Differential hippocampal gene expression and pathway analysis in an etiology-based mouse model of major depressive disorder.

We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with MDD in individuals from families with recurrent, early-onset MDD (RE-MDD). In the current study, we explored the effect of the pathogenic Creb1 allele on gene expression in the mouse hippocampus, a brain region that is altered in structure and function in MDD.

Alterations of brain anatomy in mouse model of MDD created by replacement of homologous mouse DNA sequence with an illness-associated 6-base human CREB1 promoter sequence.

We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with the development of MDD in men and women from families identified by probands with recurrent, early-onset MDD (RE-MDD). Individuals in these families are also at increased risk for childhood developmental disorders and late life neurodegenerative disorders.

No evidence of non-homologous insertions in mouse model of MDD created by replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence.

We have recently reported the creation and initial characterization of the first etiology-based recombinant mouse model of major depressive disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with the development of MDD in families identified by probands with recurrent, early-onset MDD. The current study explored whether the desired homologous recombination event at the mouse Creb1 gene that resulted in the creation of the mouse model was also accompanied by insertions of the targeting vector at unintended non-homologous locations in the mouse genome.

Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Families with recurrent, early-onset MDD (RE-MDD), a severe, familial form of MDD, have provided an important resource for identifying and characterizing genetic variants that confer susceptibility to MDD and related disorders. Previous studies identified a rare, highly penetrant A(-115)G transition within the human CREB1 promoter that reduced promoter activity in vitro and was associated with depressive disorders in RE-MDD families.

Effects of the A(-115)G variant on CREB1 promoter activity in two brain cell lines: Interactions with gonadal steroids.

Major depressive disorder (MDD) is a leading contributor to disease burden worldwide. Previous genetic studies have revealed significant evidence of linkage of the CREB1 region to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. Systematic resequencing of the CREB1 gene in affected members of these families has identified rare sequence variants at positions -656 and -115 that appear to cosegregate with unipolar mood disorders in two large multigenerational families and three small nuclear families, respectively.

D10S1423 identifies a susceptibility locus for Alzheimer's disease (AD7) in a prospective, longitudinal, double-blind study of asymptomatic individuals: results at 14 years.

Typical forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci. This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 (AD7) 234 bp allele, the APOE E4 allele, or both, after 14 years of systematic follow-up. A total of 30 incident cases of AD were detected during the first 3752 subject-years of surveillance.

Genetic linkage of region containing the CREB1 gene to depressive disorders in families with recurrent, early-onset, major depression: a re-analysis and confirmation of sex-specific effect.

A previously published model-free linkage analysis of chromosome 2q33-35, highlighted by previous case-control studies and supported by within-family analyses employing the transmission disequilibrium test, revealed evidence of sex-specific linkage of the CREB1-containing region of 2q to unipolar mood disorders among women in 81 recurrent, early-onset, major depressive disorder (RE-MDD) families. Since it has been reported that the LODPAL program from S.A.

Predicted gene sequence C10orf112 is transcribed, exhibits tissue-specific expression, and may correspond to AD7.

Case-control and prospective longitudinal studies have revealed an interaction of the anonymous D10S1423 234 bp allele with the APOE4 allele in determining the age-specific risk of Alzheimer's disease (AD). The D10S1423 polymorphism resides within intron 10 of open reading frame C10orf112, whose predicted product resembles a low-density lipoprotein receptor (NCBI Build 35.1).

Identification of a CREB-dependent serotonergic pathway and neuronal circuit regulating foraging behavior in Caenorhabditis elegans: a useful model for mental disorders and their treatments?

The cAMP-response element binding protein (CREB)-mediated cell signaling pathway is conserved through evolution and participates in a broad range of complex behaviors of divergent species including man. This study describes the integration of genetic, pharmacologic, and anatomic methods to elucidate a serotonergic signaling pathway by which the CREB homolog CRH-1 controls foraging rate (FR) in the model organism Caenorhabditis elegans, along with the complete neuronal circuit through which this pathway operates. In the anterior afferent arm of the circuit, CRH-1 controls FR by regulating the expression of tph-1, the sole structural gene for tryptophan hydroxylase, in serotonergic sensory (ADF) neurons whose post-synaptic effects are mediated through 5HT(2)-like SER-1 receptors.

Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy.

Objective: Atypical antipsychotic drugs have been used off label in clinical practice for treatment of serious dementia-associated agitation and aggression. Following reports of cerebrovascular adverse events associated with the use of atypical antipsychotics in elderly patients with dementia, the U.S.

Effects of the G(-656)A variant on CREB1 promoter activity in a neuronal cell line: interactions with gonadal steroids and stress.

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position -656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders.

Effects of the G(-656)A variant on CREB1 promoter activity in a glial cell line: interactions with gonadal steroids and stress.

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the CREB1 region to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G to A transition at position -656 in the CREB1 promoter cosegregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders.

Reduced age-related cataracts among elderly persons who reach age 90 with preserved cognition: a biomarker of successful aging?

Tissue damage due to oxidative stress has been implicated in aging, memory loss, and cataract formation. We hypothesized that persons who achieved exceptional longevity with preserved cognition (successful aging [SAG]) would exhibit a lower rate of age-related cataract (ARC) than the general population. The age-specific rates of ARC for a group of 100 (50 male, 50 female) elderly persons who reached at least age 90 years with preserved cognition were compared to the corresponding rates of ARC reported in five population-based studies.

Genetics of recurrent early-onset major depression (GenRED): final genome scan report.

Objective: The authors carried out a genomewide linkage scan to identify chromosomal regions likely to contain genes that contribute to susceptibility to recurrent early-onset major depressive disorder, the form of the disorder with the greatest reported risk to relatives of index cases.

Method: Microsatellite DNA markers were studied in 656 families with two or more such cases (onset before age 31 in probands and age 41 in other relatives), including 1,494 informative "all possible" affected relative pairs (there were 894 independent affected sibling pairs). Analyses included a primary multipoint allele-sharing analysis (with ALLEGRO) and a secondary logistic regression analysis taking the sex of each relative pair into account (male-male, male-female, female-female).

Genome survey for loci that influence successful aging: results at 10-cM resolution.

Objective: A systematic genome survey was initiated to identify loci that affect the likelihood of reaching age 90 with preserved cognition (successful aging).

Methods: The genome survey was conducted at 10-cM resolution for simple sequence tandem repeat polymorphisms (SSTRPs) that identify genes for Successful AGing (SAG loci) by virtue of linkage disequilibrium. Efficiency was enhanced by genotyping pools of DNA from 100 cognitively intact elders and 100 young (18-25 years) adults.

Research agenda for DSM-V: diagnostic categories and criteria for neuropsychiatric syndromes in dementia.

Neuropsychiatric symptoms in dementia represent a major health burden for older adults. These symptoms are often more distressing, impairing, and costly than cognitive symptoms in dementia, yet they have been less coherently categorized in the various versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The preponderance of literature on psychiatric symptoms in dementia has been in patients with Alzheimer's disease.

Effects of previous major depressive illness on cognition in Alzheimer disease patients.

Objective: Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored.

Methods: Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment.

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.

Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression.

In this report, we describe the results of the first genome-wide linkage survey for genetic loci that influence the development of unipolar Mood Disorders in 81 families identified by individuals with Recurrent, Early-Onset, Major Depressive Disorder (RE-MDD). Model-free linkage analysis was performed using genotypes for 392 highly informative polymorphisms with an average spacing of 9 cM. The highest maximum LOD score observed, 8.

Sequence variations in CREB1 cosegregate with depressive disorders in women.

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous linkage studies have identified a 451 kb region of 2q33-35 that exhibited significant evidence of linkage to Mood Disorders among women (but not men) from families with recurrent, early-onset MDD (RE-MDD), a severe and strongly familial subtype of MDD. This 451 kb region includes CREB1, an attractive susceptibility gene for MDD and related disorders.