Hereditary and sporadic beta-amyloidoses.

Cerebral amyloidoses are chronic, progressive neurodegenerative diseases that are caused by the aggregation and deposition of misfolded proteins in the central nervous system, and lead to cognitive deficits, stroke, and focal neurological dysfunction including cerebellar and extrapyramidal signs. Among them, beta-amyloidoses are a heterogenous set of conditions characterised by the deposition of beta-amyloid protein in brain parenchyma and/or vessel walls that lead to the development of two main clinico-pathological entities: Alzheimer's disease and cerebral amyloid angiopathy, which may be sporadic or familial, and may also co-exist in the same patient. The aim of this review is to describe the most important differences in the pathways leading to parenchymal and cerebrovascular beta-amyloidoses, and the main clinical, neuropathological and biochemical characteristics of the two conditions. It also discusses the phenotypes associated with a series of familial and sporadic beta-amyloidoses in more detail in order to highlight the clinical and neuropathological features that may help to distinguish the different forms of disease

A novel missense mutation in PSEN2 gene associated with a clinical phenotype of frontotemporal dementia

Background: In Familial Alzheimer's disease defects in three genes - the amyloid precursors protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14 and the presenilin 2 (PSEN2) on chromosome 1- have been identified. More than 160 pathogenic missense mutations have been described in PSEN1, with wide clinic phenotypic variability. In PSEN2 only 11 missense mutations are known, in two of which (M239V and T122R) the clinical phenotype may be frontotemporal dementia-like. Methods: We present a novel PSEN2 mutation (Y231C) in an Italian patient who seven years ago, at age 55, manifested mood and behavioural disorders characterized by apathia, delusions, physical aggressive behaviour and psychomotor agitation. Language disturbances appeared one year later and mild memory loss three years later. The neuropsychological pattern suggested a main dysfunction in posterior temporal and parietal cortex. MRI showed diffuse atrophy, especially in posterior regions. Results: The genetic study showed an A-to-G mutation in exon seven of PSEN2 gene, resulting in tyrosine to cysteine substitution at residue 231. Conclusions: This new mutation confirms the variability of the phenotypes associated with PSEN2 mutations and justified the analysis of this gene in behavioural disturbances associated with degenerative dementia, at least in Italy in which PSEN2 mutations seems more frequent than in other countries

Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases

AbstractIn clinical practice signal hyperintensity in the cortex and/or in the striatum on magnetic resonance (MR) diffusion-weighted images (DWIs) is a marker of sporadic Creutzfeldt–Jakob Disease (sCJD). MR diagnostic accuracy is greater than 90%, but the biophysical mechanisms underpinning the signal abnormality are unknown. The aim of this prospective study is to combine an advanced DWI protocol with new mathematical models of the microstructural changes occurring in prion disease patients to investigate the cause of MR signal alterations. This underpins the later development of more sensitive and specific image-based biomarkers. DWI data with a wide a range of echo times and diffusion weightings were acquired in 15 patients with suspected diagnosis of prion disease and in 4 healthy age-matched subjects. Clinical diagnosis of sCJD was made in nine patients, genetic CJD in one, rapidly progressive encephalopathy in three, and Gerstmann–Sträussler–Scheinker syndrome in two. Data were analysed with two bi-compartment models that represent different hypotheses about the histopathological alterations responsible for the DWI signal hyperintensity. A ROI-based analysis was performed in 13 grey matter areas located in affected and apparently unaffected regions from patients and healthy subjects. We provide for the first time non-invasive estimate of the restricted compartment radius, designed to reflect vacuole size, which is a key discriminator of sCJD subtypes. The estimated vacuole size in DWI hyperintense cortex was in the range between 3 and 10 µm that is compatible with neuropathology measurements. In DWI hyperintense grey matter of sCJD patients the two bi-compartment models outperform the classic mono-exponential ADC model. Both new models show that T2 relaxation times significantly increase, fast and slow diffusivities reduce, and the fraction of the compartment with slow/restricted diffusion increases compared to unaffected grey matter of patients and healthy subjects. Analysis of the raw DWI signal allows us to suggest the following acquisition parameters for optimized detection of CJD lesions: b = 3000 s/mm2 and TE = 103 ms. In conclusion, these results provide the first in vivo estimate of mean vacuole size, new insight on the mechanisms of DWI signal changes in prionopathies and open the way to designing an optimized acquisition protocol to improve early clinical diagnosis and subtyping of sCJD

Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease

Prions can be detected in blood from patients with variant Creutzfeldt-Jakob disease with high sensitivity and specificity.</jats:p

Clinical phenotypic variability in an Italian family bearing the IVS6+ 5_8delGTGA mutation in PGRN gene

Background Frontotemporal dementia (FTD) is a complex presenile disorder characterized by behavioural changes and executive functions, expression of fronto-temporal degeneration. Hereditary FTD accounts for 20-30% of cases and, in the past decade, mutations in the microtubule associated protein tau (MAPT)gene were identified as a main genetic causes of familial FTD. In 2006, mutations in the gene encoding progranulin (PGRN) were reported, to account for a wide part of the familial FTD cases. Clinically, an high phenotypic variability within and among the kindreds is reported in the familial FTD associated with PGRN mutations and occasionally the memory deficits are the first symptoms, resembling Alzheimer's disease (AD). We report an Italian family with dementia associated with a PGRN mutation characterized by a deletion of 4 base pairs inside the intron 6 of the gene, leading to haploin sufficiency In our kindred, all three affected patients carried the mutation, but presented very different clinical phenotypes, evoking FTD, AD and rapidly-progressive dementia mimicking prion disease. Methods Informations on the members of the first, second and third generations were obtained conducting interviews with relatives, while for the three patients studied, the clinical evidence of dementia symptoms and their characterization was documented directly with sequential neurological examinations, cognitive assessments and neuroimaging. Blood sample collection and DNA extraction from peripheral blood lymphocytes for genetic analysis were performed after written informed consent of the patients. Results In our pedigree, the PGRN mutated patients are affected by dementia with three different clinical pictures: FTD, AD and rapidly progressive dementia mimicking prion disease. Neuropsychological examinations supported these diagnoses, documenting generalized deficits of cortical functions in AD patient and deficits in executive functions and in language in FTD patient. Regarding neuroimaging, in the same two cases MRI results do not correspond to the clinical diagnosis. Conclusions These findings confirms the marked heterogeneity of the clinico-radiological features in patients with PGNR mutations and underline the need of considering mutations of this gene as causes of familial dementing diseases with atypical or uncommon features or discrepancies between the clinical and the neuroimaging findings

The Stimulation of Inducible Nitric-oxide Synthase by the Prion Protein Fragment 106–126 in Human Microglia Is Tumor Necrosis Factor-α-dependent and Involves p38 Mitogen-activated Protein Kinase

A synthetic peptide consisting of amino acid residues 106-126 of the human prion protein (PrP-(106--126)) has been previously demonstrated to be neurotoxic and to induce microglial activation. The present study investigated the expression of the inducible form of the nitric-oxide synthase (NOS-II) in human microglial cells treated with PrP-(106--126). Using reverse transcriptase-polymerase chain reaction, we found that PrP-(106--126) induces NOS-II gene expression after 24 h of treatment and that this effect is accompanied by a peak of nuclear factor kappa B (NF-kappa B) binding at 30 min as evaluated by electrophoretic mobility shift assay. Since our previous data demonstrated tumor necrosis factor-alpha (TNF-alpha) to be a potent inducer of NOS-II in these cells, we analyzed the expression of this cytokine in PrP-(106--126)-treated microglia. PrP-(106--126) caused the release of TNF-alpha as detected by enzyme-linked immunosorbent assay, and a blocking antibody, anti-TNF-alpha, abolished NOS-II induction elicited by this peptide. Moreover, PrP-(106-126) activates p38 mitogen-activated protein kinase, and the inhibition of this pathway determines the ablation of NF-kappa B binding induced by this fragment peptide

Brainstem Sparing in Human Prion Disease: Sleep and Autonomic Function in a Long Survival Case Report

Abstract Background: The prion diseases are characterized by sleep disruption, with FFI typically characterized also by severe autonomic dysfunction and sympathetic hyperactivity. We report the results of an extensive neurophysiological and autonomic assessment in a CJD patient carrying the D178 mutation with the uncommon homozygosity for valine at codon 129. Results: A 47years old female presented with a memory impairment followed by progressive cognitive deficits and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years, and the patient died six years after the onset of symptoms. Repeated PSG and long-term actigraphic recordings, showed a peculiar, previously undescribed, pattern characterized by conservation of a rudimental circadian and ultradian rhythm, despite dramatic sleep micro-structure deterioration. We also observed a normal autonomic physiological response to orthostatic challenge and normal dynamic autonomic modulation during wake and sleep. The post-mortem brain pathology study, showed that neuronal loss was substantial in the cerebral cortex, diencephalon and thalami, but not in brainstem nuclei. Conclusions: We hypothesize that, despite a dramatic neurological picture (i.e. akinetic mutism) and a severe sleep micro-structural alteration, the persistence of an autonomic modulation and the persistence of a rudimental circadian and ultradian oscillation, are related to the relatively conserved anatomo-functional integrity of foundamental neuronal systems in the brainstem

Mutations in MAPT give rise to aneuploidy in animal models of tauopathy

Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration

Synthetic miniprion PrP106.

Elucidation of structure and biological properties of the prion protein scrapie (PrP(Sc)) is fundamental to an understanding of the mechanism of conformational transition of cellular (PrP(C)) into disease-specific isoforms and the pathogenesis of prion diseases. Unfortunately, the insolubility and heterogeneity of PrP(Sc) have limited these studies. The observation that a construct of 106 amino acids (termed PrP106 or miniprion), derived from mouse PrP and containing two deletions (Delta 23-88, Delta 141-176), becomes protease-resistant when expressed in scrapie-infected neuroblastoma cells and sustains prion replication when expressed in PrP(0/0) mice prompted us to generate a corresponding synthetic peptide (sPrP106) to be used for biochemical and cell culture studies. sPrP106 was obtained successfully with a straightforward procedure, which combines classical stepwise solid phase synthesis with a purification strategy based on transient labeling with a lipophilic chromatographic probe. sPrP106 readily adopted a beta-sheet structure, aggregated into branched filamentous structures without ultrastructural and tinctorial properties of amyloid, exhibited a proteinase K-resistant domain spanning residues 134-217, was highly toxic to primary neuronal cultures, and induced a remarkable increase in membrane microviscosity. These features are central properties of PrP(Sc) and make sPrP106 an excellent tool for investigating the molecular basis of the conformational conversion of PrP(C) into PrP(Sc) and prion disease pathogenesis