Article

Adult Onset Leukodystrophy with Neuroaxonal Spheroids: Clinical, Neuroimaging and Neuropathologic Observations

C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Brain Pathology (Impact Factor: 4.35). 05/2008; 19(1):39-47. DOI: 10.1111/j.1750-3639.2008.00163.x
Source: PubMed

ABSTRACT Pigmented orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34-50 years with adult onset leukodystrophy. Their disease course ranged from 1.5-8 years. Three patients had progressive cognitive and behavioral changes; however, one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense Magnetic Resonance Imaging signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provide clinical-pathologic support for association pathways linking distributed neural circuits sub-serving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.

0 Followers
 · 
146 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal dominant adult-onset leukodystrophy (ADLD) is a progressive hereditary disease caused by duplication of Lamin B1 on chromosome 5q23.2. It is characterized by autonomic dysregulation, pyramidal signs, and cerebellar dysfunction. Since the first description in 1984, no authors have reported on its neurocognitive sequelae or attempted to quantify the severity of white matter changes. Herein we report a case of ADLD presenting with progressive cognitive changes leading to dementia and its associated white matter damage using diffusion MR imaging.
    Translational Neuroscience 01/2013; 4(4). DOI:10.2478/s13380-013-0142-1 · 0.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations within the colony stimulating factor 1 receptor (CSF1R) gene. While a small number of reports on imaging findings in routine MRI exist, reported imaging findings in DWI and spectroscopy are scarce, and limited to not genetically proven case reports. We assessed MRI including DWI and MR spectroscopy in six patients with HDLS and two asymptomatic mutation carriers. A total of 13 MRIs were evaluated and a score of the white-matter lesion (WML) load was calculated. The course of MR abnormalities was followed for 6-19 months in four patients and 95 months in one carrier. MRI revealed widespread white-matter lesions of patchy or confluent pattern especially in the frontal and occipital lobe. The pyramidal tract was less affected than the surrounding tissue in all symptomatic patients on conventional T2WI. Three of four cases with DWI showed small dots of diffusion restriction within WML. Spectroscopy showed increased levels of mIns, Cho and lactate while NAA was decreased. Asymptomatic mutation carriers had, for the age of the patients, unusually pronounced unspecific WMLs. No diffusion restriction or alterations in metabolite levels could be detected in asymptomatic mutation carriers. Microbleeds were not found in any patient. Diffusion restriction seems to be a typical imaging pattern visible in patients with active disease progression in HDLS. Spectroscopic findings and the absence of microbleeds differ clearly from reported findings in CADASIL and subcortical arteriosclerotic encephalopathy. While the distribution and character of WMLs in asymptomatic cases remain unspecific they are likely to represent subclinical markers of HDLS.
    Journal of Neurology 09/2014; DOI:10.1007/s00415-014-7509-2 · 3.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/- mice may play a central role in ALSP pathology. Copyright © 2014. Published by Elsevier Inc.
    Neurobiology of Disease 12/2014; 74. DOI:10.1016/j.nbd.2014.12.001 · 5.20 Impact Factor