White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis.

BACKGROUND: While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. OBJECTIVE: The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. METHODS: Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). RESULTS: A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance (R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. CONCLUSION: Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients.

Motor network efficiency and disability in multiple sclerosis.

OBJECTIVE: To develop a composite MRI-based measure of motor network integrity, and determine if it explains disability better than conventional MRI measures in patients with multiple sclerosis (MS). METHODS: Tract density imaging and constrained spherical deconvolution tractography were used to identify motor network connections in 22 controls. Fractional anisotropy (FA), magnetization transfer ratio (MTR), and normalized volume were computed in each tract in 71 people with relapse onset MS. Principal component analysis was used to distill the FA, MTR, and tract volume data into a single metric for each tract, which in turn was used to compute a composite measure of motor network efficiency (composite NE) using graph theory. Associations were investigated between the Expanded Disability Status Scale (EDSS) and the following MRI measures: composite motor NE, NE calculated using FA alone, FA averaged in the combined motor network tracts, brain T2 lesion volume, brain parenchymal fraction, normal-appearing white matter MTR, and cervical cord cross-sectional area. RESULTS: In univariable analysis, composite motor NE explained 58% of the variation in EDSS in the whole MS group, more than twice that of the other MRI measures investigated. In a multivariable regression model, only composite NE and disease duration were independently associated with EDSS. CONCLUSIONS: A composite MRI measure of motor NE was able to predict disability substantially better than conventional non-network-based MRI measures.

Changing associations between cognitive impairment and imaging in multiple sclerosis as the disease progresses.

The authors explored cross-sectional associations between MRI parameters (lesion metrics, brain volumes, magnetization transfer ratio histograms, and metabolite concentrations) and cognition in 61 patients who experienced clinically-isolated syndromes (CIS) 7 years earlier. IQ decline and poorer overall cognition were associated with T2 white-matter lesions, and slow information-processing with both T2 lesions and gray-matter atrophy. In a previous study of the same cohort, gray-matter atrophy measured shortly after CIS failed to predict development of cognitive impairment years later. Our findings suggest that gray-matter pathology, reflected by atrophy measurements, becomes increasingly important in determining cognition as MS progresses.

Diffusion MRI-based cortical complexity alterations associated with executive function in multiple sclerosis.

PURPOSE: To report a novel magnetic resonance imaging measure (diffusion orientational complexity [DOC]) in a study of people with multiple sclerosis (MS) and healthy controls and to determine patterns of abnormality, correlations with conventional diffusion measures, and associations with cognitive function. MATERIALS AND METHODS: We performed high angular resolution diffusion imaging (HARDI) and measured DOC, mean diffusivity (MD), and fractional anisotropy (FA) in 51 MS patients and 28 healthy controls. All subjects had a 2-mm isotropic HARDI scan on a 3 T scanner using a 32-channel head receiver coil. DOC, MD, and FA were measured in three regions of interest (ROIs) in frontal cortex linked to executive function, two ROIs in occipital cortex thought unlikely to affect cognition, and in the whole cortex. RESULTS: Frontal cortex DOC was significantly decreased in MS patients. DOC correlated mostly with FA but not MD in controls and with MD but not FA in people with MS. In regression models that included all three diffusion-based measures, frontal cortex DOC and frontal cortex FA independently predicted executive function scores. CONCLUSION: DOC is a new useful measure of functionally relevant cortical pathology in MS, providing information that complements conventional diffusion measures.

A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography.

Retinal nerve fibre layer (RNFL) thickness and macular volume (MV) can be measured in vivo using optical coherence tomography (OCT) providing a "window into the brain". RNFL and MV are promising biomarkers in neurological diseases. This study explores the potential of RNFL and MV to detect axonal abnormalities in vivo in schizophrenia and their correlations with clinical features. OCT was performed in 49 patients (38 schizophrenia, 11 schizoaffective disorder) and 40 healthy controls matched for age and gender. Group comparisons were made between whole retina and quadrant RNFL thickness and MV using multi-level analyses. In patients, associations were sought between RNFL and MV with symptom severity (positive/negative). Patients and controls had similar whole retina RNFL thickness (p=0.86) and MV (p=0.64), but RNFL in the right nasal quadrant of the schizoaffective group was thinner than in the schizophrenia group (p=0.02). In patients, positive symptom severity was associated with smaller MV (right ß=-0.54, p=0.02; left ß=-0.49, p=0.04). Normal MV and RNFL thickness suggests unmyelinated axons in patients with schizophrenia/schizoaffective disorder remain unaffected. Longitudinal studies using higher resolution OCT will clarify whether progressive RNFL and MV changes occur and whether they can be used as state or trait markers in schizophrenia.

Cortical abnormalities and their cognitive correlates in patients with temporal lobe epilepsy and interictal psychosis.

PURPOSE: To determine whether cortical abnormalities are more severe and widespread in patients with temporal lobe epilepsy (TLE) and interictal psychosis (IP) compared to those with TLE only (NIP) and healthy controls (HC), and to explore the associations between cortical parameters (area, thickness and volume), psychotic symptoms, and cognitive performance. METHODS: Twenty-two patients with IP (9 male; 10 hippocampal sclerosis, HS), 23 TLE nonpsychotic (NIP) patients (11 male; 13 HS) matched for duration of epilepsy and 20 HC participated. Surface-based morphometry (SBM) was used to measure cortical parameters. Cognition was examined in IP and NIP patients. Associations between cortical parameters and cognition were examined using linear mixed models adjusted by age, gender, and brain volume. KEY FINDINGS: IP patients had an earlier onset of epilepsy, more status epilepticus, and worse cognitive performance than NIP patients. In IP patients, cortical thickness was reduced in the inferior frontal gyrus (IFG), and their current IQ was associated with decreases in area, but not thickness, in regions of the frontotemporal cortex. SIGNIFICANCE: IP likely reflects the interplay of psychosis-related genetic factors and the cumulative effects of seizure activity on the brain. Cortical thinning in the IFG, a region implicated in schizophrenia, is likely to be related to seizure activity, whereas changes in IQ, associated with reductions in area of frontotemporal cortex, may be related to the presence of psychosis.

IQ and the fronto-temporal cortex in bipolar disorder.

Cognitive changes are documented in bipolar disorder (BP). Cortical volume loss, especially in prefrontal regions, has also been reported, but associations between cognition and cortical abnormalities have not been fully documented. This study explores associations between cognitive performance and cortical parameters (area, thickness and volume) of the fronto-temporal cortex in 36 BP patients (25 BPI and 11 BPII). T1-weighted volumetric MRI images were obtained using a 1.5 Tesla scanner. Cortical parameters were measured using surface-based morphometry and their associations with estimated premorbid, current IQ, visual memory, and executive function explored. Premorbid IQ was associated with frontal cortical area and volume, but no such associations were present for current cognitive performance. Cortical parameters were not different in BPI and BPII patients, but the association between current IQ and temporal cortical area was stronger in BPII patients. The pattern of cortico-cognitive associations in BPI and BPII patients merits further consideration.

The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode schizophrenia.

OBJECTIVE: Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use. METHODS: Ninety-nine patients without alcohol or substance abuse other than cannabis were divided into lifetime users and never-users of cannabis and compared on measures of premorbid function, cognition, and clinical outcome. RESULTS: Cannabis users demonstrated better cognition at psychosis onset, which was explained by higher premorbid IQ. They also showed better social function and neither measure changed over the subsequent 15 months. Cannabis users had an earlier age at onset of psychosis, and there was a strong linear relationship between age at first cannabis use and age at onset of both prodromal and psychotic symptoms. Cannabis use spontaneously declined over time with 3-quarters of users giving up altogether. Later age at first cannabis use predicted earlier cessation of use and this in turn was linked to fewer positive psychotic symptoms and days in hospital during the first 2 years. CONCLUSIONS: Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.

IQ trajectory, cognitive reserve, and clinical outcome following a first episode of psychosis: a 3-year longitudinal study.

Comparison of current and estimated premorbid IQ in schizophrenia suggests that there are subgroups with low IQ, deteriorated IQ (DIQ), or preserved IQ and that this is established by psychosis onset. There are no controlled studies examining the trajectory of these IQ subgroups longitudinally or their relationship with clinical and social outcomes. Of 129 individuals with first-episode schizophrenia or schizoaffective disorder, 25% showed stable low IQ, 31% showed stable IQ in the average/high range, and 44% demonstrated intellectual deterioration by 10 points or more. Patients in the low and deteriorated groups were equally impaired on tests of memory and executive function compared with the preserved average/high-IQ group and controls and showed more negative and disorganization symptoms than the preserved average/high-IQ group. Sixty patients and 27 controls were assessed again 1 and 3 years later. There was no evidence that those with IQ deterioration at baseline continued on a declining cognitive trajectory or that those with preserved average/high IQ experienced subsequent IQ decline. The low IQ group showed no change in IQ, whereas both the DIQ and the preserved IQ groups improved. However, the rate of improvement of these 2 subgroups was no greater than that of the healthy controls, suggesting that this reflected practice effects. Both the low and the deteriorated groups had longer index admissions, more core negative symptoms, and worse occupational outcomes at 3 years. These data suggest that following psychosis onset, IQ is stable and that it is IQ at psychosis onset rather than premorbid IQ predicts a more severe illness.

Changes in the frontotemporal cortex and cognitive correlates in first-episode psychosis.

BACKGROUND: Loss of cortical volume in frontotemporal regions has been reported in patients with schizophrenia and their relatives. Cortical area and thickness are determined by different genetic processes, and measuring these parameters separately may clarify disturbances in corticogenesis relevant to schizophrenia. Our study also explored clinical and cognitive correlates of these parameters. METHODS: Thirty-seven patients with first-episode psychosis (34 schizophrenia, 3 schizoaffective disorder) and 38 healthy control subjects matched for age and sex took part in the study. Imaging was performed on an magnetic resonance imaging 1.5-T scanner. Area and thickness of the frontotemporal cortex were measured using a surface-based morphometry method (Freesurfer). All subjects underwent neuropsychologic testing that included measures of premorbid and current IQ, working and verbal memory, and executive function. RESULTS: Reductions in cortical area, more marked in the temporal cortex, were present in patients. Overall frontotemporal cortical thickness did not differ between groups, although regional thinning of the right superior temporal region was observed in patients. There was a significant association of both premorbid IQ and IQ at disease onset with area, but not thickness, of the frontotemporal cortex, and working memory span was associated with area of the frontal cortex. These associations remained significant when only patients with schizophrenia were considered. CONCLUSIONS: Our results suggest an early disruption of corticogenesis in schizophrenia, although the effect of subsequent environmental factors cannot be excluded. In addition, cortical abnormalities are subject to regional variations and differ from those present in neurodegenerative diseases.

Brain pathology in first-episode psychosis: magnetization transfer imaging provides additional information to MRI measurements of volume loss.

BACKGROUND: Loss of brain volume in first-episode psychosis can be detected using conventional magnetic resonance imaging (MRI), but subtle changes--not leading to reduction in volume--that may contribute to clinical and cognitive abnormalities, may go undetected. Magnetization transfer imaging (MTI), a technique more sensitive to subtle neuropathological changes than conventional MRI, could yield important information on the extent and nature of structural abnormalities. METHODS: Forty-eight patients (33 males) from a population-based sample with first-episode psychosis (41 with schizophrenia and 7 with schizoaffective psychosis) and 47 healthy volunteers (27 males) were studied. Differences in magnetization transfer ratio (MTR) and white and grey matter volumes between groups were investigated. RESULTS: In patients, MTR was reduced in right entorhinal cortex, fusiform, dentate and superior frontal gyri and in left superior frontal and inferior/rostral cingulate gyri. Grey matter volume was reduced in right insula, frontal operculum and middle and superior temporal gyri and in left middle temporal gyrus. Grey matter volume increases were seen in patients in the superior frontal gyrus. White matter volume loss was found adjacent to grey matter loss. In patients MTR was lower in all areas of volumetric differences between groups suggesting that both changes may be related. Similar findings were observed when patients with schizoaffective psychosis were removed from the analysis. The correlations between clinical and MRI parameters did not survive correction for multiple comparisons. CONCLUSIONS: MTI frontal and temporal abnormalities suggesting neuroaxonal and myelin changes were more extensive in our patients than those detected with conventional MRI. Our findings also suggest that there is regional variation in the severity of structural brain abnormalities.

The relationship between IQ, memory, executive function, and processing speed in recent-onset psychosis: 1-year stability and clinical outcome.

Studies commonly report poor performance in psychotic patients compared with controls on tasks testing a range of cognitive functions, but, because current IQ is often not matched between these groups, it is difficult to determine whether this represents a generalized deficit or specific abnormalities. Fifty-three first-episode psychosis patients and 53 healthy controls, one-to-one matched for sex, age, and full-scale current IQ, were compared on Wechsler Adult Intelligence Scale (WAIS) subtests representing indices of perceptual organization, verbal comprehension, processing speed, and working memory as well as other tests of executive function and episodic memory. The groups showed an equivalent pattern of performance on all WAIS subtests except digit symbol processing speed, on which the patients were significantly worse. Patients were also worse on measures where performance correlated with digit symbol score, namely working and verbal memory tasks. Standardized residual scores for each subtest were calculated for each patient using the difference between their actual subtest score and a predicted subtest score based on their full-scale IQ and the performance of controls. Scaled scores and residual scores were examined for relationships with clinical measures. Digit symbol-scaled score was significantly correlated with concurrent negative syndrome score at baseline, and digit symbol residual score significantly predicted residual negative symptoms at 1-year follow-up. In summary, our comparison of patients and controls precisely matched for IQ revealed that processing speed was attenuated in recent-onset schizophrenia, contributed significantly to working and episodic memory deficits, and was a prognostic factor for poor outcome at 1 year.

Discrimination learning, reversal, and set-shifting in first-episode schizophrenia: stability over six years and specific associations with medication type and disorganization syndrome.

BACKGROUND: The intradimensional/extradimensional (IDED) task assesses different forms of learning from feedback. Limited evidence suggests that attentional set-shifting deteriorates over time in schizophrenia. We tested this hypothesis and examined the specificity of learning impairments identified by this task. METHOD: Two hundred sixty-two first-episode patients and 76 healthy control subjects, matched for age and premorbid IQ, were tested; 104 patients and 25 control subjects were reassessed 1 and 3 years later, and 31 patients were reassessed additionally 6 years later. RESULTS: Patients showed impaired set-shifting that correlated with current IQ and working memory, but there were no impairments when subgroups were matched on current IQ. In contrast, patients showed marked impairments in rule reversal learning that survived correction for IQ, were present in the context of intact rule abstraction, and correlated with disorganization symptoms. Patients prescribed second-generation antipsychotics were worse on set-shifting compared with first-generation, a finding not explained by demographic data, illness characteristics, or IQ. Patients and control subjects showed stable IDED performance over the first 6 years of illness, although set-shifting was inconsistent over the first year. Those with residual negative symptoms were more likely to fail the set-shifting stage at follow-up. CONCLUSIONS: First-episode schizophrenia patients can learn and generalize rules but are inflexible when rules change, reflecting reduced responsiveness to negative feedback and difficulty in switching attention. Rule-reversal is a promising target for translational studies, because it is specific, clinically relevant, and might reflect orbitofrontal dysfunction. Set-shifting is related to poor function more generally but might be sensitive to medication effects and valuable for clinical trials.

IQ as a predictor of functional outcome in schizophrenia: a longitudinal, four-year study of first-episode psychosis.

Studies of established schizophrenia have consistently found that cognitive function predicts social and clinical outcomes. The findings from first-episode studies have been more variable, with only some studies reporting predictive relationships. We tested the possibility that an index of general cognitive ability, IQ, may be a more sensitive and reliable predictor of outcome in first-episode schizophrenia than specific measures of memory and executive function. Fifty-four patients with first-episode schizophrenia or schizoaffective disorder were assessed for cognitive and social function as well as symptoms at three time points over the four years following first presentation of their psychotic illness. Regression analyses were performed to determine whether IQ and specific neuropsychological measures at first episode and one-year follow-up predicted four-year social function and residual symptoms. The effects of premorbid and concurrent IQ on outcome were also assessed. Premorbid IQ and IQ at each assessment significantly predicted social function at four-year follow-up. This relationship remained significant after the social function or symptom scores at first presentation were accounted for in the regression. Specific measures predicted certain domains of social function, but these were weaker and less consistent than IQ. The predictive values of cognition on residual symptoms were less strong; the most consistent finding was a relationship between IQ and the negative syndrome. This study suggests that early in the course of schizophrenia, general cognitive ability, as measured by IQ, is a more sensitive and reliable predictor of functional outcome than measures of specific ability.

White matter abnormalities in bipolar disorder: a voxel-based diffusion tensor imaging study.

OBJECTIVES: In bipolar disorder (BD), dysregulation of mood may result from white matter abnormalities that disrupt fronto-subcortical circuits. In this study, we explore such abnormalities using diffusion tensor imaging (DTI), an imaging technique capable of detecting subtle changes not visible with conventional magnetic resonance imaging (MRI), and voxel-based analysis. METHODS: Thirty-six patients with BD, all but two receiving antidepressants or mood stabilizers, and 28 healthy controls matched for age and gender were studied. Diffusion-weighted echoplanar images (DW-EPI) were obtained using a 1.5T scanner. Voxel-based analysis was performed using SPM 2. Differences between the groups in mean diffusivity and fractional anisotropy (FA) were explored. RESULTS: In the patient group, mean diffusivity was increased in the right posterior frontal and bilateral prefrontal white matter, while FA was decreased [corrected] in the inferior, middle temporal and middle occipital regions. The areas of increased mean diffusivity overlapped with those previously found to be abnormal using volumetric MRI and magnetization transfer imaging (MTI) in the same group of patients. CONCLUSIONS: White matter abnormalities, predominantly in the fronto-temporal regions, can be detected in patients with BD using DTI. The neuropathology of these abnormalities is uncertain, but neuronal and axonal loss, myelin abnormalities and alterations in axonal packing density are likely to be relevant. The neuroprotective effects of some antidepressants and mood stabilizers make it unlikely that medication effects could explain the abnormalities described here, although minor effects cannot be excluded.

White matter tracts in first-episode psychosis: a DTI tractography study of the uncinate fasciculus.

A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the symptoms and cognitive abnormalities of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail, and we present here a study of patients with first-episode psychosis using this technique. We studied the uncinate fasciculus (UF), the largest white matter tract that connects the frontal and temporal lobes, two brain regions significantly implicated in schizophrenia. Nineteen patients with first-episode schizophrenia and 23 controls were studied using a probabilistic tractography algorithm (PICo). Fractional anisotropy (FA) and probability of connection were obtained for every voxel in the tract, and the group means and distributions of these variables were compared. The spread of the FA distribution in the upper tail, as measured by the squared coefficient of variance (SCV), was reduced in the left UF in the patient group, indicating that the number of voxels with high FA values was reduced in the core of the tract and suggesting the presence of changes in fibre alignment and tract coherence in the patient group. The SCV of FA was lower in females across both groups and there was no correlation between the SCV of FA and clinical ratings.

Abnormal brain connectivity in first-episode psychosis: a diffusion MRI tractography study of the corpus callosum.

A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the clinical manifestations of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail and we present here a study of patients with first-episode psychosis using this technique. We selected the corpus callosum for this study because there is evidence that it is abnormal in schizophrenia. In addition, the topographical organization of its fibers makes it possible to relate focal abnormalities to specific cortical regions. Eighteen patients with first-episode psychosis and 21 healthy subjects took part in the study. A probabilistic tractography algorithm (PICo) was used to study fractional anisotropy (FA). Seed regions were placed in the genu and splenium to track fiber tracts traversing these regions, and a multi-threshold approach to study the probability of connection was used. Multiple linear regressions were used to explore group differences. FA, a measure of tract coherence, was reduced in tracts crossing the genu, and to a lesser degree the splenium, in patients compared with controls. FA was also lower in the genu in females across both groups, but there was no gender-by-group interaction. The FA reduction in patients may be due to aberrant myelination or axonal abnormalities, but the similar tract volumes in the two groups suggest that severe axonal loss is unlikely at this stage of the illness.