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Background and Objectives: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. Methods: In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD (LRRK2); (2) risk of PD dementia (GBA); (3) PD genetic risk score; and (4) secondary, medically actionable variants (BRCA1). Results: Genome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion: Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.
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BACKGROUND AND OBJECTIVES: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes. METHODS: Asymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy. RESULTS: 1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p<0.001, -2.00, [-2.55, -1.45]) disease stages in behavioral variant frontotemporal dementia regardless of mutation status. Asymptomatic GRN pathogenic gene variant carriers showed more Reactive behaviors (preoccupation with time: p=0.001, 1.11, [1.06, 1.16]; self-consciousness: p=0.003, 1.77, [1.52, 2.01]) than asymptomatic non-carriers (1.01, [0.98, 1.03]; 1.31, [1.20, 1.41]). Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia (p=0.003, -0.73, [-1.18, -0.29]). Higher scores on each subscale corresponded with higher caregiver burden (p<0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks. DISCUSSION: The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the Social Behavior Observer Checklist is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort.
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OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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Progresión de la Enfermedad , Degeneración Lobar Frontotemporal/sangre , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Proteínas de Neurofilamentos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética/tendencias , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Adulto JovenRESUMEN
OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.
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Encéfalo/patología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Proteínas tau/genética , Adulto , Anciano , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders that share clinical, pathologic, and genetic features. Persons and families affected by these conditions frequently question why they developed the disease, the expected disease course, treatment options, and the likelihood that family members will be affected. Genetic testing has the potential to answers these important questions. Despite the progress in gene discovery, the offer of genetic testing is not yet "standard of care" in ALS and FTD clinics. The authors review the current genetic landscape and present recommendations for the laboratory genetic evaluation of persons with these conditions.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Pruebas Genéticas , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/genética , Asesoramiento Genético , HumanosRESUMEN
Importance: Individuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis-associated neuropsychiatric disorders. Tuberous sclerosis-associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored. Objective: To investigate the potential association between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia. Design, Setting, and Participants: Case-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals. Main Outcomes and Measures: Tuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau181, total tau, amyloid-ß 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients. Results: Eighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis-associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B-labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [18F]flortaucipir binding in the frontal and temporal regions. Conclusions and Relevance: Adults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis-associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.
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Demencia Frontotemporal , Esclerosis Tuberosa/complicaciones , Adulto , Anciano , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones/métodos , Esclerosis Tuberosa/líquido cefalorraquídeo , Esclerosis Tuberosa/patologíaRESUMEN
OBJECTIVE: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. METHODS: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials. RESULTS: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. CONCLUSION: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
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Edad de Inicio , Enfermedades por Prión/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Ensayos Clínicos como Asunto , Femenino , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Penetrancia , Enfermedades por Prión/genética , Proteínas Priónicas/genética , Modelos de Riesgos Proporcionales , Proyectos de Investigación , Adulto JovenRESUMEN
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia, and elucidating its genetic underpinnings is critical. FTLD research centers typically recruit patient cohorts that are limited by the center's specialty and the ways in which its geographic location affects the ethnic makeup of research participants. Novel sources of data are needed to get population estimates of the contribution of variants in known FTLD-associated genes. METHODS: We compared FLTD-associated genetic variants in microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome nine open reading frame 72 (C9ORF72) from an academic research cohort and a commercial clinical genetics laboratory. Pathogenicity was assessed using guidelines of the American College of Medical Genetics and Genomics and a rule-based DNA variant assessment system. We conducted chart reviews on patients with novel or rare disease-associated variants. RESULTS: A total of 387 cases with FTLD-associated variants from the commercial (n=2,082) and 78 cases from the academic cohort (n=2,089) were included for analysis. In the academic cohort, the most frequent pathogenic variants were C9ORF72 expansions (63%, n=49), followed by GRN (26%, n=20) and MAPT (11%, n=9). Each gene's contribution to disease was similarly ranked in the commercial laboratory but differed in magnitude: C9ORF72 (89%, n=345), GRN (6%, n=24), and MAPT (5%, n=19). Of the 37 unique GRN/MAPT variants identified, only six were found in both cohorts. Clinicopathological data from patients in the academic cohort strengthened classification of two novel GRN variant as pathogenic (p.Pro166Leufs*2, p.Gln406*) and one GRN variant of unknown significance as a possible rare risk variant (p.Cys139Arg). CONCLUSION: Differences in gene frequencies and identification of unique pathogenic alleles in each cohort demonstrate the importance of data sharing between academia and community laboratories. Using shared data sources with well-characterized clinical phenotypes for individual variants can enhance interpretation of variant pathogenicity and inform clinical management of at-risk patients and families.
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Demencia Frontotemporal/genética , Mutación , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.
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Demencia/genética , Enfermedades por Prión/genética , Proteínas Priónicas/genética , Adulto , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/psicología , Demencia/metabolismo , Femenino , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Enfermedad de Gerstmann-Straussler-Scheinker/psicología , Humanos , Insomnio Familiar Fatal/genética , Insomnio Familiar Fatal/psicología , Masculino , Persona de Mediana Edad , Mutación/genética , Enfermedades por Prión/fisiopatología , Proteínas Priónicas/metabolismo , Priones/genética , Estados UnidosRESUMEN
Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.
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Codón sin Sentido , Enfermedades por Prión/genética , Enfermedades por Prión/fisiopatología , Proteínas Priónicas/genética , Adulto , Encéfalo/diagnóstico por imagen , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Linaje , Nervios Periféricos/fisiopatología , Fenotipo , Enfermedades por Prión/diagnóstico por imagenRESUMEN
OBJECTIVE: To describe psychiatric presentations in individuals with genetic mutations causing frontotemporal dementia (FTD). DESIGN: Case descriptions from five carriers of FTD-related gene mutations with symptoms associated with non-neurodegenerative psychiatric disease. SETTING: A comprehensive research program investigating genetic and non-genetic FTD at the University of California, San Francisco Memory and Aging Center. PARTICIPANTS: Three proband and two non-proband gene carriers. MEASUREMENTS: Medical history and neurological examination, neuropsychological testing, magnetic resonance and/or positron emission tomography imaging, and a genetic analysis to screen for dementia-related mutations. Genetic status was unknown at the time of initial evaluation. RESULTS: The chosen cases are illustrative of the variety of presentations of psychiatric symptoms in FTD gene carriers. In some cases, a non-neurodegenerative psychiatric illness was diagnosed based on specific symptoms, but the diagnosis may have been inappropriate based on the overall syndrome. In other cases, symptoms closely resembling those seen in non-neurodegenerative psychiatric illness did occur, in some cases immediately preceding the development of dementia, and in other cases developing a decade prior to dementia symptoms. CONCLUSIONS: Psychiatric symptoms in FTD gene carriers can be very similar to those seen in non-neurodegenerative psychiatric illness. Psychiatric symptoms with atypical features (e.g., late-life onset, insidiously worsening course) should prompt careful assessment for neurodegenerative disease. Guidelines for such an assessment should be established.
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Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/genética , Heterocigoto , Proteínas/genética , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Proteína C9orf72 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pruebas Neuropsicológicas , Tomografía de Emisión de PositronesRESUMEN
Microtubule-associated protein tau mutations result in 10-20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimer's disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 years before mean family symptom onset. Voxel-based morphometry showed frontoinsular, frontal, and mesial temporal cortical atrophy. Homozygous tau R406W mutations appear to accelerate symptom onset and drive a behavioral variant frontotemporal dementia syndrome.
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Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.
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Edad de Inicio , Anticipación Genética/genética , Sesgo , Síndrome de Creutzfeldt-Jakob/genética , Enfermedades Genéticas Congénitas/genética , Mutación/genética , Priones/genética , Adolescente , Adulto , Anciano , Niño , Simulación por Computador , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Linaje , Proteínas Priónicas , Estudios Retrospectivos , Adulto JovenRESUMEN
Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.
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Demencia Frontotemporal , Red Nerviosa/fisiopatología , Proteínas/genética , Pulvinar/fisiopatología , Anciano , Atrofia/patología , Atrofia/fisiopatología , Biomarcadores , Proteína C9orf72 , Expansión de las Repeticiones de ADN/genética , Femenino , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Demencia Frontotemporal/fisiopatología , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/patología , Pulvinar/patologíaRESUMEN
A novel point mutation resulting in a glutamate-to-glycine substitution in PRNP at codon 200, E200G with codon 129 MV polymorphism (cis valine) and type 2 PrPSc was identified in a patient with a prolonged disease course leading to pathology-proven Jakob-Creutzfeldt disease. Despite the same codon as the most common genetic form of human PRNP mutation, E200K, this novel mutation (E200G) presented with a different clinical and pathological phenotype, including prolonged duration, large vacuoles, no vacuolation in the hippocampus, severe neuronal loss in the thalamus, mild cerebellar involvement, and abundant punctate linear and curvilinear deposition of PrPSc in synaptic boutons and axonal terminals along the dendrites.
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Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Mutación Puntual , Priones/genética , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/fisiopatología , Síndrome de Creutzfeldt-Jakob/psicología , Resultado Fatal , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Persona de Mediana Edad , Pruebas Neuropsicológicas , LinajeRESUMEN
Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts.
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Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Demencia Frontotemporal/genética , MicroARNs/genética , Mutación , Neuronas/metabolismo , Anciano , Esclerosis Amiotrófica Lateral/patología , Secuencia de Bases , Diferenciación Celular , Demencia Frontotemporal/patología , Humanos , Células Madre Pluripotentes Inducidas/patología , Masculino , Neuronas/patología , FenotipoRESUMEN
OBJECTIVES: To describe the clinical features of a Brazilian kindred with C9orf72 frontotemporal dementia-amyotrophic lateral sclerosis and compare them with other described families with C9orf72 and frontotemporal dementia-amyotrophic lateral sclerosis-causing mutations. DESIGN: Report of a kindred. SETTING: Dementia center at a university hospital. PATIENTS: One kindred encompassing 3 generations. RESULTS: The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed polymerase chain reaction and Southern blot. The observed phenotypes were behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis with dementia, with significant variability in age at onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations, and more posterior atrophy on neuroimaging than is typical for frontotemporal dementia were seen. CONCLUSIONS: Behavioral variant frontotemporal dementia due to C9orf72 expansion displays some phenotypic heterogeneity and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede the diagnosis of dementia by many years and may be a distinguishing feature of this mutation.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Encéfalo/patología , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/genética , Proteínas/genética , Adulto , Edad de Inicio , Anciano , Esclerosis Amiotrófica Lateral/patología , Atrofia/patología , Brasil , Proteína C9orf72 , Familia , Femenino , Demencia Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neuroimagen , Linaje , Personalidad/genética , FenotipoRESUMEN
OBJECTIVE: To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion. METHODS: A total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS). RESULTS: All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers. CONCLUSIONS: Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.