4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy.

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: a randomized, double-blind, placebo-controlled study.

Topical capsaicin 8% was developed for the treatment of peripheral neuropathic pain. The pain reduction is associated with a reversible reduction of epidermal nerve fiber density (ENFD). During its application, topical capsaicin 8% provokes distinct pain. In a randomized, double-blind study analyzed with a block factorial analysis of variance, we tested whether cooling the skin would result in reliable prevention of the application pain without inhibiting reduction of ENFD. A capsaicin 8% patch was cut into 4 quarters and 2 each were applied for 1 hour on the anterior thighs of 12 healthy volunteers. A randomization scheme provided for 1 of the application sites of each thigh to be pretreated with EMLA and the other with placebo, whereas both application sites of 1 thigh, also randomly selected, were cooled by cool packs, resulting in a site temperature of 20°C during the entire treatment period. The maximum pain level given for the cooled sites (visual analogue scale [VAS] 1.3 ± 1.4) proved to be significantly lower than for the non-cooled sites (VAS 7.5 ± 1.9) (P < .0001). In contrast, there was no significant difference in application pain between the sites pretreated with EMLA or with placebo (VAS 4.1 ± 3.6 vs 4.8 ± 3.5, P = .1084). At all application sites, ENFD was significantly reduced by 8.0 ± 2.8 (ENF/mm ± SD, P < .0001), that is, 70%, with no significant differences between the sites with the different experimental conditions. In conclusion, cooling the skin to 20°C reliably prevents the pain from capsaicin 8% patch application, whereas EMLA does not. ENFD reduction is not inhibited by cooling.

[The way out from crisis--from the closing of the National Psychiatric and Neurologic Institute (OPNI) to Semmelweis University]. / A válságlói kivezetô út--az OPNI megszûnésétôl a Semmelweis Egyetemig.

In our recent article we attempt to sum up the circumstances of the closing-down of the National Psychiatric and Neurologic Institute (OPNI). We intend to summarize the values that may disappear by the liquidation of the institute and try to explore the possibilities how to keep them alive in the future. Most of the divisions can operate further under the umbrella of the Semmelweis University; the modus operandi and the role of the University are also covered in this article.

[Frequency of different forms of dementia at the Department of Neuropathology of the Hungarian National Institute of Psychiatry and Neurology during a 3-year period]. / Dementiával járó kórképek gyakorisága az Országos Pszichiátriai és Neurológiai Intézet hároméves neuropatológiai anyagában.

BACKGROUND: Dementia is an increasing problem in society. The underlying cause of dementia may be difficult to diagnose during life. Only neuropathologic examination gives definite diagnosis. Differences in the reported frequency may be related to factors such as the age or gender of subjects with dementia. MATERIALS AND METHODS: In our neuropathology-based study we examined 156 consecutive subjects clinically diagnosed with dementia during a 3-year period. Using histopathological criteria we calculated the frequencies of various disorders causing dementia. We studied the effect of age and gender on these frequencies. RESULTS: Alzheimer's disease was the most frequent pathologic finding (57.7%) followed by vascular dementia (43%); diffuse Lewy body disease (15.4%); argyrophilic grain dementia (12.1%), various forms of frontotemporal dementia (5.7%); and other (4.5%). The latter comprise prion disease, alcoholic encephalopathy, and hippocampal sclerosis. Mixed pathology was common: concomitant Alzheimer's disease was present in 41.6% of diffuse Lewy body disease cases and in 49.2% of vascular dementia patients. Pure disease forms are rare: Alzheimer's disease: 26.3%, vascular dementia: 17.3%, diffuse Lewy body disease: 5.1%, argyrophilic grain dementia: 2.5%. Females were overrepresented among those with Alzheimer's disease with age at death above 75 years (p < 0.02), while males were overrepresented in patients below 75 years with vascular dementia (p < 0.05). CONCLUSIONS: Our study indicates that the frequency of neurodegenerative dementias is high in the examined patients, but vascular pathology frequently influences the clinical course.

[Sleep disorders in Parkinson syndromes]. / Alvás- es eberségzavarok Parkinsonizmussal járó betegségekben.

About 90% of neurodegenerative diseases with parkinsonism are associated with sleep disorders including daytime sleepiness, sleep-related breathing disorders and parasomnias. It is hard to define what ratio of insomnia and daytime hypersomnia is caused by the antiparkinsonian treatment, by the somatic and mental-emotional symptoms of the neurodegenerative disease and by the neurodegenerative brain process itself. Recent research suggests that the latter group is more important than expected. In Parkinson syndromes the structures included in sleep regulation--mainly within the brainstem--are also affected resulting in specific sleep disorders being the primary biological symptoms of these diseases. The recently described parasomnia--REM sleep behavior disorder--has a specific significance in this respect: it may prevent by several years a high ratio of the parkinsonian disorders--especially synucleinopathies--offering the possibility of prevention by identifying the affected individuals. There seems to exist a similar although less clarified association between daytime sleepiness and Parkinson disease. Analysing the behavior of the orexin system in neurodegenerative diseases may help to learn more about this, recently described neurohumoral system and may clear the association of narcolepsy with neurodegeneration. By understanding the associations of parkinsonian disorders and sleep disorders new therapeutical strategies may be invented and may offer new aspects to understand the mechanism of them.

[Progressive multifocal leukoencephalopathy]. / Progresszív multifokális leukoencephalopathia.

Progressive multifocal leukoencephalopathy is a rare disease caused by the reactivation of an opportunistic agent, JC virus almost in every cases in immunodeficient conditions. The disease is characterized by multifocal demyelinating lesions of the central nervous system and causes death within a few months. The authors report two patients: a 67 year-old male treated because of chronic lymphoid leukemia, and a 19 year-old male having a hereditary immunodeficiency, X-linked hyper IgM syndrome. In both cases continuously progressive right, later both hemispheric signs were detected. Cerebrospinal fluid was not helpful. Brain MRI showed bilateral large, white matter lesion. The progression was not influenced by the treatment, finally both patient died ten and six weeks after the appearance of first complaints. The diagnosis was confirmed by brain biopsy and autopsy in both cases. Our cases demonstrate that progressive multifocal leukoencephalopathy can develop in various immunodeficiencies.

[Genetic background of human prion diseases]. / Az emberi prionbetegségek genetikai háttere.

Human prion diseases may be sporadic, genetic, or acquired. The human prion protein gene (PRNP) is located to chromosome 20 (20p12-ter). Mutations and polymorphisms in the PRNP are associated with prion disease. Genetic prion diseases are inherited in an autosomal dominant trait, examination of the penetrance is restricted to mutation E200K (59-89%). Mutations can be substitutions or insertions. Genetic prion diseases are classified according to the clinicopathological phenotype and comprise genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia. Base pair insertions may resemble Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker disease phenotypes, however, their unique clinicopathological presentations are also emphasized. Among the polymorphisms of the PRNP, the one at codon 129 is the most important, where methionine or valine may be encoded. This polymorphism is known to influence the phenotype of disease forms. Molecular classification of sporadic Creutzfeldt-Jakob disease also depends on the codon 129 polymorphisms in addition to the Western blot pattern of the protease resistant prion protein. According to this at least six well characterised forms of sporadic Creutzfeldt-Jakob disease are known. Influence of other genes were also investigated. Contrasting results are reported regarding the role of apolipoprotein E allele epsilon4, but presence of allele epsilon2 seems to influence the prognosis. Polymorphisms in the doppel gene or ADAM10 could not be clearly associated with Creutzfeldt-Jakob disease. Polymorphisms in the upstream and intronic regulatory region of the PRNP gene may be a risk factor for Creutzfeldt-Jakob disease. The PRNP codon 129 polymorphism was examined in non-prion diseases. Some studies suggest that this polymorphism may have influence on the cognitive decline and early onset Alzheimer's disease.

[Human prion diseases: the Hungarian experience]. / Emberi prionbetegségek: magyarországi tapasztalatok.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease is the most frequent human prion disease. Genetic forms are associated with mutations in the human prion protein gene (PRNP) and thought to comprise 5-15% of cases. Acquired forms include iatrogenic and variant Creutzfeldt-Jakob disease. The latter is associated with the bovine spongiform encephalopathy. We recently reported the high incidence of genetic Creutzfeldt-Jakob disease in Hungary. MATERIALS AND METHODS: In the present study we summarize the results of a widened investigation comprising Creutzfeldt-Jakob disease cases collected in the National Institute of Psychiatry and Neurology, Hungary in the last 12 years. We examined the disease forms and their geographical distribution. RESULTS: Our study involved 155 patients. The four major results are as follows: 1. In Hungary we detected only sporadic and genetic forms of human prion disease, while iatrogenic and variant Creutzfeldt-Jakob disease were not observed. 2. The proportion of genetic prion disease (E200K mutation), similarly to Slovakia, is higher than reported worldwide. Our observations indicate that at least every third case is genetic Creutzfeldt-Jakob disease. The mean incidence of genetic Creutzfeldt-Jakob disease (0.42/million) is unusually high. Especially the year 2006 was striking when the incidence of genetic Creutzfeldt-Jakob disease was 1.4/million. 3. More than half of genetic Creutzfeldt-Jakob disease cases lack a positive family history. 4. Some counties and the eastern part of Hungary shows elevated incidence of human prion disease. CONCLUSIONS: Differences in the geographical distribution may be related to migration and historical relationship with the Slovakian population. Based on the increased incidence of E200K mutation, genetic testing of the PRNP is recommended in all cases with atypical neuropsychiatric disorder or suspicion of prion disease.

[Diagnosis of paraneoplastic neurological syndromes]. / Paraneoplasztikus neurológiai kórképek diagnosztikája.

INTRODUCTION: Paraneoplastic neurological syndromes are rare non-metastatic manifestations of malignancy. They are differentiated from side effects of tumor therapy, tumor-associated coagulopathy, infections, metabolic, and nutritional disorders. In the majority of cases neurological symptoms precede diagnosis of associated malignancy. Detection of anti-neuronal antibodies suggests a paraneoplastic mechanism. OBJECTIVES: To summarize syndromes, diagnostic steps, and currently available diagnostic possibilities. METHODS AND RESULTS: Serum and/or cerebrospinal fluid is analysed using indirect immunfluorescence and Western blotting. The pattern of immunoreactivity suggests the type of antibody. Anti-Hu antibody immunolabels predominantly nuclei, and less the cytoplasm of central and peripheral nervous system neurons. Anti-Yo shows cytoplasmic immunoreactivity primarily of cerebellar Purkinje cells, while anti-Ri is somewhat similar to anti-Hu except that peripheral nervous tissue lacks immunoreactivity. Examination of non-neural tissue allows exclusion of nuclear immunostaining caused by other antinuclear antibodies. Western blot examination specifies the anti-neuronal antibody. CONCLUSIONS: 1. Paraneoplastic neurological syndromes may occur without defined malignancy. 2. Clinical diagnosis is supported by immunofluorescent/Western blot/ELISA detection of antibodies. 3. Knowledge of antibody may suggest the origin of malignancy. 4. Tumor and immunomodulatory therapy may be considered, however, prognosis is different in distinct tumors and syndromes.