RESUMEN
BACKGROUND: Extrapyramidal syndromes (EPS) represent neurological side effects of antipsychotic medications, characterized by motor disturbances. While previous studies have indicated the neuroprotective effects of vitamin D and A against EPS, the underlying mechanisms of this protection remain unclear. METHODS: Twenty-four adult mice were categorized into four groups: positive and negative control groups, one receiving a dopamine antagonist, and the other receiving both a dopamine antagonist and vitamins D and A. Sections of the corticobasal loop, specifically the motor cortex (M1) and basal nuclei (CPu), were prepared for Immunohistochemistry (IHC) and stained with Glial Fibrillary Acidic Protein (GFAP) to visualize reactive astrocytes. ELISA assays for TNF-α, IL-6, IL-4, IL-13, and dopamine levels were performed on homogenized brain sections. RESULTS: The EPS group exhibited a significant increase in TNF-α and IL-6 levels in M1 and CPu. Treatment with dopamine agonists and vitamin D&A resulted in significant reductions in IL-6 levels. Only the Vitamin D&A group showed a significant decline in TNF-α. The EPS group recorded significant decreases in IL-4 and IL-13, with IL-13 significantly elevated in the dopamine agonist and Vitamin D&A groups. IL-4 was notably increased in the Vitamin D&A groups. Dopamine concentration significantly declined in the EPS group, with improvements observed in the groups treated with dopamine agonists, and vitamin D&A. Reactive astrocytes were significantly expressed in the M1 and CPu of the EPS group but poorly expressed in other groups. CONCLUSIONS: EPS is linked to astrocyte activation, an upsurge in pro-inflammatory cytokines, a decline in anti-inflammatory cytokines, and dopamine in the corticobasal loop. Administration of vitamin D3 and A was found to suppres pro-inflammatory cytokines and repress anti-inflammatory cytokines associated with astrocyte activation.
Asunto(s)
Astrocitos , Enfermedades de los Ganglios Basales , Colecalciferol , Citocinas , Modelos Animales de Enfermedad , Dopamina , Actividad Motora , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Ratones , Citocinas/metabolismo , Actividad Motora/efectos de los fármacos , Colecalciferol/farmacología , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/inducido químicamente , Dopamina/metabolismo , MasculinoRESUMEN
Calcium (Ca2+) plays a central role in regulating many cellular processes and influences cell survival. Several mechanisms can disrupt Ca2+ homeostasis to trigger cell death, including oxidative stress, mitochondrial damage, excitotoxicity, neuroinflammation, autophagy, and apoptosis. Voltage-gated Ca2+ channels (VGCCs) act as the main source of Ca2+ entry into electrically excitable cells, such as neurons, and they are also expressed in glial cells such as astrocytes and oligodendrocytes. The dysregulation of VGCC activity has been reported in both Parkinson's disease (PD) and Huntington's (HD). PD and HD are progressive neurodegenerative disorders (NDs) of the basal ganglia characterized by motor impairment as well as cognitive and psychiatric dysfunctions. This review will examine the putative role of neuronal VGCCs in the pathogenesis and treatment of central movement disorders, focusing on PD and HD. The link between basal ganglia disorders and VGCC physiology will provide a framework for understanding the neurodegenerative processes that occur in PD and HD, as well as a possible path towards identifying new therapeutic targets for the treatment of these debilitating disorders.
Asunto(s)
Enfermedades de los Ganglios Basales , Enfermedad de Parkinson , Humanos , Canales de Calcio/metabolismo , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Neuronas/metabolismo , Ganglios Basales/metabolismo , Enfermedad de Parkinson/metabolismo , Calcio/metabolismoRESUMEN
Type-III sodium-dependent phosphate transporters 1 and 2 (PiT 1 and PiT 2, respectively) are proteins encoded by SLC20A1 and SLC20A2, respectively. The ubiquitous distribution of SLC20A1 and SLC20A2 mRNAs in mammalian tissues supports the housekeeping maintenance and homeostasis of intracellular inorganic phosphate (Pi), which is absorbed from interstitial fluid for normal cellular functions. SLC20A2 variants have been found in patients with idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease or primary familial brain calcification (PFBC). Thus, disrupted Pi homeostasis is considered one of the major factors in the pathogenic mechanism of IBGC. In this paper, among the causative genes of IBGC, we focused specifically on PiT2, and its potential for a therapeutic target of IBGC.
Asunto(s)
Enfermedades de los Ganglios Basales/genética , Calcinosis/genética , Enfermedades Neurodegenerativas/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Animales , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/terapia , Calcinosis/metabolismo , Calcinosis/terapia , Homeostasis/genética , Humanos , Terapia Molecular Dirigida , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/terapia , Fosfatos/metabolismo , ARN Mensajero , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismoRESUMEN
Different conformational strains of tau have been implicated in the clinicopathological heterogeneity of tauopathies. In this study, we hypothesized that distinct strains are degraded in a different manner. Lithium, a drug for bipolar disorder, had previously been reported to reduce aggregation-prone protein content by promoting autophagy. Here, we assessed the effects of lithium on tau aggregates using different tauopathy brain seeds. SH-SY5Y cells were transfected with C-terminal tau fragment Tau-CTF24 (residues 243-441), and Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain seeds were introduced. After 48-h lithium treatment, sarkosyl-insoluble fractions were prepared. Lithium treatment was found to reduce the amount of insoluble tau and p62, and increase LC3-II levels along with the number of autophagic vacuoles in AD-seeded cells. The effects were lower in case of CBD seeds, and comparable between PSP and AD seeds. An inhibitor of myo-inositol monophosphatase (IMPase) also demonstrated similar effects. Overall, the study suggested that aggregated tau protein is degraded by lithium-induced autophagy, influencing IMPase in a strain-specific manner.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedades de los Ganglios Basales/tratamiento farmacológico , Compuestos de Litio/farmacología , Parálisis Supranuclear Progresiva/tratamiento farmacológico , Proteínas tau/química , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Autofagia/efectos de los fármacos , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Humanos , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/patología , Tauopatías/tratamiento farmacológico , Tauopatías/metabolismo , Tauopatías/patologíaRESUMEN
Microtubule Associated Protein Tau (MAPT) forms proteopathic aggregates in several diseases. The G273R tau mutation, located in the first repeat region, was found by exome sequencing in a patient who presented with dementia and parkinsonism. We herein return to pathological examination which demonstrated tau immunoreactivity in neurons and glia consistent of mixed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) features. To rationalize the pathological findings, we used molecular biophysics to characterize the mutation in more detail in vitro and in Drosophila. The G273R mutation increases the aggregation propensity of 4-repeat (4R) tau and alters the tau binding affinity towards microtubules (MTs) and F-actin. Tau aggregates in PSP and CBD are predominantly 4R tau. Our data suggest that the G273R mutation induces a shift in pool of 4R tau by lower F-actin affinity, alters the conformation of MT bound 4R tau, while increasing chaperoning of 3R tau by binding stronger to F-actin. The mutation augmented fibrillation of 4R tau initiation in vitro and in glial cells in Drosophila and showed preferential seeding of 4R tau in vitro suggestively causing a late onset 4R tauopathy reminiscent of PSP and CBD.
Asunto(s)
Encéfalo/patología , Neuronas/metabolismo , Parálisis Supranuclear Progresiva/metabolismo , Tauopatías/patología , Animales , Enfermedades de los Ganglios Basales/metabolismo , Encéfalo/metabolismo , Drosophila , Mutación/genética , Neuroglía/metabolismoRESUMEN
Deposition of tau aggregates in the brain is a pathological hallmark of several neurodegenerative diseases, termed tauopathies, such as Alzheimer's disease (AD), corticobasal degeneration, and progressive supranuclear palsy (PSP). As transcellular spread of pathological tau aggregates has been implicated in disease progression, immunotherapy is being considered as a treatment for tauopathies. Here we report a detailed biochemical and biophysical characterization of the tau-binding properties of gosuranemab, a humanized monoclonal antibody directed against N-terminal tau that is currently being investigated as a treatment for AD. Binding experiments showed that gosuranemab exhibited high affinity for tau monomer, tau fibrils, and insoluble tau from different tauopathies. Epitope mapping studies conducted using X-ray crystallography and mutagenesis showed that gosuranemab bound to human tau residues 15-22. Immunodepletion of pathological human brain homogenates and transgenic mouse interstitial fluid (ISF) with gosuranemab resulted in reduced tau aggregation in tau biosensor cells. Preincubation of seed-competent AD-tau with gosuranemab significantly inhibited tau aggregation in mouse primary cortical neurons. Gosuranemab also significantly reduced unbound N-terminal tau in cerebrospinal fluid (CSF) from individuals with PSP and AD, and in ISF and CSF of treated transgenic mice. These results are consistent with the >90% target engagement observed in the CSF of some clinical trial dosing cohorts and support the evaluation of gosuranemab as a potential treatment for AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Anticuerpos Monoclonales Humanizados/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Animales , Enfermedades de los Ganglios Basales/metabolismo , Ratones Transgénicos , Neuronas/metabolismo , Parálisis Supranuclear Progresiva/metabolismo , Tauopatías/metabolismo , Tauopatías/patologíaRESUMEN
INTRODUCTION: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. METHODS: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. RESULTS: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. CONCLUSION: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.
Asunto(s)
Antipsicóticos/efectos adversos , Enfermedades de los Ganglios Basales/inducido químicamente , Enfermedades de los Ganglios Basales/genética , Farmacogenética/métodos , Pruebas de Farmacogenómica/métodos , Factores de Transcripción/genética , Animales , Enfermedades de los Ganglios Basales/metabolismo , Biología Computacional/métodos , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Ratones , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Polimorfismo de Nucleótido Simple/fisiología , Estudios Prospectivos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Factores de Transcripción/biosíntesisRESUMEN
Beta-propeller protein-associated neurodegeneration (BPAN) is categorized in Neurodegeneration with brain iron accumulation. The clinical feature of BPAN is global developmental delay in early childhood, followed rapid progression of cognitive disfunction and parkinsonism in adulthood. This case was pointed out intellectual disability at the age of 9, followed left dominant progressive parkinsonism from the age of 31. Brain MRI showed the T1-weighted signal hyperintensity of the substantia nigra with a central band of hypointensity and the T2 star weighted image hypointensity of substantia nigra and globus pallidus presenting dominant at right side. DAT SPECT also showed specific binding ratio decreased dominant in right side. She was diagnosed BPAN based on her genetic test revealing a novel mutation (c.411dupT) in WDR45. No studies reported detailed parkinsonism like laterality in BPAN. This case indicates the left dominant parkinsonism was caused by right dominant iron deposition to substantia nigra and globus pallidus in view of MRI findings and DAT SPECT.
Asunto(s)
Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/genética , Proteínas Portadoras/genética , Mutación , Enfermedades Neurodegenerativas/genética , Adulto , Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Imagen de Difusión Tensora , Femenino , Estudios de Asociación Genética , Humanos , Hierro/metabolismo , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Calcifications of the basal ganglia are frequently seen on the cerebral CT scans and particularly in the globus pallidus. Their frequency increases physiologically with age after 50 years old. However, pathological processes can also be associated with calcium deposits in the gray nuclei, posterior fossa or white matter. Unilateral calcification is often related to an acquired origin whereas bilateral ones are mostly linked to an acquired or genetic origin that will be sought after eliminating a perturbation of phosphocalcic metabolism. In pathological contexts, these calcifications may be accompanied by neurological symptoms related to the underlying disease: Parkinson's syndrome, psychiatric and cognitive disorders, epilepsy or headache. The purpose of this article is to provide a diagnostic aid, in addition to clinical and biology, through the analysis of calcification topography and the study of different MRI sequences.
Asunto(s)
Enfermedades de los Ganglios Basales , Calcinosis , Edad de Inicio , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/patología , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/epidemiología , Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/metabolismo , Calcinosis/diagnóstico , Calcinosis/epidemiología , Calcinosis/etiología , Calcinosis/metabolismo , Fosfatos de Calcio/efectos adversos , Fosfatos de Calcio/metabolismo , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Degeneración Nerviosa/diagnóstico , Degeneración Nerviosa/epidemiología , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Tomografía Computarizada por Rayos XRESUMEN
Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances1-3. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls4,5, and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau9. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats11-15. This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)16. Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE17-19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.
Asunto(s)
Enfermedades de los Ganglios Basales/patología , Corteza Cerebral/patología , Microscopía por Crioelectrón , Tauopatías/metabolismo , Tauopatías/patología , Proteínas tau/química , Proteínas tau/ultraestructura , Anciano , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Enfermedades de los Ganglios Basales/metabolismo , Química Encefálica , Corteza Cerebral/metabolismo , Encefalopatía Traumática Crónica/metabolismo , Encefalopatía Traumática Crónica/patología , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Enfermedad de Pick/metabolismo , Enfermedad de Pick/patología , Pliegue de Proteína , Proteínas tau/metabolismoAsunto(s)
Apatía , Enfermedades de los Ganglios Basales/complicaciones , Neoplasias Encefálicas/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Enfermedad de Parkinson Secundaria/etiología , Anciano , Enfermedad Cerebrovascular de los Ganglios Basales/complicaciones , Enfermedad Cerebrovascular de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Diagnóstico Diferencial , Progresión de la Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson Secundaria/diagnóstico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/metabolismoRESUMEN
Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.
Asunto(s)
Enfermedades de los Ganglios Basales/patología , Enfermedades Neurodegenerativas/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedades de los Ganglios Basales/metabolismo , Corteza Cerebral/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/metabolismoRESUMEN
An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.
Asunto(s)
Enfermedades de los Ganglios Basales/inducido químicamente , Cuerpo Estriado/efectos de los fármacos , Manganeso/toxicidad , Propiofenonas/toxicidad , Sustancia Negra/efectos de los fármacos , Animales , Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Conducta Animal , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Masculino , Manganeso/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Propiofenonas/administración & dosificación , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that show parkinsonism as their main symptom. Both PSP and CBD are sporadic tauopathies associated with hyperphosphorylated four-repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and the appearance of tufted astrocytes and globose-type neurofibrillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar dentate nuclei. Conversely, the characteristic pathologies of CBD are cortical atrophy and the appearance of astrocytic plaques and argyrophilic threads. CBD is associated with severe degeneration in the cerebral white matter, substantia nigra, and globus pallidus. Clinical symptoms depend on the topographical distribution and severity of degeneration rather than on the type of aggregated protein or inclusions. PSP and CBD present clinically differential diagnostic difficulties because of their overlapping pathological distributions.
Asunto(s)
Enfermedades de los Ganglios Basales/patología , Corteza Cerebral/patología , Parálisis Supranuclear Progresiva/patología , Enfermedades de los Ganglios Basales/metabolismo , Corteza Cerebral/metabolismo , Diagnóstico Diferencial , Humanos , Parálisis Supranuclear Progresiva/metabolismo , Proteínas tau/metabolismoRESUMEN
Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are forms of parkinsonism. PSP and CBD are 4R tauopathies and clinicopathologic overlaps exist between these two disorders. Neuropsychiatric symptoms including apathy, depression, anxiety are common features in patients with PSP and CBD. Disinhibition and impulsive behavior are also frequently observed in PSP patients, whereas hallucinations are seen only occasionally. Severe derangement in several neurotransmitter systems may account for behavioral symptoms observed in PSP and CBD, but substitutive therapy is not effective. Recent advances in genetics, epidemiology, biomarkers, pathophysiology, molecular mechanisms, and, in particular, the availability of treatments that may modify disease progression are opening new hopes in the care of these devastating disorders. MSA is a synucleinopathy with well characterized motor and autonomic dysfunction. MSA patients frequently show the presence of rapid eye movement (REM) behavior disorders, but the impact of neuropsychiatric disturbances and cognitive impairment in MSA needs further study. The availability of animal models and recent advances in the pathophysiology of α-synuclein accumulation are shedding light on the disease, opening new avenues for possible treatments.
Asunto(s)
Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/metabolismo , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/metabolismo , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/metabolismo , Enfermedades de los Ganglios Basales/terapia , Humanos , Atrofia de Múltiples Sistemas/terapia , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/terapia , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/terapia , Parálisis Supranuclear Progresiva/terapia , alfa-Sinucleína/antagonistas & inhibidores , alfa-Sinucleína/metabolismoRESUMEN
Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism.
Asunto(s)
Enfermedades de los Ganglios Basales , Encefalopatías Metabólicas Innatas , Glutatión/metabolismo , Adulto , Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/genética , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
The product of thiamine phosphokinase is the cofactor for many enzymes, including the dehydrogenases of pyruvate, 2-ketoglutarate and branched chain ketoacids. Its deficiency has recently been described in a small number of patients, some of whom had a Leigh syndrome phenotype. The patient who also had a Leigh phenotype was initially found to have a low concentration of biotin in plasma and massive urinary excretion of biotin. Despite treatment with biotin and thiamine, her disease was progressive. Mutations c.311delG and c.426Gâ¯>â¯C were found in the TPK1 gene.
Asunto(s)
Enfermedades de los Ganglios Basales/genética , Biotina/uso terapéutico , Tiamina Pirofosfoquinasa/deficiencia , Tiamina Pirofosfoquinasa/genética , Adulto , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Biotina/sangre , Biotina/orina , Femenino , Humanos , Mutación , Fenotipo , Tiamina Pirofosfoquinasa/metabolismo , Tiamina/uso terapéuticoRESUMEN
OBJECTIVE: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present. METHODS: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls. RESULTS: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004). INTERPRETATION: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526.
Asunto(s)
Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/patología , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/patología , Degeneración Nerviosa/patología , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/patología , Adulto , Atrofia/patología , Enfermedades de los Ganglios Basales/complicaciones , Enfermedades de los Ganglios Basales/metabolismo , Estudios de Casos y Controles , Trastornos Distónicos/complicaciones , Humanos , Hierro/metabolismo , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/metabolismo , Putamen/diagnóstico por imagen , Putamen/metabolismo , Putamen/patología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.