Search

Background: Frontotemporal degeneration (FTD) is the most common cause of dementia after Alzheimer's disease. To date, it has been addressed with intensive and intense research.Objective: To report on the most recent findings in the biology of FTD.Methods: Review of FTD literature.Results: FTD presents with many phenotypes that span from prefrontal syndromes to lower motor neuron disease passing through temporal, parietal and extrapyramidal syndromes. FTD includes the frontotemporal lobar atrophies clinically characterised by abnormal behaviour, progressive aphasia or semantic dementia, as well as corticobasal degeneration, progressive supranuclear palsy, progressive subcortical gliosis and FTD with motor neuron disease. The molecular classification of FTD can be traced following the immunocytochemical properties of the material accumulated in neuroectodermic cells. This procedure allows the separation of FTD with tau-positive inclusions from FTD with ubiquitin-positive inclusions, and from FTD with inclusions negative for both. Genetically, seven loci (chromosomes 3p, 9q and 17q24, one locus each; 9p and 17q21, two loci each) and four genes (MAPT, PRGN, VCP, CHMP2B) have been identified. Proteins involved are tau, progranulin, VCP, CHMP2B, Progranulin TDP43, ubiquitin and the intermediate neurofilament system. Neurodegeneration is most likely due to changes in cytoskeletal structure and in ubiquitin-dependent protein degradation activity. [ABSTRACT FROM AUTHOR]

Dementia is due to lesions destroying a large amount of circuits anatomically connected with, or functionally related to, the associative areas of the cortex and the limbic structures. Dementia is not only the clinical hallmark of neurodegenerative diseases, most often proteinopathies, primarily involving the cerebral cortex, but also a symptom frequently associated to movement disorders, or secondary to systemic or neurological, non-degenerative diseases. In the elderly, it is often the consequence of the cumulative effect of different diseases. [ABSTRACT FROM AUTHOR]

A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains unresolved. The synthesis of a peptide homologous to residues 106‐126 of the human prion protein (PrP106‐126), a sequence present in the PrP amyloid protein of Gerstmann–Sträussler–Scheinker syndrome patients, provided a tractable tool for investigating the mechanisms of neurotoxicity. Together with several other discoveries at the beginning of the 1990s, PrP106‐126 contributed to underpin the role of amyloid in the pathogenesis of protein‐misfolding neurodegenerative disorders. Later, the role of oligomers on one hand and of prion‐like spreading of pathology on the other further clarified mechanisms shared by different neurodegenerative conditions. Our original report on PrP106‐126 neurotoxicity also highlighted a role for programmed cell death in CNS diseases. In this review, we analyse the prion research context in which PrP106‐126 first appeared and the advances in our understanding of prion disease pathogenesis and therapeutic perspectives 25 years later. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy is due to β-protein accumulation in the vessel walls and occurs in normal aging, Alzheimer’s disease and hereditary cerebral hemorrhage with amyloidosis. It causes intraparenchimal and subarachnoid bleeding with hemosiderin deposits and multiple infarcts presenting with headache, stroke and epilepsy. Such lesions may contribute to cognitive impairment. So far, no therapy is available. In future, amyloid in the vessel wall might be addressed by amyloid disaggregating drugs and amyloid antibodies. [ABSTRACT FROM AUTHOR]

C.B., a right-handed 33-year-old man, presented with anterograde amnesiaafter acute heart block. Cognitive abilities were normal except for seriousimpairment of long-term episodic memory. The access to semantic informationwas fully preserved. Magnetic resonance showed high signal intensity and markedvolume loss in the hippocampus bilaterally; the left and right parahippocampalgyrus, lateral occipito–temporal gyrus, inferior temporal gyrus, andlateral temporal cortex were normal. This case underlines that global amnesiaassociated with hippocampal damage does not affect semantic memory. Althoughthe hippocampus is important in retrieving context-linked information, itsrole is not so crucial in retrieving semantic contents. Cortical areas surroundingthe hippocampus and lateral temporal areas might guide the recall of semanticinformation. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral accumulation of hyperphosphorylated tau (phospho-tau) occurs in several neurodegenerative conditions including Alzheimer disease. In prion diseases, phospho-tau deposition has been described in a rare genetic form, Gerstmann-Sträussler-Scheinker disease, but is not considered part of the neuropathological picture of Creutzfeldt-Jakob disease. Aim of this study was to investigate whether changes related to phospho-tau accumulation are present in the brain of patients with variant Creutzfeldt-Jakob disease (vCJD) that shares with Gerstmann-Sträussler-Scheinker disease abundant prion protein (PrP) deposition in amyloid form. The analysis was extended to experimental mouse models of vCJD. We detected a large number of phospho-tau-immunoreactive neuritic profiles, often clustered around PrP amyloid deposits, not only in the cerebral cortex, but also in the cerebellum of all vCJD patients examined, in the absence of Aβ. Although less constantly, phospho-tau was localized in some perikaria and dendrites. The biochemical counterpart was the presence of phospho-tau in the detergent-insoluble fraction of cerebral cortex. Phospho-tau-immunoreactive neuronal profiles were also found in association with PrP deposits in mouse models of vCJD. These findings suggest that the abnormal forms of PrP associated with vCJD trigger a tauopathy, and provide a paradigm for the early stages of tau pathology associated with cerebral amyloidoses, including Alzheimer disease. [Copyright &y& Elsevier]

An atypical case of sporadic Creutzfeldt-Jakob disease (CJD) is described in a 78-year-old woman homozygous for methionine at codon 129 of the prion protein (PrP) gene. The neuropathological signature was the presence of PrP immunoreactive plaque-like deposits in the cerebral cortex, striatum and thalamus. Western blot analysis showed a profile of the pathological form of PrP (PrP(Sc)) previously unrecognised in sporadic CJD, marked by the absence of diglycosylated protease resistant species. These features define a novel neuropathological and molecular CJD phenotype. [ABSTRACT FROM AUTHOR]

In 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To characterise flash visual evoked potentials (FVEPs) in 20 patients with Creutzfeldt–Jacob disease (CJD), and assess the relationships between spontaneous EEG patterns and the responses to individual stimuli. Methods: We analysed the shape and time course of periodic sharp wave complexes (PSWCs) and responses to 1Hz flashes. In nine patients, we applied an algorithm based on an autoregressive model with exogenous input (ARX) to estimate responses to individual random flashes and their interaction with PSWCs. Results: The FVEPs included P1 and N1 components in all patients, and the P2 peak in 18. Eight patients showed giant FVEPs (N1-P2>60 V), all of whom had an MM polymorphism in codon 129 of the prion protein gene; in seven cases, the presence of giant FVEPs correlated with a prominent and almost continuous periodic EEG pattern. Giant N1-P2 abnormally spread on the anterior scalp regions, and had a different waveform distribution from that of the PSWCs. In five patients with a normal or slightly enlarged average N1-P2 amplitude, single sweep (ARX) analysis revealed a period of relative refractoriness following individual PSWCs. In four patients with ‘giant’ FVEPs, the individual responses occurred regardless of the interval between the stimulus and previous PSWC, but their amplitude had an inverse relationship with the interval length. Conclusions: Giant responses to flash stimuli are a common finding in CJD patients (40% of our cases). Single sweep ARX analysis showed that PSWCs were followed by a period of partial refractoriness, which prevented most of the individual responses to flashes, but not giant FVEPs. The association between prominent spontaneous paroxysms and giant FVEPs suggests that both are due to a common hyperexcitable change favouring neuronal synchronisation. Significance: Our data contribute to clarifying the debated problem of the occurrence of giant FVEPs in CJD and their relationships with the spontaneous periodic EEG pattern. [Copyright &y& Elsevier]

The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative diseases occurring in infancy and adulthood. Atypical forms of these diseases have been described and are particularly represented in the late-infantile and juvenile onset groups. Recent progress in biochemistry and molecular genetics has identified some of these variants as separate disease entities while disclosing the phenotypic variability of some classic forms. We report the result of a retrospective analysis performed on a series of 27 NCL patients, 15 of which were atypical as to clinical and/or pathological findings. Most of such patients, belonging to the late-infantile onset group and displaying homogeneous clinical-pathological features, were suggestive for CLN6. The two atypical juvenile NCL patients had features which resembled the “protracted form” of the disease. Given their relative frequency, strict clinical and pathological criteria are still the most useful tools for identifying and characterizing atypical forms and for defining phenotype-genotype correlations. [ABSTRACT FROM AUTHOR]