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2.
Alzheimers Res Ther ; 16(1): 201, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39256877

ABSTRACT

BACKGROUND: The term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series. METHODS: We included all RPD patients with a disease duration < 4 years submitted to our prion disease referral centre between 2003 and 2022 who showed Lewy body pathology (LBP) in limbic or neocortical stages as primary neuropathological diagnosis, had no systemic condition justifying the rapid deterioration and were previously neurologically unimpaired. Clinical features were retrieved and compared with Creutzfeldt-Jakob disease (CJD) and rapidly progressive Alzheimer's disease (rpAD) cohorts. Neuropathological and genetic (whole exome sequencing, APOE genotyping, and C9orf72 repeat expansion analysis) characteristics of rpDLB patients were systematically investigated. We scored semi-quantitatively the LBP load and performed a α-synuclein (αSyn) RT-QuIC seeding amplification assay (SAA) on cerebrospinal fluid (CSF) and tenfold serially diluted brain homogenates from different brain areas in rpDLB patients and typical long-lasting Lewy body disease (LBD) with dementia patients as control group. RESULTS: RpDLB patients were older (p = 0.047) and presented more cognitive fluctuations (p = 0.005), visual hallucinations (p = 0.020), neuropsychiatric symptoms (p = 0.006) and seizures (p = 0.032), and fewer cerebellar (p < 0.001) and visual (p = 0.004) signs than CJD ones. Delirium onset was more common than in both CJD (p < 0.001) and rpAD (p = 0.008). Atypical LBD signs (pyramidal, myoclonus, akinetic mutism) were common. All tested patients were positive by CSF αSyn SAA. Concomitant pathologies were common, with only four cases showing relatively "pure" LBP. LBP load and αSyn seeding activity measured through αSyn RT-QuIC SAA were not significantly different between rpDLB patients and typical LBD. We found a likely pathogenic variant in GBA in one patient. CONCLUSIONS: Our results indicate that: 1) rpDLB exhibits a distinct clinical signature (2) CSF αSyn SAA is a reliable diagnostic test; 3) rpDLB is a heterogeneous neuropathological entity that can be underlain by both widespread pure LBP, or multiple copathologies 4) rpDLB is likely not sustained by distinct αSyn conformational strains; 5) genetic defects may, at least occasionally, contribute to the poor prognosis in these patients.


Subject(s)
Disease Progression , Lewy Body Disease , Humans , Lewy Body Disease/genetics , Lewy Body Disease/pathology , Lewy Body Disease/cerebrospinal fluid , Female , Male , Aged , Aged, 80 and over , Middle Aged , Brain/pathology , alpha-Synuclein/cerebrospinal fluid , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/pathology , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/diagnosis , Lewy Bodies/pathology
3.
Wiad Lek ; 77(7): 1501-1504, 2024.
Article in English | MEDLINE | ID: mdl-39241152

ABSTRACT

A 68 y.o. woman delivered to the emergency department with severe speech impairment in a somnolent state - 13 points Glasgow Coma Scale. Her relatives described a clinical manifestation: rapidly progressive dementia, visual disturbances, abnormal gait and coordination, retrograde amnesia. A 67 y. o. man delivered to the emergency department with headache, vertigo, abnormal gait and coordination, progressive extremities weakness, disorientation, memory and concentration impairment. His relatives told about extremely rapidly progression of symptoms during last three months. First clinical case presents a Heidenhain variant, second case - Brownell - Oppenheimer variant.


Subject(s)
Creutzfeldt-Jakob Syndrome , Humans , Creutzfeldt-Jakob Syndrome/diagnosis , Female , Male , Aged
4.
Elife ; 132024 Aug 07.
Article in English | MEDLINE | ID: mdl-39109999

ABSTRACT

Prions replicate via the autocatalytic conversion of cellular prion protein (PrPC) into fibrillar assemblies of misfolded PrP. While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of fibril formation in vitro have precluded the identification and mechanistic analysis of cellular proteins, which may alter PrP self-assembly and prion replication. Here, we have developed a fibril formation assay for recombinant murine and human PrP (23-231) under near-native conditions (NAA) to study the effect of cellular proteins, which may be risk factors or potential therapeutic targets in prion disease. Genetic screening suggests that variants that increase syntaxin-6 expression in the brain (gene: STX6) are risk factors for sporadic Creutzfeldt-Jakob disease. Analysis of the protein in NAA revealed, counterintuitively, that syntaxin-6 is a potent inhibitor of PrP fibril formation. It significantly delayed the lag phase of fibril formation at highly sub-stoichiometric molar ratios. However, when assessing toxicity of different aggregation time points to primary neurons, syntaxin-6 prolonged the presence of neurotoxic PrP species. Electron microscopy and super-resolution fluorescence microscopy revealed that, instead of highly ordered fibrils, in the presence of syntaxin-6 PrP formed less-ordered aggregates containing syntaxin-6. These data strongly suggest that the protein can directly alter the initial phase of PrP self-assembly and, uniquely, can act as an 'anti-chaperone', which promotes toxic aggregation intermediates by inhibiting fibril formation.


Subject(s)
Qa-SNARE Proteins , Qa-SNARE Proteins/metabolism , Qa-SNARE Proteins/genetics , Animals , Mice , Humans , Prion Proteins/metabolism , Prion Proteins/genetics , Prion Proteins/chemistry , Neurons/metabolism , Protein Aggregates , Creutzfeldt-Jakob Syndrome/metabolism , Creutzfeldt-Jakob Syndrome/genetics
5.
J Infect Dis ; 230(1): 161-171, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39052723

ABSTRACT

BACKGROUND: Atypical/Nor98 scrapie (AS) is an idiopathic infectious prion disease affecting sheep and goats. Recent findings suggest that zoonotic prions from classical bovine spongiform encephalopathy (C-BSE) may copropagate with atypical/Nor98 prions in AS sheep brains. Investigating the risk AS poses to humans is crucial. METHODS: To assess the risk of sheep/goat-to-human transmission of AS, we serially inoculated brain tissue from field and laboratory isolates into transgenic mice overexpressing human prion protein (Met129 allele). We studied clinical outcomes as well as presence of prions in brains and spleens. RESULTS: No transmission occurred on the primary passage, with no clinical disease or pathological prion protein in brains and spleens. On subsequent passages, 1 isolate gradually adapted, manifesting as prions with a phenotype resembling those causing MM1-type sporadic Creutzfeldt-Jakob disease in humans. However, further characterization using in vivo and in vitro techniques confirmed both prion agents as different strains, revealing a case of phenotypic convergence. Importantly, no C-BSE prions emerged in these mice, especially in the spleen, which is more permissive than the brain for C-BSE cross-species transmission. CONCLUSIONS: The results obtained suggest a low zoonotic potential for AS. Rare adaptation may allow the emergence of prions phenotypically resembling those spontaneously forming in humans.


Subject(s)
Brain , Creutzfeldt-Jakob Syndrome , Goats , Mice, Transgenic , Prions , Scrapie , Zoonoses , Animals , Creutzfeldt-Jakob Syndrome/transmission , Creutzfeldt-Jakob Syndrome/pathology , Creutzfeldt-Jakob Syndrome/metabolism , Humans , Scrapie/transmission , Scrapie/pathology , Mice , Zoonoses/transmission , Brain/pathology , Brain/metabolism , Sheep , Cattle , Prions/metabolism , Phenotype , Spleen/pathology , Encephalopathy, Bovine Spongiform/transmission , Encephalopathy, Bovine Spongiform/pathology , Encephalopathy, Bovine Spongiform/metabolism , Goat Diseases/transmission , Goat Diseases/pathology , Disease Models, Animal
6.
Neurobiol Dis ; 199: 106599, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38996988

ABSTRACT

OBJECTIVE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data. METHODS: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets. RESULTS: Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD. CONCLUSIONS: Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.


Subject(s)
Creutzfeldt-Jakob Syndrome , Genome-Wide Association Study , Humans , Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/drug therapy , Creutzfeldt-Jakob Syndrome/metabolism , Quantitative Trait Loci , Case-Control Studies , Mendelian Randomization Analysis , DNA Methylation/drug effects , Multiomics
7.
J Neurol Sci ; 463: 123119, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39029285

ABSTRACT

Prion diseases are caused by prions, which are proteinaceous infectious particles that have been identified as causative factors of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). Prion diseases are devastating neurodegenerative disorders in humans and many animals, including sheep, cows, deer, cats, and camels. Prion diseases are classified into sporadic and genetic forms. Additionally, a third, environmentally acquired category exists. This type includes kuru, iatrogenic CJD caused by human dura mater grafts or human pituitary-derived hormones, and variant CJD transmitted through food contaminated with bovine spongiform encephalopathy prions. Bovine spongiform encephalopathy and variant CJD have nearly been controlled, but chronic wasting disease, a prion disease affecting deer, is spreading widely in North America and South Korea and recently in Northern Europe. Recently, amyloid-beta, alpha-synuclein, and other proteins related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases were reported to have prion features such as transmission to animals. Amyloid-beta transmission to humans has been suggested in iatrogenic CJD cases and in cerebral amyloid angiopathy cases with cerebral bleeding occurring long after childhood neurosurgery with or without cadaveric dura mater transplantation. These findings indicate that diseases caused by various prions, namely various transmissible proteins, appear to be a threat, particularly in the current longevity society. Prion disease represented by CJD has obvious transmissibility and is considered to be an "archetype of various neurodegenerative diseases". Overcoming prion diseases is a top priority currently in our society, and this strategy will certainly contribute to elucidating pathomechanism of other neurodegenerative diseases and developing new therapies for them.


Subject(s)
Prion Diseases , Humans , Prion Diseases/transmission , Animals , Creutzfeldt-Jakob Syndrome/transmission , Prions/metabolism
8.
CNS Neurosci Ther ; 30(7): e14857, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39014454

ABSTRACT

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.


Subject(s)
Amyloid beta-Peptides , Biomarkers , Dementia , Disease Progression , tau Proteins , Humans , tau Proteins/blood , tau Proteins/cerebrospinal fluid , Male , Female , Aged , Middle Aged , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/blood , Prognosis , Dementia/diagnosis , Dementia/blood , Dementia/cerebrospinal fluid , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/blood , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Peptide Fragments/blood , Alzheimer Disease/diagnosis , Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Aged, 80 and over
9.
Acta Neuropathol ; 148(1): 10, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39048735

ABSTRACT

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, < 1% were transmitted by misfolded PrP, ~ 15% are inherited, and ~ 85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate localized initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of > 5000× across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a localized presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.


Subject(s)
Creutzfeldt-Jakob Syndrome , Germ-Line Mutation , Prion Proteins , Humans , Prion Proteins/genetics , Male , Female , Aged , Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/pathology , Middle Aged , Germ-Line Mutation/genetics , Brain/pathology , Aged, 80 and over , Prion Diseases/genetics , Prion Diseases/pathology , Mutation
10.
PLoS One ; 19(7): e0304528, 2024.
Article in English | MEDLINE | ID: mdl-39079175

ABSTRACT

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.


Subject(s)
Age of Onset , Creutzfeldt-Jakob Syndrome , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Humans , Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/pathology , Aged , Middle Aged , Female , Male , Phenotype , Genotype
11.
PLoS One ; 19(6): e0304603, 2024.
Article in English | MEDLINE | ID: mdl-38870196

ABSTRACT

Iatrogenic transmission of prions, the infectious agents of fatal Creutzfeldt-Jakob disease, through inefficiently decontaminated medical instruments remains a critical issue. Harsh chemical treatments are effective, but not suited for routine reprocessing of reusable surgical instruments in medical cleaning and disinfection processes due to material incompatibilities. The identification of mild detergents with activity against prions is therefore of high interest but laborious due to the low throughput of traditional assays measuring prion infectivity. Here, we report the establishment of TESSA (sTainlESs steel-bead Seed Amplification assay), a modified real-time quaking induced cyclic amplification (RT-QuIC) assay that explores the propagation activity of prions with stainless steel beads. TESSA was applied for the screening of about 70 different commercially available and novel formulations and conditions for their prion inactivation efficacy. One hypochlorite-based formulation, two commercially available alkaline formulations and a manual alkaline pre-cleaner were found to be highly effective in inactivating prions under conditions simulating automated washer-disinfector cleaning processes. The efficacy of these formulations was confirmed in vivo in a murine prion infectivity bioassay, yielding a reduction of the prion titer for bead surface adsorbed prions below detectability. Our data suggest that TESSA represents an effective method for a rapid screening of prion-inactivating detergents, and that alkaline and oxidative formulations are promising in reducing the risk of potential iatrogenic prion transmission through insufficiently decontaminated instrument surfaces.


Subject(s)
Prions , Stainless Steel , Surgical Instruments , Animals , Mice , Stainless Steel/chemistry , Decontamination/methods , Creutzfeldt-Jakob Syndrome/transmission , Creutzfeldt-Jakob Syndrome/prevention & control , Disinfection/methods , Detergents/chemistry , Detergents/pharmacology , Humans , Disinfectants/pharmacology , Oxidation-Reduction
12.
Front Public Health ; 12: 1411489, 2024.
Article in English | MEDLINE | ID: mdl-38939567

ABSTRACT

Introduction: Human prion disease (PrD), a group of fatal and transmissible neurodegenerative diseases, consists of Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker disease (GSS), and variably protease-sensitive prionopathy (VPSPr). The emergence of bovine spongiform encephalopathy (BSE) in cattle and variant CJD (vCJD) has greatly threatened public health, both in humans and animals. Since the 1990's, dozens of countries and territories have conducted PrD surveillance programs. Methods: In this study, the case numbers and alternative trends of different types of PrD globally and in various countries or territories from 1993 to 2020 were collected and analyzed based on the data from the websites of the international and national PrD surveillance programs, as well as from relevant publications. Results: The total numbers of the reported PrD and sporadic CJD (sCJD) cases in 34 countries with accessible annual case numbers were 27,872 and 24,623, respectively. The top seven countries in PrD cases were the USA (n = 5,156), France (n = 3,276), Germany (n = 3,212), Italy (n = 2,995), China (n = 2,662), the UK (n = 2,521), Spain (n = 1,657), and Canada (n = 1,311). The annual PrD case numbers and mortalities, either globally or in the countries, showed an increased trend in the past 27 years. Genetic PrD cases accounted for 10.83% of all reported PrD cases; however, the trend varied largely among the different countries and territories. There have been 485 iatrogenic CJD (iCJD) cases and 232 vCJD cases reported worldwide. Discussion: The majority of the countries with PrD surveillance programs were high- and upper-middle-income countries. However, most low- and lower-middle-income countries in the world did not conduct PrD surveillance or even report PrD cases, indicating that the number of human PrD cases worldwide is markedly undervalued. Active international PrD surveillance for both humans and animals is still vital to eliminate the threat of prion disease from a public health perspective.


Subject(s)
Global Health , Prion Diseases , Humans , Prion Diseases/epidemiology , Global Health/statistics & numerical data , Creutzfeldt-Jakob Syndrome/epidemiology , Animals , Cattle
13.
J Alzheimers Dis ; 100(1): 77-85, 2024.
Article in English | MEDLINE | ID: mdl-38848185

ABSTRACT

Background: Rapidly progressive dementia (RPD), characterized by a rapid cognitive decline leading to dementia, comprises a diverse range of disorders. Despite advancements in diagnosis and treatment, research on RPD primarily focuses on Western populations. Objective: This study aims to explore the etiology and demographics of RPD in Chinese patients. Methods: We retrospectively analyzed 323 RPD inpatients at Huashan Hospital from May 2019 to March 2023. Data on sociodemographic factors, epidemiology, clinical presentation, and etiology were collected and analyzed. Results: The median onset age of RPD patients was 60.7 years. Two-thirds received a diagnosis within 6 months of symptom onset. Memory impairment was the most common initial symptom, followed by behavioral changes. Neurodegenerative diseases accounted for 47.4% of cases, with central nervous system inflammatory diseases at 30.96%. Autoimmune encephalitis was the leading cause (16.7%), followed by Alzheimer's disease (16.1%), neurosyphilis (11.8%), and Creutzfeldt-Jakob disease (9.0%). Alzheimer's disease, Creutzfeldt-Jakob disease, and frontotemporal dementia were the primary neurodegenerative causes, while autoimmune encephalitis, neurosyphilis, and vascular cognitive impairment were the main non-neurodegenerative causes. Conclusions: The etiology of RPD in Chinese patients is complex, with neurodegenerative and non-neurodegenerative diseases equally prevalent. Recognizing treatable conditions like autoimmune encephalitis and neurosyphilis requires careful consideration and differentiation.


Subject(s)
Dementia , Tertiary Care Centers , Humans , Male , Female , Retrospective Studies , China/epidemiology , Middle Aged , Aged , Dementia/epidemiology , Dementia/etiology , Disease Progression , Alzheimer Disease/epidemiology , Neurosyphilis/epidemiology , Neurosyphilis/complications , Creutzfeldt-Jakob Syndrome/epidemiology , Frontotemporal Dementia/epidemiology , Encephalitis/epidemiology , Cognitive Dysfunction/epidemiology , Cognitive Dysfunction/etiology , Aged, 80 and over , Neurodegenerative Diseases/epidemiology
14.
Alzheimers Dement ; 20(8): 5324-5337, 2024 08.
Article in English | MEDLINE | ID: mdl-38924651

ABSTRACT

INTRODUCTION: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy. METHODS: We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients. RESULTS: N-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5). DISCUSSION: Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. HIGHLIGHTS: N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (Aß) co-pathology. N-terminal p-tau181 and p-tau231 in Aß-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Creutzfeldt-Jakob Syndrome , tau Proteins , Humans , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Female , Male , Aged , Phosphorylation , Middle Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/pathology , Cognitive Dysfunction/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Aged, 80 and over
16.
Int J Mol Sci ; 25(10)2024 May 08.
Article in English | MEDLINE | ID: mdl-38791145

ABSTRACT

The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aß42) and 40 (Aß40) in sCJD (n = 132) and non-prion RPD (np-RPD) (n = 94) patients, and healthy controls (HC) (n = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aß42/Aß40, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.


Subject(s)
Amyloid beta-Peptides , Biomarkers , Creutzfeldt-Jakob Syndrome , Dementia , Glial Fibrillary Acidic Protein , tau Proteins , Humans , Creutzfeldt-Jakob Syndrome/blood , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Female , Male , Glial Fibrillary Acidic Protein/blood , Glial Fibrillary Acidic Protein/cerebrospinal fluid , Aged , Middle Aged , Prognosis , tau Proteins/blood , tau Proteins/cerebrospinal fluid , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Dementia/blood , Dementia/diagnosis , Dementia/cerebrospinal fluid , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Neurofilament Proteins/blood , Neurofilament Proteins/cerebrospinal fluid , Disease Progression , 14-3-3 Proteins/cerebrospinal fluid , 14-3-3 Proteins/blood
17.
Age Ageing ; 53(5)2024 05 01.
Article in English | MEDLINE | ID: mdl-38706391

ABSTRACT

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease with public health implications. Mean age of onset is 68 years. Age-specific incidence declines after 80 years. This may arise from under-ascertainment or other biological features of the disease. Accurate characterisation of late-onset sCJD is important for early diagnosis, avoiding unnecessary investigations and improving ascertainment for public health purposes. OBJECTIVE: To phenotype the clinical features and investigation profile of sCJD in adults >80 years. METHODS: We analysed all probable and definite sCJD cases identified by the UK National CJD Research & Surveillance Unit over a 10-year period (2011-2021). Individuals were grouped by age of onset. Clinical features and investigation profiles were compared. RESULTS: 10.3% (123/1196) had an age of onset over 80. Median survival was shorter (3.2 vs 4.3 months; P < 0.001). Pyramidal signs (48.3% vs 34.2%; P = 0.008) and akinetic mutism (55.1% vs 33.2%; P < 0.001) were more frequent. Psychiatric symptoms (26.3% vs 39.6%; P = 0.01) and cerebellar signs (65.4% vs 78.6%, P = 0.007) were less frequent. Cognitive impairment and myoclonus were highly prevalent regardless of age. Between age groups, the diagnostic sensitivity of cerebrospinal fluid real-time quaking-induced conversion (CSF RT-QuIC) (92.9% vs 91.9%, P = 0.74) was comparable, electroencephalography was superior (41.5% vs 25.4%; P = 0.006) and MRI was inferior (67.8% vs 91.4%; P < 0.001). CONCLUSIONS: Late-onset sCJD has distinct clinical features, shorter survival and a different profile of investigation sensitivity. CSF RT-QuIC, MRI brain and specialist CJD review is recommended in older adults with a rapidly progressive neurological disorder. Autopsy is valuable when the cause remains elusive.


Subject(s)
Age of Onset , Creutzfeldt-Jakob Syndrome , Humans , Creutzfeldt-Jakob Syndrome/epidemiology , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/mortality , United Kingdom/epidemiology , Male , Female , Aged, 80 and over , Incidence , Phenotype , Magnetic Resonance Imaging , Electroencephalography
18.
JAMA Neurol ; 81(7): 775-776, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38805232

ABSTRACT

This case report describes a woman with Creutzfeldt-Jakob disease with findings largely confined to the right precentral gyrus on initial imaging.


Subject(s)
Creutzfeldt-Jakob Syndrome , Humans , Creutzfeldt-Jakob Syndrome/diagnostic imaging , Magnetic Resonance Imaging , Male , Frontal Lobe/diagnostic imaging , Frontal Lobe/physiopathology , Female , Middle Aged , Aged
19.
J Int Med Res ; 52(5): 3000605241247706, 2024 May.
Article in English | MEDLINE | ID: mdl-38717041

ABSTRACT

OBJECTIVE: To systematically review the reported cases of Creutzfeldt-Jakob disease (CJD) in Iran. METHODS: A comprehensive literature review of CJD cases in Iran was undertaken using the PubMed®, Scopus® and Google Scholar databases. In addition, the Iranian database MagIran was searched for Persian language reports. Case selection used the following criteria: (i) patients of Iranian origin; (ii) publication in peer-reviewed journals or reputable medical databases; (iii) a definitive diagnosis of CJD based on established diagnostic criteria. RESULTS: Thirteen cases from twelve reports were included in this systematic review. The majority of the cases were female (11 of 13; 84.6%). The mean ± SD age of patients at hospital admission was 59.38 ± 7.44 years. The findings of the case review suggested that the prevalence of CJD in Iran is not fully established. CJD may be misdiagnosed alongside other clinical signs. The most prevalent early indications of the disease were psychiatric and neurological in nature. A considerable delay in diagnosis was observed in some cases and there was a shortage of brain autopsy records. CONCLUSION: Efforts to improve diagnostic capabilities, promote awareness and establish monitoring systems are necessary for managing the challenges of providing an early diagnosis of CJD in Iran.


Subject(s)
Creutzfeldt-Jakob Syndrome , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/epidemiology , Creutzfeldt-Jakob Syndrome/pathology , Humans , Iran/epidemiology , Female , Male , Middle Aged , Aged , Brain/pathology , Brain/diagnostic imaging , Prevalence
20.
Prion ; 18(1): 87-88, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38722257

ABSTRACT

Authors are commenting on the evolving geographical incidence trends observed with the genetic form of Creutzfeldt-Jakob disease and discussing the diverse array of factors contributing to the heightened incidence rates observed in specific geographical regions.


Subject(s)
Creutzfeldt-Jakob Syndrome , Creutzfeldt-Jakob Syndrome/epidemiology , Humans , Incidence , Slovakia/epidemiology
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