The Molecular Pathology of Prion Diseases

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of invariably fatal neurodegenerative disorders. Uniquely, they may present as sporadic, inherited, or infectious forms, all of which involve conversion of the normal cellular prion protein (PrPC) into a pathogenic likeness of itself (PrPSc). Formation of neurotoxic PrPSc and/or loss of the normal function of native PrPC result in activation of cellular pathways ultimately leading to neuronal death. Prion diseases can affect both humans and animals, with scrapie of sheep, bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jakob disease being the most notable. This review is intended to provide an overview of the salient scientific discoveries in prion research, mainly from a molecular perspective. Further, some of the major outstanding questions in prion science are highlighted. Prion research is having a profound impact on modern medicine, and strategies for prevention and treatment of these disorders may also find application in the more common neurodegenerative diseases.peer-reviewe

Single-channel electrophysiology reveals a distinct and uniform pore complex formed by α-synuclein oligomers in lipid membranes.

Synucleinopathies such as Parkinson's disease, multiple system atrophy and dementia with Lewy bodies are characterized by deposition of aggregated α-synuclein. Recent findings indicate that pathological oligomers rather than fibrillar aggregates may represent the main toxic protein species. It has been shown that α-synuclein oligomers can increase the conductance of lipid bilayers and, in cell-culture, lead to calcium dyshomeostasis and cell death. In this study, employing a setup for single-channel electrophysiology, we found that addition of iron-induced α-synuclein oligomers resulted in quantized and stepwise increases in bilayer conductance indicating insertion of distinct transmembrane pores. These pores switched between open and closed states depending on clamped voltage revealing a single-pore conductance comparable to that of bacterial porins. Pore conductance was dependent on transmembrane potential and the available cation. The pores stably inserted into the bilayer and could not be removed by buffer exchange. Pore formation could be inhibited by co-incubation with the aggregation inhibitor baicalein. Our findings indicate that iron-induced α-synuclein oligomers can form a uniform and distinct pore species with characteristic electrophysiological properties. Pore formation could be a critical event in the pathogenesis of synucleinopathies and provide a novel structural target for disease-modifying therapy

Intravascular Large B-Cell Lymphoma Presenting as Dementia and Hemolytic Anemia

Background: Intravascular lymphoma (IVL) is an uncommon disease characterized by atypical lymphoid cells growing inside the lumina of small vessels. The diversity of clinical presentation due to possible involvement of multiple organs often complicates its diagnosis. Case Report: Here, we report on a case of IVL with rapidly progressive dementia and Coombs-negative hemolytic anemia. Interestingly, the erythrocytes exhibited a decreased osmotic resistance. Bone marrow histopathology revealed increased erythropoiesis and, finally, a small monoclonal B lymphocyte population. Cerebral magnetic resonance imaging (MRI) demonstrated few micro-bleedings. Computed tomography (CT) showed bilateral ground-glass opacity of the lungs. Within a few days, the patient developed respiratory failure and died. On post-mortem examination, intravascular large B-cell lymphoma with almost complete infiltration of the brain and lungs was diagnosed. Conclusion: IVL should be considered early in situations of unexplained neuropsychiatric disease along with markedly elevated levels of lactic dehydrogenase, anemia, and hemolysis

The Alzheimer variant of Lewy body disease: A pathologically confirmed case-control study

The objective of the study was to identify clinical features that distinguish patients with dementia with Lewy bodies (DLB), who were classified as Alzheimer's disease ( AD) patients, from patients with AD. We examined a group of 27 patients from our memory clinic, originally diagnosed with AD, of whom 6 were postmortem found to have DLB. For the present study, we compared cognitive, noncognitive and neurological symptoms between the two groups. We found that there were no differences on ratings of dementia and scales for activities of daily living. Patients with DLB performed better on the MMSE and the memory subtest of the CAMCOG, but there was no difference in any other cognitive domain. Furthermore, genetic risk factors, including family history of dementia or allele frequency of the apolipoprotein epsilon 4, did not discriminate between the two groups, and there were no differences on CCT scans. Taken together, our findings suggest that Lewy body pathology may be present in patients who do not show the typical clinical features which distinguish DLB from AD. Copyright (C) 2005 S. Karger AG, Basel

Clinical Features of Rapidly Progressive Alzheimer's Disease

Objective: To characterize clinical features, CSF biomarkers and genetic polymorphisms of patients suffering from a rapidly progressing subtype of Alzheimer's dementia (rpAD). Methods: Retrospective analyses of 32 neuropathologically confirmed cases differentially diagnosed as AD out of a group with rapidly progressive dementia. CSF biomarkers (14-3-3, tau, beta-amyloid 1-42) and genetic markers (PRNP codon 129, apolipoprotein E, ApoE, polymorphism) were determined. Results: Median survival was 26 months, age at onset 73 years. Biomarkers: mean beta-amyloid 1-42: 266 pg/ml, median tau: 491 pg/ml, 14-3-3 positive: 31%. Genetic polymorphisms showed a predominance of methionine homozygosity at PRNP codon 129 and a low frequency of ApoE4 (38%, no homozygous patients). Thirty-five symptoms were studied. Frequent symptoms were myoclonus (75%), disturbed gait (66%) and rigidity (50%). Discussion: rpAD is associated with a diversity of neurological signs even able to mimic Creutz feldt-Jakob disease. Biomarkers and genetic profile differ from those seen in classical AD. The findings on biomarkers, symptomatology and genetics may aid the differential diagnostic process. Copyright (C) 2010 S. Karger AG, Base

Krüppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation.

Krüppel-like factor 8 (KLF8) has only recently been identified to be involved in tumor cell proliferation and invasion of several different tumor entities like renal cell carcinoma, hepatocellular carcinoma and breast cancer. In the present study, we show for the first time the expression of KLF8 in gliomas of different WHO grades and its functional impact on glioma cell proliferation. In order to get information about KLF8-mRNA regulation qPCR was performed and did not reveal any significant difference in samples (n = 10 each) of non-neoplastic brain (NNB), low-grade gliomas (LGG, WHO°II) and glioblastomas (GBM, WHO°IV). Immunohistochemistry of tissue samples (n = 7 LGG, 11 AA and 12 GBM) did not show any significant difference in the fraction of KLF8-immunopositive cells of all analyzed cells in LGG (87%), AA (80%) or GBM (89%). Tissue samples from cerebral breast cancer metastasis, meningiomas but also non-neoplastic brain demonstrated comparable relative cell counts as well. Moreover, there was no correlation between KLF8 expression and the expression pattern of the assumed proliferation marker Ki67, which showed high variability between different tumor grade (9% (LGG), 6% (AA) and 15% (GBM) of Ki67-immunopositive cells). Densitometric analysis of Western blotting revealed that the relative amount of KLF8-protein did also not differ between the highly aggressive and proliferative GBM (1.05) compared to LGG (0.93; p<0.05, studens t-test). As demonstrated for some other non-glial cancer entities, KLF8-knockdown by shRNA in U87-MG cells confirmed its functional relevance, leading to an almost complete loss of tumor cell proliferation. Selective blocking of KLF8 might represent a novel anti-proliferative treatment strategy for malignant gliomas. Yet, its simultaneous expression in non-proliferating tissues could hamper this approach

Follow-up investigations of tau protein and S-100B levels in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

Background: S-100B and tau protein have a high differential diagnostic potential for the diagnosis of Creutzfeldt-Jakob disease (CJD). So far there has been only limited information available about the dynamics of these parameters in the cerebrospinal fluid (CSF). However, there is a special interest in finding biochemical markers to monitor disease progression for differential diagnosis and treatment. Patients and Methods: We analyzed CSF of 45 patients with CJD and of 45 patients with other neurological diseases for tau protein and S-100B in a follow-up setting. All diagnoses of CJD were later neuropathologically verified. A ratio between tau protein differences and the time between lumbar puncture was calculated. The same was done for S-100B. Results: Tau protein levels of 34 cases were above the cut-off level for CJD (>1,300 pg/ml) in the first CSF sample. In 7 of 11 patients with lower tau levels in the first CSF sample, tau levels rose. The above-mentioned ratio was significantly higher in the CJD group than in the group with other neurological diseases. Similar results were obtained for S-100B. Conclusion: We conclude that follow-up investigations and calculation of ratios is a useful tool in the differential diagnosis of CJD. Variations in this pattern were observed in single cases. Copyright (C) 2005 S. Karger AG, Basel

Proteomic analysis of the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

So far, only the detection of 14-3-3 proteins in cerebrospinal fluid (CSF) has been accepted as diagnostic criterion for Creutzfeldt-Jakob disease (CJD). However, this assay cannot be used for screening because of the high rate of false-positive results, whereas patients with variant CJD are often negative for 14-3-3 proteins. The aim of this study was to compare the spot patterns of CSF by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to search for a CJD-specific spot pattern. We analyzed the CSF of 28 patients {[}11 CJD, 9 Alzheimer's disease ( AD), 8 nondemented controls (NDC)] employing 2D-PAGE which was optimized for minimal volumes of CSF (0.1 ml; 7-cm strips). All samples were run at least three times, gels were silver stained and analyzed by an analysis software and manually revised. We could consistently match 268 spots which were then compared between all groups. By the use of 5 spots, we were able to differentiate CJD from AD or NDC with a sensitivity of 100%. CJD could also be distinguished from both groups by using a heuristic clustering algorithm of 2 spots. We conclude that this proteomic approach can differentiate CJD from other diseases and may serve as a model for other neurodegenerative diseases. Copyright (C) 2007 S. Karger AG, Basel

Creutzfeldt-Jakob disease and homocysteine levels in plasma and cerebrospinal fluid

Background: There is evidence that homocysteine contributes to various neurodegenerative disorders. Objective: To assess the values of homocysteine in patients with Creutzfeldt-Jakob disease (CJD) in both cerebrospinal fluid (CSF) and plasma. Methods: Study design: Case control study. Total homocysteine was quantified in CSF and plasma samples of CJD patients (n = 13) and healthy controls (n = 13). Results: Mean values in healthy controls: 0.15 mumol/l +/- 0.07 (CSF) and 9.10 mumol/l +/- 2.99 (plasma); mean values in CJD patients: 0.13 mumol/l +/- 0.03 (CSF) and 9.22 mumol/l +/- 1.81 (plasma). No significant differences between CJD patients and controls were observed (Mann-Whitney U, p > 0.05). Conclusions: The results indicate that the CSF and plasma of CJD patients showed no higher endogenous levels of homocysteine as compared to normal healthy controls. These findings provide no evidence for an additional role of homocysteine in the pathogenetic mechanisms underlying CJD neurodegeneration. Copyright (C) 2005 S. Karger AG, Basel