Cerebral White Matter Disease Research Articles

Retinal vasoreactivity as a marker for chronic ischemic white matter disease?

The cerebral microvasculature cannot be easily studied non-invasively. Because the retina and brain share embryological, anatomical and physiological similarities, studies of retinal blood vessels may prove to be useful as a surrogate marker for cerebrovascular disease. In epidemiological studies abnormal retinal arteriovenous ratios (AVRs) predict the risk of stroke and vascular dementia. However, the association between retinal vasoreactivity, cerebral small vessel ischemic disease, and cerebral blood vessel function remains unknown. Study GoalsTo examine (1) the association between cerebral ischemic white matter disease (WMD) and retinal microvessel behavior and (2) the relationship between retinal blood vessel reactivity and measures of cerebrovascular function. MethodsCohort study of 12 patients with ischemic WMD and 14 healthy controls. Retinal vasoreactivity was measured following high frequency flicker light stimulation. Middle cerebral artery (MCA) vasoreactivity was measured using transcranial Doppler ultrasound (TCD). Magnetic resonance imaging scans (MRIs) were reviewed for evidence of ischemic WMD. ResultsPatients with ischemic WMD had attenuated retinal venous (2.2%±0.27 SD, vs. controls 6%±0.7 SD, p=0.002, CI 95%) and arterial (1.9%±0.8 SD, vs. controls 4.9%±0.8 SD, p=0.004, CI 95%) vasoreactivity compared to controls. An attenuated retinal venous light flicker response was associated with a significant decrease of MCA vasoreactivity (r=0.45, p=0.05, CI 95%). Decreased AVRs, an indicator for altered retinal vessel architecture in patients with cerebral chronic ischemic WMD, were also significantly correlated with dysfunction of cerebral vasoreactivity (r=0.69, p=0.001, CI 95%). ConclusionIn this study functional and structural impairment of the retinal microvasculature were associated with ischemic WMD and measures of cerebral vascular function. Microvascular dysfunction in the eye may predict cerebral small vessel disease, but validation by larger studies is needed.

Quantitative MR imaging of two-pool magnetization transfer model parameters in myelin mutant shaking pup

Magnetization transfer (MT) imaging quantitatively assesses cerebral white matter disease through its sensitivity to macromolecule-bound protons including those associated with myelin proteins and lipid bilayers. However, traditional MT contrast measured by the MT ratio (MTR) lacks pathologic specificity as demyelination, axon loss, inflammation and edema all impact MTR, directly and/or indirectly through multiple covariances among imaging parameters (particularly MTR with T(1)) and tissue features (e.g. axon loss with demyelination). In this study, more complex modeling of MT phenomena ("quantitative" MT or qMT) was applied to a less complex disease model (the myelin mutant shaking [sh] pup, featuring hypomyelination but neither inflammation nor axon loss) in order to eliminate the covariances on both sides of the MR-pathology "equation" and characterize these important relationships free from the usual confounds. qMT measurements were acquired longitudinally in 6 sh pups and 4 age-matched controls ranging from 3 to 21 months of age and compared with histology. The qMT parameter, bound pool fraction (f), was the most distinctive between diseased and control animals; both f and longitudinal relaxation rate R(1) tracked myelination with normal aging, whereas MTR did not--presumably owing to counterbalancing MT and R(1) effects. qMT imaging provides a more accurate and potentially more specific non-invasive tissue characterization.

“Vascular Incontinence” and Normal-Pressure Hydrocephalus: Two Commonsources of Elderly Incontinence with Brain Etiologies

This paper reviewed two common sources of elderly incontinence with brain etiologies, “vascular incontinence” (a disorder of bladder control resulting from cerebral white matter disease) and normal-pressure hydrocephalus (NPH), from a neurological point of view. Both diseases manifest with gait disturbance, dementia, and urinary incontinence. Urinary frequency/ urgency (overactive bladder, OAB) often precedes urinary incontinence in both diseases, and in some patients may be the initial manifestation. While NPH is less common than vascular incontinence, at approximately one-tenth the prevalence, it is important because the symptoms can be reversed by shunt surgery or endoscopic third ventriculostomy. For vascular incontinence, early identification of risk factors and initiation of secondary prevention are necessary. Detrusor overactivity due to frontal hypofunction may underlie the bladder disorder in both diseases. Treatment options for urinary incontinence include anticholinergics, which do not easily penetrate the blood-brain barrier, or newer drugs that act on the adrenergic beta-3 receptor and other receptors.

Progressive leukoencephalopathy with intracranial calcification, congenital deafness, and developmental deterioration

We report on a 12-year-old male with a unique cerebral white matter disease. His initial symptoms were congenital hearing loss and multiple intracranial calcifications on head CT. He developed severe intellectual disability and epilepsy. MRI showed signal abnormalities in the posterior limbs of the internal capsules, thalami, and cerebral white matter. The abnormalities were progressive over time. The neuropathology revealed diffuse and severe disruption of myelin and axons of the cerebral white matter and cerebrospinal tracts. We performed various metabolic examinations, detailed pathological investigations and genetic analyses, but could not identify the cause. To our knowledge his clinical course has not been described in the literature.

Cerebral microbleeds and white matter disease: separated at birth?

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White Matter Disease Independently Predicts Progression from Mild Cognitive Impairment to Alzheimer’s Disease in a Clinic Cohort

Background: The contribution of vascular pathology to the rate of progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) remains unclear. Objective: To ascertain the relative roles of cerebral white matter disease and medial temporal atrophy (MTA) in predicting progression from MCI to AD. Methods: MCI patients with baseline MRI and ≧18 months of longitudinal follow-up were evaluated. DSM-IV-TR criteria were used to diagnose conversion to dementia. MTA and white matter hyperintensity (WMH) were quantified using the Scheltens scale and modified Fazekas scale. Results: Of a total of 171 MCI patients, 79 patients with baseline MRI and longitudinal follow-up were studied. Twenty-three MCI patients who progressed to dementia (MCI-P) were identified corresponding to a 19.4% annual risk of conversion. In MCI-P patients, the mean Mini-Mental State Examination and Montreal Cognitive Assessment decline was 1.3 and 2.9 points, respectively. MTA, periventricular WMH and deep subcortical WMH were significantly greater in the MCI-P cohort. WMH was found to predict MCI-P with an odds ratio of 7.69 (p = 0.03). Conclusion: MTA and deep subcortical WMH independently predict conversion from MCI to AD. Optimization of vascular risk factors among patients with MCI can potentially reduce the conversion from MCI to AD.

The challenge of mixed cerebrovascular disease

Stroke in general, and ischemic stroke in particular, are routinely defined using clinical criteria. Incorporating brain imaging and neuropathological findings into an expanded conceptual definition of stroke will result in a vastly increased prevalence of the disease. The resultant category of mixed cerebrovascular disease thus may include subclinical infarct, cerebral white matter disease, and cerebral microbleeds. Subclinical brain infarcts occur five times more frequently than does clinical ischemic stroke. Abnormalities of cerebral white matter are present in more than 95% of the population over the age of 65 years, and magnetic resonance imaging evidence of cerebral microbleeds is found in at least 18% of the population, beginning at the age of 60 years. Pathologic evidence supports at least a partial microvascular origin for cerebral white matter disease and cerebral microbleeds. Emphasizing mixed cerebrovascular disease as a conceptual framework allows for a focus on common underlying mechanisms and new therapeutic strategies.

Management of common central vestibular disorders

This article reviews the current literature on neurological disorders causing vestibular signs and symptoms. The review focusses on vestibular migraine, vestibular stroke syndromes, and supratentorial gait disorders. A familiar type of vestibular migraine with autosomal dominant inheritance has been linked to chromosome 5q35. In patients with vestibular migraine, vestibular testing in the asymptomatic interval, including VEMPs, produces heterogeneous and often only minor abnormalities. Migraine headaches can be triggered by vestibular stimulation suggesting that the relation of migraine and vestibular symptoms is bidirectional.Peripheral audiovestibular loss is a common accompaniment of anterior inferior cerebellar artery occlusion. Various brainstem and cerebellar stroke syndromes may mimic acute peripheral vestibular loss but can be differentiated clinically.The periventricular region and the anterior corpus callosum have been identified as specific localizations of cerebral white matter disease that interfere with gait and balance. Although vestibular migraine has been well delineated as a clinical syndrome, knowledge on its pathophysiology is scarce. To date, recommendations for treatment are based on clinical case series rather than randomized trials. Our understanding of ischemic vertigo has improved since stroke registers have provided large patient series with specific cerebellar and brainstem stroke syndromes. Cerebral white matter disease produces different clinical syndromes according to its severity and anatomical predilection.

A new concept for the neuropsychological testing in very and extreme prematures at the age of more than 5 years

There are different explanations that especially prematures with a birthweight <1000g have a lower developmental index: cerebral haemorrhages and white matter diseases (PVL), decreased growing of the brain, nutritional factors, psychological influences like stress or deprivation, intrauterine influences and genetical abnormalities, insufficient treatment or socio-economical aspects. In our opinion these questions can only be answered by neuropsychological examinations at an age >6 years.

CARASIL: Identification of the clinical concept

CARASIL (Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is the second known single-gene disorder directly affecting cerebral small vessels. The acronym CARASIL was proposed by Bowler and Hachinski (1994), based on its recessive inheritance and resemblance to CADASIL (R instead of D). The first CARASIL patients were most probably described in preliminary reports in 1965-66, and later in Japanese and English articles in 1969-1976. In 1985, the author and colleagues reported on another family of three brothers with strikingly similar clinical features, including not only neurological symptoms but also recurrent acute lumbago and premature alopecia, and cerebral white matter disease on CT scans, proposing that these characteristics can constitute a new systemic syndrome. According to our clinical and pathological/neuroradiological criteria, similar patients have been reported, almost exclusively from Japan, with a total reaching 50 until today. In five consanguineous families including ours, Hara et al. (2009) identified homozygous mutations in the HTRA1 gene on chromosome 10q25. Since no founder haplotype has been identified, the author and allied researchers suspect that this disorder will be found more widely. This review summarizes the historical background, epidemiology, characteristic clinical findings, neuroimaging, and clinical perspectives after the gene identification of this disorder.

WE-C-210A-02: Quantitative MRI of the Brain: Investigation of Cerebral Gray and White Matter Diseases

Local and global changes in braintissue volumes can be used as diagnostic markers of various neurological diseases. Even though these volumetric measurements do not provide specific information about underlying pathology, they can be used to diagnose these diseases, monitor disease progress or treatment efficacy. For example, local and global atrophies, which are observed in diseases such as multiple sclerosis and Alzheimer's disease, can be quantified to monitor disease magnitude and extent. Quantitative MRI of cerebral gray and white matters has found widespread application in brain research. Building on these progresses, some clinical applications started to emerge in recent years. The first technique utilizes high‐resolution structural MR images to investigate local and global morphological changes in the cerebral gray matter. This technique can be used longitudinally on a single patient to monitor disease progression or it can be utilized to identify morphological differences between a patient population and healthy controls. The image comparisons can be done using a voxel by voxel analysis technique, which will search the whole brain volume for group differences. On the other hand, if the investigator has an a priori hypothesis about a specific brain region, a volume of interest (VOI) can be selected manually in each image and compared. Another popular approach is to transform each image into a stereotactic space and analyze the deformation maps used in these transformations. The second technique utilizes the diffusion of water molecules to investigate the tissue structure and organization. In a medium where the molecular diffusion is restricted by cellularmembranes, the direction and magnitude of diffusion will reveal information about the microscopic structure and organization of those tissues. It has been demonstrated that the axonal membranes in major fiber tracts lead to highly anisotropicdiffusion and using this information white matter structures can be studied in great detail. The technique is called diffusion tensor imaging (DTI) and it has been used extensively to study white matter injuries in various diseases of the central nervous system. One of the most important aspects of this technique is that it provides several quantitative measurements of the cerebral white matter. For example, mean diffusivity measurement provides information about the overall water content, thus it can be used to identify local edema. On the other hand, the magnitude of anisotropy might be used as a marker of axonal fiber density and integrity, thus an indication of the overall health of a specific fiber tract. Major axonal fiber tracts can also be constructed in 3D from DTI images and measurements of fiber density, tract volume and length can be calculated. This presentation will provide an overview of imaging and analysis techniques used in image based quantification of cerebral gray matter and white matter diseases. Learning Objectives: 1. Analysis techniques used in the quantification of volumetric changes in the gray matter and potential applications. 2. DTI acquisition and processing. 3. Quantification of cerebral white matter structures based on DTI parameters. 4. Limitations of these techniques.

Outcomes of Siblings with Classical Galactosemia

To determine the long-term outcome of dietary intervention in siblings from 14 Irish families with classical galactosemia (McKusick 230400), an autosomal recessive disorder of carbohydrate metabolism and galactose-1-phosphate uridyltransferase (GALT) deficiency. Outcomes in siblings on dietary galactose restriction were studied to evaluate whether birth order (ie, time of commencement of diet) and compliance with lactose-restricted diet (galactose intake > or < 20 mg /day), assessed by dietary recall and biochemical monitoring of galactose-1-phosphate [Gal-1-P] and galactitol values, affected outcomes. The outcome variables assessed were IQ, speech, and language assessment scores, neurologic examination results, and magnetic resonance imaging (MRI) of the brain. There was a high incidence of complications in the overall group, particularly speech and language delay (77%) and low IQ (71%). There was no significant difference in outcome between earlier-treated and later-treated siblings or any correlation with mean Gal-1-P or galactitol values. In most cases, cerebral white matter disease was evident on MRI scanning, with evidence of progressive cerebellar degeneration seen in 2 highly compliant families. The subjects with a higher galactose intake did not exhibit an increased incidence of complications; conversely, those who were very compliant with dietary restrictions did not have more favorable outcomes.

Mirtazapine in Progressive Multifocal Leukoencephalopathy Associated with Polycythemia Vera

Progressive multifocal leukoencephalopathy (PML) is a usually fatal cerebral white matter disease found in patients with human immunodeficiency virus infection and other immunocompromised states. We present the case of a 63-year-old woman with polycythemia vera who developed a progressive focal neurological deficit with white matter abnormalities on magnetic resonance images of the brain that was proved on biopsy to be PML. She was treated with the serotonin reuptake inhibitor mirtazapine and remains neurologically stable, with resolution of cerebral lesions, >2 years after diagnosis. We propose that mirtazapine should be investigated further for use in PML.

MLC1 is associated with the Dystrophin-Glycoprotein Complex at astrocytic endfeet

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive cerebral white matter disease with onset in childhood, caused by mutations in the MLC1 gene. MLC1 is a protein with unknown function that is mainly expressed in the brain in astrocytic endfeet at the blood–brain and cerebrospinal fluid–brain barriers. It shares its localization at astrocytic endfeet with the dystrophin-associated glycoprotein complex (DGC). The objective of the present study was to investigate the possible association of MLC1 with the DGC. To test this hypothesis, (co)-localization of DGC-proteins and MLC1 was analyzed by immunohistochemical stainings in gliotic brain tissue from a patient with multiple sclerosis, in glioblastoma tissue and in brain tissue from an MLC patient. In control tissue, a direct protein interaction was tested by immunoprecipitation. Results revealed that MLC1 is co-localized with DGC-proteins in gliotic brain tissue. We demonstrated that both MLC1 and aquaporin-4, a member of the DGC, were redistributed in glioblastoma cells. In MLC brain tissue, we showed absence of MLC1 and altered expression of several DGC-proteins. We demonstrated a direct protein interaction between MLC1 and Kir4.1. From these results we conclude that MLC1 is associated with the DGC at astrocytic endfeet.

Chronic ischemic cerebral white matter disease is a risk factor for nonfocal neurologic injury after total aortic arch replacement

Leukoaraiosis (chronic ischemic white matter changes) on preoperative brain magnetic resonance imaging is common in patients having aortic arch surgery. This study sought to determine whether it is associated with adverse neurologic outcome in the postoperative period. Data were collected from a retrospective chart review of 142 patients in whom total aortic arch replacement was planned at the Cleveland Clinic between April 2000 and December 2004. All patients had preoperative brain magnetic resonance imaging evaluation. Leukoaraiosis severity was rated semiquantitatively using the Schelten's scale. Postoperative neurologic injuries were investigated by clinical examination and appropriate neuroimaging. They were stratified as type 1 (focal ischemic stroke) and type 2 (nonfocal neurocognitive changes, generalized seizures) injuries. The following were independent predictors of type 1 neurologic injury: age (odds ratio 1.06 [1.01-1.13], P = .02) and moderate to severe aortic atheroma (odds ratio 4.4 [1.4-9.7], P = .012). Total white matter scores (odds ratio 1.16 [1.06-1.27], P = .002) and higher preoperative hemoglobin A1c levels (odds ratio 1.8 [1.00-3.50], P = .05) were significantly associated with type 2 neurologic injuries. Survival was 96%, and 4.2% had persistent focal neurologic deficits at the time of hospital discharge. Leukoaraiosis is a significant independent predictor of nonfocal postoperative neurologic morbidity following aortic arch replacement surgery. Preoperative evaluation with magnetic resonance imaging allows identification of a patient subgroup at risk and implementation of strategies aimed at improving neurologic outcome.

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

MLC1: A Novel Protein in Distal Astroglial Processes

Megaloencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive cerebral white matter disease in children caused by mutations in the MLC1 gene. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC1 encodes a novel protein, MLC1, which is mainly expressed in the brain and leukocytes. The function is unknown, although a transport function has been suggested. In this article, we provide experimental data addressing the membrane topology and cellular localization of MLC1. We show that MLC1 contains an even number of transmembrane domains, supporting the possible transport function of MLC1. We demonstrate that MLC1 is specifically expressed in distal astroglial processes in perivascular, subependymal, and subpial regions. This localization suggests a role for MLC1 in a transport process across the blood-brain and brain-cerebrospinal fluid barriers. Astrocyte functions have long been debated. It is becoming increasingly clear that these cells are of fundamental importance in maintaining the structural and functional integrity of neural tissue. Elucidation of the function of MLC1 will contribute to a better understanding of not only the pathophysiology of the disease, but also the role of astrocytes in normal neural tissue.

Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?

The pathogenesis of and relationship between small deep (lacunar) infarcts, cerebral white matter disease (leukoaraiosis or white matter hyperintensities), and progressive cognitive impairment or dementia are much debated. We hypothesize that cerebral small-vessel endothelial (ie, blood-brain barrier) dysfunction, with leakage of plasma components into the vessel wall and surrounding brain tissue leading to neuronal damage, may contribute to the development of 3 overlapping and disabling cerebrovascular conditions: lacunar stroke, leukoaraiosis, and dementia. This hypothesis could explain the link between ischemic cerebral small-vessel disease and several apparently clinically distinct dementia syndromes. This hypothesis is supported by pathological, epidemiological, and experimental studies in lacunar stroke and leukoaraiosis and observations on the blood-brain barrier with MRI. We suspect that the potential significance of blood-brain barrier failure as a pathogenetic step linking vascular disease with common, disabling brain diseases of insidious onset has been overlooked. For example, lipohyalinosis, which has a pathological appearance of uncertain origin and is possibly responsible for some discrete lacunar infarcts, may be one end of a clinical spectrum of illness manifested by blood-brain barrier failure. Proof that blood-brain barrier failure is key to these conditions could provide a target for new treatments to reduce the effects of vascular disease on the brain and prevent cognitive decline and dementia.

Early age-related maculopathy in the cardiovascular health study

Objective To describe the prevalence of early age-related maculopathy (ARM) and its relation to atherosclerosis, lipids, hypertension, and inflammatory factors in a population studied for cardiovascular disease risk factors and outcomes. Design Population-based cohort study. Participants A biracial population of 2361 adults (ranging from 69–97 years of age; 1998 whites and 363 blacks) living in four US counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were examined during the interval from 1997 to 1998. Methods Drusen and other lesions typical of ARM were identified by examining a 45° color fundus photograph of one eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System. Main outcome measures Early ARM. Results Early ARM was present in 15.5% and late ARM in 1.3% of the cohort. The overall prevalence of any ARM was lower in blacks (9.1%) compared with whites (18.2%). While controlling for age, race, gender, and total calories consumed in the diet, factors associated with ARM were cerebral white matter disease as detected by magnetic resonance imaging (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.05, 2.16, P = 0.027), and lower serum total cholesterol (OR, per 10 mg/dl increase 0.95; 95% CI, 0.91, 0.98, P = 0.02). There were no associations between hypertension, blood pressure, common carotid artery plaque, or any systemic inflammatory factors studied and early ARM. Conclusions This population-based study documents the higher prevalence of ARM in whites compared with blacks. Although an association was found between signs of white matter disease and early ARM, there was no evidence of an association of ARM with either hypertension or inflammatory factors.

Late onset white matter disease in peroxisome biogenesis disorder.

To report late onset cerebral white matter disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD). There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes. Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies. Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination. Late-onset cerebral white matter disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-infantile onset of cerebral white matter disease