Lesion burden and cognitive morbidity in children with sickle cell disease

The effect of increased tissue injury in children with sickle cell disease and silent cerebral infarcts is not known. We determined the relationship between the extent of injury and IQ scores in children with silent cerebral infarcts. Participants were 27 children with sickle cell disease who had received magnetic resonance imaging (MRI). Children were divided into three groups: group 1, small lesion volume (n = 9, < 6.8 cm3); group 2, large lesion volume (n = 9; > 6.8 cm3); and group 3, no cerebral infarcts (n = 9). The Wechsler Full-Scale IQ was significantly lower for group 2 (mean = 76.1) when compared with group 1 (mean = 87.7) or group 3 (mean = 89.9). In children with silent cerebral infarcts, large tissue loss is associated with lower Wechsler Full-Scale IQ and small tissue loss is associated with no apparent change in IQ compared with children with no cerebral infarcts. The progressive accumulation of silent infarcts may lead to poorer intellectual functioning.     

Preliminary Study of Working Memory in Children with Stroke Related to Sickle Cell Disease

The verbal working memory abilities of children with stroke related to sickle cell disease (SCD) (n = 20) were compared to those of control children with SCD who had no history of stroke (n = 11). Memory span for one-, two-, and three-syllable words was assessed. For children with anterior infarcts, overall span was comparable to that of controls, but the typical effect of word length on span was reduced. For children with diffuse infarcts, overall span was reduced in comparison to that of controls, but the typical effect of word length on span was observed. For children with posterior infarcts, overall span was comparable to that of controls and the typical effect of word length on span was observed. These results provide preliminary evidence that patterns of working memory performance may vary across children with infarcts affecting different regions of the brain.     

Preliminary study of working memory in children with stroke related to sickle cell disease

The verbal working memory abilities of children with stroke related to sickle cell disease (SCD) (n = 20) were compared to those of control children with SCD who had no history of stroke (n = 11). Memory span for one-, two-, and three-syllable words was assessed. For children with anterior infarcts, overall span was comparable to that of controls, but the typical effect of word length on span was reduced. For children with diffuse infarcts, overall span was reduced in comparison to that of controls, but the typical effect of word length on span was observed. For children with posterior infarcts, overall span was comparable to that of controls and the typical effect of word length on span was observed. These results provide preliminary evidence that patterns of working memory performance may vary across children with infarcts affecting different regions of the brain.     

Brain atrophy as a marker of cognitive impairment in mildly disabling relapsing–remitting multiple sclerosis

Background and purpose: We have studied the relationship between neuropsychological impairment and magnetic resonance imaging (MRI) measures in mildly disabling relapsing–remitting multiple sclerosis (RRMS). Methods: We compared measures of lesion burden and atrophy in 52 patients with Expanded Disability Status Scale ≤ 3.0. Neuropsychological testing explored various cognitive domains: attention and processing speed (APS), verbal and visual memory (VerbM; VisM), visual/constructional processes (VC), executive functions and motor programming/coordination. Specific and global index scores were derived to classify patients as deteriorated or not deteriorated by comparing their performance with 51 matched normal control subjects. Brain MRI analysis included proton density (PD)‐lesion volume and T1‐hypointensity volume, measures of central atrophy, including the third ventricle width, and corpus callosum (CC). Results: Patients with either APS, MCP or Verbal Learning impairments had a higher ventricular atrophy than unimpaired. The atrophy of the CC was only associated to VisM dysfunction. Patients with VisM deficits had higher lesion load on PD images. After controlling for age and education a higher third ventricle width was the best predictor for global and specific cognitive impairment. Conclusion: Our results suggest that cognitive impairment in RR patients with mild disease is better explained by atrophic changes than by total lesion load.     

Cognitive deficits associated with frontal-lobe infarction in children with sickle cell disease

This study examined the cognitive manifestations of frontal-lobe infarction in a population of children with sickle cell disease (SCD). Forty-one patients with SCD underwent MRI. Five patients with stroke symptoms had large infarcts encroaching on the tissue of the frontal lobes. Four patients without symptoms had smaller frontal-lobe infarcts. The patients with stroke were significantly impaired on measures of intelligence, memory, and frontal-lobe function (Wisconsin Card Sorting Test, WCST) compared with both the patients with normal MRI scans ( N = 30) and a group of sibling controls ( N = 15), who did not differ from each other. Patients with covert infarction obtained scores on the intelligence tests and the WCST that fell in between those of the stroke patients and the other two groups. This trend toward impairment suggests that patients with covert infarction are at similar risk for cognitive deficits to those with stroke.     

Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease

The authors evaluated education attainment and neuropsychological deficits in children with sickle cell disease (SCD) and silent cerebral infarcts. Children with silent infarcts had twice the rate of school difficulties as children without infarcts. Eighty percent of silent infarct cases had clinically significant cognitive deficits, whereas 35% had deficits in academic skills. Children with silent cerebral infarcts show high rates of poor educational attainment, cognitive deficits, and frontal lobe injury. Poor school performance in SCD is one indicator of silent infarcts.     

Detecting white matter injury in sickle cell disease using voxel-based morphometry

OBJECTIVE: Sickle cell disease (SCD) is associated with cerebrovascular disease, cerebral infarction, and cognitive dysfunction. This study aimed to detect the presence and extent of white matter abnormalities in individuals with SCD using voxel-based morphometry (VBM). METHODS: Thirty-six children and adolescents with SCD (age range, 9-24 years) and 31 controls (8-25 years) underwent magnetic resonance investigations using T1- and T2-weighted protocols. White and gray matter density maps were obtained from three-dimensional magnetic resonance imaging (MRI) data sets. Using VBM, we compared the maps between controls and SCD individuals with silent white matter infarct lesions (SCD+L; n = 16), and those without visible abnormality (SCD-L; n = 20). RESULTS: In comparison with controls, intelligence quotients (IQs) were lower in both SCD groups irrespective of presence of visible lesions. VBM showed widespread bilateral white matter abnormalities in the SCD+L group, extending beyond the regions of focal infarction in the deep anterior and posterior white matter borderzones. Bilateral white matter abnormalities were also observed in the SCD-L group, in locations similar to those in the SCD+L group. INTERPRETATION: VBM is sensitive to detection of widespread white matter injury in SCD patients in borderzones between arterial territories even in the absence of evidence of infarction. Those changes may contribute to cognitive deficits in this population.     

Corpus callosum size, reaction time speed and variability in mild cognitive disorders and in a normative sample

Intra-individual variability in reaction time increases with age and with neurological disorders, but the neural correlates of this increased variability remain uncertain. We hypothesized that both faster mean reaction time (RT) and less intra-individual RT variability would be associated with larger corpus callosum (CC) size in older adults, and that these associations would be stronger in adults with mild cognitive disorders. A normative sample (n=432) and a sample with mild cognitive disorders (n=57) were compared on CC area, RT mean and RT variability adjusting for age, sex, education, APOE genotype, smoking, alcohol consumption, grip strength, visual acuity, handedness and lung function. Samples did not differ in CC area or intra-cranial volume. In the normative sample, simple RT (SRT) and choice RT (CRT) were negatively associated with CC area but there were minimal associations between CC area and intra-individual RT variability. In the mild cognitive disorders sample, SRT, CRT and intra-individual variability on the SRT task were associated with CC area. Increased RT variability explained up to 12.7 percent of the variance in CC area in the sample with mild cognitive disorders, but less than 1 percent of the variance in CC area in the normative sample. There were no associations with APOE genotype. We conclude that intra-individual variability is associated with CC area in mild cognitive disorders, but not in normal aging. We propose that biological limits on reserve capacity must occur in mild cognitive disorders that result in stronger brain-behavior relationships being observed.     

Corpus callosum atrophy is associated with gait disorders in patients with leukoaraiosis

Abstract Cognitive impairment and gait disturbances are the most frequent clinical findings in patients with leukoaraiosis (LA). Corpus callosum (CC) atrophy has been associated with dementia in patients with LA, as well as with gait disturbances in patients with normal pressure hydrocephalus. We investigated, in patients with LA, the possible association between gait impairment and CC atrophy, taking into account cognitive deficits and the other brain lesions commonly present in these patients. Thirty patients (M:F=21:9; mean age 72.5±6.3 years) with gait disturbances and brain CT images consistent with LA underwent an assessment of gait and a cognitive assessment of global and selective functions. Magnetic resonance imaging (MRI) was used to measure thickness and area of the CC, total LA volume, lacunar infarcts and size of lateral ventricles. We examined the effect of every MRI change on each performance measure. Reduction of CC thickness, particularly that of the anterior segment, had a significant effect on severity of gait impairment, as measured using the gait scale’s score. It was independent of any other brain changes revealed by MRI, including LA. An independent, significant association was also found between CC area and the Left Hand Praxis test results. In patients with LA, CC atrophy is associated with gait impairment independently of LA and other brain abnormalities usually present in these patients.The authors certify that they have no conflict of interest related directly or indirectly to the subject of the work.     

Corpus callosum size in children with developmental language disorder

Using high-resolution in-vivo magnetic resonance morphometry of the midsagittal area of the corpus callosum (CC) and four callosal subareas in 21 children with developmental language disorder (DLD) of the phonologic-syntactic type we found no significant anatomical differences in comparison to an age- and gender-matched normal control group. There was also no significant between-group difference when the approximately 7% smaller forebrain volume among children with DLD was accounted for by relating CC measures to forebrain volume. Only a tendency towards a larger anterior and middle CC in relation to forebrain volume was found in DLD children. In our DLD children we found the same relationship between CC midsagittal size and forebrain volume as recently reported for normal adults, namely, that the CC area increases to the two-third power of forebrain volume.     

Reduction of corpus callosum growth after severe traumatic brain injury in children

OBJECTIVE: To study effects of closed head injury (CHI) severity on development of corpus callosum (CC) in children, using MRI. BACKGROUND: Vulnerability of CC to diffuse axonal injury has been shown in adults and children by neuropathologic and MRI studies. Given continued development of CC through the second decade, serial MRI could characterize effects of CHI on CC growth in children. METHOD: MRI performed at 3 and 36 months after severe (mean age = 10.3 years, n = 25) and mild to moderate (mean age = 9.7 years, n = 28) CHI. Mild to moderate and severe CHI groups did not differ in demographic features. Morphometry of T1-weighted midsagittal CC by two operators with satisfactory interrater reliability yielded uncorrected and corrected CC volume. RESULTS: An interaction of occasion with CHI severity was present as CC area decreased from 3 to 36 months in severely injured children and increased in the mild to moderate CHI group. Uncorrected CC area was correlated with acute CHI severity and functional outcome at 36 months postinjury. CONCLUSIONS: Morphometric measurement of CC area provides a useful index of diffuse injury, which is related to functional outcome of CHI in children.     

Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys

This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys (Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11). Various brain regions were measured by MRI. Although overall brain volumes did not differ between NURSERY and CONTROL animals, corpus callosum (CC) size, measured in mid-sagittal sections, was significantly decreased in the NURSERY group. Group differences were most evident in the posterior aspects of the corpus callosum and appeared to result from changes in the number of cross-hemispheric projections rather than from a decrease in cortical gray matter volume. The decrease in corpus callosum size in the NURSERY animals persisted after 6 months of social housing in a peer-group. Rearing group differences were not found in other structures analyzed, including the hippocampus, cerebellum and anterior commissure. In cognitive testing, NURSERY animals had more difficulty acquiring the delayed non-matching to sample (DNMS) task, but showed no deficits in subsequent memory performance when a 2 or 10 min delay was imposed. The NURSERY infant monkeys were also impaired in object, but not in spatial, reversal learning, although there were no differences in a simple object discrimination task. The cognitive deficits exhibited by the NURSERY animals were significantly correlated with the alterations found in the CC. In summary, rearing environment was associated with sustained differences in cross-hemispheric projections, white matter volume and cognitive performance.     

Sex differences in the corpus callosum of patients with schizophrenia

The corpus callosum (CC) has been of interest in schizophrenia research because of its possible role in reduced lateralization and because of its sexually dimorphic characteristics. The literature has been replete with structural brain studies that have yielded equivocal results because of failure to address sex differences, handedness, and overall reductions in total brain volume (TBV) associated with schizophrenia. We performed midsagittal corpus callosum area MRI measurements on 71 chronically ill patients with schizophrenia (52 males, 19 females) and 67 controls (49 males, 18 females) using a semiautomated analytic technique subdividing the corpus callosum into five segments. Consistent with a meta-analysis [J. Neurol., Neurosurg. Psychiatry 58 (1995) 457], reductions in total CC area (after controlling for TBV and age) were found in schizophrenia patients relative to controls. However, our effect size, though not statistically significant, was -0.33 compared to -0.18 for the meta-analysis, indicating greater reductions in total CC area in our group of patients. Statistical significance was achieved only in male patients versus male controls (effect size=-0.50). The effect size remained the same when only right-handers were included in the analysis; thus, handedness did not account for this result. CC size was not related to psychiatric symptoms nor cognitive functioning in this group of patients.     

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.     

Early depressive symptoms after stroke: neuropsychological correlates and lesion characteristics

OBJECTIVE: To examine the relation between depressive symptoms and specific cognitive functions in patients with a recent stroke and to examine associations with lesion characteristics. METHODS: We studied 126 of 183 consecutive patients within 3 weeks after a first-ever symptomatic stroke (mean interval, 8.3+/-4.3 days). Presence and severity of depressive symptoms was assessed with the Montgomery Asberg Depression Rating Scale. Neuropsychological functioning was examined by means of a detailed neuropsychological examination covering six cognitive domains. We included a healthy control group (N=75) to obtain normative data for the neuropsychological examination. Functional impairment was measured with the modified Barthel Index and the modified Rankin Scale. Symptomatic and preexistent lesion characteristics were determined on CT or MRI. RESULTS: Of the included patients, 40% demonstrated mild and 12% moderate to severe depressive symptoms. Severity of depressive symptoms was related to lesion volume (p=0.008), functional impairment (all p<0.004), and degree of overall cognitive impairment (p=0.005). After adjustment for lesion size, a specific neuropsychological profile emerged in patients with moderate to severe depressive symptoms, affecting primarily memory, visual perception, and language (all p<0.05). No association was found between severity of depressive symptoms and lesion location, presence of preexistent lesions (white matter lesions and silent infarcts), and demographic factors (age, education, and gender). CONCLUSIONS: Moderate or severe symptoms of depression in the early stage poststroke are associated with a specific pattern of cognitive impairment, lesion size, and functional status. We suggest that depressive symptoms early after stroke are, at least in part, a reactive phenomenon secondary to severe cognitive and functional deficits.     

Cerebral white matter and cognition in hydrocephalic children.

Although children with hydrocephalus frequently show poor development of nonverbal cognitive skills relative to verbal skills, little is known about the neuropathologic correlates of these discrepancies. In this study, cerebral white-matter structures and lateral ventricles were measured from the magnetic resonance images of age-matched children with meningomyelocele, meningocele, and aqueductal stenosis and normal subjects. The volume of each lateral ventricle and the cross-sectional area of the corpus callosum and internal capsules were correlated with concurrent measures of verbal and nonverbal cognitive skills. The corpus callosum in the meningomyelocele and aqueductal stenosis groups was smaller. The lateral ventricles were larger, and the internal capsules were smaller, in all patient groups than in normal subjects. There were no differences in the size of the centra semiovale. Although verbal and nonverbal measures correlated positively with the size of the corpus callosum, the correlation was higher for nonverbal measures. Nonverbal measures correlated with the right, but not the left, lateral ventricle and with the area of the right and left internal capsules. Verbal measures correlated with the left, but not right, lateral ventricle and with the left, but not right, internal capsule. These results show a relationship between the corpus callosum and cognitive skills that is also influenced by hydrocephalus-related changes in the lateral ventricles and other cerebral white-matter tracts.     

Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status

OBJECTIVE: To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. BACKGROUND: Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. METHODS: Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. RESULTS: Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual-spatial and motor skills were associated with greater regional corpus callosum size. CONCLUSIONS: Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.     

Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis

BACKGROUND: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. OBJECTIVES: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. METHODS: 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. RESULTS: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = -0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. CONCLUSIONS: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.     

Malformation or damage of the corpus callosum? A clinical and MRI study

Anomalies of the corpus callosum (CC) in children can be subdivided into two main categories: Malformations (also known as dysgenesis) and damage to a previously well-formed callosum. Pre- or perinatally acquired damage may have a mainly vascular, obstructive or hypoxic-ischemic etiology, whereas endotoxins and exotoxins might also play a role. Early postnatally acquired CC damage in children is mostly of vascular or traumatic origin. In some instances the CC is thinned after chronic pressure (e.g. in hydrocephalics). Nineteen of fifty children with psychomotor retardation had CC anomalies, most of them suggestive of acquired damage. Mild forms of CC anomalies are visible with MRI, but might be missed with a CT-scan. Children with acquired CC anomalies have signs of supposed Interhemispheric Disconnection (ID), which is partly responsible for their clinical syndrome of mental and motor retardation. The likelihood of finding a CC anomaly in a child seems to be enhanced by the predictive use of neuropsychological tasks indicative for ID.     

Corpus callosum and P300 in schizophrenia

Functional abnormalities in the interhemispheric transfer via the corpus callosum in schizophrenia may result in filtering problems and information processing problems, which may in turn be related to the synchronization of cortical event-related activity. To explore whether a relationship exists between corpus callosum (CC) size, measured with in-vivo magnetic resonance imaging, and late auditory event-related P300 potentials, 50 patients with schizophrenia as well as 50 healthy controls were examined. The absolute CC size and subregional areas, as well as the CC areas adjusted for total brain volume, were not significantly different between patients with schizophrenia and controls. While no significant group differences were observed for P3a-, P3b-, PSW-amplitudes and P3b-latencies, P3a- and PSW-latencies were significantly prolonged for patients with schizophrenia. Absolute CC total size was significantly correlated with P3b-amplitudes in healthy controls (r=0.29; P=0.044). In patients with schizophrenia, significant correlations were observed between the subregion of the posterior body of the CC and positive slow wave (PSW; r=0.47; P=0.001). P3a-, P3b- and PSW-latencies were not significantly correlated to CC size in either patients with schizophrenia or healthy controls. The results are discussed in terms of the possibility that abnormalities in interhemispheric transfer may underlie the mechanisms of schizophrenia.