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Background Behavioral variant frontotemporal dementia (bvFTD) is the most common clinical presentation of FTD with considerable genetic and neuropathological heterogeneity. Here, we characterize a large cohort (n = 410) at Penn to gain new insights into bvFTD pathology and genetics in light of advances in our understanding of disease. Method Individuals meeting Rascovsky bvFTD criteria were included; individuals with primary ADNC or LBD were excluded. We characterize familial risk via 3‐generation pedigrees by Wood Criteria, report known monogenic variants, and perform a gene burden analysis to evaluate the impact of rare variants on bvFTD. We also characterize neuropathological features in a subset of individuals (n = 88). Result 410 bvFTD cases were identified, 56.3% male; mean age was 62.6 years (+/‐ 7.8); mean CDR FTLD SB was 9.0 (+/‐ 3.7). Wood's risk scoring identified 21.4% apparent sporadic; 17.8% high; 11.4% medium; 14.6% low; and 21.7% unknown familial risk, yielding a prediction of 74 genetic cases within the cohort; 107 monogenic cases were identified. In available neuropathologic data (n = 88), 59.1% were FTLD‐TDP, 39.8% FTLD‐Tau, and 1.1% FTLD‐FET. The most common secondary pathologies were ADNC (27.3%), no pathology (25%), and secondary FTLD pathology (22.7%). Secondary ADNC was slightly higher in FTLD‐Tau (31.4%) vs. FTLD‐TDP (25%); rates of any ADNC was 37% in FTLD‐Tau and 50% in FTLD‐TDP. There were 6 APOE e4/e4 carriers in the autopsy cohort, but none with ADNC. The MAPT H1/H1 haplotype was more prevalent in FTLD‐Tau (77.8%) vs. FTLD‐TDP (62%). Conclusion Our findings are consistent with previous reports indicating approximately 60% of bvFTD cases are FTLD‐TDP with slight male predominance. Surprisingly, we found high rates of co‐pathology—specifically ADNC. This was more common in FTLD‐TDP than FTLD‐Tau and not associated with APOE e4 homozygosity. High rates of clinically relevant ADNC have increasing relevance because of newly‐available disease‐modifying therapies. We found a relative MAPT H1 risk haplotype enrichment in FTLD‐Tau compared to FTLD‐TDP. We identified a 44.6% greater‐than‐expected number of monogenic cases, suggesting that bvFTD is relatively enriched for familial forms compared to the full FTD spectrum. Future work will focus on gene burden analysis to identify rare variants that contribute to disease

Behavioral variant frontotemporal dementia (bvFTD) is the most common clinical presentation of FTD with considerable genetic and neuropathological heterogeneity. Here, we characterize a large cohort (n = 410) at Penn to gain new insights into bvFTD pathology and genetics in light of advances in our understanding of disease. Individuals meeting Rascovsky bvFTD criteria were included; individuals with primary ADNC or LBD were excluded. We characterize familial risk via 3-generation pedigrees by Wood Criteria, report known monogenic variants, and perform a gene burden analysis to evaluate the impact of rare variants on bvFTD. We also characterize neuropathological features in a subset of individuals (n = 88). 410 bvFTD cases were identified, 56.3% male; mean age was 62.6 years (+/- 7.8); mean CDR FTLD SB was 9.0 (+/- 3.7). Wood's risk scoring identified 21.4% apparent sporadic; 17.8% high; 11.4% medium; 14.6% low; and 21.7% unknown familial risk, yielding a prediction of 74 genetic cases within the cohort; 107 monogenic cases were identified. In available neuropathologic data (n = 88), 59.1% were FTLD-TDP, 39.8% FTLD-Tau, and 1.1% FTLD-FET. The most common secondary pathologies were ADNC (27.3%), no pathology (25%), and secondary FTLD pathology (22.7%). Secondary ADNC was slightly higher in FTLD-Tau (31.4%) vs. FTLD-TDP (25%); rates of any ADNC was 37% in FTLD-Tau and 50% in FTLD-TDP. There were 6 APOE e4/e4 carriers in the autopsy cohort, but none with ADNC. The MAPT H1/H1 haplotype was more prevalent in FTLD-Tau (77.8%) vs. FTLD-TDP (62%). Our findings are consistent with previous reports indicating approximately 60% of bvFTD cases are FTLD-TDP with slight male predominance. Surprisingly, we found high rates of co-pathology-specifically ADNC. This was more common in FTLD-TDP than FTLD-Tau and not associated with APOE e4 homozygosity. High rates of clinically relevant ADNC have increasing relevance because of newly-available disease-modifying therapies. We found a relative MAPT H1 risk haplotype enrichment in FTLD-Tau compared to FTLD-TDP. We identified a 44.6% greater-than-expected number of monogenic cases, suggesting that bvFTD is relatively enriched for familial forms compared to the full FTD spectrum. Future work will focus on gene burden analysis to identify rare variants that contribute to disease.

Frontotemporal dementia (FTD) can arise from frontotemporal lobar degeneration (FTLD) driven by distinct proteinopathies, such as tau (FTLD-tau) or TDP-43 (FTLD-TDP), which can lead to remarkably similar clinical syndromes. Previous research (PMID:34997851) identified a predominance of tau pathology in the lower cortical layers and TDP-43 pathology in the upper cortical layers. The aim of the present study was to investigate the effect of laminar distribution of pathology on cortical architecture using cortical diffusivity metrics. Forty cases with a primary bvFTD clinical phenotype and autopsy confirmation from Penn Frontotemporal Degeneration Center were included in the study. The patients were grouped based on the primary neuropathological diagnosis: 20 FTLD-tau and 20 FTLD-TDP (Table-1). Structural and diffusion MRI (dMRI) were used to calculate whole-brain and regional cortical diffusivity measures. For each cortical region and for four macroregions (idiotypic M1, paralimbic association, association and idiotypic V1) previously explored (PMID:34997851) (Figure 1), a minicolumn-inspired cortical diffusivity measure that combines the components perpendicular to the radial minicolumns (PerpPD ) was calculated (PMID:36281682). Previous findings have shown that this measure is sensitive to tau neuropathology (PMID:37794477). For a subgroup of 17 cases, ratios of layer pathology (RLP) in four cortical regions (Figure-1) were generated. Differences in diffusion metrics at regional and macroregional level were tested with a linear model adjusting for interval between MRI scan date and autopsy date, acquisition protocol, disease duration, age and sex, with false discovery rate correction (pFDR<0.05). Partial Spearman's rank correlation was conducted, including cases from both groups, to investigate the relationship between regional PerpPD and RLP values. Regional analysis showed a significant pattern of higher PerpPD values in FTLD-tau group, involving mainly fronto-temporal regions (Figure-2). Macroregion comparisons revealed higher PerpPD in bilateral paralimbic and right association regions (Figure-1). Correlation analysis identified significant associations between ratio (RLP) values and PerpPD values in anterior cingulate, superior/middle temporal and primary visual cortex (Figure-1). Regional differences suggest that PerpPD can distinguish cortical microstructural changes in FTLD due to tau vs. TDP-43. The correlation between PerpPD values and laminar pathology ratios reinforces that PerpPD is an MRI marker sensitive to tau pathology distribution.

Transactive response DNA binding protein of 43 kDa (TDP-43) aggregates are observed in cognitive disorders of aging including frontotemporal lobar degeneration (FTLD- TDP) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Convergence and divergence in the genetic architecture of these disorders remains unclear. To further elucidate genetic modifiers of FTLD-TDP versus LATE-NC, we evaluated how genetic variants previously associated with TDP-43 proteinopathy relate to neuropathological diagnosis. We identified 393 individuals in the Penn Integrated Neurodegenerative Disease Database with: (1) neuropathological diagnosis of FTLD-TDP or LATE-NC; (2) ABC score of Alzheimer's disease neuropathologic change (ADNC); (3) SNP genotyping; (4) no pathogenic mutation (GRN, C9orf72, etc.); and (5) self-reported White race (Table 1). We evaluated 14 genetic variants (MAF > 0.1, missingness < 20%) previously associated with autopsy-confirmed FTLD-TDP, LATE-NC, or regional TDP-43 pathology, comparing SNP frequency between the FTLD-TDP and LATE-NC groups using binomial logistic regression with additive models covarying for sex and ABC score (Table 2). We excluded FTLD-TDP cases of type C or unspecified histological type in a sensitivity analysis. Most LATE-NC cases (78%) showed intermediate/high ADNC. Adjusting for sex and ADNC level, we observed higher frequency of rs12973192-G (UNC13A, β = 0.61±0.25, p = 0.013) and lower frequency of rs12425381-G (RERG, β = -0.68±0.30, p = 0.024) in FTLD-TDP versus LATE-NC at a nominal level of significance (p < 0.05). The remaining variants we studied did not differ in allele frequency between FTLD-TDP and LATE-NC after adjusting for sex and ADNC level. Excluding known and possible FTLD-TDP type C cases strengthened the associations of rs12973192-G and rs12425381-G but did not yield new associations. A variant in UNC13A appears to increase risk of FTLD-TDP relative to LATE-NC, while a variant in RERG appears to decrease risk; this is directionally concordant with previously reported associations of these variants with FTLD-TDP versus healthy controls. The potential implications of polygenic contributions to prognosis are an important area for future investigation.

Background Transactive response DNA binding protein of 43 kDa (TDP‐43) aggregates are observed in cognitive disorders of aging including frontotemporal lobar degeneration (FTLD‐ TDP) and limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC). Convergence and divergence in the genetic architecture of these disorders remains unclear. To further elucidate genetic modifiers of FTLD‐TDP versus LATE‐NC, we evaluated how genetic variants previously associated with TDP‐43 proteinopathy relate to neuropathological diagnosis. Methods We identified 393 individuals in the Penn Integrated Neurodegenerative Disease Database with: (1) neuropathological diagnosis of FTLD‐TDP or LATE‐NC; (2) ABC score of Alzheimer’s disease neuropathologic change (ADNC); (3) SNP genotyping; (4) no pathogenic mutation (GRN, C9orf72, etc.); and (5) self‐reported White race (Table 1). We evaluated 14 genetic variants (MAF > 0.1, missingness < 20%) previously associated with autopsy‐confirmed FTLD‐TDP, LATE‐NC, or regional TDP‐43 pathology, comparing SNP frequency between the FTLD‐TDP and LATE‐NC groups using binomial logistic regression with additive models covarying for sex and ABC score (Table 2). We excluded FTLD‐TDP cases of type C or unspecified histological type in a sensitivity analysis. Result Most LATE‐NC cases (78%) showed intermediate/high ADNC. Adjusting for sex and ADNC level, we observed higher frequency of rs12973192‐G (UNC13A, β = 0.61±0.25, p = 0.013) and lower frequency of rs12425381‐G (RERG, β = –0.68±0.30, p = 0.024) in FTLD‐TDP versus LATE‐NC at a nominal level of significance (p < 0.05). The remaining variants we studied did not differ in allele frequency between FTLD‐TDP and LATE‐NC after adjusting for sex and ADNC level. Excluding known and possible FTLD‐TDP type C cases strengthened the associations of rs12973192‐G and rs12425381‐G but did not yield new associations. Conclusion A variant in UNC13A appears to increase risk of FTLD‐TDP relative to LATE‐NC, while a variant in RERG appears to decrease risk; this is directionally concordant with previously reported associations of these variants with FTLD‐TDP versus healthy controls. The potential implications of polygenic contributions to prognosis are an important area for future investigation.

Background Frontotemporal dementia (FTD) can arise from frontotemporal lobar degeneration (FTLD) driven by distinct proteinopathies, such as tau (FTLD‐tau) or TDP‐43 (FTLD‐TDP), which can lead to remarkably similar clinical syndromes. Previous research (PMID:34997851) identified a predominance of tau pathology in the lower cortical layers and TDP‐43 pathology in the upper cortical layers. The aim of the present study was to investigate the effect of laminar distribution of pathology on cortical architecture using cortical diffusivity metrics. Method Forty cases with a primary bvFTD clinical phenotype and autopsy confirmation from Penn Frontotemporal Degeneration Center were included in the study. The patients were grouped based on the primary neuropathological diagnosis: 20 FTLD‐tau and 20 FTLD‐TDP (Table‐1). Structural and diffusion MRI (dMRI) were used to calculate whole‐brain and regional cortical diffusivity measures. For each cortical region and for four macroregions (idiotypic M1, paralimbic association, association and idiotypic V1) previously explored (PMID:34997851) (Figure 1), a minicolumn‐inspired cortical diffusivity measure that combines the components perpendicular to the radial minicolumns (PerpPD+) was calculated (PMID:36281682). Previous findings have shown that this measure is sensitive to tau neuropathology (PMID:37794477). For a subgroup of 17 cases, ratios of layer pathology (RLP) in four cortical regions (Figure‐1) were generated. Differences in diffusion metrics at regional and macroregional level were tested with a linear model adjusting for interval between MRI scan date and autopsy date, acquisition protocol, disease duration, age and sex, with false discovery rate correction (pFDR<0.05). Partial Spearman’s rank correlation was conducted, including cases from both groups, to investigate the relationship between regional PerpPD+ and RLP values. Result Regional analysis showed a significant pattern of higher PerpPD+ values in FTLD‐tau group, involving mainly fronto‐temporal regions (Figure‐2). Macroregion comparisons revealed higher PerpPD+ in bilateral paralimbic and right association regions (Figure‐1). Correlation analysis identified significant associations between ratio (RLP) values and PerpPD+ values in anterior cingulate, superior/middle temporal and primary visual cortex (Figure‐1). Conclusion Regional differences suggest that PerpPD+ can distinguish cortical microstructural changes in FTLD due to tau vs. TDP‐43. The correlation between PerpPD+ values and laminar pathology ratios reinforces that PerpPD+ is an MRI marker sensitive to tau pathology distribution.

Traumatic brain injury (TBI) is recognized as one major, potentially modifiable risk factor for neurodegenerative disease (NDD). Autopsy studies describe a range of neuropathologies in a proportion of individuals surviving late after TBI, most frequently the tau associated pathology, chronic traumatic encephalopathy neuropathologic change (CTE-NC). In addition to tau, other NDD pathologies are described. Of these, deposition of abnormally phosphorylated transactive response DNA-binding protein 43 (pTDP-43) has been reported in association with CTE-NC. However, to date the prevalence and distribution of pTDP-43 in CTE-NC and its distinction from pathology of wider NDD has not been formally assessed. Patients with history of exposure to repetitive mild traumatic brain injury (rmTBI) and documented NDD (n = 30), together with age-matched controls with no known TBI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT-TBI archive. Whole slide digital images of standardized brain tissue sections stained for pTDP-43 (1D3) were reviewed, and the pattern and distribution of pathology mapped. Overall, prevalence of pTDP-43 pathology was similar among rmTBI patients (40%) and their age-matched controls with NDD (33%; p = 0.7778). However, while pTDP-43 was typically localized in controls with NDD and in rmTBI patients without CTE-NC (limbic-predominant age-related TDP-43 encephalopathy [LATE] stage 1-2), in patients with CTE-NC this pathology was more often widespread and high stage (LATE stage 3; p = 0.0045). These results demonstrate rmTBI is associated with higher stage LATE pathology than in equivalent age matched controls and individuals with wider, non-TBI related NDD. Further studies are required to characterize the association between TBI and TDP-43 proteinopathy, including the contribution, if any, of this pathology to clinical sequelae of TBI related neurodegenerative disease.

There is considerable variability in the rate of clinical progression among individuals with frontotemporal dementia (FTD) and prognostic markers are lacking. Moreover, due to the rarity of postmortem data, the relationship between rate of progression and postmortem tau and TDP-43 proteinopathy is understudied. To explore the pathologic underpinnings of differences in clinical progression of FTD, we used clinical data collected by the Penn Center for Neurodegenerative Disease Research from 130 patients with autopsy-confirmed frontotemporal lobar degeneration (FTLD-tau = 62, FTLD-TDP = 68) across six domains (age at onset, survival in years, first Clinical Dementia Rating [CDR] scale score, first Mini-Mental State Examination [MMSE] score, annual change in CDR, annual change in MMSE). We used principal components analysis to scale and collapse these data into two dimensions, and k means to automatically select three clusters based on silhouette width. We used automated digital pathology to measure mean percent area occupied (AO%) by TDP-43 pathologic inclusions in up to 17 distinct autopsied brain regions. PCA (Fig 1A) Cluster 3 progressed relatively fastest and was enriched for FTLD-TDP cases and GRN mutation carriers (Table 1). Among FTLD-TDP cases, TDP type E was enriched in cluster 3 (3 of 4) and type C was enriched in cluster 1 (13 of 16). Among FTLD-tau cases, progressive supranuclear palsy was overrepresented in cluster 1 (19 of 20). Principal component 1 (PC1) negatively correlated with independent measures of functional outcomes extracted from the clinical record, including the time to develop incontinence and complete dependence in activities of daily living (Figure 1B, C). PC1 correlated with the average pathologic TDP-43 AO% in FTLD-TDP cases (Figure 2). Taken together, these results suggest that increased rate of clinical progression may relate to increased burden of TDP-43 observed postmortem. The heterogeneity in the prognosis of FTLD may be driven by biological factors, such as disease activity. Further, FTLD-TDP (especially FTLD-GRN) may associate with faster progression. Biomarkers of FTLD-TDP and/or improved access to mutation testing may improve prognostication in the care of FTD.

Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) constitute a clinicopathologic spectrum with multifaceted heterogeneities. Brain transcriptomics may help to identify molecular subtypes of FTD and/or ALS but this testing is only possible at autopsy and thus is cross-sectional and representative of end-stage disease. Subtype and Stage Inference (SuStaIn) is an unsupervised machine-learning algorithm that was employed to identify temporal dynamics of data-driven subtypes of ALS and FTD. We utilized transcriptomic RNA-seq data from frontal cortex tissue provided by the NYGC ALS Consortium including individuals with FTD (n = 27), ALS (n = 118), ALS-FTD (n = 23), and non-neurological controls (n = 42). After quality control, 19,817 genes were adjusted for age, sex, RIN, contributing site, and cell-type proportion. Weighted gene co-expression network analysis (WGCNA) constructed co-expression modules and the module eigengene of each module was compared between FTD-ALS and controls. The significantly up-regulated or down-regulated modules underwent functional enrichment analyses for biological annotations. We then utilized the gene expression profiles of significant modules to train the SuStaIn model to identify molecular subtypes with distinct gene expression trajectories. WGCNA identified 16 modules, of which 9 were differentially expressed in case-control comparisons with functional enrichment in pathways such as \"neuronal system\", \"nucleic acid metabolism\", \"protein biosynthesis and metabolism\", \"immune system\", and \"mitochondrion\" (Fig. 1). The SuStaIn model identified three novel molecular subtypes (Fig. 2): one had early evidence of altered gene expression in \"protein biosynthesis and metabolism\" and \"mitochondrion\" (ProteoMetabolic/Mitochondrial subtype); another initially involved pathways related to \"neuronal system\", and \"nucleic acid metabolism\" (Neuronal/NucleoMetabolic subtype); and one subtype had initial involvement of \"immune system\" (Immune subtype). The ProteoMetabolic/Mitochondrial and Neuronal/NucleoMetabolic subtypes had lower frequencies of ALS compared to the Immune subtype which had a lower frequency of FTD and ALS-FTD. Moreover, the Immune subtype exhibited a higher frequency of bulbar-onset and lower frequency of cognitive-onset than the other two subtypes. Our results revealed three data-driven molecular subtypes within the FTD-ALS spectrum with distinct patterns of early gene pathway involvement. This may contribute to further understanding of potential molecular mechanisms driving some of the heterogeneity and provides the first application of SuStaIn in identifying temporal dynamics of brain transcriptomics.

Background Telomeres are repetitive DNA sequences at the ends of chromosomes which contribute to maintaining chromosomal stability. Telomere shortening is a hallmark of aging and shorter blood leukocyte telomere length (LTL) has been associated with increased risk for age‐related diseases, however, little is understood about the biology of brain telomeres and how they may be involved in disease. Considering the increased neuropathologic burden of phosphorylated tau (ptau) with age, we investigated how shorter brain telomere length (brain‐TL) may relate to increased ptau burden. Methods We studied a cohort of 112 individuals with primary age‐related tauopathy (PART), a neuropathological diagnosis characterized by mild‐to‐moderate tau burden (Braak=I‐IV) primarily in the medial temporal lobe, with the relative absence of amyloid‐beta plaques (CERAD=0). These individuals had both brain‐TL (mean length by telomere qPCR, blinded) and DNA methylation measures from the frontal cortex, along with semi‐quantitative Aperio ptau measures from the hippocampus. A subset (n = 81) had SNP genotyping data available. In an independent cohort (n = 10, Braak=0‐VI, CERAD=0‐3), we performed quantitative fluorescence in‐situ hybridization (FISH) microscopy to measure the average ratio of telomere to centromere DNA content in nuclei from the frontal and visual cortices. Results In linear regression models, frontal cortex brain‐TL did not relate to age. When age‐adjusted, shorter brain‐TL related to higher hippocampal ptau (β=‐1.06, CI=‐1.92–‐0.195, p = 0.017). A previously established DNA methylation model predictive of hippocampal ptau partially mediated the relationship between brain‐TL and hippocampal ptau (proportion mediated=0.664, CI=0.246–1.33, p = 0.012, Figure 1). A polygenic score for LTL did not relate to either age, brain‐TL or hippocampal ptau. With FISH, we observed that individuals with CERAD=0 had shorter telomeres in the frontal cortex compared to individuals with CERAD=3. Within the CERAD=0 group, an individual with Braak=II had shorter telomeres than an individual with Braak=I. These patterns were not observed in the visual cortex. Conclusions In a PART cohort, shorter frontal cortex brain‐TL was related to higher hippocampal ptau, and this relationship was partially mediated by a DNA methylation model predictive of hippocampal ptau. A polygenic score for LTL was not predictive of brain‐TL or hippocampal ptau. Together, this further emphasizes the importance of tissue‐specific epigenetic modifiers of age‐related ptau neuropathology.