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PURPOSE: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. METHODS: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. RESULTS: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. CONCLUSION: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.
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Metilación de ADN , Trastornos del Neurodesarrollo , Humanos , Metilación de ADN/genética , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/genética , GenomaRESUMEN
Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid ß-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
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Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Enfermedades Musculares , 3-Hidroxiacil-CoA Deshidrogenasas , Adolescente , Cardiomiopatías , Niño , Preescolar , Coenzima A , Diagnóstico Tardío , Ácidos Grasos/metabolismo , Humanos , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades del Sistema Nervioso , RabdomiólisisRESUMEN
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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Cognición/fisiología , Demencia Frontotemporal/genética , Sustancia Gris/diagnóstico por imagen , Mutación , Progranulinas/genética , Sustancia Blanca/diagnóstico por imagen , Anciano , Biomarcadores , Encéfalo/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Demencia Frontotemporal/sangre , Demencia Frontotemporal/diagnóstico por imagen , Humanos , Lenguaje , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Pruebas Neuropsicológicas , FenotipoRESUMEN
The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. To test whether somatic variants in neural progenitor cells during brain development might lead to semantic dementia, we compared deep exome sequencing data of DNA derived from brain and blood of 16 semantic dementia cases. Somatic variants observed in brain tissue and absent in blood were validated using amplicon sequencing and digital PCR. We identified two variants in exon one of the TARDBP gene (L41F and R42H) at low level (1-3%) in cortical regions and in dentate gyrus in two semantic dementia brains, respectively. The pathogenicity of both variants is supported by demonstrating impaired splicing regulation of TDP-43 and by altered subcellular localization of the mutant TDP-43 protein. These findings indicate that somatic variants may cause semantic dementia as a non-hereditary neurodegenerative disease, which might be exemplary for other late-onset neurodegenerative disorders.
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Proteínas de Unión al ADN/genética , Demencia Frontotemporal/etiología , Demencia Frontotemporal/genética , Proteinopatías TDP-43/complicaciones , Proteinopatías TDP-43/genética , Empalme Alternativo , Química Encefálica/genética , ADN/genética , Exoma , Exones/genética , Femenino , Demencia Frontotemporal/psicología , Variación Genética/genética , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Semántica , Proteinopatías TDP-43/psicología , Secuenciación del ExomaRESUMEN
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/patología , Endofenotipos , Demencia Frontotemporal/diagnóstico por imagen , Imagen Multimodal , Anisotropía , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Imagen de Difusión Tensora , Diagnóstico Precoz , Femenino , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Sustancia Gris/patología , Heterocigoto , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Pruebas Neuropsicológicas , Síntomas Prodrómicos , Progranulinas/genética , Sustancia Blanca/patología , Proteínas tau/genéticaRESUMEN
PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.
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Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/genética , Mapeo Cromosómico/métodos , Exoma/genética , Femenino , Pruebas Genéticas/economía , Estudio de Asociación del Genoma Completo/métodos , Humanos , Recién Nacido , Cuidado Intensivo Neonatal , Masculino , Estudios Retrospectivos , Secuenciación del Exoma/economía , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. METHODS: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). RESULTS: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs =-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs =-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. CONCLUSION: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.
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Demencia Frontotemporal/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Anciano , Estudios de Casos y Controles , Estudios Transversales , Femenino , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/mortalidad , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
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Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD (n = 49), primary progressive aphasia (PPA; n = 52), Alzheimer's dementia (AD; n = 41), psychiatric disorders (n = 18), presymptomatic mutation carriers (n = 58) and controls (n = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension 'frontal-behavioural symptoms'. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Humanos , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/genética , Demencia Frontotemporal/psicología , Enfermedad de Alzheimer/diagnóstico , Síntomas Conductuales , CuidadoresRESUMEN
BACKGROUND: Progressive supranuclear palsy (PSP) patients often exhibit cognitive decline and behavioural changes during the disease course. In a subset, these symptoms may be the presenting manifestation and can be similar to those in frontotemporal dementia (FTD). However, correlation studies between quantitative imaging measures and detailed neuropsychological assessment are scarce. The aim of this study was to investigate the functional role of affected brain regions in cognition in PSP compared with controls and subsequently examine these regions in FTD patients with known tau pathology (FTD tau). METHODS: 21 PSP patients, 27 healthy controls and 11 FTD tau patients were enrolled. All participants underwent neuropsychological testing and technetium-99m-hexamethyl-propylenamine-oxime single photon emission CT. Regression slope analyses were performed in statistical parametric mapping to find significant associations between neuropsychological test results and brain perfusion. RESULTS: PSP patients showed hypoperfusion in the midcingulate cortex (MCC) of which the posterior part correlated with Stroop III and Weigl. In FTD tau patients, MCC involvement was located more anterior and correlated with Stroop III and Wisconsin Card Sorting Test concepts. The degree of hypoperfusion in the anterior cortex and MCC in the disorders differed in the subgenual anterior cingulate cortex only. CONCLUSIONS: The posterior part of the MCC is prominently involved in the neurodegenerative process of PSP, and the severity of its hypoperfusion correlated with the extent of executive dysfunction. In FTD tau, this cognitive domain was associated with anterior MCC involvement. The degree of hypoperfusion in these regions did not differ between PSP and FTD tau. These observations provide insight into the role of the cingulate cortex in cognitive dysfunction in these neurodegenerative disorders and warrant further investigations.
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Demencia Frontotemporal/fisiopatología , Demencia Frontotemporal/psicología , Neuroimagen Funcional/psicología , Giro del Cíngulo/irrigación sanguínea , Parálisis Supranuclear Progresiva/fisiopatología , Anciano , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/fisiopatología , Femenino , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/metabolismo , Neuroimagen Funcional/métodos , Giro del Cíngulo/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Compuestos de Organotecnecio , Oximas , Radiofármacos , Parálisis Supranuclear Progresiva/complicaciones , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/psicología , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tomografía Computarizada de Emisión de Fotón Único/psicología , Proteínas tau/metabolismoRESUMEN
Pre-symptomatic frontotemporal dementia (FTD) mutation carriers and first-degree family members that are 50% at-risk for FTD may experience symptoms of anxiety and depression as a result of the ambiguity of when or if symptoms of the disease will manifest. We conducted a pilot study to investigate the use of an online mindfulness-based stress reduction (MBSR) course to reduce symptoms of anxiety and depression in presymptomatic frontotemporal dementia (FTD) mutation carriers and individuals 50% at-risk. Seven known mutation carriers and six individuals 50% at-risk completed a standardized 8-week MBSR course, and filled out pre- and post and two-month follow-up questionnaires. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS). Measures of psychological distress (SCL-90-R), coping style (UCL), quality of life (SF-36) and mindfulness skills (FFMQ) were administered as secondary outcome. Group effects were analyzed with repeated measures ANOVA or Friedman's test, and the individual reliability change index (RCI) was calculated per participant for each outcome measure. Semi-quantitative data included an evaluation and process measure post-intervention. Significant decline was found on the HADS-A post-intervention and after 2 months (p = 0.01), with 54% and 62% of participants demonstrating a clinically significant RCI, respectively. On the HADS-D, significant decline was found 2 months post-intervention (p = 0.04), which was driven by 23% of participants whom had a clinically significant RCI. Additional changes were found between baseline and post-intervention on the seeking distraction and reassuring thoughts subscales of the UCL, the depression and interpersonal sensitivity subscales of the SCL, the observe subscale of the FFMQ, and on physical role limitations of the SF-36 (all p < 0.05). The process evaluation form indicated that the course was found beneficial by participants, and that they applied it in a wide range of everyday situations. This exploratory pilot study indicates the feasibility of MBSR in reducing anxiety and depression in presymptomatic FTD mutation carriers and 50% at-risk individuals. A randomized controlled trial is necessary to replicate these results.
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OBJECTIVE: To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48. METHODS: We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members. RESULTS: Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent cognitive decline and behavioral changes. Whole-exome sequencing identified a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3. Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was present in 1 case. CONCLUSIONS: This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48 and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark of the disease. Future studies will provide more insight into its pathologic heterogeneity.
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The aim of this study was to explore whether variants in LRP10, recently associated with Parkinson's disease and dementia with Lewy bodies, are observed in 2 large cohorts (discovery and validation cohort) of patients with progressive supranuclear palsy (PSP). A total of 950 patients with PSP were enrolled: 246 patients with PSP (n = 85 possible (35%), n = 128 probable (52%), n = 33 definite (13%)) in the discovery cohort and 704 patients with definite PSP in the validation cohort. Sanger sequencing of all LRP10 exons and exon-intron boundaries was performed in the discovery cohort, and whole-exome sequencing was performed in the validation cohort. Two patients from the discovery cohort and 8 patients from the validation cohort carried a rare, heterozygous, and possibly pathogenic LRP10 variant (p.Gly326Asp, p.Asp389Asn, and p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554∗, p.Arg661Cys). In conclusion, possibly pathogenic LRP10 variants occur in a small fraction of patients with PSP and may be overrepresented in these patients compared with controls. This suggests that possibly pathogenic LRP10 variants may play a role in the development of PSP.
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Variación Genética/genética , Proteínas Relacionadas con Receptor de LDL/genética , Parálisis Supranuclear Progresiva/genética , Anciano , Estudios de Cohortes , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Secuenciación del ExomaRESUMEN
INTRODUCTION: Neurofilament light chain (NfL) is a promising biomarker in neurodegenerative diseases. Elevated NfL levels in CSF and blood have been observed in a growing number of neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease. We studied serum NfL levels in patients with progressive supranuclear palsy (PSP) in relation to disease severity and survival. METHODS: Serum NfL levels were determined cross-sectionally in a retrospective cohort of 131 patients with PSP and 95 healthy controls. Detailed clinical examination was performed and disease severity was assessed by several rating scales. RESULTS: We found that serum NfL levels in PSP were twice as high as those in controls, and that NfL levels correlated with worse functional, motor and cognitive functioning. During follow-up, 119 PSP patients had died, and higher NfL levels were associated with a shorter survival. CONCLUSION: This study provides evidence that serum NfL is a relevant and promising biomarker in PSP for disease severity, and may be used as a prognostic tool to predict survival in clinical practice.
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Proteínas de Neurofilamentos/sangre , Parálisis Supranuclear Progresiva/sangre , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
OBJECTIVE: To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort. METHODS: CSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS). RESULTS: NfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau). CONCLUSION: NfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.
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Demencia Frontotemporal/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Afasia Progresiva Primaria/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/líquido cefalorraquídeo , Fosforilación , Pronóstico , Sensibilidad y Especificidad , Parálisis Supranuclear Progresiva/líquido cefalorraquídeoRESUMEN
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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Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/psicología , Adulto , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Femenino , Estudios de Seguimiento , Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multinivel , Mutación , Pruebas Neuropsicológicas , Síntomas Prodrómicos , Pronóstico , Progranulinas , Curva ROC , Análisis de Regresión , Proteínas tau/genéticaRESUMEN
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.
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OBJECTIVE: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. METHODS: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. RESULTS: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. INTERPRETATION: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.
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Mutations in the progranulin (PGRN) gene have recently been identified in frontotemporal lobar degeneration with ubiquitin inclusions linked to chromosome 17q21. We report here the finding of two novel frameshift mutations and three possible pathogenic missense mutations in the PGRN gene. Furthermore, we determined the frequency of PGRN mutations in familial cases recruited from a large population-based study of frontotemporal lobar degeneration carried out in The Netherlands.