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BACKGROUND AND OBJECTIVES: Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. METHODS: In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline. RESULTS: We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p < 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p < 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p < 0.001), but conversion-free follow-up time varied greatly across participants. DISCUSSION: NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.
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Demência Frontotemporal , Doença de Pick , Humanos , Biomarcadores , Proteína C9orf72/genética , Estudos de Coortes , Estudos Transversais , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Filamentos Intermediários , Proteínas de Neurofilamentos , Proteínas tau/genéticaRESUMO
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.
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Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Proteína C9orf72/genética , Doenças Neuroinflamatórias , Progranulinas , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Proteínas tau/metabolismo , Proteínas de Ligação a DNA/metabolismoRESUMO
BACKGROUND: Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers. METHODS: We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). RESULTS: CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores. CONCLUSIONS: Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.
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Demência Frontotemporal , Doença de Pick , Biomarcadores , Proteína C9orf72/genética , Estudos de Coortes , Complemento C1q , Proteínas do Sistema Complemento/genética , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , HumanosRESUMO
Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.
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Demência Frontotemporal , Biomarcadores , Proteína C9orf72/genética , Complemento C1q , Estudos Transversais , Progressão da Doença , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Proteína Glial Fibrilar Ácida , Humanos , Estudos Longitudinais , Mutação , Proteínas tau/genéticaRESUMO
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder clinically characterized by behavioral, language, and motor symptoms, with major impact on the lives of patients and their families. TDP-43 proteinopathy is the underlying neuropathological substrate in the majority of cases, referred to as FTLD-TDP. Several genetic causes have been identified, which have revealed some components of its pathophysiology. However, the exact mechanisms driving FTLD-TDP remain largely unknown, forestalling the development of therapies. Proteomic approaches, in particular high-throughput mass spectrometry, hold promise to help elucidate the pathogenic molecular and cellular alterations. In this review, we describe the main findings of the proteomic profiling studies performed on human FTLD-TDP brain tissue. Subsequently, we address the major biological pathways implicated in FTLD-TDP, by reviewing these data together with knowledge derived from genomic and transcriptomic literature. We illustrate that an integrated perspective, encompassing both proteomic, genetic, and transcriptomic discoveries, is vital to unravel core disease processes, and to enable the identification of disease biomarkers and therapeutic targets for this devastating disorder.
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Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Proteinopatias TDP-43/metabolismo , Animais , Humanos , Proteômica/métodosRESUMO
OBJECTIVE: Progranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way. METHODS: We included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes. RESULTS: Language functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA. CONCLUSION: Degeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.
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Cognição/fisiologia , Demência Frontotemporal/genética , Substância Cinzenta/diagnóstico por imagem , Mutação , Progranulinas/genética , Substância Branca/diagnóstico por imagem , Idoso , Biomarcadores , Encéfalo/diagnóstico por imagem , Progressão da Doença , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico por imagem , Humanos , Idioma , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Testes Neuropsicológicos , FenótipoRESUMO
Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.
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Demência Frontotemporal/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Presenilina-1/genética , Proteínas Serina-Treonina Quinases/genética , Proteína com Valosina/genética , Sequenciamento do Exoma , Proteínas tau/genéticaRESUMO
Frontotemporal dementia is a highly heritable and devastating neurodegenerative disease. About 10-20% of all frontotemporal dementia is caused by known pathogenic mutations, but a reliable tool to predict clinical conversion in mutation carriers is lacking. In this retrospective proof-of-concept case-control study, we investigate whether MRI-based and cognition-based classifiers can predict which mutation carriers from genetic frontotemporal dementia families will develop symptoms ('convert') within 4 years. From genetic frontotemporal dementia families, we included 42 presymptomatic frontotemporal dementia mutation carriers. We acquired anatomical, diffusion-weighted imaging, and resting-state functional MRI, as well as neuropsychological data. After 4 years, seven mutation carriers had converted to frontotemporal dementia ('converters'), while 35 had not ('non-converters'). We trained regularized logistic regression models on baseline MRI and cognitive data to predict conversion to frontotemporal dementia within 4 years, and quantified prediction performance using area under the receiver operating characteristic curves. The prediction model based on fractional anisotropy, with highest contribution of the forceps minor, predicted conversion to frontotemporal dementia beyond chance level (0.81 area under the curve, family-wise error corrected P = 0.025 versus chance level). Other MRI-based and cognitive features did not outperform chance level. Even in a small sample, fractional anisotropy predicted conversion in presymptomatic frontotemporal dementia mutation carriers beyond chance level. After validation in larger data sets, conversion prediction in genetic frontotemporal dementia may facilitate early recruitment into clinical trials.
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BACKGROUND: Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk. METHODS: We acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E ε4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation). RESULTS: MAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses. CONCLUSIONS: Concluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD.
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Doença de Alzheimer/diagnóstico por imagem , Demência Frontotemporal/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Vias Neurais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico Precoce , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Predisposição Genética para Doença , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Vias Neurais/patologia , Substância Branca/patologiaRESUMO
BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia. METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia. FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; p<0·0001) and non-carriers (8 pg/mL [6-11]; p<0·0001), and was higher in converters than in non-converting carriers (19 pg/mL [17-28] vs 8 pg/mL [6-11]; p=0·0007; adjusted for age). During follow-up, NfL increased in converters (b=0·097 [SE 0·018]; p<0·0001). In symptomatic mutation carriers overall, NfL did not change during follow-up (b=0·017 [SE 0·010]; p=0·101) and remained elevated. Rates of NfL change over time were associated with rate of decline in Mini Mental State Examination (b=-94·7 [SE 33·9]; p=0·003) and atrophy rate in several grey matter regions, but not with change in Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale score (b=-3·46 [SE 46·3]; p=0·941). INTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker. FUNDING: ZonMw and the Bluefield project.
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Demência Frontotemporal/sangue , Demência Frontotemporal/genética , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/genética , Adulto , Idoso , Biomarcadores/sangue , Proteína C9orf72/genética , Estudos de Coortes , Feminino , Demência Frontotemporal/diagnóstico por imagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Neuroimaging MRI data in scientific research is increasingly pooled, but the reliability of such studies may be hampered by the use of different hardware elements. This might introduce bias, for example when cross-sectional studies pool data acquired with different head coils, or when longitudinal clinical studies change head coils halfway. In the present study, we aimed to estimate this possible bias introduced by using different head coils to create awareness and to avoid misinterpretation of results. We acquired, with both an 8 channel and 32 channel head coil, T1-weighted, diffusion tensor imaging and resting state fMRI images at 3T MRI (Philips Achieva) with stable acquisition parameters in a large group of cognitively healthy participants (n = 77). Standard analysis methods, i.e., voxel-based morphometry, tract-based spatial statistics and resting state functional network analyses, were used in a within-subject design to compare 8 and 32 channel head coil data. Signal-to-noise ratios (SNR) for both head coils showed similar ranges, although the 32 channel SNR profile was more homogeneous. Our data demonstrates specific patterns of gray and white matter volume differences between head coils (relative volume change of 6 to 9%), related to altered image contrast and therefore, altered tissue segmentation. White matter connectivity (fractional anisotropy and diffusivity measures) showed hemispherical dependent differences between head coils (relative connectivity change of 4 to 6%), and functional connectivity in resting state networks was higher using the 32 channel head coil in posterior cortical areas (relative change up to 27.5%). This study shows that, even when acquisition protocols are harmonized, the results of standardized analysis models can be severely affected by the use of different head coils. Researchers should be aware of this when combining multiple neuroimaging MRI datasets, to prevent coil-related bias and avoid misinterpretation of their findings.
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BACKGROUND: Multimodal MRI-based classification may aid early frontotemporal dementia (FTD) diagnosis. Recently, presymptomatic FTD mutation carriers, who have a high risk of developing FTD, were separated beyond chance level from controls using MRI-based classification. However, it is currently unknown how these scores from classification models progress as mutation carriers approach symptom onset. In this longitudinal study, we investigated multimodal MRI-based classification scores between presymptomatic FTD mutation carriers and controls. Furthermore, we contrasted carriers that converted during follow-up ('converters') and non-converting carriers ('non-converters'). METHODS: We acquired anatomical MRI, diffusion tensor imaging and resting-state functional MRI in 55 presymptomatic FTD mutation carriers and 48 healthy controls at baseline, and at 2, 4, and 6 years of follow-up as available. At each time point, FTD classification scores were calculated using a behavioural variant FTD classification model. Classification scores were tested in a mixed-effects model for mean differences and differences over time. RESULTS: Presymptomatic mutation carriers did not have higher classification score increase over time than controls (p=0.15), although carriers had higher FTD classification scores than controls on average (p=0.032). However, converters (n=6) showed a stronger classification score increase over time than non-converters (p<0.001). CONCLUSIONS: Our findings imply that presymptomatic FTD mutation carriers may remain similar to controls in terms of MRI-based classification scores until they are close to symptom onset. This proof-of-concept study shows the promise of longitudinal MRI data acquisition in combination with machine learning to contribute to early FTD diagnosis.
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Diagnóstico Precoce , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Imagem Multimodal , Mutação , Sintomas Prodrômicos , Adulto , Idoso , Proteína C9orf72/genética , Estudos de Casos e Controles , Feminino , Heterozigoto , Humanos , Estudos Longitudinais , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Neuroimagem , Testes Neuropsicológicos , Progranulinas/genética , Fatores de Tempo , Proteínas tau/genéticaRESUMO
BACKGROUND: Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. METHODS: Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). RESULTS: The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUCâ¯=â¯0.582, pâ¯= 0.078). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.642 (pâ¯= 0.032). The best multimodal model combined radial diffusivity and white matter density features (AUCâ¯=â¯0.684, pâ¯= 0.004). CONCLUSIONS: FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.
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In genetic frontotemporal dementia, cross-sectional studies have identified profiles of presymptomatic neuroanatomical loss for C9orf72 repeat expansion, MAPT, and GRN mutations. In this study, we characterize longitudinal gray matter (GM) and white matter (WM) brain changes in presymptomatic frontotemporal dementia. We included healthy carriers of C9orf72 repeat expansion (n = 12), MAPT (n = 15), GRN (n = 33) mutations, and related noncarriers (n = 53), that underwent magnetic resonance imaging at baseline and 2-year follow-up. We analyzed cross-sectional baseline, follow-up, and longitudinal GM and WM changes using voxel-based morphometry and cortical thickness analysis in SPM and tract-based spatial statistics in FSL. Compared with noncarriers, C9orf72 repeat expansion carriers showed lower GM volume in the cerebellum and insula, and WM differences in the anterior thalamic radiation, at baseline and follow-up. MAPT mutation carriers showed emerging GM temporal lobe changes and longitudinal WM degeneration of the uncinate fasciculus. GRN mutation carriers did not show presymptomatic neurodegeneration. This study shows distinct presymptomatic cross-sectional and longitudinal patterns of GM and WM changes across C9orf72 repeat expansion, MAPT, and GRN mutation carriers compared with noncarriers.
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Imagem de Tensor de Difusão , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Neuroimagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Idoso , Proteína C9orf72/genética , Estudos Transversais , Expansão das Repetições de DNA/genética , Feminino , Demência Frontotemporal/patologia , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Progranulinas/genética , Proteínas tau/genéticaRESUMO
Developing and validating sensitive biomarkers for the presymptomatic stage of familial frontotemporal dementia is an important step in early diagnosis and for the design of future therapeutic trials. In the longitudinal Frontotemporal Dementia Risk Cohort, presymptomatic mutation carriers and non-carriers from families with familial frontotemporal dementia due to microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations underwent a clinical assessment and multimodal MRI at baseline, 2-, and 4-year follow-up. Of the cohort of 73 participants, eight mutation carriers (three GRN, five MAPT) developed clinical features of frontotemporal dementia ('converters'). Longitudinal whole-brain measures of white matter integrity (fractional anisotropy) and grey matter volume in these converters (n = 8) were compared with healthy mutation carriers ('non-converters'; n = 35) and non-carriers (n = 30) from the same families. We also assessed the prognostic performance of decline within white matter and grey matter regions of interest by means of receiver operating characteristic analyses followed by stepwise logistic regression. Longitudinal whole-brain analyses demonstrated lower fractional anisotropy values in extensive white matter regions (genu corpus callosum, forceps minor, uncinate fasciculus, and superior longitudinal fasciculus) and smaller grey matter volumes (prefrontal, temporal, cingulate, and insular cortex) over time in converters, present from 2 years before symptom onset. White matter integrity loss of the right uncinate fasciculus and genu corpus callosum provided significant classifiers between converters, non-converters, and non-carriers. Converters' within-individual disease trajectories showed a relatively gradual onset of clinical features in MAPT, whereas GRN mutations had more rapid changes around symptom onset. MAPT converters showed more decline in the uncinate fasciculus than GRN converters, and more decline in the genu corpus callosum in GRN than MAPT converters. Our study confirms the presence of spreading predominant frontotemporal pathology towards symptom onset and highlights the value of multimodal MRI as a prognostic biomarker in familial frontotemporal dementia.
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Encéfalo/patologia , Endofenótipos , Demência Frontotemporal/diagnóstico por imagem , Imagem Multimodal , Anisotropia , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Imagem de Tensor de Difusão , Diagnóstico Precoce , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Substância Cinzenta/patologia , Heterozigoto , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Testes Neuropsicológicos , Sintomas Prodrômicos , Progranulinas/genética , Substância Branca/patologia , Proteínas tau/genéticaRESUMO
Objective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72,MAPT, and GRN mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72,MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left-right asymmetry analyses on GRN mutation carriers versus noncarriers. Results: Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers - characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar - albeit less extensive - patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left-right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC. Interpretation: This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic "fingerprint." Our findings corroborate the notion of FTD as a network-based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease-tracking and -staging in presymptomatic to early-stage familial FTD.
RESUMO
Background: Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods: Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results: The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUCâ¯=â¯0.570, pâ¯=â¯0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (pâ¯=â¯0.021). The best multimodal model combined radial diffusivity and white matter density features (AUCâ¯=â¯0.680, pâ¯=â¯0.005). Conclusions: FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.
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Doenças Assintomáticas , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Heterozigoto , Imageamento por Ressonância Magnética/métodos , Mutação/genética , Adulto , Doenças Assintomáticas/classificação , Imagem de Tensor de Difusão/classificação , Imagem de Tensor de Difusão/métodos , Feminino , Demência Frontotemporal/classificação , Humanos , Imageamento por Ressonância Magnética/classificação , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/classificação , Imagem Multimodal/métodos , Estudos RetrospectivosRESUMO
INTRODUCTION: We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD). METHODS: Presymptomatic MAPT (n = 15) and GRN mutation carriers (n = 31), and healthy controls (n = 39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression. RESULTS: MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p < 0.05). Cognitive decline in ScreeLing phonology (p = 0.046) and letter fluency (p = 0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p = 0.025) for an underlying MAPT mutation. DISCUSSION: Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD.
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Demência Frontotemporal/diagnóstico , Demência Frontotemporal/psicologia , Adulto , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Feminino , Seguimentos , Demência Frontotemporal/genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multinível , Mutação , Testes Neuropsicológicos , Sintomas Prodrômicos , Prognóstico , Progranulinas , Curva ROC , Análise de Regressão , Proteínas tau/genéticaRESUMO
BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. METHODS: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. RESULTS: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. CONCLUSION: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.