Telomere length and bipolar disorder

Variation in telomere length is heritable and is currently considered a promising biomarker of susceptibility for neuropsychiatric disorders, particularly because of its association with memory function and hippocampal morphology. Here, we investigate telomere length in connection to familial risk and disease expression in bipolar disorder (BD). We used quantitative polymerase chain reactions and a telomere-sequence to single-copy-gene-sequence ratio method to determine telomere length in genomic DNA extracted from buccal smears from 63 patients with BD, 74 first-degree relatives (49 relatives had no lifetime psychopathology and 25 had a non-BD mood disorder) and 80 unrelated healthy individuals. Participants also underwent magnetic resonance imaging to determine hippocampal volumes and cognitive assessment to evaluate episodic memory using the verbal paired associates test. Telomere length was shorter in psychiatrically-well relatives (p=0.007) compared to unrelated healthy participants. Telomere length was also shorter in relatives (regardless of psychiatric status; p<0.01) and patients with BD not on lithium (p=0.02) compared to lithium-treated patients with BD. In the entire sample, telomere length was positively associated with left and right hippocampal volume and with delayed recall. This study provides evidence that shortened telomere length is associated with familial risk for BD. Lithium may have neuroprotective properties that require further investigation using prospective designs

Cognitive functioning in familial and nonfamilial groups at high-risk for schizophrenia

Differences in the cognitive profiles of schizophrenic individuals who are family history positive and those who are family history negative have been reported throughout the literature. The purpose of this study was to clarify the cognitive deficits that characterize familial and nonfamilial groups at high-risk for schizophrenia. High-risk was defined as (1) Genetic relatedness to an individual with schizophrenia, or (2) Extreme scores on a measure of schizotypy (i.e., Chapman Scales of Psychosis Proneness). Twenty-three subjects were administered a battery of neuropsychological tests. ANOVAs revealed a significant interaction effect on a measure of verbal learning and a double dissociation on auditory and visual working memory tasks. It appears that familial risk may be more associated with deficits on tasks that rely upon rapid encoding and organization of visual information, while nonfamilial risk demonstrated a greater association with abnormalities in left hemisphere mediated verbal abilities

Towards person-centered neuroimaging markers for resilience and vulnerability in Bipolar Disorder

Improved clinical care for Bipolar Disorder (BD) relies on the identification of diagnostic markers that can reliably detect disease-related signals in clinically heterogeneous populations. At the very least, diagnostic markers should be able to differentiate patients with BD from healthy individuals and from individuals at familial risk for BD who either remain well or develop other psychopathology, most commonly Major Depressive Disorder (MDD). These issues are particularly pertinent to the development of translational applications of neuroimaging as they represent challenges for which clinical observation alone is insufficient. We therefore applied pattern classification to task-based functional magnetic resonance imaging (fMRI) data of the n-back working memory task, to test their predictive value in differentiating patients with BD (n=30) from healthy individuals (n=30) and from patients' relatives who were either diagnosed with MDD (n=30) or were free of any personal lifetime history of psychopathology (n=30). Diagnostic stability in these groups was confirmed with 4-year prospective follow-up. Task-based activation patterns from the fMRI data were analyzed with Gaussian Process Classifiers (GPC), a machine learning approach to detecting multivariate patterns in neuroimaging datasets. Consistent significant classification results were only obtained using data from the 3-back versus 0-back contrast. Using contrast, patients with BD were correctly classified compared to unrelated healthy individuals with an accuracy of 83.5%, sensitivity of 84.6% and specificity of 92.3%. Classification accuracy, sensitivity and specificity when comparing patients with BD to their relatives with MDD, were respectively 73.1%, 53.9% and 94.5%. Classification accuracy, sensitivity and specificity when comparing patients with BD to their healthy relatives were respectively 81.8%, 72.7% and 90.9%. We show that significant individual classification can be achieved using whole brain pattern analysis of task-based working memory fMRI data. The high accuracy and specificity achieved by all three classifiers suggest that multivariate pattern recognition analyses can aid clinicians in the clinical care of BD in situations of true clinical uncertainty regarding the diagnosis and prognosis

Influence of a Serotonin Transporter Promoter Polymorphism (5-HTTLPR) on Corticolimbic Abnormalities in Bipolar Disorder An Integrated Genetics and Functional MRI Study

Bipolar disorder (BD) is associated with abnormalities of the subgenual anterior cingulate cortex (sgACC) and the amygdala, components of a corticolimbic neural system that subserves emotional regulation. The short s allele - as opposed to the long l allele - of a serotonin transporter promoter (5-HTTLPR) polymorphism is associated with more severe course features of BD and impaired functional connectivity between the sgACC and amygdala in healthy control (HC) individuals. This study tests the hypothesis that the s allele influences the dysfunction in the sgACC-amygdala neural system in BD. Twenty-six euthymic BD participants (17 s carriers, 9 ll) and 43 HC participants (31 s, 12 ll) completed an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, sgACC activation was significantly lower (p \u3c 0.05) in the BD versus the HC group, and in HC and BD s carriers compared to HC and BD ll individuals respectively. In the sgACC region where BD activation was less than HC, response to emotional faces was lowest in the BD s group, suggesting that the s allele may contribute to more severe sgACC dysfunction in a subset of individuals that represent a distinct genetically-derived subtype within the heterogeneous BD clinical phenotype. Thus, sgACC dysfunction may be an endophenotype of BD, and the s allele appears to influence this dysfunction in a subset of BD individuals. Future treatment may be optimized for this subset, by targeting treatments to affect this system, and by further study of treatment response amongst those who carry the s allele

The neuropsychological correlates of individuals at risk for bipolar I disorder

Bipolar disorder is now recognized as a severe psychiatric disorder characterized by extreme mood swings and cognitive deficits, most notably in the domains of verbal learning, executive function, and sustained attention. Neurocognitive deficits have been proposed as vulnerability markers or endophenotypes for the development of bipolar disorder. However, few research studies have examined whether neurocognitive deficits also exist in individuals at risk for bipolar disorder or first-degree relatives. This study examined neurocognitive function in individuals with bipolar disorder, their first-degree relatives, and a normal control group. Results indicated that individuals with bipolar disorder and their unaffected relatives demonstrated neuropsychological deficits in comparison to the normal control group in the domains of visuospatial/constructional abilities, executive function, and visual learning and memory. In general, the unaffected relatives demonstrated an intermediate level of performance in comparison to the normal control and bipolar group. After adjustment for mood symptomotology, significant differences remained only in the visuospatial/constructional and executive function domains. Individuals with bipolar disorder also demonstrated a differential right versus left hemisphere deficit with respect to neurocognitive tasks, providing support for the theory of right hemisphere dysfunction in bipolar affective disorder. Deficits on specific neuropsychological tests, most notably Digit Symbol, Block Design, and Judgment of Line Orientation may be indicative of cognitive endophenotypes for bipolar disorder. Replication studies are needed to identify these deficits as neurocognitive phenotypes and to further examine hemispheric functioning in bipolar affective disorder