Carl Johan Ekman

Manic episodes are associated with grey matter volume reduction — a voxel-based morphometry brain analysis

Ekman CJ, Lind J, Rydén E, Ingvar M, Landén M. Manic episodes are associated with grey matter volume reduction — a voxel‐based morphometry brain analysis.

Neurocognitive function in bipolar disorder: a comparison between bipolar I and II disorder and matched controls

BackgroundCognitive deficits have been documented in patients with bipolar disorder. Further, it has been suggested that the degree and type of cognitive impairment differ between bipolar I and bipolar II disorder, but data is conflicting and remains inconclusive. This study aimed to clarify the suggested differences in cognitive impairment between patients with bipolar I and II disorder in a relatively large, clinically stable sample while controlling for potential confounders.Methods67 patients with bipolar I disorder, 43 with bipolar II disorder, and 86 randomly selected population-based healthy controls were compared. A number of neuropsychological tests were administered, assessing verbal and visual memory and executive functions. Patients were in a stable phase during testing.ResultsPatients with bipolar type I and type II were cognitively impaired compared to healthy controls, but there were no statistically significant differences between the two subtypes. The strongest predictor of cognitive impairment within the patient group was current antipsychotic treatment.ConclusionsThe present study suggests that the type and degree of cognitive dysfunction is similar in bipolar I and II patients. Notably, treatment with antipsychotics - but not a history of psychosis - was associated with more severe cognitive impairment. Given that patients with bipolar I disorder are more likely to be on antipsychotic drugs, this might explain why some previous studies have found that patients with type I bipolar disorder are more cognitively impaired than those with type II.

Altered concentrations of amyloid precursor protein metabolites in the cerebrospinal fluid of patients with bipolar disorder.

Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer’s disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid β, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid β1-42, amyloid β38/β40/β42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid β42/amyloid β38 and the amyloid β42/amyloid β40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid β1-42, or amyloid β38/β40/β42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients.

Blood-cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment

Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined.

Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment

Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.

Markers of glutamate signaling in cerebrospinal fluid and serum from patients with bipolar disorder and healthy controls

Glutamate is the major excitatory neurotransmitter in the brain. Aberrations in glutamate signaling have been linked to the pathophysiology of mood disorders. Increased plasma levels of glutamate as well as higher glutamine+glutamate levels in the brain have been demonstrated in patients with bipolar disorder as compared to healthy controls. In this study, we explored the glutamate hypothesis of bipolar disorder by examining peripheral and central levels of amino acids related to glutamate signaling. A total of 215 patients with bipolar disorder and 112 healthy controls from the Swedish St. Göran bipolar project were included in this study. Glutamate, glutamine, glycine, L-serine and D-serine levels were determined in serum and in cerebrospinal fluid using high performance liquid chromatography with fluorescence detection. Serum levels of glutamine, glycine and D-serine were significantly higher whereas L-serine levels were lower in patients with bipolar disorder as compared to controls. No differences between the patient and control group in amino acid levels were observed in cerebrospinal fluid. The observed differences in serum amino acid levels may be interpreted as a systemic aberration in amino acid metabolism that affects several amino acids related to glutamate signaling.

Elevated Concentrations of Neurofilament Light Chain in the Cerebrospinal Fluid of Bipolar Disorder Patients

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.

Cognitive functioning in clinically stable patients with bipolar disorder I and II.

Objectives Bipolar disorder is accompanied by cognitive impairments, which persists during euthymic phases. The purpose of the present study was to identify those neuropsychological tests that most reliably tell euthymic bipolar patients and controls apart, and to clarify the extent to which these cognitive impairments are clinically significant as judged from neuropsychological norms. Methods Patients with bipolar disorder (type I: n = 64; type II: n = 44) and controls (n = 86) were examined with a comprehensive neuropsychological test battery yielding 47 measures of executive functioning, speed, memory, and verbal skills. Multivariate analysis was used to build a model of cognitive performance with the ability to expose underlying trends in data and to reveal cognitive differences between patients and controls. Results Patients with bipolar disorder and controls were partially separated by one predictive component of cognitive performance. Additionally, the relative relevance of each cognitive measure for such separation was decided. Cognitive tests measuring set shifting, inhibition, fluency, and searching (e.g., Trail Making Test, Color-Word) had strongest discriminating ability and most reliably detected cognitive impairments in the patient group. Conclusions Both bipolar disorder type I and type II were associated with cognitive impairment that for a sizeable minority is significant in a clinical neuropsychological sense. We demonstrate a combination of neuropsychological tests that reliably detect cognitive impairment in bipolar disorder.

CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment

Persistent cognitive impairment in the euthymic state of bipolar disorder is increasingly recognized. Mounting evidence also suggests an association between neuroinflammation and cognitive dysfunction. The purpose of this study was to test if cerebrospinal fluid (CSF) markers of neuroinflammation could account for cognitive impairment in bipolar disorder. Hierarchical linear regression models were applied to account for performance in five cognitive domains using CSF neuroinflammatory biomarkers as predictors in patients with bipolar disorder type I and II (N=78). The associations between these biomarkers and cognition were further tested in healthy age- and sex-matched controls (N=86). In patients with bipolar disorder, the CSF biomarkers accounted for a significant proportion of the variance in executive functions (42.8%, p=<.0005) independently of age, medication, disease status, and bipolar subtype. The microglial marker YKL-40 had a high impact (beta=-.99), and was the only biomarker that contributed individually. CSF biomarkers were not associated with cognitive performance in healthy controls. The CSF neuroinflammation biomarker YKL-40 is associated with executive performance in euthymic bipolar disorder, but not in healthy controls.

Manic episodes are related to changes in frontal cortex: a longitudinal neuroimaging study of bipolar disorder 1

Higher numbers of manic episodes in bipolar patients has, in cross-sectional studies, been associated with less grey matter volume in prefrontal brain areas. Longitudinal studies are needed to determine if manic episodes set off progressive cortical changes, or if the association is better explained by premorbid brain conditions that increase risk for mania. We followed patients with bipolar disorder type 1 for 6 years. Structural brain magnetic resonance imaging scans were performed at baseline and follow-up. We compared patients who had at least one manic episode between baseline and follow-up (Mania group, n = 13) with those who had no manic episodes (No-Mania group, n = 18). We used measures of cortical volume, thickness, and area to assess grey matter changes between baseline and follow-up. We found significantly decreased frontal cortical volume (dorsolateral prefrontal and inferior frontal cortex) in the Mania group, but no volume changes in the No-Mania group. Our results indicate that volume decrease in frontal brain regions can be attributed to the incidence of manic episodes.