Prion propagation and toxicity occur in vitro with two-phase kinetics specific to strain and neuronal type.

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that occur in humans and animals. The neuropathological hallmarks of TSEs are spongiosis, glial proliferation, and neuronal loss. The only known specific molecular marker of TSEs is the abnormal isoform (PrP(Sc)) of the host-encoded prion protein (PrP(C)), which accumulates in the brain of infected subjects and forms infectious prion particles.

Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes.

Aims: Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease-related prion protein (PrP(Sc) ) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP(Sc) deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt-Jakob disease (sCJD; n=100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP(Sc) molecular types.

Combined diffusion imaging and MR spectroscopy in the diagnosis of human prion diseases.

Background And Purpose: The physiopathologic bases underlying the signal intensity changes and reduced diffusibility observed in prion diseases (TSEs) are still poorly understood. We evaluated the interest of MRS combined with DWI both as a diagnostic tool and a way to understand the mechanism underlying signal intensity and ADC changes in this setting.

Materials And Methods: We designed a prospective study of multimodal MR imaging in patients with suspected TSEs.

Loss of cerebellar granule neurons is associated with punctate but not with large focal deposits of prion protein in Creutzfeldt-Jakob disease.

Whether aggregates of prion protein (PrP) reflect neurotoxicity or are neuroprotective in prion diseases is unclear. To address this question, we performed a clinicopathologic study of cerebellar granular neurons in 100 patients affected with sporadic Creutzfeldt-Jakob disease (CJD). There was significant loss of these neurons in the subset of cases with Val/Val genotype at PRNP Codon 129 and Molecular Isotype 2 of abnormal PrP (sporadic CJD-VV2) (n=32) compared with both the other CJD subtypes and to controls.

Wernicke encephalopathy and Creutzfeldt-Jakob disease.

We assessed the prevalence of Wernicke encephalopathy (WE) in all 657 cases suspected of Creutzfeldt-Jakob (CJD) referred from 2001 to 2006 to the French Neuropathology Network of CJD. Clinical, biological and imaging data were reviewed when the diagnosis of WE was made at autopsy. No CJD was found in five cases suspected of sporadic CJD.

Regulating factors of PrP glycosylation in Creutzfeldt-Jakob disease--implications for the dissemination and the diagnosis of human prion strains.

Objective: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease.

In vivo detection of thalamic gliosis: a pathoradiologic demonstration in familial fatal insomnia.

Background: Increasing evidence supports the usefulness of brain magnetic resonance imaging (MRI) for the diagnosis of human prion diseases. From the neuroradiological point of view, fatal familial insomnia is probably the most challenging to diagnose because brain lesions are mostly confined to the thalamus.

Objective: To determine whether multisequence MRI of the brain can show thalamic alterations and establish pathoradiologic correlations in a patient with familial fatal insomnia.

Human prion diseases: from antibody screening to a standardized fast immunodiagnosis using automation.

Demonstration of pathological prion protein accumulation in the central nervous system is required to establish the diagnosis of transmissible subacute encephalopathies. In humans, this is frequently achieved using prion protein immunohistochemistry in paraffin-embedded tissue, a technique that requires multiple epitope retrieval and denaturing pretreatments. In addition to being time-consuming, this procedure induces tissue alterations that preclude accurate morphological examination.

Differentiation of sCJD and vCJD forms by automated analysis of basal ganglia intensity distribution in multisequence MRI of the brain--definition and evaluation of new MRI-based ratios.

We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence magnetic resonance imaging (MRI) of the brain. One common feature of most forms of prion protein diseases is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted magnetic resonance (MR) images. We employ T1, T2, and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei.

New ratios for the detection and classification of CJD in multisequence MRI of the brain.

We present a method for the analysis of deep grey brain nuclei for accurate detection of human spongiform encephalopathy in multisequence MRI of the brain. We employ T1, T2 and FLAIR-T2 MR sequences for the detection of intensity deviations in the internal nuclei. The MR data are registered to a probabilistic atlas and normalised in intensity prior to the segmentation of hyperintensities using a foveal model.

Truncated PrP(c) in mammalian brain: interspecies variation and location in membrane rafts.

A key molecular event in prion diseases is the conversion of cellular prion protein (PrP(c)) into an abnormal misfolded conformer (PrP(sc)). The PrP(c) N-terminal domain plays a central role in PrP(c) functions and in prion propagation. Because mammalian PrP(c) is found as a full-length and N-terminally truncated form, we examined the presence and amount of PrP(c) C-terminal fragment in the brain of different species.

The N-terminal cleavage of cellular prion protein in the human brain.

Human brain cellular prion protein (PrP(c)) is cleaved within its highly conserved domain at amino acid 110/111/112. This cleavage generates a highly stable C-terminal fragment (C1). We examined the relative abundance of holo- and truncated PrP(c) in human cerebral cortex and we found important inter-individual variations in the proportion of C1.

The tissue-specific methylation of the human tyrosine hydroxylase gene reveals new regulatory elements in the first exon.

The methylation status of CpG dinucleotides located in or near regulatory elements affects gene expression. The CpG-rich sequence located outside the 5' promoter region of the human Tyrosine Hydroxylase (TH) gene appears to influence the functional effect of the adjacent intronic HUMTH01 microsatellite. In order to identify new regulatory elements in this region acting on gene expression, the methylation profile of the TH CpG island was investigated using the bisulfite sequencing method.

Changes in vascularization in substantia nigra pars compacta of monkeys rendered parkinsonian.

The degeneration of nigral dopaminergic neurons in Parkinson's disease is believed to be associated with a glial reaction and inflammatory changes. In turn, local factors may induce changes in vascularization and contribute to neuronal vulnerability. Among these factors, Vascular Endothelial Growth Factor (VEGF) is released in adults under pathological conditions and is thought to induce angiogenesis.

Compassionate use of quinacrine in Creutzfeldt-Jakob disease fails to show significant effects.

Quinacrine has been reported as an antiprion agent and proposed as an immediately applicable treatment for Creutzfeldt-Jakob disease (CJD). The authors report the results of an open compassionate procedure to which 32 CJD patients had access. In some genotypic subgroups, a slight but nonsignificant increase in survival was observed, likely due to biased inclusion of long-term surviving patients.

Brain targeting through the autonomous nervous system: lessons from prion diseases.

The human central nervous system (CNS) is targeted by diverse pathogens that use distinct pathways to bypass the blood-brain barrier, such as trafficking into the brain via infected blood cells or using retrograde axonal transport through sensory or motor fibers. Prions are transmissible agents that induce a devastating subacute neurodegeneration when they successfully reach the CNS. Two recent studies focusing on pathways of prion neuroinvasion provide converging evidence that, in the case of peripheral transmission, such as human consumption of contaminated tissue, the infectious agent uses the sympathetic noradrenergic neurons to reach the CNS after early replication in lymphoid tissues.

The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease.

Prion epizoonoses spread from animals consumed by humans raise the question of which pathways lead to prion neuroinvasion after oral exposure of humans. Here we show that neurons of sympathetic ganglia of patients with variant Creutzfeldt-Jakob disease (vCJD) accumulate the abnormal isoform of the protein prion. This observation shows the involvement of the sympathetic nervous system in the pathogenesis of vCJD and suggests a role for GUT-associated sympathetic neurons in prion propagation in humans after oral contamination.

Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease.

Degeneration of dopaminergic neurones during Parkinson's disease is most extensive in the subpopulation of melanized-neurones located in the substantia nigra pars compacta. Neuromelanin is a dark pigment produced in the dopaminergic neurones of the human substantia nigra and has the ability to bind a variety of metal ions, especially iron. Post-mortem analyses of the human brain have established that oxidative stress and iron content are enhanced in association with neuronal death.

Different chromogranin immunoreactivity between prion and a-beta amyloid plaque.

Brain lesions in Creutzfeldt-Jakob disease (CJD) include spongiform change, neuronal loss, amyloid plaques, astrogliosis and microglial activation. Microglia are thought to play a key role in prion-induced neurodegeneration. However, the intermediate molecules supporting relationships between neurons and microglia are still unknown.

Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease.

Dopaminergic neurones degenerate during Parkinson's disease and cell loss is most extensive in the subpopulation of melanized neurones located in the substantia nigra pars compacta. Iron accumulation, together with a lack of up-regulation of the iron-storing protein, ferritin, has been reported and may contribute to increased oxidative stress in this region. We investigated the binding activity of iron regulatory protein-1 (IRP1) to the iron-responsive element that precludes ferritin mRNA translation, in the substantia nigra of a group of parkinsonian patients who presented a statistically significant reduction in the number of nigral melanized-neurones and an increased iron content, together with unchanged H-ferritin and L-ferritin subunit levels as compared to matched controls.

Increased expression and redistribution of the antiapoptotic molecule Bcl-xL in Parkinson's disease.

In the present study, we tried to clarify the potentially protective role of Bcl-x(L), an anti-apoptotic member of the Bcl-2 family of proteins, in Parkinson's disease (PD). Using in situ hybridization on human postmortem mesencephalon sections, we show that in PD patients Bcl-x(L) mRNA expression per dopaminergic neuron was almost double that of controls. We also show that, ultrastructurally, this effect may be mediated by a redistribution of Bcl-x(L) from the cytosol to the outer mitochondrial membrane.

Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA.

On the basis of the functional model of the basal ganglia developed in the 1980s and the neuropathological findings in Huntington's disease (HD), changes in the neuronal activity of the basal ganglia have previously been proposed to explain the abnormal movements observed in this pathology. In particular, it has been stated that the neurodegenerative process affecting the basal ganglia in the disease should provoke a hypoactivity in the internal segment of the pallidum (GPi) that could explain choreic movements observed in the disease. To test this functional hypothesis, we performed an in situ hybridization study on control and HD brains postmortem, taking cytochrome oxidase subunit I (COI) mRNAs expression as index of neuronal activity.

FADD: A link between TNF family receptors and caspases in Parkinson's disease.

Fas-associating protein with a death domain (FADD) is a proximal adaptor protein of the tumor necrosis factor (TNF) receptor family death pathway. This human postmortem study showed a significant decrease in the percentage of FADD-immunoreactive dopaminergic (DA) neurons in the substantia nigra pars compacta of patients with PD compared with controls (-24.8%).