Specific clinical signs and symptoms are predictive of clinical course in sporadic Creutzfeldt-Jakob disease.

BACKGROUND AND PURPOSE: Akinetic mutism is thought to be an appropriate therapeutic end-point in patients with sporadic Creutzfeldt-Jakob disease (sCJD). However, prognostic factors for akinetic mutism are unclear and clinical signs or symptoms that precede this condition have not been defined. The goal of this study was to identify prognostic factors for akinetic mutism and to clarify the order of clinical sign and symptom development prior to its onset. METHODS: The cumulative incidence of akinetic mutism and other clinical signs and symptoms was estimated based on Japanese CJD surveillance data (455 cases) collected from 2003 to 2008. A proportional hazards model was used to identify prognostic factors for the time to onset of akinetic mutism and other clinical signs and symptoms. RESULTS: Periodic synchronous discharges on electroencephalography were present in the majority of cases (93.5%). The presence of psychiatric symptoms or cerebellar disturbance at sCJD diagnosis was associated with the development of akinetic mutism [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.14-1.99, and HR 2.15, 95% CI1.61-2.87, respectively]. The clinical course from cerebellar disturbance to myoclonus or akinetic mutism was classified into three types: (i) direct path, (ii) path via pyramidal or extrapyramidal dysfunction and (iii) path via psychiatric symptoms or visual disturbance. CONCLUSIONS: The presence of psychiatric symptoms or cerebellar disturbance increased the risk of akinetic mutism of sCJD cases with probable MM/MV subtypes. Also, there appear to be sequential associations in the development of certain clinical signs and symptoms of this disease.

Survival to akinetic mutism state in Japanese cases of MM1-type sporadic Creutzfeldt-Jakob disease is similar to Caucasians.

BACKGROUND: It is not known whether the clinical course of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases differs from that of Caucasian sCJD cases. PATIENTS AND METHODS: To investigate the clinical course of Japanese sCJD, clinical findings from 29 patients with Japanese MM1-type sCJD were retrospectively evaluated and compared to Caucasian sCJD findings. RESULTS: Survival of Japanese MM1-type sCJD up to the time of akinetic mutism state is similar to that of Caucasian subjects. However, the total disease duration of Japanese patients was approximately three times longer. CONCLUSIONS: The present observations indicate that Japanese sCJD cases generally show a longer disease duration because of the longer survival period after reaching the akinetic mutism state.

Actions of the Japanese Pancreas and Islet Transplantation Association regarding transplanted human islets isolated using Liberase HI.

PURPOSE: The potential for introducing transmissible spongiform encephalopathy (TSE) into islet cells was indicated by recognizing that Liberase HI is isolated from Clostridium histolyticum grown in media containing brain-heart infusion broth. A national team within the Japanese Pancreas and Islet Transplantation Association implemented an islet transplantation program in Japan using Liberase HI. The program comprised 65 islet isolations from non-heart-beating donors and 34 transplants into 18 patients. Herein, we have summarized how the Association followed these recipients over the long term. PROCEDURES: We established an ad hoc committee to follow recipients transplanted with islets isolated using Liberase HI after becoming informed of the associated dangers of using this enzyme. We also stopped islet transplantations using Liberase. The committee addressed the major concerns of the risk of the collagenase being contaminated with TSE and of the recipient follow-up. All recipients were examined by diffusion MRI and EEG and then scheduled for evaluation and follow-up by specialists in Creutzfeldt-Jakob disease (CJD). Bioassays of bovine spongiform encephalopathy prions in the enzyme proceeded using knock-in mice expressing bovine prion protein. These assays could detect contaminating prions at a dilution of 1 × 10(4). After inactivating its collagenase activity, Liberase HI was injected into the abdominal cavities of knock-in mice. Four months later, prion infectivity in Liberase HI was evaluated by immunohistochemical staining and Western blotting of spleen homogenates using anti-prion protein antibodies. MAIN FINDINGS: Western blotting and immunohistochemical staining did not detect prions in Liberase HI. Diffusion MRI and EEG evaluations performed by CJD specialists confirmed that none of the transplanted recipients had CJD. CONCLUSIONS: Three years of follow-up revealed that none of the Japanese recipients of islet transplants developed CJD. Prion bioassays showed that the Liberase HI used to isolate islets for transplantation was free of infectious TSE prions.

Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate.

Treatment with intraventricular pentosan polysulphate (PPS) might be beneficial in patients with Creutzfeldt-Jakob disease. We report a 68-year-old woman with sporadic Creutzfeldt-Jakob disease who received continuous intraventricular PPS infusion (1-120 microg/kg/day) for 17 months starting 10 months after the onset of clinical symptoms. Treatment with PPS was well tolerated but was associated with a minor, transient intraventricular hemorrhage and a non-progressive collection of subdural fluid. The patient's overall survival time was well above the mean time expected for the illness but still within the normal range. Post-mortem examination revealed that the level of abnormal protease-resistant prion protein in the brain was markedly decreased compared with levels in brains without PPS treatment. These findings suggest that intraventricular PPS infusion might modify the accumulation of abnormal prion proteins in the brains of patients with sporadic Creutzfeldt-Jakob disease.

Changes in expression of sensory organ-specific microRNAs in rat dorsal root ganglia in association with mechanical hypersensitivity induced by spinal nerve ligation.

Chronic neuropathic pain caused by peripheral nerve injury is associated with global changes in gene expression in damaged neurons. To understand the molecular mechanisms underlying neuropathic pain, it is essential to elucidate how nerve injury alters gene expression and how the change contributes to the development and maintenance of chronic pain. MicroRNAs are non-protein-coding RNA molecules that regulate gene expression in a wide variety of biological processes mainly at the level of translation. This study investigated the possible involvement of microRNAs in gene regulation relevant to neuropathic pain. The analyses focused on a sensory organ-specific cluster of microRNAs that includes miR-96, -182, and -183. Quantitative real-time polymerase chain reaction (qPCR) analyses confirmed that these microRNAs were highly enriched in the dorsal root ganglion (DRG) of adult rats. Using the L5 spinal nerve ligation (SNL) model of chronic neuropathic pain, we observed a significant reduction in expression of these microRNAs in injured DRG neurons compared to controls. In situ hybridization and immunohistochemical analyses revealed that these microRNAs are expressed in both myelinated (N52 positive) and unmyelinated (IB4 positive) primary afferent neurons. They also revealed that the intracellular distributions of the microRNAs in DRG neurons were dramatically altered in animals with mechanical hypersensitivity. Whereas microRNAs were uniformly distributed within the DRG soma of non-allodynic animals, they were preferentially localized to the periphery of neurons in allodynic animals. The redistribution of microRNAs was associated with changes in the distribution of the stress granule (SG) protein, T-cell intracellular antigen 1 (TIA-1). These data demonstrate that SNL induces changes in expression levels and patterns of miR-96, -182, and -183, implying their possible contribution to chronic neuropathic pain through translational regulation of pain-relevant genes. Moreover, SGs were suggested to be assembled and associated with microRNAs after SNL, which may play a role in modification of microRNA-mediated gene regulation in DRG neurons.

A putative amino acid transporter of the solute carrier 6 family is upregulated by lithium and is required for resistance to lithium toxicity in Drosophila.

Lithium is an efficacious drug for the treatment of mood disorders, and its application is also considered a potential therapy for brain damage. However, the mechanisms underlying lithium's therapeutic action and toxic effects in the nervous system remain largely elusive. Here we report on the use of a versatile genetic model, the fruit fly Drosophila melanogaster, to discover novel molecular components involved in the lithium-responsive neurobiological process. We previously identified CG15088, which encodes a putative nutrient amino acid transporter of the solute carrier 6 (SLC6) family, as one of the genes most significantly upregulated in response to lithium treatment. This gene was the only SLC6 gene induced by lithium, and was thus designated as Lithium-inducible SLC6 transporter or List. Either RNA interference (RNAi)-mediated knockdown or complete deletion of List resulted in a remarkable increase in the susceptibility of adult flies to lithium's toxic effects, whereas transgenic expression of wild-type List significantly suppressed the lithium hypersensitive phenotype of List-deficient flies. Other ions such as sodium, potassium and chloride did not induce List upregulation, nor did they affect the viability of flies with suppressed List expression. These results indicate that lithium's biochemical or physical properties, rather than general osmotic responses, are responsible for the lithium-induced upregulation of List, as well as for the lithium-susceptible phenotype observed in List knockdown flies. Interestingly, flies became significantly more susceptible to lithium toxicity when List RNAi was specifically expressed in glia than when it was expressed in neurons or muscles, which is consistent with potential glial expression of List. These results show that the List transporter confers resistance to lithium toxicity, possibly as a consequence of its amino acid transporter activity in CNS glia. Our results have provided a new avenue of investigation toward a better understanding of the molecular and cellular mechanisms that underlie lithium-responsive neurobiological process.

The Drosophila TRPA channel, Painless, regulates sexual receptivity in virgin females.

Transient receptor potential (TRP) channels play crucial roles in sensory perception. Expression of the Drosophila painless (pain) gene, a homolog of the mammalian TRPA1/ANKTM1 gene, in the peripheral nervous system is required for avoidance behavior of noxious heat or wasabi. In this study, we report a novel role of the Pain TRP channel expressed in the nervous system in the sexual receptivity in Drosophila virgin females. Compared with wild-type females, pain mutant females copulated with wild-type males significantly earlier. Wild-type males showed comparable courtship latency and courtship index toward wild-type and pain mutant females. Therefore, the early copulation observed in wild-type male and pain mutant female pairs is the result of enhanced sexual receptivity in pain mutant females. Involvement of pain in enhanced female sexual receptivity was confirmed by rescue experiments in which expression of a pain transgene in a pain mutant background restored the female sexual receptivity to the wild-type level. Targeted expression of pain RNA interference (RNAi) in putative cholinergic or GABAergic neurons phenocopied the mutant phenotype of pain females. However, target expression of pain RNAi in dopaminergic neurons did not affect female sexual receptivity. In addition, conditional suppression of neurotransmission in putative GABAergic neurons resulted in a similar enhanced sexual receptivity. Our results suggest that Pain TRP channels expressed in cholinergic and/or GABAergic neurons are involved in female sexual receptivity.

Clinical features and diagnosis of dura mater graft associated Creutzfeldt Jakob disease.

BACKGROUND: A subset of patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) demonstrates atypical clinical features and plaque formation in the brain (plaque type). OBJECTIVE: To elucidate the frequency and clinical features of plaque type dCJD in comparison with the non-plaque type. METHODS: We analyzed clinicopathologic findings of 66 patients who had been registered as having dCJD by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, between April 1999 and February 2006. RESULTS: 1) Analysis of pathologically confirmed dCJD patients (n = 23) demonstrated plaque type dCJD in 11 patients (48%). In contrast to the non-plaque type with classic CJD features, the plaque type commonly presented with ataxic gait as an initial manifestation, relatively slow progression of neurologic symptoms, and no or late occurrence of periodic sharp-wave complexes (PSWCs) on EEG. MRI, especially diffusion-weighted images, and CSF 14-3-3 protein and neuron specific enolase (NSE) showed high diagnostic sensitivities for plaque as well as non-plaque types. 2) Analysis of clinically diagnosed dCJD patients (n = 34) demonstrated that 7 patients (21%) had atypical clinical features without PSWCs, probably corresponding to plaque type dCJD. CONCLUSION: The frequency of the plaque type in dura mater graft-associated Creutzfeldt-Jakob disease is apparently higher than previously recognized. For the clinical diagnosis of the plaque type dura mater graft-associated Creutzfeldt-Jakob disease, MRI and CSF markers would be useful, in addition to the core features, i.e., onset with ataxic gait disturbance, relatively slow progression, and no or late occurrence of periodic sharp-wave complexes on EEG.

The MM2-cortical form of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance.

A subclass of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by onset with visual symptoms (Heidenhain variant) has been reported to belong to the MM1 or MV1 type according to Parchi's classification. The authors report a 65-year-old woman with MM2-cortical sCJD with slowly progressive visual disturbance as the initial symptom. Diffusion-weighted MRIs revealed hyperintensity in both occipital cortices at an early stage.

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Involvement of the peripheral nervous system in human prion diseases including dural graft associated Creutzfeldt-Jakob disease.

OBJECTIVE: To investigate abnormal prion protein (PrP) deposition in the peripheral nervous system (PNS) in human prion diseases. METHODS: Eight patients with prion diseases were examined: three with sporadic Creutzfeldt-Jakob disease (sCJD), two with dural graft associated CJD (dCJD), one with Gerstmann-Straussler-Scheinker disease (GSS) with a PrP P102L mutation (GSS102), and two with a P105L mutation (GSS105). An atypical case of sCJD with PrP plaques in the brain presented clinically with peripheral neuropathy, and showed demyelination in 12% of the teased fibres of the sural nerve. The PNS was investigated by immunohistochemical and western blotting analyses of PrP. RESULTS: In immunohistochemical studies, granular PrP deposits were detected in some neurones of dorsal root ganglia and a few fibres of peripheral nerves and spinal posterior roots in one sCJD and two dCJD patients, but not in GSS102 or GSS105 patients. The atypical case of sCJD with peripheral neuropathy showed no obvious PrP deposition in the nerves. Western blotting analysis of the PNS from the dCJD patients revealed a small amount of protease K resistant PrP in the dorsal root ganglia and peripheral nerves. CONCLUSIONS: Abnormal PrP deposition occurs in the dorsal root ganglia and peripheral nerves in sCJD and dCJD. The PrP deposits in the PNS are not correlated with clinical manifestation of peripheral neuropathy in CJD.

MRI characteristics of sporadic CJD with valine homozygosity at codon 129 of the prion protein gene and PrPSc type 2 in Japan.

Two Japanese sporadic Creutzfeld-Jakob disease (sCJD) patients with valine homozygosity at codon 129 of the prion protein gene and protease-resistant prion protein (PrP(Sc)) type 2 (VV2) are described. In contrast with Western countries, this type of sCJD is very rare in Japan. In 123 sCJD cases, only two were recognised as VV2 by the Japanese CJD surveillance committee. The clinical symptoms and pathological findings of the patients were similar to those of European and US patients. The noteworthy finding of diffusion weighted MRI (DWI) was that an abnormal high intensity covered a wide range of the thalamus including the dorsomedial nucleus, the pulvinar, and the ventral anterior, lateral, and posterolateral nuclei. This thalamic pattern has not been recognised in sCJD with methionine homozygosity and PrP(Sc) type 1 (MM1) or methionine/valine heterozygosity and PrP(Sc) type 1 (MV1) which comprises the vast majority of sCJD. This finding may be characteristic to VV2 and may distinguish it from MM1, MV1, and variant CJD. DWI can provide a very important clue for the antemortem diagnosis of VV2 subjects.

Clinical features of Creutzfeldt-Jakob disease with V180I mutation.

The authors describe the clinical features of Creutzfeldt-Jakob disease (CJD) with the causative point mutation at codon 180. The symptoms never started with visual or cerebellar involvement. The patients showed slower progression of the disease compared with sporadic CJD. They never showed periodic sharp and wave complexes in EEG. MRI demonstrated remarkable high-intensity areas with swelling in the cerebral cortex except for the medial occipital and cerebellar cortices. These characteristic MRI findings are an important clue for an accurate premortem diagnosis.

Sporadic Creutzfeldt-Jakob disease with MM1-type prion protein and plaques.

The authors report a 75-year-old woman with atypical sporadic Creutzfeldt-Jakob disease (CJD) characterized by MM1-type prion protein (PrP) (methionine homozygosity at codon 129 in the PrP gene and type-1 protease-resistant PrP) and PrP plaques. This patient is the first case of sporadic CJD with plaque-forming MM1-type PrP, suggesting either a shared prion strain with the plaque-forming subset of dural graft-associated CJD or shared host genetic factors that are unrelated to the PrP genotype.

Scrapie removal using Planova virus removal filters.

As a possible method for reducing the risk of transmissible spongiform encephalopathy (TSE) infection, Planova virus removal filters were tested for their ability to remove scrapie agent ME7. Albumin solution was spiked with high-titre ME7 and filtered through three different pore sizes of Planova filters. Infectivity of the pre- and post-filtration samples was assayed in log dilutions by intracerebral inoculation into C57B1/6 mice. Filtration of albumin solution in the absence or presence of a detergent (Sarkosyl) with Planova 35N (35+/-2 nm mean pore size) removed the contaminating scrapie agent with reduction factors of 4.93 log10 and 1.61 log10, respectively. Filtration, both in the absence and presence of detergent with Planova 15N (15+/-2 nm mean pore size), and in the presence of detergent with Planova 10N (9+/-2 nm mean pore size), showed high levels of scrapie reduction of >5.87 log10, >4.21 log10, and >3.80 log10, respectively, with no residual infectively detected in any of the filtrate samples. The effectiveness of Planova 35N filtration for the removal of infectivity of this TSE agent is greatly reduced in the presence of a strong detergent, but Planova filters with 15 nm or smaller pore size membranes can remove such infectivity at high reduction rates.

Catalog of 434 single-nucleotide polymorphisms (SNPs) in genes of the alcohol dehydrogenase, glutathione S-transferase, and nicotinamide adenine dinucleotide, reduced (NADH) ubiquinone oxidoreductase families.

An approach based on development of a large archive of single-nucleotide polymorphisms (SNPs) throughout the human genome is expected to facilitate large-scale studies to identify genes associated with drug efficacy and side effects, or susceptibility to common diseases. We have already described collections of SNPs present among various genes encoding drug-metabolizing enzymes. Here we report SNPs for such enzymes at additional loci, including 8 alcohol dehydrogenases, 12 glutathione S-transferases, and 18 belonging to the NADH-ubiquinone oxidoreductase family. Among DNA samples from 48 Japanese volunteers, we identified a total of 434 SNPs at these 38 loci: 27 within coding elements, 52 in 5' flanking regions, five in 5' untranslated regions, 293 in introns, 20 in 3' untranslated regions, and 37 in 3' flanking regions. The ratio of transitions to transversions was approximately 2.1 to 1. Among the 27 coding SNPs, 13 were nonsynonymous changes that resulted in amino acid substitutions. Our collection of SNPs derived from this study should prove useful for investigations designed to detect associations between genetic variations and common diseases or responsiveness to drug therapy.

Severe brain atrophy in a case of thalamic variant of sporadic CJD with plaque-like PrP deposition.

A 30-year-old woman presented with ataxic gait and progressive mental deterioration, and 3 years later developed myoclonus in the limbs. Subsequently, she lapsed into an akinetic state and died more than 6 years after the onset of disease. The brain weighed 670 g, and preferential degeneration was found in the medial thalamus and the inferior olivary nucleus. In the cerebrum and cerebellum, gliosis and neuronal depletion were only mild and disintegration of the parenchymal structures was inconspicuous, despite pronounced atrophy. The patient had methionine homozygosity at codon 129 of the PrP gene and protease-resistant PrP type 2 in the brain. On PrP immunostaining, plaque-like deposits were detected in the cerebral and cerebellar cortices. Severe brain atrophy such as in the present case has never been described in the thalamic variant of sporadic CJD.