Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany.

BACKGROUND: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD. OBJECTIVE: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype. METHODS: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type. RESULTS: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes. CONCLUSION: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.

Doxycycline in early CJD: a double-blinded randomised phase II and observational study.

OBJECTIVES: The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival. RESULTS: Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)). CONCLUSIONS: On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD. TRIAL REGISTRATION NUMBER: EudraCT 2006-003934-14; Results.

Clinical findings and diagnosis in genetic prion diseases in Germany.

To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG.

Psychiatric symptoms in patients with sporadic Creutzfeldt-Jakob disease in Germany.

BACKGROUND: Psychiatric symptoms in sporadic Creutzfeldt-Jakob disease (sCJD) are still not sufficiently evaluated. AIM: To describe psychiatric symptoms in sCJD with respect to molecular subtype. METHOD: Patients in this retrospective study were classified according to established diagnostic criteria. 248 sCJD patients with known molecular subtype were recruited from January 1993 to December 2004 and investigated. Psychiatric symptoms were defined according to Möller and colleagues and the AMDP system (Study Group for Methods and Documentation in Psychiatry) and were collected by direct examination by study physicians or extracted from medical documentation. Our data were compared with published data on variant CJD (vCJD). RESULTS: Psychiatric symptoms were common in sCJD patients (90%) and mostly found already at the disease onset (agitation in 64% of the patients, hallucinations in 45%, anxiety in 50%, depression in 37%). All psychiatric symptoms but illusions were found early in the disease course. Psychiatric symptoms in sCJD were less frequent than in vCJD. CONCLUSIONS: We provide the first detailed analysis of psychiatric symptoms in a large group of patients with sCJD with respect to differences concerning frequency and time point of occurrence of psychiatric symptoms between molecular subtypes. These data suggest that psychiatric symptoms occurring early in the disease course are common not only in vCJD but also in other CJD types.

First symptom and initial diagnosis in sporadic CJD patients in Germany.

To describe the first symptom/sign and first diagnosis in patients with sporadic Creutzfeldt-Jakob disease (sCJD) in Germany with respect to M129V polymorphism of the prion protein gene and prion protein type. Data on the first symptom/sign and first diagnosis were studied in 492 sCJD patients with probable and definite sCJD and known M129V polymorphism. Unspecific prodromal symptoms such as headache, fatigue, sleep disturbances, "peculiar feeling in the head", photophobia or weight loss were found in about 10 % of the patients. No prodromal symptoms were found in MV2 and VV1 patients. Dementia was the most common first symptom (37 %) followed by cerebellar (34 %), visual (15 %), and psychiatric disturbances (14 %). The CJD diagnosis was the first diagnosis in only 35 % of the patients (in 42 % of MM, 28 % of MV, and 24.5 % of VV patients). We provide a detailed analysis on clinical presentation and first diagnosis in a large group of patients with sCJD with respect to M129V genotype and prion protein type. These data emphasize the importance of knowledge about CJD and especially rare CJD types among physicians of different specializations. Our findings may improve early recognition of atypical CJD forms.

Ziprasidone versus clozapine in the treatment of dually diagnosed (DD) patients with schizophrenia and cannabis use disorders: a randomized study.

BACKGROUND AND OBJECTIVES: Clozapine is considered to be particularly effective in the treatment of dually diagnosed (DD) patients with psychosis and substance use disorders. However, its use is restricted by potentially severe side effects. The aim of the present pilot study was to compare the effects of clozapine with the newer second generation antipsychotic (SGA) ziprasidone in DD-patients. METHODS: Thirty (n = 30) patients with schizophrenia and cannabis abuse/dependence were randomized to ziprasidone or clozapine and were followed up for up to 12 months. RESULTS: Cannabis use was reduced in both groups during follow-up. Clozapine treatment was associated with less positive symptoms of schizophrenia, more side effects and poorer compliance with treatment. CONCLUSIONS: Results from this small pilot RCT suggest beneficial effects of both clozapine and ziprasidone in the treatment of cannabis use disorders in psychotic patients. Larger-scale RCTs are needed in order to assess advantages and disadvantages of the different SGAs in dually diagnosed populations.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.

Amyloid-ß 1-42 levels are modified by apolipoprotein E ε4 in Creutzfeldt-Jakob disease in a similar manner as in Alzheimer's disease.

The presence of apolipoprotein E (ApoE) ε4 allele is a risk factor for Alzheimer's disease (AD) and associated with a more pronounced reduction of amyloid-ß 1-42 (Aß1-42) in the cerebrospinal fluid (CSF). Because a decrease of Aß1-42 and increase of tau protein levels, both important biomarkers for AD, are also reported in Creutzfeldt-Jakob disease (CJD), we analyzed if a similar relationship can be observed in this rapid progressive dementia. Our study included 309 patients with sporadic CJD (147 neuropathologically confirmed and 162 probable cases). We analyzed the role of ApoE ε4 in sporadic CJD (sCJD), in particular the influence on the CSF-markers 14-3-3 protein, tau protein, neuron-specific enolase, S100 protein, Aß1-42, and Aß1-40. No differences in the ApoE ε4 allele frequency and ApoE genotype distribution between sCJD and published healthy controls were observed. The ApoE ε4 allele had no effect on disease duration or age at onset. We detected a dose-dependent ApoE ε4 effect on the decrease of Aß1-42 in sCJD. ApoE ε4 carriers with one ApoE ε4 allele showed significantly reduced Aß1-42 values (p < 0.0001) in comparison with non-carriers. ApoE ε4 allele is not a risk factor for sCJD but modifies the Aß1-42 levels in CSF in a similar manner as in AD. Based on our results in sCJD patients, we hypothesize that the ApoE ε4 effect on Aß1-42 values might not be disease-specific.

Total prion protein levels in the cerebrospinal fluid are reduced in patients with various neurological disorders.

We performed a study on levels of the total prion protein (PrP) in humans affected by different neurological diseases and assessed the influence of several factors such as age, gender, and disease severity on the cerebrospinal fluid PrP levels. PrP-ELISA technique was used to analyze cerebrospinal fluid (CSF) samples. 293 CSF samples of patients with Creutzfeldt-Jakob-disease (CJD), Alzheimer's disease, dementia with Lewy-bodies, Parkinson's disease, multiple sclerosis, cerebral ischemia, generalized epileptic seizures, and meningitis and encephalitis in comparison to controls were analyzed. We found a significant reduction of CSF PrP levels in patients suffering from all neurodegenerative disorders analyzed. This group exhibited mean PrP values of 164 ng/ml while non-neurodegenerative disorder patients and healthy controls showed PrP levels of 208 ng/ml and 226 ng/ml, respectively. CSF levels correlated with disease severity in CJD, Alzheimer's disease, and dementia with Lewy-bodies. The finding of decreased PrP levels in the CSF of patients not only with CJD but also in other neurodegenerative disorders is intriguing. Age-, gender-, and genetic-specific factors might be involved in the PrP c regulation.

Increased frequency of positive family history of dementia in sporadic CJD.

OBJECTIVE: To analyze whether a positive family history of dementia (PFHD) is more common in sporadic CJD (sCJD) than in healthy/population controls and to study associated risk factors. PATIENTS/METHODS: Six hundred and eighty-five sCJD patients and 659 sex-/age-matched controls were included. A PFHD in parents/grandparents/siblings was evaluated. The PRNP M129V polymorphism and ApoE genotype in sCJD with/without PFHD were determined by PCR. RESULTS: PFHD was found in 12.1% of sCJD patients and 5.6% of controls (p<0.001). No significant difference in M129V polymorphism was found between sCJD with and without PFHD. Thirty-six percent of sCJD patients with PFHD, 26% without PFHD and 19% of healthy controls had at least one ApoE4 allele. Compared to controls, ApoE4 allele frequency (p=0.005) and proportion of ApoE4 allele carriers (p=0.019) were significantly higher in sCJD with PFHD. INTERPRETATION: A higher frequency of the ApoE4 allele in sCJD with a PFHD could be indicative of an additional risk factor in CJD.

Brain biopsy in patients with suspected Creutzfeldt-Jakob disease.

OBJECT: Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disorder with diagnostic criteria defined as a combination of clinical symptoms, electroencephalography findings, cerebrospinal fluid (CSF) analysis, and MR imaging results. Special subtypes are known to present with an atypical course and test findings that can complicate the clinical diagnosis. In such patients a brain biopsy can support the clinical approach. METHODS: The authors studied the records on 26 brain biopsies conducted in patients with suspected CJD who had been referred to the CJD Surveillance Unit in Germany between 1993 and 2005. RESULTS: Of the 26 included patients, 11 suffered from neuropathologically confirmed CJD, which in 5 cases had been deemed clinically "probable" and in 2 had been deemed "possible." The disease in the remaining 4 patients had been categorized as "other" prior to neuropathological confirmation of CJD. The results of 15 brain biopsies showed no features of prion disease. None of these 15 patients had received a probable diagnosis of CJD, 4 had a possible diagnosis, and 11 had received a diagnosis of "other." Three of the cases classified as other and none of those with CJD presented with pleocytosis in the CSF. In 73% of the other cases, biopsy sampling did not reveal any results characteristic of CJD but did not provide specific findings on which to base a differential diagnosis. Autopsy confirmed the biopsy diagnosis of CJD in all cases, and additionally confirmed that CJD was not present in 3 patients who had nondiagnostic biopsy results. CONCLUSIONS: Biopsy sampling may be helpful in the diagnostic approach to rare cases of dementia for which a reliable diagnosis cannot be established on the basis of clinical symptoms, CSF parameters, electroencephalography, and MR imaging results.

Quantitative analysis of transthyretin, tau and amyloid-beta in patients with dementia.

We carried out a quantitative analysis of transthyretin (TTR), total tau protein and amyloid-beta (Abeta) peptide (1-40 and 1-42) in the lumbar cerebrospinal fluid of 106 patients with different forms of dementia including Alzheimer's disease (AD), Creutzfeldt-Jakob-disease (CJD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and normal pressure hydrocephalus (NPH) in comparison to healthy controls. Our study revealed that Abeta_{1-42} levels were decreased in all patients irrespective of dementia type. Tau protein levels were abnormal in all degenerative dementia except of NPH. Tau levels did not allow differential diagnosis of dementia type except for CJD, where we observed extremely high CSF levels. In other dementia types, levels were elevated in a similar range. Transthyretin levels were selectively decreased in AD and NPH, thus revealing the potential of this protein to be used as additional biomarker in the neurochemical differential diagnosis of AD. A significant negative correlation of TTR CSF levels and disease severity in AD was observed.

Novel PRNP mutation in a patient with a slow progressive dementia syndrome.

BACKGROUND: Creutzfeldt-Jakob disease is a rare neurodegenerative disorder with a worldwide incidence of 1.5 per million inhabitants. About 10-15% of all cases of Creutzfeldt-Jakob disease are of genetic origin and display a large variety in clinical presentation (regarding disease duration, age at onset, and others). The goal of this report was to describe the clinical features and diagnostic tests in a patient with a novel prion protein gene (PRNP) D202G mutation. CASE REPORT: A 71-year-old patient had all the clinical signs of Creutzfeldt-Jakob disease (CJD) but an extremely prolonged disease duration of 16 years. The 14-3-3 protein test was positive, while MRI and EEG did not show CJD typical changes. Family history was positive for cerebellar and dementia disorders without definite diagnoses. Full-length sequencing of the prion protein gene (PRNP) showed a new D202G mutation associated with valine on codon 129 of unknown significance. Methionine/valine heterozygosity at codon 129 was found. CONCLUSIONS: These findings highlight the value of 14-3-3 and gene analysis in unclear neurological disorders to detect possibly atypical presentations of prion disorders. The significance of this new mutation will remain unclear until further such patients are reported.

Fatal familial insomnia: Clinical features and early identification.

Our aim was to develop a detailed clinical description of fatal familial insomnia in a large patient group with respect to the M129V genotype. Data on 41 German fatal familial insomnia patients were analyzed. Clinical features, 14-3-3 proteins in the cerebrospinal fluid, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, polysomnography, and electroencephalography were studied. Age at disease onset, disease duration, and clinical syndrome varied depending on the codon 129 genotype. Because the sensitivity of the most diagnostic tests is low in fatal familial insomnia, detailed clinical investigation is extremely important. Polysomnography may help to support the diagnosis.

ApoE distribution and family history in genetic prion diseases in Germany.

We analyzed the ApoE genotype in patients with genetic prion diseases (gPD) with respect to family history (FH) of dementia/prion disease (PD) compared to non-demented controls. Fifty-nine gPD patients and 51 sex-/age-matched controls were included. A positive FH of dementia and PD (PFH) were evaluated. The prion protein gene (PRNP) codon 129 and ApoE genotype were determined by polymerase chain reaction (PCR). The frequency of FH of neurodegenerative disorder/prion disease/dementia varied in different PRNP mutations. PFH was found in 87% of D178N patients, but was rarer in others. Although the ApoE genotype distribution was not significantly different between gPD patients and controls, the protective E2 alleles were more frequent in controls than in patients without a PFH and even less frequent in those with a PFH (18, 16, and 11%). E4 alleles as a risk factor of Alzheimer's disease were more common in controls and patients with a PFH than in those without PFH (25, 21, and 13%). No effect of the codon 129 genotype was detected. Only about two-thirds of gPD patients had PFH of PD, while in one-third, PFH of slowly progressive dementia was reported. Underreporting of PFH of gPD may play a role; however, the varying PFH frequency across various mutations is not explained by this factor only.

Molecular subtype-specific clinical diagnosis of prion diseases.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare transmissible disease caused by accumulation of pathological prion protein (PrP(sc)) in the CNS. According to the codon 129 polymorphism (methionine or valine) and the prion protein type 1 or 2, a classification into distinct subtypes was established. Further analysis of these subtypes detected atypical clinical forms with longer disease duration or younger age at onset. The CJD subtype influences sensitivity of the technical investigations such as 14-3-3 in CSF, periodic sharp wave complexes in the EEG or hyperintense basal ganglia in MRI. A further characterization of these subtypes is important for reliable diagnosis and identification of rare disease variants. The aim is to establish specific patterns of test results and clinical findings. These improvements in diagnostics may be the reason for the apparent increase in sCJD incidence in Germany from 0.9 in 1994 to 1.6 in a million in 2005. Despite careful surveillance, no patient with variant CJD has been detected to date in Germany. Here we present the data of the CJD surveillance of the last 13 years. Additionally, the improvements in diagnostics and differential diagnosis are discussed.

Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis.

BACKGROUND: The analysis of markers in the cerebrospinal fluid (CSF) is useful in the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, the time at which the study of these markers is most sensitive remains controversal. OBJECTIVE: To assess the influence of time of sampling on the value of CSF tests in the diagnosis of sCJD. METHOD: In the framework of a multinational European study, we studied the results of 14-3-3, S100b, neurone specific enolase (NSE) and tau protein in 833 CSF samples from sCJD patients at different stages of disease and in 66 sequentially repeated lumbar punctures (LP). RESULTS: 14-3-3 and tau protein tended to increase in sensitivity from onset (88%, 81%) to the advanced stage (91%, 90%). This was significant only in the methionine-valine (MV) heterozygous group of patients at codon 129. The absolute levels of S100b (p < 0.05), NSE and tau protein increased in the last stage of disease. High levels of tau protein, NSE and S100b were associated with shorter survival times (p < 0.01). Sixty-six sCJD patients underwent repeated LP. These sCJD patients were younger, had longer disease durations and were more frequently MV at codon 129 (p < 0.001) than the whole group. 14-3-3 sensitivity increased from 64% to 82% in the second LP (p = 0.025) and 88% sCJD patients had at least one positive result. CONCLUSIONS: Sensitivity and absolute levels of CJD markers increased with disease progression and were modulated by the codon 129 genotype. Early negative results should be inter-preted with caution, especially in young patients or those who are MV at codon 129.

Brain-derived proteins in the CSF: do they correlate with brain pathology in CJD?

BACKGROUND: Brain derived proteins such as 14-3-3, neuron-specific enolase (NSE), S 100b, tau, phosphorylated tau and Abeta1-42 were found to be altered in the cerebrospinal fluid (CSF) in Creutzfeldt-Jakob disease (CJD) patients. The pathogenic mechanisms leading to these abnormalities are not known, but a relation to rapid neuronal damage is assumed. No systematic analysis on brain-derived proteins in the CSF and neuropathological lesion profiles has been performed. METHODS: CSF protein levels of brain-derived proteins and the degree of spongiform changes, neuronal loss and gliosis in various brain areas were analyzed in 57 CJD patients. RESULTS: We observed three different patterns of CSF alteration associated with the degree of cortical and subcortical changes. NSE levels increased with lesion severity of subcortical areas. Tau and 14-3-3 levels increased with minor pathological changes, a negative correlation was observed with severity of cortical lesions. Levels of the physiological form of the prion protein (PrPc) and Abeta1-42 levels correlated negatively with cortical pathology, most clearly with temporal and occipital lesions. CONCLUSION: Our results indicate that the alteration of levels of brain-derived proteins in the CSF does not only reflect the degree of neuronal damage, but it is also modified by the localization on the brain pathology. Brain specific lesion patterns have to be considered when analyzing CSF neuronal proteins.

Clinical features and diagnosis of the MM2 cortical subtype of sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To describe clinical features and diagnostic tests of the MM2 cortical subtype in sporadic Creutzfeldt-Jakob disease. METHODS: Clinical symptoms, magnetic resonance imaging studies, electroencephalograms, and cerebrospinal fluid markers were studied in 12 patients with genetically and neuropathologically verified sporadic Creutzfeldt-Jakob disease. Histological findings were semiquantitatively evaluated. RESULTS: Compared with classical sporadic Creutzfeldt-Jakob disease, the disease duration was prolonged (median, 14 months). All patients had dementia and early and prominent neuropsychological signs such as spatial disorientation, aphasia, or apraxia. Alzheimer disease was the most frequent initial diagnosis (33%). Increased S100B protein in the cerebrospinal fluid was found in 100%; the 14-3-3 protein test was positive in 91%. Electroencephalograms revealed periodic sharp wave complexes in 42%. T2-weighted magnetic resonance imaging showed basal ganglia hyperintensities in only 1 patient, and cortical hyperintensities were not necessarily present. Severe cortical damage was the most prominent histological feature. CONCLUSIONS: The S100B (100%) and 14-3-3 (91%) protein investigations were the most sensitive diagnostic tests. Prolonged disease duration, dementia as the only typical Creutzfeldt-Jakob disease symptom for a longer time, and low sensitivity of magnetic resonance imaging studies and electroencephalograms make the diagnosis in the MM2 cortical subtype difficult. Therefore, detailed clinical investigation is especially important in this sporadic Creutzfeldt-Jakob disease subtype. We suggest that rapidly progressive dementia with early and prominent neuropsychological deficits in older patients should lead to suspicion of the MM2 cortical subtype even if other neurological deficits are absent. At least some cases of MM2 cortical sporadic Creutzfeldt-Jakob disease may be misdiagnosed as rapidly progressive Alzheimer disease.

Clinical findings and diagnostic tests in the MV2 subtype of sporadic CJD.

Atypical clinical course and low sensitivity of established diagnostic tests are the main diagnostic problems in the MV2 subtype of sporadic Creutzfeldt-Jakob disease (sCJD). Clinical symptoms and signs, MRI, EEG and biochemical CSF markers were studied in 26 patients. Histological findings were semiquantitatively evaluated. Compared with typical sCJD, the disease duration was prolonged (median 12 months). Dementia, ataxia and psychiatric symptoms were present in all patients. Extrapyramidal signs were observed in 88%. T2-weighted MRI showed basal ganglia hyperintensities in 90%. Increased thalamic signal intensity was detected in 88% on diffusion-weighted MRI. Increased CSF tau-protein was found in 83%, and the 14-3-3 test was positive in 76%. The EEG revealed periodic sharp wave complexes in only two patients. Kuru plaques, severe thalamic and basal ganglia gliosis and spongiform changes, and neuronal loss in the pulvinar were the prominent histological features. At least one of the three diagnostic tests (MRI, tau- and 14-3-3 protein) supported the clinical diagnosis in all patients. MRI was the most sensitive of the diagnostic tests applied. Thalamic hyperintensities were observed unusually frequently. Prolonged disease duration, early and prominent psychiatric symptoms, absence of typical EEG, thalamic hyperintensities on MRI and relatively low 14-3-3 protein sensitivity may be suspicious for variant CJD. However, distinct sensory symptoms and young age at onset, which are often found in the latter, are not common in the MV2 subtype, and the pulvinar sign was observed in only one case.