RESUMEN
Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Neuronas , Envejecimiento , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , ADN , Exones , Genómica , Hipocampo/citología , Humanos , Tasa de Mutación , Neuronas/patología , Nucleótidos , Corteza Prefrontal/citología , Secuenciación Completa del GenomaRESUMEN
The developmental potential of human pluripotent stem cells suggests that they can produce disease-relevant cell types for biomedical research. However, substantial variation has been reported among pluripotent cell lines, which could affect their utility and clinical safety. Such cell-line-specific differences must be better understood before one can confidently use embryonic stem (ES) or induced pluripotent stem (iPS) cells in translational research. Toward this goal we have established genome-wide reference maps of DNA methylation and gene expression for 20 previously derived human ES lines and 12 human iPS cell lines, and we have measured the in vitro differentiation propensity of these cell lines. This resource enabled us to assess the epigenetic and transcriptional similarity of ES and iPS cells and to predict the differentiation efficiency of individual cell lines. The combination of assays yields a scorecard for quick and comprehensive characterization of pluripotent cell lines.
Asunto(s)
Metilación de ADN , Células Madre Embrionarias/fisiología , Perfilación de la Expresión Génica/normas , Células Madre Pluripotentes Inducidas/fisiología , Diferenciación Celular , Línea Celular , Células Madre Embrionarias/citología , Humanos , Células Madre Pluripotentes Inducidas/citologíaRESUMEN
The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.
Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Células Madre Pluripotentes Inducidas , Enfermedad de Pick , Animales , Humanos , Ratones , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas Motoras/metabolismoRESUMEN
Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-ß or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Enfermedad de Pick , Humanos , Enfermedad de Alzheimer/genética , Proteínas de Unión al ADN/genética , Empalme del ARN , ARN Mensajero/genética , Estatmina/genéticaRESUMEN
Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , MicroARNs/uso terapéutico , Superóxido Dismutasa-1/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/genética , Dependovirus , Resultado Fatal , Silenciador del Gen , Terapia Genética , Vectores Genéticos , Humanos , Inyecciones Espinales , Masculino , Meningoencefalitis , Persona de Mediana Edad , Mutación , Prueba de Estudio Conceptual , Médula Espinal/química , Médula Espinal/patología , Superóxido Dismutasa-1/análisis , Superóxido Dismutasa-1/genética , Capacidad Vital , Adulto JovenRESUMEN
Tau aggregation within neurons is a critical feature of Alzheimer's disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the formation of tau aggregates in a prion-like manner and propagate through connected neurons during the progression of disease. Both soluble and aggregated forms of tau are thought to have neurotoxic properties. In addition, different strains of misfolded tau may cause differential neurotoxicity. In this work, we present an accelerated human neuronal model of tau-induced neurotoxicity that incorporates both soluble tau species and tau aggregation. Using patient-derived induced pluripotent stem cell (iPSC) neurons expressing a tau aggregation biosensor, we develop a cell culture system that allows continuous assessment of both induced tau aggregation and neuronal viability at single-cell resolution for periods of >1 week. We show that exogenous tau "seed" uptake, as measured by tau repeat domain (TauRD) reporter aggregation, increases the risk for subsequent neuronal death in vitro These results are the first to directly visualize neuronal TauRD aggregation and subsequent cell death in single human iPSC neurons. Specific morphologic strains or patterns of TauRD aggregation are then identified and associated with differing neurotoxicity. Furthermore, we demonstrate that familial AD iPSC neurons expressing the PSEN1 L435F mutation exhibit accelerated TauRD aggregation kinetics and a tau strain propagation bias when compared with control iPSC neurons.SIGNIFICANCE STATEMENT Neuronal intracellular aggregation of the microtubule binding protein tau occurs in Alzheimer's disease and related neurodegenerative tauopathies. Tau aggregates are believed to spread from neuron to neuron via prion-like misfolded tau seeds. Our work develops a human neuronal live-imaging system to visualize seeded tau aggregation and tau-induced neurotoxicity within single neurons. Using an aggregation-sensing tau reporter, we find that neuronal uptake and propagation of tau seeds reduces subsequent survival. In addition, human induced pluripotent stem cell (iPSC) neurons carrying an Alzheimer's disease-causing mutation in presenilin-1 undergo tau seeding more rapidly than control iPSC neurons. However, they do not show subsequent differences in neuronal survival. Finally, specific morphologies of tau aggregates are associated with increased neurotoxicity.
Asunto(s)
Células Madre Pluripotentes Inducidas/efectos de los fármacos , Síndromes de Neurotoxicidad/patología , Tauopatías/patología , Proteínas tau/toxicidad , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Supervivencia Celular , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Presenilina-1/biosíntesis , Presenilina-1/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.
RESUMEN
BACKGROUND: Intracranial foreign body granuloma (FBG) is a rare inflammatory reaction to retained foreign material, manifesting acutely or months to years following neurosurgical procedures. Radiographically, FBG can mimic tumor progression, and tissue biopsy may be required to guide management. MATERIALS AND METHODS: In this retrospective case series, we present unique clinico-radiographic and histopathological features of six neuro-oncological patients diagnosed with FBG between 2007 and 2019. RESULTS: All six patients (4 women and 2 men, aged 29-54 [median, 30.5] years) had undergone surgical resection of a low- (n = 4) or high-grade (n = 2) glioma. FBG manifestation postsurgery ranged from 1 day to 4 years and was predominantly asymptomatic (n = 5/6). Magnetic resonance imaging universally demonstrated one or multiple peripherally enhancing lesion(s) adjacent to the resection cavity. Histopathology in all (n = 4/4) resected specimens demonstrated an inflammatory reaction to foreign material, confirming FBG. CONCLUSION: Intracranial FBG constitutes a rare but challenging treatment-related condition effectively managed by surgery, with important therapeutic implications in neuro-oncology.
Asunto(s)
Neoplasias Encefálicas , Granuloma de Cuerpo Extraño , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagen , Femenino , Granuloma de Cuerpo Extraño/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Estudios RetrospectivosAsunto(s)
Accidentes por Caídas , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/genética , Debilidad Muscular/etiología , Proteínas Priónicas/genética , Anciano , Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/diagnóstico , Diagnóstico Diferencial , Familia , Resultado Fatal , Femenino , Asesoramiento Genético , Humanos , Imagen por Resonancia Magnética , Debilidad Muscular/genética , MutaciónRESUMEN
BACKGROUND: The 2016 World Health Organization Classification of Central Nervous System Tumors categorizes gliomatosis cerebri growth pattern (GC) as a subgroup of diffuse infiltrating gliomas, defined by extent of brain involvement on magnetic resonance imaging (MRI). Clinical and radiographic features in GC patients are highly heterogeneous; however, prognosis has historically been considered poor. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective search for patients at our institution meeting radiographic criteria of primary, type I GC (defined as diffuse tumor infiltration without associated tumor mass and contrast enhancement on MRI) and analyzed their clinical, imaging, and histopathologic features. RESULTS: A total of 34 patients met radiographic criteria of primary, type I GC, and 33 had a confirmed histologic diagnosis of an infiltrating glial neoplasm. Age >47 years at diagnosis was associated with worse overall survival (OS) compared with age ≤47 years (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01-1.07, p = .003). Patients with grade 2 tumors demonstrated a trend for improved OS compared with those with grade 3 tumors (HR 2.65, 95% CI 0.99-7.08, p = .051). Except for brainstem involvement, extent or location of radiographic involvement did not detectably affect clinical outcome. IDH mutation status identified a subgroup of GC patients with particularly long survival up to 25 years and was associated with longer time to progression (HR 4.81, 95% CI 0.99-23.47, p = .052). CONCLUSION: Patients with primary, type I GC do not uniformly carry a poor prognosis, even in the presence of widespread radiographic involvement. Consistent with other reports, IDH mutation status may identify patients with improved clinical outcome. Molecular characterization, rather than MRI features, may be most valuable for prognostication and management of GC patients. IMPLICATIONS FOR PRACTICE: Patients with gliomatosis cerebri growth pattern (GC) constitute a challenge to clinicians, given their wide range of clinical, histologic, and radiographic presentation, heterogeneous outcome patterns, and the lack of consensus on a standardized treatment approach. This study highlights that radiographic extent of disease-albeit category-defining-does not detectably influence survival and that IDH mutations may impact clinical outcome. Practicing oncologists should be aware that select GC patients may demonstrate exceptionally favorable survival times and prognosticate patients based on molecular markers, rather than imaging features alone.
Asunto(s)
Neoplasias Neuroepiteliales/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Neuroepiteliales/patología , Estudios Retrospectivos , Adulto JovenAsunto(s)
Encéfalo/patología , Trastornos de la Memoria/etiología , Trastornos de la Personalidad/etiología , Enfermedad de Pick/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad , Conducta , Encéfalo/diagnóstico por imagen , Diagnóstico Diferencial , Resultado Fatal , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Pick/complicaciones , Enfermedad de Pick/patología , Macroglobulinemia de Waldenström/complicaciones , Proteínas tau/análisisRESUMEN
OBJECTIVE: Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. METHODS: We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. RESULTS: The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. INTERPRETATION: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128.
Asunto(s)
Encéfalo/patología , Carbolinas/metabolismo , Tauopatías/patología , Proteínas tau/genética , Anciano , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Flúor/metabolismo , Neuroimagen Funcional , Humanos , Masculino , Persona de Mediana Edad , Mutación , Tomografía de Emisión de Positrones , Ensayo de Unión Radioligante , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/patología , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Tritio/metabolismo , Proteínas tau/metabolismoAsunto(s)
Corazón/diagnóstico por imagen , Pulmón/patología , Prolapso de la Válvula Mitral/diagnóstico , Válvula Mitral/patología , Infarto del Miocardio/diagnóstico , Tos/etiología , Diagnóstico Diferencial , Ecocardiografía , Electrocardiografía , Fiebre/etiología , Humanos , Hipoxia/etiología , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares/diagnóstico , Masculino , Persona de Mediana Edad , Insuficiencia de la Válvula Mitral/diagnóstico , Insuficiencia de la Válvula Mitral/etiología , Prolapso de la Válvula Mitral/etiología , Infarto del Miocardio/complicaciones , Radiografía Torácica , Taquicardia Sinusal/diagnósticoRESUMEN
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of TREX1 (3-prime repair exonuclease-1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient's multisystem presentation, retinal involvement interpreted as "retinal vasculitis," and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy.
Asunto(s)
Exodesoxirribonucleasas/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Fosfoproteínas/genética , Insuficiencia Renal Crónica/diagnóstico , Enfermedades de la Retina/diagnóstico , Enfermedades Vasculares/diagnóstico , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Masculino , Insuficiencia Renal Crónica/genética , Enfermedades de la Retina/genética , Enfermedades Vasculares/genéticaAsunto(s)
Encéfalo/patología , Síndrome MELAS/diagnóstico , Acidosis Láctica , Adulto , Disfunción Cognitiva/etiología , ADN Mitocondrial/análisis , Diagnóstico Diferencial , Resultado Fatal , Genes Mitocondriales , Pérdida Auditiva Sensorineural/etiología , Humanos , Síndrome MELAS/complicaciones , Síndrome MELAS/genética , Síndrome MELAS/patología , Imagen por Resonancia Magnética , Masculino , Trastornos Migrañosos/etiología , Músculo Esquelético/patología , Mutación , Convulsiones/etiología , Accidente Cerebrovascular/diagnósticoRESUMEN
Human pluripotent stem cells are a promising source of differentiated cells for developmental studies, cell transplantation, disease modeling, and drug testing. However, their widespread use even for intensely studied cell types like spinal motor neurons is hindered by the long duration and low yields of existing protocols for in vitro differentiation and by the molecular heterogeneity of the populations generated. We report a combination of small molecules that within 3 weeks induce motor neurons at up to 50% abundance and with defined subtype identities of relevance to neurodegenerative disease. Despite their accelerated differentiation, motor neurons expressed combinations of HB9, ISL1, and column-specific markers that mirror those observed in vivo in human embryonic spinal cord. They also exhibited spontaneous and induced activity, and projected axons toward muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1(+)/LHX3(-)). Access to high-yield cultures of human limb-innervating motor neuron subtypes will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays.
Asunto(s)
Extremidades/inervación , Neuronas Motoras/fisiología , Células-Madre Neurales/fisiología , Animales , Axones/fisiología , Calcio/fisiología , Señalización del Calcio/fisiología , Diferenciación Celular/fisiología , Células Cultivadas , Embrión de Pollo , ADN Complementario/biosíntesis , ADN Complementario/genética , Femenino , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Proteínas de Homeodominio/genética , Humanos , Inmunohistoquímica , Proteínas con Homeodominio LIM/genética , Masculino , Ratones , Neuronas Motoras/metabolismo , Células-Madre Neurales/metabolismo , Técnicas de Placa-Clamp , Complejo Silenciador Inducido por ARN , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Médula Espinal/citología , Médula Espinal/embriología , Trasplante de Células Madre/métodos , Factores de Transcripción/genéticaAsunto(s)
Neoplasias Encefálicas/diagnóstico , Germinoma/diagnóstico , Ginecomastia/etiología , Hipogonadismo/diagnóstico , Encéfalo/patología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/terapia , Diagnóstico Tardío , Diabetes Insípida/diagnóstico , Diabetes Insípida/etiología , Diagnóstico Diferencial , Germinoma/complicaciones , Germinoma/terapia , Humanos , Hipogonadismo/etiología , Imagen por Resonancia Magnética , Masculino , Convulsiones , Testículo/patología , Adulto JovenRESUMEN
A basic assumption underlying induced pluripotent stem cell (iPSC) models of neurodegeneration is that disease-relevant pathologies present in brain tissue are also represented in donor-matched cells differentiated from iPSCs. However, few studies have tested this hypothesis in matched iPSCs and neuropathologically characterized donated brain tissues. To address this, we assessed iPSC-neuron production of ß-amyloid (Aß) Aß40, Aß42, and Aß43 in 24 iPSC lines matched to donor brains with primary neuropathologic diagnoses of sporadic AD (sAD), familial AD (fAD), control, and other neurodegenerative disorders. Our results demonstrate a positive correlation between Aß43 production by fAD iPSC-neurons and Aß43 accumulation in matched brain tissues but do not reveal a substantial correlation in soluble Aß species between control or sAD iPSC-neurons and matched brains. However, we found that the ApoE4 genotype is associated with increased Aß production by AD iPSC-neurons. Pathologic tau phosphorylation was found to be increased in AD and fAD iPSC-neurons compared to controls and positively correlated with the relative abundance of longer-length Aß species produced by these cells. Taken together, our results demonstrate that sAD-predisposing genetic factors influence iPSC-neuron phenotypes and that these cells are capturing disease-relevant and patient-specific components of the amyloid cascade.
Asunto(s)
Péptidos beta-Amiloides , Encéfalo , Células Madre Pluripotentes Inducidas , Neuronas , Proteínas tau , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Fosforilación , Encéfalo/patología , Encéfalo/metabolismo , Neuronas/metabolismo , Neuronas/patología , Femenino , Masculino , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Persona de Mediana Edad , Anciano , Donantes de TejidosRESUMEN
We present open-source tools for 3D analysis of photographs of dissected slices of human brains, which are routinely acquired in brain banks but seldom used for quantitative analysis. Our tools can: (i) 3D reconstruct a volume from the photographs and, optionally, a surface scan; and (ii) produce a high-resolution 3D segmentation into 11 brain regions per hemisphere (22 in total), independently of the slice thickness. Our tools can be used as a substitute for ex vivo magnetic resonance imaging (MRI), which requires access to an MRI scanner, ex vivo scanning expertise, and considerable financial resources. We tested our tools on synthetic and real data from two NIH Alzheimer's Disease Research Centers. The results show that our methodology yields accurate 3D reconstructions, segmentations, and volumetric measurements that are highly correlated to those from MRI. Our method also detects expected differences between post mortem confirmed Alzheimer's disease cases and controls. The tools are available in our widespread neuroimaging suite "FreeSurfer" ( https://surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools ).