Cause Of Early-onset Dementia Research Articles

Research trends and hotspots for frontotemporal dementia from 2000 to 2022: a bibliometric analysis.

Frontotemporal dementia (FTD) is a neurodegenerative disease with clinical, pathological, and genetic heterogeneity. FTD is receiving increasing attention because it is the second leading cause of early-onset dementia after Alzheimer's disease. This study aimed to analyse the research trends and hotspots of FTD from 2000 to 2022 using bibliometrics. Papers related to FTD from 2000 to 2020 were systematically searched through the Web of Science Core Collection (WOSCC). Citespace and Vosviewer software were used to visually analyse the retrieved data of countries/regions, institutions, journals, authors, references, and keywords. Microsoft Excel was used to generate the annual publications and growth trends. There were 10,227 papers included in the bibliometric analysis. The annual publication output on FTD has increased significantly from 2000 to 2022, with papers published in 934 academic journals and 87 countries/regions. The Journal of Alzheimer's Disease was the most popular, with 488 papers about FTD. The most productive countries/regions, institutions, and authors are the United States (n = 4,037), the University of California San Francisco (n = 687), and Miller, Bruce L. (n = 427), respectively. The article by Katya Rascovsky and her colleagues published on Brain in 2011 was the most cocited paper, with 625 citations. The research hotspots in this field were the clinical diagnostic criteria, subdivision, and pathological mechanism of FTD, such as tau protein, chromosome 17, progranulin, TDP-43, and C9orf72. The future research direction is based on biomarkers and pathological mechanisms to diagnose and differential diagnose FTD from the aspects of behavior, neuropathology, neuroimaging, and serum markers.

Distribution of neuropsychiatric profiles and comorbid diseases in dementia subtypes

Objectives: Alzheimer’s disease (AH) is the most prevalent cause of dementia, followed closely by vascular dementia. Mixed vascular-Alzheimer’s dementia (MVAD) is more evident in individuals aged 80 and above. Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after AH. Vascular risk factors play important role in the pathogenesis of dementia syndromes. Behavioral and psychological symptoms represent a significant portion of the non-cognitive manifestations in dementia patients. This study aimed to evaluate the distribution of chronic diseases, behavioral disorders, psychiatric findings, and medication use in patients followed with different dementia diagnoses. Methods: Prevalance of chronic diseases, behavioral disorders, psychiatric findings as well as the usage of antidepressant and antipsychotic medications among patients followed up in dementia outpatient clinics with the diagnosis of AD, mild cognitive impairment (MCI), vascular dementia (VaD), FTD, and MVAD were investigated. Neuropsychiatric inventory (NPI) was applied to the patients. Results: Four hundred and fifty-five patients were accepted in the study. The patients were distributed as follows: AD (n=303, female/male: 187/115, age = 78±8 years), MCI (n=53, female/male: 31/22, age = 69±10 years), VaD (n=31, female/male: 18/13, age = 68±9 years), FTD (n=32, female/male: 17/15, age = 68±9 years), and MVAD (n=36, female/male: 16/20, age = 76±10 years). Both AD and MVAD groups were significantly older than the other groups (F = 23.2, P<0.0001). The ratio of comorbid chronic diseases was 80% in the AD group, 72% in the MCI group, 91% in the VaD group, 59% in the FTD group, and 93% in the MVAD group. In the whole group, antipsychotic drug use was 27.5% and antidepressant drug use was 28.9%. The mean NPI score was 32.9±28 in antipsychotic users and 16±19 in non-users (P<0.0001). The mean NPI of antidepressant users was 17.6±19 and 21.9±25 (P=0.055) in non-users. Conclusion: There is a comorbid chronic disease burden in all dementia subtypes, although at varying intensities, and as the chronic disease burden increases, behavioral disorders and psychotic findings increase, and accordingly, the use of antipsychotics also increases.

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.

Frontotemporal lobar degeneration.

Frontotemporal lobardegeneration (FTLD)is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau(FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise.

Alteration of microglial metabolism and inflammatory profile contributes to neurotoxicity in a hiPSC-derived microglia model of frontotemporal dementia 3

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, with no current treatment options. FTD linked to chromosome 3 (FTD3) is a rare sub-form of the disease, caused by a point mutation in the Charged Multivesicular Body Protein 2B (CHMP2B). This mutation causes neuronal phenotypes, such as mitochondrial deficiencies, accompanied by metabolic changes and interrupted endosomal-lysosomal fusion. However, the contribution of glial cells to FTD3 pathogenesis has, until recently, been largely unexplored. Glial cells play an important role in most neurodegenerative disorders as drivers and facilitators of neuroinflammation. Microglia are at the center of current investigations as potential pro-inflammatory drivers. While gliosis has been observed in FTD3 patient brains, it has not yet been systematically analyzed. In the light of this, we investigated the role of microglia in FTD3 by implementing human induced pluripotent stem cells (hiPSC) with either a heterozygous or homozygous CHMP2B mutation, introduced into a healthy control hiPSC line via CRISPR-Cas9 precision gene editing. These hiPSC were differentiated into microglia to evaluate the pro-inflammatory profile and metabolic state. Moreover, hiPSC-derived neurons were cultured with conditioned microglia media to investigate disease specific interactions between the two cell populations. Interestingly, we identified two divergent inflammatory microglial phenotypes resulting from the underlying mutations: a severe pro-inflammatory profile in CHMP2B homozygous FTD3 microglia, and an “unresponsive” CHMP2B heterozygous FTD3 microglial state. These findings correlate with our observations of increased phagocytic activity in CHMP2B homozygous, and impaired protein degradation in CHMP2B heterozygous FTD3 microglia. Metabolic mapping confirmed these differences, revealing a metabolic reprogramming of the CHMP2B FTD3 microglia, displayed as a compensatory up-regulation of glutamine metabolism in the CHMP2B homozygous FTD3 microglia. Intriguingly, conditioned CHMP2B homozygous FTD3 microglia media caused neurotoxic effects, which was not evident for the heterozygous microglia. Strikingly, IFN-γ treatment initiated an immune boost of the CHMP2B heterozygous FTD3 microglia, and conditioned microglia media exposure promoted neural outgrowth. Our findings indicate that the microglial profile, activity, and behavior is highly dependent on the status of the CHMP2B mutation. Our results suggest that the heterozygous state of the mutation in FTD3 patients could potentially be exploited in form of immune-boosting intervention strategies to counteract neurodegeneration.

The lived experience of reconstructing identity in response to genetic risk of frontotemporal degeneration and amyotrophic lateral sclerosis.

With the increasing availability of predictive genetic testing for adult-onset neurodegenerative conditions, it is imperative that we better understand the impact of learning one's risk status. Frontotemporal degeneration (FTD) is the second most prevalent cause of early-onset dementia. About one-third of patients have an identifiable genetic etiology, and some genetic variants that cause FTD can also cause amyotrophic lateral sclerosis (ALS). To understand individuals' risk perception and broader experience of living at risk, we completed semi-structured telephone interviews with 14 asymptomatic adults who tested positive for a variant known to cause risk for FTD and/or ALS. We conducted a thematic analysis, and within the core topic of identity, we derived three themes: conceptualization of FTD and ALS as a threat to identity, enduring uncertainty and dread, and varying centrality of risk status to identity. FTD and ALS risk raised fundamental issues for participants related to the essence of personhood, challenged them to confront Cartesian dualism (the philosophy of mind-body separation), and exposed how time, relationships, and social roles have affected their understanding of the nature of the self. Our findings provide important insight into how being at genetic risk shapes an individual's identity. We conclude that genetic counseling interventions that allow for identity exploration, anticipatory guidance, and uncertainty management should be utilized when supporting persons at risk.

Prevalence, demographics and etiologies of early-onset dementia in Brazil: a retrospective cohort (P1-12.010)

<h3>Objective:</h3> To describe clinical features, demographics and causes of early-onset dementia in two quaternary outpatient clinics in Brazil. <h3>Background:</h3> Dementia is a growing concern worldwide and is a major cause of disability and impairment to basic activities of daily living. In Latin America, dementia is a leading cause of disease burden. However, few studies evaluate the prevalence and characteristics of EOD in Latin America. <h3>Design/Methods:</h3> Electronic medical records of consecutive, patients seen at two outpatient clinics in 2021, were retrospectively examined. Inclusion criteria included a diagnosis of dementia according to DSM-V and onset at or before 65 years-old. <h3>Results:</h3> 625 EMRs were reviewed. 102 were classified as EOD, yielding a prevalence of 16.3%. 54 (52.9%) were females. Mean age at onset was 56.8 years. Mean years of education was 8.48. Etiologies found were Alzheimer’s (40; 39.2%), Vascular dementia (7; 6.8%), Alzheimer’s and vascular (5; 4.9%), Frontotemporal dementia (12; 11.7%), dementia with parkinsonian features - LBD, PSP, MSA (5; 4.9%), multifactorial (9; 8.8%), others (11; 10.7%), and unknown/under investigation (13; 12.7%). No differences were found when comparing age at onset, age at admission, initial MMSE and schooling years among different causes. Positive first-degree family history of dementia was frequent (36.2%). Genetic causes included mutations in PSEN1, APP and TYROBP. <h3>Conclusions:</h3> Prevalence and proportion of different dementia types matched previously reported cohorts from developed countries (Harvey &amp; Rossor, 2003). Differences were noted when comparing with a previous Brazilian cohort of EOD (Fujihara et al, 2004), mainly a higher prevalence of AD and lower prevalence of vascular dementia. No difference was found when comparing mean schooling years, initial MMSE, age at onset and at admission among different causes of EOD. <b>Disclosure:</b> Mr. Mahler Ferreira Oliveira has nothing to disclose. Miss Solti has nothing to disclose. Leonel Takada has nothing to disclose. Sonia Brucki has nothing to disclose.

Multidimensional Clinical Assessment in Frontotemporal Dementia and Its Spectrum in Latin America and the Caribbean: A Narrative Review and a Glance at Future Challenges.

Frontotemporal dementia (FTD) is the third most common form of dementia across all age groups and is a leading cause of early-onset dementia. The Frontotemporal dementia (FTD) includes a spectrum of diseases that are classified according to their clinical presentation and patterns of neurodegeneration. There are two main types of FTD: behavioral FTD variant (bvFTD), characterized by a deterioration in social function, behavior, and personality; and primary progressive aphasias (PPA), characterized by a deficit in language skills. There are other types of FTD-related disorders that present motor impairment and/or parkinsonism, including FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The FTD and its associated disorders present great clinical heterogeneity. The diagnosis of FTD is based on the identification through clinical assessments of a specific clinical phenotype of impairments in different domains, complemented by an evaluation through instruments, i.e., tests and questionnaires, validated for the population under study, thus, achieving timely detection and treatment. While the prevalence of dementia in Latin America and the Caribbean (LAC) is increasing rapidly, there is still a lack of standardized instruments and consensus for FTD diagnosis. In this context, it is important to review the published tests and questionnaires adapted and/or validated in LAC for the assessment of cognition, behavior, functionality, and gait in FTD and its spectrum. Therefore, our paper has three main goals. First, to present a narrative review of the main tests and questionnaires published in LAC for the assessment of FTD and its spectrum in six dimensions: (i) Cognitive screening; (ii) Neuropsychological assessment divided by cognitive domain; (iii) Gait assessment; (iv) Behavioral and neuropsychiatric symptoms; (v) Functional assessment; and (vi) Global Rating Scale. Second, to propose a multidimensional clinical assessment of FTD in LAC identifying the main gaps. Lastly, it is proposed to create a LAC consortium that will discuss strategies to address the current challenges in the field.

Shared transcriptomic signature between Huntington's disease and early-onset Alzheimer's disease.

Neurodegenerative diseases share common pathological features, including progressive loss of neurons and protein misfolding, which ultimately culminates in dementia. Interestingly, dementia is not restricted to elderly people. In fact, many diseases have been identified as causes of early-onset dementia (< 65 years of age) such as Huntington's disease (HD) and early-onset Alzheimer's disease (EOAD). Importantly, disease-specific genetic mutations have already been identified for EOAD and HD. Thus, one could suggest that the molecular link between EOAD and HD may arise from alterations at the transcriptomic level, which is yet to be determined. In keeping with this, we hypothesized that EOAD and HD share a transcriptomic signature. In this work, we aimed at identifying transcriptome similarities between both diseases. We collected data sample of postmortem cerebral cortex from 6 AD (GSE33000, GSE118553, GSE122063, GSE39420, GSE44770, GSE44771) and 1 HD (GSE33000) microarray studies in the Gene Expression Omnibus, a public transcriptomic data repository. Of note, only subjects with age at death under 65 were selected (EOAD: n = 65, controls: n = 266; HD: n = 158, controls: n = 158). Differential expression and functional enrichment analyses were performed for each group versus their respective age-matched controls. We identified 1,260 differentially expressed genes (476 up- and 784 down-regulated genes) and 675 enriched gene ontology (GO) terms between EOAD and HD. The GO terms were grouped in 11 clusters of biological processes (Table 1). Cluster observation suggests a link in the apoptotic signaling, immune response and synaptic transmission processes in both diseases. Our results demonstrate a transcriptomic signature shared by EOAD and HD. Unveiling the similarities between EOAD and HD at the transcriptomic level could advance our knowledge about the pathogenesis of these diseases and may help developing therapeutic strategies targeting early-onset neurodegenerative diseases.

Sour aversion in frontotemporal dementia: a case report and review on physiologic-anatomic mechanisms

ABSTRACT Frontotemporal dementia (FTD) is a common cause of early-onset dementia characterized by behavioral and personality changes, as well as, altered eating habits. FTD is associated with complex changes in neural networks of gustatory processing which may be responsible for eating abnormalities. Here, we present a 66-years-old lady suffered from behavioral variant of FTD with an interesting symptom of food aversion, typically sour foods.

Interaction of the Frontotemporal Dementia-Associated Protein TMEM106B With VAMP8 in Lysosome-Autophagosome Fusion

Frontotemporal lobar degeneration (FTLD) is a leading cause of early-onset dementia, but the pathological mechanisms underlying this disorder are not well understood. Common variants in the gene encoding Transmembrane Protein 106B (TMEM106B) increase genetic risk for FTLD with TAR DNA-binding Protein 43 (TDP-43) inclusions (FTLD-TDP-43), and variants associated with increased TMEM106B expression confer greater disease risk. Here, we demonstrate that TMEM106B expression increases the formation of enlarged autolysosomes and elucidate the molecular mechanism underlying this phenotype. By immunoprecipitating TMEM106B and identifying co-immunoprecipitated proteins by mass spectrometry (IP-MS), we found that TMEM106B interacts with the Vesicle-associated membrane protein 8 (VAMP8), a SNARE protein known to mediate lysosome-autophagosome fusion. TMEM106B and VAMP8 co-localize in lysosomes, and their interaction is dependent on lysosomal pH. Knockdown of VAMP8, or its partner in lysosome-autophagosome fusion Syntaxin-17 (Stx17), rescues the TMEM106B-induced vacuolar phenotype of enlarged autolysosomes. Moreover, deacidification of lysosomes in HeLa cells and iPSC-neurons abrogates co-localization of TMEM106B and VAMP8, with redistribution of VAMP8 to the cell periphery. Taken together, our data suggest that TMEM106B modulates VAMP8-Stx17-mediated lysosome-autophagosome fusion, in a lysosomal pH-dependent manner.

Brain atrophy patterns in patients with frontotemporal dementia: voxel-based morphometry

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by language and behaviour deficits, which is considered the second most common cause of early-onset dementia. Detection of brain atrophy patterns is important for FTD diagnosis. However, the visual assessment of magnetic resonance imaging data may not be sensitive enough requiring the use of objective gray matter (GM) volume determination method. The study was aimed to assess the GM atrophy pattern in patients with FTD compared to control group patients using voxel-based morphometry (VBM). The study included 16 patients with FTD (12 patients with nonfluent agrammatic variant primary progressive aphasia (nfvPPA), three patients with behavioral variant of FTD, and one patient with logopenic variant PPA) and 10 healthy volunteers. VBM of patients with FTD and healthy controls revealed three significant (pFWE-corr &lt; 0.05) atrophy areas in the left inferior frontal, left fusiform, and left supramarginal gyri. Taking into account the predominance of patients with nfvPPA in the group of FTD patients, the additional VBM of this group and control group was carried out, which revealed a distinct atrophy pattern: the reduced GM volume was detected in the left inferior frontal and left middle frontal gyri (pFWE-corr &lt; 0.05). The results obtained indicate that regardless of the clinical variant, there is a certain atrophy pattern characteristic of FTD, which involves both frontotemporal areas and parietal lobe. The example of nfvPPA shows that each variant of the disease is associated with distinct localization of atrophy.

Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants

BackgroundFrontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease. It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pathology is found in most FTD and ALS cases. It plays a role in transcription, translation and serves as a shuttle between the nucleus and cytoplasm. Prior to its aggregation, TDP-43 exists as polyubiquitinated, hyperphosphorylated C-terminal fragments that correlate well with FTD disease progression. Because of the importance of TDP-43 in these diseases, reagents that can selectively recognize specific toxic TDP variants associated with onset and progression of FTD can be effective diagnostic and therapeutic tools.ResultsWe utilized a novel atomic force microscopy (AFM) based biopanning protocol to isolate single chain variable fragments (scFvs) from a phage display library that selectively bind TDP variants present in human FTD but not cognitively normal age matched brain tissue. We then used the scFvs (FTD-TDP1 through 5) to probe post-mortem brain tissue and sera samples for the presence of FTD related TDP variants. The scFvs readily selected the FTD tissue and sera samples over age matched controls. The scFvs were used in immunohistochemical analysis of FTD and control brain slices where the reagents showed strong staining with TDP in FTD brain tissue slice. FTD-TDP1, FTD-TDP2, FTD-TDP4 and FTD-TDP5 all protected neuronal cells against FTD TDP induced toxicity suggesting potential therapeutic value.ConclusionsThese results show existence of different disease specific TDP variants in FTD individuals. We have identified a panel of scFvs capable of recognizing these disease specific TDP variants in postmortem FTD tissue and sera samples over age matched controls and can thus serve as a biomarker tool.

Frontotemporal Dementia Rating Scale (FTD-FRS): Linguistic and Cultural Adaptation in Russia

Introduction. Frontotemporal dementia (FTD) is a neurodegenerative disease and is the second most frequent cause of early-onset dementia (before 65 years). Quantitative assessment of disease severity can be an essential tool for predicting and objectively assessing the rate of disease progression, which is vital not only for clinical practice but also for research. There are no specialized Russian language scales for evaluating the severity of dementia in FTD, and the use of functional assessment scales developed for patients with Alzheimer disease for this purpose leads to erroneous diagnosis and reduces the quality of research. The aim of this work was to perform linguistic and cultural adaptation and validation of the Russian version of the Frontotemporal Dementia Rating Scale (FTD-FRS). Materials and methods: Forward and back translations of the scale and its materials, pilot testing, development of the Russian language version with the help of a linguist and neurologists specializing in working with patients with cognitive impairments were performed. Results. After completing the forward and back translations, the expert commission removed inaccuracies in the translation of the scale materials. Pilot testing was carried out on 10 patients with FTD. Researchers did not have any difficulties understanding and interpreting the instructions. After this stage, the final edition of the Russian version of the scale was adopted. The article contains the main text of the scale and a link to the full version of the scale with the main text and instructions. Conclusion. A Russian language version of the Frontotemporal Dementia Rating Scale has been published for the first time. The first stage of validation (linguistic and cultural adaptation) was performed in the Research Center of Neurology. There is ongoing work to evaluate the psychometric properties of the Russian language version.

Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency

BackgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.MethodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X−/− KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X.ResultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X−/− KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X−/− KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X−/− KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice.ConclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Uncovering pathophysiological changes in frontotemporal dementia using serum lipids

Blood serum is enriched in lipids and has provided a platform to understand the pathogenesis of a number of human diseases with improved diagnosis and development of biomarkers. Understanding lipid changes in neurodegenerative diseases is particularly important because of the fact that lipids make up >50% of brain tissues. Frontotemporal dementia (FTD) is a common cause of early onset dementia, characterized by brain atrophy in the frontal and temporal regions, concomitant loss of lipids and dyslipidemia. However, little is known about the link between dyslipidemia and FTD pathophysiology. Here, we utilized an innovative approach – lipidomics based on mass spectrometry – to investigate three key aspects of FTD pathophysiology – mitochondrial dysfunction, inflammation, and oxidative stress. We analyzed the lipids that are intrinsically linked to neurodegeneration in serum collected from FTD patients and controls. We found that cardiolipin, acylcarnitine, lysophosphatidylcholine, platelet-activating factor, o-acyl-ω-hydroxy fatty acid and acrolein were specifically altered in FTD with strong correlation between the lipids, signifying pathophysiological changes in FTD. The lipid changes were verified by measurement of the common disease markers (e.g. ATP, cytokine, calcium) using conventional assays. When put together, these results support the use of lipidomics technology to detect pathophysiological changes in FTD.

Genetic Diversity in Frontotemporal Dementia

Frontotemporal dementia is a progressive neurodegenerative disorder with high clinical, genetic, and pathomorphological diversity It is the third most common cause of dementia in all ages and the most common cause of early onset dementia (below 65). Despite its multifactorial nature, up to 40% of patients have a family history where the autosomal dominant inheritance type is seen in a quarter of cases. In this review, we describe key genes whose mutations can result in the development of frontotemporal dementia, the possible pathogenic mechanisms of the degenerative process, and provide information on the clinical features of the disease for different genetic variants. Special emphasis is placed on the frontotemporal dementia phenotype that is associated with amyotrophic lateral sclerosis.

Longitudinal analysis of brain atrophy in Alzheimer's disease and frontotemporal dementia.

ObjectivesAlzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are among the leading causes of early-onset dementia. This study aimed to assess the rate of whole brain atrophy by comparing bvFTD and AD.MethodsTwo patients (one man with AD, and one woman with bvFTD) had neuropsychological and neuroimaging assessment by using automated techniques for cross-sectional and longitudinal atrophy measurements.ResultsIn the patient with AD, magnetic resonance imaging (MRI) showed decreased bilateral hippocampal and mesial-temporal volume. However, conventional images showed no difference between baseline (T0) and after 1 year (T1). In the patient with bvFTD, MRI showed bilateral frontotemporal lobe atrophy and a moderate increase in atrophy between T0 and T1, particularly in the temporal lobes. A cross-sectional cerebral volume examination showed a considerable reduction in brain volume in the patient with bvFDT and a moderate reduction in the patient with AD. A longitudinal cerebral volume examination showed a lower percentage brain volume change in the patient with bvFTS compared with the patient with AD.ConclusionsOur results suggest that bvFTD has more neurodegenerative progression. MRI findings should be considered as a reliable marker of disease progression in the brain. Our findings offer potential for monitoring treatment outcomes.

Frontotemporal Dementia Knowledge Scale: Development and Preliminary Psychometric Properties.

Frontotemporal dementia (FTD) accounts for ∼10% of dementia cases and is the most common cause of early-onset dementia. However, no well-validated instrument currently exists to measure knowledge about FTD. In this study, we used systematic scale development procedures to create a scale to measure knowledge of FTD based on a contemporary understanding of the disease. Standard scale development methods were used to create items and evaluate their psychometric properties. A total of 72 health care professionals and 102 caregivers of people with FTD responded to items measuring FTD knowledge, general dementia knowledge, crystallized intelligence, experience with FTD, and demographic information. The Frontotemporal Dementia Knowledge Scale (FTDKS) contains 18 items that cover key, basic knowledge about FTD in the domains of risk factors, symptoms, course, caregiving, and treatment. The scale uses a 4-point True/False format with a Don't Know option and takes ∼5 minutes to complete. In the current sample the FTDKS had good psychometric properties in terms of reliability and validity. The FTDKS can be used with health care professionals and caregivers of people with FTD to assess their knowledge about the disease. The scale may be useful to evaluate knowledge in clinical care and educational program contexts.