Definite Creutzfeldt-Jakob Disease Research Articles

Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologies.

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

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme

IntroductionIncorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients.Methods250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC.Results27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative.ConclusionsIndividuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

A Study of Clinical Profile, Radiological and Electroencephalographic Characteristics of Sporadic Creutzfeldt-Jakob Disease From a Tertiary Care Hospital.

Background Sporadic Creutzfeldt-Jakob disease (CJD), the most common form of human prion disease, is the archetypal diagnosis in this category. However, the spectrum of possible diagnoses is wide, encompassing various treatable conditions. A lack of standardized diagnostic criteria and a tendency to opt for brain biopsies and clinical autopsies can be limiting factors in reaching a conclusive diagnosis. Objective This study aims to retrospectively analyze clinical and investigative findings in patients referred to a specialized neurology clinic exhibiting rapidly progressive dementia. These patients were ultimately diagnosed with Probable sporadic Creutzfeldt-Jakob disease (CJD) based on the 2018 CDC criteria for sporadic CJD. Materials and Methods This study included cases of CJD diagnosed based on clinical, electrophysiological, and imaging parameters at a tertiary care hospital in India from 2016 to 2020. The diagnostic criteria proposed by the CDC (Centers for Disease Control and Prevention) were employed to categorize patients as definite, probable, or possible CJD cases. All patients underwent MRI (magnetic resonance imaging) imaging and EEG ( electroencephalography) recording, while diagnostic brain biopsies were not conducted due to a lack of consent from close relatives. Results This observational descriptive study comprised four patients diagnosed with Probable sporadic CJD (sCJD), all of whom were female. The patients exhibited an age range of 57 to 75 years at the onset of the disease, with a mean age of onset at 67.5 years. Unfortunately, all patients succumbed to the disease within 6 months of its onset. Rapidly progressive dementia was a common symptom in all cases. Additionally, patient one and patient four displayed myoclonus and dystonia, patient two exhibited myoclonus and akinetic mutism, and patient three had myoclonus, chorea, and ataxia. MR brain imaging, including T2 sequence, FLAIR sequence, and DWI/ADC mapping, was performed on all patients, revealing both cortical gray matter and deep gray matter (basal ganglia) T2/FLAIR hyperintensities with DWI restriction. A cortical ribboning pattern was observed in all cases. EEG results indicated generalized delta slow waves with triphasic complexes in three patients, while patient three alone displayed periodic sharp wave complexes at a frequency of 1 per 1 - 1.5 seconds. Conclusion MRI with DWI and ADC brain mapping emerges as the most valuable diagnostic tool for patients with clinical presentations suggesting sCJD. In this study, all patients displayed restricted diffusion, as confirmed by ADC mapping. Regrettably, the characteristic features of sCJD with restricted diffusion in the cortex, thalamus, and basal ganglia may often elude detection by radiologists outside specialized centers, resulting in diagnostic delays. Conversely, when basal ganglia or cortical signal abnormalities are detected in conjunction with parenchymal swelling, alternative diagnoses such as encephalitis or lymphoma should be considered, as parenchymal swelling is not a typical feature of sCJD as revealed by MRI.

Biomarkers and clinical presentations in Creutzfeldt‐Jakob Disease

AbstractBackgroundThe ability to detect malformed prion proteins using real‐time quaking‐induced conversion (RT‐QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt‐Jakob disease (CJD), facilitating earlier recognition of affected patients. Recognizing this, we evaluated the frequency of clinical features and biomarker results at initial evaluation in patients with CJD and determined the relationship between these early features and CJD diagnosis and prognosis.MethodClinical data were extracted from the electronic medical records of patients with probable or definite (pathologically confirmed) CJD assessed at Mayo Clinic from 2014‐2021. Diagnoses of probable CJD were established by clinical consensus, referencing the Centers for Disease Control and Prevention diagnostic criteria. Clinical features and biomarkers results were evaluated at presentation, and associations with CJD diagnosis and symptomatic disease duration determined.ResultOne‐hundred fifteen patients were included (40, [35%] with definite CJD). Mean age‐at‐symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD (e.g., stereotyped EEG abnormalities (16%), CSF 14‐3‐3 (60%)) was poor. Biomarkers with good diagnostic sensitivity included RT‐QuIC (93%), t‐tau levels &gt;1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%). Multivariable linear regression confirmed shorter survival for patients with myoclonus (125.9 days, 95%CI 23.3‐15.5, p=0.026), visual/cerebellar signs (180.19 days, 95%CI 282.2‐78.2, p&lt;0.001), positive 14‐3‐3 (193 days, 95%CI 304.9‐82.9; p&lt;0.001), and elevated t‐tau levels (each 1000 pg/ml increase was associated with a nine‐day shorter time‐to‐death, 95%CI 1‐18; p=0.041).ConclusionCSF RT‐QuIC and elevated t‐tau levels, and stereotyped MRI abnormalities continue to be strongly associated with the diagnosis in the modern era, while other clinical findings (myoclonus) and biomarkers results traditionally ascribed to CJD (e.g., PSWC on EEG, 14‐3‐3) offered less value in the diagnostic evaluation. Detection of visual or cerebellar features, myoclonus, CSF 14‐3‐3, and t‐tau levels may predict disease duration, justifying inclusion in the evaluation of CJD‐suspected patients.

Improving Early Recognition of Creutzfeldt-Jakob Disease Mimics.

Diagnostic criteria emphasize the use of sensitive and disease-specific tests to distinguish patients with rapidly progressive dementia (RPD) due to Creutzfeldt-Jakob disease (CJD) vs other causes (mimics). These tests are often performed in specialized centers, with results taking days to return. There is a need to leverage clinical features and rapidly reporting tests to distinguish patients with RPD due to CJD from those due to other causes (mimics) early in the symptomatic course. In this case-control series, clinical features and the results of diagnostic tests were compared between mimics (n = 11) and patients with definite (pathologically proven, n = 33) or probable CJD (with positive real-time quaking-induced conversion [RT-QuIC], n = 60). Patients were assessed at Mayo Clinic Enterprise or Washington University from January 2014 to February 2021. Mimics were enrolled in prospective studies of RPD; mimics met the diagnostic criteria for probable CJD but did not have CJD. Mimics were ultimately diagnosed with autoimmune encephalitis (n = 6), neurosarcoidosis, frontotemporal lobar degeneration with motor neuron disease, dural arteriovenous fistula, cerebral amyloid angiopathy with related inflammation, and systemic lupus erythematous with polypharmacy. Age at symptom onset, sex, presenting features, and MRI and EEG findings were similar in CJD cases and mimics. Focal motor abnormalities (49/93, 11/11), CSF leukocytosis (4/92, 5/11), and protein >45 mg/dL (39/92, 10/11) were more common in mimics (p < 0.01). Positive RT-QuIC (77/80, 0/9) and total tau >1149 pg/mL (74/82, 2/10) were more common in CJD cases (all p < 0.01). Protein 14-3-3 was elevated in 64/89 CJD cases and 4/10 mimics (p = 0.067). Neural-specific autoantibodies associated with autoimmune encephalitis were detected within the serum (5/9) and CSF (5/10) of mimics; nonspecific antibodies were detected within the serum of 9/71 CJD cases. Immune-mediated, vascular, granulomatous, and neurodegenerative diseases may mimic CJD at presentation and should be considered in patients with early motor dysfunction and abnormal CSF studies. The detection of atypical features-particularly elevations in CSF leukocytes and protein-should prompt evaluation for mimics and consideration of empiric treatment while waiting for the results of more specific tests.

Analysis of Clinical Features, Diagnostic Tests, and Biomarkers in Patients With Suspected Creutzfeldt-Jakob Disease, 2014-2021

Detection of prion proteins in cerebrospinal fluid (CSF) using real-time quaking-induced conversion (RT-QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt-Jakob disease (CJD), facilitating earlier and more complete recognition of affected patients. It is unclear how expanded recognition of affected patients may affect the diagnostic and prognostic relevance of clinical features and diagnostic tests historically associated with CJD. To evaluate clinical features and diagnostic testing in patients presenting with CJD and determine the associations of these features with prognosis. This cohort study incorporated data from electronic medical records of patients with CJD treated at Mayo Clinic Enterprise tertiary care centers in Rochester, Minnesota; Jacksonville, Florida; and Scottsdale, Arizona. Participants included patients with definite or probable CJD assessed from 2014 to 2021. Data were analyzed October 2021 to January 2022. Dominant presentation, clinical features, and diagnostic tests associated with CJD. The outcomes of interest were the sensitivity and prognostic value of clinical features and accessible diagnostic tests at presentation with possible CJD. A total of 115 patients were identified, including 40 patients (35%) with definite CJD. Mean (SD) age at symptom onset was 64.8 (9.4) years, and 68 patients were women (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD was poor (eg, stereotyped electroencephalography anomalies: 17 of 105 patients [16%]; elevated CSF protein 14-3-3 levels: 54 of 90 patients [60%]). By comparison, biomarkers with good diagnostic sensitivity at presentation included RT-QuIC (66 of 71 patients [93%]), CSF total tau (T-tau) level greater than 1149 pg/mL (81 of 92 patients [88%]), and characteristic signal anomalies on magnetic resonance imaging (88 of 115 patients [77%]). Multivariable linear regression confirmed shorter survival in patients with myoclonus (difference, -125.9 [95% CI, -236.3 to -15.5] days; P = .03), visual or cerebellar signs (difference, -180.2 [95% CI, -282.2 to -78.2] days; P < .001), elevated CSF protein 14-3-3 levels (difference, -193 [95% CI, -304.9 to -82.9] days; P < .001), and elevated T-tau level (difference for every 1000 pg/mL elevation, -9.1 [95% CI, -17.7 to -1.0] days; P = .04). These findings suggest that CSF RT-QuIC, elevated CSF T-tau level, and stereotyped magnetic resonance imaging anomalies were associated with the diagnosis of CJD, while other clinical findings (eg, myoclonus), stereotyped electroencephalography anomalies, and CSF protein 14-3-3 levels offered less diagnostic value. Visual or cerebellar features, myoclonus, and CSF 14-3-3 and T-tau levels may be associated with disease duration, justifying continued inclusion in the evaluation of patients suspected to have CJD.

Alzheimer's disease cerebrospinal fluid biomarkers differentiate patients with Creutzfeldt-Jakob disease and autoimmune encephalitis.

Autoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt-Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE. Patients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total-tau, phosphorylated181 tau and amyloid-β42 levels were compared. Of 11 CJD cases, four were autopsy proven; the rest had positive real-time quaking-induced conversion testing. Disease-associated autoantibodies were detected in 8/15 cases of AE: leucine-rich glioma-inactivated 1 and neuronal intermediate filaments (two cases each), and N-methyl-d-aspartate receptor, contactin-associated protein-like 2, dipeptidyl-peptidase-like protein 6 and immunoglobulin-like cell adhesion molecule IgLON family member 5. Total-tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17-2.11, p < 0.05, c=0.93). Total-tau was elevated in 91% of CJD cases (median > 1300, range 236->1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total-tau was elevated in 20% of AE cases (median 158, range 80->1300 pg/ml). Total-tau was greater in CJD than AE. Given that amyloid-β42 and phosphorylated181 tau were comparable, the ratio differences were probably driven by elevated total-tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia.

P.003 CJD in the modern era: The value of clinical features and diagnostic tests

Background: The advent of real-time quaking-induced conversion (RT-QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt-Jakob disease (CJD) facilitating earlier recognition of affected patients. Recognizing this, we evaluated the performance of clinical features and diagnostic tests for CJD in the modern era. Methods: Clinical data were extracted from the electronic medical records of 115 patients with probable or definite CJD assessed at Mayo Clinic from 2014-2021. Clinical features and diagnostic tests were evaluated at presentation, and associations with diagnosis and prognosis determined. Results: Mean age-at-symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD was poor (stereotyped EEG abnormalities, 16%; CSF 14-3-3, 60%). Conversely, RT-QuIC (93%), t-tau &gt;1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%) identified most patients. Multivariable linear regression confirmed shorter days-to-death in patients with myoclonus (125.9, CI95% 23.3-15.5, p=0.026), visual/cerebellar signs (180.19, CI95% 282.2-78.2, p&lt;0.001), positive 14-3-3 (193, CI95% 304.9-82.9; p&lt;0.001), and elevated t-tau (9.0, CI95% 1.0-18.0, for every 1000 pg/ml elevation; p=0.041). Conclusions: CSF RT-QuIC and elevated t-tau, and stereotyped MRI abnormalities were consistently detected in CJD patients. Myoclonus, EEG findings, and CSF protein 14-3-3 were less useful in the modern era.

Clinical and prognostic features of Heidenhain variant of Creutzfeldt−Jakob disease: A retrospective case series study

Heidenhain variant of Creutzfeldt-Jakob disease (CJD) remains a diagnostic challenge in clinical practice. We aimed to describe the clinical and prognostic features of Heidenhain cases, through a case series study. We retrospectively reviewed the definite or probable CJD cases admitted to two tertiary referral university hospitals over a decade to identify Heidenhain cases and investigated their survival status by telephone follow-up. Their clinical characteristics, neuroimaging features, electroencephalography (EEG) results, cerebrospinal fluid profiles, and PRNP gene mutations were also analyzed. Of a total of 85 CJD cases, 20 (24%) Heidenhain cases (11 women [55%]; median age, 64years [range, 44-72years]) were identified. The median survival time was 22weeks (range, 5-155weeks). The median duration of isolated visual symptoms was 3weeks (range, 1-12weeks). The most common early visual symptom was blurred vision (16/20, 80%), followed by diplopia (6/20, 30%). The prevalence significantly increased for complex visual hallucination (p=0.005) and cortical blindness (p=0.046) as the disease progressed. The positive rate of serial magnetic resonance images (20/20, 100%) was higher than that of serial EEGs (16/20, 80%). Two patients (2/10, 20%) had pathogenic PRNP mutations, E196A and T188K, respectively. Heidenhain cases with PRNP mutations had significantly longer survival time than those without PRNP mutations (p=0.047). Besides blurred vision (80%), diplopia (30%) was also a frequent early visual symptom among Heidenhain cases. Heidenhain phenotype can occur in genetic CJD cases. PRNP mutation status might be an important prognostic factor for Heidenhain cases.

Prognostic Features of Sporadic Creutzfeldt-Jakob Disease: An Analysis of Taiwan's Nationwide Surveillance.

To study the prognostic features of Creutzfeldt-Jakob disease (CJD) and shed light on its future therapy. Retrospective cohort study of a longitudinal national cohort of the Taiwan Centers for Disease Control. All patients with suspected CJD are reported to the CJD surveillance unit of the Taiwan Centers for Disease Control. An expert committee discussed the reported cases and designated a consensus-based diagnosis. From 1996 to 2020, a total of 809 cases were referred to the CJD surveillance unit for confirmation; of these, 441 cases (women, n= 230) were determined to be sporadic CJD. We investigated the clinical manifestations and laboratory findings for 400 patients diagnosed with definite or probable sporadic CJD. We used Kaplan-Meier analyses and Cox proportional hazards model to identify prognostic factors. The mean age of onset was 67 ± 9.9years. The mean survival duration was 13.3 ± 14.2 (median 10) months. The leading clinical symptoms were myoclonus (73%) and akinetic mutism (54%). For PRNP polymorphism, 99% of patients (195/197) showed a methionine homozygous genotype at codon 129 (M129M). The sensitivity of periodic sharp wave complexes (PSWCs) on electroencephalograms (EEGs) was 59.7%. The sensitivity of cerebrospinal fluid 14-3-3 protein and total tau protein (>1200 pg/mL) were 69.7% and 75.6%, respectively. Younger patients lived longer than those aged ≥65years [hazard ratio (HR) 0.466, P < .001]. Women had a better survival probability in the first 3years than their male counterparts (HR 0.712, P= .005). PSWCs had a persistent negative effect on survival (HR 0.788, P < .05). Although uncommon, epileptic seizures were the only clinical prognostic factor for survival time (HR 0.768, P < .05). PSWCs can be used as an EEG biomarker for prognosis. Epileptic seizures, though not common, are the only clinical prognostic factor for a short survival. We found that a lower age of onset and female gender favor the survival of patients with sCJD. PSWCs are EEG biomarkers unfavorable for survival, and so are epileptic seizures.

Three cases of Creutzfeldt-Jakob disease presenting with a predominant dysexecutive syndrome.

Creutzfeldt-Jakob disease (CJD) is a rare, uniformly fatal prion disease. Although CJD commonly presents with rapidly progressive dementia, ataxia, and myoclonus, substantial clinicopathological heterogeneity is observed in clinical practice. Unusual and predominantly cognitive clinical manifestations of CJD mimicking common dementia syndromes are known to pose as an obstacle to early diagnosis and prognosis. We report a series of three patients with probable or definite CJD (one male and two females, ages 52, 58 and 68) who presented to our tertiary behavioral neurology clinic at Mayo Clinic Rochester that met criteria for a newly defined progressive dysexecutive syndrome. Glucose hypometabolism patterns assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) strongly resembled those of dysexecutive variant of Alzheimer's disease (dAD). However, magnetic resonance imaging (MRI) demonstrated restricted diffusion in neocortical areas and deep nuclei, while cerebrospinal fluid biomarkers indicated abnormal levels of 14-3-3, total-tau, and prion seeding activity (RT-QuIC), establishing the diagnosis of CJD. Electroencephalogram (EEG) additionally revealed features previously documented in atypical cases of CJD. This series of clinical cases demonstrates that CJD can present with a predominantly dysexecutive syndrome and FDG-PET hypometabolism typically seen in dAD. This prompts for the need to integrate information on clinical course with multimodal imaging and fluid biomarkers to provide a precise etiology for dementia syndromes. This has important clinical implications for the diagnosis and prognosis of CJD in the context of emerging clinical characterization of progressive dysexecutive syndromes in neurodegenerative diseases like dAD.

Spatial Epidemiology of Sporadic Creutzfeldt-Jakob Disease in Apulia, Italy

Background: Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by prions that is randomly distributed in all countries, with an overall yearly mortality rate of about 1–2 cases per million people. On a few occasions, however, sporadic CJD occurred with higher than expected rates, but further investigations failed to recognize any convincing causal link. In Italy, cluster analyses of sporadic CJD cases have not been performed previously. Objective: To investigate the geographical distribution of sporadic CJD using municipality geographical data of Apulia with the aim of detecting spatial clusters of disease. Patients and Methods: Patients included in this study were diagnosed as probable or definite sporadic CJD and were residents of the Apulia Region (Italy). Bayesian hierarchical models with spatially structured and unstructured random components were used to describe the spatial pattern of the disease and to assess the extent of heterogeneity among municipalities. The Kulldorff-Nagarwalla scan test and the flexible spatial scan statistic were used for detecting spatial clusters. Results: Smoothed Bayesian relative risks above the null value were observed in a few adjacent municipalities in the north and middle areas of Apulia. However, both the circular scanning method and the flexible spatial scan statistic identified only a single cluster in the central part of the region. Conclusion: Geographical analyses and tests for spatial randomness identified a restricted area with an unusually high number of sporadic CJD cases in the Apulia region of Italy. Environmental and genetic risk factors other than mutations in the prion protein gene however, need to be investigated.

Author response: Teaching NeuroImages: DWI and EEG findings in Creutzfeldt-Jakob disease.

We thank Drs. Yuan and Hu for their comments on our article.1 We agree that CSF testing for prions, particularly the real-time quaking-induced conversion assay (RT-QuiC), which is superseding 14-3-3 as the test of choice in many centers, can be helpful in confirming the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) in suspected cases.2 We did not pursue such testing in our patient. She already met the proposed updated diagnostic criteria for probable CJD based on having rapidly progressive dementia (criterion A); myoclonus, cerebellar signs, extrapyramidal signs (3 of the B criteria, only 2 required); EEG periodic sharp discharges and MRI diffusion-weighted imaging abnormalities in caudate and putamen (2 of the C criteria, only 1 required); and no indication of an alternative diagnosis on routine investigations (criterion D; however, some may consider CSF to be an important routine investigation, though it carries safety risks in suspected prion disease). Nevertheless, to establish the diagnosis of definite CJD, as Drs. Yuan and Hu indicated, prion disease would need to be identified by standard neuropathologic or immunocytochemical techniques, or positive RT-QuiC of CSF or nasal brushings.

Editors' note: Teaching NeuroImages: DWI and EEG findings in Creutzfeldt-Jakob disease

In “Teaching NeuroImages: DWI and EEG findings in Creutzfeldt-Jakob disease,” Ganesh et al. described a patient with rapidly progressive dementia who was found to have lateralized periodic discharges and cortical ribboning that was more right than left, which they concluded was consistent with Creutzfeldt-Jakob disease (CJD). Drs. Yuan and Hu commented that while these findings are sufficient to diagnose sporadic CJD, neuropathology or 14-3-3 CSF results would help clarify whether this was familial CJD, iatrogenic CJD, or a new variant of CJD. Drs. Ganesh and Yeung replied that they did not pursue further testing because their patient met the diagnostic criteria for probable CJD, and that establishing a diagnosis of definite CJD would require neuropathology or immunohistochemistry results consistent with CJD or positive real-time quaking-induced conversion assay. In “Teaching NeuroImages: DWI and EEG findings in Creutzfeldt-Jakob disease,” Ganesh et al. described a patient with rapidly progressive dementia who was found to have lateralized periodic discharges and cortical ribboning that was more right than left, which they concluded was consistent with Creutzfeldt-Jakob disease (CJD). Drs. Yuan and Hu commented that while these findings are sufficient to diagnose sporadic CJD, neuropathology or 14-3-3 CSF results would help clarify whether this was familial CJD, iatrogenic CJD, or a new variant of CJD.

CSF EXPLORATORY BIOMARKER STUDY FOR (DIFFERENTIAL) DIAGNOSIS OF FRONTOTEMPORAL LOBAR DEGENERATION

There is a need for biomarkers allowing early and differential diagnosis between frontotemporal lobar degeneration (FTLD) and other dementias. Notable candidates include routine Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers (pTau181P, hTau, Aβ1-42), non-phosphorylated tau fraction (pTau rel), neurofilament light chain (NF-light), phosphorylated neurofilament heavy chain (pNF-H), progranulin and cathepsin D. Using a cohort of definite FTLD patients, we aimed to explore the performance of these CSF biomarkers. Definite FTLD patients (n=45), clinically diagnosed AD patients (n=45), definite Creutzfeldt-Jakob disease (CJD) patients (n=20) and cognitively healthy controls (n=20) were included in this study. FTLD-TDP (n=28, including 10 GRN and 17 C9orf72 mutation carriers), FTLD-tau (n=10) and FTLD-other (n=7) subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation. CSF biomarker levels were quantified using commercially available ELISA kits for pTau181P, hTau and Aβ1-42 (INNOTEST ELISAs, Fujirebio Europe, Belgium); hTAU total and pTAU rel (AJ Roboscreen, IBL International GmbH, Germany); NF-light (UmanDiagnostics, IBL International GmbH, Germany); pNF-H (EnCor Biotechnology Inc., USA); progranulin (Adipogen Inc., Korea); cathepsin D (Calbiochem, Merck KGaA, Germany). CSF progranulin levels were significantly lower in FTLD-TDP patients as compared to the FTLD-tau subgroup, due to low levels in GRN mutation carriers. To differentiate between FTLD and AD, pTau181P was the best single marker (AUC=0.922). For further differentiation between FTLD and AD patients, a decision tree was constructed, which showed an added value for NF-light and total tau, correctly classifying 90.8% of the patients (Figure 1). Differentiation between FTLD and controls still proves difficult, with NF-light being the best single marker (AUC=0.700). A decision tree showed that besides NF-light, Aβ1-42 could aid as well, correctly classifying 80.6% of the subjects. The easiest differentiation was that between FTLD and CJD with pTau rel as the best single marker (AUC=0.999). pNF-H and cathepsin D did not contribute to (differential) diagnosis of FTLD. Using single markers, pTau181P and hTau together with NF-light can correctly classify up to 90.8% of FTLD and AD dementia patients. Differentiation between FTLD and controls remains suboptimal, even when combining NF-light and Aβ1-42 (correct classification of 80.6%). Decision tree for differential diagnosis between FTLD and AD patients, with an overall correct classification of 90.8%. pTau181P, phosphorylated tau; hTau, total tau; NF-light, neurofilament light chain.

Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease.

Objective:To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD).Methods:The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998–2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX.Results:In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies.Conclusions:It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits.

Creutzfeldt-Jakob disease mortality in Canada, 1998 to 2013.

Human prion diseases, known collectively as Creutzfeldt-Jakob disease (CJD), are fatal, infectious neurodegenerative disorders that occur in all human populations. To summarize national surveillance data for CJD in Canada between January 1, 1998, and December 31, 2013. Detailed investigations were conducted of individual suspected CJD cases, with collaboration between Canadian health professionals and investigators affiliated with a central CJD surveillance registry operated by the Public Health Agency of Canada. Data were collected on the clinical profile, family history, and results of paraclinical and laboratory investigations, including post-mortem neuropathological examination. A total of 662 deaths from definite and probable CJD were identified in Canadian residents during the study period, comprising 613 cases of sporadic CJD (92.6%), 43 cases of genetic prion disease (6.5%), 4 cases of iatrogenic CJD (0.6%), and 2 cases of variant CJD disease (0.3%). The overall crude mortality rate for sporadic CJD was 1.18 per million per year [95% confidence interval (CI): 1.08,1.27]. Age-specific rates ranged from 0.05 [95% CI: 0.03,0.08] in persons under 50 years of age to 7.11 [95% CI: 6.20,8.11] in those aged 70 to 79. A significant net upward trend in age-adjusted rates was observed over the study period. Standardized mortality ratios, calculated for 10 individual Canadian provinces with reference to national average mortality rates, did not differ significantly from 1.0. Creutzfeldt-Jakob disease remains rare in Canada, although mortality rates vary by two orders of magnitude between older and younger age groups. The upward trend in age-standardized sporadic CJD mortality rate over the study period can be better accounted for by gradually improving case ascertainment than by a real increase in incidence.

Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial

Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.

Determination of Neuronal Antibodies in Suspected and Definite Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients. To determine the frequency of NSA-abs in the cerebrospinal fluid of patients with suspected CJD and in patients with pathologically confirmed (ie, definite) CJD. A mixed prospective (suspected) and retrospective (definite) CJD cohort study was conducted in a reference center for detection of NSA-abs. The population included 346 patients with suspected CJD and 49 patients with definite CJD. Analysis of NSA-abs in cerebrospinal fluid with brain immunohistochemistry optimized for cell-surface antigens was performed. Positive cases in the suspected CJD group were further studied for antigen specificity using cell-based assays. All definite CJD cases were comprehensively tested for NSA-abs, with cell-based assays used for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), N-methyl-d-aspartate (NMDA), and glycine (GlY) receptors. Neuronal surface antigens were detected in 6 of 346 patients (1.7%) with rapid neurologic deterioration suggestive of CJD. None of these 6 patients fulfilled the diagnostic criteria for probable or possible CJD. The target antigens included CASPR2, LGI1, NMDAR, aquaporin 4, Tr (DNER [δ/notch-like epidermal growth factor-related receptor]), and an unknown protein. Four of the patients developed rapidly progressive dementia, and the other 2 patients had cerebellar ataxia or seizures that were initially considered to be myoclonus without cognitive decline. The patient with Tr-abs had a positive 14-3-3 test result. Small cell lung carcinoma was diagnosed in the patient with antibodies against an unknown antigen. All patients improved or stabilized after appropriate treatment. None of the 49 patients with definite CJD had NSA-abs. A low, but clinically relevant, number of patients with suspected CJD had potentially treatable disorders associated with NSA-abs. In contrast, none of 49 patients with definite CJD had NSA-abs, including NMDAR-abs, GlyR-abs, LGI1-abs, or CASPR2-abs. These findings suggest that cerebrospinal fluid NSA-abs analysis should be included in the diagnostic workup of patients with rapidly progressive central nervous system syndromes, particularly when they do not fulfill the diagnostic criteria of probable or possible CJD.

Voltage-gated potassium channel complex antibodies in Creutzfeldt-Jakob disease

Clinical presentations of Creutzfeldt-Jakob disease (CJD) can be mimicked by those of immune-mediated encephalopathies, including limbic encephalitis with anti-voltagegated potassium channel (VGKC) complex antibodies [1, 2]. To date, anti-VGKC complex antibodies have been reported to be negative in CJD [1], thereby regarded as important to differentiate non-CJD dementia from CJD [3]. Here we report a patient with definite CJD who had serum anti-VGKC complex antibodies. A 60-year-old seaman acutely presented with blurred vision, disturbance in depth perception and light discrimination, difficulty recalling Chinese characters, and right-left disorientation. An ophthalmologist found no abnormality in his eyes. Two months later, he underwent a brain magnetic resonance imaging including diffusionweighted imaging, which showed hyperintensity signals in the bilateral occipital and parietal cortices. Neurologically, there were object agnosia, left hemineglect, dressing apraxia, Gerstmann syndrome, ideomotor apraxia, and instant memory disturbance. He also developed visual hallucinations such as flaming fire, and got agitated. Three months after onset, he got confused after taking one tablet of zolpidem and was admitted to a psychiatric department. Neurological examination on admission demonstrated the following findings: fluctuating levels of consciousness, difficulty in word recall, extinction; visual disturbance, poor pursuit eye movement, mild dysarthria; increased muscle tonus and myoclonus predominantly in the left; Myerson sign, snout reflex, increased jaw jerk and deep tendon reflexes predominantly in the left, bilateral Babinski and Chaddock signs; and he was bedridden. Serum antinuclear, anti-thyroid peroxidase, anti-thyroglobulin antibodies were negative and sodium levels were normal. No malignant tumors were found. Cell count was 2/mm, protein level was 27 mg/dl, 14-3-3 protein was positive, and total tau protein level was 3,420 pg/ml (cut-off value, 1,300 pg/ml) in the cerebrospinal fluid. Initial electroencephalography revealed slow waves, and periodic sharp wave complexes were present 23 weeks after onset. The analysis of PRNP revealed a substitution of methionine to arginine at codon 232. He received no immunotherapy. He died 8.5 months after onset and underwent necropsy of the left parietotemporal lobe. Neuropathological examination revealed neuronal loss, spongiform change, gemistocytic astrocytosis (Fig. 1a), and synaptic deposition of PrP (Fig. 1b) in the cerebral cortex, confirming the diagnosis of definite CJD. Western-blot analysis showed type 1 PrP. The titer of anti-VGKC complex antibodies, measured with radioimmunoassay using rabbit brain homogenates and K. Fujita (&) Y. Izumi R. Kaji Department of Clinical Neuroscience, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan e-mail: kof@clin.med.tokushima-u.ac.jp