MAPT Mutations Research Articles

Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.Method317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.ResultFigure 1 shows significant (corrected p<.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p<.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.ConclusionFamilial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.

Deciphering the role of p‐tau, iron and MAOB in neurobiological basis of F18‐flortaucipir signal with voxel‐to‐voxel histology to PET analysis in different tauopathies

AbstractBackgroundFlortaucipir F18 was the first FDA approved PET tracer to detect tau pathology. Previous studies show that Flortaucipir is more sensitive to Alzheimer’s disease (AD) tau than four‐repeat tauopathies. Furthermore, the neurobiological basis of low Flortaucipir signal remain unclear, especially in basal ganglia. In this study, we aimed to identify the contributions of p‐tau (Ser 202), iron and MAOB to Flortaucipir signal in different tauopathies by performing voxel‐to‐voxel correlations between histological inclusion density maps and ante‐mortem flortaucipir PET uptake.MethodCoronal slides of ∼1cm thickness from four tauopathy cases (AD, progressive supranuclear palsy, corticobasal degeneration, and FTLD due to MAPT mutation P305S) and one FTLD‐TDP type‐A case were processed following a computational/histopathology pipeline (Ushizima, Chen, et al. 2021), allowing for whole 3D reconstruction of the histological maps at microscopical level, point‐by‐point aligned to their corresponding MRI T1 images (Figure 1). Serial 120 µm‐thick histological slides underwent immunohistochemistry to p‐tau (Ser 202, CP‐13) and MAOB, and Perl’s iron staining. Density of pathological changes per voxel (1.22×1.22×120um³) was measured using convolution neural network algorithm. Flortaucipir images were thresholded at 1.2 SUVR. Spearman’s bivariate and multiple linear regressions were used to compare Flortaucipir PET uptake to histological CP13/iron/MAOB counterparts. We examined both areas with high Flortaucipir PET uptake and high histological CP13/iron/MAOB burden.ResultTable 1 show patient features. Figure 2 depicts voxel‐to‐voxel correlations result in scatter plot and bivariate/multiple linear regression analysis.ConclusionThe correlation of CP13 (p‐Tau) to Flortaucipir was higher in AD than other tauopathies. Iron deposits contributed to Flortaucipir uptake in regions both with or without histopathologically confirmed p‐tau, including basal ganglia, whereas MAOB contribution was almost null in gray matter. The time gap between PET and autopsy and lower PET resolution compared to histology may explain the moderate regression coefficients, but other unexplored contributors cannot be discarded. Voxel‐to‐voxel histology to neuroimaging correlations allow for investigating multiple components of the neurological basis of PET. We are finalizing the regression analysis based on areas of high histological burden.

Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.Method317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.ResultFigure 1 shows significant (corrected p<.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p<.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.ConclusionFamilial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.

Preliminary Data on the Rural‐Urban Commuting Area Codes for the ALLFTD Cohort

AbstractBackgroundThe rural‐urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural‐urban distribution of participants may provide important insights for clinical trial planning.MethodsThe current RUCA codes are generated from the 2010 decennial census and the 2006‐10 American Community Survey data. The codes are numbers (1‐10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows.ResultsRUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia‐related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small‐town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small‐town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small‐town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small‐town, 2.8% rural.ConclusionsAdditional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design.

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.

Neurite‐based white matter alterations in MAPT mutation carriers: A multi‐shell diffusion MRI study in the ALLFTD consortium

AbstractBackgroundWe aimed to assess axonal integrity in MAPT mutation carriers and early white matter (WM) neurodegeneration in asymptomatic carriers using traditional diffusion tensor imaging (DTI) measurements, i.e., fractional anisotropy (FA) and mean diffusivity (MD), and neurite orientation dispersion and density imaging (NODDI).MethodWe included available multi‐shell diffusion MRI data from 21 MAPT mutation carriers (16 asymptomatic; 5 symptomatic) and 31 non‐carrier family members as controls from the ALLFTD consortium. We used linear mixed‐effect models to assess WM abnormalities measured with FA and MD, neurite density index (NDI) and orientation dispersion index (ODI), combined across hemispheres. Separate models were conducted in all MAPT mutation carriers relative to controls while accounting for relatedness and age, then in symptomatic and asymptomatic carriers relative to controls. ComBat was used to harmonize data across sites.ResultIn models contrasting all MAPT carriers versus controls, WM alterations involved the cingulum bundle (FA, ODI), fronto‐temporal, entorhinal (FA, MD, NDI), and the inferior temporal WM (FA) after correcting for multiple comparisons (Fig. 1). In models contrasting symptomatic and asymptomatic MAPT carriers versus controls, symptomatic carriers had widespread involvement of the fronto‐temporal WM including the cingulum (FA, ODI), entorhinal (MD, FA, NDI), amygdala (MD, NDI) and inferior temporal (FA) areas after correcting for multiple comparisons. Asymptomatic carriers showed higher entorhinal MD and lower inferior temporal and cingulum FA relative to controls, and a more widespread pattern of higher ODI involved the medial temporal, superior temporal and occipital WM as well as long association and projection fibers including the internal capsule, cingulate bundle and fronto‐occipital fasciculi, although they were not statistically significant after correction for multiple comparisons.ConclusionTraditional DTI and novel NODDI measurements revealed some extent of overlap as well as divergences in patterns of WM abnormalities, indicating axonal loss is a feature of neurodegeneration in MAPT mutation carriers. Our results suggest that traditional DTI and novel NODDI measurements may have different sensitivities to WM alterations in MAPT mutation carriers, and that axon‐based metrics, particularly ODI measurements, may be more sensitive to the early WM involvement during the asymptomatic stage of the disease.

Deciphering the role of p‐tau, iron and MAOB in neurobiological basis of F18‐flortaucipir signal with voxel‐to‐voxel histology to PET analysis in different tauopathies

AbstractBackgroundFlortaucipir F18 was the first FDA approved PET tracer to detect tau pathology. Previous studies show that Flortaucipir is more sensitive to Alzheimer’s disease (AD) tau than four‐repeat tauopathies. Furthermore, the neurobiological basis of low Flortaucipir signal remain unclear, especially in basal ganglia. In this study, we aimed to identify the contributions of p‐tau (Ser 202), iron and MAOB to Flortaucipir signal in different tauopathies by performing voxel‐to‐voxel correlations between histological inclusion density maps and ante‐mortem flortaucipir PET uptake.MethodCoronal slides of ∼1cm thickness from four tauopathy cases (AD, progressive supranuclear palsy, corticobasal degeneration, and FTLD due to MAPT mutation P305S) and one FTLD‐TDP type‐A case were processed following a computational/histopathology pipeline (Ushizima, Chen, et al. 2021), allowing for whole 3D reconstruction of the histological maps at microscopical level, point‐by‐point aligned to their corresponding MRI T1 images (Figure 1). Serial 120 µm‐thick histological slides underwent immunohistochemistry to p‐tau (Ser 202, CP‐13) and MAOB, and Perl’s iron staining. Density of pathological changes per voxel (1.22×1.22×120um³) was measured using convolution neural network algorithm. Flortaucipir images were thresholded at 1.2 SUVR. Spearman’s bivariate and multiple linear regressions were used to compare Flortaucipir PET uptake to histological CP13/iron/MAOB counterparts. We examined both areas with high Flortaucipir PET uptake and high histological CP13/iron/MAOB burden.ResultTable 1 show patient features. Figure 2 depicts voxel‐to‐voxel correlations result in scatter plot and bivariate/multiple linear regression analysis.ConclusionThe correlation of CP13 (p‐Tau) to Flortaucipir was higher in AD than other tauopathies. Iron deposits contributed to Flortaucipir uptake in regions both with or without histopathologically confirmed p‐tau, including basal ganglia, whereas MAOB contribution was almost null in gray matter. The time gap between PET and autopsy and lower PET resolution compared to histology may explain the moderate regression coefficients, but other unexplored contributors cannot be discarded. Voxel‐to‐voxel histology to neuroimaging correlations allow for investigating multiple components of the neurological basis of PET. We are finalizing the regression analysis based on areas of high histological burden.

Global platform trial design for tau (MAPT) mutation carriers

AbstractBackgroundPathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers.MethodALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD.ResultFive treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect.ConclusionPlatform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure.

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 < 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).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.

Galectin-3 is upregulated in frontotemporal dementia patients with subtype specificity.

Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential. We examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored. Gal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3. Our findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers.

Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia.

We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis. The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants. TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P<0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected. TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients.

Long non-coding RNA SNHG8 drives stress granule formation in tauopathies

Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer’s disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.

Omics profile of iPSC-derived astrocytes from Progressive Supranuclear Palsy (PSP) patients

IntroductionProgressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy and, to date, the pathophysiological mechanisms in PSP that lead to Tau hyperphosphorylation and neurodegeneration are not clear. In some brain areas, Tau pathology in glial cells appears to precede Tau aggregation in neurons. The development of a model using astrocyte cell lines derived from patients has the potential to identify molecules and pathways that contribute to early events of neurodegeneration. We developed a model of induced pluripotent stem cells (iPSC)-derived astrocytes to investigate the pathophysiology of PSP, particularly early events that might contribute to Tau hyperphosphorylation, applying omics approach to detect differentially expressed genes, metabolites, and proteins, including those from the secretome. MethodsSkin fibroblasts from PSP patients (without MAPT mutations) and controls were reprogrammed to iPSCs, further differentiated into neuroprogenitor cells (NPCs) and astrocytes. In the 5th passage, astrocytes were harvested for total RNA sequencing. Intracellular and secreted proteins were processed for proteomics experiments. Metabolomics profiling was obtained from supernatants only. ResultsWe identified hundreds of differentially expressed genes. The main networks were related to cell cycle re-activation in PSP. Several proteins were found exclusively secreted by the PSP group. The cellular processes related to the cell cycle and mitotic proteins, TriC/CCT pathway, and redox signaling were enriched in the secretome of PSP. Moreover, we found distinct sets of metabolites between PSP and controls. ConclusionOur iPSC-derived astrocyte model can provide distinct molecular signatures for PSP patients and it is useful to elucidate the initial stages of PSP pathogenesis.

A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3ʹ splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.

Epigenetic Age Acceleration in Frontotemporal Lobar Degeneration: A Comprehensive Analysis in the Blood and Brain.

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge, and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Mutation ∆K281 in MAPT causes Pick’s disease

Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas–Braak silver. They were not labelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of tau filaments was made of residues K254-F378 of 3R Tau and was indistinguishable from that of Pick’s disease. We conclude that MAPT mutation ∆K281 causes Pick’s disease.

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.

Phenoconversion and disease progression observed in mutation carriers of familial Frontotemporal Lobar Degeneration in the ALLFTD Consortium

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f‐FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention.Method169 f‐FTLD participants carrying mutations in the main FTLD‐associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD &gt; = 1) and “mild to overt” (0.5 to &gt; = 1).ResultDefinite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2‐4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow‐up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10).ConclusionLongitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD‐associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.