborating evidence from various animal model studies and human case reports suggests that AD can be potentially transmissible.

Rapid Neurological Decline due to Creutzfeldt-Jakob Disease.

Creutzfeldt-Jakob Disease (CJD) is an exceedingly rare condition with an incidence of one case per million people worldwide. It is diagnosed with symptoms of rapid neurological decline, positive CSF biomarkers, and diagnostic findings on MRI and EEG. There is no known effective therapy for CJD and prompt diagnosis is required to prepare for the expected disease prognosis and goals of care discussions.

Preanalytical Considerations of Handling Suspected Creutzfeldt-Jakob Disease Specimens Within the Clinical Pathology Laboratories: A Survey-Based Approach.

Background: Creutzfeldt-Jakob disease (CJD) is a rare, fatal, and transmissible neurodegenerative disorder caused by prion proteins. Handling specimens from individuals with suspected or confirmed cases presents a safety challenge to hospital workers including clinical laboratory staff. As no national guidelines exist, the clinical pathology laboratory must establish protocols for handling these specimens to ensure sufficient protective measures. This study aims to explore how various medical institutions manage CJD specimens, as a first step toward developing standardized preanalytical protocols for safe specimen handling by health care professionals. Methods: An electronic survey was generated and disseminated to diplomats of the American Board of Clinical Chemistry and was posted on the Listserv platform of the American Society for Microbiology and the Artery forum of the Association for Diagnostics and Laboratory Medicine. The survey evaluated various procedures and precautions implemented, the nature of the specimens processed, and whether they are processed in-house or sent to reference laboratories. Results: A total of 49 responses were collected. Most respondents (64%) noted their laboratories process specimens with a clinical suspicion of CJD regardless of the level of suspicion, 13% handled specimens only if the degree of suspicion was low, and 16% did not process specimens in-house at all. Among those who process CJD specimens, practices varied greatly, including different levels of precautions, use of biological safety cabinets, aliquoting, disposal, and disinfection procedures. Conclusions: A lack of standardization across laboratories exists for the handling of specimens of patients with suspected CJD. This study summarizes the approaches reported by survey respondents, providing a rationale for developing protocols for the safe handling of these specimens and highlighting the need to develop uniform universal standardized processing procedures.

Detection of brain MRI abnormalities before symptom onset in case of Creutzfeldt–Jakob disease with compound heterozygous PRNP mutation (V180I/M232R)

In an 81-year-old man, brain diffusion-weighted MRI revealed punctate high-intensity lesions in the bilateral frontal cortex. Three months later, these lesions had extended into the cerebral cortices. Six months after the original MRI, the patient developed cognitive decline. Clinically, he appeared to have Creutzfeldt-Jakob disease (CJD) based on brain MRI and cerebrospinal fluid examination findings. We identified a compound heterozygous mutation (V180I/M232R) in PRNP and diagnosed him with genetic CJD. This case of CJD with a compound heterozygous PRNP mutation had a relatively old onset, slowly progressive course, and low frequency of periodic synchronous discharges. Additionally, we detected CJD-associated brain MRI abnormalities before symptom onset. Reports of presymptomatic CJD such as the present case are important for the development of new therapeutic agents for CJD.

Reconfigured metabolism brain network in asymptomatic Creutzfeldt-Jakob disease.

Investigating brain metabolic networks is crucial for understanding the pathogenesis and functional alterations in Creutzfeldt-Jakob disease (CJD). However, studies on presymptomatic individuals remain limited. This study aimed to examine metabolic network topology reconfiguration in asymptomatic carriers of the PRNP G114V mutation. Seven asymptomatic PRNP G114V mutation carriers from a familial genetic CJD (gCJD) cohort, 43 CJD patients, and 35 healthy controls were included. All participants underwent neuropsychological assessments, genetic testing, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI scans. Voxel-based gray matter volume and FDG PET standardized uptake value ratios (SUVRs) were analyzed between asymptomatic PRNP G114V mutation carriers and healthy controls and between CJD patients and controls. Graph theory and sparse inverse covariance estimation (SICE) were used to assess the whole-brain metabolic connectomes and topological properties. Spatial independent component analysis (ICA) was used to evaluate subnetworks, including the default mode network (DMN), salience network (SN), and central executive network (CEN). With respect to global properties, assortativity was significantly increased in asymptomatic carriers, which was consistent with the findings in CJD patients. We revealed lost hubs in the right anterior cingulate, left ventral prefrontal lobe, left parahippocampal gyrus, and left lingual gyrus and reconfigured hubs in prefrontal lobes, including right ventromedial prefrontal cortex, right anterior prefrontal cortex, and right middle frontal gyrus of the orbit in asymptomatic carriers compared with healthy controls, which overlapped with the comparisons between CJD patients and controls. Alterations in the local parameters and metabolic connectivity in the left parahippocampal gyrus were most pronounced. Among the subnetworks, asymptomatic carriers presented higher assortativity and lower hierarchy in the SN, whereas the global parameters of the DMN and CEN were not significantly altered. The DMN and SN showed partial hypoconnectivity and hyperconnectivity, whereas the CEN mainly showed significantly enhanced connectivity in asymptomatic PRNP carriers. This study revealed altered brain metabolic topology and connectomics in asymptomatic PRNP G114V mutation carriers, which could be detected before gray matter or regional metabolic changes, suggesting that metabolism topology reconfiguration may serve as a sensitive imaging biomarker for investigating early CJD pathological changes.

Chaperone-mediated disaggregation of infectious prions releases particles that seed new prion formation in a strain-specific manner.

The mammalian prion protein can form infectious, nonnative, and protease resistant aggregates (PrPD), which cause lethal prion diseases like human Creutzfeldt-Jakob disease. PrPD seeds the formation of new infectious prions by interacting with and triggering the refolding of the normally soluble mammalian prion protein, PrPC, into more PrPD. Refolding of misfolded proteins in the cell is carried out by molecular chaperones such as Grp78. We have recently shown that Grp78 sensitizes PrPD to proteases, indicating structural alterations and leading to its degradation. However, the process of chaperone-mediated PrPD disaggregation, the chaperones involved, and the effect of disaggregation on PrPD seeding activity are unclear. We have now monitored the structural modification, disaggregation, and seeding activity of PrPD from twomouse adapted prion strains, 22L and 87V, in the presence of Grp78 and two forms of the Hsp110 disaggregase chaperone family, Hsp105 and Apg-2. We found that both forms of Hsp110 induced similar amounts of disaggregation and structural change in the protease resistant cores of PrPD from both strains. However, 22L PrPD was more susceptible to destabilization and disaggregation by the chaperones than 87V. Surprisingly, despite disaggregation of both strains, only the 22L PrPD aggregates released by the chaperones had seeding activity, with both forms of Hsp110 enhancing the Grp78 mediated release of these aggregates. Our data show that disassembly of PrPD by Grp78 and Hsp110 chaperones can release seeding particles of PrPD in a strain-specific manner, potentially facilitating prion replication and spread.

The burden of medical contraindications to corneal donation: Time for review.

Corneal graft (keratoplasty) is the most common allograft in the world, but the imbalance between the number of donors and the number of patients waiting for transplants is abysmal on a global scale and varies enormously from one country to another. The risk of transmission of systemic diseases from donor to recipient is demonstrably low. In over 50 years and an estimated 2.5 million transplants, only 8 cases of rabies, 2 cases of hepatitis B and 2 cases of Creutzfeldt-Jakob disease (CJD) have been documented. Conversely, other cases of rabies, HIV, hep C, hep B and CJD have not been transmitted via keratoplasty. The list of medical contraindications (CI) to corneal donation also includes diseases for which no actual, only theoretical, risk has been identified, in particular, neurodegenerative diseases, hematological malignancies, melanomas, tumors of the central nervous system, neoplastic meningitis and lymphangitic carcinomatosis. Their contribution to the reduction in the potential donor pool has not previously been investigated. We analyzed 45 months of exhaustive data from the hospital coordination for organ and tissue procurement at St-Etienne University Hospital (01/01/2020 to 06/09/2023). Out of the 2349 consecutive potential donors' files analyzed by the coordination team,1346 (57%) had an CI to donation. The identification of a neurodegenerative disease was the most frequent, accounting for 16% of the files examined and 29% of CIs. Of these, 75% were related to cognitive disorders. The 5 diseases or families of diseases for which there is only theoretical risk of transmission equated to a loss of 712 potential donors, corresponding to 30% of the files examined and 53% of all CIs. Of the 1003 deceased without CI, 738 families (74%) were contacted. No objection to donation was received in 52% of cases, enabling 385 procurements to be carried out. Removing these 5 CIs would have increased the number of donors by 71% (658 instead of 385). The potential pool of corneal donors is significantly restricted by a group of CIs introduced decades ago in response to a theoretical transmission of disease. A substantive amount of evidence now suggests that many CIs now need to be reviewed, modified or discarded altogether. This approach will result in a highly significant worldwide increase in the availability of corneas for transplant and have an immediate and major impact in reducing corneal blindness across the globe. We propose that this reduction in CIs be accompanied by a prospective evaluation process, by allocating the corneas of these donors to patients aged 75 years and over, and by monitoring them for a minimum of 5 years.

Creutzfeldt-Jakob disease: Cases of nomenclatural misrepresentation due to ‘tortured phrases’

Creutzfeldt-Jakob disease: Cases of nomenclatural misrepresentation due to ‘tortured phrases’

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

ABSTRACT 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.

Mood Alterations in the Prodromal Phase of Sporadic Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, rapidly progressive and fatal neurodegenerative disease. Definite sCJD diagnosis can only be made post mortem, and little is known about the prodromal phase of the disease. To compare drug prescription patterns before the clinical onset of sCJD between patients and matched controls for exploration of potential risk factors and to assess correlations between drug exposure and sCJD survival. This retrospective analysis was designed as a case-control study, with data collected from January 2013 to December 2020 and analyzed in 2023. Follow-up was available until December 2020. Cases were collected from the Austrian Reference Centre for Human Prion Diseases, which receives all suspected cases at a national level in Austria. The analyses were conducted at a single center. Patients with autopsy-confirmed sCJD were linked with insurance claims data, and a minimum of 10 control individuals were matched by sex, age at onset, and area of residence for each patient with sCJD. Medication prescribed to 10% or more of the cohort with sCJD up to 5 years before symptom onset or the matching date in the control cohort. Drug prescription before symptom onset or the matching date was compared between patients with sCJD and controls using conditional regression, and prescriptions in the cohort with sCJD were assessed for correlation with survival using Cox proportional hazard models. A total of 129 patients with sCJD (median [IQR] age, 68.9 [62.4-75.5] years; 67 female [51.9%]) and 1350 controls (median [IQR] age, 69.0 [62.2-75.3] years; 700 female [51.9%]) were included. As compared with controls, patients with sCJD were found to have significantly higher odds of being prescribed selective serotonin reuptake inhibitors (SSRIs) in the year preceding disease onset (odds ratio, 2.86; 95% CI, 1.63-4.95; P < .001). SSRI prescription rates started to increase 3 years before symptom onset in the cohort with sCJD. Results of this case-control study provide evidence for prodromal mood alterations as early as 3 years before symptom onset in patients with sCJD. Although sCJD remains an extremely rare cause of mood alterations, increased vigilance for neurodegenerative diseases in this setting could eventually help to extend the diagnostic window.

Diagnostic Challenges in Sporadic Creutzfeldt-Jakob Disease: A Case Study of Typical Clinical Presentation with Negative Findings

Diagnostic Challenges in Sporadic Creutzfeldt-Jakob Disease: A Case Study of Typical Clinical Presentation with Negative Findings

Neurofilament Light Chain Levels in Serum and Cerebrospinal Fluid Do Not Correlate with Survival Times in Patients with Prion Disease.

Prion diseases, including Creutzfeldt-Jakob disease (CJD), are deadly neurodegenerative disorders characterized by the buildup of abnormal prion proteins in the brain. This accumulation disrupts neuronal functions, leading to the rapid onset of psychiatric symptoms, ataxia, and cognitive decline. The urgency of timely diagnosis for effective treatment necessitates the identification of strongly correlated biomarkers in bodily fluids, which makes our research crucial. In this study, we employed a fully automated multiplex ELISA (Ella®) to measure the concentrations of 14-3-3 protein, total tau protein, and neurofilament light chain (NF-L) in cerebrospinal fluid (CSF) and serum samples from patients with prion disease and analyzed their link to disease prognosis. However, in North American and European cases, we did not confirm a correlation between NF-L levels and survival time. This discrepancy is believed to stem from differences in treatment policies and measurement methods between Japan and the United States. Nonetheless, our findings suggest that NF-L concentrations could be an early diagnostic marker for CJD patients with further enhancements. The potential impact of our findings on the early diagnosis of CJD patients is significant. Future research should focus on increasing the number of sCJD cases studied in Japan and gathering additional evidence using next-generation measurement techniques.

The Diagnostic Value of Cerebrospinal Fluid Neurogranin in Neurodegenerative Diseases.

Synaptic pathology is crucial in neurodegenerative diseases (NDs), and numerous studies show a correlation between synaptic proteins and the rate of cognitive decline in Alzheimer's disease, Parkinson's disease, dementia, and Creutzfeldt-Jacob's disease. Due to the fact that altered synaptic function is considered a core feature of the pathophysiology of neurodegenerative disorders, synaptic proteins, such as neurogranin, may serve as a biomarker of these diseases. Neurogranin is a postsynaptic protein located in the cell bodies and dendrites of neurons, foremost in the cerebral cortex, hippocampus, and striatum. It has been established that neurogranin is involved in synaptic plasticity and long-term potentiation. Literature data indicate that cerebrospinal fluid neurogranin may be useful as a biomarker for more accurate diagnosis and prognosis of neurodegenerative diseases. In this review, the diagnostic value of cerebrospinal fluid neurogranin in most common neurodegenerative diseases is examined.

Interpretable deep learning survival predictions in sporadic Creutzfeldt–Jakob disease

BackgroundSporadic Creutzfeldt–Jakob disease (sCJD) is a rapidly progressive and fatal prion disease with significant public health implications. Survival is heterogenous, posing challenges for prognostication and care planning. We developed a survival model using diagnostic data from comprehensive UK sCJD surveillance.MethodsUsing national CJD surveillance data from the United Kingdom (UK), we included 655 cases of probable or definite sCJD according to 2017 international consensus diagnostic criteria between 01/2017 and 01/2022. Data included symptoms at diagnosis, CSF RT-QuIC and 14-3-3, MRI and EEG findings, as well as sex, age, PRNP codon 129 polymorphism, CSF total protein and S100b. An artificial neural network based multitask logistic regression was used for survival analysis. Model-agnostic interpretation methods was used to assess the contribution of individual features on model outcome.ResultsOur algorithm had a c-index of 0.732, IBS of 0.079, and AUC at 5 and 10 months of 0.866 and 0.872, respectively. This modestly improved on Cox proportional hazard model (c-index 0.730, IBS 0.083, AUC 0.852 and 0863) but was not statistically significant. Both models identified codon 129 polymorphism and CSF 14-3-3 to be significant predictive features.ConclusionssCJD survival can be predicted using routinely collected clinical data at diagnosis. Our analysis pipeline has similar levels of performance to classical methods and provide clinically meaningful interpretation which help deepen clinical understanding of the condition. Further development and clinical validation will facilitate improvements in prognostication, care planning, and stratification to clinical trials.

From kuru to BSE: a comprehensive review of prion diseases

Prions are protein molecules that naturally occur in neural membranes (PrP). These components challenge our understanding due to their multiple functions, which are not yet fully unraveled. Structural changes can convert these molecules into a pathogenic form, known as PrPSc, causing insoluble aggregates that lead to neurodegenerative diseases, such as Creutzfeldt-Jakob disease, Fatal Familial Insomnia, and Gerstmann-Sträussler-Scheinker disease. These diseases have a long incubation period, approximately 30 years, without early detection by common diagnostic tests, highlighting the complexity of prion diseases. Once symptoms appear, prion diseases progress rapidly and are fatal, with an average life expectancy of just one year. Diagnosis is challenging; after symptom onset, a series of differential diagnoses is necessary, including electroencephalography, magnetic resonance imaging, computed tomography, and cerebrospinal fluid analysis, to exclude other degenerative diseases such as Alzheimer’s. Due to the rapid and devastating progression of symptoms, treatment is palliative, focused on providing comfort to the individual.