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Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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Apolipoproteínas E , Demencia Frontotemporal , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas tau , Humanos , Demencia Frontotemporal/genética , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Femenino , Anciano , Polimorfismo de Nucleótido Simple , Sitios Genéticos , Persona de Mediana Edad , Estudios de Casos y Controles , Proteínas de la MielinaRESUMEN
BACKGROUND: Symptoms of behavioral variant frontotemporal dementia (bvFTD) overlap with primary psychiatric disorders (PPD) making diagnosis challenging. Serum neurofilament light (sNfL) is a candidate biomarker to distinguish bvFTD from PPD, but large-scale studies in PPD are lacking. OBJECTIVE: Determine factors that influence sNfL from a large database of PPD patients, and test its diagnostic accuracy. DESIGN, SETTINGS, SUBJECTS, MEASUREMENTS: Clinical data of people aged 40-81 were obtained from healthy subjects (n = 69), and patients with PPD (n = 848) or bvFTD (n = 82). sNfL was measured using Simoa technology on an HD-X instrument. Data were analyzed using general linear models, and Receiver Operating Characteristic (ROC) curve analyses to determine global and age-specific sNfL cutoffs to distinguish bvFTD from PPD, using the Youden Index. RESULTS: sNfL increased with age, while sex, BMI and diabetes status were modestly associated with sNfL. sNfL was slightly higher in PPD than healthy subjects (14.1 versus 11.7 pg/mL), when controlling for covariates. sNfL was markedly lower in PPD than bvFTD (14.1 versus 44.1 pg/mL). sNfL could differentiate PPD from bvFTD with an AUC = 0.868, but the effect was driven by the younger subjects between age 40-60 years at a cutoff of 16.0 pg/mL. No valid cutoff was detected over age 60, however, values of sNfL above 38.5 pg/mL, or below 13.9 pg/mL, provided 90% diagnostic certainty of bvFTD or PPD, respectively. CONCLUSION: PPD have mildly elevated sNfL compared to healthy subjects but much lower than bvFTD. Results support the use of sNfL as a biomarker to differentiate PPD from bvFTD at age 60 or below, but accuracy decreases in older ages.
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Biomarcadores , Demencia Frontotemporal , Trastornos Mentales , Proteínas de Neurofilamentos , Humanos , Persona de Mediana Edad , Femenino , Masculino , Demencia Frontotemporal/sangre , Demencia Frontotemporal/diagnóstico , Anciano , Proteínas de Neurofilamentos/sangre , Adulto , Diagnóstico Diferencial , Biomarcadores/sangre , Anciano de 80 o más Años , Trastornos Mentales/sangre , Trastornos Mentales/diagnóstico , Factores de Edad , Estudios de Casos y Controles , Curva ROCRESUMEN
BACKGROUND AND PURPOSE: Behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), such as mood, psychotic, and autism spectrum disorders, share similar clinical characteristics of behavior and social cognition. Better understanding of clinical progression in bvFTD and PPD is essential for adequate disease monitoring and trial design. METHODS: In this longitudinal study (N = 89), patients with bvFTD and PPD with at least one follow-up assessment were included from the Social Brain Project of the Alzheimer Center Amsterdam. Behavioral change and social cognitive decline were assessed via informant-rated questionnaires (Cambridge Behavioral Inventory-Revised, Frontal Behavioral Inventory [FBI], Stereotypy Rating Inventory, Frontotemporal Dementia Rating Scale, Revised Self-Monitoring Scale [RSMS]-caregiver) and patient assessment (Ekman 60-Faces Test, RSMS-patient, Emotional Contagion Scale). Clinical trajectories (median = 1.4 years, interquartile range = 1.0-2.2) were examined using linear mixed models. In a subsample, associations with baseline serum neurofilament light (sNfL) were examined. RESULTS: At baseline, behavioral and social cognitive symptoms were similar between diagnosis groups, except for poorer emotion recognition in bvFTD. Over time, behavioral symptoms worsened in bvFTD, whereas most measures remained stable and the FBI improved in PPD. Regarding social cognition, emotion recognition and caregiver-reported socioemotional sensitivity worsened in bvFTD and remained stable in PPD. Patient-reported social cognitive measures did not change over time. Higher sNfL was associated with faster behavioral change. CONCLUSIONS: Trajectories of behavior and social cognition differentiate bvFTD from PPD, provided that social cognition is not patient-reported. Therefore, we stress the need to optimize longitudinal social cognitive assessment in bvFTD. sNfL may be a useful prognostic marker of behavioral progression in neuropsychiatric populations.
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The biological definition of Alzheimer's disease using CSF biomarkers requires abnormal levels of both amyloid (A) and tau (T). However, biomarkers and corresponding cutoffs may not always reflect the presence or absence of pathology. Previous studies suggest that up to 32% of individuals with autopsy-confirmed Alzheimer's disease show normal CSF p-tau levels in vivo, but these studies are sparse and had small sample sizes. Therefore, in three independent autopsy cohorts, we studied whether or not CSF A+T- excluded Alzheimer's disease based on autopsy. We included 215 individuals, for whom ante-mortem CSF collection and autopsy had been performed, from three cohorts: (i) the Amsterdam Dementia Cohort (ADC) [n = 80, 37 (46%) Alzheimer's disease at autopsy, time between CSF collection and death 4.5 ± 2.9 years]; (ii) the Antwerp Dementia Cohort (DEM) [n = 92, 84 (91%) Alzheimer's disease at autopsy, time CSF collection to death 1.7 ± 2.3 years]; and (iii) the Alzheimer's Disease Neuroimaging Initiative (ADNI) [n = 43, 31 (72%) Alzheimer's disease at autopsy, time CSF collection to death 5.1 ± 2.5 years]. Biomarker profiles were based on dichotomized CSF Aß1-42 and p-tau levels. The accuracy of CSF AT profiles to detect autopsy-confirmed Alzheimer's disease was assessed. Lastly, we investigated whether the concordance of AT profiles with autopsy diagnosis improved when CSF was collected closer to death in 9 (10%) DEM and 30 (70%) ADNI individuals with repeated CSF measurements available. In total, 50-73% of A+T- individuals and 100% of A+T+ individuals had Alzheimer's disease at autopsy. Amyloid status showed the highest accuracy to detect autopsy-confirmed Alzheimer's disease (accuracy, sensitivity and specificity in the ADC: 88%, 92% and 84%; in the DEM: 87%, 94% and 12%; and in the ADNI cohort: 86%, 90% and 75%, respectively). The addition of CSF p-tau did not further improve these estimates. We observed no differences in demographics or degree of Alzheimer's disease neuropathology between A+T- and A+T+ individuals with autopsy-confirmed Alzheimer's disease. All individuals with repeated CSF measurements remained stable in Aß1-42 status during follow-up. None of the Alzheimer's disease individuals with a normal p-tau status changed to abnormal; however, four (44%) DEM individuals and two (7%) ADNI individuals changed from abnormal to normal p-tau status over time, and all had Alzheimer's disease at autopsy. In summary, we found that up to 73% of A+T- individuals had Alzheimer's disease at autopsy. This should be taken into account in both research and clinical settings.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Proteínas tau , Biomarcadores , Sensibilidad y Especificidad , Fragmentos de PéptidosRESUMEN
BACKGROUND: Patients displaying clinical features of behavioural variant of frontotemporal dementia (bvFTD) but lacking both neuroimaging abnormalities and clinical progression are considered to represent the phenocopy syndrome of bvFTD (phFTD). Extensive clinical overlap between early phase bvFTD and phFTD hampers diagnostic distinction. We aimed to assess the diagnostic value of clinician-rated, self-reported and caregiver-reported symptoms for clinical distinction between phFTD and bvFTD. METHODS: There were 33 phFTD and 95 probable bvFTD patients included in the study (total N = 128). Clinician-rated, self-reported tests and caregiver-reported symptoms were compared between phFTD and bvFTD on social cognition, behaviour, mood and activities of daily living (ADL). Scores were compared between groups, followed by multiple logistic regression analysis, adjusted for age and sex. Receiver operating characteristic curves were plotted to assess diagnostic value. RESULTS: Using clinician-rated and self-reported tests, phFTD patients performed better on facial emotion recognition and reported more depressive symptoms. Caregiver-reported behavioural symptoms indicated higher behavioural and ADL impairment in phFTD compared to bvFTD. Facial emotion recognition provided highest diagnostic accuracy for distinction of phFTD from bvFTD (area under the curve (AUC) 0.813 95% CI 0.735-0.892, P < 0.001, sensitivity 81%, specificity 74%) followed by depressive symptoms (AUC 0.769 95% 0.674-0.864, P < 0.001 sensitivity 81%, specificity of 63%). CONCLUSION: Social cognition tests are most suitable for distinction of phFTD from bvFTD. Caregiver-reported questionnaires and phFTD diagnosis seemed inversely correlated, showing more symptoms in phFTD. Further research is needed on phFTD aetiology and in caregivers taking into account disease burden to assess what explains this discrepancy between clinician-rated and caregiver-based tools.
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Demencia Frontotemporal , Pruebas Neuropsicológicas , Cognición Social , Humanos , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/psicología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Cuidadores/psicología , Actividades Cotidianas/psicología , Diagnóstico Diferencial , Autoinforme , FenotipoRESUMEN
OBJECTIVES: Distinguishing sporadic behavioral variant of frontotemporal dementia (bvFTD) from late-onset primary psychiatric disorders (PPD) remains challenging with the lack of robust biomarkers. An early bvFTD misdiagnosis in PPD cases and vice-versa is common. Little is known about diagnostic (in)stability over longer period of time. We investigated diagnostic instability in a neuropsychiatric cohort up to 8 years after baseline visit and identified which clinical hallmarks contribute to diagnostic instability. DESIGN: Diagnoses of participants of the late-onset frontal lobe (LOF) study were collected from the baseline visit (T0) and the 2-year follow-up visit (T2). Clinical outcomes were retrieved 5-8 years after baseline visit (Tfinal). Endpoint diagnoses were categorized into bvFTD, PPD and other neurological disorders (OND). We calculated the total amount of participants that switched diagnosis between T0-T2 and T2-Tfinal. Clinical records of participants that switched diagnosis were assessed. RESULTS: Of the 137 patients that were included in the study, the final diagnoses at Tfinal were bvFTD 24.1% (n = 33), PPD 39.4% (n = 54), OND 33.6% (n = 46) and unknown 2.9% (n = 4). Between T0 and T2, a total of 29 (21.2%) patients switched diagnosis. Between T2 and Tfinal, 8 (5.8%) patients switched diagnosis. Prolonged follow-up identified few cases with diagnostic instability. Major contributors to diagnostic instability where a nonconverting diagnosis of possible bvFTD and a probable bvFTD diagnosis based on informant-based history and an abnormal FDG-PET scan whilst having a normal MRI. CONCLUSION: Considering these lessons, a FTD diagnosis remains stable enough to conclude that 2 years is sufficient to say if a patient with late-life behavioral disorder has FTD.
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Demencia Frontotemporal , Humanos , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/psicología , Pruebas Neuropsicológicas , Estudios Prospectivos , Lóbulo Frontal/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND AND PURPOSE: Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD. METHODS: The total sample (N = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons. RESULTS: Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, F(2, 48) = 6.095, p = 0.004; bvFTD-controls p = 0.001, 95% confidence interval [CI] -892.64, -239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; F(2, 48) = 3.423, p = 0.041; bvFTD-PPD p = 0.022, 95% CI -986.38, -79.47) and controls (mean difference 7.8%; bvFTD-controls p = 0.043, 95% CI -765.91, -12.76). CONCLUSIONS: In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Humanos , Demencia Frontotemporal/psicología , Pruebas Neuropsicológicas , Reconocimiento en Psicología , Emociones , Cognición , Enfermedad de Alzheimer/diagnósticoRESUMEN
Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Humanos , Anciano , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/terapia , Demencia Frontotemporal/psicología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Pruebas Neuropsicológicas , Lenguaje , Europa (Continente)RESUMEN
BACKGROUND: Adequate detection of symptoms and disease progression in behavioural variant frontotemporal dementia (bvFTD) is complex. Dementia cohorts usually utilize cognitive and functional measures, which fail to detect dominant behavioural and social cognitive deficits in bvFTD. Moreover, since patients typically have a loss of insight, caregivers are important informants. This is the first qualitative study to investigate caregiver relevant symptoms during the disease course of bvFTD, aiming to improve tools for diagnosis, progression, and future clinical trials. METHODS: Informal caregivers of patients in different disease stages of bvFTD (N = 20) were recruited from the neurology outpatient clinic of the Amsterdam UMC and a patient organization for peer support in the Netherlands. Their perspectives on clinical relevance were thoroughly explored during individual semi-structured interviews. Inductive content analysis with open coding was performed by two researchers independently to establish overarching themes and patterns. RESULTS: Caregivers reported a variety of symptoms, in which (i) loss of emotional connection, (ii) preoccupation and restlessness, and (iii) apathy and dependency compose major themes of relevance for diagnosis and treatment. Within heterogeneous disease trajectories, symptom presence differed between stages and among individuals, which is relevant in the context of progression and outcome measures. Significant socio-emotional changes dominated in early stages, while severe cognitive, behavioural, and physical deterioration shifted focus from predominant personality change to quality of life in later stages. CONCLUSIONS: Caregiver perspectives on target symptoms in bvFTD differ according to clinical stage and patient-caregiver characteristics, with significant socio-emotional changes characterizing early stages. These findings call for more appropriate tools and symptomatic treatments, as well as a personalized approach in treatment of bvFTD and a focus on early stage interventions in clinical trial design.
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Cuidadores , Demencia Frontotemporal , Humanos , Cuidadores/psicología , Manejo de la Enfermedad , Demencia Frontotemporal/psicología , Demencia Frontotemporal/terapia , Ensayos Clínicos como Asunto , Proyectos de InvestigaciónRESUMEN
Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation (BDPP) rescues impairment of hippocampus-dependent memory in a mouse model of sleep deprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase ß-1 (p70S6K). In additional mechanistic studies in vitro, we identified the brain bioavailable phenolic metabolites derived from the metabolism of dietary BDPP that are responsible for the attenuation of SD-mediated memory impairments. On the basis of high-throughput bioavailability studies of brain bioavailable metabolites after dietary BDPP treatment, we found that select polyphenol metabolites [ e.g., cyanidin-3'- O-glucoside and 3-(3'-hydroxyphenyl) propionic acid] were able to rescue mTOR and p70S6K phosphorylation in primary cortico-hippocampal neuronal cultures, as well as rescue 4E-BP1 phosphorylation in response to treatment with 4EGI-1, a specific inhibitor of eIF4E-eIF4G interaction. Our findings reveal a previously unknown role for dietary polyphenols in the rescue of SD-mediated memory impairments via mechanisms involving the promotion of protein translation.-Frolinger, T., Smith, C., Cobo, C. F., Sims, S., Brathwaite, J., de Boer, S., Huang, J., Pasinetti, G. M. Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.
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Disfunción Cognitiva , Hipocampo , Neuronas , Polifenoles/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Privación de Sueño , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Factor 4E Eucariótico de Iniciación/metabolismo , Factores Eucarióticos de Iniciación , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Neuronas/metabolismo , Neuronas/patología , Fosfoproteínas/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Privación de Sueño/tratamiento farmacológico , Privación de Sueño/metabolismo , Privación de Sueño/patologíaRESUMEN
BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer's disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases. OBJECTIVE: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages. METHODS: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models. CONCLUSIONS: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design.
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Acetamidas , Demencia Frontotemporal , Isotiocianatos , Humanos , Demencia Frontotemporal/genética , Estudios Prospectivos , Pronóstico , Pruebas Neuropsicológicas , BiomarcadoresRESUMEN
Diagnosis of Frontotemporal dementia (FTD) and the specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD- Tau and FTLD-TDP) is challenging, and thus fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort including patients with FTD (n = 189), Alzheimer's Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 68). Forty three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (AUC: 0.96) or AD (AUC: 0.91). Custom multiplex panels confirmed the highly accurate discrimination between FTD and controls (AUCs > 0.96) or AD (AUCs > 0.88) in three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau, but no reproducible classification model could be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic setting.
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Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by diverse and prominent changes in behavior and personality. One of the greatest challenges in bvFTD is to capture, measure and predict its disease progression, due to clinical, pathological and genetic heterogeneity. Availability of reliable outcome measures is pivotal for future clinical trials and disease monitoring. Detection of change should be objective, clinically meaningful and easily assessed, preferably associated with a biological process. The purpose of this scoping review is to examine the status of longitudinal studies in bvFTD, evaluate current assessment tools and propose potential progression markers. A systematic literature search (in PubMed and Embase.com) was performed. Literature on disease trajectories and longitudinal validity of frequently-used measures was organized in five domains: global functioning, behavior, (social) cognition, neuroimaging and fluid biomarkers. Evaluating current longitudinal data, we propose an adaptive battery, combining a set of sensitive clinical, neuroimaging and fluid markers, adjusted for genetic and sporadic variants, for adequate detection of disease progression in bvFTD.
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Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant frontotemporal dementia. This retrospective analysis drew its population from two clinical samples recruited from memory clinics at university hospitals in the USA and The Netherlands. Individuals with sporadic behavioural variant frontotemporal dementia were enrolled between 2000 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. The study population consisted of 186 individuals with sporadic behavioural variant frontotemporal dementia (113 males and 73 females), mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus [60.2 years (8.54)] versus individuals who did not [57.76 (8.05)], 95% confidence interval > 0.41, P = 0.02. Education was not associated with age at onset (ß = -0.05, P = 0.75). The presence of a right paracingulate sulcus was associated with an 83% increased risk of death per year after age at onset (hazard ratio 1.83, confidence interval [1.09-3.07], P < 0.02), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus (P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant frontotemporal dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant frontotemporal dementia that may be important in the design of trials for future therapeutic approaches.
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Background: Frontotemporal dementia is the second most common form of early onset dementia (< 65 years). Despite this there are few known disease modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant Frontotemporal Dementia. Methods: This retrospective analysis drew it's population from two clinical samples recruited from memory clinics at University Hospitals in The United States of America and The Netherlands. Individuals with sporadic behavioural variant Frontotemporal Dementia were enrolled between 2004 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. Results: The study population consisted of 186 individuals with sporadic behavioural variant Frontotemporal Dementia, (113 males and 73 females) mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus (60.2 years (SD 8.54)) versus individuals who did not (57.76 (8.05)), 95% CI >0.41, P = 0.02. Education was not associated with age at onset (ß = -0.05, P =0.75). Presence of a right paracingulate sulcus was associated with a 119% increased risk of death per year after age at onset (HR 2.19, CI [1.21 - 3.96], P <0.01), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus ( P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Conclusion: Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant Frontotemporal Dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant Frontotemporal Dementia which may be important in the design of trials for future therapeutic approaches.
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BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is generally considered a young-onset dementia, although age at onset is highly variable. While several studies indicate clinical differences regarding age at onset, no biomarker validated cohort studies with updated clinical criteria have been performed. OBJECTIVE: We aimed to examine behavior, cognition, and mortality over the full age spectrum in a cohort of bvFTD patients with neuroimaging, genetic, or histopathological confirmation and exclusion of positive Alzheimer's disease biomarkers or severe cerebrovascular damage. METHODS: In total, 315 patients with a clinical diagnosis of probable or definite bvFTD were included from the Amsterdam Dementia Cohort and grouped into quartiles by age-at-diagnosis. Neuropsychiatric symptoms and cognitive functioning were assessed with the neuropsychiatric inventory, the geriatric depression scale and a neuropsychological test battery. Data on mortality was obtained from the Dutch municipal register. Associations between age-at-diagnosis and clinical features and mortality risk were examined. RESULTS: Age-at-diagnosis ranged from 26 to 85 years and established quartiles with mean ages of 52±6, 61±2, 66±2, and 74±3 years. In the total sample, 44.4%exceeded an age of 65 years at time of diagnosis. Earlier age-at-diagnosis was associated with more severe behavioral symptoms, while later age-at-diagnosis was associated with more severe memory impairment. Unexpectedly, mortality risk was not associated with age-at-diagnosis. CONCLUSION: In bvFTD, symptom profile is associated with age-at-diagnosis. This should be taken into account with regard to diagnostics, patient management, and trial design. Additionally, based on our sample, the prevalence of late-onset bvFTD is higher than generally thought.
Asunto(s)
Demencia Frontotemporal/fisiopatología , Mortalidad , Pruebas Neuropsicológicas , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Ansiedad/fisiopatología , Ansiedad/psicología , Apatía/fisiología , Deluciones/fisiopatología , Deluciones/psicología , Femenino , Demencia Frontotemporal/psicología , Alucinaciones/fisiopatología , Alucinaciones/psicología , Humanos , Inhibición Psicológica , Genio Irritable/fisiología , Masculino , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Trastornos del Humor/fisiopatología , Trastornos del Humor/psicología , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. OBJECTIVE: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. METHODS: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; nâ=â654), non-fluent variant primary progressive aphasia (nfvPPA; nâ=â99), semantic variant primary progressive aphasia (svPPA; nâ=â117), and right temporal variant frontotemporal dementia (rtvFTD; nâ=â40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. RESULTS: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, pâ=â0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, pâ=â0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal. CONCLUSION: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.
Asunto(s)
Afasia Progresiva Primaria , Demencia Frontotemporal , Distribución por Sexo , Femenino , Demencia Frontotemporal/clasificación , Demencia Frontotemporal/genética , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , SemánticaRESUMEN
Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10-9, rs117204439: OR = 4.9, P = 6.0 × 10-9) and replication analysis (P < 1.1 × 10-3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10-58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10-260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.