APOE gene polymorphisms and susceptibility to Creutzfeldt–Jakob disease

Associations between apolipoprotein E (APOE) gene polymorphisms and Creutzfeldt–Jakob disease (CJD) have been reported, but the results from many of these studies are conflicting. To investigate the association between APOE polymorphisms and CJD risk, we performed a meta-analysis. We used odds ratios (OR) with 95% confidence intervals (CI) to assess the strength of the association. The frequency of putative risk alleles in control subjects was estimated with the Mantel-Haenszel method. Cochran’s Q statistic and the inconsistency index (I²) were used to test heterogeneity. Egger’s test and an inverted funnel plot were used to assess bias. Our study included 11 published case–control studies with APOE genotyping, involving a total of 1001 CJD patients and 1211 controls. Overall, the APOE 34 (OR 1.37, 95% CI: 1.09–1.72), and APOE 44 (OR 3.16, 95% CI: 1.37–7.26) genotypes and the APOE 4 (OR 1.41, 95% CI: 1.08–1.85) allele were associated with an increased risk of CJD, and the APOE 33 (OR 0.81, 95% CI: 0.67–0.97) genotype tended to protect against CJD. However, we did not find significant evidence supporting associations of the APOE 22 (OR 1.15, 95% CI: 0.45–2.93), APOE 23 (OR 0.84, 95% CI: 0.64–1.09), or APOE 24 (OR 1.40, 95% CI: 0.70–2.77) genotypes, nor the APOE 2 (OR 1.02, 95% CI: 0.73–1.42) or APOE 3 (OR 0.82, 95% CI: 0.65–1.02) alleles with CJD using a fixed-effects model. Our results support a genetic association between APOE polymorphisms and CJD.     

Cerebral amyloid angiopathy with co-localization of prion protein and beta-amyloid in an 85-year-old patient with sporadic Creutzfeldt–Jakob disease

We report on an 85-year-old woman with hypertensive cerebral arteriolosclerosis who presented with rapidly progressive encephalopathy leading to death within 4 months. Magnetic resonance imaging showed mild cortical atrophy consistent with her age and diffuse leukoaraiosis. Her CSF 14–3–3 protein was positive. Neuropathology showed severe spongiform change and gliosis in the grey matter and immunohistochemistry revealed diffuse prion protein deposition in a predominant synaptic pattern. She had no family history of neurological disorder and genotyping did not show any prion protein gene mutation, in keeping with a diagnosis of sporadic Creutzfeldt–Jakob disease. There was also diffuse amyloid angiopathy involving the cortical and leptomeningeal arterioles of the cerebral hemispheres and cerebellum and the capillaries of the grey matter. The amyloid angiopathy expressed beta-amyloid but also prion protein and double immunostaining confirmed co-localization of both proteins in many vessel walls. Alzheimer’s type pathology was restricted to a few diffuse beta-amyloid plaques in the entorhinal cortex and rare tangles in the hippocampus. Deposition of prion protein in cerebral vessels has been reported in a single case of stop codon 145 mutation of the PRNP gene. Co-localization of beta-amyloid and prion protein in the same amyloid plaque has been described in elderly patients with Creutzfeldt–Jakob or Gerstmann–Sträussler–Scheinker diseases but only exceptionally in cerebral amyloid angiopathy. In this patient, hypertensive cerebrovascular disease may have contributed to the failure to eliminate both proteins from the brain.     

MRI sequence findings in sporadic Creutzfeldt–Jakob disease

MRI has had an important role in the diagnosis of Creutzfeldt–Jakob disease (CJD). The aim of our study was to compare the efficacy of different MRI sequences among six biopsy-proven patients with sporadic CJD (sCJD) and seven patients with probable sCJD. These 13 patients with CJD aged from 36 years to 75 years (mean age: 55.5 years) were evaluated with T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) MRI and diffusion-weighted imaging (DWI). The characteristic MRI lesion pattern was found to be bilateral, symmetric and hyperintense signal changes in the basal ganglia and cortical regions. Two major lesion patterns were identified in all patients involving the cortex and basal ganglia. No signal abnormality was found in the thalamus. We found lesions in the cortex and basal ganglia in 7/13 patients (54%), isolated cortical involvement in 2/13 patients (15%), and isolated basal ganglia lesions in 4/13 patients (31%). The cortical involvement was widespread (in at least two regions) and usually included the frontal or occipital lobes (9/13, 69%) on DWI. Only one patient showed moderate high-signal intensity in the basal ganglia on T2-weighted MRI. T1-weighted MRI revealed no signal intensity abnormalities. We conclude that high signal changes in the basal ganglia and cerebral cortex on FLAIR and DWI are useful in the diagnosis of sCJD. Isolated cortical involvement on DWI and FLAIR should lead to a suspicion of CJD. DWI is the most sensitive MRI technique in the diagnosis of CJD, which supports an amendment to the clinical diagnostic criteria for sCJD to include findings from MRI.     

Redefining periodic patterns on electroencephalograms of patients with sporadic Creutzfeldt–Jakob disease

Objective

We aimed to redefine various periodic patterns (PPs) observed on electroencephalography (EEG) in patients with sporadic Creutzfeldt–Jakob disease (sCJD) using the American Clinical Neurophysiology Society’s (ACNS) Criteria.

Corticobasal syndrome due to sporadic Creutzfeldt–Jakob disease: a review and neuropsychological case report

Objective: Creutzfeldt–Jakob disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disease with neuropsychological sequelae. This study highlighted a rare presentation of CJD (e.g. corticobasal syndrome [CBS]), reviewed updated diagnostic criteria and procedures for CJD (e.g. diffusion weighted imaging [DWI], real-time quaking-induced conversion [RT-QuIC]), and discussed differential diagnoses. Method: Case report methodology focused on a 68-year-old, Hispanic, right-handed man with 11 years of education. He presented with a 1–2-month history of gait and motor difficulties (e.g. rigidity, myoclonus). Results: After evaluation, a ‘cortical ribboning’ pattern on DWI and positive RT-QuIC was integrated with performance on neurobehavioral exam (i.e. alien limb phenomenon, unilateral ideomotor apraxia) and neuropsychological testing (i.e. frontal-parietal dysfunction pattern) to reach a diagnosis of sCJD-CBS. The patient expired 3 months after onset of symptoms. Conclusions: This literature review and case report highlighted the importance of staying abreast of developments in neurological literature and the added value of neuropsychology, when integrated with newer procedures, for confirming and excluding diagnostic considerations.     

Temporal evolution of sporadic Creutzfeldt–Jakob disease monitored by 3-Tesla MR spectroscopy

Journal of Neurology -     

Familial Creutzfeldt–Jakob disease homozygous to the E200K mutation: clinical characteristics and disease course

Journal of Neurology - To characterize the demographic, clinical features and disease course of familial Creutzfeldt–Jakob disease (fCJD) patients homozygous to the E200K mutation. The...     

The Braak hypothesis in prion disease with a focus on Creutzfeldt–Jakob disease

This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt–Jakob disease (CJD). In CJD, we can speculate on the pathological onset region to some degree in reference to the clinical symptoms and magnetic resonance imaging findings. Although relating the Braak hypothesis to prion disease is not straightforward, the following could be proposed based on experimental and previously reported case observations. Pathogenic abnormal prion protein (PrP) deposition in the central nervous system (CNS) probably begins several months or years before clinical symptom onset, signifying the potentiality of a preclinical stage, similar to α-synuclein deposition in Parkinson's disease (PD) and amyloid-β/tau deposition in Alzheimer's disease (AD). Unlike in PD and AD, the initial clinical symptoms of CJD vary by case, and thus the onset lesions must also be various and multiple in the CNS. Based on the pathological findings, particularly of PrP deposition extensively observed in the CNS gray matter of autopsy cases, it could be speculated that in the early disease stage, including the preclinical stage, abnormal PrP spreads from the onset region without directionality or hierarchy. Because each CNS region shows either vulnerability to or resistance against PrP deposition and pathological progression in prion disease, the lesion distribution shows system degeneration. Although pathologically combined cases of type 1 and type 2 PrP patterns are often recognized, type 1 and type 2 PrP patterns must never shift toward each other during the disease course; in other words, the original type of PrP deposition in each region presumably remains unchanged in each case. According to the several observations and corresponding speculations, there are at least partial similarities between prion disease and protein propagation, as explained by the Braak hypothesis, in terms of pathological lesion progression, but several noted contradictions preclude the hypothesis from comprehensively accounting for prion disease.     

Novel prion protein gene mutation at codon 196 (E196A) in a septuagenarian with Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease (CJD) is a rare and rapidly progressive neurodegenerative disease of the central nervous system, which may occur in inherited, acquired (variant and iatrogenic), or spontaneous (sporadic) forms. We report a 76-year-old Chinese man with CJD found to have a novel mutation in the prion protein gene (PRNP). The 14-3-3 protein was positive in the cerebrospinal fluid; diffusion-weighted MRI revealed ribbon-like high signal intensity in the bilateral cortices; and electroencephalography showed typical periodic synchronous discharge. CJD was diagnosed based on characteristic clinical manifestations. Interestingly, a point mutation of PRNP at codon 196 (E196A: GAG → GCG) was detected. In conclusion, we identified a patient with CJD with a novel PRNP mutation, which expands the spectrum of PRNP mutations in CJD.     

Visual art therapy in sporadic Creutzfeldt–Jakob disease: a case study

ABSTRACT

This paper describes the diagnostic and treatment utility of visual art therapy in a case of sporadic Creutzfeldt–Jakob disease. Visual art therapy was compared longitudinally with clinical and neuroimaging data over five-month period in an autopsy-confirmed case of sporadic Creutzfeldt–Jakob disease of MM2-cortical subtype. Art therapy sessions and content were useful in ascertaining neuropsychiatric symptoms during the course of her illness. Art therapy offered a unique emotional and cognitive outlet as illness progressed.

Patients and families affected by sporadic Creutzfeldt–Jakob disease may benefit from art therapy despite the rapidly progressive nature of the illness. Art therapy can also be useful for assessment of patients with sporadic Creutzfeldt–Jakob disease by healthcare professionals.     

Comparison of diffusion-weighted MRI with 18F-fluorodeoxyglucose-positron emission tomography/CT and electroencephalography in sporadic Creutzfeldt–Jakob disease

18F-fluorodeoxyglucose-positron emission tomography/CT (18F-FDG PET/CT) scanning may be a useful tool for early diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD), as it may reveal lowered cellular glucose transport and metabolism in the cortex, cerebellum and basal ganglia. The aim of the present study was to compare the findings from PET/CT, MRI and electroencephalography (EEG) for patients with sCJD, to explore whether typical sites or reliable patterns of regional metabolic change could be found and to evaluate the results of diagnostic imaging in the light of clinical symptomatology. Five patients with biopsy-confirmed sCJD and nine with probable sCJD (aged 36–68 years) were evaluated using PET/CT, diffusion-weighted (DW)-MRI and EEG. In 13 of the 14 patients (92.86%), PET/CT imaging detected extra regions with abnormalities in addition to the hyperintense areas shown with DW-MRI. Two patients with no abnormal DW-MRI findings in the basal ganglia had bilateral extrapyramidal signs accompanied by basal ganglia hypometabolism on PET. Eight patients (57.14%) had decreased FDG uptake in the thalamic nuclei on PET scans; however, DW-MRI did not identify corresponding hyperintense changes in the thalamic nuclei. In 11 patients (78.57%), DW-MRI revealed more regions with abnormalities than EEG, and 10 patients (71.43%) had DW-MRI abnormalities in the thalamic nuclei and basal ganglia that EEG was unable to detect. There was a high level of correspondence among the PET/CT, DW-MRI and EEG results, with PET revealing more abnormal regions than the other imaging modalities. In the absence of neuropathological findings, FDG-PET could improve the accuracy of sCJD diagnosis when combined with DW-MRI and EEG, particularly for differentiating sCJD from paraneoplastic syndromes. Our results suggest that PET/CT is able to detect sCJD at an earlier stage and with greater sensitivity than DW-MRI.     

Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification

Six subtypes of sporadic Creutzfeldt–Jakob disease with distinctive clinico-pathological features have been identified largely based on two types of the abnormal prion protein, PrP^Sc, and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrP^Sc types has been reported but with inconsistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classification of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrP^Sc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrP^Sc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identified the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the co-occurrence of pathological variants sharing PrP^Sc type 2. In contrast, molecular typing best detected the concurrent PrP^Sc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classification and are of importance for future epidemiologic and transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt–Jakob disease.     

Association of sporadic Creutzfeldt–Jakob disease with homozygous genotypes at PRNP codons 129 and 219 in the Korean population

Human prion protein gene (PRNP) is considered an important gene in determining the incidence of human transmissible spongiform encephalopathies or prion diseases. Polymorphisms of PRNP at codon 129 in Europeans and codon 219 in Japanese may play an important role in the susceptibility to sporadic Creutzfeldt–Jakob disease (CJD); data regarding codon 129 in the Japanese population have led to divergent interpretations. In order to determine which, if any, of the PRNP genotypes in Korean people are associated with sporadic CJD, we examined the genotype and allelic distributions of human PRNP polymorphisms in 150 patients with sporadic CJD. All Korean sporadic CJD patients were Met/Met at codon 129, Glu/Glu at codon 219 and undeleted at the octarepeat region of PRNP. Our study showed significant differences in genotype frequency of PRNP at codon 129 (χ ²=8.8998, P=0.0117) or 219 (χ ²=12.6945, P=0.0004) between sporadic CJD and normal controls. Furthermore, the genotype frequency of the heterozygotes for codons 129 and/or 219 showed a significant difference between the normal population and sporadic CJD patients (χ ²=21.0780, P<0.0001).