Diffuse White Matter Disease Research Articles

VP29.04: Prenatal diagnosis of Leigh disease caused due to novel mutation in ISCA2 gene in nuclear DNA

Leigh disease/subacute necrotising encephalopathy also known as the multiple mitochondrial dysfunctions syndrome (MMDS) type 4 is a Mitochondrial disease which can be caused by mutations of nuclear or mitochondrial DNA. Leigh disease is inherited in an autosomal recessive manner and each pregnancy will carry the 25% risk of the fetus to be affected with it. Diagnosis of most of the cases of Leigh's disease is postnatal and retrospective as the disease manifests between the ages of 2 to 7 months of life with a triad of neurodevelopmental regression, optic atrophy with nystagmus, and diffuse white matter disease. To date, there is no cure for affected patients, and treatment options are mostly unsatisfactory. Prenatal ultrasound findings and immediate postnatal course of cases affected with Leigh Disease are unremarkable in most of the cases. Herewith we describe a prenatal molecular diagnosis of Leigh disease caused by ISCA2 (Iron-Sulphur cluster assembly 2) gene mutation - c.174G > A (p.Gln58(=)). Prenatal diagnosis was sought after establishing the genetic basis of Leigh disease in the previously affected index child having typical symptoms of the disease. Both parents were also identified as heterozygous carriers of same ISCA2 gene mutation. High degree of suspicion is required to achieve prenatal diagnosis of Leigh disease which can be easily missed prenatally. To the best of our knowledge, this is the first case report of Prenatal diagnosis of Leigh disease caused due to novel mutation in ISCA2 gene. Achieving prenatal diagnosis of Leigh syndrome helped parents to make well informed decision about continuation/termination of pregnancy as the disease will cause tremendous socio-economic and emotional burden to them. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

Are morphological and structural MRI characteristics related to specific cognitive impairments in neurofibromatosis type 1 (NF1) children?

NF1 children have cognitive disorders, especially in executive functions, visuospatial, and language domains, the pathophysiological mechanisms of which are still poorly understood. A correlation study was performed from neuropsychological assessments and brain MRIs of 38 NF1 patients and 42 controls, all right-handed, aged 8-12 years and matched in age and gender. The most discriminating neuropsychological tests were selected to assess their visuospatial, metaphonological and visuospatial working memory abilities. The MRI analyses focused on the presence and location of Unidentified Bright Objects (UBOs) (1), volume analysis (2) and diffusion analysis (fractional anisotropy and mean diffusivity) (3) of the regions of interest including subcortical structures and posterior fossa, as well as shape analysis of subcortical structures (4). The level of attention, intelligence quotient, age and gender of the patients were taken into account in the statistical analysis. Then, we studied how diffusion and volumes parameters were associated with neuropsychological characteristics in NF1 children. NF1 children present different brain imaging characteristics compared to the control such as (1) UBOs in 68%, (2) enlarged total intracranial volume, involving all subcortical structures, especially thalamus, (3) increased MD and decreased FA in thalamus, corpus callosum and hippocampus. These alterations are diffuse, without shape involvement. In NF1 group, brain microstructure is all the more altered that volumes are enlarged. However, we fail to find a link between these brain characteristics and neurocognitive scores. While NF1 patients have obvious pathological brain characteristics, the neuronal substrates of their cognitive deficits are still not fully understood, perhaps due to complex and multiple pathophysiological mechanisms underlying this disorder, as suggested by the heterogeneity observed in our study. However, our results are compatible with an interpretation of NF1 as a diffuse white matter disease.

TSEN54 missense variant in Standard Schnauzers with leukodystrophy.

We report a hereditary leukodystrophy in Standard Schnauzer puppies. Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect. Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.

Clinical Reasoning: A 47-year-old man with diffuse white matter disease and rapidly progressive dementia

A 47-year-old right-handed man without previous medical history presented to the University of Miami Memory Disorder Clinic for evaluation of progressive cognitive decline over a period of 4 months. He was initially noticed to have difficulty in finding his keys and documents and was not able to recall whether he had eaten lunch or dinner. The patient also had word-finding difficulties as well as remembering the meaning of a specific word. Upon further questioning, he also endorsed experiencing poor concentration and difficulty carrying out familiar tasks and for this reason he had to stop working. Additionally, there was also a reported weight loss of 20 pounds over the last 4 months. There was no known family history of dementia.

Diffuse White Matter Disease and Rapidly Progressive Dementia Secondary to Non-Paraneoplastic Voltage-Gated Calcium Channels Antibody (P2.2-018)

Diffuse White Matter Disease and Rapidly Progressive Dementia Secondary to Non-Paraneoplastic Voltage-Gated Calcium Channels Antibody (P2.2-018)

Leukoaraiosis severity predicts rate of decline in primary progressive aphasia

ABSTRACTBackground: The rate of decline in language in primary progressive aphasia (PPA) is highly variable and difficult to predict at baseline. The severity of diffuse white matter disease (leukoaraiosis), a marker of overall brain health, may substantially influence the rate of decline.Aims: To test the hypothesis that leukoaraiosis is associated with a steeper decline in naming in PPA.Methods and procedures: In this longitudinal, observational study, 29 individuals with PPA (all variants) were administered the Boston Naming Test (BNT) at baseline and 1 year later. Two raters evaluated leukoaraiosis on baseline MRI, using the Cardiovascular Health Study scale. We evaluated the effects of leukoaraiosis severity, age, education, and baseline BNT on decline measured by change in BNT accuracy with multivariable linear regression. We also evaluated the effects of these variables on the dichotomized outcome of faster decline in BNT (worst 50%) versus slower decline (best 50%) using logistic regression.Outcomes and results: Taken together, leukoaraiosis, age, education, and baseline BNT score predicted change in BNT score (F(3, 25) = 8.12; p = 0.0006). Change in BNT score was predicted by severity of leukoaraiosis (t = −3.81; p = 0.001) and education (t = −2.45; p = 0.022), independently of the other variables. When we dichotomized outcome into upper 50th percentile versus lower 50th percentile (faster decline), faster decline was predicted by all variables together (chi-squared = 13.91; p = 0.008). However, only leukoaraiosis independently predicted outcome (OR = 2.80; 95%CI: 1.11 to 7.03). For every 1 point increase on the CHS rating scale, there was 2.8 times higher chance of showing faster decline in naming.Conclusion: Severity of leukoaraiosis is associated with steeper decline in naming in PPA. This imaging marker can aide in prognosis and planning by caregivers and stratification of participants in clinical trials.

Multiple Mitochondrial Dysfunctions Syndrome 4 Due to ISCA2 Gene Defects: A Review.

Multiple mitochondrial dysfunctions syndrome 4, caused by ISCA2 gene defects (OMIM #616370), was first described by Al-Hassnan et al in 2015. To date, 20 cases have been reported: 13 females and 7 males from 18 different families. All cases are from Saudi Arabia except those from one Italian family. Typically, the patients have normal antenatal and birth history and attain normal development initially. Rapid deterioration occurs between 2 and 7 months of age, with the triad of neurodevelopmental regression, optic atrophy with nystagmus, and diffuse white matter disease. Magnetic resonance imaging findings include 75% of patients have cerebellar white matter abnormalities, and the spinal cord was affected in 55%. Magnetic resonance spectroscopy showed elevated glycine peaks in 2 (10%) cases and elevated lactate peaks in 5 (25%) cases. Biochemical abnormalities include high cerebrospinal fluid glycine and lactate and high plasma glycine and lactate, but these findings were not consistent. Diagnosis is based on the detection of biallelic mutations in the ISCA2 gene. To date, no curative treatment has been discovered, and disease management is exclusively supportive. In this report, the authors review the published cases of ISCA2 gene defects and retrospectively characterize disease phenotypes, the affected biochemical pathways, neuroradiological abnormalities, diagnosis, genetics, and treatment.

Neurovascular Ageing and Age-Related Diseases.

Proper functioning of the brain is dependent on integrity of the cerebral vasculature. During ageing, a number of factors including aortic or arterial stiffness, autonomic dysregulation, neurovascular uncoupling and blood-brain barrier (BBB) damage will define the dynamics of brain blood flow and local perfusion. The nature and extent of ageing-related cerebrovascular changes, the degree of involvement of the heart and extracranial vessels and the consequent location of tissue pathology may vary considerably. Atheromatous disease retarding flow is a common vascular insult, which increases exponentially with increasing age. Arteriolosclerosis characterized as a prominent feature of small vessel disease is one of the first changes to occur during the natural history of cerebrovascular pathology. At the capillary level, the cerebral endothelium, which forms the BBB undergoes changes including reduced cytoplasm, fewer mitochondria, loss of tight junctions and thickened basement membranes with collagenosis. Astrocyte end-feet protecting the BBB retract as part of the clasmatodendrotic response whereas pericyte coverage is altered. The consequences of these microvascular changes are lacunar infarcts, cortical and subcortical microinfarcts, microbleeds and diffuse white matter disease, which involves myelin loss and axonal abnormalities. The deeper structures are particularly vulnerable because of the relatively reduced density of the microvascular network formed by perforating and penetrating end arteries. Ultimately, the integrity of both the neurovascular and gliovascular units is compromised such that there is an overall synergistic effect reflecting on ageing associated cerebral perfusion and permeability. More than one protagonist appears to be involved in ageing-related cognitive dysfunction characteristically associated with the neurocognitive disorders.

The nature, consequences, and management of neurological disorders in chronic kidney disease.

Perhaps no other organ in the body is affected as often and in as many ways as the brain is in patients with chronic kidney disease (CKD). Several factors contribute to the neurological disorders in CKD including accumulation of uremic toxins, metabolic and hemodynamic disorders, oxidative stress, inflammation, and impaired blood brain barrier among others. The neurological disorders in CKD involve both peripheral and central nervous system. The peripheral neurological symptoms of CKD are due to somatic and cranial peripheral neuropathies as well as a myopathy. The central neurological symptoms of CKD are due to the cortical predominantly cortical, or subcortical lesions. Cognitive decline, encephalopathy, cortical myoclonus, asterixis and epileptic seizures are distinct features of the cortical disorders of CKD. Diffuse white matter disease due to ischemia and hypoxia may be an important cause of subcortical encephalopathy. A special and more benign form of subcortical disorder caused by brain edema in CKD is termed posterior reversible encephalopathy. Subcortical pathology especially when it affects the basal ganglia causes a number of movement disorders including Parkinsonism, chorea and dystonia. A stimulus-sensitive reflex myoclonus is believed to originate from the medullary structures. Sleep disorder and restless leg syndrome are common in CKD and have both central and peripheral origin. This article provides an overview of the available data on the nature, prevalence, pathophysiology, consequences and treatment of neurological complications of CKD.

Concepts and opportunities for repair in cerebral microvascular disease and white matter stroke.

Diffuse changes in white matter resulting from cerebral microvascular disease contribute to cognitive impairment (Jokinen et al., 2011), declines in global functionality (Inzitari et al., 2009), and even death (Debette and Markus, 2010). Twenty years ago, estimations of the clinical incidence of cerebral microvascular disease approached 11 million per year in the US alone (Leary and Saver, 2003). More recent estimations suggest the prevalence of diffuse white matter disease and silent brain infarction approaches 20% and increases dramatically in the presence of cardiovascular risk factors (Fanning et al., 2014). Two common clinical presentations of cerebral microvascular disease include diffuse lesions resulting in T2/FLAIR signal abnormality on MRI scans throughout the white matter. Highly related to this diffuse form, is the classic lacunar infarction, with imaging evidence suggesting that new infarcts occur at the leading edge of prior T2/FLAIR signal abnormality (Duering et al., 2013), with subtle changes in axonal diffusivity occurring in the same region (Maillard et al., 2011). Cellular events within this white matter penumbral region are therefore a likely contributor to the progressive nature of white matter disease. Despite the growing prevalence of cerebral microvascular disease, there are no known efficacious treatment strategies to prevent the progression or repair the injury burden of ischemic white matter lesions. In part, this results from a comparative lack of understanding about the precise pathophysiology of cerebral microvascular disease nor the resultant cellular biology that underlies diffuse or focal changes in white matter. This lack of understanding exists because of limitations on the ability to appropriately model white matter lesions in an easily accessible animal model such as the mouse. With the recent development of several variations in a mouse model of focal white matter stroke (Nunez et al., 2016), the field is poised for significant advances in understanding the cellular mechanisms underlying white matter lesions resulting from cerebral microvascular disease and to identify leading strategies to repair ischemic white matter lesions. Here, we outline the neurobiologic concepts and major strategies for repair of diffuse cerebral microvascular disease and white matter stroke (Figure 1).

Focal Necrosis and Disturbed Myelination in the White Matter of Newborn Infants: A Tale of Too Much or Too Little Oxygen

White matter disease in preterm infants comes along with focal destructions or with diffuse myelination disturbance. Recent experimental work with transgenic mice paves the way for a unifying molecular model for both types of brain injury, placing oxygen sensing by oligodendrocyte precursor cells (OPCs) at the center stage. Mice genetically altered to mimic high local oxygen tension in oligodendroglia lineage cells (via deletion of hypoxia-inducible factor, HIF) develop white matter disease resembling cystic periventricular leukomalacia within the first 7 days of life. Mice in which local hypoxia is mimicked in oligodendroglial cells (via genetic inhibition of HIF decay) display arrested OPC maturation and subsequent hypomyelination, reminiscent of the diffuse white matter disease observed in preterm infants and infants with congenital heart disease. These recent experimental findings on oxygen sensing and myelination are awaiting integration into a clinical framework. Gene regulation in response to hyperoxia or hypoxia, rather than oxidative stress, may be an important mechanism underlying neonatal white matter disease.

Small blood vessels: big health problems: National Institute of Neurological Disorders and Stroke update.

Because of the aging of our population, the burden of dementia is projected to double worldwide in the next generation, making it one of the greatest challenges faced by healthcare systems globally. Cerebral small-vessel disease is a major contributor to age-related cognitive impairment. Recent epidemiological research provides evidence that hypertension, cerebral infarction, and diffuse white matter disease (leukoaraiosis) are associated with increased risk of cognitive impairment. Most people who die with a diagnosis of dementia have a mixture of Alzheimer and vascular disease. Studies from Europe have reported recent decreases in dementia risk as might be expected from the decreased stroke risk that occurred over a similar time period. Although these correlative studies are important, we have not yet established causality. Besides control of blood pressure, there are no targeted therapies that exist for small-vessel disease. The National Institute of Neurological Disorders and Stroke (NINDS)–funded Secondary Prevention of Small Subcortical Strokes study showed a strong trend toward a decrease in recurrent stroke with aggressive blood pressure …

Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain.

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.

Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation

The objective of this work is to report on a series of five patients with adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia (ALSP). ALSP is a rare adult-onset leukodystrophy, which encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmentary orthochromatic leukodystrophy. This was a retrospective chart review and literature review. Five previously healthy women presented with a rapidly progressive neurological disorder at ages 39, 37, 40, 30, and 47, respectively. All five individuals were initially diagnosed as suffering from multiple sclerosis. The clinical courses of the five patients were dominated by progressive spastic quadriparesis (patient 5, newly diagnosed, has paraparesis at this time) and dementia. Brain magnetic resonance imaging (MRI) showed diffuse cerebral atrophy, corpus callosal atrophy, and diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions. Three patients showed involvement of pyramidal tracts from motor cortex to the brainstem. Cerebrospinal fluid was normal in all cases. Diagnosis of ALSP was established by biopsy (two cases) and autopsy (two cases). Histopathology showed the presence of neuroaxonal spheroids in all four cases and pigmented glia in three. In the fifth case, diagnosis was established by genetic analysis alone that showed a disease-causing mutation in the colony-stimulating factor 1 receptor (CSF1R) gene. Genetic analysis was done in three patients with available DNA, and identified the disease-causing mutation in all three, including a novel mutation F828S. ALSP may be suspected in adults with rapid to subacute progression of neurological disease when (1) MRI shows corpus callosal atrophy on a background of generalized brain atrophy and diffuse white matter disease without postcontrast enhancement, (2) CSF studies are normal, and (3) studies for systemic inflammatory diseases and specific leukodystrophies are normal. Diagnosis may be made without histopathological evidence when a disease-causing mutation is demonstrated in the CSF1R gene.

Clinical, Imaging and Histopathological Features of Adult Onset Leukoencephalopathy with Neuroaxonal Spheroids and Pigmented Glia: A Report of 4 Cases (P02.149)

Objective: To report on a series of 4 patients with Adult onset Leukoencephalopathy with Neuroaxonal Spheroids and Pigmented glia (ALSP). Background ALSP is a rare adult onset leukodystrophy, encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), which had previously been considered separate entities. Design/Methods: Retrospective chart review. Results: Four previously healthy women presented with a rapidly progressive neurological disorder with insidious onset at age 39, 37, 40, and 30 respectively, and were initially diagnosed as multiple sclerosis (MS). One patient had a sister who was diagnosed with MS and died 18 months later, and another had multiple female family members spanning four generations that died soon after being diagnosed with MS or dementia. The other 2 did not have a family history. The clinical courses of the 4 patients were stereotypical with progressive spastic quadriparesis and progressive neurological decline. The major features seen on brain MRI included diffuse cerebral atrophy with corpus callosal atrophy evident at an early stage, diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions, and involvement of pyramidal tracts from motor cortex to the brainstem in two patients who had late stage MRIs. Cerebrospinal fluid was normal in all cases. The correct diagnosis of ALSP was established by biopsy (2 cases) and autopsy (2 cases). Histopathology showed the presence of neuroaxonal spheroids in all cases and pigmented glia in two. Conclusions: ALSP may be suspected in adults with rapid to subacute progression of neurological disease, when (i) MRI shows corpus callosal atrophy on a background of generalized brain atrophy, diffuse white matter disease without postcontrast enhancement, (ii) CSF studies are normal, and (iii) studies for systemic inflammatory diseases and specific leukodystrophies are normal. However, despite suggestive MRI changes reported in our series, a brain biopsy remains essential for definitive diagnosis. Disclosure: Dr. Kleinfeld has nothing to disclose. Dr. Mobley has nothing to disclose. Dr. Wegner has nothing to disclose. Dr. Pawate has nothing to disclose.

Delayed Post-Hypoxic Leukoencephalopathy: A Case Report and Literature Review (P06.179)

Objective: To report a case of delayed post-hypoxic leukoencephalopathy (DPHL) and review the literature. Background DPHL has been described after exposure to opiates, benzodiazepines, carbon monoxide, surgical anesthesia and other agents. Since the first description in 1979, fewer than 20 cases have been reported, and information on clinical, imaging and especially histopathological features is scanty. Design/Methods: Chart review and literature search using PubMed. Results: A 52-year-old man with a history of tobacco and marijuana use was found unresponsive at home in January 2011. He was admitted to the intensive care unit, intubated, and treated for aspiration pneumonia. Upon extubation he appeared to be cognitively intact, but shortly thereafter experienced a cognitive decline, became unresponsive, and was transferred to neurology service in February. MRI of the brain showed diffuse nonspecific white matter disease and EEG showed moderate generalized nonspecific cerebral dysfunction. He was treated with vancomycin, ceftriaxone, and acyclovir for presumed encephalitis but cerebrospinal fluid showed no infectious etiology. As he continued to be in a persistent vegetative state a brain biopsy was performed and showed intact grey matter but extensive white matter degeneration with vacuolization, reactive astrocytosis, and a robust macrophage infiltrate. He was discharged to a skilled nursing facility with minimal change in his neurological status. By April, he began to communicate and move his left side purposefully. A repeat MRI in July continued to show necrotic white matter. He continued to improve and at the last follow-up in July 2011, he was oriented to self, place and time, and had normal speech and naming. Conclusions: DPHL typically occurs 1-2 weeks after apparent recovery from an insult. MRI shows extensive white matter changes with sparing of brainstem and cerebellum. As our case shows, extensive recovery can occur. Disclosure: Dr. Andresen has nothing to disclose. Dr. Kleinfeld has nothing to disclose. Dr. Pawate has nothing to disclose.

MRI Findings in Lymphomatosis Cerebri: Description of a Case and Revision of the Literature

Lymphomatosis cerebri (LC) is a rare form of primary central nervous system lymphoma; we report a case of LC mainly involving the brainstem and cerebellum. This diagnosis should be considered in patients presenting with diffuse white matter disease, and a subacute clinical history of cognitive deficits, ataxic gait, and personality changes. We present our findings along with a review of the neuroradiological literature.

Quality and Quantity of Diffuse and Focal White Matter Disease and Cognitive Disability of Patients with Multiple Sclerosis

Using high-field magnetic resonance imaging (MRI), we investigated the relationships between white matter (WM) lesion volume (LV), normal-appearing WM (NAWM) normalized volume, WM-lesion and NAWM magnetization transfer ratios (MTRs), brain parenchyma fraction (BPF), and cognitive impairment (CI) in multiple sclerosis (MS). Twenty-four patients and 24 healthy volunteers (age, sex, and years of education-matched) underwent a 3.0 Tesla (3T) scan and evaluation of depression, fatigue, and CI using the Minimal Assessment of Cognitive Function in MS (MACFIMS) battery. In this clinically relatively well-preserved cohort of patients (median score on the Expanded Disability Status Scale=1.5), CI was detected on Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and Controlled Oral Word Association Test. MT data were available in 19 pairs on whom correlation analyses were performed. Associations were seen between SDMT and normalized NAWM volume (P=.034, r=.502), CVLT-II long delay and normalized NAWM volume (P=.012, r=.563), WM-LV (P=.024, r=.514), and BPF (P=.002, r=.666). The use of 3T MRI in a sample of clinically stable MS patients shows the importance of WM disease in hampering processing speed and word retrieval.

Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.