Genetic Frontotemporal Dementia Research Articles

Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results

Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

Distinctive cell-free DNA methylation characterizes presymptomatic genetic frontotemporal dementia.

Methylation of plasma cell-free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls. cfDNA was isolated from cross-sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome-wide methylation of cfDNA was determined using a high-resolution sequencing technique (MeD-seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families). Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription-start-site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin-dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes. A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.

Executive Summary of 2023 International Conference of the Korean Dementia Association (IC-KDA 2023): A Report From the Academic Committee of the Korean Dementia Association.

The Korean Dementia Association (KDA) has been organizing biennial international academic conferences since 2019, with the International Conference of the KDA (IC-KDA) 2023 held in Busan under the theme 'Beyond Boundaries: Advancing Global Dementia Solutions.' The conference comprised 6 scientific sessions, 3 plenary lectures, and 4 luncheon symposiums, drawing 804 participants from 35 countries. Notably, a Korea-Taiwan Joint Symposium addressed insights into Alzheimer's disease (AD). Plenary lectures by renowned scholars explored topics such as microbiome-related AD pathogenesis, social cognition in neurodegenerative diseases, and genetic frontotemporal dementia (FTD). On the first day, specific presentations covered subjects like the gut-brain axis and neuroinflammation in dementia, blood-based biomarkers in AD, and updates in AD therapeutics. The second day's presentations addressed recent issues in clinical neuropsychology, FTD cohort studies, and the pathogenesis of non-AD dementia. The Academic Committee of the KDA compiles lecture summaries to provide comprehensive understanding of the advanced dementia knowledge presented at IC-KDA 2023.

Association of novel CSF biomarker candidates with cortical thickness in genetic frontotemporal dementia

AbstractBackgroundA novel panel of 14 proteins measured in the CSF could separate individuals with genetic frontotemporal dementia (FTD) from controls, with most significant findings observed for neurofilament medium (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4) [1]. However, it is currently unknown whether these altered protein levels in the CSF reflect neurodegenerative changes in the brain. The aim of this study was to explore the cross‐sectional associations between the previously identified CSF biomarker candidates and cortical thickness in presymptomatic and symptomatic mutation carriers, and whether those associations differ by FTD mutation type.MethodWe have analyzed T1 MRI scans alongside concurrent CSF samples from 202 individuals from the GENFI cohort, belonging to families that carry FTD mutations in either C9orf72, GRN or MAPT genes. The study sample included symptomatic mutation carriers, presymptomatic mutation carriers and non‐carrier controls. Cortical thickness was estimated with FreeSurfer and CSF protein levels were measured via a multiplexed antibody‐based suspension bead array. The correlations between regional cortical thickness and protein levels were calculated via linear regression.ResultAltered levels of NEFM, AQP4, APOA1, PTPRN2, CTSS, SERPINA3, C4, AMPH and CD14 were all correlated with increased atrophy of at least one cortical region. Some effects were mutation specific, but NEFM, AQP4 and APOA1 correlated with atrophy in all mutation groups. We also observed mutation specific effects for 10 of the proteins. CTSS levels were only correlated with cortical atrophy in C9orf72 mutation carriers while NPTX2, VGF and PTPRN2 correlated with atrophy in GRN mutation carriers. In MAPT mutation carriers, 6 different proteins correlated with atrophy in the right temporal pole.ConclusionThe proposed fluid biomarker candidates continue to show promise and further longitudinal studies will contribute to elucidate their relationship to cortical atrophy and their prognostic value in genetic FTD.[1] Bergström et al. Mol Neurodegener. 2021; 16(1):79

Familial relatedness in genetic frontotemporal dementia cohorts: findings from the international Frontotemporal Dementia Prevention Initiative

AbstractBackgroundGiven the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large‐scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses.MethodsGenome‐wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy‐Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two‐stage approach, to calculate pairwise identity‐by‐descent (IBD) estimates and KING coefficients, followed by family‐network identification and pedigree reconstruction using PRIMUS.ResultsFirst, we calculated IBD estimates among all participants by restricting pairs to those with estimates&gt;0.1875 (up to second‐degree relatives). Overall, we identified a total of 292 second‐degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD‐causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi‐site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry‐based analysis among participants with estimated European ancestry, using the KING‐robust algorithm.ConclusionsThese lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies.

Association of low frequency variants with regional cortical grey matter volumes in genetic frontotemporal dementia: Results from GENFI

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative condition characterized by heterogeneous clinical, pathological, and genetic features. Mutations in three genes account for the majority of autosomal dominant FTD: GRN, MAPT, and C9orf72. We tested whether gene‐based aggregate burden of genome‐wide low‐frequency variants contribute to variation in regional cortical and subcortical grey matter volumes in the GENetic Frontotemporal dementia Initiative (GENFI), after controlling for effects of autosomal dominant mutations.MethodGENFI recruits symptomatic and presymptomatic participants from families segregating genetic FTD. We included 517 participants with genotype (Neurochip; imputed against TOPMed), and T1w‐MRI brain volumetric data. Gene‐based burden tests that aggregate the number of uncommon/rare variants by gene were used to examine the association of low‐frequency variants (minor allele frequency: 0.000001 to &lt;0.05) with regional cortical and subcortical grey matter volumes, controlling for age, sex, total intracranial volume, mutation status, population stratification, and family membership (kinship matrix). In two separate analyses, we used the following set of annotations to account for (i) loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous, (ii) insertions, deletions, and frameshift mutations (indel‐fs).ResultOf the 517 participants (300 women), 307 were mutation carriers (symptomatic = 82). For LOF mutations (731 genes tested; significance threshold: p = 0.05/731 = 6.8×10−5), aggregate burden of variants in BSND were associated with lower volumes in: temporal (p = 6.6×10−6), left insula (p = 5.0×10−5), and ventromedial prefrontal cortical (p = 2.8×10−5) regions. For indel‐fs mutations (826 genes tested; significance threshold: p = 0.05/826 = 6.05×10−5), aggregate burden of variants in: (i) E2F2 was associated with lower volumes in occipital (p = 8.7×10−6) regions; (ii) TMEM61 was associated with lower volumes in left temporal (p = 7.8×10−7), and left cingulate regions (p = 5.5×10−5); (iii) KDM4A‐AS1 was associated with lower volumes in the right temporal (p = 3.2×10‐7) region. All genes are variably expressed in the brain.ConclusionIdentification of deleterious or protective low‐frequency variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication of results followed by functional studies are needed.

Optimising remote sampling of NfL and GFAP using blood cards in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort

AbstractBackgroundIn recent years, blood‐based biomarkers have become key measures in the study of dementia, including frontotemporal dementia (FTD), with use in diagnosis and clinical trial outcomes. Remote collection of blood samples provides a more accessible and cost‐effective alternative to regular clinic visits and allows for more frequent measures to be taken. This is particularly relevant as we progress into an era of clinical trials in FTD. The aim of this current study was to assess whether neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), markers previously shown be increased in genetic forms of FTD, can be measured using dried blood cards and to optimise the protocol for this.Method10 participants from the University College London GENFI study (three C9orf72 mutation carriers, four GRN mutation carriers and three mutation negative controls) were included in this pilot study. Blood samples were collected by venepuncture from each participant: one sample for plasma analysis and one sample which was used to pipette whole blood on to a blood card. NfL and GFAP concentrations were subsequently quantified using the Simoa multiplex Neurology 4‐Plex A (N4PA) assay in both plasma and the dried blood card. Total protein concentration was measured with the Bradford protein assay and used to correct for variable concentrations of blood card spots. The effect of incubation temperature and time as well as freeze thaw cycles were also assessed as part of the optimisation process.ResultIn this pilot cohort, blood card GFAP concentration (BSA corrected) very strongly correlated with matched plasma GFAP (r = 0.897, p = 0.0004), whilst blood card NfL concentration (BSA corrected) strongly correlated with matched plasma NfL (r = 0.721, p = 0.0234). Incubation temperature impacted total protein concentration in the blood cards, but freeze‐thaw and incubation time did not.ConclusionThis pilot study shows that NfL and GFAP concentrations can be successfully quantified using dried blood cards and results strongly correlate with plasma measures. Future work will involve investigating whether these biomarkers can be measured in blood cards obtained with capillary blood through lancet‐based fingerprick collection and assessing the feasibility of home collection.

Developing a mass spectrometric assay to measure granulin peptides in CSF for progranulin‐associated frontotemporal dementia

AbstractBackgroundPathogenic mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), inducing a reduced biofluid concentration of the progranulin protein (PGRN). PGRN is a cysteine‐rich glycoprotein with essential roles in inflammation and lysosomal function, made up of 7 granulin peptides and 1 paragranulin. The role of these peptides is unclear, but existing data suggests they may have contradictory roles to full‐length PGRN. With the development of numerous clinical trials aiming to treat progranulin‐associated FTD (FTD‐GRN) by increasing full‐length PGRN, it is important to establish effective outcome measures to assess treatment success and further our understanding of PGRN’s biology. Here, we aimed to develop an assay to quantify granulin peptides in cerebrospinal fluid (CSF) and determine whether they contribute to the pathology of FTD‐GRN.MethodBased on previously published explorative data of endogenous CSF peptides, 12 peptides spanning the progranulin sequence, were selected for the development of targeted assays using a quadrupole Orbitrap hybrid mass spectrometer (Fusion Tribrid, Thermo). An analytical protocol was optimised involving reduction, alkylation, molecular weight cut‐off filtration and solid phase extraction, and using isotope labelled heavy standards for quantification. Additionally, tandem mass tag (TMT) proteomics was used to analyse tryptic peptides spanning granulin and paragranulin sequence regions in 248 CSF samples from the Genetic FTD initiative (GENFI) including 56 GRN mutation carriers and 76 mutation‐negative controls.ResultPreliminary results reveal the presence of three endogenous peptides in CSF, which based on sequence matching, likely represent granulin 6 and 7 alongside the paragranulin peptide. TMT results showed significantly reduced relative peptide intensity across the granulin regions in GRN carriers CSF compared to controls (p&lt;0.0001), but no significant difference in the paragranulin region (p&gt;0.33).ConclusionThese findings indicate that two granulins and paragranulin are quantifiable in CSF and may have key roles in progranulin biology and potentially FTD pathology. This is supported by TMT results of differential CSF paragranulin levels compared to granulins. Continuing work will quantify CSF granulin concentrations in the GENFI cohort to assess whether these peptides have key roles in FTD‐GRN’s underlying biology and as potential outcome measures in trials.

A portable eye tracking experiment for the assessment of cognitive impairment in presymptomatic frontotemporal dementia

AbstractBackgroundEye tracking can be useful for measuring cognitive function in frontotemporal dementia (FTD), as the tasks do not require behavioural or verbal responses. However, most systems are highly expensive and require experiments to be conducted in artificial environments. We developed a fully portable eye tracking protocol using the Tobii Pro Nano, a small, low‐cost eye tracker. The aim was to investigate if the portable experiment can detect presymptomatic impairment in FTD using instructionless tasks of social cognition.MethodParticipants were recruited from the Genetic FTD Initiative (GENFI), including 41 mutation carriers (mean age = 43.0, standard deviation (SD) = 11.0), and 14 non‐carriers (mean age = 40.4, SD = 7.14). Participants completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and three non‐target) followed by a target emotion word and then the original four images alongside the emotion word. A dwell time change score was calculated by subtracting the percentage dwell time for the target image before the word appeared from the percentage dwell time after the word appeared. A lower dwell time change score signifies impaired performance. Linear mixed effects models were used to compare performance on each of the tests, with the dwell time change score included as the variable of interest and age, target type (target, non‐target), and genetic status (carrier, non‐carrier) included in the model as fixed effects.ResultThe average (standard deviation) mean percentage dwell time change score in the target image was lower at 52.2% (15.8) for the mutation carriers compared with 56.5% (7.01) for non‐carriers on the simple emotion task (p = 0.006), and 23.4% (11.2) for carriers compared with 27.3% (7.46) for non‐carriers on the complex emotion task (p = 0.076).ConclusionThese eye tracking tasks may be a useful tool for assessing deficits in social cognition in presymptomatic FTD, something that has been difficult to measure with pen and paper neuropsychometry. Therefore, this portable eye tracking experiment has the potential to be a low‐cost biomarker for monitoring the progression of FTD in clinical trials, both at home and in the clinic.

DTI changes of thalamic subregions in genetic frontotemporal dementia: findings from the GENFI cohort

AbstractBackgroundAtrophy of thalamic subregions has been observed across the spectrum of frontotemporal dementia (FTD). To gain better insight into underlying tissue changes, we investigated how thalamic subregional fractional anisotropy (FA) and mean diffusivity (MD) derived from diffusion tensor imaging (DTI) are altered in genetic FTD.MethodWe used our newly developed thalamus segmentation tool, which jointly combines structural and diffusion input MRI data, to segment thalami and extract thalamic subregional FA and MD values for 163 genetic mutation carriers and 126 non‐carriers with suitable 3T MRI data from the GENetic FTD Initiative (GENFI). Mutation carriers were divided according to their genetic diagnosis and CDR®+NACC FTLD global scores into presymptomatic/prodromal (≤0.5: 41 C9orf72, 59 GRN, 34 MAPT) and symptomatic (≥1: 8 C9orf72, 11 GRN, 10 MAPT) groups. Mean FA and MD values for thalamic subregions were obtained using diffusion tensors interpolated in the log domain and weighted by segmentation posterior probabilities. Thalamic subregional FA and MD values for presymptomatic and symptomatic mutation carriers within each genetic group were compared with non‐carriers using analysis of covariance with bootstrapping, where age, scanner type, and sex were covariates. We corrected for multiple comparisons and calculated percentage changes in adjusted FA and MD mean values for mutation carriers relative to non‐carriers.ResultThe only significant change at the presymptomatic stage was found for C9orf72 expansion carriers, who showed FA reduction in the intralaminar subregion (5%) (Figure 1, Table 1). In symptomatic C9orf72 expansion carriers, FA was reduced in the laterodorsal (21%), lateral posterior (13%), anteroventral (13%) and intralaminar (11%) subregions. Symptomatic MAPT mutation carriers also showed FA reduction in the laterodorsal (15%) and anteroventral (11%) subregions. No significant FA reductions were found for GRN mutation carriers and no significant MD changes were observed for any group after correction for multiple comparisons.ConclusionWe detected FA reductions of thalamic subregions only for C9orf72 expansion carriers at the presymptomatic stage, and for C9orf72 and MAPT mutation carriers at the symptomatic stage. Combined with the lack of robust MD changes, our findings may warrant further assessment of thalamic microstructure with more advanced diffusion models.

Using GENFI participant engagement to inform observational research and clinical trials

AbstractBackgroundIt is vital that we include the views of individuals with frontotemporal dementia (FTD) and their families in the design of clinical trials. This study aims to establish what types of trials and treatments individuals with familial FTD would like to participate in.Methods135 participants from the GENFI cohort of at‐risk genetic FTD family members (34% of whom were known mutation carriers) completed a structured online questionnaire about clinical trials via Qualtrics. There was a total of 27 questions with a mix of multiple choice and free text questions. Topics included willingness to participate, understanding about likely proximity to symptom onset, and willingness to undertake different methods of therapeutic drug delivery including gene therapies.Results54% of individuals were definitely willing to participate in clinical trials with 39% stating it would depend on what the specific trial involved. Only 6% said they would not take part in a trial. The presence of a placebo group was a factor in trial participation with 31% stating they would decline to take part if there was a chance they did not receive the active drug. In light of a recent study suggesting plasma neurofilament light chain (NfL) may be a marker of proximity to symptom onset, we asked people if they would be willing to find out their NfL level as part of the trial, and 85% said they would. Most individuals said they would be willing to have IV infusions or lumbar punctures as part of the trial, although this did depend on the frequency with which they were required. For trials where drug administration would require more invasive measures, e.g. injections directly into the cisterna magna or the brain itself, only about 50% of people said they would be willing to take part. Lastly, if participation in a gene therapy trial precluded an individual from participating in future studies, only 30% said they would definitely consider being involved.ConclusionsObservational studies and clinical trials are designed to make a difference to people’s lives, and it is important to consider patients and family members throughout the development pipeline of treatments.

Examining longitudinal changes of disease severity scores in familial forms of frontotemporal dementia within the GENFI cohort

AbstractBackgroundThe CDR®+NACC FTLD Sum of Boxes (SB) score is a well‐established measure of disease severity in frontotemporal dementia (FTD), however, few studies have assessed longitudinal changes in score within familial forms of FTD.Method343 participants from the Genetic FTD Initiative (77 mutation‐negative controls, 109 C9orf72 expansion carriers, 105 GRN mutation carriers, and 52 MAPT mutation carriers), with available scores on the CDR®+NACC FTLD‐SB and the FTD Rating Scale (FRS) at baseline and follow‐up, were examined. Using the baseline FRS percentage scores, mutation carriers were stratified into four groups: asymptomatic/very mild (100‐97%), mild (96‐80%), moderate (79‐41%), and severe (40‐0%). Linear regression models with bootstrapping were used to assess annualised change in CDR®+NACC FTLD‐SB scores across genetic groups between participants' first and follow‐up visit.Result C9orf72 and GRN mutation carriers in the moderate and severe groups, as well as mild GRN carriers, showed significantly greater change than controls (p &lt; 0.050). No significant differences in change scores were observed between MAPT mutation carriers and controls. Comparisons within genetic groups revealed that both the moderate and severe GRN and C9orf72 expansion carriers showed larger annualised change relative to their asymptomatic/very mild counterparts (p &lt; 0.001 and p = 0.037; p = 0.028 and p &lt; 0.001, respectively). The moderate GRN and severe C9orf72 groups also demonstrated greater annualised score changes than their respective mild counterparts (p &lt; .001; p = 0.001). For MAPT mutation carriers, no significant changes were observed. Between genetic group comparisons revealed significant change score differences between the moderate individuals, with GRN mutation carriers showing a greater change than the C9orf72 and MAPT groups (both p &lt; 0.001), and the C9orf72 group showing a larger annualised change than the MAPT mutation carriers (p = 0.041).ConclusionThe CDR®+NACC FTLD‐SB detects significant changes in disease severity from baseline to a first follow‐up visit in familial forms of FTD, with GRN mutation carriers showing the greatest annualised change.

Altered plasma protein profiles in genetic FTD – a GENFI study

BackgroundPlasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia.MethodsBlood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins.ResultsWe found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers.ConclusionWe identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia.

Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline. We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p < 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p < 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p < 0.001), but conversion-free follow-up time varied greatly across participants. NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

ObjectiveTo identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. ConclusionsLanguage deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.

Hypothalamic volumes predict sleep dysfunction in genetic frontotemporal dementia

AbstractBackgroundSleep dysfunction is common in neurodegenerative disorders, however, its neural correlates, remain poorly characterized in genetic frontotemporal dementia (FTD). Atrophy in two hypothalamic nuclei, the suprachiasmatic nucleus and the lateral hypothalamic area, important for sleep regulation, may be related to this dysfunction. Thus, we examined changes in cerebral and hypothalamic structure across the lifespan in genetic FTD and their relations to measures of sleep dysfunction.MethodData was retrieved from the Genetic Frontotemporal Dementia Initiative (GENFI). T1‐weighted structural MRI images and scores on the Cambridge Behavioural Inventory‐Revised (CBI‐R) sleep subscale were obtained from subjects with mutations causative of FTD (n = 491, scan number = 1029) and healthy controls (n = 321, scan number = 739). MRI images were processed for cortical thickness using CIVET 2.1 and hypothalamic volumes using a deep learning segmentation algorithm (Billot et al., NeuroImage 2020). Using linear mixed‐effects models, we examined changes in sleep dysfunction, vertex‐wise differences in cortical thickness, and volumetric changes in hypothalamic regions in mutation carriers compared to controls. Further, using linear mixed‐effects models, we examined associations between cortical and hypothalamic atrophy and changes in the CBI‐R sleep subscale while controlling for age, sex, scanning site, and disease severity based on the MMSE.ResultMutation carriers showed greater sleep dysfunction across the lifespan, and this increased closer to the predicted onset of symptoms, compared to controls (p &lt; 0.01), with MAPT carriers having greater dysfunction overall (figure 1). All mutation carriers showed patterns of cortical thinning (figure 2) commensurate with the literature (p &lt; 0.05, FDR corrected). Further, cortical thinning in frontal and parietal regions were associated with greater sleep disturbance in C9orf72 and GRN mutation carriers (p &lt; 0.05, FDR corrected) (figure 3). Lastly, MAPT mutation carriers showed consistently significant hypothalamic volume loss across the lifespan (figure 4) (p &lt; 0.01) and reduced hypothalamic volumes were related to increased sleep dysfunction (p &lt; 0.05) (Figure 5).ConclusionThese findings suggest that while cortical thinning in C9orf72 and GRN carriers non‐specifically correlate with increased sleep dysfunction, the increased sleep dysfunction observed in MAPT carriers may be attributable to increased hypothalamic atrophy.

Longitudinal brain atrophy rates in presymptomatic genetic frontotemporal dementia

AbstractBackgroundIn light of upcoming clinical trials for genetic frontotemporal dementia (FTD), it is important to identify at what age brain atrophy rates start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We aimed to investigate longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD, using normative brain volumetry software.Method34 GRN, eight MAPT, and 14 C9orf72 presymptomatic mutation carriers underwent longitudinal volumetric T1‐weighted MRI of the brain with a one‐ to two‐year interval (mean number of scans = 3.5, SD = 1.6). Images were automatically analyzed with Quantib® ND which consisted of volume measurements (CSF and grey + white matter) of lobes (left, right, and combined), cerebellum, and hippocampus. All volumes were compared to reference centile curves based on a large population‐derived sample of non‐demented individuals (n = 4951). Mixed‐effects models were fitted to analyze atrophy rates of the different gene groups as a function of age, and were corrected for sex, head coil, and scanner software version.ResultAtrophy rates of the total brain, frontal lobe, and temporal lobe differed between gene groups (all p&lt;0.002). GRN mutation carriers declined faster than the reference centile curves for all brain areas, though relative volumes remained between 5th and 75th percentile between the ages of 45 – 70. In MAPT mutation carriers, frontal lobe volume was already at the 5th percentile at age 45, and showed further decline between the ages 50‐60. Temporal lobe volume started in the 50th percentile at age 45, but showed fastest decline over time compared to other brain structures. Frontal, temporal, parietal and cerebellar volume already started below the 5th percentile compared to the reference centile curves at age 45 for C9orf72 mutation carriers, but there was minimal decline over time until the age of 60.ConclusionWe provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease‐tracking and staging biomarkers in genetic FTD.

Reconfigured metabolism brain network in asymptomatic microtubule‐associated protein tau mutation carriers: A graph‐theoretical analysis

AbstractBackgroundStudies exploring topologic properties of the metabolic network in the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce, which may be important for understanding brain function and disease pathogenesis. This study aimed to explore FTD‐specific patterns of metabolism topology reconfiguration in asymptomatic microtubule‐associated protein tau (MAPT) mutation carriers.MethodSix asymptomatic carriers of MAPT P301L mutation were compared with 12 non‐carriers who were all from the same large family of FTD. For comparison, we included 32 behavioral‐variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and hybrid PET/MRI scan. Voxel‐wise gray matter volume and standardized uptake value ratio were calculated and compared for structural MRI and FDG‐PET, separately. The sparse inverse covariance estimation (SICE) method was applied to topologic properties and metabolic connectomes of brain functional networks derived from 18F‐fluorodeoxyglucose PET/MRI data. Independent component analysis was used to explore metabolic connectivity in the salience (SN) and default mode networks (DMN).ResultThe mean estimated years from symptom onset was 8.33 ± 1.875 years in the mutation carrier group. The asymptomatic MAPT carriers show no significant differences in cognitive tests, gray matter volume and FDG uptake compared to non‐carriers. They also retained normal global parameters of metabolism network, but not for bvFTD patients. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers, which is consistent with the findings in bvFTD patients. Similarly, significant differences in local parameters of these nodes were observed in asymptomatic carriers. The reduction in connectivity was marked in lost hub regions during the asymptomatic stage. Functional connectivity within the SN and DMN was enhanced in asymptomatic carriers, while reduced in bvFTD patients.ConclusionOur findings showed that asymptomatic MAPT carriers were initially involved in medial prefrontal areas and actively compensated in task‐related regions. Topologic properties of the metabolic network may contribute to further investigations and monitoring of the earliest stages of FTD in individuals with genetic backgrounds.