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PLoS One ; 14(7): e0218111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31283791


Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

Schizophr Bull ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31206164


BACKGROUND: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. METHODS: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. RESULTS: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Ann Clin Transl Neurol ; 6(3): 456-465, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30911569


Objective: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Neuroscience ; 330: 39-49, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27233617


Damage to the mammillothalamic tract (MTT) produces memory impairments in both humans and rats, yet it is still not clear why this diencephalic pathway is vital for memory. One suggestion is that it is an important route for midbrain inputs to reach a wider cortical and subcortical network that supports memory. Consistent with this idea, MTT lesions produce widespread hypoactivity in distal brain regions as measured by the immediate-early gene, c-fos. To determine whether these findings were selective to c-fos or reflected more general changes in neuronal function, we assessed the effects of MTT lesions on the expression of the immediate-early gene protein, Zif268 and the metabolic marker, cytochrome oxidase, in the retrosplenial cortex and hippocampus. The lesions decreased levels of both activity markers in the superficial and deep layers of the retrosplenial cortex in both its granular and dysgranular subregions. In contrast, no significant changes were observed in the hippocampus, despite the MTT-lesioned animals showing marked impairments on T-maze alternation. These findings are consistent with MTT lesions providing important, indirect inputs for normal retrosplenial cortex functioning. These distal functional changes may contribute to the memory impairments observed after MTT lesions.

Córtex Cerebral/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hipocampo/metabolismo , Corpos Mamilares/metabolismo , Tálamo/metabolismo , Análise de Variância , Animais , Contagem de Células , Córtex Cerebral/patologia , Estudos de Coortes , Modelos Animais de Doenças , Estimulação Elétrica , Hipocampo/patologia , Imuno-Histoquímica , Corpos Mamilares/lesões , Corpos Mamilares/patologia , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Vias Neurais/lesões , Vias Neurais/metabolismo , Vias Neurais/patologia , Ratos , Tálamo/lesões , Tálamo/patologia
Neurosci Biobehav Rev ; 54: 108-19, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25107491


It has long been assumed that the main function of the mammillary bodies is to provide a relay for indirect hippocampal inputs to the anterior thalamic nuclei. Such models afford the mammillary bodies no independent role in memory and overlook the importance of their other, non-hippocampal, inputs. This review focuses on recent advances that herald a new understanding of the importance of the mammillary bodies, and their inputs from the limbic midbrain, for anterior thalamic function. It has become apparent that the mammillary bodies' contribution to memory is not dependent on afferents from the subicular complex. Rather, the ventral tegmental nucleus of Gudden is a vital source of inputs that support memory processes within the medial mammillary bodies. In parallel, the lateral mammillary bodies, via their connections with the dorsal tegmental nucleus of Gudden, are critical for generating head-direction signals. These two parallel, but distinct, information streams converge on the anterior thalamic nuclei and support different aspects of spatial memory.

Núcleos Anteriores do Tálamo/citologia , Núcleos Anteriores do Tálamo/fisiologia , Corpos Mamilares/citologia , Corpos Mamilares/fisiologia , Memória/fisiologia , Animais , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Memória Espacial/fisiologia
Neurobiol Aging ; 34(7): 1799-806, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23465714


Retinal ganglion cells (RGCs) may be regarded as a target biomarker in Alzheimer's disease (AD). We therefore explored the possibility that RGC degeneration, rather than cell loss, is an early marker of neuronal degeneration in a murine model of AD. RGC dendritic morphology and dendritic spine densities of CA1 hippocampal pyramidal neurons were quantified in 14-month-old transgenic mice expressing the APP(SWE) (amyloid precusor protein-Swedish mutation) mutation (Tg2576). The dendritic integrity of RGCs was found to be significantly reduced in the absence of significant RGC loss in Tg2576 mice compared with age-matched wild-type controls. In hippocampal CA1 pyramidal neurons, we observed dendritic spines to be present at a lower frequency from the same animals, but this did not reach significance. Synaptic and mitochondrial protein expression markers (PSD95 [postsynaptic density protein 95], synaptophysin, and Mfn2 [mitofusin 2]) showed no significant changes in RGC synaptic densities but a highly significant change in mitochondrial morphology with a marked reduction in the integrity of the mitochondrial cristae. Our findings suggest that, in a well-characterized mouse model of AD, RGC dendritic atrophy precedes cell loss, and this change may be because of accumulations of amyloid-ß. Because RGC dendrites are confined to the inner plexiform layer of the retina, imaging techniques that focus on this layer, rather than the loss of RGCs, may provide a sensitive biomarker for monitoring neural damage in AD.

Doença de Alzheimer/patologia , Dendritos/patologia , Modelos Animais de Doenças , Degeneração Retiniana/patologia , Células Ganglionares da Retina/patologia , Animais , Dendritos/química , Dendritos/ultraestrutura , Feminino , Camundongos , Camundongos Transgênicos , Células Ganglionares da Retina/química , Células Ganglionares da Retina/ultraestrutura