Brain-specific proteins in the diagnosis of dementia

With the mean age of the population increasing, the number of patients with dementia is likely to increase. Although Alzheimer's disease is the most common form of dementia, it is recognised that other forms of dementia are more prevalent than initially thought. As drug therapies become available, it will become important to obtain an accurate clinical diagnosis. Creutzfeldt-Jakob disease (CJD) is a rare type of dementia but with the emergence of the new variant form of this disease which affects young patients, and is thought to be related to the ingestion of meat or meat products from cattle affected with bovine spongiform encephalopathy (BSE), it is possible that it may become more common. These concerns have led to the search for diagnostic tests which may help in the early diagnosis of these forms of dementia. This study investigated whether measurement of cerebrospinal fluid (CSF) brain- specific proteins could be used in the assessment of patients with dementia. Four proteins were investigated: S-100b, an astrocytic protein; and three neuronal proteins, neurone-specific enolase, tau protein and 14-3-3. A two site sandwich ELISA was developed and evaluated for the measurement of S-100b. Levels of all four brain-specific proteins were raised in the majority of patients with sporadic CJD. The presence of CSF 14-3-3 had the best combination of sensitivity and specificity for detecting sporadic CJD. CSF 14-3-3 has recently been included in the diagnostic criteria for probable sporadic CJD. The value of measurement of these proteins in the new variant, iatrogenic and familial forms of CJD was also investigated. None of the CSF brain-specific proteins investigated was of value in the diagnosis of Alzheimer's disease

Brain and Cerebrospinal Fluid α-Synuclein Real-Time Quaking-Induced Conversion Identifies Lewy Body Pathology in LRRK2-PD

ABSTRACTBackground<jats:p/>The neuropathology of Parkinson's disease (PD) associated with leucine‐rich repeat kinase 2 (LRRK2) mutations (LRRK2‐PD) is heterogeneous and varies with the type of mutation. There are only a few studies evaluating seeding aggregation assays to detect α‐synuclein (α‐syn) in patients with LRRK2‐PD.Objective<jats:p/>We aimed to investigate whether α‐syn real‐time quaking induced conversion (RT‐QuIC) is a sensitive biomarker of synucleinopathy in LRRK2‐PD.Methods<jats:p/>We studied α‐syn RT‐QuIC in brain tissue and postmortem ventricular cerebrospinal fluid (CSF) of LRRK2‐PD cases with and without Lewy‐type pathology.Results<jats:p/>The accuracy of α‐syn RT‐QuIC in substantia nigra and CSF samples of patients with LRRK2‐PD was 100%. The test also obtained 100% sensitivity to detect misfolded α‐syn in substantia nigra of cases with idiopathic PD and was negative in the substantia nigra of all the control brains without Lewy‐type pathology.Conclusions<jats:p/>Substantia nigra and ventricular CSF RT‐QuIC discriminates with high sensitivity and specificity LRRK2 cases with Lewy‐type pathology from those without it. RT‐QuIC assay could be of particular interest in the selection of cases for clinical trials in this genetic form of PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Impact of the COVID‐19 pandemic on Creutzfeldt–Jakob disease surveillance and patient care in the United Kingdom

BACKGROUND AND PURPOSE: Creutzfeldt–Jakob disease (CJD) is lethal and transmissible. We assessed the impact of the COVID‐19 pandemic on UK CJD surveillance. We hypothesized that (i) disruptions prolonged diagnostic latency; (ii) autopsy rates declined; and (iii) COVID‐19 infection negatively affected diagnosis, care, and survival. METHODS: We retrospectively investigated the first year of the pandemic, using the preceding year as a comparator, quantifying numbers of individuals assessed by the UK National CJD Research & Surveillance Unit for suspected CJD, time to diagnosis, disease duration, and autopsy rates. We evaluated the impact of COVID‐19 status on diagnosis, care, and survival in CJD. RESULTS: A total of 148 individuals were diagnosed with CJD in the pandemic (from a total of 166 individuals assessed) compared to 141 in the comparator (from 145 assessed). No differences were identified in disease duration or time to diagnosis. Autopsy rates were unchanged. Twenty individuals had COVID‐19; 60% were symptomatic, and 10% had severe disease. Disruptions in diagnosis and care were frequently identified. Forty percent of COVID‐19‐positive individuals died; however, COVID‐19 status did not significantly alter survival duration in CJD. CONCLUSIONS: The COVID‐19 pandemic has not impacted UK CJD case ascertainment or survival, but diagnostic evaluation and clinical care of individuals have been affected

Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification

A patient with a heterozygous variant of Creutzfeldt-Jakob disease (CJD) with a methionine/valine genotype at codon 129 of the prion protein gene was recently reported. Using an ultrasensitive and specific protein misfolding cyclic amplification–based assay for detecting variant CJD prions in cerebrospinal fluid, we discriminated this heterozygous case of variant CJD from cases of sporadic CJD

Homomorphisms and Higher Extensions for Schur algebras and symmetric groups

This paper surveys, and in some cases generalises, many of the recent results on homomorphisms and the higher Ext groups for q-Schur algebras and for the Hecke algebra of type A. We review various results giving isomorphisms between Ext groups in the two categories, and discuss those cases where explicit results have been determined

Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease

OBJECTIVE: Current cerebrospinal fluid (CSF) tests for sporadic Creutzfeldt-Jakob disease (sCJD) are based on the detection of surrogate markers of neuronal damage such as CSF 14-3-3 which are not specific for sCJD. A number of prion protein conversion assays have been developed, including real-time quaking induced conversion (RT-QuIC). The objective of this study is to investigate whether CSF RT-QuIC analysis could be used as a diagnostic test in sCJD. METHODS: An exploratory study was undertaken which analysed 108 CSF samples from patients with neuropathologically confirmed sCJD or from control patients. Of the 108 CSF samples 56 were from sCJD patients (30 female, 26 male, aged 31–84 years; 62.3 ± 13.5 years) and 52 were from control patients (26 female, 26 male, aged 43–84 years; 67.8 ± 10.4 years). A confirmatory group of 118 patients were subsequently examined which consisted of 67 cases of neuropathologically confirmed sCJD (33 female, 34 male, aged 39–82 years; 67.5 ± 9.0 years) and 51 control cases (26 female, 25 male, aged 36–87 years; 63.5 ± 11.6 years). RESULTS: The exploratory study showed that RT-QuIC analysis had a sensitivity of 91% and a specificity of 98% for the diagnosis of sCJD. These results were confirmed in the confirmatory study which showed that CSF RT-QuIC analysis had a sensitivity and specificity of 87% and 100% respectively. INTERPRETATION: This study shows that CSF RT-QuIC analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests