RESUMO
Olfaction is a fundamental sense that plays a vital role in daily life in humans, and can be altered in neuropsychiatric and neurodegenerative diseases. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) using conventional echo-planar-imaging (EPI) based sequences can be challenging in brain regions important for olfactory processing, such as the olfactory bulb (OB) and orbitofrontal cortex, mainly due to the signal dropout and distortion artifacts caused by large susceptibility effects from the sinonasal cavity and temporal bone. To date, few studies have demonstrated successful fMRI in the OB in humans. T2-prepared (T2prep) BOLD fMRI is an alternative approach developed especially for performing fMRI in regions affected by large susceptibility artifacts. The purpose of this technical study is to evaluate T2prep BOLD fMRI for olfactory functional experiments in humans. Olfactory fMRI scans were performed on 7T in 14 healthy participants. T2prep BOLD showed greater sensitivity than GRE EPI BOLD in the OB, orbitofrontal cortex and the temporal pole. Functional activation was detected using T2prep BOLD in the OB and associated olfactory regions. Habituation effects and a bi-phasic pattern of fMRI signal changes during olfactory stimulation were observed in all regions. Both positively and negatively activated regions were observed during olfactory stimulation. These signal characteristics are generally consistent with literature and showed a good intra-subject reproducibility comparable to previous human BOLD fMRI studies. In conclusion, the methodology demonstrated in this study holds promise for future olfactory fMRI studies in the OB and other brain regions that suffer from large susceptibility artifacts.
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OBJECTIVE: Personality affects an individual's ability to cope with the burden of chronic disease. However, the impact of personality on quality of life (QoL) in Parkinson's disease (PD) is not well characterized. The goal of this study is to determine the effect of personality on QoL in PD. METHODS: The study included 92 patients with idiopathic PD from Baltimore-Washington area movement disorder neurology clinics. QoL was assessed using the 37-item Parkinson's disease Quality of Life Questionnaire (PDQL) total score, and the Neuroticism-Extraversion-Openness Inventory was used to determine personality traits. RESULTS: Step-wise regression models examined the contribution of personality, depression, demographic, and PD variables on PDQL-assessed QoL. Neuroticism, conscientiousness, years of education, and depression explained 42% of the variance in the PDQL total score after adjusting for other disease variables. High neuroticism (ß = -0.727, 95% confidence interval (CI) -1.125, -0.328, p < 0.0001) and depression (ß = -9.058, 95%CI -17.46, -0.657, p = 0.035) negatively affected the PDQL, while high conscientiousness (ß = 0.468, 95%CI 0.078, 0.858, p = 0.019), and years of education (ß = 1.441, 95%CI 0.371, 2.510, p = 0.009) were positive factors. CONCLUSIONS: Personality can have a positive or negative influence on QoL in PD. PD patients with otherwise similar disease burdens and depressive symptoms may experience different levels of QoL depending on the level of neurotic or conscientious personality traits. Therefore, when interpreting patient responses on the PDQL, it is important to understand whether they reflect aspects of PD, that is, motor impairment and depression, which are amenable to treatment or whether they reflect personality traits.
Assuntos
Depressão , Doença de Parkinson , Personalidade , Qualidade de Vida , Adaptação Psicológica , Idoso , Depressão/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroticismo , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Transtornos da Personalidade , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Depression in Parkinson disease (PD) is a common problem that worsens quality of life and causes disability. However, little is known about the longitudinal impact of depression on disability in PD. This study examined the association between disability and DSM-IV-TR depression status across six years. METHODS: Longitudinal cohort study with assessments at study entry, year two, four, and six conducted in the Morris K. Udall Parkinson Disease Research Center. Recruitment totaled 137 adult men and women with idiopathic PD in which up to six years of data on demographic, motor, and non-motor variables was collected. Movement disorder specialists used the structured interview for DSM-IV-TR depressive disorders and the Northwestern Disability Scale to assess depression and disability. A generalized linear mixed model was fitted with Northwestern Disability Scale score as the dependent variable to determine the effect of baseline depression status on disability. RESULTS: A total of 43 participants were depressed at baseline compared to 94 without depression. Depressed participants were more likely to be female, were less educated, were less likely to take dopamine agonists, and more likely to have motor fluctuations. Controlling for these variables, symptomatic depression predicted greater disability compared to both never depressed (p = 0.0133) and remitted depression (p = 0.0009). Disability associated with symptomatic depression at baseline was greater over the entire six-year period compared to participants with remitted depressive episodes or who were never depressed. CONCLUSIONS: Persisting depression is associated with a long-term adverse impact on daily functioning in PD. Adequate treatment or spontaneous remission of depression improves ADL function.
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Transtorno Depressivo/complicações , Pessoas com Deficiência/psicologia , Doença de Parkinson/psicologia , Atividades Cotidianas , Adulto , Idoso , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Qualidade de Vida , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Huntington's disease (HD) is a neurodegenerative disease caused by cytosine-adenine-guanine (CAG)-repeat expansion in the huntingtin (HTT) gene. Early changes that may precede clinical manifestation of movement disorder include executive dysfunction. The aim of this study was to identify functional network correlates of impaired higher cognitive functioning in relation to HD stage. Blood-oxygenation-level-dependent (BOLD) functional-magnetic resonance imaging (fMRI) and structural-MRI were performed in 53 subjects with the HD-mutation (41 prodromals, 12 early affected) and 52 controls. Disease stage was estimated for each subject with HD-mutation based on age, length of the CAG-repeat expansion mutation and also putaminal atrophy. The Tower of London test was administered with three levels of complexity during fMRI as a challenge of executive function. Functional brain networks of interest were identified based on cortical gray matter voxel-clusters with significantly enhanced task-related functional coupling to the medial prefrontal cortex (MPFC) area. While prodromal HD-subjects showed similar performance levels as controls, multivariate analysis of task-related functional coupling to the MPFC identified reduced connectivity in prodromal and early manifest HD-subjects for a cluster including mainly parts of the left premotor area. Secondary testing indicated a significant moderator effect for task complexity on group differences and on the degree of correlation to measures of HD stage. Our data suggest that impaired premotor-MPFC coupling reflects HD stage related dysfunction of cognitive systems involved in executive function and may be present in prodromal HD-subjects that are still cognitively normal. Additional longitudinal studies may reveal temporal relationships between impaired task-related premotor-MPFC coupling and other brain changes in HD.
Assuntos
Função Executiva/fisiologia , Doença de Huntington/psicologia , Córtex Pré-Frontal/fisiopatologia , Adulto , Mapeamento Encefálico , Progressão da Doença , Feminino , Lateralidade Funcional/fisiologia , Humanos , Proteína Huntingtina , Doença de Huntington/fisiopatologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia , Proteínas do Tecido Nervoso/genética , Testes Neuropsicológicos , Oxigênio/sangue , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologiaRESUMO
OBJECTIVES: White matter hyperintensities (WMH) are more common in subjects with bipolar disorder (BP) than in healthy subjects (HS). Few studies have examined the effect of the diagnostic type of bipolar illness on WMH burden, and none have approached this question through a direct measurement of the volume of affected white matter in relationship to familiality. In this pilot study, we utilized a volumetric measurement of WMH to investigate the relationship between the total volume of WMH and the familiality and type of BP. METHODS: Forty-five individuals with bipolar I disorder (BP-I) with psychotic features, BP-I without psychotic features, or bipolar II disorder (BP-II), seven of their unaffected relatives, and 32 HS were recruited for participation. T-2 weighted magnetic resonance imaging scans were obtained on all subjects, and the total volume of all WMH for each subject was measured in cubic centimeters. The significance of difference between groups was tested using ANOVA with post-hoc adjustment for multiple comparisons. Further, we used logistic regression to test for trends between symptom load and total WMH volume. RESULTS: The mean total volume of WMH in BP-I patients with psychotic features was significantly higher (p < 0.05) than that of HS. Further, we observed a positive linear trend by familiality and type of affectedness when comparing mean total WMH volume of HS, unaffected family members, subjects with BP-II, and BP-I with and without a history of psychosis (p < 0.05). CONCLUSIONS: Based on a quantitative technique, WMH burden appears to be associated with familiality and type of BP. The significance of these findings remains to be fully elucidated.
Assuntos
Transtorno Bipolar/patologia , Encéfalo/patologia , Leucoencefalopatias/complicações , Fibras Nervosas Mielinizadas/patologia , Adulto , Análise de Variância , Transtorno Bipolar/complicações , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , MasculinoRESUMO
Huntington's Disease (HD) is a neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat-expansion in the Huntingtin (HTT) gene. Diagnosis of HD is classically defined by the presence of motor symptoms; however, cognitive and depressive symptoms frequently precede motor manifestations, and may occur early in the prodromal phase. There are sparse data so far on functional brain correlates of depressive symptoms in prodromal HD. A Stroop color-naming test was administered to 32 subjects in the prodromal phase of HD and 52 expansion-negative controls while performing functional magnetic resonance imaging at 3Tesla. Networks of functional connectivity were identified using group independent component analysis, followed by an analysis of functional network interactions. A contrast of temporal regression-based beta-weights was calculated as a reflection of Stroop-interference related activity and correlated with Center for Epidemiologic Studies Depression (CES-D) scores. For secondary analysis, patients were stratified into two subgroups by median split of CAG repeat-length. Stroop performance was independent of HTT mutation-carrier status and CES-D score. Stroop-interference-related activity of the ventromedial prefrontal cortex-node of the default-mode network, calculated by temporal-regression beta-weights, was more highly correlated with depressive symptoms in subjects in the prodromal phase of HD than in controls, differing significantly. The strength of this correlation and its difference from controls increased when a subgroup of patients with longer CAG repeat lengths was analyzed. These findings suggest that depressive symptoms in prodromal HD subjects may reflect altered functional brain network activity in the context of early HD-related brain alterations.
Assuntos
Transtorno Depressivo/fisiopatologia , Doença de Huntington/fisiopatologia , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Sintomas Prodrômicos , Teste de Stroop , Adenina , Adulto , Citosina , Análise Mutacional de DNA , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Feminino , Carga Genética , Guanina , Giro do Cíngulo/fisiopatologia , Humanos , Proteína Huntingtina , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Estatística como Assunto , Expansão das Repetições de TrinucleotídeosRESUMO
Huntington's disease (HD) is a neurodegenerative disorder characterized by early cognitive decline that progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aimed to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high-field-strength magnetic resonance spectroscopy (MRS) at 7 Tesla. Twelve individuals with the HD mutation in premanifest or early-stage disease versus 12 healthy controls underwent (1)H magnetic resonance spectroscopy (7.2 mL voxel in the posterior cingulate cortex) at 7 Tesla, and also T1-weighted structural magnetic resonance imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (-9.6%, P = .02) and glutamate (-10.1%, P = .02) levels than did controls. In contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r(2) = 0.50, P = .01) and glutamate (NAA) (r(2) = 0.64, P = .002) in HD subjects. Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in the early stages of HD. N-acetylaspartate and glutamate magnetic resonance spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor.
Assuntos
Ácido Aspártico/análogos & derivados , Encéfalo/metabolismo , Transtornos Cognitivos/etiologia , Doença de Huntington/complicações , Doença de Huntington/patologia , Adulto , Análise de Variância , Ácido Aspártico/metabolismo , Encéfalo/patologia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Doença de Huntington/genética , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Análise de Regressão , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment. Here, we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Nootrópicos/uso terapêutico , Piracetam/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Amnésia/complicações , Mapeamento Encefálico , Estudos de Casos e Controles , Comportamento de Escolha/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Método Duplo-Cego , Feminino , Hipocampo/irrigação sanguínea , Humanos , Processamento de Imagem Assistida por Computador , Levetiracetam , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Oxigênio/sangue , Estimulação Luminosa , Piracetam/uso terapêutico , Estatística como AssuntoRESUMO
Huntington's Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD. Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3T). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity. Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy. Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD.
Assuntos
Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Doença de Huntington/fisiopatologia , Adulto , Mapeamento Encefálico , Progressão da Doença , Feminino , Neuroimagem Funcional , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologiaAssuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 9 , Expansão das Repetições de DNA , Demência Frontotemporal/genética , Proteínas/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Proteína C9orf72 , Erros de Diagnóstico , Feminino , Demência Frontotemporal/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We have previously reported strong linkage on chromosome 10q in pedigrees transmitting Alzheimer's disease through the mother, overlapping with many significant linkage reports including the largest reported study. Here, we report the most comprehensive fine mapping of this region to date. In a sample of 638 late-onset Alzheimer's disease (LOAD) cases and controls including 104 maternal LOAD cases, we genotyped 3,884 single nucleotide polymorphisms (SNPs) covering 15.2 Mb. We then used imputations and publicly available data to generate an extended dataset including 4,329 SNPs for 1,209 AD cases and 839 controls in the same region. Further, we screened eight genes in this region for rare alleles in 283 individuals by nucleotide sequencing, and we tested for possible monoallelic expression as it might underlie our maternal parent of origin linkage. We excluded the possibility of multiple rare coding risk variants for these genes and monoallelic expression when we could test for it. One SNP, rs10824310 in the PRKG1 gene, showed study-wide significant association without a parent of origin effect, but the effect size estimate is not of sufficient magnitude to explain the linkage, and no association is observed in an independent genome-wide association studies (GWAS) report. Further, no causative variants were identified though sequencing. Analysis of cases with maternal disease origin pointed to a few regions of interest that included the genes PRKG1 and PCDH15 and an intergenic interval of 200 Kb. It is likely that non-transcribed rare variants or other mechanisms involving these genomic regions underlie the observed linkage and parent of origin effect. Acquiring additional support and clarifying the mechanisms of such involvement is important for AD and other complex disorder genetics research.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Ligação Genética , Predisposição Genética para Doença , Idoso , Proteínas Relacionadas a Caderinas , Caderinas/genética , Mapeamento Cromossômico , Feminino , Loci Gênicos , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We previously reported strong genetic linkage on chromosome 14q to Alzheimer's disease (AD) using the presence of co-morbid hallucinations as a covariate. Those results suggested the presence of a gene increasing the risk for a genetically homogeneous form of AD characterized by the absence of comorbid hallucinations. Here we report our follow up of that study through the analysis of single nucleotide polymorphisms (SNPs) in five functional candidate genes. This work provides significant evidence of association for the gene coding for neuroglobin (NGB), a nervous system globin known to protect cells against amyloid toxicity and to attenuate the AD phenotype of transgenic mice. On further experiments we found that NGB expression is reduced with increasing age and lower in women consistent with their increased risk. NGB expression is up-regulated in the temporal lobe of AD patients consistent with a response to the disease process, as reported for NGB and hypoxia. We speculate that a compromised response due to DNA variation might increase the risk for AD. Our and others' data strongly support the involvement of NGB in AD.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14/genética , Globinas/genética , Alucinações/genética , Proteínas do Tecido Nervoso/genética , Transtornos Psicóticos/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Estudos de Casos e Controles , Feminino , Seguimentos , Globinas/metabolismo , Alucinações/complicações , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neuroglobina , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/complicações , Valores de Referência , Fatores Sexuais , Lobo Temporal/metabolismoRESUMO
We performed linkage analysis for age at onset (AAO) in the total Alzheimer's disease (AD) NIMH sample (N = 437 families). Families were subset as late-onset (320 families, AAO > or = 65) and early/mixed (117 families, at least 1 member with 50 < AAO < 65). Treating AAO as a censored trait, we obtained the gender and APOE adjusted residuals in a parametric survival model and analyzed the residuals as the quantitative trait (QT) in variance-component linkage analysis. For comparison, AAO-age at exam (AAE) was analyzed as the QT adjusting for affection status, gender, and APOE. Heritabilities for residual and AAO-AAE outcomes were 66.3% and 74.0%, respectively for the total sample, 56.0% and 57.0% in the late-onset sample, and 33.0% for both models in the early/mixed sample. The residual model yielded the largest peaks on chromosome 1 with LOD = 2.0 at 190 cM in the total set, LOD = 1.7 at 116 cM on chromosome 3 in the early/mixed subset, and LOD = 1.4 at 71 and 86 cM, respectively, on chromosome 6 in the late-onset subset. For the AAO-AAE outcome model the largest peaks were identified on chromosome 1 at 137 cM (LOD = 2.8) and chromosome 6 at 69 cM (LOD = 2.3) and 86 cM (LOD = 2.2) all in the late-onset subset. Additional peaks with LOD > or = 1 were identified on chromosomes 1, 2, 3, 6, 8, 9, 10, and 12 for the total sample and each subset. Results replicate previous findings, but identify additional suggestive peaks indicating the genetics of AAO in AD is complex with many chromosomal regions potentially containing modifying genes.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Mapeamento Cromossômico , Ligação Genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Cromossomos Humanos , Família , Feminino , Genética Populacional/métodos , Genoma Humano , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , National Institute of Mental Health (U.S.) , Estados UnidosRESUMO
Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes-considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs (ARPs). Multipoint, model-free ARP linkage analysis was performed. Genome-wide significant evidence for linkage was observed on 10q21.2 (LOD=3.3) and genome-wide suggestive evidence was observed on 9q22.33 (LOD=2.5) and 19q13.32 (LOD=2.0). One further region on 9p21.3 was identified with an LOD score>1. We observe no evidence to suggest that more than one locus is responsible for the linkage to 10q21.2, although this linked region may harbour more than one susceptibility gene. Evidence of allele-sharing heterogeneity between the original collection sites was observed on chromosome 9 but not on chromosome 10 or 19. Evidence for an interaction was observed between loci on chromosomes 10 and 19. Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large-scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2.
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Doença de Alzheimer/genética , Mapeamento Cromossômico , Ligação Genética , Genoma Humano , Idade de Início , Doença de Alzheimer/epidemiologia , Apolipoproteínas E/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 9/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Genótipo , Humanos , Escore Lod , Masculino , Linhagem , IrmãosRESUMO
We describe a new collection of publicly available software tools for performing quantitative neuroimage analysis. The tools perform semi-automatic brain extraction, tissue classification, Talairach alignment, and atlas-based measurements within a user-friendly graphical environment. They are implemented as plug-ins for MIPAV, a freely available medical image processing software package from the National Institutes of Health. Because the plug-ins and MIPAV are implemented in Java, both can be utilized on nearly any operating system platform. In addition to the software plug-ins, we have also released a digital version of the Talairach atlas that can be used to perform regional volumetric analyses. Several studies are conducted applying the new tools to simulated and real neuroimaging data sets.
Assuntos
Anatomia Artística , Encéfalo/anatomia & histologia , Processamento de Imagem Assistida por Computador/métodos , Ilustração Médica , Software , Algoritmos , HumanosRESUMO
Alzheimer's disease (AD) is a disabling neurodegenerative disorder with onset commonly in late life. Three genes have been identified causing earlier onset AD, and a fourth has been shown to be a risk factor for late onset AD (LOAD), while many more yet unrecognized genes are thought to contribute to susceptibility. Many studies have reported linkage to LOAD on human chromosome 10, where we have identified a parent of origin effect [Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD. Am J Med Genet B Neuropsychiatr Genet 141:537-540, (2006), Bassett SS, Avramopoulos D, Fallin D. Am J Med Genet 114:679-686, (2002)]. In this paper, we report on a gene in this region that shows reduced expression with increasing age, reduced expression in females across ages, and further reduction in LOAD patients. In concordance with the observed parent of origin effect on the linkage, this reduction is more pronounced in patients with an affected mother. We discovered this gene while studying the alkaline ceramidase gene (ASAH2); it is a partial paralog of ASAH2, and we call it ASAH2L. It is the result of a partial duplication of ASAH2 on chromosome 10q11.23, just downstream from the sequence with promoter activity. ASAH2L has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start sites that might produce novel proteins. It is expressed in all the tissues we tested including the brain and is an interesting example of the generation of a new gene. Comparison of primate and other mammal genomes suggests that ASAH2L is human specific. Further research would be necessary to determine the function of the ASAH2L transcript and explore any possible involvement in neurodegeneration.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10 , Duplicação Gênica , Regulação da Expressão Gênica , Idade de Início , Idoso , Idoso de 80 Anos ou mais , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA/genética , Valores de ReferênciaRESUMO
Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 9/genética , Escore Lod , Mapeamento Físico do Cromossomo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Estudos de Coortes , Família , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , National Institute of Mental Health (U.S.) , Estados UnidosRESUMO
Genes for complex disorders have proven hard to find using linkage analysis. The results rarely reach the desired level of significance and researchers often have failed to replicate positive findings. There is, however, a wealth of information from other scientific approaches which enables the formation of hypotheses on groups of genes or genomic regions likely to be enriched in disease loci. Examples include genes belonging to specific pathways or producing proteins interacting with known risk factors, genes that show altered expression levels in patients or even the group of top scoring locations in a linkage study. We show here that this hypothesis of enrichment for disease loci can be tested using genome-wide linkage data, provided that these data are independent from the data used to generate the hypothesis. Our method is based on the fact that non-parametric linkage analyses are expected to show increased scores at each one of the disease loci, although this increase might not rise above the noise of stochastic variation. By using a summary statistic and calculating its empirical significance, we show that enrichment hypotheses can be tested with power higher than the power of the linkage scan data to identify individual loci. Via simulated linkage scans for a number of different models, we gain insight in the interpretation of genome scan results and test the power of our proposed method. We present an application of the method to real data from a late-onset Alzheimer's disease linkage scan as a proof of principle.
Assuntos
Ligação Genética/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Modelos Genéticos , Doença de Alzheimer/epidemiologia , Genômica , Humanos , Linhagem , Irmãos , Estatísticas não ParamétricasRESUMO
The pathology of Huntington's disease (HD) is characterized by diffuse brain atrophy, with the most substantial neuronal loss occurring in the caudate and putamen. Recent evidence suggests that there may be more widespread neuronal degeneration with significant involvement of extrastriate structures, including white matter. In this study of pre-symptomatic carriers of the HD genetic mutation, we have used diffusion tensor imaging to examine the integrity and organization of white matter in a group of individuals who previously demonstrated abnormalities in response to a functional magnetic resonance imaging paradigm. Our results indicate that, before the onset of manifest HD, there are regional decreases in fractional anisotropy, indicating early white matter disorganization.
Assuntos
Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética , Doença de Huntington/patologia , Adulto , Anisotropia , Atrofia/patologia , Núcleo Caudado/patologia , Feminino , Humanos , Masculino , Degeneração Neural/patologia , Putamen/patologiaRESUMO
Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, we report results demonstrating a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. We also demonstrate that there is a significant association with a NRG1 SNP (single nucleotide polymorphism), rs392499, with ADP, chi2 = 7.0, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. Our results suggest that NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families.