White Matter Reduction Research Articles

Gray and white matter reduction in hyposmic subjects — A voxel-based morphometry study

The absence of olfactory input causes structural brain remodelling in humans. Mainly, the olfactory bulb and cortical olfactory areas are involved in this process. The aim of our study was to investigate volume changes of the gray and white matter in a group of subjects with an impaired but not complete loss of olfaction (hyposmia). Magnetic resonance images of hyposmic subjects and an age- and sex-matched control group were acquired on a 3 T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. The analysis revealed significant gray matter volume loss in the insular cortex, anterior cingulate cortex, orbitofrontal cortex, cerebellum, fusiform gyrus, precuneus, middle temporal gyrus and piriform cortex. In the VBM white matter analysis areas of volume loss were found underneath the insular cortex, in the cerebellum and middle frontal gyrus. All areas of white matter atrophy were spatially connected to areas of gray matter volume loss except the middle frontal gyrus alterations. No significant gray or white matter volume increases could be observed. The pattern of gray matter alterations was similar to that known from anosmic subjects with a lower extent. To our knowledge, we report here for the first time on white matter volume alterations in patients with olfactory deficit.

Voxel-based morphometry and epilepsy

Voxel-based morphometry is an automated technique for MRI analyses, developed to study differences in brain morphology and frequently used to study patients with diverse disorders. In epilepsy, it has been used to investigate areas with reduction or increase of gray and white matter, in different syndromes (i.e., temporal lobe epilepsy, focal cortical dysplasia and generalized epilepsies). In temporal lobe epilepsy, voxel-based morphometry showed gray/white matter atrophy extending beyond the atrophic hippocampus. These widespread abnormalities have been associated with seizure frequency, epilepsy duration, incidence of precipitating factors, cognitive dysfunction and surgical outcome. In generalized epilepsies, gray matter abnormalities were identified mainly in the thalamus and frontal cortex, reinforcing the role of the thalamocortical network in the mechanisms of generalized seizures.

A Morphometric Analysis of Neuroanatomic Abnormalities in Traumatic Brain Injury

Cognitive and structural brain abnormalities are common following traumatic brain injury (TBI). The authors compared cognition and brain structure in 14 TBI survivors and 28 matched healthy comparison subjects. TBI survivors showed reduced cerebral volume, due mainly to white matter changes, and poorer attention, psychomotor speed, and memory. Severity of white matter abnormality correlated with worse performance on several cognitive measures that distinguished between groups. Using voxel-based morphometry, regions of reduced white matter concentration were found throughout the cerebrum along with more localized gray matter reductions. Findings suggest that diffuse rather than focal aspects of TBI contribute most to cognitive outcome.

Early Hyperglycemia Is a Risk Factor for Death and White Matter Reduction in Preterm Infants

The objective of this study was to determine whether hyperglycemia during the first week of life in extremely preterm (EPT) infants was associated with increased mortality rates and with cerebral injury, as assessed with MRI of the brain, at term-equivalent age. All 143 EPT infants (gestational ages of <27 weeks) who were born at Karolinska University Hospital between January 2004 and December 2006 and were alive at 24 hours were eligible. Of the 118 surviving infants, 24 were excluded for various reasons. MRI was performed for the 94 included survivors at term age, with a 1.5-T system, and scans were scored for gray matter/white matter (WM) abnormalities. Of the 25 infants who died before term age, 6 were excluded because of missing glucose documentation and the remaining 19 were included. Hyperglycemia was defined as plasma glucose levels of >8.3 mmol/L. Hyperglycemia occurring on the first day of life was identified as an independent risk factor for death (adjusted odds ratio: 3.7 [95% confidence interval: 1.3-10.6]; P = .01). Hyperglycemia occurring on the first day of life also was a risk factor for WM reduction, as determined through MRI, at term-equivalent age (adjusted odds ratio: 3.1 [95% confidence interval: 1.0-9.2]; P = .04). In this population-based cohort of EPT infants, hyperglycemia on the first day of life was associated with increased mortality rates and brain damage, as reflected by WM reduction at term age.

The progression of regional atrophy in premanifest and early Huntington's disease: a longitudinal voxel-based morphometry study

BackgroundUnbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntington's disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of...

NPY mRNA expression in the prefrontal cortex: Selective reduction in the superficial white matter of subjects with schizoaffective disorder

BackgroundAlterations in the inhibitory circuitry of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia include reduced expression of the messenger RNA (mRNA) for somatostatin (SST), a neuropeptide present in a subpopulation of γ-aminobutyric acid (GABA) neurons. Neuropeptide Y (NPY) is expressed in a subset of SST-containing interneurons and lower levels of NPY mRNA have also been reported in schizophrenia spectrum disorders. However, whether the alterations in these two transcripts identify the same, particularly vulnerable, subset of GABA neurons has not been examined. MethodsWe used in situ hybridization to quantify NPY mRNA levels in DLPFC gray and white matter from 23 pairs of subjects with schizophrenia or schizoaffective disorder and matched normal control subjects; results were compared to those from a previous study of SST mRNA expression in the same subjects. ResultsIn contrast to SST mRNA, NPY mRNA levels were not significantly lower in the gray matter of subjects with schizophrenia or schizoaffective disorder. However, NPY, but not SST, mRNA expression was significantly lower in the superficial white matter of subjects with schizoaffective disorder. ConclusionThese findings suggest that the alterations in SST-containing interneurons in schizophrenia and schizoaffective disorder are selective for the subset that do not express NPY mRNA, and that lower NPY mRNA expression in the superficial white matter may distinguish subjects with schizoaffective disorder from those with schizophrenia.

White matter reduction in patients with schizophrenia as revealed by voxel-based morphometry: An activation likelihood estimation meta-analysis

Schizophrenia is thought to be a mental disorder caused by the disconnection of brain regions. Cumulative evidence of white matter deficit in patients with schizophrenia has been reported using voxel-based morphometry (VBM), but these studies have not been quantitatively reviewed. In the study reported herein, we used activation likelihood estimation (ALE) analysis to quantitatively estimate focal white matter abnormalities in patients with schizophrenia. Seventeen studies that compared the white matter deficit of patients with schizophrenia and healthy controls were ascertained. The frontal white matter regions and internal capsule revealed consistent white matter reduction in patient groups relative to healthy controls, suggesting a clear focal white matter deficit in patients with schizophrenia. These results support the macro-circuit theory of white matter change in schizophrenia.

Methods of MRI-based structural imaging in the aging monkey

Rhesus monkeys, whose typical lifespan can be as long as 30 years in the presence of veterinary care, undergo a cognitive decline as a function of age. While cortical neurons are largely preserved in the cerebral cortex, including primary motor and visual cortex as well as prefrontal association cortex there is marked breakdown of axonal myelin and an overall reduction in white matter predominantly in the frontal and temporal lobes. Whether the myelin breakdown is diffuse or specific to individual white matter fiber pathways is important to be known with certainty. To this end the delineation and quantification of specific frontotemporal fiber pathways within the frontal and temporal lobes is essential to determine which structures are altered and the extent to which these alterations correlate with behavioral findings. The capability of studying the living brain non-invasively with MRI opens up a new window in structural–functional and anatomic–clinical relationships allowing the integration of information derived from different scanning modalities in the same subject. For instance, for any particular voxel in the cerebrum we can obtain structural T1-, diffusion- and magnetization transfer- magnetic resonance imaging (MRI) based information. Moreover, it is thus possible to follow any observed changes longitudinally over time. These acquisitions of multidimensional data in the same individual within the same MRI experimental setting would enable the creation of a data base of integrated structural MRI-behavioral correlations for normal aging monkeys to elucidate the underlying neurobiological mechanisms of functional senescence in the aging non-human primate.

Mutation in the AP4M1 Gene Provides a Model for Neuroaxonal Injury in Cerebral Palsy

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.

The effect of ageing on grey and white matter reductions in schizophrenia

Total brain volume and, in particular gray matter (GM) volume is reduced in patients with schizophrenia and recent studies suggest there is greater progressive loss of brain volume in the patients with schizophrenia than in normal controls. However, as the longitudinal studies do not include life-long follow-up, it is not clear if this occurs across the lifespan or only in the early phase of the illness. In this study we investigated this by studying the effects of age on brain tissue volumes in schizophrenia ( n = 34, age range = 27–65 years)to test the prediction that there is a progressive loss in grey matter volume with increasing age in patients compared to healthy controls ( n = 33, age range = 18–73 years). The results showed there was diminished relative GM volume loss with age in patients with schizophrenia compared to controls — in contrast to our prediction. However, there was increased relative white matter (WM) loss with age in schizophrenia. The results also replicated previous findings that patients with schizophrenia have significantly lower total (1509 versus 1596 mm 3) and regional GM volume (755 versus 822 mm 3) and increased cerebrospinal fluid (CSF) volume when compared to matched healthy volunteers. Overall these findings indicate that the proportion of grey matter in schizophrenia is reduced compared to controls early in the illness, and this difference diminishes with age; the corresponding effect in the proportion of WM is an increase with age compared to controls. This suggests that illness related factors may differentially affect grey and white matter, with implications for understanding the pathophysiology of schizophrenia and related psychotic disorders.

Whole-brain voxel-based morphometry of white matter in mild cognitive impairment

Purpose The purpose of this study was to analyze whole-brain white matter changes in mild cognitive impairment (MCI). Materials and methods We studied 14 patients with MCI and 14 age- and sex-matched healthy control subjects using voxel-based morphometry (VBM) on T1-weighted 3D datasets. The data were collected on a 3T MR system and analyzed by SPM2 to generate white matter volume maps. Results Voxel-based morphometry revealed diffusively reduced white matter in MCI prominently including the bilateral temporal gyrus, the right anterior cingulate, the bilateral superior and medial frontal gyrus and right parietal angular gyrus. White matter reduction was more prominent in anterior regions than that in posterior regions. Conclusion Whole-brain white matter reduction in MCI patients detected with VBM has special distribution which is in line with the white matter pathology of MCI.

Prefrontal and anterior cingulate cortex abnormalities in Tourette Syndrome: evidence from voxel-based morphometry and magnetization transfer imaging

BackgroundPathophysiological evidence suggests an involvement of fronto-striatal circuits in Tourette syndrome (TS). To identify TS related abnormalities in gray and white matter we used optimized voxel-based morphometry (VBM) and magnetization transfer imaging (MTI) which are more sensitive to tissue alterations than conventional MRI and provide a quantitative measure of macrostructural integrity.MethodsVolumetric high-resolution anatomical T1-weighted MRI and MTI were acquired in 19 adult, unmedicated male TS patients without co-morbidities and 20 age- and sex-matched controls on a 1.5 Tesla neuro-optimized GE scanner. Images were pre-processed and analyzed using an optimized version of VBM in SPM2.ResultsUsing VBM, TS patients showed significant decreases in gray matter volumes in prefrontal areas, the anterior cingulate gyrus, sensorimotor areas, left caudate nucleus and left postcentral gyrus. Decreases in white matter volumes were detected in the right inferior frontal gyrus, the left superior frontal gyrus and the anterior corpus callosum. Increases were found in the left middle frontal gyrus and left sensorimotor areas. In MTI, white matter reductions were seen in the right medial frontal gyrus, the inferior frontal gyrus bilaterally and the right cingulate gyrus. Tic severity was negatively correlated with orbitofrontal structures, the right cingulate gyrus and parts of the parietal-temporal-occipital association cortex bilaterally.ConclusionOur MRI in vivo neuropathological findings using two sensitive and unbiased techniques support the hypothesis that alterations in frontostriatal circuitries underlie TS pathology. We suggest that anomalous frontal lobe association and projection fiber bundles cause disinhibition of the cingulate gyrus and abnormal basal ganglia function.

Neurobehavior at Term and White and Gray Matter Abnormalities in Very Preterm Infants

To examine the relationship between very preterm infant neurobehavior at term and concurrent magnetic resonance-defined cerebral abnormalities. 168 very preterm infants (birth weight <1250 g or gestation <30 weeks) were examined at term with 2 standardized neurobehavioral assessments, the Revised Hammersmith Neonatal Neurological Examination and the Neonatal Intensive Care Unit Network Neurobehavioral Scale. The relationship between composite neurobehavioral scores and qualitative white and gray matter abnormalities on magnetic resonance imaging was determined. Poorer neurobehavioral performance related to magnetic resonance-defined cerebral abnormalities. Composite neurobehavioral scores related to the total grade of white matter abnormality, and worse neurobehavior related most strongly to 2 components of this grade: white matter signal abnormalities and reduction in white matter volumes. Neurobehavior was not related to the total grade of gray matter abnormality. However, delayed gyral maturation, a component of the total gray matter grade, was related to poorer performance on both neurobehavioral scales. Very preterm infant neurobehavior at term is related to concurrent cerebral abnormalities in both white and gray matter defined by qualitative magnetic resonance imaging.

Review: Role of developmental inflammation and blood–brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases

The causes of most neurological disorders are not fully understood. Inflammation and blood-brain barrier dysfunction appear to play major roles in the pathology of these diseases. Inflammatory insults that occur during brain development may have widespread effects later in life for a spectrum of neurological disorders. In this review, a new hypothesis suggesting a mechanistic link between inflammation and blood-brain barrier function (integrity), which is universally important in both neurodevelopmental and neurodegenerative diseases, is proposed. The role of inflammation and the blood-brain barrier will be discussed in cerebral palsy, schizophrenia, Parkinson's disease, Alzheimer's disease and multiple sclerosis, conditions where both inflammation and blood-brain barrier dysfunction occur either during initiation and/or progression of the disease. We suggest that breakdown of normal blood-brain barrier function resulting in a short-lasting influx of blood-born molecules, in particular plasma proteins, may cause local damage, such as reduction of brain white matter observed in some newborn babies, but may also be the mechanism behind some neurodegenerative diseases related to underlying brain damage and long-term changes in barrier properties.

Association between symptom severity and internal capsule volume in obsessive-compulsive disorder

Neurobiological models support an involvement of white matter tracts in the pathophysiology of obsessive-compulsive disorder (OCD), but there has been little systematic evaluation of white matter volumes in OCD using magnetic resonance imaging (MRI). We investigated potential differences in the volume of the cingulum bundle (CB) and anterior limb of internal capsule (ALIC) in OCD patients ( n = 19) relative to asymptomatic control subjects ( n = 15). White matter volumes were assessed using a 1.5T MRI scanner. Between-group comparisons were carried out after spatial normalization and image segmentation using optimized voxel-based morphometry. Correlations between regional white matter volumes in OCD subjects and symptom severity ratings were also investigated. We found significant global white matter reductions in OCD patients compared to control subjects. The voxel-based search for regional abnormalities (with covariance for total white matter volumes) showed no specific white matter volume deficits in brain portions predicted a priori to be affected in OCD (CB and ALIC). However, large clusters of significant positive correlation with OCD severity scores were found bilaterally on the ALIC. These findings provide evidence of OCD-related ALIC abnormalities and suggest a connectivity dysfunction within frontal-striatal-thalamic-cortical circuits. Further studies are warranted to better define the role of such white matter alterations in the pathophysiology of OCD, and may provide clues for a more effectively targeting of neurosurgical treatments for OCD.

Studies on the Value of Diffusion‐Weighted MR Imaging in the Early Prediction of Periventricular Leukomalacia

Periventricular leukomalacia (PVL) is the most common cerebral injury in premature infants. While cranial ultrasonography and conventional magnetic resonance imaging (MRI) offer little for its early diagnosis, still they are much favored at present. Based on the pathologic mechanism of ischemic cerebral injury in PVL, we attempt to elucidate the effects of diffusion-weighted MR imaging (DWI) for the early diagnosis of PVL. Twelve cases of PVL in premature infants confirmed by MRI examinations were included in the current study. All cases underwent DWI in addition to conventional MR imaging (T1-weighted [T1W] and T2-weighted [T2W]) 7 days, 2 weeks, and 4 approximately 8 weeks after birth, respectively. Initial DWI examination (carried out at an average of 4.5 days after birth) revealed symmetrical and diffuse high signal in bilateral periventricular areas in all cases, while conventional MRI demonstrated normal signal. DWI examination of 2 weeks later showed irregular inhomogeneous signals in cerebral white matter, while conventional MRI revealed hyperintensity on T1WI and slight hypointensity on T2WI in corresponding areas. Four weeks later, DWI revealed various intensities of cystic low signals beside lateral ventricles, while conventional MRI showed hypointensity on T1WI and hyperintensity on T2WI in corresponding lesion, ie, change in cystic PVL. Four months later, conventional MRI evidenced gradual shrink and disappearance of cystic cavity, reduction in cerebral white matter, and ventricle enlargement. Symmetrical, diffuse hyperintensity in both lateral periventricular white matter on DWI was the earliest sign of PVL in premature infants. Imaging abnormalities provided by DWI had a close correlation with the results obtained by conventional MRI performed at the advanced stage of PVL, which suggests that DWI may be an important sequence for the early evaluation of cerebral white matter injury as well as for the prediction of PVL occurrence in premature infants.

In vivo voxel-based relaxometry in amyotrophic lateral sclerosis

We applied voxel-based relaxometry (VBR) in 12 ALS patients and 12 matched healthy controls and compared the results with those of voxel-based morphometry (VBM). VBR revealed a reduced relaxation rate in the right precentral gyrus and ventral pons. Individual region of interest (ROI)-based analysis of R2 maps confirmed our VBR results. VBM depicted a reduction of white matter in the paracentral lobules and in the right middle cerebellar peduncle. Our data suggests that VBR and ROI analysis of R2 maps may have a higher sensitivity in detecting local tissue atrophy in the motor cortex and along the corticospinal tract than VBM. Larger prospective studies are necessary to evaluate the usefulness and relevance of VBR and ROI-based analysis of R2 maps in clinical practice.

Early-onset dementia with prolonged occipital seizures

Kufs disease is the adult-onset form of neuronal ceroid lipofuscinosis (NCL). Its two clinical phenotypes are type A (progressive myoclonus epilepsy with dementia) and type B (behavioral abnormalities and dementia, associated with pyramidal and extrapyramidal signs). We describe the clinical evolution of an atypical case characterized by progressive dementia and focal occipital seizures. A healthy 37-year-old woman began showing memory deficits and behavioral disturbances (apathy, lack of inhibitions, untidiness). After 4 years, she developed rare clusters of tonic-clonic seizures, as well as focal seizures originating from the temporo-occipital regions, clinically associated with visual hallucinations, wandering, and agitation. When she was 44 years old, neuropsychological assessment revealed severe frontotemporal dementia. MRI showed cortical atrophy and, on T2-weighted images, hypointensity of the basal ganglia, and hyperintensity and reduction of the deep white matter. On the basis of these findings, a diagnosis of Kufs disease was hypothesized. A skin biopsy was negative, but electron microscopy examination of a right frontal lobe brain biopsy revealed the presence of typical storage material (fingerprint inclusions). The patient never developed myoclonus or extrapyramidal signs. Kufs disease is difficult to diagnose on account of its heterogeneous clinical pattern and pathologic features, and the lack of a specific genetic locus alteration. The neuropsychological pattern and MRI findings observed in patients with early-onset frontotemporal dementia and seizure disorder suggest that Kufs disease should be considered in their differential diagnosis. Extracerebral biopsy can be nondiagnostic, and when alternative diagnoses have been ruled out, cerebral biopsy should be considered.

Brain Magnetic Resonance Imaging Structural Changes in a Pedigree of Asymptomatic Progranulin Mutation Carriers

Mutations in the progranulin (PGRN) gene have been recently demonstrated as a cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusion (FTD-U). Neuropathologic, clinical, and neuroimaging features associated with PGRN mutations have been carefully described. No studies on asymptomatic subjects carrying pathogenetic PGRN mutations are available yet. These would be crucial for establishing the timing of brain changes and bringing new insight into disease pathogenesis and disease course. The aim of this study was to evaluate structural brain morphology using diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) in asymptomatic carriers of PGRN delCACT mutation belonging to a four-generation FTLD pedigree (mean age, 37.0 +/- 12.0). The evaluation of the family proband presenting with progressive nonfluent aphasia at 53 years of age, revealed left frontotemporal hypoperfusion and atrophy. VBM analysis of gray and white matter reductions revealed no differences between asymptomatic carriers (n = 7) and controls (n = 15), and between no-carriers (n = 10) and controls (p < 0.001). DTI analysis revealed a reduction in fractional anisotropy in healthy PGRN mutation carriers in the left uncinate fasciculus, connecting the orbito-frontal regions to the temporal pole, and in the left inferior occipitofrontal fasciculus, connecting the parieto-occipital cortex to the dorsolateral frontal cortex (p < 0.001). No significant difference in fractional anisotropy between no-carriers and controls was found. Our data indicate loss of white matter integrity as an early preclinical feature in familial FTD that might antedate the onset of specific neurologic features. Alteration of fiber tracts within the perisylvian language network might represent the early hallmark of subsequent aphasia onset. The study of other pedigrees of asymptomatic PGRN mutation carriers is warranted.

White matter alterations in schizophrenic patients with pronounced negative symptomatology and with positive family history for schizophrenia

In recent years, in vivo and post-mortem studies detected structural brain changes in schizophrenia. The aim of our analysis was to investigate potential changes of white matter in schizophrenic patients compared to controls, and the relationship to clinical characteristics. Fifty male, right-handed schizophrenic patients who met DSM-IV criteria for schizophrenia were recruited. Fifty right-handed, age- and sex-matched subjects without a psychiatric disorder were enrolled as controls. Volumes of white matter in several brain regions were measured by 1.5 T MRI using a volumetry and segmentation software (BRAINS). Regions of interest including frontal, temporal, parietal, occipital and subcortical areas were determined using Talairach spaces. No significant differences in white matter volumes of total brain tissue and regions of interest were detected between patients and controls. A significant reduction of white matter in parietal cortex of right hemisphere was found in a subgroup of patients with pronounced negative symptoms. Furthermore, patients with first-grade relatives suffering from schizophrenia showed a reduction of subcortical white matter in the right hemisphere. Our results indicate that subgroups of schizophrenic patients show alterations of white matter in distinct brain regions, including the right parietal lobe.