Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Inflammatory plasma profile in genetic symptomatic and presymptomatic Frontotemporal Dementia - A GENFI study.

BACKGROUND: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI). METHODS: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]. RESULTS: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1ß, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged. CONCLUSION: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease.

Are we social enough? Use of social media among members of the Italian Society of Neurology for the study of dementia.

BACKGROUND: Clinical researchers increasingly embrace social media in their professional lives. The digital revolution has provided new routes for sharing data, disseminating results, and promoting the impact of scientific findings. In this study, we explored the attitude of the members of the Italian Society of Neurology for the study of dementia (SINdem) to use social media with the aim to set up possible corrective actions to maximize digitalization benefits at the individual and community levels. METHOD: An ad hoc designed survey was implemented and distributed to the SINdem and SINdem4Juniors communities. It explored the different use of social media taking into account frequency, type of social media use (active vs passive; professional vs private). Descriptive statistical analyses were performed alongside statistical comparisons to highlight possible differences in the use. RESULTS: We collected 133 answers showing a prominent use of social media in private life (t(132) = 21.1, p < 0.001), with SINdem4Juniors members showing a higher private use compared to the older SINdem colleagues. Professional use was mainly limited to passive activities such as following others' social profiles (t(132) = 11.9, p < 0.001). DISCUSSION: Overall scenario suggests that professional use of social media is very limited in both SINdem and SINdem4juniors communities. This evidence points to an urgent need for training interventions and top-down strategies aimed at improving collaboration, dissemination, and sharing through social media among individuals belonging to the same scientific-professional community.

Utility of visual rating scales in primary progressive aphasia.

INTRODUCTION: Differential diagnosis among subjects with Primary Progressive Aphasia (PPA) can be challenging. Structural MRI can support the clinical profile. Visual rating scales are a simple and reliable tool to assess brain atrophy in the clinical setting. The aims of the study were to establish to what extent the visual rating scales could be useful in the differential diagnosis of PPA, to compare the clinical diagnostic impressions derived from routine MRI interpretations with those obtained using the visual rating scale and to correlate results of the scales in a voxel-based morphometry (VBM) analysis. METHOD: Patients diagnosed with primary progressive aphasia (PPA) according to current criteria from two centers-Ospedale Maggiore Policlinico of Milan and Hospital Clínic de Barcelona-were included in the study. Two blinded clinicians evaluated the subjects MRIs for cortical atrophy and white matter hyperintensities using two protocols: routine readings and the visual rating scale. The diagnostic accuracy between patients and controls and within PPA subgroups were compared between the two protocols. RESULTS: One hundred fifty Subjects were studied. All the scales showed a good to excellent intra and inter-rater agreement. The left anterior temporal scale could differentiate between semantic PPA and all other variants. The rater impression after the protocol can increase the accuracy just for the logopenic PPA. In the VBM analysis, the scores of visual rating scales correlate with the corresponding area of brain atrophy. CONCLUSION: The Left anterior temporal rating scale can distinguish semantic PPA from other variants. The rater impression after structured view improved the diagnostic accuracy of logopenic PPA compared to normal readings. The unstructured view of the MRI was reliable for identifying semantic PPA and controls. Neither the structured nor the unstructured view could identify the nonfluent and undetermined variants.

Clinical utility of diffusion MRI-derived measures of cortical microstructure in a real-world memory clinic setting.

OBJECTIVE: To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). METHODS: The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. RESULTS: A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A-T-. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A-T- progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A-T- patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). INTERPRETATION: Results support the clinical utility of cortical microstructure to aid prognosis, especially in A-T- patients. Further work will investigate other complexities of the real-world clinical setting, including A-T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.

Clinical validity of the Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB) in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. METHODS: One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. RESULTS: Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. CONCLUSIONS: Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

Long Non-Coding RNA Profile in Genetic Symptomatic and Presymptomatic Frontotemporal Dementia: A GENFI Study.

Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood. Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI). Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72, MAPT, and GRN, including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC). Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression. Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs' relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications.