Patterns of cerebral white matter damage and cognitive impairment in adolescents born very preterm

There is increasing evidence about the presence of white matter damage in subjects with a history of premature birth, even in those classified as good outcome because of an apparently normal development. Although intellectual performance is within normal limits in premature children it is significantly decreased compared to paired controls. The purpose of this study was to investigate the relationship between a lower performance intelligence quotient and white matter damage in preterm adolescents. The sample comprised 44 adolescents (mean age ± S.D.: 14.4 ± 1.6 years) born before 32 weeks of gestational age and 43 term-born adolescents (14.5 ± 2.1 years). Individual voxel-based morphometry analyses demonstrated that 35/44 (80%) preterm subjects had white matter abnormalities. The centrum semiovale and the posterior periventricular regions were the most frequently affected areas. Correlation analysis showed that in preterms the performance intelligence quotient correlated with the whole-brain white matter volume (r = 0.32; P = 0.036) but not with grey matter volume. Complementary analysis showed that low scores in the Digit Symbol subtest, a measure of processing speed, in the preterm group correlated with reductions in white matter concentration. These results suggest that white matter damage is highly common and that it persists until adolescence. Hence, diffuse white matter loss may be responsible for performance intelligence quotient and processing speed decrements in subjects with very preterm birth.     

Executive functioning in preschool children born very preterm: relationship with early white matter pathology.

Despite evidence for executive dysfunction in school-aged preterm children, less is known about the early development of these difficulties or their underlying neuropathology. This study used prospective longitudinal data from a regional cohort of 88 very preterm and 98 full-term comparison children to examine the executive functioning (EF) of preschool children born very preterm. The relationship between the severity of neonatal cerebral white matter (WM) abnormalities on magnetic resonance imaging (MRI) at term equivalent and children's EF at ages two and four years (corrected age) was examined. At age four, very preterm children with WM abnormalities performed less well than full-term children on the Detour Reaching Box, a measure of behavioral inhibition and cognitive flexibility, even after controlling for child IQ, SES, and medical background. Examination of patterns of EF performance between the ages of 2 and 4 years showed that the performance of all groups improved with age. However, very preterm children with mild and moderate-severe WM abnormalities were characterized by higher rates of consistent performance impairments. These findings support the presence of early and persistent executive difficulties in preschool children born very preterm, and highlight the importance of white matter pathology in the development of executive impairments.     

Development of brain white matter and math computation ability in children born very preterm and full-term

Children born very preterm (VPT; <32 weeks’ gestation) have alterations in brain white matter and poorer math ability than full-term (FT) peers. Diffusion-weighted magnetic resonance imaging studies suggest a link between white matter microstructure and math in VPT and FT children, although longitudinal studies using advanced modelling are lacking. In a prospective longitudinal cohort of VPT and FT children we used Fixel-Based Analysis to investigate associations between maturation of white matter fibre density (FD), fibre-bundle cross‐section (FC), and combined fibre density and cross‐section (FDC) and math computation ability at 7 (n = 136 VPT; n = 32 FT) and 13 (n = 130 VPT; n = 44 FT) years, as well as between change in white matter and math computation ability from 7 to 13 years (n = 103 VPT; n = 21 FT). In both VPT and FT children, higher FD, FC and FDC in visual, sensorimotor and cortico-thalamic/thalamo-cortical white matter tracts were associated with better math computation ability at 7 and 13 years. Longitudinally, accelerated maturation of the posterior body of the corpus callosum (FDC) was associated with greater math computation development. White matter-math associations were similar for VPT and FT children. In conclusion, white matter maturation is associated with math computation ability across late childhood, irrespective of birth group.     

Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis

Aim The aim of this article was to clarify the impact and consequences of very preterm birth (born <32wks of gestation) and/or very low birthweight ([VLBW], weighing <1500g) on brain volume development throughout childhood and adolescence. Method The computerized databases PubMed, Web of Knowledge, and EMBASE were searched for studies that reported volumetric outcomes during childhood or adolescence using magnetic resonance imaging and included a term‐born comparison group. Fifteen studies were identified, encompassing 818 very preterm/VLBW children and 450 term‐born peers. Average reductions in the total brain volume, white matter volume, grey matter volume, and in the size of the cerebellum, hippocampus, and corpus callosum were investigated using meta‐analytic methods. Results Very preterm/VLBW children were found to have a significantly smaller total brain volume than the comparison group (d=?0.58; 95% confidence interval [CI] ?0.43 to ?0.73; p<0.001), smaller white matter volume (d=?0.53; CI ?0.40 to ?0.67; p<0.001), smaller grey matter volume (d=?0.62; CI ?0.48 to ?0.76; p<0.001), smaller cerebellum (d=?0.74; CI ?0.56 to ?0.92; p<0.001), smaller hippocampus (d=?0.47; CI ?0.26 to ?0.69; p<0.001), and smaller corpus callosum (d=?0.71; CI ?0.34 to ?1.07; p<0.001). Reductions have been associated with decreased general cognitive functioning, and no relations with age at assessment were found. Interpretation Very preterm/VLBW birth is associated with an overall reduction in brain volume, which becomes evident in equally sized reductions in white and grey matter volumes, as well as in volumes of diverse brain structures throughout childhood and adolescence.     

Brain motor excitability and visuomotor coordination in 8-year-old children born very preterm

ObjectiveOur study aimed to test in 8 years old children born very prematurely whether a faulty primary motor cortex (M1) functioning could parallel visuomotor coordination difficulties.MethodsTen very preterm children (PT; gestational age ?32 weeks; 6 boys; 8 years 6 months, SD 4 months) were compared to seven healthy term peers (4 boys; 8 years 4 months, SD 4 months). Clinical assessment comprised two standardized tests for motor skills and visuomotor coordination. Transcranial magnetic stimulation (TMS) was applied over M1 area of the preactivated first dorsal interosseous muscle to measure the corticomotor excitability and the short intracortical inhibition (SICI).ResultsPT scores were significantly lower on the Developmental Test of Visual-Motor Integration (p = 0.0018) and on the Movement Assessment Battery for Children (p = 0.038). In parallel, the dominant hemisphere worked differently with no SICI in PT (p = 0.009) and more variability of corticomotor excitability (p = 0.001).ConclusionsThese intertwined neurophysiological findings suggest that a faulty motor programming in the dominant M1 of PT could explain visuomotor coordination deficits.SignificanceOur study contributes to the understanding of possible mechanisms that underlie motor difficulties commonly observed in children who were born premature. In addition, the effectiveness of rehabilitation interventions may be better understood by applying TMS as an outcome measure in the future.     

Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease leading to gray matter atrophy and brain network reconfiguration as a response to increasing tissue damage. We evaluated whether white matter network reconfiguration appears subsequently to gray matter damage, or whether the gray matter degenerates following alterations in white matter networks. MRI data from 83 patients with clinically isolated syndrome and early relapsing–remitting MS were acquired at two time points with a follow‐up after 1 year. White matter network integrity was assessed based on probabilistic tractography performed on diffusion‐weighted data using graph theoretical analyses. We evaluated gray matter integrity by computing cortical thickness and deep gray matter volume in 94 regions at both time points. The thickness of middle temporal cortex and the volume of deep gray matter regions including thalamus, caudate, putamen, and brain stem showed significant atrophy between baseline and follow‐up. White matter network dynamics, as defined by modularity and distance measure changes over time, were predicted by deep gray matter volume of the atrophying anatomical structures. Initial white matter network properties, on the other hand, did not predict atrophy. Furthermore, gray matter integrity at baseline significantly predicted physical disability at 1‐year follow‐up. In a sub‐analysis, deep gray matter volume was significantly related to cognitive performance at baseline. Hence, we postulate that atrophy of deep gray matter structures drives the adaptation of white matter networks. Moreover, deep gray matter volumes are highly predictive for disability progression and cognitive performance.     

Neonatal echovirus encephalitis with white matter necrosis

The authors report a case of neonatal echovirus encephalitis associated with white matter necrosis. The pattern of illness in the neonatal period was diphasic, marked by hyperthermia and the occurrence of seizures. Echovirus was recovered from the cerebrospinal fluid. Cerebral magnetic resonance imaging (MRI) performed at one month of age showed right periventricular white matter necrosis. The infant exhibited mild left hemiparesis. Cerebral MRI at 6 months of age showed a delay in myelination in the right hemisphere. Echovirus encephalitis in the neonate can cause brain damage.     

Broad white matter impairment in multiple system atrophy

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by the widespread aberrant accumulation of α‐synuclein (α‐syn). MSA differs from other synucleinopathies such as Parkinson''s disease (PD) in that α‐syn accumulates primarily in oligodendrocytes, the only source of white matter myelination in the brain. Previous MSA imaging studies have uncovered focal differences in white matter. Here, we sought to build on this work by taking a global perspective on whole brain white matter. In order to do this, in vivo structural imaging and diffusion magnetic resonance imaging were acquired on 26 MSA patients, 26 healthy controls, and 23 PD patients. A refined whole brain approach encompassing the major fiber tracts and the superficial white matter located at the boundary of the cortical mantle was applied. The primary observation was that MSA but not PD patients had whole brain deep and superficial white matter diffusivity abnormalities (p < .001). In addition, in MSA patients, these abnormalities were associated with motor (Unified MSA Rating Scale, Part II) and cognitive functions (Mini‐Mental State Examination). The pervasive whole brain abnormalities we observe suggest that there is widespread white matter damage in MSA patients which mirrors the widespread aggregation of α‐syn in oligodendrocytes. Importantly, whole brain white matter abnormalities were associated with clinical symptoms, suggesting that white matter impairment may be more central to MSA than previously thought.     

Extensive abnormality of brain white matter integrity in pathological gambling

Several magnetic resonance imaging (MRI) studies in substance use disorders have shown brain white matter integrity abnormalities, but there are no studies in pathological gambling, a form of behavioral addiction. Our objective was to investigate possible changes in regional brain gray and white matter volumes, and axonal white matter integrity in pathological gamblers compared to healthy controls. Twenty-four subjects (12 clinically diagnosed male pathological gamblers and 12 age-matched healthy male volunteers) underwent structural and diffusion weighted brain MRI scans, which were analyzed with voxel-based morphometry and tract based spatial statistics. In pathological gamblers, widespread lower white matter integrity (lower fractional anisotropy, higher mean diffusivity) was seen in multiple brain regions including the corpus callosum, the cingulum, the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the anterior limb of internal capsule, the anterior thalamic radiation, the inferior longitudinal fascicle and the uncinate/inferior fronto-occipital fascicle. There were no volumetric differences in gray or white matter between pathological gamblers and controls. The results suggest that pathological gambling is associated with extensive lower integrity of several brain white matter tracts. The diffusion abnormality closely resembles previous findings in individuals with substance addictions.     

Brain white matter impairment in congenital adrenal hyperplasia

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis. Past reports suggested that brain white matter could be involved in CAH. OBJECTIVE: To detect the presence, and possible changes over time, of brain white matter abnormalities in patients with CAH. DESIGN: Neurological examination and brain magnetic resonance imaging (MRI) that were repeated in 12 patients after a mean interval of 11 years. SETTING: Pavia, northern Italy.Patients Twenty-two patients with CAH. MAIN OUTCOME MEASURES: Evaluation of clinical neurological findings and brain MRI T2-weighted images. RESULTS: Ten (45%) of 22 patients with CAH had white matter abnormalities (diffuse in 4 cases, focal in 3 cases, and both diffuse and focal in 3 cases) on MRI. The MRI findings never changed over repeated assessments. CONCLUSIONS: Subclinical brain white matter involvement is frequent in CAH. This might be due to hormonal imbalance during brain development or corticosteroid treatments. Our study findings indicate that a relationship with demyelinating diseases can also be suggested. Diagnosis of CAH should be suspected in young subjects with brain MRI white matter abnormalities that are not otherwise explicable.     

Microglial reaction in axonal crossroads is a hallmark of noncystic periventricular white matter injury in very preterm infants

Disabilities after brain injury in very preterm infants have mainly been attributed to noncystic periventricular white matter injury (PWMI). We analyzed spatiotemporal patterns of PWMI in the brains of 18 very preterm infants (25-29 postconceptional weeks [pcw]), 7 preterm infants (30-34 pcw), and 10 preterm controls without PWMI. In very preterm infants, we examined PWMI in detail in 2 axonal crossroad areas in the frontal lobe: C1 (lateral to the lateral angle of the anterior horn of the lateral ventricle, at the exit of the internal capsule radiations) and C2 (above the corpus callosum and dorsal angle of the anterior horn). These brains had greater microglia-macrophage densities and activation but lesser astroglial reaction (glial fibrillary acidic protein and monocarboxylate transporter 1 expression) than in preterm cases with PWMI. In preterm infants, scattered necrotic foci were rimmed by axonal spheroids and ionized calcium binding adaptor molecule 1-positive macrophages. Diffuse lesions near these foci consisted primarily of hypertrophic and reactive astrocytes associated with fewer microglia. No differences in Olig2-positive preoligodendrocytes between noncystic PWMI and control cases were found. These data show that the growing axonal crossroad areas are highly vulnerable to PWMI in very preterm infants and highlight differences in glial activation patterns between very preterm and preterm infants.     

Extensive abnormality of brain white matter integrity in pathological gambling

This study aimed to examine the subjective awareness of everyday dysexecutive function and the ‘objective’ executive function in individuals with schizotypal personality features. Forty-nine individuals with schizotypal personality disorder (SPD) proneness (25 negative schizotypy and 24 non-negative schizotypy were identified using cluster analysis) and 44 non-SPD individuals completed a battery of ‘objective’ executive function tests and a self-reported Dysexecutive Questionnaire (DEX) on everyday executive problems. The findings showed that individuals with SPD proneness including negative schizotypy and non-negative schizotypy did not have significant worse performance than non-SPD in most of ‘objective’ executive function tests, but self-reported significantly disproportionate more dysexecutive problems than non-SPD. Furthermore, SPD proneness, especially negative schizotypy was found to give undependable estimation on their everyday dysexecutive function while non-negative schizotypy was not. The current findings suggest that the subjective awareness of dysexecutive function may precede actual ‘objective’ executive function impairments in a subtype of SPD (non-negative schizotypy) and the subjective complaint of the daily dysexecutive behavior in SPD proneness, especially negative schizotypy might result from their unreliable estimation of executive function.     

Ischemic white matter damage and cognitive impairment

White matter damage may play an important role in the pathogenesis of vascular dementia. White matter abnormalities are easily visualized as white matter high‐intensity lesions (WML) on T2‐weighted magnetic resonance images. The extent of WML may be an indicator of cognitive impairment, in particular, impairment related to frontal lobe dysfunction. However, it is unclear whether the extent of WML is an independent predictor of cognitive impairment. In patients with extensive WML, atrophy of the corpus callosum may be an important predictor of global cognitive impairment. We investigated the relationship between the extent of WML and callosal size with cognitive function in patients who had been diagnosed with lacunar stroke or no specific neurological disease. Multivariate analysis showed that only callosal size and age were significant independent predictors of mini‐mental state examination scores (a measure of global cognitive function), whereas only the extent of WML was an independent predictor of the score on the verbal fluency task (a measure of frontal lobe function). Callosal atrophy may be an important predictor of global cognitive impairment in patients with WML, whereas the extent of WML per se may be related to impairment of frontal lobe function independent of callosal atrophy. White matter high‐intensity lesions with callosal atrophy may indicate a severe form of white matter damage with axonal loss, the degree of which may determine the severity of global cognitive impairment. Our longitudinal study revealed an association between progression of WML and vascular risk factor status during follow up in patients with initially mild WML. Early detection of WML without callosal atrophy at a stage of subtle cognitive impairment and slowing the progression of WML to a severe form with callosal atrophy might prevent the development of dementia.     

Abnormal white matter appearance on term FLAIR predicts neuro-developmental outcome at 6 years old following preterm birth

Preterm infants are at significant risk of neuro-developmental disorders at school-age. MRI is a potentially useful screening tool of such disorders. Using FLAIR imaging in the preterm infants at term, here we demonstrate that abnormal low-intensity signal in the white matter predicts the neuro-developmental outcome at 6 years.

Study design

Clinical factors associated with white matter appearance on MRI obtained at term were investigated in 210 preterm infants.

Results

Low-intensity signal on FLAIR imaging was commonly observed (69%) at <2 months corrected-age. Its incidence correlated with corrected-age at scan, maternal pyrexia and cystic periventricular leukomalacia. Low-intensity signal on FLAIR significantly correlated with performance and full-scale developmental quotients, whereas diffuse high-intensity signal on T2-weighted imaging correlated only with the full-scale developmental quotient at 6 years (n = 75, WISC-R). FLAIR imaging, but not T2-weighted imaging, predicted mild neuro-developmental delay.

Conclusions

FLAIR appeared to detect subtle white matter injury related with neuro-developmental disorders at school-age, whereas T2-weighted imaging seemed to identify relatively more severe injury. FLAIR is a potentially sensitive screening tool that is readily available and easily interpretable.