RESUMO
The role of mitochondria in steroidogenesis is well established. However, the specific effects of mitochondrial dysfunction on androgen synthesis are not fully understood. In this study, we investigate the effects of various mitochondrial and metabolic inhibitors in H295R adrenal cells and perform a comprehensive analysis of steroid and metabolite profiling. We report that mitochondrial complex I inhibition by rotenone shifts cells toward anaerobic metabolism with a concomitant hyperandrogenic phenotype characterized by rapid stimulation of dehydroepiandrosterone (DHEA, 2â¯h) and slower accumulation of androstenedione and testosterone (24â¯h). Screening of metabolic inhibitors confirmed DHEA stimulation, which included mitochondrial complex III and mitochondrial pyruvate carrier inhibition. Metabolomic studies revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA production as a common metabolic marker of hyperandrogenic inhibitors. The current study sheds light on a direct interplay between energy metabolism and androgen biosynthesis that could be further explored to identify novel molecular targets for efficient treatment of androgen excess disorders.
RESUMO
Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype-phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.
Assuntos
Hiperplasia Suprarrenal Congênita , Transtorno 46,XY do Desenvolvimento Sexual , Estudos de Associação Genética , Fosfoproteínas , Humanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/metabolismo , Transtorno 46,XY do Desenvolvimento Sexual/genética , Insuficiência Adrenal/genética , Insuficiência Adrenal/metabolismo , Mutação , Colesterol/metabolismo , FenótipoRESUMO
Cholesterol is the precursor of all steroids, but how cholesterol flux is controlled in steroidogenic tissues is poorly understood. The cholesterol exporter ABCG1 is an essential component of the reverse cholesterol pathway and its global inactivation results in neutral lipid redistribution to tissue macrophages. The function of ABCG1 in steroidogenic tissues, however, has not been explored. To model this, we inactivated Abcg1 in the mouse adrenal cortex, which led to an adrenal-specific increase in transcripts involved in cholesterol uptake and de novo synthesis. Abcg1 inactivation did not affect adrenal cholesterol content, zonation, or serum lipid profile. Instead, we observed a moderate increase in corticosterone production that was not recapitulated by the inactivation of the functionally similar cholesterol exporter Abca1. Altogether, our data imply that Abcg1 controls cholesterol uptake and biosynthesis and regulates glucocorticoid production in the adrenal cortex, introducing the possibility that ABCG1 variants may account for physiological or subclinical variation in stress response.
Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Córtex Suprarrenal , Colesterol , Animais , Camundongos , Córtex Suprarrenal/metabolismo , Transporte Biológico , Colesterol/metabolismo , Corticosterona , Glucocorticoides , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
Introduction: In patients with Parkinson's disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer's disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods: In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results: During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions: In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.
RESUMO
CONTEXT: Polycystic ovary syndrome (PCOS) is defined by androgen excess and ovarian dysfunction in the absence of a specific physiological diagnosis. The best clinical marker of androgen excess is hirsutism, while the best biochemical parameter is still a matter of debate. Current consensus guidelines recommend, among other hormones, serum free testosterone as an important serum parameter to measure androgen excess. Recently, however, novel active androgens and androgen metabolic pathways have been discovered. OBJECTIVE: To assess the contribution of novel androgens and related steroid biosynthetic pathways to the serum steroid pool in PCOS women in comparison to healthy controls. DESIGN: This is a case control study, wherein PCOS was diagnosed according to the AE-PCOS 2009 criteria. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry. SETTING: Yeditepe University and associated clinics in Istanbul, Turkey, together with Bern University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS: 42 PCOS women and 42 matched, healthy control women. MAIN OUTCOME MEASURES: Assessment of 34 steroids compartmentalized in four androgen related pathways: the classic androgen pathway, the backdoor pathway, the C11-oxy backdoor pathway, and the C11-oxy (11ß-hydroxyandrostenedione) pathway. RESULTS: Metabolites of all four pathways were identified in healthy and PCOS women. Highest concentrations were found for progesterone in controls and androstenedione in PCOS. Lowest levels were found for 11-ketotestosterone in controls compared to PCOS, and for 20α-hydroxyprogesterone in PCOS compared to controls. PCOS also had higher serum testosterone levels compared to the controls. PCOS women had overall higher levels of steroid metabolites of all four androgen pathways compared to healthy controls. CONCLUSIONS: Novel alternative pathways contribute to the androgen production in healthy and PCOS women. Hyperandrogenism in PCOS is characterized by an overall increase of serum androgens in the classic, backdoor and C11-oxy pathways. While monogenetic disorders of steroid biosynthesis can be recognized by a specific pattern in the steroid profile, no diagnostic pattern or classifier was found in the serum for PCOS.
Assuntos
Hiperandrogenismo , Síndrome do Ovário Policístico , Feminino , Humanos , Síndrome do Ovário Policístico/metabolismo , Androgênios/metabolismo , Estudos de Casos e Controles , Esteroides , Testosterona/metabolismo , Hiperandrogenismo/complicaçõesRESUMO
INTRODUCTION: The key feature that distinguishes mild cognitive impairment (MCI) from dementia is the absence of significant functional decline because of cognitive impairment. In Parkinson's disease patients (PD) with MCI (PD-MCI), the effect of cognitive impairment on complex instrumental daily activities, such as medication management, is not well established. METHOD: 26 patients with PD-MCI (diagnosed to Level 2 Movement Disorders Society diagnostic criteria) and 32 idiopathic PD patients without cognitive impairment participated in the study. A detailed neuropsychological testing battery (including tests for attention and working memory, executive functions, language, visuospatial functions, episodic memory) and various prospective memory tasks were applied to the patients. Medication taking behaviors were evaluated using two different methods based on the performance (medication management ability assessment) and self-reporting (adherence scale). RESULTS: The PD-MCI group obtained significantly lower scores in medication management assessment and made more mistakes on following prescription instructions (e.g., they took more or less tablets and did not use medications as instructed with regard to meal times). Cognitive areas predicting success in medication management performance were language, event-based prospective memory and visuospatial functions. There was no significant difference between the two groups' self-reporting of adherence. CONCLUSION: Mild cognitive impairment in patients with PD adversely affects medication management. Diagnosing MCI in PD is important to ensure that the appropriate measures can be taken to provide support and improve the medication management process. Adherence assessments based on self-reporting may not provide reliable and sensitive information in patients with PD-MCI.
Assuntos
Disfunção Cognitiva , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Conduta do Tratamento Medicamentoso , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Função Executiva , Testes Neuropsicológicos , Cooperação e Adesão ao TratamentoRESUMO
INTRODUCTION: Anticholinergic burden may be an important risk factor for the cognitive impairment. Especially in polypharmacy, even drugs with low anticholinergic effects may contribute to a significant anticholinergic burden. The drugs with anticholinergic effects are used in treatment of motor and nonmotor symptoms of Parkinson's disease (PD). Therefore, it is important to screen for polypharmacy and anticholinergic burden in PD patients with mild cognitive impairment (MCI). METHODS: This cross-sectional study was conducted with 58 patients with PD. PD-MCI was diagnosed according to MDS Level 2 Comprehensive Assessment. Cognitive performance (attention - working memory, executive functions, language, memory, and visuospatial functions) of patients was evaluated. The anticholinergic burden was scored by Anticholinergic Cognitive Burden (ACB) Scale, Anticholinergic Risk Scale (ARS), and Anticholinergic Drug Scale (ADS). RESULTS: There was no significant difference in anticholinergic burden between PD-MCI and PD-normal cognition. A significant concordance was observed between ACB, ARS, and ADS scores (p < 0.001; Kendall's W = 0.653). While the variable predicting anticholinergic burden was the total number of drugs for ACB and ADS scales, it was the number of antiparkinson drugs for ARS scale. CONCLUSION: Patients with PD are at high risk for polypharmacy and anticholinergic burden. Anticholinergic burden should be considered in the selection of drugs, especially for comorbidities in patients with PD. No significant correlation was found between the cognition and anticholinergic burden in patients with PD-MCI. Although the risk scores of antiparkinson and other drugs were different among the 3 scales, significant concordance was observed between scales.
Assuntos
Disfunção Cognitiva , Doença de Parkinson , Humanos , Antagonistas Colinérgicos/efeitos adversos , Estudos Transversais , Polimedicação , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , CogniçãoRESUMO
Adrenarche is an early event in sexual maturation in prepubertal children and corresponds to the postnatal development of the adrenocortical zona reticularis (zR). However, the molecular mechanisms that govern the onset and maturation of zR remain unknown. Using tissue laser microdissection combined with transcript quantification and immunodetection, we showed that the human zR receives low levels of cholesterol in comparison with other adrenal layers. To model this metabolic condition, we challenged adrenal cells in vitro using cholesterol deprivation. This resulted in reprogramming the steroidogenic pathway toward inactivation of 3-beta-hydroxysteroid dehydrogenase type 2 (HSD3B2), increased CYB5A expression, and increased biosynthesis of dehydroepiandrosterone (DHEA), 3 key features of zR maturation during adrenarche. Finally, we found that cholesterol deprivation leads to decreased transcriptional activity of POU3F2, which normally stimulates the expression of HSD3B2 by directly binding to its promoter. These findings demonstrate that cholesterol deprivation can account, at least in part, for the acquisition of a zR-like androgenic program in humans.
Assuntos
Glândulas Suprarrenais , Adrenarca , Glândulas Suprarrenais/metabolismo , Adrenarca/fisiologia , Androgênios/metabolismo , Criança , Desidroepiandrosterona/metabolismo , Humanos , Zona Reticular/metabolismoRESUMO
OBJECTIVES: Leptin resistance is one of the important causes of obesity in children. Besides known causes of leptin resistance like mutations in leptin and leptin receptor genes, overexpression of SOCS3 in arcuate nucleus is a potential cause of leptin resistance. We aimed to determine the effects of circulating miRNAs on leptin resistance in obese children by targeting SOCS3 pathway. METHODS: miRNAs potentially targeting SOCS3 were determined by using online target prediction databases. Polymorphisms in miRNA target sequences were determined by using online genome browsers. miRNA expression levels of obese (n=35) and non-obese (n=30) children were determined by qPCR method, genotyping were performed by real-time PCR method and serum leptin, leptin receptor and SOCS3 levels were measured by ELISA method. RESULTS: miRNA profiling have shown that serum miR-218-5p levels are significantly (p<0.05) increased in accordance with serum leptin levels in obese children. CONCLUSIONS: In this study we used target prediction methods for evaluating potential miRNAs which may involve in development of leptin resistance. We have shown that miR-218-5p might be taking part in leptin resistance in obese children.
Assuntos
MicroRNAs , Obesidade Infantil , Criança , Humanos , Leptina/metabolismo , MicroRNAs/genética , Obesidade Infantil/genética , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
BACKGROUND: Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ. CASE PRESENTATION: Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease. CONCLUSIONS: In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.
Assuntos
Epilepsias Mioclônicas Progressivas , Estudos de Associação Genética , Humanos , Proteínas de Membrana Lisossomal/genética , Epilepsias Mioclônicas Progressivas/genética , Epilepsias Mioclônicas Progressivas/patologia , Fenótipo , Receptores Depuradores/genéticaRESUMO
INTRODUCTION: The majority of Parkinson's disease (PD) ensue late-onset with a complex spectrum of environmental and genetic risk factors. Awareness of genetic causes in patients with PD is essential for genetic counseling and future genotype-oriented therapeutic developments. METHODS: Large pathogenic changes in eight PD-related genes and small pathogenic sequence variants in 22 PD-related genes were investigated simultaneously in 82 PD patients from 79 families where clinical evaluations were performed. The phenotypic characteristics of the patients with molecular changes were examined for genotype-phenotype relations. RESULTS: Pathogenic variants in SNCA, PRKN, DJ-1, FBXO7, and GBA genes were determined in 25 patients from 24 families (24/79, 30%). Associated variants were found in PRKN in 14, SNCA in three, FBXO7 in two, and DJ-1 in one patient. A novel homozygous deletion (c.491delT, p.(V164Dfs*13) (SCV001733595)) leading to protein truncation in the PRKN gene was identified in two patients from the same family. Furthermore, heterozygous GBA gene variants were detected in five patients from different families. CONCLUSION: It has been shown that the most common cause of genetically transmitted PD is the PRKN gene, while LRRK2 does not play an essential role in this selected population. It has been suggested that even if the autosomal recessive inheritance is expected, genes with autosomal dominant effects such as SNCA should not be overlooked and suggested for investigation. Our study is also the first for evaluating the pathogenic GBA variants' frequency in PD patients from Turkey.
Assuntos
Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Adulto , Proteínas F-Box , Feminino , Variação Genética , Genótipo , Glucosilceramidase , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Proteína Desglicase DJ-1 , Deleção de Sequência , Turquia , Ubiquitina-Proteína Ligases , alfa-SinucleínaRESUMO
INTRODUCTION: Missense variants and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson's Disease (PD). METHODS: Two families of Turkish origins with PD were studied; the SNCA coding region was analyzed by Sanger sequencing, and by whole exome sequencing (WES) in the index patient of the first and the second family, respectively. Co-segregation studies and haplotype analysis across the SNCA locus were carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein. RESULTS: We identified a novel heterozygous SNCA variant, c.215C > T (p.Thr72Met), segregating with PD in a total of four members in the two families. A shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common ancestor. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. In silico analysis of a tetrameric α-syn structural model revealed that Threonine 72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially destabilize the tetramer. CONCLUSION: We present clinical, genetic, and functional data supporting a causative role of the SNCA c.215C > T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the PD-causing SNCA missense variants, and how they lead to neurodegeneration.
Assuntos
Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/genética , Feminino , Haplótipos , Humanos , Pessoa de Meia-Idade , Linhagem , TurquiaRESUMO
Just as its clinical heterogeneity, genetic basis of Frontotemporal dementia (FTD) is also diverse and multiple molecular pathways are thought to be involved in disease pathogenesis. In the present study, FTD- related genes were evaluated in a Turkish cohort of 175 index FTD patients with a gene panel including GRN, MAPT, TARDBP, FUS, CHMP2B and VCP genes. Potential genetic associations were prospected in 16 patients (9.1%); five variants (p.(Gly35Glufs) and p.(Cys253Ter) in GRN; p.(Arg95Cys) in VCP; p.(Met405Val) in TARDBP and p.(Pro636Leu) in MAPT) were classified as pathogenic (P) or likely pathogenic (LP), in four familial and one sporadic patients. Three novel variants in MAPT, CHMP2B and FUS were also identified in familial cases. The most common pathogenic variants were observed in the GRN gene with a frequency of 1.14% (2/175) and this rate was 4.57% (8/175), including variants of uncertain significance (VUS). In this study with the largest cohort of Turkish FTD patients, GRN and MAPT variants were identified as the most common genetic associations; and rare causes like VCP, TARDBP, CHMP2B and FUS variants are recommended to be considered in patients with compatible clinical findings.
Assuntos
Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Progranulinas/genética , Proteínas tau/genética , Idoso , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína FUS de Ligação a RNA/genética , Turquia/epidemiologia , Proteína com Valosina/genéticaRESUMO
BACKGROUND AND PURPOSE: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. METHOD: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. RESULTS: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. CONCLUSION: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.
Assuntos
Demência Frontotemporal , Lipodistrofia , Glicoproteínas de Membrana/genética , Osteocondrodisplasias , Receptores Imunológicos/genética , Panencefalite Esclerosante Subaguda , Adulto , Encéfalo/diagnóstico por imagem , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Humanos , Imageamento por Ressonância Magnética , NeuroimagemRESUMO
BACKGROUND: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD. METHODS: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. RESULTS: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (pâ=â0.012). Significant increased connectivityConclusion:Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.
Assuntos
Doença de Gaucher , Glucosilceramidase/química , Doença de Parkinson , Glucosilceramidase/genética , Heterozigoto , Humanos , Mutação/genéticaRESUMO
Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism, and WD patients can present with neurologic symptoms. We aimed to report the general characteristics and prognosis of a Turkish series of WD patients with neurological manifestations. A total of 12,352 patients were screened from the patient database, and 53 WD patients were included. Patients were classified based on the predominant neurological syndrome type including tremor, dystonia, parkinsonism, or discrete neurological signs and were classified as having "good outcome," "stable," and "poor outcome" according to their treatment response. There were 32 male and 21 female patients, aged 20-66 years. The mean follow-up was 11.3 ± 4.56 years. Sixty-two percent of patients presented predominantly with neurological symptoms. Neurological WD diagnosis was established after a mean time delay of 2.3 years from the WD diagnosis. The most common neurological manifestation was dystonia, followed by tremor and parkinsonism. Fifteen patients had a family history of WD. Consanguinity was present in 20 patients. Patients were treated with D-penicillamine, trientine, zinc salts, or their combinations. Besides the main treatments, 41 patients were on symptomatic treatment for neurologic symptoms. Thirty-six patients had a "good outcome," five patients were stable, and six patients had "poor outcome." Post-chelation neurological worsening was observed in 11 patients. WD should be considered in differential diagnosis in any patient with unexplained neurologic symptoms. Early diagnosis is important, and appropriate treatment should be promptly initiated to prevent progressive and irreversible damage, with good prognosis and stable disease in the majority of the patients with treatment compliance.
Assuntos
Distonia , Degeneração Hepatolenticular , Cobre , Distonia/diagnóstico , Distonia/epidemiologia , Distonia/etiologia , Feminino , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/epidemiologia , Humanos , Masculino , Penicilamina/uso terapêutico , Tremor/diagnóstico , Tremor/epidemiologia , Tremor/etiologiaRESUMO
INTRODUCTION: The most prominent risk factor of Alzheimer's disease (AD) is aging. Aging also influences the physical appearance. Our clinical experience suggests that patients with AD may appear younger than their actual age. Based on this empirical observation, we set forth to test the hypothesis with human and computer-based estimation systems. METHOD: We compared 50 early-stage AD patients with 50 age and sex-matched controls. Facial images of all subjects were recorded using a video camera with high resolution, frontal view, and clear lighting. Subjects were recorded during natural conversations while performing Mini-Mental State Examination, including spontaneous smiles in addition to static images. The images were used for age estimation by 2 methods: (1) computer-based age estimation; (2) human-based age estimation. Computer-based system used a state-of-the-art deep convolutional neural network classifier to process the facial images contained in a single-video session and performed frame-based age estimation. Individuals who estimated the age by visual inspection of video sequences were chosen following a pilot selection phase. The mean error (ME) of estimations was the main end point of this study. RESULTS: There was no statistically significant difference between the ME scores for AD patients and healthy controls (p = 0.33); however, the difference was in favor of younger estimation of the AD group. The average ME score for AD patients was lower than that for healthy controls in computer-based estimation system, indicating that AD patients were on average estimated to be younger than their actual age as compared to controls. This difference was statistically significant (p = 0.007). CONCLUSION: There was a tendency for humans to estimate AD patients younger, and computer-based estimations showed that AD patients were estimated to be younger than their real age as compared to controls. The underlying mechanisms for this observation are unclear.
Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer , Aparência Física , Estatística como Assunto/métodos , Fatores Etários , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Metodologias Computacionais , Feminino , Humanos , Masculino , Gravação em VídeoRESUMO
Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.
Assuntos
Doença de Parkinson/genética , Proteína Desglicase DJ-1/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Análise Mutacional de DNA , Feminino , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Adulto JovemRESUMO
AIM: Sports activities provide social interaction for humans. Commitment to a given team is a salient feature of being a sports fan and becomes a prominent part of self-identification for fanatics. Emotion, subjective hedonic experience, and non-romantic love are related to fan behaviors. Few studies have evaluated the neural basis of sports fanaticism. METHODS: Thirty men, including 16 football fanatics and 14 non-fanatics, with a mean age of 27.4 ± 6.4 years (range, 20-48 years) were enrolled. Subjects underwent functional MRI while watching a set of goals scored by favorite, rival, and neutral teams. RESULTS: The analysis of variance in a general linear model revealed a significant Group × Condition interaction effect in the bilateral dorsal anterior cingulate cortex (dACC) that was more prominent in the left hemisphere. In the post-hoc comparisons, fanatics showed increased activation in bilateral dACC, supplementary motor area, superior frontal cortex, right dorsolateral prefrontal cortex, and right insula for Favorite > Neutral contrast and an increased activation in bilateral dACC and supplementary motor area for Rival > Neutral contrast. Seed-based connectivity analyses using the areas with significant activation differences revealed increased connectivity between dACC and several regions, including the left posterior lateral temporal area, insula, bilateral medial temporal area, and medial superior frontal area as well as the basal ganglia in fanatics compared to non-fanatics. CONCLUSION: Our results suggest that football fanatics exhibit a different brain activation and connectivity pattern from non-fanatics, both under favorable and unfavorable conditions. This brain activity and connectivity pattern under emotionally laden conditions may represent higher responses to rewards, higher emotional valence attribution, and stronger motivational state of football fanatics, which might underlie their unusual behavioral responses.
Assuntos
Gânglios da Base/fisiologia , Emoções/fisiologia , Giro do Cíngulo/fisiologia , Córtex Motor/fisiologia , Córtex Pré-Frontal/fisiologia , Futebol/psicologia , Adulto , Gânglios da Base/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: The aim of this study was to evaluate the role of polymorphisms of stromal cell-derived factor-1 (SDF-1) and chemokine receptor-4 (CXCR4) genes in dementia susceptibility in a Turkish population. SUBJECTS AND METHODS: The study group included 61 dementia patients, while the control group comprised 82 healthy individuals. Gene polymorphisms of SDF-1 3'A G801A (rs1801157) and CXCR4 C138T (rs2228014) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: A significantly reduced risk for developing dementia was found for the group bearing an A allele for SDF-1 3'A polymorphism (p=0.009; χ2=6.812; OR=0.626; 95%CI= 0.429-0.913). The frequency of the CXCR4 TT and TC genotype was significantly lower in patients with dementia compared to controls (p=0.028; χ2=5.583; OR=0.215; 95%CI=0.05-0.914); (p=0.027; χ2=4.919; OR=0.484; 95% CI=0.246-0.955). Additionally, combined genotype analysis showed that the frequency of SDF1 GA-CXCR4 CC was significantly lower in patients with dementia in comparison with those of controls (p=0.049; OR=0.560; 95% CI= 0.307±1.020). CONCLUSIONS: Our study provides new evidence that SDF1 A and CXCR4 T alleles may be associated with a decreased dementia risk. The present study is important because to our knowledge, it is the first one to be conducted in a Turkish population to date, but we believe that more patients and controls are needed to obtain statistically significant results.