Relationship between clock drawing test performance and regional cerebral blood flow in Alzheimer's disease: a single photon emission computed tomography study

The clock drawing test (CDT) is a useful tool for screening cognitive impairment. Previous neuropsychological studies have revealed that CDT performance requires several cognitive functions including semantic memory, visuospatial function and executive function. However, the neural substrates involved remain to be elucidated. The aim of the present study was to identify the brain regions responsible for CDT performance in patients with Alzheimer's disease (AD). Twenty-six patients satisfying the National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD underwent the CDT and the Mini-Mental State Examination (MMSE), together with a N-isopropyl-p-[123I] iodoamphetamine (IMP) single photon emission computed tomography measurements of the resting regional cerebral blood flow (rCBF). The CDT score correlated significantly with the MMSE score (r=0.582; P < 0.05). Stepwise multiple regression analysis revealed that the MMSE score and the left posterior temporal rCBF were major predictors of CDT score. These findings suggest that the CDT score may reflect the severity of dementia, and that it has a close relationship with the left posterior temporal function. Our findings provide the first functional neuroimaging evidence for the neural substrates involved in CDT performance.     

Discriminant validity and neuroanatomical correlates of rule monitoring in frontotemporal dementia and Alzheimer's disease

Despite the predominant frontal neuropathology of frontotemporal dementia (FTD), traditional measures of executive functioning do not reliably distinguish FTD from Alzheimer's disease (AD). Performance monitoring is an executive function that is associated with frontal lobe integrity and may be disrupted in FTD. The current study adopted a component process approach to evaluate the discriminant validity and neuroanatomical correlates of performance monitoring (i.e., rule monitoring) during an executive spatial planning task. Forty-four participants with FTD, 30 with AD, and 27 healthy comparison (HC) subjects completed the Delis-Kaplan Executive Function System (D-KEFS) Tower task. A subset of patients underwent structural magnetic resonance imaging to obtain regional measures of cortical volumes. FTD and AD groups demonstrated significantly poorer overall achievement scores on the Tower test relative to the HC sample, but did not differ from one another. In contrast, the FTD group committed significantly more rule violation errors than both HC and AD groups, indicating poorer performance monitoring. In addition, poorer overall achievement correlated with smaller brain volumes in several regions, including bilateral frontal and parietal regions, whereas an increased number of rule violations correlated specifically with decreased bilateral frontal volume. Both left and right frontal volumes remained significant predictors of rule violation errors after controlling for the contribution of overall achievement on the task and all other brain regions. Findings are consistent with literature implicating the frontal lobes in performance monitoring and highlight the importance of characterizing the component processes of performance failures in the cognitive assessment of FTD and AD.     

Callosal atrophy correlates with temporal lobe volume and mental status in Alzheimer's disease

BACKGROUND: Recent studies have reported significant atrophy of the corpus callosum (CC) in Alzheimer's Disease (AD). However, it is currently unknown whether CC atrophy is associated with specific cortical volume changes in AD. Moreover, possible atrophy in extra-callosal commissures has not been examined to date. The purpose of the present study was to quantify atrophy in two cerebral commissures [the CC and the anterior commissure (AC)], to correlate this measure with cognitive status, and to relate commissural size to independent measures of temporal lobe volume in AD patients. METHODS: A sample of AD patients and of age- and education-matched normal control subjects (NCs) underwent MRI and a cognitive test battery including the Dementia Rating Scale and Mini Mental State examination. Mid-sagittal regional areas within CC and AC were measured along with superior, middle and inferior temporal lobes volumes. RESULTS: Alzheimer's Disease patients had significantly smaller callosa than did NCs. The callosal regions most affected in AD included the midbody, isthmus and genu. The isthmus and midbody areas of the CC were positively correlated with cognitive performance and with superior temporal lobe volume in AD patients. The mid-sagittal area of the AC and the superior temporal volumes did not differ between AD patients and NCs. CONCLUSIONS: The study demonstrated that the regional morphology of the CC correlates with current cognitive status and temporal lobe atrophy in AD. As well, the lack of difference for the AC suggests that commissural atrophy in AD is regionally specific.     

Cortical signature of clock drawing performance in Alzheimer's disease and mild cognitive impairment

It is unclear whether clock drawing test (CDT) performance relies on a widely distributed cortical network, or whether this test predominantly taps into parietal cortex function. So far, associations between cortical integrity and CDT impairment in Alzheimer's disease (AD) and mild cognitive impairment (MCI) largely stem from cortical volume analyses. Given that volume is a product of thickness and surface area, investigation of the relationship between CDT and these two cortical measures might contribute to better understanding of this cognitive screening tool for AD. 38 patients with AD, 38 individuals with MCI and 31 healthy controls (HC) underwent CDT assessment and MRI at 3 Tesla. The surface-based analysis via Freesurfer enabled calculation of cortical thickness and surface area. CDT was scored according to the method proposed by Shulman and related to the two distinct cortical measurements. Higher CDT scores across the entire sample were associated with cortical thickness in bilateral temporal gyrus, the right supramarginal gyrus, and the bilateral parietal gyrus, respectively (p < 0.001 CWP corr.). Significant associations between CDT and cortical thickness reduction in the parietal lobe remained significant when analyses were restricted to AD individuals. There was no statistically significant association between CDT scores and surface area (p < 0.001 CWP corr.). In conclusion, CDT performance may be driven by cortical thickness alterations in regions previously identified as “AD vulnerable”, i.e. regions predominantly including temporal and parietal lobes. Our results suggest that cortical features of distinct evolutionary and genetic origin differently contribute to CDT performance.     

Executive dysfunction in frontotemporal dementia is related to abnormalities in frontal white matter tracts

Cognitive deficits in behavioral-variant frontotemporal dementia (bvFTD) and AD are linked to frontal and temporal lobe gray matter (GM) pathology. The aim of this study was to assess the relative contribution of white (WM) and GM abnormalities to cognitive dysfunction in bvFTD and AD. Fractional anisotropy (FA) for the corpus callosum, cingulum (Cg), and uncinate fasciculus (Unc) was determined in 17 bvFTD and 10 AD patients who underwent neuropsychological testing. Regressions were performed to assess the relative contribution of WM and GM abnormalities to cognitive deficits. Multiple regression analysis revealed that in bvFTD, the left anterior Cg FA was related to executive function, the right anterior Cg FA to visual-spatial attention and working memory, the right posterior Cg to visual-constructional abilities and the left Unc FA to Modified Trails Errors. After adding corresponding GM volumes, the left anterior Cg FA, the right anterior cingulate FA, the right posterior cingulate FA and the left uncinate FA remained significant predictors of the cognitive tasks. In the AD group, the left posterior Cg FA and right descending Cg FA were related to visual recall performance but did not remain significant predictors when GM volumes were added to the regression. These results suggest that reduced integrity of specific WM tracts contribute to cognitive deficits observed in bvFTD after accounting for GM atrophy. In AD, memory impairment was related to WM tract injury but this relationship was no longer observed when GM volumes were included.     

Neural correlates of impaired performance on the clock drawing test in Alzheimer's disease

To identify the neural correlates for impaired performance on the clock drawing test (CDT) in patients with Alzheimer's disease (AD), we examined the relationship between the CDT performances and the regional cerebral blood flow (rCBF) in 100 AD patients. The patients were equally divided into a mildly impaired CDT group, a severely impaired CDT group, and two normal CDT groups, with age and dementia severity matched. Between-group comparisons revealed that rCBF reduction in the posterolateral region of the left temporal lobe was consistently associated with mild to severe impairment of the CDT in AD. Correlation analysis also showed that the rCBF in the left posterolateral temporal cortex was linearly correlated with CDT performance. The CDT scores in AD were significantly improved for the copy condition relative to the drawing-to-command condition. These findings suggest that CDT performance has a close relationship with the left posterior temporal function, and that semantic memory deficit may at least partly contribute to impaired CDT performance in AD.     

Structural MRI volumetric analysis in patients with organic amnesia, 2: correlations with anterograde memory and executive tests in 40 patients

BACKGROUND: Cognitive-MRI correlations have often been studied in disorders in which there are multiple cognitive deficits and widespread cortical atrophy, such as Alzheimer's dementia. In such circumstances, the interpretation of any single cognitive-structural correlation is equivocal. Only by measuring differing cognitive functions and a wide range of brain structures in patients with a varying distribution of lesions or atrophy can specific brain-cognitive relations be determined in neurological disorder. METHOD: In the present study, a clear set of anatomical criteria and detailed MRI segmentation procedures were applied to measure whole brain, and left and right frontal, temporal lobe, anterolateral and medial temporal volumes, as well as thalamic cross sectional areas in 40 patients with organic amnesia (from various diseases) and 10 healthy controls. RESULTS: Within the total patient group, anterograde memory measures correlated significantly with medial temporal, hippocampal, and thalamic measurements. A spatial memory measure correlated significantly with hippocampal volume, and temporal context memory with frontal volume. After a factor analysis of the cognitive measures, the association between anterograde memory and hippocampal volume was corroborated. Forgetting rates and subjective memory evaluations did not show any significant MR correlations and, of executive tests employed, only card sorting categories correlated significantly with frontal volume. CONCLUSION: Loss of volume in key brain structures (for example, hippocampus, thalamus) is detectable on quantitative MRI, and this loss of volume correlates significantly with impaired performance on measures of anterograde memory function. Correlations with hippocampal volume did not indicate a specific role in either recall or verbal memory, as opposed to recognition or visual memory.     

Regional white matter hyperintensities in normal aging, single domain amnestic mild cognitive impairment, and mild Alzheimer’s disease

Few studies have examined white matter hyperintensities (WMH) along the cognitive continuum between single-domain amnestic mild cognitive impairment (sd-aMCI) and Alzheimer’s disease (AD). The aims of our study were to explore relationships between the extent and location of WMH and disease severity along the cognitive continuum and to determine whether differences in the distribution of WMH could be predictive of specific patterns of cognitive impairment. We compared cognitive function, vascular risk factors, and regional (frontal lobe, parieto-occipital [PO] lobe, temporal lobe, periventricular [PV] white matter and deep white matter) WMH volume in 37 patients with mild AD, 23 patients with sd-aMCI, and 24 age-matched and education-matched normal controls. A quantitative volumetric method was applied to measure WMH burden. Total and regional WMH burdens, except for those in the temporal lobe, were significantly correlated with age (p < 0.01). We found a trend toward increasing WMH volume with disease severity, higher in AD than in sd-aMCI and lowest in the controls. Total WMH volume was associated with the global cognitive test score. In multiple linear regression analysis, PV WMH volume, but not deep WMH volume, strongly predicted performances on the Controlled Oral Word Association test and the Color Word Stroop test after adjusting for important demographic variables. Only PO WMH volume was a significant predictor of a cognitive test score when frontal and temporal WMH volumes were simultaneously entered into the regression model. The extent and distribution of WMH, especially in the PV and PO regions, were associated with disease severity and reduced cognition.     

MRI study of caudate nucleus volume in Parkinson's disease with and without dementia with Lewy bodies and Alzheimer's disease

OBJECTIVE: To compare whole brain and caudate volume on MRI in subjects with Parkinson's disease without cognitive impairment (PD), Parkinson's disease with dementia with Lewy bodies (PD + DLB), Alzheimer's disease (AD) and normal control subjects. To examine the relationship between caudate volume and cognitive impairment, depression and movement disorder. METHOD: Whole brain and caudate volumes were segmented from volumetric 1.5-tesla magnetic resonance imaging (MRI) scans of older subjects with PD (n = 28; mean age 75.5 years), PD + DLB (n = 20; 73.0 years), AD (n = 27; 77.5 years) and normal controls (n = 35; 74.9 years). RESULTS: Subjects with AD had significantly reduced whole brain and caudate volume compared to controls and those with PD. Caudate atrophy in AD was proportionate to whole brain atrophy. There were no significant differences in whole brain or caudate volume between controls, PD and PD + DLB. There were no significant correlations between caudate volume and either global cognitive function, executive performance or processing speed. CONCLUSIONS: Caudate atrophy occurs in AD but not PD without dementia. Caudate atrophy is not regionally specific but part of generalised brain volume loss. Structural changes in the caudate, as assessed by in vivo MRI, do not appear to contribute to the cognitive impairment observed amongst patients with PD, PD + DLB or AD. Results indicate that the executive and attentional dysfunctions associated with PD and DLB are unlikely to be a direct and specific consequence of caudate atrophy as assessed on MRI.     

Cognitive decline in AD and mild cognitive impairment is associated with global brain damage

OBJECTIVE: To investigate the relationships between structural damage in the whole brain, the temporal lobes, and the frontal lobes and cognitive decline at old age. The authors hypothesized that widespread brain damage as quantified using magnetization transfer imaging (MTI) is related to global cognitive decline, whereas regional damage to the temporal lobes is related to memory impairment, and regional damage to the frontal lobes is related to executive dysfunctioning. METHODS: Cognitive function of 22 patients with probable AD, 13 patients with mild cognitive impairment (MCI), and 28 elderly controls was assessed using an extensive neuropsychological test battery. Structural damage in the whole brain, the temporal lobes, and the frontal lobes was estimated using volumetric MTI analysis. Associations between MTI measures and neuropsychological tests were investigated using Pearson correlation analysis. RESULTS: MTI measures of the whole brain, as well as the temporal and the frontal lobes, were strongly associated with global cognitive deterioration and impairment in memory, orientation, language, praxis, gnosis, and executive functioning. However, there were no specific cognitive correlates of regional brain damage to the temporal and frontal lobes. CONCLUSIONS: Using whole brain volumetric magnetization transfer imaging, the authors demonstrated that cognitive decline in patients with mild cognitive impairment and AD is associated with widespread structural brain damage. As there were no specific relationships between regional brain damage and impairment of specific cognitive functions, pathology in AD and mild cognitive impairment is much more generalized than was expected.     

Extrahippocampal integrity in temporal lobe epilepsy and cognition: Thalamus and executive functioning

Chronic temporal lobe epilepsy (TLE) is characterized by the presence of extra-hippocampal brain abnormality and cognitive impairment in both memory and nonmemory domains. However, the link between structural integrity and cognition has not frequently been studied. Forty-six patients with TLE and 61 age-matched controls were studied to determine the predictive relationship between baseline thalamic volume and performance on measures of executive functioning evaluated 4 years later. As expected, the TLE group had lower baseline thalamic volumes than controls and also performed more poorly on measures of executive functioning. Total thalamic volume significantly predicted subsequent performance on all three measures of executive functioning. These findings were maintained when both hippocampal volume and frontal lobe volume were taken into account. These findings add to a growing literature demonstrating a link between extra-hippocampal volume abnormalities and cognitive functioning in TLE.     

Structural brain differences and cognitive functioning related to body mass index in older females

Little is known about the effect of obesity on brain structures and cognition in healthy older adults. This study examined the association between body mass index (BMI), regional volume differences in gray and white matter measured by magnetic resonance imaging (MRI), and cognitive functioning in older females. Participants included 95 community‐dwelling older females (ages 52–92 years) who underwent extensive neuropsychological testing and high‐resolution MRI scanning. Optimized voxel‐based morphometry techniques were employed to determine the correlation between BMI and regional gray and white matter volumes. Volumes of significant regions were then correlated with cognitive functioning. Higher BMI was associated with decreased gray matter volumes in the left orbitofrontal, right inferior frontal, and right precentral gyri, a right posterior region including the parahippocampal, fusiform, and lingual gyri, and right cerebellar regions, as well as increased volumes of white matter in the frontal, temporal, and parietal lobes, even when hypertension was considered. Compared to normal weight women, obese women performed poorer on tests of executive functioning. Smaller gray matter volume in the left orbitofrontal region was associated with lower executive functioning. Additionally, despite the lack of significant group differences in memory and visuomotor speed, gray and white matter volumes predicted performance on these measures. The results provide additional evidence for a negative link between increased body fat and brain functioning in older females. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Regional distribution of white matter hyperintensities in vascular dementia, Alzheimer's disease and healthy aging

BACKGROUND: White matter hyperintensities (WMH) on MRI scans indicate lesions of the subcortical fiber system. The regional distribution of WMH may be related to their pathophysiology and clinical effect in vascular dementia (VaD), Alzheimer's disease (AD) and healthy aging. METHODS: Regional WMH volumes were measured in MRI scans of 20 VaD patients, 25 AD patients and 22 healthy elderly subjects using FLAIR sequences and surface reconstructions from a three-dimensional MRI sequence. RESULTS: The intraclass correlation coefficient for interrater reliability of WMH volume measurements ranged between 0.99 in the frontal and 0.72 in the occipital lobe. For each cerebral lobe, the WMH index, i.e. WMH volume divided by lobar volume, was highest in VaD and lowest in healthy controls. Within each group, the WMH index was higher in frontal and parietal lobes than in occipital and temporal lobes. Total WMH index and WMH indices in the frontal lobe correlated significantly with the MMSE score in VaD. Category fluency correlated with the frontal lobe WMH index in AD, while drawing performance correlated with parietal and temporal lobe WMH indices in VaD. CONCLUSIONS: A similar regional distribution of WMH between the three groups suggests a common (vascular) pathogenic factor leading to WMH in patients and controls. Our findings underscore the potential of regional WMH volumetry to determine correlations between subcortical pathology and cognitive impairment.     

Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer's disease and behavioral variant frontotemporal dementia

Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer's disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of 94 neurologically healthy controls were studied for comparison. In AD, poor figure copy correlated significantly with right parietal cortex volumes but not with right dorsolateral prefrontal cortex volumes, whereas in bvFTD, figure copy performance correlated significantly with right dorsolateral prefrontal cortex volumes and there was only a trend with right parietal cortex volumes. The cognitive processes associated with figure copy performance also differed by diagnostic group such that figure copy was associated with spatial perception and attention in AD and with spatial planning and working memory in bvFTD. Spatial planning accounted for unique variance in the figure copy performance of bvFTD even after accounting for spatial perception, attention, and working memory. These results suggest that figure copy performance in AD and bvFTD is not anatomically specific and is differentially impacted by bottom-up and top-down aspects of visual spatial processing. Alternative methods of visual spatial assessment for dementia evaluations are proposed.     

Metabolic alterations associated with impaired clock drawing in Lewy body dementia

The clock drawing test (CDT) is a widely used dementia screening instrument that assesses executive and visuospatial abilities; studies in patients with Alzheimer's disease (AD) suggest frontoposterior networks to be involved in clock drawing. Clock drawing errors are also often observed in dementia with Lewy bodies (DLB), but the functional neuroanatomical substrate of impaired clock drawing has not been firmly established in this disorder. The present study was designed to provide initial evidence for brain metabolic alterations associated with CDT performance in DLB. Twenty-one patients with DLB were enrolled. CDT ratings were correlated with the regional cerebral metabolic rate of glucose (rCMRglc) measured by ¹⁸F-fluoro-2-deoxy-glucose positron emission tomography (¹⁸F-FDG PET) in the statistical parametric mapping software package SPM5, controlling for overall cognitive impairment as measured by the Mini-Mental-State Examination (MMSE) score. There was a significant negative association between test scores and rCMRglc in a left-hemispheric posterofrontal network including the temporoparietal and dorsal pre-motor cortices and the precuneus. The present study provides evidence for a direct association between frontoparietal dysfunction and impaired CDT performance in DLB. These findings also suggest that the CDT is an appropriate screening instrument for this disorder and that metabolic dysfunction, and therefore disease severity, is mirrored by performance on the test.     

Parkinson's disease is associated with hippocampal atrophy.

Patients with Parkinson's disease (PD) may have hippocampal atrophy compared with controls. We compared hippocampal, and extra-hippocampal volumes between PD, PDD (patients with PD who have mild cognitive impairment or dementia), Alzheimer's disease (AD) and controls using volumetric magnetic resonance imaging (MRI). Participants (10 patients with PD, 10 with PDD, 11 with AD, and 12 control subjects) had an informant interview, neurological examination, and psychometric testing. Established, reliable methods were used to measure the hippocampus, parahippocampal gyrus, temporal, frontal, and parieto-occipital lobes. Correction for intracranial volume was carried out before comparison. There was no age difference between groups (mean age, 74 years). On the Clinical Dementia Rating scale (CDR) cognitive impairment was mild (CDR = 0.5) in the majority of PDD and AD patients. Hippocampal (P < 0.0004) volumes were smaller in the patient groups. Effect sizes compared with the control group were: PD, 0.66; PDD, 1.22; and AD, 1.81. The other volumes did not differ significantly. Among PD and PDD patients, recognition memory (r = 0.54, P = 0.015) and Mini-Mental State Examination scores (r = 0.56, P = 0.01) correlated with left, but not right hippocampal volume. In conclusion, hippocampal volume showed a pattern (Control > PD > PDD > AD) suggesting progressive hippocampal volume loss in PD. Volumetric MRI imaging might provide an early marker for dementia in PD.     

Clock drawing test in institutionalized patients with schizophrenia compared with Alzheimer's disease patients

The impaired performance of Alzheimer's disease (AD) patients on the clock drawing test (CDT) relative to age-matched normal controls is a well-documented finding in the literature. On the other hand, there is sparse information regarding the use of this test in schizophrenia. We examined three groups of subjects matched for gender and education: institutionalized patients with schizophrenia (n = 32), patients with AD (n = 32), and normal controls (n = 36). The CDT ("free-drawn", "pre-drawn", and three "examiner" conditions) and Mini-Mental State Examination (MMSE) were administered to all participants. In patients with schizophrenia, symptom severity was assessed with the Brief Psychiatric Rating Scale (BPRS). Patients with schizophrenia were significantly younger than AD patients and normal controls (56.78 versus 71.41 and 66.25, respectively), and normal controls had significantly higher MMSE scores than patients with schizophrenia and AD (27.58 versus 20.75 and 18.44, respectively). In all of the clock conditions, the two patient groups performed significantly poorer than the normal controls, with the exception of the "pre-drawn" clock in which AD patients also performed worse than patients with schizophrenia. Age and duration of illness did not correlate significantly with CDT scores. When MMSE scores were used as a covariate, all significant differences on the CDT among the three groups disappeared, with the exception of the "pre-drawn" clock (AD patients had lower scores than both control and schizophrenia groups). In patients with schizophrenia, scores on the BPRS were not related with any CDT variable. Institutionalized patients with schizophrenia and AD patients showed similar deficits on a neuropsychological test sensitive to changes in visual-analytic function, attention, receptive language, and executive functions such as planning, organization, and simultaneous processing.     

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer''s disease compared to normal controls

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimer's disease (AD) who had no non-cognitive symptoms. While both patient groups has smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.     

Extratemporal atrophy in patients with complex partial seizures of left temporal origin

Total cerebral, temporal lobe, hippocampal, caudate, and lenticular nuclei volumes were quantified from magnetic resonance images of 21 patients with left temporal lobe epilepsy and medically intractable complex partial seizures. These regional brain volumes were compared with the same measures in 19 controls. No significant differences in total cerebral, left temporal lobe, right temporal lobe, or total temporal lobe volumes were found. As expected, left hippocampal volumes were significantly smaller in the patients with epilepsy than in control subjects. The left hippocampus-to-right hippocampus volume ratio was significantly lower in patients than in control subjects. In addition to left hippocampal volumes, mean left thalamic, left caudate, and bilateral lenticular volumes were significantly smaller in the patients with epilepsy than in control subjects. The left-to-right thalamic volume ratio was also significantly lower in the patients with epilepsy compared with control subjects, but there were no significant group differences in caudate or lenticular ratios. These results show that medically intractable temporal lobe epilepsy is associated with volume loss in brain structures outside the presumably involved hippocampus. The pathophysiological significance of our findings is uncertain. They could be related to the underlying cause of the disorder. However, volume loss also may reflect damage due to involvement of these structures in recurrent seizure activity.     

Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia

OBJECTIVE: Poor executive functioning is a core deficit in schizophrenia and has been linked to frontal lobe alterations. We aimed to identify (1) prefrontal cerebral areas in which decreased volume is linked to executive dysfunction in schizophrenia; and (2) areas throughout the brain that are volumetrically related to the prefrontal area identified in the first analysis, thus detecting more extended volumetric networks associated with executive functioning. METHOD: Fifty-three outpatients with schizophrenia and 62 healthy controls, matched for age, gender and handedness, were recruited. High-resolution images were acquired on a 1.5 tesla scanner and regional gray and white matter volumes were analyzed by voxel-based morphometry within SPM5 (statistical parametric mapping, University College London, UK). Executive functioning was assessed using the Wisconsin Card Sorting Test (WCST). RESULTS: Twenty-one patients with poor executive functioning showed reduced dorsolateral prefrontal and anterior cingulate gray matter volume as compared to 30 patients with high WCST performance, with a maximum effect in the left dorsolateral prefrontal cortex. Left dorsolateral prefrontal gray matter volume predicted WCST performance after controlling for possible confounding effects of global cognitive functioning, verbal attention span, negative symptoms, illness duration and education. In this area, both patient groups had less gray matter than healthy controls. Left dorsolateral prefrontal gray matter volume was positively related to dorsal prefrontal, anterior cingulate and parietal gray matter volume; and negatively related to thalamic, cerebellar, pontine and right parahippocampal gray matter volume. CONCLUSIONS: Volumetric alterations in prefrontal-thalamic-cerebellar gray matter networks may lead to executive dysfunction in schizophrenia.