Materiały źródłowe

• #1 Advanced tests for early and accurate diagnosis of Creutzfeldt–Jakob disease | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2016.65

  Early and accurate diagnosis of Creutzfeldt-Jakob disease (CJD) is essential to avoid iatrogenic transmission and to distinguish CJD from potentially treatable dementias. […] Diagnosis of CJD in living patients is challenging, mainly because the disease phenotypes are highly heterogeneous, and detection of the misfolded protein in the brain tissue is often not feasible. […] Supportive investigations such as EEG, MRI and cerebrospinal fluid biomarkers have a relatively low diagnostic sensitivity and specificity in CJD. […] Diagnosis of CJD has been markedly improved by novel ultrasensitive seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), which are based on amplified prion detection. […] RT-QuIC is specific and highly sensitive for sporadic CJD, whereas PMCA is extremely sensitive for detecting variant CJD prions in biological fluids and in extraneural or lymphatic tissues.

• #1 Creutzfeldt-Jakob disease – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/creutzfeldt-jakob-disease/diagnosis-treatment/drc-20371230

  A brain biopsy or an exam of brain tissue after death, known as an autopsy, is the gold standard to confirm the presence of Creutzfeldt-Jakob disease, known as CJD. But health care providers often can make an accurate diagnosis before death. They base a diagnosis on your medical and personal history, a neurological exam, and certain diagnostic tests. […] A neurological exam may point to Creutzfeldt-Jakob disease (CJD) if you’re experiencing: […] In addition, health care providers commonly use these tests to help detect CJD: […] Electroencephalogram, also known as an EEG. This test measures the brain’s electrical activity. It’s done by placing small metal discs called electrodes on the scalp. electroencephalogram (EEG) results of people with CJD and variant CJD show a pattern that’s not typical.

• #1 Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD) | Pathology | School of Medicine | Case Western Reserve University

  https://case.edu/medicine/pathology/research/national-prion-disease-pathology-surveillance-center/human-prion-diseases/diagnostic-criteria-creutzfeldt-jakob-disease-cjd

  According to the latest diagnostic criteria released by the Centers for Disease Control and Prevention (CDC) in 2018, a definite diagnosis of CJD can only be determined through positive brain tissue testing. This would include standard neuropathological techniques (i.e., histology and immunohistochemistry); and/or western blot confirmed protease-resistant PrP. This testing is usually performed at the time of autopsy. […] Confirming or ruling out a diagnosis of CJD in a living patient can be difficult. A patient can be considered as having probable CJD if they fulfil the following criteria and other appropriate diseases have been ruled out. […] A positive result on at least one of the following laboratory tests: EEG suggestive of CJD (periodic sharp wave complexes), a positive 14-3-3 CSF test in patients with a disease duration of fewer than 2 years, high signal in caudate/putamen on magnetic resonance imaging (MRI) brain scan and/or at least two cortical regions (temporal, parietal, occipital) either on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR). […] Genetic forms of the disease can be determined through genetic sequencing on blood samples.

• #1 Creutzfeldt Jakob Disease

  https://www.sfn.org/sitecore/content/home/brainfacts2/diseases-and-disorders/neurological-disorders-az/diseases-a-to-z-from-ninds/creutzfeldt-jakob-disease

  Creutzfeldt-Jakob disease (CJD) is a rare, degenerative, invariably fatal brain disorder. […] Tests that help in the diagnosis of CJD include electroencephalography (which measures brain waves), detection of certain proteins in the fluid that surrounds the brain and spinal cord, and magnetic resonance imaging. […] The only way to confirm a diagnosis of CJD is by brain biopsy or autopsy. […] Because a correct diagnosis of CJD does not help the individual, a brain biopsy is discouraged unless it is need to rule out a treatable disorder.

• #1 Creutzfeldt-Jakob disease – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/creutzfeldt-jakob-disease/diagnosis-treatment/drc-20371230

  Magnetic resonance imaging (MRI). This imaging uses radio waves and a magnetic field to create detailed images of the head and body. MRI is especially useful in looking for brain disorders. MRI creates high-resolution images. People with CJD have characteristic changes that can be detected on certain MRI scans. […] Spinal fluid tests. Spinal fluid surrounds and cushions the brain and spinal cord. In a test called a lumbar puncture, also known as a spinal tap, a small amount of spinal fluid is taken for testing. This test can rule out other diseases that cause similar symptoms to CJD. It also can detect levels of proteins that may point to CJD or variant Creutzfeldt-Jakob disease (vCJD). […] A newer test called real-time quaking-induced conversion (RT-QuIC) can detect the presence of the prion proteins that cause CJD. This test can diagnose CJD before death, unlike an autopsy.

• #1 Creutzfeldt Jakob Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507860/

  The World Health Organization published diagnostic criteria for CJD in 1998, which relied on the clinical, EEG, and CSF findings. However, advanced diagnostic procedures like MRI and genetic testing have made those criteria obsolete. […] Brain MRI is a more sensitive and specific test for variant CJD than CSF 1433 protein and was found to be accurate in about 90% of cases. […] CSF protein biomarkers, including the 1433 protein, total tau (T-tau), and neuron-specific enolase (NSE), are markers of rapid neurodegeneration. These tests can help diagnose CJD but are not specific to the condition. […] In 2012, the American Academy of Neurology recommended ordering CSF 14-3-3 only when CJD is strongly suspected. […] The National Prion Disease Pathology Surveillance Center launched a new diagnostic test in April 2015 called „second-generation Real Time-Quaking-Induced Conversion (RT-QuIC),” which is highly sensitive and specific for CJD. […] Brain tissue biopsy or postmortem examination of the brain confirms the diagnosis of CJD. However, not all areas of the brain are affected by the disease. Imaging studies must target subcortical structures where abnormal features are most likely found.

• #1 Diagnostic challenge of rapidly progressing sporadic Creutzfeldt-Jakob disease | BMJ Case Reports

  https://casereports.bmj.com/content/12/9/e230535

  Brain MRI is one of the most informative diagnostic tools when assessing sCJD antemortem. […] MRI can detect the characteristic sCJD changes reliably according to recent studies, with 91% sensitivity and 95% specificity with DWI and FLAIR sequences. […] EEG is another important investigation when evaluating a patient with potential CJD. […] Another invaluable diagnostic test is the CSF analysis. […] The CSF study for CJD is tested at certain national reference centres with expertise on CJD. […] The gold-standard investigation for the diagnosis of CJD remains to be a brain biopsy. […] Therefore, a diagnosis of CJD should depend on a combination of clinical findings and non-invasive investigations including serology, MRI, EEG and CSF analysis.

• #1 Creutzfeldt–Jakob disease – Wikipedia

  https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease

  The Real-Time Quaking-Induced Conversion (RT-QuIC) assay has a diagnostic sensitivity of more than 80% and a specificity approaching 100%, tested in detecting PrPSc in CSF samples of people with CJD. It is therefore suggested as a high-value diagnostic method for the disease. […] MRI with diffusion weighted inversion (DWI) and fluid-attenuated inversion recovery (FLAIR) shows a high signal intensity in certain parts of the cortex (a cortical ribboning appearance), the basal ganglia, and the thalami. […] In recent years, studies have shown that the tumour marker neuron-specific enolase (NSE) is often elevated in CJD cases; however, its diagnostic utility is seen primarily when combined with a test for the 14-3-3 protein.

• #1

  https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/diagnosis/

  A diagnosis of Creutzfeldt-Jakob disease (CJD) is usually based on medical history, symptoms and a series of tests. […] The only way to confirm a diagnosis of CJD is to examine the brain tissue by carrying out a brain biopsy or, more commonly, after death in a post-mortem examination of the brain. […] Specialist services at the National CJD Research and Surveillance Unit in Edinburgh and the National Prion Clinic in London advise local teams when making a diagnosis. […] A clinical neurologist will rule out other conditions with similar symptoms. […] They’ll also check for some common signs of CJD by carrying out the following tests: an MRI brain scan uses strong magnetic fields and radio waves to produce a detailed image of the brain, and can show up abnormalities particular to CJD; an EEG records brain activity and may pick up abnormal electrical patterns seen in sporadic CJD; a lumbar puncture a procedure where a needle is inserted into the lower part of the spine to draw out a sample of cerebrospinal fluid (which surrounds your brain and spinal cord) so it can be tested for a certain protein that indicates you may have CJD; a prototype blood test for variant CJD has also been developed by the prion unit at the Medical Research Council (MRC) and is available through the National Prion Clinic; tonsil biopsy a small piece of tissue can be taken from the tonsils and checked for the abnormal prions found in variant CJD (they’re not present in other types of CJD); genetic test a simple blood test to find out whether you have a mutation (fault) in the gene that produces normal protein; a positive result may indicate familial (inherited) prion disease.

• #1 Creutzfeldt-Jakob disease: diagnosis and nursing care issues | Nursing Times

  https://www.nursingtimes.net/archive/creutzfeldt-jakob-disease-diagnosis-and-nursing-care-issues-20-05-2005/

  As with sporadic CJD, diagnosis depends on the exclusion of other treatable diseases. The three tests that can assist in the diagnosis are an MRI brain scan, a tonsil biopsy and analysis of the cerebrospinal fluid for the 14-3-3 protein. […] In the majority of cases, an MRI scan showing a pulvinar sign, together with the relevant clinical picture, can lead to a diagnosis of probable vCJD without the need for any invasive procedures. […] A definite diagnosis depends on the study of brain tissue either at post-mortem or following a brain biopsy.

• #1 Creutzfeldt-Jakob disease (CJD): Symptoms, causes, and treatment

  https://www.medicalnewstoday.com/articles/185884

• #1 The diagnosis of Creutzfeldt–Jakob disease in a SARS-CoV-2-infected patient should be confirmed by brain biopsy or autopsy | The Egyptian Journal of Neurology, Psychiatry and Neurosurgery | Full Text

  https://ejnpn.springeropen.com/articles/10.1186/s41983-024-00880-2

  The diagnosis of sporadic CJD was made on the basis of clinical presentation (rapidly progressive decline, depression, gait disturbance, incontinence, mutism), cerebral MRI (small infarcts, atrophy), hybrid FDG-PET (putaminal and thalamic diffusion restriction, bifrontal hypometabolism), and elevated 14-3-3 in the cerebrospinal fluid (CSF). […] According to the most recent diagnostic criteria published by the Centers for Disease Control and Prevention in 2018, a firm diagnosis of CJD can only be made by a positive brain tissue test. This includes standard neuropathological techniques (i.e., histology and immunohistochemistry) and/or Western blot confirmed protease-resistant prion protein. This test can be performed at either a brain biopsy or an autopsy. […] The diagnosis of definite CJD should be confirmed by a brain biopsy or autopsy, despite the logistic and financial challenges. In addition, all alternative causes of rapid cognitive decline must be ruled out before diagnosing CJD.

• #1 Creutzfeldt-Jakob Disease (CJD) – PsychDB

  https://www.psychdb.com/geri/dementia/creutzfeldt-jakob-disease-cjd

  CJD is caused by transmissible agents known as prions. Prions are small, infectious, protein-containing particles (PrPSc) that replicate over a period of time, replacing normal prion proteins (PrPC) and leading to neurotoxicity. […] Prion disease is diagnosed with least one of the characteristic biomarker features: cortical ribboning or lesions on magnetic resonance imaging with DWI (diffusion-weighted imaging) or FLAIR (fluid-attenuated inversion recovery). […] Tau or 14-3-3 protein in cerebrospinal fluid can be used to discriminate CJD from other neurodegenerative diseases. […] Real-time quaking-induced conversion (RT-QuIC), also called protein misfolding cyclic amplification (PMCA) is the most sensitive and specific test for diagnosing sporadic CJD. […] Characteristic triphasic waves and periodic sharp-and-slow (discharges) wave complexes can be seen on electroencephalogram. […] The gold standard diagnosis for CJD is neuropathologic examination (i.e. – brain biopsy). […] It is important to recognize that EEG has low sensitivity for CJD, and the non-specificity of CSF protein 14-3-3 elevation for CJD as well.

• #1 Creutzfeldt-Jakob Disease (CJD) – Brain, Spinal Cord, and Nerve Disorders – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/brain-spinal-cord-and-nerve-disorders/prion-diseases/creutzfeldt-jakob-disease-cjd

  Electroencephalography (EEG) is usually done to check for characteristic abnormalities in the electrical activity of the brain, which occur in 65% of people with CJD. However, these changes occur late in the disease and may not be present all the time. […] However, examination after death (autopsy) is critical because it is the only way to confirm the diagnosis and type of prion disease.

• #1 Variant Creutzfeldt–Jakob disease – Wikipedia

  https://en.wikipedia.org/wiki/Variant_Creutzfeldt%E2%80%93Jakob_disease

  A normal or an abnormal EEG, but not the diagnostic EEG changes often seen in classic CJD.[2] […] Duration of illness of over 6 months.[2] […] Routine investigations do not suggest an alternative, non-CJD diagnosis.[2] […] No history of getting human pituitary growth hormone or a dura mater graft from a cadaver.[2] […] No history of CJD in a first degree relative or prion protein gene mutation in the person.[2] […] vCJD is a separate condition from classic CreutzfeldtJakob disease (though both are caused by PrP prions).[9] Both classic and variant CJD are subtypes of CreutzfeldtJakob disease.

• #1 Case report of rapid onset cognitive and functional decline: Diagnosis of sporadic Creutzfeldt–Jakob disease

  https://www1.racgp.org.au/ajgp/2018/march/diagnosis-of-sporadic-creutzfeldt-jakob-disease

  CreutzfeldtJakob disease (CJD) was first described by neurologists Creutzfeldt and Jakob in the 1920s, with the modern interpretation made by Miller Fisher in 1960. […] Diagnostically, CJD is a challenging condition to detect premortem because of non-specific clinical manifestations. Definitive diagnosis requires identification of PRPCJD, the pathological form of PRP, in a brain biopsy. […] Suggestive investigation with cerebrospinal fluid (CSF) protein 14-3-3 has a sensitivity and specificity of 92% and 80% respectively. […] Magnetic resonance imaging (MRI), either diffusion-weighted MRI or fluid attenuation inversion recovery (FLAIR), features have 9192.3% and 93.895% sensitivity and specificity respectively. […] Electroencephalography (EEG) showing patterns typical of CJD has a reported 64% sensitivity and 91% specificity for diagnosis.

• #1 American Academy of Neurology: Neurology Resources | AAN

  https://www.aan.com/PressRoom/Home/PressRelease/1105

  The guideline determined that the 14-3-3 protein test can be useful when the probability of the person having Creutzfeldt-Jakob disease is between 20 percent and 90 percent. […] Muayqil noted that only doctors experienced in diagnosing dementia should determine whether the 14-3-3 protein test is needed and how results should be interpreted.

• #1 Frontiers | Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1072952/full

  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). 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. A definite diagnosis of prion disease requires the histological assessment of brain tissue generally and immunodetection of PrPSc. Over the last 20 years, the capacity to diagnose CJD pre-mortem confidently has progressed significantly, due to advances in brain magnetic resonance imaging (MRI) and CSF biomarker detection. Until recently, 14-3-3 and total Tau (T-tau) proteins in CSF were most commonly applied. Based on international experience in carefully selected patients, elevated concentrations of 14-3-3 or T-tau proteins in CSF have ~90% sensitivity and specificity for sCJD. Recently, the development of highly specific diagnostic biomarker assays, based on protein amplification techniques, such as RT-QuIC have improved the confident pre-mortem diagnosis of CJD. The RT-QuIC assay generates through successive rounds of shaking and incubation a detectable signal from miniscule amounts of PrPSc. Overall, the clinical diagnosis of “probable CJD” before death, or in the absence of an autopsy, has been significantly improved through the expansion of the supplementary investigations beyond a typical electroencephalogram (EEG), to include typical brain MRI features, CSF 14-3-3 protein detection, CSF T-tau protein estimation and most recently the RT-QuIC assay. The present study is a collaboration of the NDDL with the ANCJDR, which aims to determine whether the Roche automated immunoassay Elecsys® platform can improve the precision of T-tau protein CSF estimation, traditionally determined by standardized ELISA, and enhance diagnostic sensitivity. The Elecsys® system has demonstrated good analytical performance and correlation with other available assays, with low variability and reduced testing time. In addition, we compared the utility of CSF T-tau vs. 14-3-3 in the diagnosis of sCJD. The RT-QuIC assay performed at 92.7% sensitivity and 100% specificity. Importantly, our study has shown that CJD is still a differential diagnosis in a setting of negative RT-QuIC and positive 14-3-3 and/or tau CSF biomarker results. This study supports the proposal to amend the established WHO criteria for the clinical diagnosis of sCJD in a recent review of diagnostic criteria.

• #1 CJD EVALUATION, (CREUTZFELDT-JAKOB DISEASE) CSF | LABCORP OKLAHOMA, INC. | Test Directory

  https://www.labcatalog.net/tests/?test=30278

  CJD Evaluation, (Creutzfeldt-Jakob disease) CSF […] This evaluation is intended for use in patients with suspected Creutzfeldt-Jakob disease (CJD) and other human prion diseases. CJD is a rare and fatal neurodegenerative disorder that predominantly affects the brain and is caused by misfolded prion proteins (PrP[Sc]). CJD accounts for more than 90% of human prion diseases. Initial symptom onset is heterogenous but commonly includes rapidly progressive dementia, cerebellar ataxia, and myoclonus. The timeline of symptom progression and the pattern of symptom evolution can be divergent across patients and CJD subtypes, making an accurate diagnosis based on clinical presentation alone challenging. The inclusion of biomarkers with high diagnostic accuracy has improved the differentiation of CJD and related prion diseases from treatable neurological conditions with overlapping phenotypes. The real-time quaking-induced conversion (RT-QuIC) assay in cerebrospinal fluid (CSF) has been established to have strong clinical utility for early and accurate diagnosis of CJD through numerous independent studies. Furthermore, the robustness and reproducibility of the RT-QuIC assay for CJD across laboratories has been demonstrated through international ring trials. The clinical sensitivity and specificity of second-generation RT-QuIC assays in CSF have been consistently reported to be greater than or equal to 92% and greater than or equal to 99%, respectively. Despite the high diagnostic accuracy of the assay, RT-QuIC results should be interpreted in the appropriate clinical context along with other clinical and paraclinical findings. A definitive diagnosis of sporadic prion disease can be established only through neuropathological assessment of brain tissue. Unexpectedly negative RT-QuIC test results should prompt careful consideration of the differential diagnosis. If there is high suspicion of prion disease, repeat RT-QuIC testing may be warranted. A small subset of cases initially negative by RT-QuIC may become positive as the disease progresses. However, RT-QuIC may be persistently negative in a small proportion of patients with definitive prion disease. False-negative RT-QuIC results are most often encountered in cases of genetic prion disease (eg, fatal familial insomnia and Gerstmann-Straussler-Scheinker disease) and in atypical sporadic prion disease subtypes (eg, MM2 cortical subtype) that have slower indolent disease progression. Other CSF biomarkers have been utilized to support the diagnosis of CJD, including 14-3-3, total Tau measurement, and the ratio of total Tau to phosphorylated Tau at threonine 181. Recent studies have indicated that the Tau ratio (total Tau to pT181-Tau or vice versa) has a very high diagnostic accuracy, which exceeds that provided by total Tau or 14-3-3 enzyme-linked immunosorbent assays (ELISA). In a cohort of probable/definite CJD cases and controls tested utilizing the Roche Total-Tau and p-Tau (threonine 181) Elecsys assays, the optimized cut-off value for total Tau (>393 ng/L) had a clinical sensitivity and specificity of 92.3% and 88.3% for CJD, respectively; and the optimized cut-off value for the total Tau to p-Tau ratio (>18) has a clinical sensitivity and specificity of 97.4% and 95.9% for CJD, respectively. Importantly, total Tau or total Tau to p-Tau ratios utilize assay-dependent cut-off values, and cut-off values from one assay are not transferable to different assay platforms.

• #1 A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts

  https://www.mdpi.com/2035-8377/16/5/79

  Initial workup should include laboratory tests for dementia, such as serum chemistry panel, liver enzymes, ammonium levels, complete blood count, erythrocyte sedimentation rate (with blood cultures if any infection suspected), evaluation of the thyroid function, tests for neurosyphilis, and measurement of the B12 and folate levels, as well as serum levels of anti-thyroperoxidase antibodies to rule out Hashimoto encephalopathy. […] A series of protein markers identified in the CSF have rather high sensitivity and specificity, being valuable aids in the diagnosis of CJD: […] The family of 14-3-3 proteins was the first CSF biomarker to be used in diagnosing CJD. […] The microtubule-associated protein tau (total tau—t-tau) as a marker of neuroaxonal degeneration is also largely used as a surrogate marker for the pre-mortem diagnosis of CJD.

• #1 A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts

  https://www.mdpi.com/2035-8377/16/5/79

  Alpha-synuclein also shows significant increases, even more pronounced than in Parkinson’s disease or dementia with Lewy bodies, with a sensitivity of around 90%. […] The preferred imaging modality for suspected CJD is a MRI. […] The overall sensitivity of MRI abnormalities ranges between 69 and 92%, depending also on the expertise of the neuroradiologist. […] The World Health Organization proposed the following criteria for diagnosing sporadic Creutzfeldt-Jakob disease: […] Confirmed (definite) CJD: neuropathological confirmation, confirmation of protease-resistant prion protein (PrP) (immunocytochemistry or Western blot), Presence of scrapie-associated fibrils. […] These criteria have a 92% sensitivity for detecting probable sporadic CJD, rising to almost 98% when all investigations are performed.

• #1 CJDE – Overview: Creutzfeldt-Jakob Disease Evaluation, Spinal Fluid

  https://www.mayocliniclabs.com/test-catalog/overview/620374

  Assessment of Creutzfeldt-Jakob disease or other human prion disease in patients with rapidly progressive dementia. […] This evaluation is intended for use in patients with suspected Creutzfeldt-Jakob disease (CJD) and other human prion diseases. CJD is a rare and fatal neurodegenerative disorder that predominantly affects the brain and is caused by misfolded prion proteins (PrP[Sc]). […] The real-time quaking-induced conversion (RT-QuIC) assay in cerebrospinal fluid (CSF) has been established to have strong clinical utility for early and accurate diagnosis of CJD through numerous independent studies. […] The clinical sensitivity and specificity of second-generation RT-QuIC assays in CSF have been consistently reported to be greater than or equal to 92% and greater than or equal to 99%, respectively.

• #1 Cerebrospinal Fluid Diagnostic Tests | Pathology | School of Medicine | Case Western Reserve University

  https://case.edu/medicine/pathology/divisions/national-prion-disease-pathology-surveillance-center/human-prion-diseases/cerebrospinal-fluid-diagnostic-tests

  For many years, the only antemortem clinical laboratory test available for prion disease was limited to the detection of 14-3-3 and total Tau proteins in CSF. […] In 2015, the NPDPSC introduced 2nd Generation Real-Time Quaking Induced Conversion test, or RT-QuIC, to aid in the diagnosis of prion disease from CSF samples. […] 2nd Generation RT-QuIC has a sensitivity of 90.3% across all forms of prion disease and a specificity of 98.5% among patients being screened for prion disease based on concerning symptoms in an autopsy confirmed sample. […] A positive RT-QuIC test carries a 98% predictive value for prion disease, but RT-QuIC is not positive for all cases of prion disease. […] In case of a negative RT-QuIC result, the following should be considered: […] Are any other tests suggestive of prion disease?

• #1 CJDE – Overview: Creutzfeldt-Jakob Disease Evaluation, Spinal Fluid

  https://www.mayocliniclabs.com/test-catalog/overview/620374

  A definitive diagnosis of sporadic prion disease can be established only through neuropathological assessment of brain tissue. […] Unexpectedly negative RT-QuIC test results should prompt careful consideration of the differential diagnosis. […] Other CSF biomarkers have been utilized to support the diagnosis of CJD, including 14-3-3, total Tau measurement, and the ratio of total Tau to phosphorylated Tau at threonine 181. […] The National Prion Disease Pathology Surveillance Center (NPDPSC) coordinates autopsies and neuropathologic examinations on suspected prion disease cases. […] A positive real-time quaking-induced conversion (RT-QuIC) is supportive of prion disease and, in the correct clinical context, fulfills the Centers of Disease Control and Prevention diagnostic criteria of probable prion disease.

• #1 Advanced tests for early and accurate diagnosis of Creutzfeldt–Jakob disease | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2016.65

  Recently, novel ultrasensitive seeding assays, based on the amplified detection of PrPCJD, have improved the diagnostic process; for example, real-time quaking-induced conversion (RT-QuIC) is a sensitive method to detect prion-seeding activity in brain homogenate from humans with any subtype of sporadic CJD. […] RT-QuIC can also be used for in vivo diagnosis of CJD: its diagnostic sensitivity in detecting PrPCJD in CSF samples is 96%, and its specificity is 100%. […] Recently, we provided evidence that RT-QuIC of olfactory mucosa brushings is a 97% sensitive and 100% specific for sporadic CJD. […] These assays provide a basis for definitive antemortem diagnosis of prion diseases and, in doing so, improve prospects for reducing the risk of prion transmission. […] Moreover, they can be used to evaluate outcome measures in therapeutic trials for these as yet untreatable infections.

• #1 [Creutzfeldt-Jakob disease: diagnosis, incidence, prevention and treatment] — Oxford Big Data Institute

  https://www.bdi.ox.ac.uk/publications/937765

  Creutzfeldt-Jakob disease (CJD) is a rare, neurodegenerative disorder belonging to the spongiform encephalopathies. […] Diagnostic information can be obtained by EEG, testing cerebrospinal fluid for the presence of the 14-3-3 protein, MRI, brain biopsy, tonsil biopsy, and postmortem brain examination. […] Some tests, such as MRI and postmortem brain examination, can be used to distinguish between CJD and vCJD. […] Pathological prions in a tonsil biopsy are only found with vCJD.

• #1 FAQs – CJD Foundation

  https://cjdfoundation.org/faqs/

  How can we be sure that the clinical diagnosis of CJD is correct? Each individual case of CJD can be assigned to one of three forms: sporadic, genetic, or acquired (variant or iatrogenic). The diagnostic methods may vary depending on the type. In sporadic CJD, the spinal fluid test has improved the diagnostic accuracy while the patient is alive, and it is now included as one of the diagnostic criteria along with the electroencephalogram (EEG) and MRI. Spinal fluid and MRI have become increasingly reliable methods of diagnosing classic CJD. In recent years, RT-QuIC has been developed and fine-tuned to detect CJD with sensitivity and specificity in the high 90 percentile. Recent studies have identified methods of reaching virtually 100% accuracy through RT-QuIC. MRI images, when reviewed by a neuroradiologist trained to detect CJD, can also be very accurate indicators of CJD. Examination of brain tissue is the only known method of detecting CJD with 100% certainty. While brain biopsy is an option, it is not recommended for CJD patients unless used to rule out other treatable conditions (and biopsy could potentially miss affected areas of the brain). Full brain biopsy post mortem is recommended to confirm any prion disease diagnosis, as well as to determine the subtype and to determine whether the disease is a genetic form. (Note: In the U.S., RT-QuIC is available only from through the National Prion Disease Pathology Surveillance Center. For information on RT-QuIC, second opinions on MRIs, and full brain autopsy, contact our HelpLine, or follow this link for the latest news reported in the Annals of Neurology.) However, the only way to currently be sure of the diagnosis is by brain biopsy or autopsy. In genetic CJD, the diagnosis depends on development of particular neurological symptoms and the identification of a PrP gene mutation by genetic analysis. In acquired CJD, iatrogenic CJD is diagnosed on the basis of symptoms developing in someone with a relevant exposure. In vCJD, diagnosis is very difficult while the patient is alive, unless the diagnosis of vCJD is suspected and tonsil biopsy is carried out. An MRI scan may prove to be useful, however, a definitive diagnosis depends on examination of brain tissue or lymphoreticular tissue such as the tonsils.

• #1 Cerebrospinal Fluid Diagnostic Tests | Pathology | School of Medicine | Case Western Reserve University

  https://case.edu/medicine/pathology/divisions/national-prion-disease-pathology-surveillance-center/human-prion-diseases/cerebrospinal-fluid-diagnostic-tests

  Brain MRI: Is the MRI suggestive of prion disease? Brain MRI’s suggestive of prion disease typically demonstrate hyperintensity on DWI in the basal ganglia and/or at least two cortical areas (excluding frontal cortex). […] Consider PRNP genetic testing, especially in the presence of family history or similar symptoms. […] Is the brain MRI suggestive of variant CJD, which generally demonstrates the pulvinar sign of FLAIR sequences?

• #1 CJD Diagnostic Criteria | Classic CJD | CDC

  https://www.cdc.gov/creutzfeldt-jakob/hcp/clinical-overview/diagnosis.html

  Diagnosed by standard neuropathological techniques […] Neuropsychiatric disorder plus positive RT-QuIC in cerebrospinal fluid (CSF) or other tissues. […] A positive result on at least one of the following laboratory tests: a typical EEG (periodic sharp wave complexes) during an illness of any duration […] The absence of a positive result for any of the four tests above that would classify a case as „probable” […] To meet the definition for an iatrogenic case, the case must meet the following criteria: Progressive cerebellar syndrome in a recipient of human cadaveric-derived pituitary hormone […] Have definite or probable CJD and definite or probable CJD in a first-degree relative.

• #1 Creutzfeldt-Jakob disease | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/creutzfeldt-jakob-disease?lang=us

  Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy that results in rapidly progressive dementia and death usually within a year from onset. The vast majority are sporadic, but familial and acquired forms are occasionally encountered. […] The United State of America’s Centers for Disease Control and Prevention (CDC) defines the following diagnostic criteria: definite: diagnosed by standard neuropathological and/or immunocytochemically and/or Western blot confirmed protease-resistant PrP and/or presence of scrapie-associated fibrils; probable: neuropsychiatric disorder plus positive RT-QuIC in CSF or other tissues or rapidly progressive dementia; and at least two out of the following four clinical features: myoclonus; visual or cerebellar signs; pyramidal/extrapyramidal signs; akinetic mutism AND a positive result on at least one of the following laboratory tests: typical EEG; positive 14-3-3 CSF assay with disease duration 2 years; DWI or FLAIR high signal in the caudate/putamen or at least cortical regions (temporal, parietal, occipital) AND without routine investigations indicating an alternative diagnosis. […] A definitive diagnosis requires a brain biopsy, although in many institutions the difficulty involved in sterilizing equipment renders a biopsy undesirable.

• #1 Case report: challenges in making the diagnosis of sporadic Creutzfeldt-Jakob disease – McWhorter – Journal of Emergency and Critical Care Medicine

  https://jeccm.amegroups.org/article/view/6763/html

  The Center for Disease Control and Prevention (CDC) outlines two diagnostic pathways for probable sCJD. The first one includes neuropsychiatric disorder plus positive RT-QuIC in CSF or other tissues. The second pathway requires three components: symptoms, supportive diagnostic studies, and exclusion of alternative diagnoses. […] MRI, EEG, and CSF studies are common diagnostic modalities to help to include and exclude wide range of differential diagnoses of neurological diseases. MRI is the most useful in the diagnosis of CJD and maybe the most sensitive test during early stages of disease, with 83% to 92% sensitivity, and 87% to 95% specificity. […] Our patients second supportive study was EEG. […] The third diagnostic exam was our patients CSF assay. […] In conclusion, we presented diagnostic challenges in a rare case of sCJD which progressed to death within 3 months of symptoms onset. We followed the outline of CDC diagnostic criteria for probable sCJD after other differential diagnoses were excluded.

• #1 CJD Differential Diagnosis | Memory and Aging Center

  https://memory.ucsf.edu/dementia/rapidly-progressive-dementias/cjd-differential-diagnosis

  The disease course of CJD is highly variable and may mimic many other neurological disorders. The first step is to rule out alternative diagnoses. […] A diagnosis of probable CJD requires an extensive exclusionary work up. It is important to rule out these conditions before confirming prion disease.

• #1 Creutzfeldt Jakob Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507860/

  Creutzfeldt-Jakob disease (CJD) is a rare, fatal degenerative brain disorder caused by prion proteins. This condition belongs to a group of transmissible spongiform encephalopathies affecting people worldwide, with an incidence of 1 case per million per year. Approximately 350 cases are diagnosed annually in the United States. Death occurs in nearly 70% of patients within a year. Prompt and accurate diagnosis of CJD impacts intervention strategies and overall outcomes. […] Describe the Creutzfeldt-Jakob disease evaluation process from the clinical encounter to the interpretation of laboratory and imaging results. […] Creutzfeldt-Jakob disease is often a diagnostic challenge as it presents similarly to other conditions presenting with RPD. The following are the recommended initial screening tests for evaluating RPD: Complete blood count, Complete metabolic panel, Blood magnesium, Rapid plasma reagin, Erythrocyte sedimentation rate, Antinuclear antibody, C-reactive protein, Thyroid function tests, Vitamin B12 level, HIV test, Lyme disease titer, Autoimmune antibodies, Urinalysis, CSF studies, including glucose, oligoclonal bands, and cell count with differential, CSF 14-3-3 protein (a test for prion disease), Venereal disease research laboratory (VDRL) test.

• #1 A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts

  https://www.mdpi.com/2035-8377/16/5/79

  Creutzfeldt-Jakob disease is a rare neurodegenerative and invariably fatal disease with a fulminant course once the first clinical symptoms emerge. Its incidence appears to be rising, although the increasing figures may be related to the improved diagnostic tools. […] For a long time, the diagnosis was possible only post-mortem by showing the spongiform modifications induced in the brain, but in recent years, more sophisticated laboratory evaluations and brain imaging studies can aid in diagnosing the disease earlier. Nonetheless, the diagnosis is often delayed by several months from the onset of the first symptoms, much to the distress of patients, who witness the rapid decline of their health and of their family members. […] The diagnosis of sporadic CJD is challenging, because patients present with a wide range of non-specific symptoms and signs, but the disease is known as rapidly progressing dementia-associating visual and cerebellar signs, myoclonus, the patients develop rapidly akinetic mutism, and the mean survival is about 6 months.

• #1 FAQs – CJD Foundation

  https://cjdfoundation.org/faqs/

  Is CJD research currently being conducted? Yes, public and private institutions and government agencies around the world are engaged in researching all aspects of CJD for the ultimate purpose of finding the means for preventing, treating and curing this disease. Among the many areas being studied are the unique nature of the infectious agent and how it destroys the brain. Scientists are also trying to ascertain which factors affect infectivity, susceptibility to disease and the onset of symptoms. Many researchers are trying to develop new, reliable diagnostic tests that can detect the disease before symptoms of the disease occur. Such pre-clinical tests in people can be useful, not only for the development of therapies before significant damage occurs, but also to ensure the safety from transmissible agents to blood, blood products, organs and surgical instruments.

• #1 Creutzfeldt-Jakob disease (CJD) | Britannica

  https://www.britannica.com/science/Creutzfeldt-Jakob-disease

  Creutzfeldt-Jakob disease (CJD), rare fatal degenerative disease of the central nervous system. […] Diagnosis of CJD typically entails spinal tap, electroencephalography, and other procedures to assess neurological function in order to rule out conditions that might produce similar symptoms. Diagnosis is confirmed through brain biopsy, in which a small section of tissue is removed from the brain and examined in a laboratory. […] Scientists are developing tests capable of detecting prions in cerebrospinal fluid and blood. Such tests could enable early diagnosis and improve prion screening for blood transfusions. […] There is no known cure for CJD, nor can the progression of the disease be delayed by medication or surgery. Hence, treatment is supportive, being aimed primarily at minimizing pain and discomfort.

• #1 Exploring the Potential of Biomarkers for Early Diagnosis and Management of Sporadic Creutzfeldt – Jakob disease; A Review

  https://www.neurologyletters.com/article_177557.html

  The development of effective biomarkers has the potential to significantly impact the diagnosis and management of sCJD, ultimately improving patient outcomes. With early detection, physicians can initiate early treatments and interventions to slow disease progression and improve patient quality of life. Additionally, biomarkers can aid in monitoring disease progression, enabling physicians to adjust treatment plans accordingly. […] Identifying and validating biomarkers for sCJD diagnosis and management is crucial for improving the accuracy and speed of diagnosis, as well as the development of effective treatments for this devastating condition. […] CSF biomarkers have emerged as a promising tool for diagnosing and managing sCJD, a disease characterised by the abnormal accumulation of misfolded prion protein leading to neurodegeneration and characteristic clinical features such as rapidly progressive dementia, myoclonus, and ataxia.

• #1

  https://link.springer.com/article/10.1007/s00415-023-11962-1

  To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD). […] The diagnosis of probable CJD in living patients is achieved by the presence of specific neurological signs, brain MRI, EEG and the detection of 14-3-3 proteins in the CSF. […] MRI diagnostic criteria for CJD have been outlined in 2009 and included increased MRI signal, either in DWI or FLAIR, in the cortex and/or basal ganglia. […] In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. […] Current diagnostic criteria for CJD refer to MRI signal abnormalities in DWI and/or FLAIR sequences in temporal-parietal-occipital cortical regions as core diagnostic features. […] DWI changes are a hallmark of CJD and should be carefully searched when dealing with RPD patients.

• #1 Creutzfeldt-Jakob Disease | Conditions | UCSF Health

  https://www.ucsfhealth.org/conditions/creutzfeldt-jakob-disease

  Creutzfeldt-Jakob disease (CJD) is typically a rapidly progressive dementia. Early diagnosis is important because the underlying cause of the dementia may be treatable. […] If CJD is suspected, you may undergo a series of tests. Your doctor will conduct a neurological examination and other tests such as a spinal tap to rule out more common and treatable forms of dementia and an electroencephalogram (EEG) to record the brain’s electrical pattern, which can identify a specific abnormality that sometimes occurs in CJD. […] One of the most effective diagnostic tools is a magnetic resonance imaging (MRI) brain scan, which can reveal patterns of abnormal brain signals characteristic of CJD. […] In rare cases, when the diagnosis is not clear, a brain biopsy is performed. A neurosurgeon removes a small piece of tissue from the abnormal area of the brain and the tissue is examined by a neuropathologist. Generally, an MRI is sufficient and this procedure is not necessary.

• #1 Creutzfeldt–Jakob disease: From presentation to palliative care

  https://www1.racgp.org.au/ajgp/2024/october/creutzfeldt-jakob-disease

  Table 3 outlines investigations that can help diagnose CJD. […] Currently there are no treatments for CJD. Symptomatic and supportive care with palliative care involvement helps manage symptoms and support patients and families. […] A recent study from the UK using prion protein monoclonal antibody (PRN100) in humans showed that it appeared to be safe and reached encouraging CSF and brain tissue concentrations. […] A multidisciplinary approach will assist the GP, patient and family through diagnosis, symptom management and end-of-life care. […] There are no consensus guidelines for the palliative management of this rare disease. A holistic focus with a multidisciplinary team is essential. […] Research shows that families advocate for a multidisciplinary team and support by healthcare providers familiar with CJD.

• #1 Creutzfeldt-Jakob disease: a rapidly progressing form of dementia — DPUK

  https://www.dementiasplatform.uk/news-and-media/blog/creutzfeldt-jakob-disease-a-rapidly-progressing-form-of-dementia

  Fortunately, when CJD is suspected, there are some highly accurate tests. The rapid progression of symptoms suggests to clinicians that a patient has CJD. Tools that can help with diagnosis include brain scans like MRI plus procedures like lumbar punctures where a sample of spinal fluid is taken to test for certain proteins. Usually the diagnosis can be made confidently in life. […] Unfortunately, there is no treatment able to slow or stop the progression of CJD, but prion protein itself is the obvious target for experimental treatment. Management includes providing accurate information, psychological support, and optimising care. Existing therapies are limited to treating symptoms.

• #2

  https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/diagnosis/

  A diagnosis of Creutzfeldt-Jakob disease (CJD) is usually based on medical history, symptoms and a series of tests. […] The only way to confirm a diagnosis of CJD is to examine the brain tissue by carrying out a brain biopsy or, more commonly, after death in a post-mortem examination of the brain. […] Specialist services at the National CJD Research and Surveillance Unit in Edinburgh and the National Prion Clinic in London advise local teams when making a diagnosis. […] A clinical neurologist will rule out other conditions with similar symptoms. […] They’ll also check for some common signs of CJD by carrying out the following tests: an MRI brain scan uses strong magnetic fields and radio waves to produce a detailed image of the brain, and can show up abnormalities particular to CJD; an EEG records brain activity and may pick up abnormal electrical patterns seen in sporadic CJD; a lumbar puncture a procedure where a needle is inserted into the lower part of the spine to draw out a sample of cerebrospinal fluid (which surrounds your brain and spinal cord) so it can be tested for a certain protein that indicates you may have CJD; a prototype blood test for variant CJD has also been developed by the prion unit at the Medical Research Council (MRC) and is available through the National Prion Clinic; tonsil biopsy a small piece of tissue can be taken from the tonsils and checked for the abnormal prions found in variant CJD (they’re not present in other types of CJD); genetic test a simple blood test to find out whether you have a mutation (fault) in the gene that produces normal protein; a positive result may indicate familial (inherited) prion disease.

• #2 Creutzfeldt-Jakob disease | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/creutzfeldt-jakob-disease?lang=us

  Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy that results in rapidly progressive dementia and death usually within a year from onset. The vast majority are sporadic, but familial and acquired forms are occasionally encountered. […] The United State of America’s Centers for Disease Control and Prevention (CDC) defines the following diagnostic criteria: definite: diagnosed by standard neuropathological and/or immunocytochemically and/or Western blot confirmed protease-resistant PrP and/or presence of scrapie-associated fibrils; probable: neuropsychiatric disorder plus positive RT-QuIC in CSF or other tissues or rapidly progressive dementia; and at least two out of the following four clinical features: myoclonus; visual or cerebellar signs; pyramidal/extrapyramidal signs; akinetic mutism AND a positive result on at least one of the following laboratory tests: typical EEG; positive 14-3-3 CSF assay with disease duration 2 years; DWI or FLAIR high signal in the caudate/putamen or at least cortical regions (temporal, parietal, occipital) AND without routine investigations indicating an alternative diagnosis. […] A definitive diagnosis requires a brain biopsy, although in many institutions the difficulty involved in sterilizing equipment renders a biopsy undesirable.

• #2 Creutzfeldt-Jakob Disease (CJD) | Doctor

  https://patient.info/doctor/creutzfeldt-jakob-disease

  Clinicians caring for patients with CJD or suspected CJD of all types, should inform the local Consultant in Communicable Disease Control or their equivalent in Scotland. Cases should also be reported jointly to the NCJDSU and the National Prion Clinic. […] Brain biopsy is only considered if there is a good chance of another diagnosis. Tonsil biopsy in nvCJD can help with diagnosis. […] Electroencephalography (EEG) shows periodic wave complexes in sporadic CJD unlike nvCJD. Further biochemical markers in the CSF, namely 14-3-3, may be useful in sporadic CJD where the clinical manifestations have been present for under 2 years. […] MRI can help distinguish between sporadic CJD and nvCJD. In nvCJD there is changes including high signal in the posterior thalamus (has high sensitivity and specificity). On the other hand, in sporadic CJD there is increased intensity in the caudate and putamen.

• #2 Creutzfeldt-Jakob Disease (CJD) – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/prion-diseases/creutzfeldt-jakob-disease-cjd

  Creutzfeldt-Jakob disease should be considered in older patients with rapidly progressive dementia, especially if accompanied by myoclonus or ataxia. […] CJD is suspected in symptomatic younger patients when they have been exposed to prion-contaminated beef in the United Kingdom or other at-risk countries or who have a family history of CJD (familial CJD). Rarely, sCJD develops in young patients, but in such patients, other diseases must be excluded. […] The best noninvasive diagnostic test for CJD is Diffusion-weighted MRI. […] It can detect evolving areas of hyperintensity (bright areas) in the cortical ribbon and/or basal ganglia, which strongly suggest CJD. […] A CSF test, called real-time quaking-induced conversion (RT-QuIC), amplifies and detects minimal amounts of prion activity in CSF; this test is more accurate than previous CSF tests, with a sensitivity of about 90% and a specificity of about 99% for prion diseases. […] EEG can sometimes be helpful in diagnosis. Results are positive in about 65% of patients with CJD; EEG shows characteristic periodic sharp waves, but this pattern typically occurs late in the disease, may be transient, and does not occur in all cases of CJD.

• #2 A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts

  https://www.mdpi.com/2035-8377/16/5/79

  Initial workup should include laboratory tests for dementia, such as serum chemistry panel, liver enzymes, ammonium levels, complete blood count, erythrocyte sedimentation rate (with blood cultures if any infection suspected), evaluation of the thyroid function, tests for neurosyphilis, and measurement of the B12 and folate levels, as well as serum levels of anti-thyroperoxidase antibodies to rule out Hashimoto encephalopathy. […] A series of protein markers identified in the CSF have rather high sensitivity and specificity, being valuable aids in the diagnosis of CJD: […] The family of 14-3-3 proteins was the first CSF biomarker to be used in diagnosing CJD. […] The microtubule-associated protein tau (total tau—t-tau) as a marker of neuroaxonal degeneration is also largely used as a surrogate marker for the pre-mortem diagnosis of CJD.

• #2 CJD EVALUATION, (CREUTZFELDT-JAKOB DISEASE) CSF | LABCORP OKLAHOMA, INC. | Test Directory

  https://www.labcatalog.net/tests/?test=30278

  CJD Evaluation, (Creutzfeldt-Jakob disease) CSF […] This evaluation is intended for use in patients with suspected Creutzfeldt-Jakob disease (CJD) and other human prion diseases. CJD is a rare and fatal neurodegenerative disorder that predominantly affects the brain and is caused by misfolded prion proteins (PrP[Sc]). CJD accounts for more than 90% of human prion diseases. Initial symptom onset is heterogenous but commonly includes rapidly progressive dementia, cerebellar ataxia, and myoclonus. The timeline of symptom progression and the pattern of symptom evolution can be divergent across patients and CJD subtypes, making an accurate diagnosis based on clinical presentation alone challenging. The inclusion of biomarkers with high diagnostic accuracy has improved the differentiation of CJD and related prion diseases from treatable neurological conditions with overlapping phenotypes. The real-time quaking-induced conversion (RT-QuIC) assay in cerebrospinal fluid (CSF) has been established to have strong clinical utility for early and accurate diagnosis of CJD through numerous independent studies. Furthermore, the robustness and reproducibility of the RT-QuIC assay for CJD across laboratories has been demonstrated through international ring trials. The clinical sensitivity and specificity of second-generation RT-QuIC assays in CSF have been consistently reported to be greater than or equal to 92% and greater than or equal to 99%, respectively. Despite the high diagnostic accuracy of the assay, RT-QuIC results should be interpreted in the appropriate clinical context along with other clinical and paraclinical findings. A definitive diagnosis of sporadic prion disease can be established only through neuropathological assessment of brain tissue. Unexpectedly negative RT-QuIC test results should prompt careful consideration of the differential diagnosis. If there is high suspicion of prion disease, repeat RT-QuIC testing may be warranted. A small subset of cases initially negative by RT-QuIC may become positive as the disease progresses. However, RT-QuIC may be persistently negative in a small proportion of patients with definitive prion disease. False-negative RT-QuIC results are most often encountered in cases of genetic prion disease (eg, fatal familial insomnia and Gerstmann-Straussler-Scheinker disease) and in atypical sporadic prion disease subtypes (eg, MM2 cortical subtype) that have slower indolent disease progression. Other CSF biomarkers have been utilized to support the diagnosis of CJD, including 14-3-3, total Tau measurement, and the ratio of total Tau to phosphorylated Tau at threonine 181. Recent studies have indicated that the Tau ratio (total Tau to pT181-Tau or vice versa) has a very high diagnostic accuracy, which exceeds that provided by total Tau or 14-3-3 enzyme-linked immunosorbent assays (ELISA). In a cohort of probable/definite CJD cases and controls tested utilizing the Roche Total-Tau and p-Tau (threonine 181) Elecsys assays, the optimized cut-off value for total Tau (>393 ng/L) had a clinical sensitivity and specificity of 92.3% and 88.3% for CJD, respectively; and the optimized cut-off value for the total Tau to p-Tau ratio (>18) has a clinical sensitivity and specificity of 97.4% and 95.9% for CJD, respectively. Importantly, total Tau or total Tau to p-Tau ratios utilize assay-dependent cut-off values, and cut-off values from one assay are not transferable to different assay platforms.

• #2 Advanced tests for early and accurate diagnosis of Creutzfeldt–Jakob disease | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2016.65

  Recently, novel ultrasensitive seeding assays, based on the amplified detection of PrPCJD, have improved the diagnostic process; for example, real-time quaking-induced conversion (RT-QuIC) is a sensitive method to detect prion-seeding activity in brain homogenate from humans with any subtype of sporadic CJD. […] RT-QuIC can also be used for in vivo diagnosis of CJD: its diagnostic sensitivity in detecting PrPCJD in CSF samples is 96%, and its specificity is 100%. […] Recently, we provided evidence that RT-QuIC of olfactory mucosa brushings is a 97% sensitive and 100% specific for sporadic CJD. […] These assays provide a basis for definitive antemortem diagnosis of prion diseases and, in doing so, improve prospects for reducing the risk of prion transmission. […] Moreover, they can be used to evaluate outcome measures in therapeutic trials for these as yet untreatable infections.

• #2 Frontiers | Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1072952/full

  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). 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. A definite diagnosis of prion disease requires the histological assessment of brain tissue generally and immunodetection of PrPSc. Over the last 20 years, the capacity to diagnose CJD pre-mortem confidently has progressed significantly, due to advances in brain magnetic resonance imaging (MRI) and CSF biomarker detection. Until recently, 14-3-3 and total Tau (T-tau) proteins in CSF were most commonly applied. Based on international experience in carefully selected patients, elevated concentrations of 14-3-3 or T-tau proteins in CSF have ~90% sensitivity and specificity for sCJD. Recently, the development of highly specific diagnostic biomarker assays, based on protein amplification techniques, such as RT-QuIC have improved the confident pre-mortem diagnosis of CJD. The RT-QuIC assay generates through successive rounds of shaking and incubation a detectable signal from miniscule amounts of PrPSc. Overall, the clinical diagnosis of “probable CJD” before death, or in the absence of an autopsy, has been significantly improved through the expansion of the supplementary investigations beyond a typical electroencephalogram (EEG), to include typical brain MRI features, CSF 14-3-3 protein detection, CSF T-tau protein estimation and most recently the RT-QuIC assay. The present study is a collaboration of the NDDL with the ANCJDR, which aims to determine whether the Roche automated immunoassay Elecsys® platform can improve the precision of T-tau protein CSF estimation, traditionally determined by standardized ELISA, and enhance diagnostic sensitivity. The Elecsys® system has demonstrated good analytical performance and correlation with other available assays, with low variability and reduced testing time. In addition, we compared the utility of CSF T-tau vs. 14-3-3 in the diagnosis of sCJD. The RT-QuIC assay performed at 92.7% sensitivity and 100% specificity. Importantly, our study has shown that CJD is still a differential diagnosis in a setting of negative RT-QuIC and positive 14-3-3 and/or tau CSF biomarker results. This study supports the proposal to amend the established WHO criteria for the clinical diagnosis of sCJD in a recent review of diagnostic criteria.

• #2 Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD) | Pathology | School of Medicine | Case Western Reserve University

  https://case.edu/medicine/pathology/research/national-prion-disease-pathology-surveillance-center/human-prion-diseases/diagnostic-criteria-creutzfeldt-jakob-disease-cjd

  According to the latest diagnostic criteria released by the Centers for Disease Control and Prevention (CDC) in 2018, a definite diagnosis of CJD can only be determined through positive brain tissue testing. This would include standard neuropathological techniques (i.e., histology and immunohistochemistry); and/or western blot confirmed protease-resistant PrP. This testing is usually performed at the time of autopsy. […] Confirming or ruling out a diagnosis of CJD in a living patient can be difficult. A patient can be considered as having probable CJD if they fulfil the following criteria and other appropriate diseases have been ruled out. […] A positive result on at least one of the following laboratory tests: EEG suggestive of CJD (periodic sharp wave complexes), a positive 14-3-3 CSF test in patients with a disease duration of fewer than 2 years, high signal in caudate/putamen on magnetic resonance imaging (MRI) brain scan and/or at least two cortical regions (temporal, parietal, occipital) either on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR). […] Genetic forms of the disease can be determined through genetic sequencing on blood samples.

• #2 SciELO Brazil – Diagnostic approach in a patient with Creutzfeldt-Jakob disease Diagnostic approach in a patient with Creutzfeldt-Jakob disease

  https://www.scielo.br/j/dn/a/T9HCs9V6ZxTJRK74LhqT6Pt/

  The present case study demonstrates the importance of an appropriate investigation in situations of RPD. This investigation involves the search of autoimmune encephalitis, central nervous system (CNS) infections, and metabolic and demyelinating conditions. […] The possibility of performing RT QUIC in suspected cases is extremely important, given its high specificity in prion disease diagnosis. […] In summary, patient in this report presented a typical clinical picture, corroborated by a typical MRI and EEG, and also high titers of 14-3-3 protein in the CSF, in addition to positive RT QUIC.

• #2 Diagnostic challenge of rapidly progressing sporadic Creutzfeldt-Jakob disease | BMJ Case Reports

  https://casereports.bmj.com/content/12/9/e230535

  Antemortem assessment of sporadic Creutzfeldt-Jakob disease (sCJD) can be significantly hampered due to its rarity, low index of clinical suspicion and its non-specific clinical features. […] This case underscores the importance of considering CJD as a potential diagnosis for rapidly progressive dementia. Serology tests, EEG, MRI and CSF study are invaluable diagnostic tools when assessing for sCJD. Appropriate use of those diagnostic tests, along with a detailed clinical examination, can successfully and promptly exclude other differential diagnoses and confirm sCJD. […] Given the rare incidence and non-specific clinical features of CJD, it is not uncommon for it to be missed as a potential diagnosis. […] Hence, in addition to a detailed clinical history and examination, early use of appropriate investigations involving MRI, EEG, blood and cerebrospinal fluid (CSF) analysis is crucial in excluding other differentials and at the same time, confirming probable sCJD.

• #2 Exploring the Potential of Biomarkers for Early Diagnosis and Management of Sporadic Creutzfeldt – Jakob disease; A Review

  https://www.neurologyletters.com/article_177557.html

  The most commonly used CSF biomarkers for sCJD are 14-3-3 protein, total tau protein (tau), and neuron-specific enolase (NSE). These biomarkers have demonstrated high sensitivity and specificity in identifying sCJD patients, particularly when combined. […] The use of biomarkers in diagnosing and managing sCJD has been a topic of interest in recent years. Biomarkers are measurable indicators of biological processes that can provide valuable information about the presence, severity, and progression of a disease. […] One of the most significant benefits of using biomarkers in sCJD is the potential for early and accurate diagnosis. […] The use of biomarkers, such as the presence of 14-3-3 protein in CSF or abnormal prion protein in brain tissue, aid in diagnosing sCJD with higher sensitivity and specificity, allowing for earlier detection and more accurate diagnosis. […] Future research in the field of sCJD biomarkers should focus on developing more reliable and specific tests that can accurately diagnose the disease at an early stage.

• #3 Creutzfeldt-Jakob Disease | National Institute of Neurological Disorders and Stroke

  https://www.ninds.nih.gov/health-information/disorders/creutzfeldt-jakob-disease

  To diagnose CJD, a healthcare provider, typically a neurologist, will do a physical exam and ask about the persons medical history. Depending on the findings, a doctor can use a few other tests to help diagnose CJD: […] The only way to confirm a diagnosis of CJD is by brain biopsy or an autopsy. In a brain biopsy, which is now rarely done, a neurosurgeon removes a small piece of tissue from the living person’s brain so it can be examined by a neuropathologist. This procedure may be dangerous for the person and is generally discouraged unless it is needed to rule out a treatable disorder. In an autopsy, the whole brain is examined after death.

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