The microtubule associated protein, tau, is implicated in a multitude of neurodegenerative disorders that are collectively termed as tauopathies. These disorders are characterized by the presence of tau aggregates within the brain of afflicted individuals. Mutations within the MAPT gene that encodes the tau protein form the genetic backdrop for familial forms of tauopathies, such as frontotemporal dementia (FTD), but the molecular consequences of such alterations and their pathological effects are unclear. We sought to investigate the conformational properties of the aggregates of three tau mutants: A152T, P301L, and R406W, all implicated within FTD, and compare them to those of the native form (WT-Tau 2N4R). Our immunochemical analysis reveals that mutants and WT tau oligomers exhibit similar affinity for conformation-specific antibodies but have distinct morphology and secondary structure. Additionally, these oligomers possess different dye-binding properties and varying sensitivity to proteolytic processing. These results point to conformational variety among them. We then tested the ability of the mutant oligomers to cross-seed the aggregation of WT tau monomer. Using similar array of experiments, we found that cross-seeding with mutant aggregates leads to the formation of conformationally unique WT oligomers. The results discussed in this paper provide a novel perspective on the structural properties of oligomeric forms of WT tau 2N4R and its mutant, along with shedding some light on their cross-seeding behavior.

Despite the efforts to identify fluid biomarkers to improve diagnosis of Frontotemporal dementia (FTD), only a few candidates have been described in recent years. In a previous study, we identified three circulating miRNAs (miR-92a-3p, miR-320a and miR-320b) differentially expressed in FTD patients with respect to healthy controls and/or Alzheimer\'s disease (AD) patients. Now, we investigated whether those changes could be due to miRNAs contained in neuron-derived extracellular vesicles (NDEVs). We also evaluated miRNAs content in total plasma EVs and in CSF samples. The analysis of plasma NDEVs carried out on 40 subjects including controls (n = 13), FTD (n = 13) and AD (n = 14) patients, showed that both miR-92a-3p and miR-320a levels were triplicated in the FTD group if compared with CT and AD patients. Increased levels of the same miRNAs were found also in CSF derived from FTD group compared to CTs. No differences were observed in expression levels of miR-320b among the three groups. Worthy of note, all miRNAs analysed were increased in an FTD cell model, MAPT IVS10 + 16 neurons. Our results suggest that miR-92a and miR-320a in NDEVs could be proposed as FTD biomarkers.

UNASSIGNED: Young onset dementia (YOD) by its nature is difficult to diagnose. Despite involvement of multidisciplinary neurogenetics services, patients with YOD and their families face significant diagnostic delays. Genetic testing for people with YOD currently involves a staggered, iterative approach. There is currently no optimal single genetic investigation that simultaneously identifies the different genetic variants resulting in YOD.
UNASSIGNED: This review discusses the advances in clinical genomic testing for people with YOD. Whole genome sequencing (WGS) can be employed as a \'one stop shop\' genomic test for YOD. In addition to single nucleotide variants, WGS can reliably detect structural variants, short tandem repeat expansions, mitochondrial genetic variants as well as capture single nucleotide polymorphisms for the calculation of polygenic risk scores.
UNASSIGNED: WGS, when used as the initial genetic test, can enhance the likelihood of a precision diagnosis and curtail the time taken to reach this. Finding a clinical diagnosis using WGS can reduce invasive and expensive investigations and could be cost effective. These advances need to be balanced against the limitations of the technology and the genetic counseling needs for these vulnerable patients and their families.

BACKGROUND: Frontotemporal dementia (FTD) can be phenotypically divided into behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). However, the neural underpinnings of this phenotypic heterogeneity remain elusive.
METHODS: Cortical morphology, white matter hyperintensities (WMH), diffusion tensor image analysis along the perivascular space (DTI-ALPS), and their interrelationships were assessed in subtypes of FTD. Neuroimaging-transcriptional analyses on the regional cortical morphological deviances among subtypes were also performed.
RESULTS: Changes in cortical thickness, surface area, gyrification, WMH, and DTI-ALPS were subtype-specific in FTD. The three morphologic indices are related to whole-brain WMH volume and cognitive performance, while cortical thickness is related to DTI-ALPS. Neuroimaging-transcriptional analyses identified key biological pathways linked to the formation and/or spread of TDP-43/tau pathologies.
CONCLUSIONS: We found subtype-specific changes in cortical morphology, WMH, and glymphatic function in FTD. Our findings have the potential to contribute to the development of personalized predictions and treatment strategies for this disorder.
CONCLUSIONS: Cortical morphologic changes, white matter hyperintensities (WMH), and glymphatic dysfunction are subtype-specific. Cortical morphologic changes, WMH, and glymphatic dysfunction are inter-correlated. Cortical morphologic changes and WMH burden contribute to cognitive impairments.

Alzheimer\'s disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

UNASSIGNED: 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.
UNASSIGNED: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI).
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.

BACKGROUND: A dataset[1,2] of electroencephalography(EEG) of frontotemporal dementia(FTD), alzheimer`s disease(AD) patients and healthy control(HC) were classified using convolutional neural network(CNN) and evaluated its performances METHOD: EEG dataset containing 88 subjects is downsampled and sliced into 10 seconds. Total dataset was divided into train, test and validation sets for each subject. CNN structure was used to extract temporal and spatial features from EEG and classify patients into 3 groups(FTD/AD/HC). Cross entropy loss was calculated to train the model using adam optimizer. Classification performances were measured to validate model such as accuracy, confusion matrix, AUC(area under curve), F1 Score.
RESULTS: After training, validation accuracy was 95.35% and macro-averaged AUC was 0.9962. F1 score was 0.9469 and the minimum validation accuracy measured among subjects was 57.14% in FTD group. For AD group average accuracy was 92.79%, and for FTD group average accuracy was 97.52%. Average accuracy of healthy control group was 95.26%.
CONCLUSIONS: We implemented CNN model that can classify EEG of dementia patients with very high performances without expert-designed feature engineering process. These results imply that deep learning based approach is most promising for EEG-based patient classification.

BACKGROUND: The ALLFTD (ARTFL-LEFFTDS Longitudinal Frontemporal Lobar Degeneration) study is an NIH-funded effort to prepare for clinical trials in sporadic (s-FTLD) and familial (f-FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. ALLFTD represents the merger and continuation of two prior studies: Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS).
METHODS: ALLFTD recruits participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD-ALS, CBS or PSP), with strong family histories of FTLD, or known FTLD-associated genetic variants within the family. 26 sites in North America enroll participants for clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants; participants are requested to return annually for follow-up evaluation. All participants are genotyped for dementia-associated mutations. Participants also enroll in the FTD Disorders Registry for follow-up surveys. A subset of participants undergo remote assessment via the ALLFTD app. Visits conducted under ARTFL and LEFFTDS are included in the ALLFTD dataset.
RESULTS: ALLFTD has been successful in developing methods to conduct remote or hybrid visits and in actively evaluating participants. Since ALLFTD began in January 2020, 1034 participants (736 new; 298 previously enrolled in ARTFL or LEFFTDS) have been evaluated in the longitudinal arm; an additional 119 participants have been participated in a shortened, biofluid-focused visit. 349 have returned for follow-up visits. Including prior participants, the ALLFTD dataset contains 3871 visits from 2343 individuals. 1277 people have sporadic syndromes; 1045 were enrolled as familial. Among s-FTLD, bvFTD is the most common phenotype (32.8%) followed by PSP (15.9%). 61.4% of f-FTLD participants were clinically normal at first visit; bvFTD is the most common syndrome in symptomatic f-FTLD (40%). 477 are confirmed carriers of FTLD-associated genetic mutations. MRIs were obtained for 2594 visits; 3492 visits have associated blood biospecimens banked; 978 visits have associated CSF samples.
CONCLUSIONS: The ALLFTD consortium is actively evaluating participants across North America to better characterize FTLD syndromes and support the planning and development of FTLD clinical trials. Longitudinal datasets including clinical, genetic, and imaging data are available by request.

BACKGROUND: Semantic and socioemotional knowledge, including person recognition, can be altered in frontotemporal dementia (FTD), and is often associated with the right temporal lobe variant. Using data from the Genetic FTD Initiative, we investigated person recognition deficits in genetic FTD.
METHODS: 901 GENFI participants (279 mutation negative controls, 280 C9orf72 mutation carriers (MCs), 101 MAPTMCs and 241 GRN MCs) were grouped using the Clinical Dementia Rating scale plus National Alzheimer\'s Coordinating Centre Frontotemporal Lobar Degeneration (CDR plus NACC FTLD) global score where 0 denotes asymptomatic, 0.5 as prodromal, and 1+ as mild to severe symptoms (C9orf72: 135 = 0, 48 = 0.5, 97 = 1+; GRN: 143 = 0, 35 = 0.5, 63 = 1+; MAPT: 50 = 0, 20 = 0.5, 31 = 1+). Person recognition (PR) was assessed using a single question within a structured clinical questionnaire, scoring the ability to recognise people who should be familiar by face or voice to them, with a value between 0 (absent) to 3 (severe), similar to the CDR scale. The percentage of participants with PR deficits was calculated for each group. Logistic regression with bootstrapping compared the PR score between groups with age, gender, and education as covariates.
RESULTS: 16.1% of C9orf72 MCs (0 = 0.7%, 0.5 = 2.1%, 1+ = 44.3%), 7.5% of GRN (0 = 0.0%, 0.5 = 8.6%, 1+ = 23.8%) and 17.8% of MAPT carriers (0 = 2%, 0.5 = 10%, 1+ = 48.4%) showed PR deficits. Mean (standard deviation) severity in each group was: C9orf72 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.6(0.9); GRN 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.2(0.6); MAPT 0 = 0.0(0.2), 0.5 = 0.1(0.3), 1+ = 0.6(0.8). Each of the symptomatic genetic groups had a significantly greater PR deficit than the control group (p<0.001), with the prodromal MAPT (p = 0.006) and GRN (p<0.001) groups also showing a greater impairment than controls. There was a trend to significance in the C9orf72asymptomatic and prodromal groups compared with controls (p = 0.058 and p = 0.059 respectively). Symptomatic C9orf72 and MAPT carriers showed greater impairment than the symptomatic GRN carriers (both p = 0.005).
CONCLUSIONS: Person recognition is a key early marker of disease in some individuals with genetic FTD and further imaging analyses will help to reveal the underlying mechanism of this deficit.

BACKGROUND: The C9orf72-repeat expansion (C9RE) is the most prevalent genetic cause of frontotemporal dementia (FTD). Since its discovery, studies have shown that both family history (FH) and medical history of FTD patients carrying a C9RE are often not only positive for dementia, but also for psychiatric disorders and late-onset behavioural change. Conversely, finding a C9RE carrier in a primary psychiatric disorder (PPD) cohort is rare. These findings justify clinicians to test for the C9RE, regardless of FH, when diagnosing a patient with FTD but not to screen for C9REs in PPD cohorts. It is unknown what the frequency is of C9RE in cases presenting with late-onset behavioural change. Therefore, we investigated the diagnostic value of screening for C9RE in cases with late-onset behavioural change.
METHODS: Patients with late-onset (>45years) behavioural change referred to the Alzheimer Center Amsterdam between 2011 and 2023, that received a baseline diagnosis of FTD or non-FTD were included. Genetic screening was performed and mutation carriers other than C9RE were excluded. The cohort was devided in C9RE-carriers and non-carriers. FH data was retrieved. Positive FH (FH+) was defined as having a first-degree relative with dementia or psychiatry, negative FH (FH-) without a first-degree relative with dementia or psychiatry. Distribution of FH(+/-) between C9RE-carriers and non-carriers was studied. Within the C9RE-carriers, distribution of FH between FTD and non-FTD diagnosis was measured. Distributions were compared using chi-squared tests.
RESULTS: A total of n = 344, of which 16,2% C9RE-carriers, were included. Of the C9RE-carriers, 66.7% had a FH+ versus 35.7% of the non-carriers (p = 4.36e-05). Within the C9RE-carriers group, n = 34 cases received a FTD diagnosis of which n = 20 had a FH- (58.5%) versus n = 20 cases receiving a non-FTD diagnosis of which n = 14 (70%) having a FH- (p-value = 0.596, table 1).
CONCLUSIONS: Within a cohort of late-onset behavioural change, 14 cases (4.2% of total cohort) received a non-FTD diagnosis, had a negative FH for dementia and psychiatry but turned out to have a C9RE. This shows late-onset behavioural change is enriched with C9RE, regardless of FH or baseline diagnosis, and suggests that screening for C9RE is of both diagnostic and prognostic value in late-onset behavioural disorders.