Tailored behavioural tests reveal early and progressive cognitive deficits in M1000 prion disease.

Prion diseases are pathogenically linked to the normal cellular prion protein (PrPC) misfolding into abnormal conformers (PrPSc), with PrPSc accumulation underpinning both transmission and neurotoxicity. Despite achieving this canonical understanding, however fundamental questions remain incompletely resolved, including the level of pathophysiological overlap between neurotoxic and transmitting species of PrPSc and the temporal profiles of their propagation. To further investigate the likely time of occurrence of significant levels of neurotoxic species during prion disease development, the well characterised in vivo M1000 murine model was employed. Following intracerebral inoculation, detailed serial cognitive and ethological testing at specified time points suggested subtle transition to early symptomatic disease from ∼50% of the overall disease course. In addition to observing a chronological order for impaired behaviours, different behavioural tests also showed distinctive profiles of evolving cognitive impairments with the Barnes maze demonstrating a relatively simple linear worsening of spatial learning and memory over an extended period while in contrast a conditioned fear memory paradigm previously untested in murine prion disease demonstrated more complex alterations during disease progression. These observations support the likely production of neurotoxic PrPSc from at least just prior to the mid-point of murine M1000 prion disease and illustrate the likely need to tailor the types of behavioural testing across the time course of disease progression for optimal detection of cognitive deficits.

Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings.

INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.

Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc.

Although considerable evidence supports that misfolded prion protein (PrPSc) is the principal component of "prions", underpinning both transmissibility and neurotoxicity, clear consensus around a number of fundamental aspects of pathogenesis has not been achieved, including the time of appearance of neurotoxic species during disease evolution. Utilizing a recently reported electrophysiology paradigm, we assessed the acute synaptotoxicity of ex vivo PrPSc prepared as crude homogenates from brains of M1000 infected wild-type mice (cM1000) harvested at time-points representing 30%, 50%, 70% and 100% of the terminal stage of disease (TSD). Acute synaptotoxicity was assessed by measuring the capacity of cM1000 to impair hippocampal CA1 region long-term potentiation (LTP) and post-tetanic potentiation (PTP) in explant slices. Of particular note, cM1000 from 30% of the TSD was able to cause significant impairment of LTP and PTP, with the induced failure of LTP increasing over subsequent time-points while the capacity of cM1000 to induce PTP failure appeared maximal even at this early stage of disease progression. Evidence that the synaptotoxicity directly related to PrP species was demonstrated by the significant rescue of LTP dysfunction at each time-point through immuno-depletion of >50% of total PrP species from cM1000 preparations. Moreover, similar to our previous observations at the terminal stage of M1000 prion disease, size fractionation chromatography revealed that capacity for acute synpatotoxicity correlated with predominance of oligomeric PrP species in infected brains across all time points, with the profile appearing maximised by 50% of the TSD. Using enhanced sensitivity western blotting, modestly proteinase K (PK)-resistant PrPSc was detectable at very low levels in cM1000 at 30% of the TSD, becoming robustly detectable by 70% of the TSD at which time substantial levels of highly PK-resistant PrPSc was also evident. Further illustrating the biochemical evolution of acutely synaptotoxic species the synaptotoxicity of cM1000 from 30%, 50% and 70% of the TSD, but not at 100% TSD, was abolished by digestion of immuno-captured PrP species with mild PK treatment (5µg/ml for an hour at 37°C), demonstrating that the predominant synaptotoxic PrPSc species up to and including 70% of the TSD were proteinase-sensitive. Overall, these findings in combination with our previous assessments of transmitting prions support that synaptotoxic and infectious M1000 PrPSc species co-exist from at least 30% of the TSD, simultaneously increasing thereafter, albeit with eventual plateauing of transmitting conformers.

PrPSc Oligomerization Appears Dynamic, Quickly Engendering Inherent M1000 Acute Synaptotoxicity.

Prion diseases are neurodegenerative disorders pathogenically linked to cellular prion protein (PrPC) misfolding into abnormal conformers (PrPSc), with PrPSc underpinning both transmission and synaptotoxicity. Although the biophysical features of PrPSc required to induce acute synaptic dysfunction remain incompletely defined, we recently reported that acutely synaptotoxic PrPSc appeared to be oligomeric. We herein provide further insights into the kinetic and requisite biophysical characteristics of acutely synaptotoxic ex vivo PrPSc derived from the brains of mice dying from M1000 prion disease. Pooled fractions of M1000 PrPSc located within the molecular weight range approximating monomeric PrP (mM1000) generated through size exclusion chromatography were found to harbor acute synaptotoxicity equivalent to preformed oligomeric fractions (oM1000). Subsequent investigation showed mM1000 corresponded to PrPSc rapidly concatenating in physiological buffer to exist as predominantly, closely associated, small oligomers. The oligomerization of PrP in mM1000 could be substantially mitigated by treatment with the antiaggregation compound epigallocatechin gallate, thereby maintaining the PrPSc as primarily nonoligomeric with completely abrogated acute synaptotoxicity; moreover, despite epigallocatechin gallate treatment, pooled oM1000 remained oligomeric and acutely synaptotoxic. A similar tendency to rapid formation of oligomers was observed for PrPC when monomeric fractions derived from size exclusion chromatography of normal brain homogenates (mNBH) were pooled, but neither mNBH nor preformed higher-order NBH complexes (oNBH) were acutely synaptotoxic. Oligomers formed from mNBH could be reduced to mainly monomers (<100 kDa) after enzymatic digestion of nucleic acids, whereas higher-order PrP assemblies derived from pooled mM1000, oM1000, and oNBH resisted such treatment. Collectively, these findings support that oligomerization of PrPSc into small multimeric assemblies appears to be a critical biophysical feature for engendering inherent acute synaptotoxicity, with preformed oligomers found in oM1000 appearing to be stable, tightly self-associated ensembles that coexist in dynamic equilibrium with mM1000, with the latter appearing capable of rapid aggregation, albeit initially forming smaller, weakly self-associated, acutely synaptotoxic oligomers.

Prion acute synaptotoxicity is largely driven by protease-resistant PrPSc species.

Although misfolding of normal prion protein (PrPC) into abnormal conformers (PrPSc) is critical for prion disease pathogenesis our current understanding of the underlying molecular pathophysiology is rudimentary. Exploiting an electrophysiology paradigm, herein we report that at least modestly proteinase K (PK)-resistant PrPSc (PrPres) species are acutely synaptotoxic. Brief exposure to ex vivo PrPSc from two mouse-adapted prion strains (M1000 and MU02) prepared as crude brain homogenates (cM1000 and cMU02) and cell lysates from chronically M1000-infected RK13 cells (MoRK13-Inf) caused significant impairment of hippocampal CA1 region long-term potentiation (LTP), with the LTP disruption approximating that reported during the evolution of murine prion disease. Proof of PrPSc (especially PrPres) species as the synaptotoxic agent was demonstrated by: significant rescue of LTP following selective immuno-depletion of total PrP from cM1000 (dM1000); modestly PK-treated cM1000 (PK+M1000) retaining full synaptotoxicity; and restoration of the LTP impairment when employing reconstituted, PK-eluted, immuno-precipitated M1000 preparations (PK+IP-M1000). Additional detailed electrophysiological analyses exemplified by impairment of post-tetanic potentiation (PTP) suggest possible heightened pre-synaptic vulnerability to the acute synaptotoxicity. This dysfunction correlated with cumulative insufficiency of replenishment of the readily releasable pool (RRP) of vesicles during repeated high-frequency stimulation utilised for induction of LTP. Broadly comparable results with LTP and PTP impairment were obtained utilizing hippocampal slices from PrPC knockout (PrPo/o) mice, with cM1000 serial dilution assessments revealing similar sensitivity of PrPo/o and wild type (WT) slices. Size fractionation chromatography demonstrated that synaptotoxic PrP correlated with PK-resistant species >100kDa, consistent with multimeric PrPSc, with levels of these species >6 ng/ml appearing sufficient to induce synaptic dysfunction. Biochemical analyses of hippocampal slices manifesting acute synaptotoxicity demonstrated reduced levels of multiple key synaptic proteins, albeit with noteworthy differences in PrPo/o slices, while such changes were absent in hippocampi demonstrating rescued LTP through treatment with dM1000. Our findings offer important new mechanistic insights into the synaptic impairment underlying prion disease, enhancing prospects for development of targeted effective therapies.

Prion protein "gamma-cleavage": characterizing a novel endoproteolytic processing event.

The cellular prion protein (PrP(C)) is a ubiquitously expressed protein of currently unresolved but potentially diverse function. Of putative relevance to normal biological activity, PrP(C) is recognized to undergo both α- and ß-endoproteolysis, producing the cleavage fragment pairs N1/C1 and N2/C2, respectively. Experimental evidence suggests the likelihood that these processing events serve differing cellular needs. Through the engineering of a C-terminal c-myc tag onto murine PrP(C), as well as the selective use of a far-C-terminal anti-PrP antibody, we have identified a new PrP(C) fragment, nominally 'C3', and elaborating existing nomenclature, 'γ-cleavage' as the responsible proteolysis. Our studies indicate that this novel γ-cleavage event can occur during transit through the secretory pathway after exiting the endoplasmic reticulum, and after PrP(C) has reached the cell surface, by a matrix metalloprotease. We found that C3 is GPI-anchored like other C-terminal and full length PrP(C) species, though it does not localize primarily at the cell surface, and is preferentially cleaved from an unglycosylated substrate. Importantly, we observed that C3 exists in diverse cell types as well as mouse and human brain tissue, and of possible pathogenic significance, γ-cleavage may increase in human prion diseases. Given the likely relevance of PrP(C) processing to both its normal function, and susceptibility to prion disease, the potential importance of this previously underappreciated and overlooked cleavage event warrants further consideration.

Alzheimer's disease biomarker utilization at first referral enhances differential diagnostic precision with simultaneous exclusion of Creutzfeldt-Jakob disease.

Most suspected Creutzfeldt-Jakob disease (CJD) cases are eventually diagnosed with other disorders. We assessed the utility of investigating Alzheimer's disease (AD) biomarkers and neurofilament light (NfL) in patients when CJD is suspected. The study cohort consisted of cerebrospinal fluid (CSF) samples referred for CJD biomarker screening wherein amyloid beta 1-42 (Aß1-42), phosphorylated tau 181 (p-tau181), and total tau (t-tau) could be assessed via Elecsys immunoassays (n = 419) and NfL via enzyme-linked immunosorbent assay (ELISA; n = 161). In the non-CJD sub cohort (n = 371), 59% (219/371) had A+T- (abnormal Aß1-42 only) and 21% (79/371) returned A+T+ (abnormal Aß1-42 and p-tau181). In the 48 CJD subjects, a similar AD biomarker profile distribution was observed. To partially address the prevalence of likely pre-symptomatic AD, NfL was utilized to assess for neuronal damage. NfL was abnormal in 76% (25/33) of A+T- subjects 40 to 69 years of age, 80% (20/25) of whom had normal t-tau. This study reinforces AD as an important differential diagnosis of suspected CJD, highlighting that incorporating AD biomarkers and NfL at initial testing is worthwhile.

Malignant neoplasm of lacrimal gland with pulmonary metastasis.

Adenoid cystic carcinomas (ACC) make up 3%-5% of head and neck malignancies. They have a high propensity to metastasise, in particular to the lungs. A 65-year-old male diagnosed with a right lacrimal gland ACC T2N0M0 (surgically resected 12 years prior) presented with an incidentally noted 1.2 cm right lower lobe lung nodule seen on MRI liver. Subsequent imaging confirmed a non-FDG avid 1.6 cm solitary ovoid subpleural lesion, percutaneous biopsy confirmed adenocarcinoma. A surgical metastasectomy was performed and recovery was complete. Prognosis in ACC is improved with radical management of metastatic disease. Rather than a simple chest radiograph, more detailed imaging, such as MRI or CT scanning may increase the probability of early detection of pulmonary metastasis and, thereby facilitate radical treatment and improve survival.

Chronic mild stress induces differential depression-like symptoms and c-Fos and 5HT1A protein levels in high-anxiety female Long Evans rats.

Depression and anxiety disorders overlap in clinical populations, suggesting common mechanisms that may be further investigated in reliable animal models. We used filial 8 female Long-Evans rats bred for high (HAn; n = 19) and low anxiety (LAn)-like behavior (n = 21) to assess forced swim test mobility strategies and chronic mild stress (CMS)-induced depression-like symptoms. We measured (1) weight, (2) fur piloerection, (3) sweet food consumption, (4) grooming behavior, and (5) circulating estradiol (E2). One month after CMS terminated and following a terminal forced swim test, brains were processed for immunohistochemistry targeting c-Fos and serotonin 1 A receptor (5-HT1AR) protein in the paraventricular nucleus (PVN) of the hypothalamus. HAn female rats showed increased anxiety-like behavior (i.e., lower open to closed arm ratios, increased closed arm entries), more swimming (i.e., mobility), and less floating (i.e., immobility) behavior in the forced swim test. Overall, HAn females weighed less than their LAn counterparts. After chronic mild stress, HAn lines displayed even greater mobility and consumed fewer Froot Loops™. Fur and grooming analyses indicated no significant differences in mean counts across experimental groups. One month after CMS, cycling E2 concentrations (pg/ml) did not differ between HAn and LAn animals. Elevated c-Fos and 5-HT1AR expression were observed in the PVN, where HAn CMS rats expressed the most c-Fos and 5-HT1AR immunoreactivity. In summary, outbred HAn rats show robust anxiety-like behavior, exhibit more mobility in the forced swim test, and are more sensitive to chronic mild stress-induced grooming and decline in palatable food ingestion.

Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease.

The most frequently utilized biomarkers to support a pre-mortem clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) include concentrations of the 14-3-3 and total tau (T-tau) proteins, as well as the application of protein amplification techniques, such as the real time quaking-induced conversion (RT-QuIC) assay, in cerebrospinal fluid (CSF). Utilizing CSF from a cohort of neuropathologically confirmed (definite) sCJD (n = 50) and non-CJD controls (n = 48), we established the optimal cutpoints for the fully automated Roche Elecsys® immunoassay for T-tau and the CircuLexTM 14-3-3 Gamma ELISA and compared these to T-tau protein measured using a commercially available assay (INNOTEST hTAU Ag) and 14-3-3 protein detection by western immunoblot (WB). These CSF specimens were also assessed for presence of misfolded prion protein using the RT-QuIC assay. T-tau showed similar diagnostic performance irrespective of the assay utilized, with ~90% sensitivity and specificity. The 14-3-3 protein detection by western blot (WB) has 87.5% sensitivity and 66.7% specificity. The 14-3-3 ELISA demonstrated 81.3% sensitivity and 84.4% specificity. RT-QuIC was the single best performing assay, with a sensitivity of 92.7% and 100% specificity. Our study indicates that a combination of all three CSF biomarkers increases sensitivity and offers the best chance of case detection pre-mortem. Only a single sCJD case in our cohort was negative across the three biomarkers, emphasizing the value of autopsy brain examination on all suspected CJD cases to ensure maximal case ascertainment.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2022.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2022: Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2022. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2022, a total of 599 domestic CSF specimens were referred for diagnostic testing and 79 persons with suspected human prion disease were formally added to the national register. As of 31 December 2022, just under half of the 79 suspect case notifications (36/79) remain classified as 'incomplete'; 15 cases were classified as 'definite' and 23 as 'probable' prion disease; five cases were excluded through neuropathological examination. For 2022, fifty-five percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia during 2022.

Comprehensive clinical, radiological, pathological and biochemical analysis required to differentiate VV1 sporadic Creutzfeldt-Jakob disease from suspected variant CJD.

Background: A diagnosis of variant Creutzfeldt-Jakob disease (vCJD), the zoonotic prion disease related to transmission of bovine spongiform encephalopathy, can carry enormous public health ramifications. Until recently, all vCJD clinical cases were confined to patients displaying methionine homozygosity (MM) at codon 129 of the prion protein gene (PRNP). The recent diagnosis of vCJD in a patient heterozygous (MV) at codon 129 reignited concerns regarding a second wave of vCJD cases, with the possibility of phenotypic divergence from MM vCJD and greater overlap with sporadic CJD (sCJD) molecular subtypes. Method and results: We present a case of CJD with clinico-epidemiological and radiological characteristics creating initial concerns for vCJD. Thorough case evaluation, including data provided by genetic testing, autopsy and neuropathological histological analyses, provided a definitive diagnosis of the rare VV1 molecular subtype of sCJD. Conclusion: Distinguishing vCJD from sCJD is of vital public health importance and potentially more problematic with the development of non-MM vCJD cases. The patient described herein demonstrates that in addition to the clinico-epidemiological profile, combined supplementary pathological, biochemical and critical radiological analysis may be necessary for confident discrimination of sCJD, especially rare sub-types, from vCJD.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2021.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2021. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2021, a total of 548 domestic CSF specimens were referred for 14-3-3 protein testing; 73 persons with suspected human prion disease were formally added to the national register. As of 31 December 2021, just over half of the 73 suspect case notifications (37/73) remain classified as 'incomplete'; 17 cases were classified as 'definite' and 13 as 'probable' prion disease; six cases were excluded through either detailed clinical follow-up (two cases) or neuropathological examination (four cases). For 2021, sixty-four percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia.

Footedness and Postural Asymmetry in Amateur Dressage Riders, Riding in Medium Trot on a Dressage Simulator.

This study explored the relationship between footedness and postural asymmetry in equestrian riders. 28 female riders completed the Waterloo Footedness Questionnaire- Revised (WFQ-R), giving a score for footedness. They then took part in a test on a riding simulator where measures of saddle force, stirrup force, and degree of lateral tilt of the pelvic, trunk, and shoulder segments were taken over a period of 20 seconds in trot. Symmetry indices were calculated for stirrup force and saddle force. There were no significant correlations between WFQ-R score and any of the measures of postural symmetry. Only a very small number (n=3) participants showed a marked footedness, with the majority of the sample being classed as 'mixed footed' based on test scores. This, coupled with data loss for some participants in each of the parameters, means direct comparison of footedness groups was difficult. However, the variation of asymmetry in the mixed footed group supports the idea that footedness does not have a significant impact on the rider's posture. There was a correlation between trunk lean and stirrup force symmetry index (r=0.537, P=0.021) showing the trunk leaned towards the side of higher stirrup force. There was a significant negative correlation between pelvic obliquity and shoulder tilt (r= -0.481, P=0.023) with 59% of the sample showing pelvic obliquity and shoulder tilt in opposite directions. The findings indicate that there is little effect of footedness on postural asymmetries in the rider. Research should now consider other causal factors to support riders to become more symmetrical.

Erratum to: Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2020.

Erratum to Commun Dis Intell (2018) 2021;45 (https://doi.org/10.33321/cdi.2021.45.38).

The Three Glycotypes in the London Classification System of Sporadic Creutzfeldt-Jakob Disease Differ in Disease Duration.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of CJD and is believed to be caused by the misfolding and aggregation of endogenous prion protein. Several classification systems have been developed to correlate the molecular characteristics of these misfolded prions (PrPSc) to the heterogeneous clinical presentations of sCJD. A central component of these systems is glycotyping, which involves the interpretation of the results of western immunoblotting of the protease-resistant fragment of the misfolded prion protein (PrPres). The two main classification systems differ in their recognition of a unique banding pattern on electrophoretic gels correlating to a putative clinical subtype. The perpetuation of both classification systems within scientific literature is, in part, due to a paucity of high-level evidence that conclusively addresses the merit of recognising each unique banding pattern. Here, 110 post-mortem confirmed cases of sCJD collected at the Australian Creutzfeldt-Jakob Disease Registry (ANCJDR) between 1993 and 2018 were analysed and classified as per the London classification system. The data presented here demonstrated that sCJD cases with 'type 1' and 'type 2' PrPSc as defined by the London classification system differ in their disease duration. No other differences in clinical phenotype or biological characteristics were found to be statistically significant. These findings highlight the importance of sample size and replicability in analyses of this rare disease process. Recognising these glycotypes as phenotypically distinct may represent 'best practice' in the collection and processing of sCJD samples within international registries for research purposes.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2020.

ABSTRACT: Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2020. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2020, 510 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2020, just over half (44 cases) of the 85 suspect case notifications remain classified as 'incomplete'; 27 cases were excluded through either detailed clinical follow-up (9 cases) or neuropathological examination (18 cases); 18 cases were classified as 'definite' and eleven as 'probable' prion disease. For 2020, sixty percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia.

Markers of A1 astrocytes stratify to molecular sub-types in sporadic Creutzfeldt-Jakob disease brain.

Astrocytes are glial cells of the central nervous system that become reactive under conditions of stress. The functional properties of reactive astrocytes depend on their stimulus that induces the upregulation of specific genes. Reactive astrocytes are a neuropathological feature of prion disorders; however, their role in the disease pathogenesis is not well understood. Here, we describe our studies of one polarization state of reactive astrocytes, termed A1 astrocytes, in the frontal cortex region of 35 human sporadic Creutzfeldt-Jakob disease brains encompassing a range of molecular sub-types. Examination of two mRNA markers of A1 astrocytes, C3 and GBP2, revealed a strong linear correlation between the two following their log-normalization (P = 0.0011). Both markers were found upregulated in the sporadic Creutzfeldt-Jakob disease brain compared with age-matched control tissues (P = 0.0029 and 0.0002, for C3log and GBP2log, respectively), and stratifying samples based on codon 129 genotype revealed that C3log is highest in homozygous methionine and lowest in homozygous valine patients, which followed a linear trend (P = 0.027). Upon assessing other disease parameters, a significant positive correlation was found between GBP2log and disease duration (P = 0.031). These findings provide evidence for a divergence in the astrocytic environment amongst patients with sporadic Creutzfeldt-Jakob disease based on molecular sub-type parameters of disease. While more research will be needed to determine the global changes in the genomic profiles and resulting functional properties of reactive astrocytes in disease, considering the evidence demonstrating that A1 astrocytes harbour neurotoxic properties, the changes seen in C3log and GBP2log in the current study may reflect differences in pathogenic mechanisms amongst the sporadic Creutzfeldt-Jakob disease sub-types associated with the A1 polarization state.

The cellular prion protein beyond prion diseases.

The cellular prion protein (PrPC), a cell surface glycoprotein originally identified for its central role in prion diseases (also called transmissible spongiform encephalopathies), has recently been implicated in the pathogenesis of other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, by acting as a toxicity-transducing receptor for different misfolded protein isoforms, or in some case by exerting neuroprotective effects. Interestingly, PrPC has also been reported to play unexpected functions outside the nervous system, for example by contributing to myelin homeostasis, regulating specific processes of the immune system and participating in various aspects of cancer progression. Collectively, these observations point to a much broader role for PrPC in physiological and disease processes than originally assumed. In this manuscript, we provide an overview of what is known about the role of PrPC beyond prion disorders and discuss the potential implications of targeting this protein in different diseases.