Search

Background: Semantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients. Methods: Fifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry. Results: sbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants. Conclusion: We replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD. [ABSTRACT FROM AUTHOR]

Background: Rapidly progressive cognitive impairment is a diagnostic criterion in Creutzfeldt-Jakob disease (CJD), but the diagnosis is usually reached when an analysis of cognitive aspects is no longer possible. Objective: This study aims to delineate the cognitive phenotypes preceding severe dementia in CJD compared to secondary metabolic encephalopathies (SME) with rapid cognitive impairment. Methods: Patients with rapidly progressive neurological symptoms underwent neuropsychological evaluation, analysis of cerebrospinal fluid (CSF) and codon 129 polymorphism of the prion protein gene (PRNP), magnetic resonance imaging (MRI), and single positron emission computed tomography (99mTcSPECT). CSF real-time quaking-induced conversion analysis was applied in CJD patients. Based on literature and clinical expertise, cognitive profiles were correlated with brain areas. Results: Thirty-one patients were diagnosed with CJD (n = 17) or SME; 77 cases of CJD were extracted from the literature. In patients with CJD, verbal initiative, lexical search, long-term memory, attention, and abstract reasoning were the most frequently impaired abilities. Cognitive profiles were mainly related to dysfunction in fronto-temporal areas. Furthermore, they were consistent with areas of hypoperfusion detected by 99mTc SPECT in six patients and cortical and subcortical MRI hyperintensities in eight and 14 patients, respectively, and were similar to those described in the literature. In contrast, cognitive profiles were different from those in SME characterized by visuospatial and constructive deficits relating to posterior brain areas. Conclusion: In CJD, clinical and neuropsychological analyses outline a salient cognitive phenotype suggestive of fronto-temporal dysfunction preceding severe dementia. This phenotype is different from that observed in other rapidly progressive encephalopathies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age.Objectives: To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants.Methods: Biomarkers of amyloid-β deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS).Results: We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases.Conclusions: This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results. [ABSTRACT FROM AUTHOR]

In up to 31% of FTD cases, a family history is described, mostly associated with mutations in progranulin ( I GRN) i , I C9ORF72, i and microtubule-associated protein tau ( I MAPT) i genes, with I MAPT i mutations responsible for 5-10% of all genetic cases of FTD [[1]]. I MAPT i mutations have been previously described in patients with AD presentation at onset, in particular a different mutation at the same codon as our case, R406W [[5]]. The clinical phenotypes of I MAPT i mutation carriers are variable and characterized by more frequent disinhibited behavior and semantic impairment with respect to FTD patients carrying mutations in other genes. [Extracted from the article]

All other authors' affiliation should be "Neurology and Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milano, Italy". The original article can be found online at https://doi.org/10.1007/s10072-021-05795-x B Correction to: Neurological Sciences (2022) b https://doi.org/10.1007/s10072-021-05795-x Originally, the article has an error in Affiliations. Author Grisoli only pertains to the Neuroradiology Unit. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Cortico-basal syndrome (CBS) is a rare neurodegenerative disease characterised by movement and cognitive disorders. It occurs along the spectrum of fronto-temporal lobar degeneration (FTLD), which also includes fronto-temporal dementia (FTD) and progressive supranuclear palsy (PSP). FTLD has recently been shown to be associated with mutations in GRN gene, coding for progranulin, a multifunctional secreted glycoprotein involved in cell cycle, inflammation and tissue repair. We describe the case of a 73-year-old man suffering from CBS with a family history of cognitive disorders belonging to the clinical spectrum of FTLD. Sequencing analysis of GRN in this patient revealed that the C157KfsX97 null mutation has been already described by Le Ber et al. in a French patient affected by an apparently sporadic form of FTD. This report confirms the variability of clinical phenotypes associated with the same mutation and emphasises the importance of genetic analysis in cases with a clear familiarity, as well as in apparently sporadic forms. [ABSTRACT FROM AUTHOR]

Objective To describe a new dementia phenotype of Gerstmann-Straussler-Scheinker disease (GSS) in a previously unreported Italian family. Design Longitudinal clinical and neuropsychological assessment, combined with magnetic resonance imaging (MRI), single positron emission tomography (SPECT) and molecular genetic studies. Setting Neuropsychology Laboratory, and Division of Neuropathology and Neurology, “C. Besta” National Neurological Institute. Patients and participants Three members of the family. Measurements and results. Standardised neuropsychological tests were used to determine cognitive patterns. The proband had a history of primary dementia characterised by loss of initiative, planning, behaviour control, awareness, language and memory; the two relatives suffered from progressive ataxia. MRI of the demented patient revealed brain atrophy with a hyperintense signal in the frontal cortex; SPECT revealed decreased perfusion in the left temporal and parietal cortex and left thalamus. The two ataxic patients showed cerebellar atrophy with no signs of altered perfusion. Analysis of the PRNP gene showed a proline/leucine substitution at codon 102 in all three patients, associated with methionine/valine heterozygosity at the polymorphic codon 129. Conclusions Primary dementia with prominent frontotemporal signs is a new phenotypical expression of P102L-related GSS that coexists in the same family with the ataxic form of the disease. This remarkable variability suggests that still unidentified genetic or acquired factors may modulate the manifestations of GSS. Genetic examination of the PRNP should be included in the diagnostic work-up of patients with poorly classifiable dementia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Familial Frontotemporal Dementia Associated With the Novel MAPT Mutation T427M," published in the June 6, 2005 issue.