Cerebellar Cognitive Affective Syndrome Improved by Donepezil.

Cerebellar damage can cause not only disturbance in motor control but also higher brain dysfunction known as cerebellar cognitive affective syndrome (CCAS). Although CCAS has a high prevalence, the precise mechanism and effective medications are unknown. We herein report a CCAS patient whose symptoms were ameliorated with the cholinesterase inhibitor donepezil. N-isopropyl-p-123I-iodoamphetamine-single-photon emission computed tomography showed improvement in hypoperfusion in the contralateral frontal and parieto-temporal lobes. Some projections with cholinergic transmission might form a functional connectivity between the cerebellum and contralateral association cortices, and cholinergic dysfunction is involved in CCAS pathophysiology. Donepezil might be worth considering for some CCAS patients.

Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to-isoleucine substitution at codon 180 on the prion protein gene.

Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrPres at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrPres in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrPres were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease.

A Score for Predicting Paroxysmal Atrial Fibrillation in Acute Stroke Patients: iPAB Score.

BACKGROUND: Detection of paroxysmal atrial fibrillation (PAF) after a stroke is challenging. The purpose of this study was to develop a clinical score to predict PAF in a cohort of acute ischemic stroke patients prospectively and to validate it in an independent cohort. METHODS: Consecutive acute ischemic stroke patients without permanent atrial fibrillation were enrolled in a derivation sample (n = 294) or a validation sample (n = 155). We developed a score for predicting PAF by independent risk factors derived from a logistic regression analysis of the derivation cohort and validated the score in the external cohort. RESULTS: Multivariate analysis in the derivation cohort identified 3 variables independently associated with PAF. We calculated a score from these variables (history of arrhythmia or antiarrhythmic agent use [yes, 3 points], left atrial dilation [≥40 mm, 1 point], brain natriuretic peptide [BNP, ≥50 pg/mL, 1 point; ≥90 pg/mL, 2 points; ≥150 pg/ml, 3 points], total score, 0-7). The iPAB score (identified by past history of arrhythmia or antiarrhythmic agent use, atrial dilation, and BNP elevation) predicted PAF in the derivation (c statistic, .90) and validation (.94) cohorts at levels statistically superior to other biomarkers and clinical scores. For a total score 2 or more, the sensitivity and specificity were 93% and 71%, respectively. For a total score of 4 or more, the corresponding values were 60% and 95%. CONCLUSIONS: Our prospective study suggests that this simple risk score superior to other scores help clinicians predict PAF or identify good candidates for further evaluation to detect PAF.

Clinical features of genetic Creutzfeldt-Jakob disease with V180I mutation in the prion protein gene.

OBJECTIVES: Genetic Creutzfeldt-Jakob disease (CJD) due to V180I mutation in the prion protein gene (PRNP) is of great interest because of the differences from sporadic CJD and other genetic prion diseases in terms of clinical features, as well as pathological and biochemical findings. However, few systematic observations about the clinical features in patients with this unique mutation have been published. Therefore, the goal of this study was to relate this mutation to other forms of CJD from a clinical perspective. DESIGN: We analysed clinical symptoms, prion protein genetics, biomarkers in cerebrospinal fluid (CSF) and MRI of patients. PARTICIPANTS: 186 Japanese patients with the V180I mutation in PRNP. RESULTS: Our results indicate that the V180I mutation caused CJD at an older age, with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance compared with classical sporadic CJD with methionine homozygosity at codon 129 of PRNP. Cognitive impairment was the major symptom. Diffuse hyperintensity of the cerebral cortex in diffusion-weighted MRI might be helpful for diagnosis. Owing to the low positivity of PrP(Sc) in the CSF, genetic analysis was often required for a differential diagnosis from slowly progressive dementia. CONCLUSIONS: We conclude that the V180I mutation in PRNP produces a late-developing and slow-developing, less severe form of CJD, whose lesions are uniquely distributed compared with sporadic and other genetic forms of CJD.

Evaluating prion models based on comprehensive mutation data of mouse PrP.

The structural details of the essential entity of prion disease, fibril prion protein (PrP(Sc)), are still elusive despite the large body of evidence supporting the prion hypothesis. Five major working models of PrP(Sc) structure, which are not compatible with each other, have been proposed. However, no systematic evaluation has been performed on those models. We devised a method that combined systematic point mutation with threading on knowledge-based amino acid potentials. A comprehensive mutation experiment was performed on mouse prion protein, and the PrP(Sc) conversion efficiency of each mutant was examined. The models were evaluated based on the mutation data by using the threading method. Although the data turned out to be rather more consistent with the models that assumed a conversion of the N-terminal region of core PrP into a ß helix than with others, substantial modifications were also required to further improve the current model based on recent experimental results.

Amino acid conditions near the GPI anchor attachment site of prion protein for the conversion and the GPI anchoring.

Prion protein (PrP) is a glycosylphosphatidylinositol (GPI)-anchored protein, and the C-terminal GPI anchor signal sequence (GPI-SS) of PrP is cleaved before GPI anchoring. However, mutations near the GPI anchor attachment site (the omega site) in the GPI-SS have been recognized in human genetic prion diseases. Moreover, the omega site of PrP has not been identified except hamster, though it is known that amino acid restrictions are very severe at the omega and omega+2 sites in other GPI-anchored proteins. To investigate the effect of mutations near the omega site of PrP on the conversion and the GPI anchoring, and to discover the omega site of murine PrP, we systematically created mutant murine PrP with all possible single amino acid substitutions at every amino acid residue from codon 228 to 240. We transfected them into scrapie-infected mouse neuroblastoma cells and examined the conversion efficiencies and the GPI anchoring of each mutant PrP. Mutations near the omega site altered the conversion efficiencies and the GPI anchoring efficiencies. Especially, amino acid restrictions for the conversion and the GPI anchoring were severe at codons 230 and 232 in murine PrP, though they were less severe than in other GPI-anchored proteins. Only the mutant PrPs presented on a cell surface via a GPI anchor were conversion competent. The present study shows that mutations in the GPI-SS can affect the GPI anchoring and the conversion efficiency of PrP. We clarified for the first time the omega site of murine PrP and the amino acid conditions near the omega site for the conversion as well as GPI anchoring.

Heterozygous inhibition in prion infection: the stone fence model.

The human PrP gene (PRNP) has two major polymorphic codons: 129 for methionine (M) or valine (V) and 219 for glutamate (E) or lysine (K). The PRNP heterozygotes appear to be protected from sporadic CJD compared to the PRNP homozygotes. The molecular mechanism responsible for these protective effects of PRNP heterozygosity has remained elusive. In this review, we describe the inhibition of PrP conversion observed in a series of transmission studies using PRNP heterozygous animal models. In vCJD infection, the conversion incompetent human PrP 129V molecules showed an inhibitory effect on the conversion of human PrP 129M molecules in the 129M/V heterozygous mice. Furthermore, though the human PrP 219E and PrP 219K were both conversion competent in vCJD infection, these conversion competent PrP molecules showed an inhibitory effect in the 219E/K heterozygous animals. To explain this heterozygous inhibition, we propose a possible mechanism designated as the stone fence model.

Human prion protein (PrP) 219K is converted to PrPSc but shows heterozygous inhibition in variant Creutzfeldt-Jakob disease infection.

Prion protein gene (PRNP) E219K is a human polymorphism commonly occurring in Asian populations but is rarely found in patients with sporadic Creutzfeldt-Jakob disease (CJD). Thus the polymorphism E219K has been considered protective against sporadic CJD. The corresponding mouse prion protein (PrP) polymorphism variant (mouse PrP 218K) is not converted to the abnormal isoform (PrP(Sc)) and shows a dominant negative effect on wild-type PrP conversion. To define the conversion activity of this human molecule, we herein established knock-in mice with human PrP 219K and performed a series of transmission experiments with human prions. Surprisingly, the human PrP 219K molecule was converted to PrP(Sc) in variant CJD infection, and the conversion occurred more efficiently than PrP 219E molecule. Notably the knock-in mice with PRNP codon 219E/K showed the least efficient conversion compared with their hemizygotes with PRNP codon 219E/0 or codon 219K/0, or homozygotes with PRNP codon 219E/E or codon 219K/K. This phenomenon indicated heterozygous inhibition. This heterozygous inhibition was observed also in knock-in mice with PRNP codon 129M/V genotype. In addition to variant CJD infection, the human PrP 219K molecule is conversion-competent in transmission experiments with sporadic CJD prions. Therefore, the protective effect of PRNP E219K against sporadic CJD might be due to heterozygous inhibition.

[Establishment of the concept of prion diseases].

The history of prion diseases is derived from descriptions of scrapie of sheep and goats in the eighteenth century. In 1920, Creutzfeldt-Jakob disease was reported as the first case of human prion diseases, which was recognized as subacute spongiform encephalopathy, one of neurodegenerative diseases. Afterwards, many transmission experiments were performed, which lead to the establishment of the fundamental concept, transmissible spongiform encephalopathy(TSE). The infectious agent was supposed to be a novel virus, so TSE was classified into slow virus infection. In 1982, Prusiner investigated the infectious fraction of scrapie-infected brain homogenate, defined the infectious agent as proteinaceous infectious particles that resist inactivation by procedures that modify nucleic acid and newly designated as prion after virion in viral infection.