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INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. Highlights: 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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: 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). METHODS: 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). RESULTS: 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. DISCUSSION: 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. Highlights: 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. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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). Results: 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. Interpretation: A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage. [ABSTRACT FROM AUTHOR]

Background: Atrophy 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. Method: We 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. Result: The 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. Conclusion: We 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. [ABSTRACT FROM AUTHOR]

Neuroinflammation has been implicated in frontotemporal lobar degeneration (FTLD) pathophysiology, including in genetic forms with microtubule‐associated protein tau (MAPT) mutations (FTLD‐MAPT) or chromosome 9 open reading frame 72 (C9orf72) repeat expansions (FTLD‐C9orf72). Iron accumulation as a marker of neuroinflammation has, however, been understudied in genetic FTLD to date. To investigate the occurrence of cortical iron accumulation in FTLD‐MAPT and FTLD‐C9orf72, iron histopathology was performed on the frontal and temporal cortex of 22 cases (11 FTLD‐MAPT and 11 FTLD‐C9orf72). We studied patterns of cortical iron accumulation and its colocalization with the corresponding underlying pathologies (tau and TDP‐43), brain cells (microglia and astrocytes), and myelination. Further, with ultrahigh field ex vivo MRI on a subset (four FTLD‐MAPT and two FTLD‐C9orf72), we examined the sensitivity of T2*‐weighted MRI for iron in FTLD. Histopathology showed that cortical iron accumulation occurs in both FTLD‐MAPT and FTLD‐C9orf72 in frontal and temporal cortices, characterized by a diffuse mid‐cortical iron‐rich band, and by a superficial cortical iron band in some cases. Cortical iron accumulation was associated with the severity of proteinopathy (tau or TDP‐43) and neuronal degeneration, in part with clinical severity, and with the presence of activated microglia, reactive astrocytes and myelin loss. Ultra‐high field T2*‐weighted MRI showed a good correspondence between hypointense changes on MRI and cortical iron observed on histology. We conclude that iron accumulation is a feature of both FTLD‐MAPT and FTLD‐C9orf72 and is associated with pathological severity. Therefore, in vivo iron imaging using T2*‐weighted MRI or quantitative susceptibility mapping may potentially be used as a noninvasive imaging marker to localize pathology in FTLD. [ABSTRACT FROM AUTHOR]

Background: The 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. Method: 343 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 < 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 < 0.001 and p = 0.037; p = 0.028 and p < 0.001, respectively). The moderate GRN and severe C9orf72 groups also demonstrated greater annualised score changes than their respective mild counterparts (p <.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 < 0.001), and the C9orf72 group showing a larger annualised change than the MAPT mutation carriers (p = 0.041). Conclusion: The 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. [ABSTRACT FROM AUTHOR]

Background: Previous research in genetic frontotemporal dementia (FTD) has suggested that the FTD Rating Scale (FRS) may be a more sensitive measure of disease severity than the Clinical Dementia Rating scale plus National Alzheimer's Coordinating Centre Frontotemporal Lobar Degeneration score (CDR+NACC FTLD). This study aims to assess the potential of longitudinal measurement of the FRS to track disease trajectory, using data from the Genetic FTD Initiative (GENFI). Method: 119 mutation negative controls and 270 mutation carriers (52 MAPT, 107 GRN, 111 C9orf72) from the GENFI cohort completed the FRS at their baseline and follow‐up visits. Participants were grouped by disease severity according to their CDR+NACC FTLD global score at the baseline visit, which generated five mutation groups: asymptomatic (0), prodromal (0.5), mild (1), moderate (2), and severe (3), plus the control group. Annualised FRS change scores were generated for each participant (mean interval between visits = 1.3 years, standard deviation = 0.6). For each of the genetic groups, correlations with annualised change score for the MMSE and the CDR+NACC FTLD SOB were performed. Result: As disease becomes more severe, the annualised change in FRS was larger, peaking at the moderate stage: asymptomatic 0.6 (8.0), prodromal ‐5.1, (23.2), mild ‐7.2 (24.8), moderate ‐7.8 (11.6), severe ‐1.8 (8.2). The moderate group was significantly different from controls (p = 0.018) and the asymptomatic group (p = 0.030). The annualised change in FRS negatively correlated with the annualised change in CDR+NACC FTLD Sum of Boxes (Rho = ‐0.4, p<0.001) and positively correlated with the annualised change in MMSE (Rho = 0.3, p = 0.001) in GRN MCs but not in MAPT or C9orf72. Conclusion: The FRS shows promise as a sensitive clinical outcome measure, but only at certain stages of the disease. More sophisticated modelling utilising the wider GENFI cohort will help to establish the real potential for use in clinical settings. [ABSTRACT FROM AUTHOR]

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. Method: 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. Result: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Image‐based machine learning models are promising to aid diagnosis in dementia, e.g. by diagnostic classification or estimating cognitive performance. However, the contribution of vascular pathology is often ignored, although many patients have mixed pathologies. This may hamper model generalizability from research setting to clinical practice, as the models are generally developed on populations with lower vascular burden than is encountered clinically. This study aims to evaluate whether model generalizability is influenced by differences in vascular pathology load between training and test groups, represented by white matter hyperintensities (WMHs). Method: We developed a convolutional neural network to estimate cognitive performance through ADAS13. We included 4791 timepoints from 1632 ADNI subjects. To mimic differences in vascular burden between research and clinical populations, we split the data into a low, middle and high WMH load group using WMH ratio tertiles (WMH volume corrected for intracranial volume). The model was applied to maps derived from T1‐weighted and FLAIR brain MRI using voxel‐based morphometry: model 1 (gray matter density map (GMDM), age, sex), model 2 (GMDM, WMH density map (WMHDM), age, sex) and model 3 (GMDM, log(WMH ratio), age, sex) (Fig. 1). First, we trained all models on the low WMH load group, meaning to test on the high WMH load group to assess generalizability. Second, we trained models 1 and 2 on all data. Mean Absolute Error (MAE) served as the performance metric. Result: The models trained on the low WMH load group (MAE = 5.08 – 5.41) performed similar to constant value prediction (MAE = 5.63) (Fig. 2, circles). Using all data, models did train successfully (model 1: MAE = 5.64, model 2: MAE = 6.31, constant value: MAE = 7.39) (Fig. 2, crosses). Because of the suboptimal model training in the low WMH load group, especially for individuals with higher ADAS13 scores which were underrepresented in the data (Fig. 3), we could not evaluate generalizability to the high WMH load group. Conclusion: This study was unable to provide new insight into the influence of vascular pathology on the generalizability of machine learning models in dementia. More clinically representative data is needed, covering the full cognitive performance spectrum and higher vascular pathology loads. [ABSTRACT FROM AUTHOR]

Background: At present, there are limited fluid biomarkers which measure the underlying pathophysiology of frontotemporal dementia (FTD). Approximately a third of people with FTD have a genetic cause where the pathological basis is well understood. Studying fluid biomarkers in these genetic forms therefore allows greater insight into the relationship between the measure and the underlying disease mechanism. Based on prior work identifying synaptic and lysosomal dysfunction as common mechanisms across the different forms of FTD, we performed a targeted search of proteins related with synapses and the lysosomal pathway on an unbiased proteomic dataset generated from the GENetic FTD Initiative (GENFI) study. Method: The dataset was obtained from a total of 248 cerebrospinal fluid samples (CSF) from the GENFI cohort including 109 presymptomatic (44 C9orf72, 39 GRN, 26 MAPT) and 63 symptomatic (34 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 76 mutation‐negative controls where Tandem Mass Tag (TMT) proteomics had been performed. We selected the clusters obtained from a Gene Ontology analysis that corresponded to the terms "synapse" and "lysosome" and generated a list of proteins related to each category. We then analysed the differences in each specific protein between genetic groups. Result: A total of 42 of the synaptic proteins preselected were significantly changed in symptomatic MAPT mutation carriers, 70 in symptomatic GRN mutation carriers, and 92 in the symptomatic C9orf72 group. Among all of these, there were only 9 proteins that overlapped in the three genetic forms. This list included reelin, which was significantly decreased in each symptomatic group when compared to controls (MAPT p‐value = 0.0016, GRN = 0.0008, C9orf72 = 0.0064), and calretinin, which was significantly increased in symptomatic groups compared to controls (MAPT = 0.0260, GRN = 0.0000, C9orf72 = 0.0100). We then used the same approach to study lysosomal proteins, and found that 38 proteins were significantly changed in symptomatic MAPT, 31 in the symptomatic GRN group and 41 in symptomatic C9orf72 expansion carriers. Conclusion: This study provides new insights into candidate markers to assess synaptic and lysosomal dysfunction in FTD. [ABSTRACT FROM AUTHOR]

Background: Pathogenic 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. Method: Based 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. Result: Preliminary 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<0.0001), but no significant difference in the paragranulin region (p>0.33). Conclusion: These 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. [ABSTRACT FROM AUTHOR]

Background: Rare TREM2 variants are major risk factors for Alzheimer's disease (AD), but TREM2 variants may also confer a higher risk for other neurodegenerative diseases and a lower probability for cognitively healthy aging. We studied the TREM2 burden associated with different types of dementia and cognitively healthy centenarians (CHCs). Method: We included participants of the 100‐Plus Study, Amsterdam Dementia Cohort, Longitudinal Aging Study Amsterdam and various Dutch memory clinics. TREM2 variants (R47H, R62H, Q33X, R62C, T96K) were genotyped with a high density array or imputed using standard methods (TOPMED reference panel). To avoid family bias and ethnic differences, related individuals and those of non‐European ancestry were excluded. Frequencies of individual variants and the burden of TREM2 variants were compared in AD dementia, dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), cognitively normal controls and CHCs (correcting for 5 principal components). Result: We identified 242 carriers of TREM2 mutations and 6,683 controls without a TREM2 mutation with a mean age of 69 years (SD ±14 years), 50% female (Table 1). TREM2 variants were significantly associated with AD dementia (OR 1.4, 95%CI 1.1‐1.8, p = 0.01) (Table 2). R47H conferred the highest risk for AD (OR 2.8, 95%CI 1.4‐5.6, p = 0.004), compared to 1.3‐fold increased risk of R62H (95%CI 0.9‐1.7, p = 0.11). The carrier frequency was not increased in DLB (OR 1.4, 95%CI 0.7‐2.6, p = 0.34) and was not increased in FTD compared to controls (OR 0.59, 95%CI 0.3‐1.3, p = 0.18). Of interest, the allele frequency of TREM2 variants in centenarians is half of the expected frequency (OR = 0.46, 95%CI 0.1‐1.1, p = 0.10), and only concerns R62H. Conclusion: We replicate the association of TREM2 with increased risk of AD. In contrast to previous reports no association was observed with DLB or FTD. Cognitively healthy centenarians show a negative trend for TREM2 allele frequency suggesting that carrying a TREM2 variant decreases chances of survival to extreme age. [ABSTRACT FROM AUTHOR]

Background: Sleep 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. Method: Data 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. Result: Mutation carriers showed greater sleep dysfunction across the lifespan, and this increased closer to the predicted onset of symptoms, compared to controls (p < 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 < 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 < 0.05, FDR corrected) (figure 3). Lastly, MAPT mutation carriers showed consistently significant hypothalamic volume loss across the lifespan (figure 4) (p < 0.01) and reduced hypothalamic volumes were related to increased sleep dysfunction (p < 0.05) (Figure 5). Conclusion: These 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. [ABSTRACT FROM AUTHOR]

Introduction: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). Methods: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. Results: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. Discussion: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. Highlights: We investigated brain network predictors of dementia symptom onsetFrontotemporal dementia results in characteristic dynamic network patternsAlterations in network dynamics are associated with neuropsychological impairmentNetwork dynamic changes predict symptomatic conversion in presymptomatic carriersNetwork dynamic changes are associated with longitudinal cognitive decline [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia‐derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL‐40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation‐negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias‐corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini‐Mental State Examination (MMSE) score using non‐parametric partial correlations adjusting for age. Age‐adjusted z‐scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL‐40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL‐40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia‐derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials. [ABSTRACT FROM AUTHOR]

The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of Frontotemporal Lobar Degeneration (FTLD)–related disorders and their characteristics are not well known. The "FRONTotemporal dementia Incidence European Research Study" (FRONTIERS) is designed to fill this gap. Methods: FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long‐lasting experience in FTLD‐related disorders and comprehensive regional referral networks, enabling incidence estimation over well‐defined geographical areas. Endpoints: The primary endpoints are (1) the incidence of FTLD‐related disorders across Europe; (2) geographic trends of FTLD‐related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD‐related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. Expected impacts: FRONTIERS will improve the understanding of FTLD‐related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Development of endpoints for clinical trials in frontotemporal dementia (FTD) is increasingly urgent. In other neurodegenerative diseases composite scores are often used as outcome measures but are, as of yet, lacking in FTD. The aim of this study was to create gene‐specific cognitive composite scores for MAPT, GRN and C9orf72 mutation carriers and provide recommendations on recruitment and trial duration. Method: 69 C9orf72, 41 GRN, 28 MAPT mutation carriers with a CDR® plus NACC‐FTLD global score ≥0.5 and 275 controls completed a neuropsychological battery covering five cognitive domains. Logistic regression was used to identify the combination of tests that discriminated best between mutation carrier groups and controls. Weighted averages of the test scores in the models were calculated based on the regression coefficients (GENFI‐cog). Sample size estimates were calculated for individual tests and composite. The treatment effect was estimated as the mean difference between CDR® plus NACC‐FTLD 0.5 and 1 groups. Time‐to‐event analysis was used to determine the fraction of patients within GENFI that converted from CDR® plus NACC‐FTLD 0.5 to ≥1. Result: The most sensitive model in C9orf72 mutation carriers included a combination of executive, social cognitive and visuoconstructive tests (Table 1). A combination of executive, social cognitive, semantic and memory tests was most sensitive in GRN mutation carriers, and a combination of social cognitive, attention, semantic and memory tests in MAPT mutation carriers, resulted in the most sensitive model. The estimated sample size to detect a treatment effect was lower for the composite than for most individual tests (Table 2). A Kaplan‐Meier curve (Figure 1) showed that after three years 50% of individuals convert from CDR® plus NACC‐FTLD global score 0.5 to 1 or more. Conclusion: We created gene‐specific cognitive composite scores for C9orf72, GRN and MAPT mutation carriers (GENFI‐cog) which resulted in substantially lower estimated sample sizes to detect a treatment effect than most individual cognitive tests. Only 50% of patients with a CDR® plus NACC‐FTLD of 0.5 convert to ≥1 in a three‐year period. GENFI‐cog has potential as a cognitive endpoint for upcoming trials and the results from this study provide important information concerning trial duration and sample sizes. [ABSTRACT FROM AUTHOR]

Background: Connections among brain regions allow pathological perturbations to spread from a single source node to multiple nodes. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the network architecture (Seeley et al., 2009, Neuron), but how bvFTD‐related atrophy patterns relate to the network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture, such that connected regions display similar atrophy patterns. Method: Deformation‐based morphometry (DBM) was used to estimate regional changes in tissue volume density from T1‐weighted magnetic resonance images of 75 genetic bvFTD patients and 247 healthy controls (GENFI, http://genfi.org.uk/). We used linear mixed effects model to obtain a bvFTD‐related atrophy map, controlling for age, sex and aquision site. Structural and functional connectivity (SC and FC), derived from an independent sample of 70 healthy participants (Griffa et al., 2019, Zenodo), were used to estimate mean neighbor atrophy values of each region. Relationship between node and neighbor atrophy was examined by correlating neighbor atrophy with nodal atrophy. Statistical significance of the analyses was assessed using a spatial autocorrelation‐preserving null model. Analyses were replicated in an independent dataset (FTLDNI, AG032306) with 70 sporadic bvFTD patients and 123 healthy controls. Result: Distributed atrophy patterns were observed in bvFTD, mainly targeting areas associated with limbic intrinsic network and insular cytoarchitectonic class (Fig 1a). A node’s atrophy was significantly correlated with atrophy of its connected neighbors (e.g. high resolution: r=0.58, p=0.006 and r=0.54, p=0.0006, for SC‐ and FC‐ defined neighbors respectively) (Fig 2c). Relationship between node and neighbor atrophy was consistent across resolutions and greater in empirical networks compared to null networks. While a number of frontotemporal regions were identified as potential disease epicenters, anterior insula was the most likely one. Results were consistent in the sporadic cohort (Fig 1b&2d). Conclusion: Using connectivity models and rigorous statistical analyses that account for spatial autocorrelation, we demonstrate that bvFTD‐related neurodegeneration is conditioned by connectome architecture, accounting for 30‐40% of variance in atrophy. Atrophy is most profound in regions associated with insular cortex. [ABSTRACT FROM AUTHOR]

Background: Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for the majority of the inheritance: C9orf72, GRN and MAPT. Synaptic dysfunction is a common mechanism in all of them and the use of fluid biomarkers could be helpful to improve the diagnostic accuracy and useful as a readout of cellular dysfunction within therapeutic trials. Method: A total of 193 cerebrospinal fluid samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT), 55 symptomatic mutation carriers (26 C9orf72, 17 GRN, 12 MAPT) and 61 mutation‐negative controls were measured using a microflow LC PRM‐MS set‐up targeting 15 synaptic proteins: 14‐3‐3 proteins (eta, zeta/delta and epsilon), AP‐2 complex subunit beta, beta‐synuclein, gamma‐synuclein, complexin‐2, neurogranin, neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), neuronal pentraxin 2 (NPTX2), phosphatidylethanolamine‐binding protein 1 (PEBP‐1), rab GDP dissociation inhibitor α (rab GDIα), syntaxin‐1B and syntaxin‐7. Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Result: Eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: 14‐3‐3‐eta, beta‐synuclein, gamma‐synuclein, neurogranin, PEBP‐1, rab GDIα, syntaxin‐1B and syntaxin‐7. In contrast, NPTX1 and NPTX2 were affected in all three genetic groups (decreased compared to controls), with NPTXR being affected in C9orf72 and GRN mutation carriers only (decreased compared to controls). No changes were seen in presymptomatic mutation carriers in these proteins. Figure 1 contains p‐values for all significant changes. Conclusion: Differential involvement of synaptic markers is seen in the genetic forms of FTD, with impairment particularly in those with MAPT mutations, with only the neuronal pentraxins affected in GRN and C9orf72 mutation carriers. Further work is needed to explore correlations with clinical and imaging biomarkers, whether there are changes in the late presymptomatic period, and how these markers change over time. [ABSTRACT FROM AUTHOR]

Background: A 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. Method: We 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. Result: Altered 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. Conclusion: The 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 [ABSTRACT FROM AUTHOR]

Introduction: We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT). Methods: The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [C9orf72], 163 progranulin [GRN], and 73 microtubule‐associated protein tau [MAPT]) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel‐based morphometry to investigate the underlying neural substrates of the FCSRT. Results: All symptomatic mutation carrier groups and presymptomatic MAPT mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic C9orf72 group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic GRN mutation carriers. Performance on the FCSRT correlated with executive function, particularly in C9orf72 mutation carriers, but also with memory and naming tasks in the MAPT group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in C9orf72 and GRN, but mainly temporal areas in MAPT mutation carriers. Discussion: The FCSRT detects presymptomatic deficits in C9orf72‐ and MAPT‐associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD. [ABSTRACT FROM AUTHOR]

Background: Genetic frontotemporal dementia (FTD) is highly heterogeneous, with carriers of mutations in the same gene manifesting different phenotypes. Using in vivo MR images from the Genetic FTD Initiative (GENFI), we aimed to identify subgroups within the same genetic group whose brains were affected differently. Method: Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3T T1‐weighted MRI scans for 479 carriers (198 GRN, 202 C9orf72, and 79 MAPT mutation carriers). W‐scores for 85 volumes of interest were computed from a linear regression model carried out on 298 non‐carrier cognitively normal controls adjusting for the effect of age, sex, total intracranial volume and scanner type. Cluster analyses with the Ward agglomerating method were performed on all w‐scores while considering the three genetic groups independently. The identified clusters were then compared for age, estimated years from onset, global and sum of boxes scores of the CDR® plus NACC FTLD (at baseline and after one year), neurofilament light chain (NfL) levels in the plasma and w‐scores in brain regions typically showing early atrophy (Kruskal‐Wallis test). Result: We identified three clusters among the GRN mutation carriers and four in the MAPT and C9orf72 groups, which were all significantly different for the variables reported in the Table (p‐value<0.003). For all three genetic groups, one cluster was formed by patients with a clinical diagnosis of FTD, with more extensive atrophy and increased disease severity. For the remaining clusters, there seemed to be an association with disease severity for MAPT and GRN mutation carriers but not so for C9orf72 expansion carriers where clinical scores were not clearly associated with a specific cluster. Conclusion: By only looking at regional brain volumes, we were able to detect different clusters within carriers of mutations in the same gene, with C9orf72 expansion carriers being the most heterogenous group. Further investigations with specific cognitive, clinical and biomarkers correlates, including further follow‐up visits, are needed. [ABSTRACT FROM AUTHOR]

Background: Mutations in MAPT are associated with frontotemporal dementia (FTD), but little is known about the progression in its early stages. We aimed at identifying the presence of early brain changes in MAPT mutation carriers. Method: We included 3T MRIs from 84 MAPT carriers [27 symptomatic: mean(SD) age 58(8) years; 57 presymptomatic: 40(11) years] from the Genetic FTD Initiative (GENFI) and from 77 age‐matched non‐carrier healthy controls (44(14) years). Based on their expected years to symptom onset (EYO), we divided the presymptomatic carriers into early (n=35, <‐10 years) and late (n=22, >‐10 years) groups. First, we performed voxel‐based morphometry (VBM) comparing 24 symptomatic carriers with 32 controls to identify the regions of interest (ROIs) which were atrophic in the symptomatic stage of MAPT. We then used automated and manual segmentations to extract these ROI volumes in all carriers. To remove the effect of age, gender, total intracranial volume and scanner type, we transformed the volumes into w‐scores, considering the controls as the reference group. A w‐score of <‐1.28 (corresponding to the 10th percentile) was considered abnormal. Result: From the VBM we identified seven structures significantly atrophic in symptomatic carriers: the nucleus accumbens, amygdala, hippocampus, orbitofrontal cortex, temporal pole, anterior insula and hypothalamus. The percentage of early presymptomatic carriers with abnormal w‐scores was 14% for nucleus accumbens and hippocampus, and 20% orbitofrontal cortex. In the late group, 36% showed abnormal amygdala and temporal pole, 27% abnormal hippocampus, 32% abnormal anterior insula and 9% abnormal hypothalamus. In the symptomatic group, the percentages were higher: nucleus accumbens (41%), amygdala, hippocampus and temporal pole (85%), orbitofrontal cortex (56%), anterior insula (93%) and hypothalamus (48%). Conclusion: Abnormal limbic regions are a frequent feature in presymptomatic MAPT carriers, showing early structural changes before symptom onset. Further investigations on the associated cognitive and white matter changes are ongoing. [ABSTRACT FROM AUTHOR]

Background: Genetic frontotemporal dementia is highly heterogeneous, with different progression patterns seen between individuals. Using in vivo MR images from the Genetic FTD Initiative (GENFI), we aimed to identify clinical progression in genetic mutation carriers from their brain volumes at baseline. Method: Cortical and subcortical volumes of interest (VOIs) were generated using automated parcellation methods on volumetric 3T T1‐weighted MRI scans for 480 carriers (198 GRN, 202 C9orf72, 80 MAPT). W‐scores for 79 VOIs were computed from a linear regression model carried out on 298 non‐carrier cognitively normal controls adjusting for the effect of age, sex, total intracranial volume and scanner type. Carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score (CDR‐GS): asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). Cut‐off points for each VOI were derived from Youden indices estimated with ROC curves to distinguish between CDR‐GS=0 and CDR‐GS≥1 within each gene. CDR‐GS=0.5 carriers (30 GRN, 32 C9orf72, 13 MAPT) were classified as 'normal' or 'abnormal' based on these cut‐off points. We compared the CDR® plus NACC FTLD sum‐of‐boxes scores (CDR‐SOB) at one year follow‐up in these two groups. Result: Compared to those with normal baseline volumes, C9orf72 expansion carriers at CDR‐GS=0.5 showed significantly higher CDR‐SOB scores at follow‐up if they had abnormal volumes in the total frontal (+5 points), orbitofrontal (+3), dorsolateral prefrontal (+6), or anterior cingulate (+4) cortices, the basal‐paralaminar amygdala region (+2), CA1 region of the hippocampus (+4), total hippocampus (+6), cerebellar lobule VIIIb (+4), or lateral ventricles (+8). GRN mutation carriers showed significantly higher CDR‐SOB scores if their volumes were abnormal in the frontal (+10), parietal (+14), insula (+8), orbitofrontal (+12), or medial parietal (+7) cortices, or the total hippocampus (+10). MAPT mutation carriers with abnormal volumes in the lobule VI and dentate nucleus had 1 point higher CDR‐SOB scores at follow‐up. Conclusion: Abnormal baseline volumes in specific VOI within each of the genetic groups were related to worse CDR‐SOB scores over time. Future studies including longer follow‐up intervals and other longitudinal biomarkers are needed to explore this further. [ABSTRACT FROM AUTHOR]

Objective: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features.Methods: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors.Results: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002).Interpretation: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. ANN NEUROL 2020;87:950-961. [ABSTRACT FROM AUTHOR]

Background: In 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. Method: 34 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. Result: Atrophy rates of the total brain, frontal lobe, and temporal lobe differed between gene groups (all p<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. Conclusion: We 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. [ABSTRACT FROM AUTHOR]

Objective: To identify novel CSF biomarkers in GRN‐associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high‐resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor‐type tyrosine‐protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin‐A (CHGA), and V‐set and transmembrane domain‐containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN‐associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers. [ABSTRACT FROM AUTHOR]

Objective: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.Methods: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.Results: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%).Interpretation: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748. [ABSTRACT FROM AUTHOR]

Background: Genetic mutations in the microtubule‐associated protein tau (MAPT) cause frontotemporal lobar degeneration (FTLD‐MAPT), associated with severe frontotemporal atrophy antemortem, and highly heterogeneous tau immunoreactivity postmortem, with differential involvement of 3‐repeats (3R) or 4‐repeats (4R) tau isoforms. To date, there are limited data objectively measuring tau burden in FTLD‐MAPT, or directly comparing specific mutation groups. These novel data can help elucidate patterns of regional spread and associated neuronal loss, and shed light on pathologic heterogeneity in tauopathies. Method: We digitally quantified burden of AT8‐positive tau pathology using validated digital methods in a cohort of 35 FTLD‐MAPT autopsy cases with 9 different mutations (4R mutations: P301L=16, IVS10+16=4, N279K=1; 3R mutations: G272V=5; L266V=2; 3R+4R mutations: R406W=3; L315R=2; G389R=1; S320F=1). We examined the relationship between quantitative measurements of tau burden and ordinal scores of neuronal loss (0‐3) in a maximum of nine available grey matter (GM) regions. Regional analysis of tau burden was performed in a subset of six regions with most available data using linear mixed‐effects modeling, adjusting for disease duration and neuronal loss. Result: Overall, digitally quantified GM tau burden correlated positively with neuronal loss (beta=1.7, p<0.001), however a subset of GM samples (39/179, 22%) showed relatively low tau pathology in combination with severe neuronal loss. This was particularly prominent in specific mutations (χ2=33.0, p<0.001) irrespective of region, i.e. in 7/11 (64%) GM samples of L315R, 11/24 (46%) of G272V, and 2/6 (33%) of S320F, and showed some regional variability (χ2=34.9, p<0.001) across the cohort, occurring most frequently in the frontal (6/8, 75%) and temporal (9/20, 45%) pole. Regional analysis of tau burden in all FTLD‐MAPT found that maximally affected regions were the parahippocampal gyrus (PHG), anterior cingulate cortex (ACC) and temporal pole (TP) (F=53.5, p<0.001). Sub‐analyses found that 4R mutations were most affected in PHG and TP (F=29.7, p<0.001), while 3R mutations in ACC (F=13.0, p<0.001), and 3R+4R mutations in ACC and inferior parietal lobule (F=53.6, p<0.001). Conclusion: Heterogeneity in severity and distribution of pathology in FTLD‐MAPT may in part be related to underlying mutation and tau isoform conformation, which may help improve the understanding of disease pathogenesis and progression. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a group of young‐onset neurodegenerative syndromes characterized by changes in social cognition, behaviour, language, and psychiatric symptoms, the latter being increasingly recognized to be part of the early clinical presentation. The pathology of FTD, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR‐DNA binding protein 43 (TDP‐43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. Method: In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level in a cohort of 150 brain donors. The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features such as hallucinations and delusions, were scored and compared across pathological groups. Result: Our cohort consisted of 68.6% FTLD donors (35.3% TDP‐43, 28% tau, and 5.3% FUS) and 31.4% non‐FTLD donors with a clinical diagnosis of FTD and a different pathological substrate such as Alzheimer's disease (23%). The presence of hyperorality pointed to FTLD rather than non‐FTLD pathology (P < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP‐43 pathology (P = 0.02), including but not limited to C9orf72 repeat expansion carriers. The presence of perseverative or compulsive behaviour was more common in the TDP‐B and TDP‐C subtypes (P = 0.002). Conclusion: Our findings indicate that neuropsychiatric features are common in FTLD and can form an important indicator of underlying pathology. In order to further improve diagnostic accuracy and to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Background: Distinct pathologies accumulate in multiple brain regions (BR) and shape the heterogeneous clinical presentation of frontotemporal dementia (FTD). It is unknown how regional pathological burden links to symptoms, what the role of co‐occurring pathologies is, and whether the localization of pathology might be a bigger contributor to symptoms than the type of pathology. Our aim is to investigate how early FTD symptoms correlate to the burden of multiple pathologies throughout the brain. Method: Post‐mortem brain tissue of frontotemporal lobar degeneration (FTLD) donors from the Netherlands brain bank was dissected into twenty standard BR and stained for TAR DNA‐binding protein 43 (TDP‐43), tau, fused‐in‐sarcoma (FUS), amyloid‐beta (Aβ), and alpha‐synuclein. The burden of each pathological protein in each BR was quantified. All clinical records were reviewed to assess psychiatric, behavioral, language, and motor symptoms in the first three years from disease onset. Whole‐brain clinico‐pathological partial correlations were assessed using the heterogeneous correlation function (R 3.6.1). The local false discovery rate threshold was set at 0.01. Result: Eighty‐eight FTLD brain donors were studied, including 46 TDP‐43, 35 tau, and 7 FUS. Significant positive partial correlations (p < 0.01) were found between hippocampal TDP‐43 pathology and hallucinations (R = 0.23), perseverative‐compulsive behavior (R = 0.25), depression (R = 0.28), and mania (R = 0.32). Tau pathology in the substantia nigra and locus coeruleus was linked to depression (R = 0.25, R = 0.24). Both TDP‐43 and Aβ in the subthalamus were associated with severe disinhibition (R = 0.23, R = 0.25), while apathy correlated with both TDP‐43 and tau burden in the parietal lobe (R = 0.27, R = 0.24). Parkinsonism was linked to TDP‐43 burden in the substantia nigra (R = 0.33). Conclusion: Neuropsychiatric symptoms of FTD are linked to pathology burden in BR beyond the frontal lobes, including subcortical structures such as the hippocampus, the substantia nigra and locus coeruleus. Co‐occurring pathologies are not simple bystanders, but could play a role in configuring FTD clinical phenotype. Different pathologies in the same BR correlate with the same symptoms. [ABSTRACT FROM AUTHOR]

Background: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by impaired word comprehension and semantic memory. The consistent neuropathological diagnosis is FTD‐TDP subtype C, with TDP‐43 protein aggregates in the temporal cortex and dentate gyrus of the hippocampus. Despite this striking clinicopathological concordance, the pathophysiological mechanisms remain largely unknown. Method: We assessed the relative protein abundance changes in laser capture micro‐dissected dentate gyrus of 15 SD patients and 14 age‐ and sex‐matched non‐demented controls using a label‐free quantitative proteomics approach. We identified proteins and biological pathways that might be uniquely altered in SD, by comparing to 9 other large FTD and Alzheimer's Disease (AD) proteomics datasets of cortical brain tissue. Validation experiments on selected candidate proteins are ongoing, including immunoblotting. Result: 145 of all 2414 detected proteins showed differential abundance (FDR<5%) in SD patients. 73 proteins were observed in at least 2 other proteomics studies in FTD/AD. The remaining 72 proteins (29 not observed, 43 in 1 out of 9 studies) were regarded as potentially SD specific and selected for further analyses. Functional enrichment revealed an overrepresentation of the cell‐cell adherens junction and the cadherin‐catenin complex, represented by multiple upregulated proteins within this complex, including CDH2/N‐cadherin, CTNNB1/β‐catenin, and JUP/plakoglobin. Conclusion: Our findings indicate an SD specific upregulation of cell adhesion proteins constituting the cadherin‐catenin complex at the synaptic membrane. Validation of several proteins by immunoblotting is currently being performed. This study contributes to an improved understanding of the disease processes in SD, and demonstrates the value of quantitative proteomics to differentiate the pathophysiological mechanisms of specific subtypes of dementia. [ABSTRACT FROM AUTHOR]