Orso Bugiani

Neuropathological Diagnostic-criteria for Creutzfeldt-jakob-disease (cjd) and Other Human Spongiform Encephalopathies (prion Diseases)

Neuropathological diagnostic criteria for Creutzfeldt‐Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD ‐ sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immuno‐reactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann‐Sträussler‐Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population).

Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.

The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.

Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals

A polyclonal antibody to a 28 residue synthetic peptide, homologous to the NH2 terminal region of amyloid beta-protein, was employed in a study of the frontal and temporal cortex of 8 Alzheimer patients and 13 non-demented individuals aimed to define the relationship of immunolabelled to argyrophilic, congophilic and thioflavine S-positive cortical lesions. In Alzheimer patients, this antiserum labelled not only senile plaques and congophilic angiopathy, but also cortical deposits that were neither argyrophilic, congophilic nor thioflavine S-positive and were unrelated to degenerating neurites, tangle-bearing neurons or congophilic angiopathy. Similar lesions were observed in 4 of 13 non-demented individuals, in the absence of tangles, plaques or congophilic angiopathy, and in one in association with plaques. Such deposits might have been due to amyloid precursors still lacking the beta-pleated sheet molecular conformation responsible for amyloid tinctorial and optical properties.

Staging of Neurofibrillary Pathology in Alzheimer's Disease: A Study of the BrainNet Europe Consortium

It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimers disease (AD), the presence of hyperphosphorylated tau (HP‐tau) and β‐amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD‐related HP‐tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD‐related immunohistochemically (IHC) detected HP‐tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7‐µm‐thick sections was based on assessment of IHC labeled HP‐tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.

Down patients: Extracellular preamyloid deposits precede neuritic degeneration and senile plaques

Using anti-SP28 (a polyclonal antibody to a 28 residue synthetic peptide homologous to the NH2-terminal region of the Alzheimer amyloid beta-protein) to investigate the cerebral cortex of 6 Down patients aged 6-55 y, we found that, besides senile plaques and congophilic vessels, extracellular deposits unrelated to degenerating neurites, tangle-bearing neurons or congophilic vessels were labelled. These deposits were similar to the extracellular deposits previously observed in the cerebral cortex of Alzheimer patients and non-demented individuals. The material accumulated in the deposits did not react with Congo red, thioflavine S or, on some occasions, silver salts and therefore might have been constituted by beta-protein precursors lacking the molecular conformation of amyloid fibrils. Age-related analysis of the cortical lesions in Down patients suggested that such extracellular deposits precede degenerating neurites and evolve into senile plaques.

Phenotypic variability of Gerstmann-Straussler-Scheinker disease is associated with prion protein heterogeneity

Abstract. Gerstmann-StrSussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the priori protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.

Prion Protein Amyloidosis

The prion protein (PrP) plays an essential role in the pathogenesis of a group of sporadic, genetically determined and infectious fatal degenerative diseases, referred to as “prion diseases”, affecting the central nervous system of humans and other mammals. The cellular PrP is encoded by a single copy gene, highly conserved across mammalian species. In prion diseases, PrP undergoes conformational changes involving a shift from α‐helix to β‐sheet structure. This conversion is important for PrP amyloidogenesis, which occurs to the highest degree in the genetically determined Gerstmann‐Sträussler‐Scheinker disease (GSS) and prion protein cerebral amyloid angiopathy (PrP‐CAA), while it is less frequently seen in other prion diseases. GSS and PrP‐CAA are associated with point mutations of the prion protein gene (PRNP); these conditions show a broad spectrum of clinical presentation, the main signs being ataxia, spastic paraparesis, extrapyramidal signs and dementia. In GSS, parenchyma! amyloid may be associated with spongiform changes or neurofibrillary lesions; in PrP‐CAA, vascular amyloid is associated with neurofibrillary lesions. A major component of the amyloid fibrils in the two diseases is a 7 kDa peptide, spanning residues 81–150 of PrP.

Amyloid protein of Gerstmann-Sträussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N-terminal glycine at codon 58.

Gerstmann‐Sträussler‐Scheinker (GSS) disease is a familial neurological disorder pathologically characterized by amyloid deposition in the cerebrum and cerebellum. The GSS amyloid is immunoreactive to antisera raised against the hamster prion protein (PrP) 27–30. This is a proteinase K‐resistant glycoprotein of 27–30 kd that is derived from an abnormal isoform of a neuronal glycoprotein of 33–35 kd designated PrPSc and is a molecular marker of amyloid fibrils isolated from animals with scrapie and humans with related disorders. We have purified and characterized proteins extracted from amyloid plaque cores isolated from two patients of the Indiana kindred of GSS disease. We found that the major component of GSS amyloid is an 11 kd degradation product of PrP, whose N‐terminus corresponds to the glycine residue at position 58 of the amino acid sequence deduced from the human PrP cDNA. In addition, amyloid fractions contained larger PrP fragments with apparently intact N‐termini and amyloid P component. These findings suggest that the disease process leads to proteolytic cleavage of PrP, generating an amyloidogenic peptide that polymerizes into insoluble fibrils. The N‐terminal cleavage of PrP in GSS disease occurs at a tryptophan‐glycine peptide bond identical to that cleaved by proteinase K in vitro to generate PrP 27–30 from hamster PrPSc at codon 90. Since no mutations of the structural PrP gene have been found in the Indiana family of GSS disease, it is conceivable that factors other than the primary structure of PrP play a crucial role in the process of amyloid formation and the development of clinical neurologic dysfunction.

Gerstmann-Sträussler-Scheinker disease. II: Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family

Azzarelli et al reported an Indiana kindred affected by a hereditary disorder, characterized clinically by ataxia, parkinsonism, and dementia. Recently, we studied neuropathologically the 3rd and 4th cases that came to autopsy among the patients of this family. As in 2 patients examined previously, amyloid plaques were widespread throughout the cerebrum and the cerebellum, whereas neurofibrillary tangles were numerous in the cerebral cortex, the hippocampus, and the substantia innominata. Amyloid plaques were not recognized by polyclonal antibodies against the Alzheimers disease amyloid A4 protein, but did contain epitopes recognized by antibodies against a prion protein. Spongiform changes were occasionally observed and were mild. Our findings indicate that this familial disorder is a form of or is related to Gerstmann-Sträussler-Scheinker disease. The consistent presence of numerous neurofibrillary tangles may be important in differentiating a distinct subgroup of patients with familial Gerstmann-Sträussler-Scheinker disease, and indicates that a disturbance of the cytoskeleton might be part of the neuronal pathology of Gerstmann-Sträussler-Scheinker disease.

Sporadic Creutzfeldt-Jakob disease: Co-occurrence of different types of PrPSc in the same brain

Article abstract Phenotypic heterogeneity of sporadic Creutzfeldt-Jakob disease (CJD) has been linked to biochemically distinct types of the protease-resistant form of the prion protein (type 1 and type 2 PrPSc). We investigated 14 cases of sporadic CJD and found that both type 1 and type 2 PrPSc coexisted in 5 subjects. The distinct PrPSc isoforms were associated with different patterns of PrP deposition and severity of spongiform changes, suggesting that the PrPSc type plays a central role in determining the neuropathologic profile of CJD.