Another meta-analysis found that differences between bipolar type I and II are negligible with the exception of memory and semantic fluency [ 8 ]. Whereas there is some evidence of cognitive deterioration during the course of illness [ 7 , 9 ], most cognitive functions appear to remain persistently impaired over time [ 10 ]. Meta-analyses of structural magnetic resonance imaging MRI studies report morphological differences between persons with bipolar disorder and controls [ 11 , 12 ], but these structural abnormalities have not been linked to cognitive deficits [ 13 ].
It is hence undecided whether the neuroimaging findings in bipolar disorder indicate a neurodegenerative process, a premorbid condition, effects of alcohol intake, altered hormone levels, or medication effects [ 14 ]. In two recent studies, we investigated the applicability of cerebrospinal fluid CSF biomarkers to study neurodegenerative processes in bipolar disorder [ 15 , 16 ].
The physiological role of APP is not fully understood, but it has been linked to synaptic formation and repair as well as axonal regeneration [ 17 ]. APP has also been suggested to be important for neural connectivity, plasticity, and activity, as well as for memory functions. In the subsequent study, however, we found higher mean CSF concentrations of neurofilament light chain protein NFL in persons with bipolar disorder compared to controls [ 15 ]. NFL is a cytoskeletal constituent of intermediate filaments.
Cerebrospinal Fluid Magnesium Level in Different Neurological Disorders
Taken together, these previous studies suggested that altered APP metabolism and axonal injury might occur in bipolar disorder. CSF biomarkers of neurodegeneration have been linked to cognitive impairment in other disorders [ 18 , 21 ]. It is hence not farfetched to suggest that they might also be associated with cognitive dysfunction in bipolar disorder.
Clarifying this issue is important for at least two reasons. First, it might yield insights as to the biological underpinnings of cognitive impairment in bipolar disorder, which in turn is important for identifying treatment targets to alleviate cognitive impairment. Second, biomarkers of neurodegeneration might prove useful to predict worsening of cognitive function during the course of illness.
If biomarkers could help identifying vulnerable individuals, targeted intervention programs to prevent cognitive decline could be developed.
Regression models with five aggregated cognitive domains were applied using CSF biomarkers as predictors and covariates as appropriate. The models were repeated in healthy age- and sex-matched controls to determine if observed associations were disease dependent. The St.
About The Event
The procedures in this project have been described in detail elsewhere [ 22 ]. In brief, patients were enrolled at the bipolar outpatient unit at the Northern Stockholm Psychiatric Clinic Stockholm, Sweden. The inclusion criteria for the St. Exclusion criteria were inability to complete the standard clinical assessment or incapability of providing informed consent.
The ADE includes a social anamnesis, and a medical history. The lifetime severity of bipolar disorder is rated using the 7-point Likert scale Clinical Global Impression CGI , which ranges from healthy to extremely ill. The ADE and M. To minimize risk of inter-rater bias, a best-estimate diagnostic decision was made based on all information available at admission by a consensus panel of experienced board certified psychiatrists specialized in bipolar disorder.
All available sources of information, encompassing patient interview, case records and, if available, interview with the next of kin, were utilized in the diagnostic assessment. Both the CSF sampling and the cognitive examination procedures were carried out when patients were in a euthymic mood.
Controls were included to evaluate the extent to which CSF biomarkers play a specific role in bipolar disorder. Age- and sex-matched healthy, population-based controls were randomly selected by Statistics Sweden and contacted by mail. Given an expected response rate of , seven invitations were sent out per enrolled patient.
Cerebrospinal Fluid in Neurology and Psychiatry
Fourteen percent of the invited controls responded to the invitation to participate, and were subjected to a preliminary telephone screening to exclude severe mental health, neurological problems, and substance abuse. Thus, 75 individuals were excluded due to drug use, no longer willing to participate, or somatic illness. Eligible persons were scheduled for a personal examination and investigated to exclude mental illness by a psychiatrist using the M.
The control subjects underwent blood-sampling, lumbar puncture, neuropsychological testing and self-rating scales. The procedures were identical in patients and controls, except that controls completed all investigations during the same day, whereas CSF sampling and the neuropsychological testing occurred at separate occasions for patients. Controls presenting potentially pathological findings were discussed between examining clinician, primary investigator, and study coordinator at case conferences. Exclusion criteria were: any current psychiatric disorder, a family history of schizophrenia or bipolar disorder in first-degree relatives, drug or alcohol abuse based on DUDIT and AUDIT as well as serum levels of carbohydrate-deficient transferrin , neurological conditions except mild migraines, pregnancy, untreated endocrine disorders, dementia, and severe personality disorder.
The study was approved by the Regional Ethics Committee in Stockholm case no. After complete description of the study, all enrolled patients and controls consented orally and in writing to participate in the study. To reduce the risk of diurnal fluctuations, lumbar puncture was performed at — AM after night fasting.
For ethical reasons, patients were not taken off their prescribed medication at the time of the sampling. All samples were thawed and refrozen once before analysis. The administered neuropsychological test battery accords the recent recommendations from the International Society for Bipolar Disorders [ 29 ] covering cognitive domains deemed important for characterizing cognition in bipolar disorder. Verbal tests were mixed with nonverbal in each session and the sequence of tests was administered in a way that reduced the risk of contamination on the memory tests.
Licensed psychologists administered all tests to the patients whereas trained psychology students under supervision by a licensed psychologist administered tests to the healthy controls. In general, two sessions were required for patients and one for controls. Scores on the neuropsychological tests were used to create summary indices of the specific cognitive domains guided by common measurement properties and reference literature [ 30 , 31 ].
In order to combine the scores from different tests, we converted the raw scores on each of the tests to z-scores using the mean and SD of the healthy controls and averaged the z-scores of the tests within a given cognitive domain to yield a domain score. This procedure was applied for patients as well as controls. Specific neuropsychological tests and functions measured are displayed in Table 1. The purpose of analyzing cognitive domains rather than individual cognitive tests is to succinctly communicate the underlying measuring entities [ 32 ], decrease the test-specific associations, and to reduce the potential alpha inflation resulting from a larger battery of tests.
The primary outcome of this study was the ability of the CSF biomarkers to explain cognitive performance in bipolar disorder. The applicability of the biomarkers to account for cognitive performance was further tested in the healthy age- and sex-matched controls. Preliminary analyses were performed to ensure no violation of the following prerequisites for regression: linearity, normality, absence of multicollinearity, and homoscedasticity.
Variables that violated requirements for linearity were transformed as appropriate and variables that were highly inter-correlated were excluded for the model of interest. Linear regression was performed to assess the degree to which CSF biomarkers can explain the variance in the aggregated cognitive domain scores. CSF biomarkers were entered as independent variables in all models.
The following variables were included as covariates for patients: age, sex, bipolar subtype, CGI, MADRS, YMRS, treatment with any mood stabilizer, lithium, anticonvulsants, antidepressants, antipsychotics, benzodiazepines, and anxiolytics non-benzodiazepine anti-anxiety medication. For healthy controls, age and sex were the only applicable covariate. We report the adjusted r 2 of the model, the standardized beta values, and the p -value two-tailed tests of the individual variables.
Analysis of variance and chi-square, where applicable, were used for group comparisons. Alpha correction was not applied. To test if the covariates accounted for the influence of the CSF biomarkers on cognition, mediation effects were assessed using bootstrapping for continuous mediators and logistic mediation analysis for dichotomous mediators medication. The current study included 82 cases of bipolar disorder type I and II that had completed sampling of CSF and cognitive examination Table 2. The patient sample was predominantly female Most patients were bipolar type I and a majority were prescribed mood stabilizers such as lithium, valproate, or lamotrigine To investigate if the associations between CSF biomarkers and cognitive performance were specific to bipolar disorder, this study also included healthy controls Table 2.
Data from the St.
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However, in the present study, only subjects that had completed both cognitive testing and lumbar puncture were included. Whereas a smaller percentage was accounted for when working memory was removed from the domain adj. We also performed a separate analysis of the association between working memory and CSF biomarkers and found that the CSF biomarkers explained a significant proportion of the variance in working memory performance adj.
Lower age and use of anticonvulsants and antipsychotics were positively associated with speed and attention, whereas use of benzodiazepines had a negative impact. Use of anxiolytics except benzodiazepines was associated with increased performance, whereas benzodiazepine use was associated with reduced performance. Use of anticonvulsants was negatively associated with verbal functioning. Use of lithium and lower age was positively associated with visuospatial functions.
Figures display actual and predicted visuospatial performance in z-scores in bipolar disorder 1A and healthy controls 1B. In patients with bipolar disorder only sex and age were associated with visuospatial functions adj. Mediation effects were not found for any of the covariates included in the regression models results not displayed ; CSF biomarkers and covariates contributed independently to the variance observed in the cognitive domains.
CSF biomarkers did not account for any variance in cognitive performance for the controls. The only significant predictors of cognitive performance in healthy controls were sex and age for visuospatial functions Fig 1B and sex for verbal functions Table 5.