Accelerated white matter aging in schizophrenia: role of white matter blood perfusion

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18–63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia.     

Early and late onset Alzheimer's disease patients have distinct patterns of white matter damage

We investigated patterns of white matter (WM) loss in 18 early onset (EO) and 24 late onset (LO) Alzheimer's disease (AD) patients compared with 42 healthy controls (HC), and explored relationships of WM atrophy and apolipoprotein E (ApoE) genotype. Subjects underwent magnetic resonance imaging (MRI). Patterns of WM were assessed using voxel-based morphometry. Compared with healthy controls, LOAD patients had a selective parahippocampal WM loss, while EOAD patients experienced a more widespread pattern of posterior WM atrophy. The distinct regional distribution of WM atrophy reflected the topography of gray matter (GM) loss. ApoE ε4 status was associated with a greater parahippocampal WM loss in both AD groups. The greater WM atrophy in EOAD than LOAD fits with the evidence that EOAD is a more aggressive form of the disease. The ApoE ε4 effect on WM damage in AD is restricted to specific WM regions and does not seem to be related to age of onset.     

Combined analyses of gray matter voxel-based morphometry and white matter tract-based spatial statistics in pediatric bipolar mania

Background

Ample evidence has suggested the presence of gray matter (GM) and white matter (WM) abnormalities in bipolar disorder (BD) patients, including pediatric bipolar disorder (PBD). However, little research has been done in PBD patients that carefully classify the mood states. The aim of the present study is to investigate the brain structural changes in PBD-mania children and adolescents.

Methods

Eighteen children and adolescents with bipolar mania (male/female, 6/12) aged 10–18 years old and 18 age- and sex-matched healthy controls were included in the present study. The 3D T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) data were obtained on a Siemens 3.0 T scanner. Voxel-based morphometry (VBM) analysis and tract-based spatial statistics (TBSS) analysis were conducted to compare the gray matter volume and white matter fractional anisotropy (FA) value between patients and controls. Correlations of the MRI data of each survived area with clinical characteristics in PBD patients were further analyzed.

Results

As compared with the control group, PBD-mania children showed decreased gray matter volume in the left hippocampus. Meanwhile, significant lower FA value was detected in the right anterior cingulate (AC) in the patient group. No region of increased gray matter volume or FA value was observed in PBD-mania. The hippocampal volume was negatively associated with the Young Mania Rating Scale (YMRS) score when controlling for clinical characteristics in PBD-mania patients, however, there was no significant correlation of FA value of the survived area with illness duration, the onset age, number of episodes, or the YMRS score in PBD-mania patients.

Limitation

The present outcomes require replication in larger samples and verification in medication free subjects.

Conclusions

Our findings highlighted that extensive brain structural lesions (including GM and WM) were existed in PBD-mania. The widespread occurrence of structural abnormalities mainly located in the anterior limbic network (ALN) which suggested that this network might contribute to emotional and cognitive dysregulations in PBD.     

White matter microstructural damage in Alzheimer's disease at different ages of onset

White matter (WM) microstructural damage and its relationship with cortical abnormalities were explored in early-onset Alzheimer's disease (EOAD) compared with late-onset AD (LOAD) patients. Structural and diffusion tensor magnetic resonance images were obtained from 22 EOAD patients, 35 LOAD patients, and 40 healthy controls. Patterns of WM microstructural damage and cortical atrophy, as well as their relationships, were assessed using tract-based spatial statistics, tractography and voxel-based morphometry. Compared with LOAD, EOAD patients had a more severe and distributed pattern of WM microstructural damage, in particular in the posterior fibers of cingulum and corpus callosum. In both groups with Alzheimer's disease, but especially in LOAD patients, correlations between cingulum and corpus callosum fractional anisotropy and parietal, temporal, and frontal cortical volumes were found. In conclusion, WM microstructural damage is more severe in EOAD compared with LOAD patients. Such damage follows different patterns of topographical distribution in the 2 patient groups.     

Aging of cerebral white matter

White matter (WM) occupies a large volume of the human cerebrum and is mainly composed of myelinated axons and myelin-producing glial cells. The myelinated axons within WM are the structural foundation for efficient neurotransmission between cortical and subcortical areas. Similar to neuron-enriched gray matter areas, WM undergoes a series of changes during the process of aging. WM malfunction can induce serious neurobehavioral and cognitive impairments. Thus, age-related changes in WM may contribute to the functional decline observed in the elderly. In addition, aged WM becomes more susceptible to neurological disorders, such as stroke, traumatic brain injury (TBI), and neurodegeneration. In this review, we summarize the structural and functional alterations of WM in natural aging and speculate on the underlying mechanisms. We also discuss how age-related WM changes influence the progression of various brain disorders, including ischemic and hemorrhagic stroke, TBI, Alzheimer's disease, and Parkinson's disease. Although the physiology of WM is still poorly understood relative to gray matter, WM is a rational therapeutic target for a number of neurological and psychiatric conditions.     

Treatment adherence in bipolar I and schizoaffective disorder,bipolar type

Background

Poor adherence rates in Bipolar Disorder type I (BDI) and Schizoaffective Disorder, bipolar type (SAD) may be high This study was aimed at comparing the clinical correlates of adherence to treatment and the course of illness in BDI and SAD patients.

Methods

75 SAD and 150 BDI DSM-IV outpatients were included. Adherence was assessed on the basis of patients’ and care-givers’ reports and serum levels, when available. Socio-demographic, clinical and treatment variables were collected and compared between diagnostic subsamples and then between goodly and poorly adherent patients. Multiple logistic regressions were performed, controlling for diagnostic subsample differences, to identify correlates of adherence in BDI and SAD groups.

Results

Poor adherence was highly prevalent both in BDI (32%) and in SAD patients (44%), with no significant differences between diagnostic categories. Presence of psychotic symptoms (p=0.029), higher number of manic relapses (p<0.001), comorbidity with personality disorders (p=0.002), and lithium therapy (p=0.003) were associated with poor adherence to treatment. Diagnostic subgroup analyses showed different predictive models, with the BDI poorly adherent subsample being more likely to include comorbid personality and manic recurrences and the SAD poorly adherent subsample being less clinically predictable.

Limitations

The cross-sectional nature of the study limits de capacity to ascertain the direction of the relationship between certain variables.

Conclusions

Rates of poor adherence to oral treatments are similar in SAD and BDI. BDI patients with comorbid personality and substance use disorders are likely to be poorly adherent. Treatment adherence may be more difficult to predict in SAD patients.     

Preliminary evidence that long-term estrogen use reduces white matter loss in aging

Despite numerous studies showing neurotrophic and neuroprotective effects of estrogen in animal models, the long-term effects of estrogen use on brain morphology in older women are not known. Thus, we compared ventricular, cerebrospinal fluid, white matter, and grey matter volumes estimated from magnetic resonance images of postmenopausal women with more than 20 years exposure to unopposed estrogen, women who were not on estrogen, and young healthy women. Estrogen users had significantly smaller ventricles and greater white matter volumes than non-users, but hormone exposure did not affect grey matter volumes. Young healthy women had significantly smaller ventricles, less cerebrospinal fluid and more grey matter than both groups of older women. However, they had comparable white matter volumes to older women on estrogen. These findings suggest that long-term estrogen protects against white matter loss in aging. This adds to findings from other studies suggesting estrogen is neuroprotective of the hippocampus and other regions in older women.     

Microstructural changes and atrophy in brain white matter tracts with aging

Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography was used to investigate microstructural and volumetric abnormalities of the major brain white matter (WM) tracts with aging in 84 healthy subjects. Linear relationships were found between age and mean diffusivity (MD) increase and fractional anisotropy (FA) decrease in all WM tracts, except the right cingulum and bilateral uncinate, where a linear correlation with age was found for FA only. Quadratic model fitted better MD and FA values of several tracts, including the corpus callosum, limbic pathways, and bilateral association, and corticospinal tracts. Age-related MD and FA abnormalities were associated with radial diffusivity increase in all WM tracts, while axial diffusivity changes were characterized by a considerable variation from a tract to another. A linear negative relationship with age was found for the volumes of the left cingulum and fornix, while the quadratic model fitted better age-related volume loss of corpus callosum and right inferior fronto-occipital fasciculus. Diffusion tensor magnetic resonance imaging may shed light into the complex pathological substrates of WM changes with aging.     

Distortions in rest-activity rhythm in aging relate to white matter hyperintensities

Distortions in the rest–activity rhythm in aging are commonly observed. Neurodegenerative changes of the suprachiasmatic nucleus have been proposed to underlie this disrupted rhythm. However, based on previous studies, it can be proposed that white matter hyperintensities (WMH) may also play a role in the altered rest–activity rhythm in aging. The present study focused on the rest–activity rhythm, as assessed with actigraphy, and WMH in nondemented aging. With regard to the rest–activity rhythm, the interdaily stability (IS), intradaily variability (IV) and the amplitude (AMP) of the rhythm were of interest. The white matter hyperintensities were examined separately for the periventricular (PVH) and deep white matter (DWMH) regions, while distinguishing between the various locations within these regions (e.g. occipital PVH). The results indicated that frontal DWMH related to both IS and AMP. A reduction in the most active 10-h period mediated the relationship between frontal DWMH and AMP. Possible underlying mechanisms of these associations are discussed.     

The clinical significance of creativity in bipolar disorder

Clinical implications of the high rates of creativity within bipolar disorder (BD) have not been explored. The aim of this review is to outline these implications by (i) reviewing evidence for the link between creativity and BD, (ii) developing a provisional model of mechanisms underpinning the creativity–BD link, (iii) describing unique challenges faced by creative-BD populations, and (iv) systematically considering evidence-based psychosocial treatments in the light of this review. While more research into the creativity–BD nexus is urgently required, treatment outcomes will benefit from consideration of this commonly occurring phenotype.     

Improvements in white matter micro-structural integrity of right uncinate fasciculus and left fronto-occipital fasciculus of remitted first-episode medication-naïve panic disorder patients

Objective:

We designed this study to investigate neural correlates of white matter micro-structural integrity of remitted patients with first-episode, medication-naïve and very late-onset panic disorder

Method:

Twenty-one remitted patients with panic disorder completed treatment course with treatment of escitalopram (dose range around 10–15 mg/d). Twenty-one healthy controls were also enrolled into this study. Patients and controls all received 3-Tesla magnetic resonance imaging diffusion tensor imaging scanning at baseline and 6th week. We utilized FDT (FMRIB's Diffusion Toolbox v2.0) function of FSL (FMRIB Software Library) to calculate fractional anisotropy (FA). We compared FA values of patients and controls at baseline and 6th week to estimate the changes of FA of remitted patient group and inter-scan bias of controls. FA outputs of remitted patients and controls were compared by independent t test.

Results:

We found increased FA in some regions of right uncinate fasciculus and left fronoto-occipital fasciculus after remission in patient group (corrected p<0.05). Reduced FA of other regions of right uncinate fasciculus was still observed in remitted patients when they were compared to the control group.

Conclusion:

Subtle changes of white matter micro-structural integrity after remission might represent neural correlates of treatment effects for first-episode, medication-naïve and very late-onset panic disorder.     

Psychotherapy of bipolar disorder: a review

Background: Bipolar disorder is often only partially treated by medication alone, which has led to recent developments in the adjunctive psychological treatment of bipolar disorder. This paper aims to examine the current evidence for effectiveness of psychological interventions for bipolar disorder and to identify issues for future research in this area. Method: A review of outcome studies of psychological interventions reported since 1990, including psychoeducation, cognitive-behavioural, interpersonal and social rhythm and psychoanalytic therapy. Results: The research to date indicates that a range of psychological approaches appear to benefit people with bipolar disorder. The clearest evidence is for individual CBT which impacts on symptoms, social functioning and risk of relapse. Limitations: Many studies lack appropriate control groups and standardised measures of symptoms and diagnosis. Better designed studies would reduce the risk of over-estimates of effect sizes and subsequent failure to replicate. Further developments of psychotherapy need to be based on clear theoretical models of bipolar disorder. Conclusions: Many current studies are uncontrolled and of poor quality leading to a risk of over-estimating effectiveness of some interventions. Suggestions are made for future research including improving quality of studies, basing treatment developments on clear theoretical models and identifying specific treatment components for particular phases of the bipolar illness course.     

Neuroimaging-based markers of bipolar disorder: evidence from two meta-analyses

Background

Bipolar disorder (BD) is often misdiagnosed or tardily detected, leading to inadequate treatment and devastating consequences. The identification of objective biomarkers, such as functional and structural brain abnormalities of BD might improve diagnosis and help elucidate its pathophysiology.

Methods

To identify neurobiological markers of BD, two meta-analyses, one of functional neuroimaging studies related to emotional processing and a second of structural whole-brain neuroimaging studies in BD were conducted in the present study. Conducting a literature search on studies published up to September 2009 we identified 28 studies that were eligible for the meta-analyses: 13 functional magnetic resonance imaging studies, related to emotional processing and 15 structural imaging studies using whole-brain voxel-based morphometry. Only studies comparing patients with bipolar disorder to healthy controls were considered. Data were extracted or converted to a single anatomical reference (Talairach space). The activation likelihood estimation technique was used to assess the voxel-wise correspondence of results between studies.

Results

In patients with BD, decreased activation and diminution of gray matter were identified in a cortical-cognitive brain network that has been associated with the regulation of emotions. By contrast, patients with BD exhibited increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses. The present study provides evidence for functional and anatomical alterations in BD in brain networks associated with the experience and regulation of emotions.

Conclusions

These alterations support previously proposed neurobiological models of BD and might represent valid neurobiological markers of the disorder. The specificity of these results to unipolar depression remains to be explored.     

A structural equation modeling investigation of age-related variance in executive function and DTI measured white matter damage

Cognitive changes in normal aging have been explained by the frontal-executive hypothesis, but the assumptions made by this hypothesis concerning the neurobiological causes are still a matter of debate. Executive functions (EF) may activate neural networks that include disparate grey matter regions, and rely on the integrity of white matter connections. In 118 adults (50–90 years old) from the GENIE study, white matter integrity was measured using diffusion tensor imaging, and information processing speed, fluid intelligence and EF were assessed. A theory-driven structural equation model was developed to test associations between variables. The model was revised, removing non-significant paths. The adjusted model explained well the covariance in our data; and suggested that the reduction in white matter integrity associated with age directly affected only working memory. Fluid intelligence was mediated by all measured cognitive variables. The results suggest that white matter integrity may be particularly important for abilities activating complex neural networks, as occurs in working memory. Integration of the information processing speed and frontal-executive hypotheses may provide important information regarding common, unique, and mediating factors in cognitive aging.     

Regional brain gray matter abnormalities in patients with bipolar II disorder: A comparison study with bipolar I patients and healthy controls

Despite the high prevalence and clinical significance of bipolar II disorder (BD II), the underlying pathophysiology is not well explored in previous studies. The purpose of the current study was to investigate brain gray matter abnormalities in BD II. High resolution magnetic resonance brain images from 23 BD II patients, 23 sex- and age-matched patients with bipolar I disorder (BD I) and 23 healthy controls were acquired and processed according to the optimized voxel-based morphometry protocol. The processed gray matter tissue volumes were compared among the three groups. Both the BD II and BD I group showed gray matter deficits in the ventromedial prefrontal regions, compared to controls. The BD I group had widespread gray matter reductions in the bilateral frontal, temporal, parietal and parahippocampal cortices, compared to controls. However, gray matter reductions in these regions were not found in the BD II group. With a less conservative statistical threshold, the BD II group showed additional gray matter deficits in the anterior limbic cortices. Our data suggest that gray matter deficits in the ventromedial prefrontal and anterior limbic cortices are common in both BD II and BD I. On the other hand, different pattern of gray matter abnormalities between BD II and BD I found in this study supports that two subtypes may have different neurobiological characteristics.     

Regional white matter hyperintensities: aging,Alzheimer's disease risk,and cognitive function

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E ε4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.     

Anxiety,stress and perfectionism in bipolar disorder

Background

Previous reports have highlighted perfectionism and related cognitive styles as a psychological risk factor for stress and anxiety symptoms as well as for the development of bipolar disorder symptoms. The anxiety disorders are highly comorbid with bipolar disorder but the mechanisms that underpin this comorbidity are yet to be determined.

Method

Measures of depressive, (hypo)manic, anxiety and stress symptoms and perfectionistic cognitive style were completed by a sample of 142 patients with bipolar disorder. Mediation models were used to explore the hypotheses that anxiety and stress symptoms would mediate relationships between perfectionistic cognitive styles, and bipolar disorder symptoms.

Results

Stress and anxiety both significantly mediated the relationship between both self-critical perfectionism and goal attainment values and bipolar depressive symptoms. Goal attainment values were not significantly related to hypomanic symptoms. Stress and anxiety symptoms did not significantly mediate the relationship between self-critical perfectionism and (hypo)manic symptoms.

Limitations

1.

These data are cross-sectional; hence the causality implied in the mediation models can only be inferred.

2.

The clinic patients were less likely to present with (hypo)manic symptoms and therefore the reduced variability in the data may have contributed to the null findings for the mediation models with (hypo)manic symptoms.

3.

Those patients who were experiencing current (hypo)manic symptoms may have answered the cognitive styles questionnaires differently than when euthymic.

Conclusion

These findings highlight a plausible mechanism to understand the relationship between bipolar disorder and the anxiety disorders. Targeting self-critical perfectionism in the psychological treatment of bipolar disorder when there is anxiety comorbidity may result in more parsimonious treatments.     

Symptomatic and functional outcome of bipolar disorder in Butajira, Ethiopia

BACKGROUND: Limited information is available on the outcome of bipolar disorder in developing countries. OBJECTIVE: To describe the symptomatic and functional outcome of bipolar disorder. METHODS: The psychoses and affective disorder modules of the CIDI were used to screen 68,378 individuals by a door-to-door survey of a defined district in Ethiopia. In addition, key informants were used to identify individuals with probable major mental illnesses. SCAN interviews were completed at the second stage to confirm the diagnosis. A total of 315 cases of bipolar disorder were identified, of which 264 (69 recent-onset and 195 prevalent cases) were prospectively followed for a mean of 2.5 (range 1-4) years by baseline and annual clinical assessments using symptom rating scales. Functional dimensions of the SF-36 scale were used to describe functional outcome. Random coefficient analyses were used to evaluate potential correlates of outcome. RESULTS: The magnitudes of mania and depression symptoms were elevated at baseline but improved with follow-up, although the improvement was less marked for depression. Sociodemographic or clinical variables were not associated with the improvements in symptomatic outcome. Between 35% and 47% of the recent-onset cases had functional role restrictions, while 42-52% of long-standing cases had such restrictions during the follow-up years. Similarly, social and physical functioning deficits were also present in 52-86% and 35-47% of recent-onset and long-standing cases, respectively. The magnitude of depression and mania symptoms was associated with poor functional outcome, while male sex, rural residence and being married were associated with better functional outcome. CONCLUSION: Although there were improvements in function with follow-up, between one-third and one-half of cases continued to have functional deficits.     

A three generations nation-wide population study of family load estimates in bipolar disorder with different age at onset

Objectives

This nation-wide register-based study investigates how often bipolar disorder (BD) occurs in affected families compared to control families by estimating the family load as a random effect; this effect measures the degree of dependence among family members in relation to BD. Furthermore, the study addresses the impact of certain risk factors, namely, sex, age at onset of BD, degree of urbanization, year of birth, month of birth, and maternal and paternal age at birth.

Method

A total of N=1204 children and adolescent psychiatric cases born between 1950 and 1997 and registered in the Danish Central Psychiatric Register (DPCR) developed BD before the age of 58 years. N=3553 controls without any psychiatric diagnosis were matched for age, gender, and region of residence. Psychiatric diagnoses were also obtained on the relatives, e.g. parents, siblings, and offspring as a part of the Danish Three Generation Study (3GS). A family component was obtained by using different regression models.

Results

Familial factors accounted for 20% of the variation in disease outcome when controlling for year and month of birth, sex, and degree of urbanization. Only female sex was associated with an increased hazard ratio of BD. Also having a mother, father or a sibling with the disorder was proven to be a significant risk factor. Furthermore, case relatives did not develop BD earlier than control relatives.

Conclusion

These findings based on a very large and representative dataset provide further and very solid evidence for the high family aggregation of BD.     

Behavioral Activation System (BAS) differences in bipolar I and II disorder

Background

A growing body of evidence supports the Behavioral Activation System (BAS) dyresgulation model of bipolar disorder, however its application to bipolar II disorder is limited. The current study examines its potential relevance to bipolar I and II disorders. We specifically sought to determine whether bipolar sub-types would differ in terms of BAS sensitivity, and examined for differential prospective relationships between BAS sensitivity and bipolar I and II symptom expression.

Method

Participants were recruited from the Sydney-based Black Dog Institute. Diagnostic groups were derived on the basis of agreement between clinician and DSM-IV diagnoses from structured interviews. Baseline measures of BAS sensitivity, mood symptoms and anxiety were completed. Self-rated mood was assessed over a 6-month period. Clinician-rated mood status was re-assessed at follow-up to determine the predictive utility of BAS scores.

Results

The sample comprised 151 bipolar participants (69 bipolar I, 82 bipolar II). BAS-Drive and Reward Responsiveness scores were significantly higher in bipolar I disorder participants. BAS sub-scale scores were uniquely positively associated with mood variability in bipolar I and II disorder. BAS-Drive and Reward Responsiveness scores were positively associated with bipolar I hypo(mania), and with the former also positively associated with bipolar II depression. BAS scores did not predict bipolar I or II mood episode status at 6-month follow-up.

Limitations

BAS sensitivity was self-reported; inability to establish independence of BAS scores from residual symptoms; lack of controlling for medication effects; inability to determine the influence of life events; length of follow-up period may have not been sufficient to evaluate the predictive utility of BAS sensitivity for mood episodes or detect course of illness differences across bipolar sub-types.

Conclusions

Differences in BAS sensitivity and associations with mood variability were quantified in bipolar I and II disorder, suggesting the need for tailored treatments for these separate conditions. Further investigation of the role of the BAS in bipolar sub-types is warranted.