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.

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.

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 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.

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.

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).

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.

Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2019.

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 2019. 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 2019, 513 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 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as 'incomplete'; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as 'definite' and seven as 'probable' prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified.

KANSL1 variation is not a major contributing factor in self-limited focal epilepsy syndromes of childhood.

BACKGROUND: KANSL1 haploinsufficiency causes Koolen-de Vries syndrome (KdVS), characterized by dysmorphic features and intellectual disability; amiable personality, congenital malformations and seizures also commonly occur. The epilepsy phenotypic spectrum in KdVS is broad, but most individuals have focal seizures with some having a phenotype resembling the self-limited focal epilepsies of childhood (SFEC). We hypothesized that variants in KANSL1 contribute to pathogenesis of SFEC. MATERIALS AND METHODS: We screened KANSL1 for single nucleotide variants in 90 patients with SFEC. We then screened a cohort of 208 patients with two specific SFEC syndromes, childhood epilepsy with centrotemporal spikes (CECTS) and atypical childhood epilepsy with centrotemporal spikes (ACECTS) for KANSL1 variants. The second cohort was also used to evaluate minor allelic variants that appeared overrepresented in the initial cohort. RESULTS: One variant, p.Lys104Thr, was predicted damaging and appeared overrepresented in our 90-patient cohort compared to Genome Aggregation Database (gnomAD) allele frequency (0.217 to 0.116, with no homozygotes in gnomAD). However, there was no difference in p.Lys104Thr allele frequency in the follow-up CECTS/ACECTS cohort and controls. Four rare KANSL1 variants of uncertain significance were identified in the CECTS/ACECTS cohort. DISCUSSION: Our data do not support a major role for KANSL1 variants in pathogenesis of SFEC.

Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-ß Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

BACKGROUND: The cerebrospinal fluid (CSF) amyloid-ß (Aß)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aß imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aß amyloid ligands. METHODS: Aß pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹8F-flutemetamol, or ¹8F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aß(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. RESULTS: CSF Aß(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aß(1-42) provided greater accuracy, predicting MCI/AD with Aß pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aß(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS: CSF Aß(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aß imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

Accumulation of Aß peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aß peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by ß-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aß signaling to neurons.

Surveillance of Creutzfeldt-Jakob disease in Australia: update to December 2011.

The Australian National Creutzfeldt-Jakob disease Registry (ANCJDR) is a Commonwealth Government-funded surveillance unit, responsible for the ascertainment of all cases of human transmissible spongiform encephalopathy (also known as prion diseases) in Australia. Having been in operation for 18 years, the activities of the ANCJDR have evolved and expanded over this timeframe, with the ANCJDR providing clinical, diagnostic and infection control advice and service. This update provides a review of the activities of the ANCJDR during 2011 and analysis of both prospective and retrospective (to 1970) data collected from 1993 to 31 December 2011.

Surveillance of Creutzfeldt-Jakob disease in Australia: update to December 2010.

Since the establishment of the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR) its activities have expanded from prospectively investigating additional iatrogenic Creutzfeldt-Jakob disease cases to include: retrospective ascertainment to 1970; provision of expert opinions in the area of infection control management; provide diagnostic testing services for all suspect cases; and maintenance of national and international collaborations in conjunction with routine surveillance responsibilities. An update of the ANCJDR's surveillance activities and outcomes between 1 April and 31 December 2010 is herein presented, including a summation of a recent publication by the ANCJDR. The shorter reporting period is due to a contractual change with the Department of Health and Ageing in 2010, resulting in the reporting timeframe shifting to align with full calendar years.

Acute exposure to prion infection induces transient oxidative stress progressing to be cumulatively deleterious with chronic propagation in vitro.

Neuronal loss is a pathological feature of prion diseases for which increased reactive oxygen species (ROS) and consequent oxidative stress is one proposed mechanism. The processes underlying ROS production in prion disease and the precise relationship to misfolding of the prion protein remain obscure. Using cell culture models of prion infection we found that cells demonstrate a rapid, prion protein (PrP) dependent, increase in intracellular ROS following exposure to infectious inoculum. ROS production correlated with internalisation and increased intracellular protease resistant PrP (PrP(Res)). The ROS increase was predominantly lysosomal in origin but not sustained, with cells adapting within 48 hours. Overall ROS levels remained normal in the chronically prion infected cell population; however a subpopulation characterised by loss of membrane phosphatidylserine asymmetry exhibited highly peroxidised intracellular aggregates that localised with PrP and intense caspase activation. These apoptotic cells showed increased ROS closely correlating with increased PrP(Res). Our findings demonstrate that a PrP-dependent, transient, increase in intracellular ROS is characteristic of acute cellular prion infection, while chronic phases of prion infection in vitro are associated with a significant subpopulation manifesting apoptosis accompanying heightened oxidative stress and increased PrP(Res) burden. Such observations strengthen the direct links between heightened ROS and ongoing prion propagation with eventual cellular demise.

Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion.

The development of technologies for the in vitro amplification of abnormal conformations of prion protein (PrP(Sc)) has generated the potential for sensitive detection of prions. Here we developed a new PrP(Sc) amplification assay, called real-time quaking-induced conversion (RT-QUIC), which allows the detection of ≥1 fg of PrP(Sc) in diluted Creutzfeldt-Jakob disease (CJD) brain homogenate. Moreover, we assessed the technique first in a series of Japanese subjects and then in a blind study of 30 cerebrospinal fluid specimens from Australia, which achieved greater than 80% sensitivity and 100% specificity. These findings indicate the promising enhanced diagnostic capacity of RT-QUIC in the antemortem evaluation of suspected CJD.

Iatrogenic Creutzfeldt-Jakob disease in Australia: time to amend infection control measures for pituitary hormone recipients?

From 1967, the Australian Human Pituitary Hormone Program offered treatment for short stature and infertility using human cadaver-acquired pituitary hormones (human growth hormone [hGH] and human pituitary gonadotrophin [hPG]). The program was suspended in 1985 when a growth-hormone recipient in the United States developed Creutzfeldt-Jakob disease (CJD), an incurable and rapidly progressive neurodegenerative disorder. Since this time, recipients have lived with the significant anxiety that they have an elevated risk of developing CJD. Furthermore, additional CJD infection control measures are required when recipients undergo some types of surgery. As it is 20 years since the last Australian pituitary hormone recipient developed CJD, we evaluated the risk for Australian recipients of developing iatrogenic CJD, and compared Australian data with data from New Zealand and selected other countries who had pituitary hormone programs. Our evaluation indicates that pituitary hormone recipients in Australia have the lowest risk of developing iatrogenic CJD, and that Australia is the only country not to have experienced ongoing CJD-related deaths. Thus, we believe that: in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting; and in the Australian hPG recipient cohort, if another 5 years elapses with no further occurrence of CJD in this group, the hPG recipient cohort could also be considered as not requiring additional infection control measures in the health care setting. These recommendations should not be misunderstood as implying that there is no ongoing risk, but that the risk is acceptably low and generally in keeping with guidelines that stratify the risk.