Brain Pathology (Brain Pathol )

Publisher: International Society of Neuropathology, Blackwell Publishing

Description

Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.

  • Impact factor
    4.74
  • 5-year impact
    5.05
  • Cited half-life
    5.90
  • Immediacy index
    1.00
  • Eigenfactor
    0.01
  • Article influence
    1.60
  • Website
    Brain Pathology website
  • Other titles
    Brain pathology (Zurich, Switzerland: Online)
  • ISSN
    1750-3639
  • OCLC
    60627054
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Blackwell Publishing

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • Publisher's version/PDF cannot be used
    • On author's server, institutional server or subject-based server
    • Server must be non-commercial
    • Publisher copyright and source must be acknowledged with set statement ("The definitive version is available at www.blackwell-synergy.com")
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Microglia and macrophages play a central role for demyelination in Theiler's murine encephalomyelitis (TME) virus-infection, a commonly used infectious model for chronic-progressive multiple sclerosis. In order to determine dynamic changes of microglia/macrophage polarization in TME, the spinal cord of SJL mice was investigated by gene expression profiling and immunofluorescence. Virus persistence and demyelinating leukomyelitis was confirmed by immunohistochemistry and histology. Electron microscopy revealed continuous myelin loss together with abortive myelin repair during the late chronic infection phase, indicative of incomplete remyelination. A total of 59 genes out of 151 M1- and M2-related genes were differentially expressed in TMEV-infected mice over the study period. The onset of virus-induced demyelination was associated with a dominating M1-polarization, while mounting M2-polarization of macrophages/microglia together with sustained prominent M1-related gene expression were present during the chronic progressive phase. Molecular results were confirmed by immunofluorescence, showing an increased spinal cord accumulation of CD16/32+ M1-, arginase-1+ M2- and Ym1+ M2-type cells associated with progressive demyelination. The present study provides a comprehensive database of M1/M2-related gene expression involved in the initiation and progression of demyelination supporting the hypothesis that perpetuating interaction between virus and macrophages/microglia induces a vicious circle with persistent inflammation and impaired myelin repair in TME.
    Brain Pathology 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Huntington's disease (HD), an autosomal dominantly inherited polyglutamine or CAG-repeat disease along with somatomotor, oculomotor, psychiatric, and cognitive symptoms presents clinically with impairments of elementary and complex visual functions, as well as altered visual evoked potentials (VEP). Previous volumetric and pathoanatomical postmortem investigations pointed to an involvement of Brodmann's primary visual area 17 (BA17) in HD. Since the involvement of BA17 could be interpreted as an early-onset brain neurodegeneration we further characterized this potential primary cortical site of HD-related neurodegeneration neuropathologically and performed an unbiased estimation of the absolute nerve cell number in thick gallocyanin stained frontoparallel tissue sections through the striate area of seven control individuals and seven HD patients using Cavalieri's principle for volume and the optical disector for nerve and glial cell density estimations. This investigation showed a reduction of the estimated absolute nerve cell number of BA17 in the HD patients (71.044.037 ± 12.740.515 nerve cells) of 32% in comparison to the control individuals (104.075.067 ± 9.424.491 nerve cells) (Mann-Whitney U-test; p < 0.001). Additional pathoanatomical studies showed that nerve cell loss was most prominent in the outer pyramidal layer III, the inner granular layers IVa and IVc, as well as in the multiform layer VI of BA17 of the HD patients. Our neuropathological results in BA17 confirm and extend previous postmortem, biochemical and in vivo neuroradiological HD findings and offer suitable explanations for the elementary and complex visual dysfunctions, as well as for the altered VEP observed in HD patients.
    Brain Pathology 12/2014;
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    ABSTRACT: Melanotic tumors of the nervous system show overlapping histological characteristics but differ substantially in their biological behavior. In order to achieve a better delineation of such tumors, we performed an in-depth molecular characterization. 18 melanocytomas, 12 melanomas, 14 melanotic and 14 conventional schwannomas (control group) were investigated for methylome patterns (450k array), gene mutations associated with melanotic tumors and copy number variants (CNV). The methylome fingerprints assigned tumors to entity-specific groups. Methylation groups also showed a substantial overlap with histology-based diagnosis suggesting that they represent true biological entities. On the molecular level, melanotic schwannomas were characterized by a complex karyotype with recurrent monosomy of chromosome 22q and variable whole chromosomal gains and recurrent losses commonly involving chromosomes 1, 17p and 21. Melanocytomas carried GNAQ/11 mutations and presented with CNV involving chromosome 3 and 6. Melanomas were frequently mutated in the TERT promoter, harbored additional oncogene mutations and showed recurrent chromosomal losses involving chromosome 9, 10 and 6q as well as gains of 22q. Together, melanotic nervous system tumors have several distinct mutational and chromosomal alterations and can reliably be distinguished by methylome profiling.
    Brain Pathology 11/2014;
  • Brain Pathology 11/2014; 24(6).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter pathological changes within the cerebellum; and demyelination and inflammatory cell infiltrates appear commonly. Since Purkinje cell axons are the sole output of the cerebellar cortex understanding pathological processes within these cells is crucial to develop strategies to prevent their loss and thus reduce ataxia. We studied pathological changes occurring within Purkinje cells of the cerebellum. Using immunohistochemical techniques, we found changes in neurofilament phosphorylation states within Purkinje cells, including loss of dephosphorylated neurofilament and increased phosphorylated and hyperphosphorylated neurofilament. We also found Purkinje axonal spheroids and Purkinje cell loss, both of which occurred predominantly within areas of leucocortical demyelination within the cerebellar cortex. These changes have important implications for the study of cerebellar involvement in multiple sclerosis and may help design therapies to reduce the burden of ataxia in the condition.
    Brain Pathology 11/2014;
  • Brain Pathology 11/2014; 24(6).
  • [Show abstract] [Hide abstract]
    ABSTRACT: The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of “neuroinflammation” indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the “translocation” function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of “neuroinflammation.”
    Brain Pathology 11/2014; 24(6).
  • Brain Pathology 11/2014; 24(6).
  • Brain Pathology 11/2014; 24(6).
  • Brain Pathology 11/2014; 24(6).
  • Brain Pathology 11/2014; 24(6).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation was once a clearly defined term denoting pathological immune processes within the central nervous system (CNS). Historically, this term was used to indicate the four hallmarks of peripheral inflammaton that occur following severe CNS injuries, such as stroke, injury or infection. Recently, however, the definition of neuroinflammation has relaxed to the point that it is often now assumed to be present when even only a single classical hallmark of inflammation is measured. As a result, a wide range of disorders, from psychiatric to degenerative diseases, are now assumed to have an integral inflammatory component. Ironically, at the same time, research has revealed unexpected nonclassical immune actions of immune mediators and cells in the CNS in the absence of pathology, increasing the likelihood that homeostatic and adaptive immune processes in the CNS will be mistaken for neuroinflammation. Thus, we suggest reserving the term neuroinflammation for contexts where multiple signs of inflammation are present to avoid erroneously classifying disorders as inflammatory when they may instead be caused by nonimmune etiologies or secondary immune processes that serve adaptive roles.
    Brain Pathology 11/2014; 24(6).
  • Brain Pathology 11/2014; 24(6).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammatory mechanisms contribute to the brain pathology resulting from human immunodeficiency virus (HIV) infection. Magnetic resonance spectroscopy (MRS) has been touted as a suitable method for discriminating in vivo markers of neuroinflammation. The present MRS study was conducted in four groups: alcohol dependent (A, n = 37), HIV-infected (H, n = 33), alcohol dependent + HIV infected (HA, n = 38) and healthy control (C, n = 62) individuals to determine whether metabolites would change in a pattern reflecting neuroinflammation. Significant four-group comparisons were evident only for striatal choline-containing compounds (Cho) and myo-inositol (mI), which follow-up analysis demonstrated were due to higher levels in HA compared with C individuals. To explore the potential relevance of elevated Cho and mI, correlations between blood markers, medication status and alcohol consumption were evaluated in H + HA subjects. Having an acquired immune deficiency syndrome (AIDS)-defining event or hepatitis C was associated with higher Cho; lower Cho levels, however, were associated with low thiamine levels and with highly active antiretroviral HIV treatment (HAART). Higher levels of mI were related to greater lifetime alcohol consumed, whereas HAART was associated with lower mI levels. The current results suggest that competing mechanisms can influence in vivo Cho and mI levels, and that elevations in these metabolites cannot necessarily be interpreted as reflecting a single underlying mechanism, including neuroinflammation.
    Brain Pathology 11/2014; 24(6).
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    ABSTRACT: More than 80 years ago, Pio Del Rio-Hortega recognized that one of the “main controversial points in regard to the microglia” is “whether it belongs to the reticulo-endothelial system [i.e. monocytes and macrophages] and possesses the ordinary characteristics of this system or has a more specialized function.” The notion of microglia having functions that are different from those of other macrophages has gained significant support in recent years. The brain represents a unique environment and shows species, developmental and regional specialization. Thus, any consideration of microglial activity has to be thought of in this tissue context. Contexts may be normal (health, physiology) or disease conditions showing either primary or secondary microglial involvement. Subclinical, reversible “soft pathologies” (Kreutzberg) such as pain that involves microglia also exist. Here, we examine a multilayered approach to understanding microglia that illustrates the emergent character of the microglial (population) phenotype. Accordingly, terms such as microglial “activation” and microgliosis, which are of increasing importance for our understanding of neurological disorders, need to be filled with refined meaning. It is suggested that the pathophysiological context guides nomenclatorial considerations; for example, development, trauma or pain-associated microglia is preferred over the traditional but less distinctive “microglial activation.” This should also help to tease out the different functional subtypes currently hidden under the umbrella term “neuroinflammation,” which is being applied so widely that it has become effectively useless in practice and even inhibits research progress because both true and pseudo-inflammation are covered by this term.
    Brain Pathology 11/2014; 24(6).
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    ABSTRACT: In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regards to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbour of the brca1 gene (NBR1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 effect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.
    Brain Pathology 10/2014;
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    ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioural abnormalities is warranted. Previously, we have reported that the Chilean rodent Octodon degus (O.degus) could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report several histopathological markers associated with the onset-progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and changes in the expression of proteins related to metabolic control, including the 5'AMP-activated protein kinase (AMPK), peroxisome proliferative activated receptor γ coactivator-1α (PGC-1α) and the autophagy markers such as LC3 and p62. With these data, we suggest that the O. degus could represent a new model for AD research and also a powerful tool in the search for therapeutics strategies against of AD.
    Brain Pathology 10/2014;
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    ABSTRACT: Prognostic significance of histological anaplasia and BRAFV600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma (PXA). Median age at diagnosis was 21.5 yrs (31 pediatric, 43 adult) and median follow-up 7.6 years. Anaplasia (PXA-AF), defined as mitotic index ≥ 5/10HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 (R132H). Mitotic index ≥5/10HPF and necrosis were associated with decreased overall survival (OS) (p=0.0005 and p=0.0002, respectively). In all cases except 2, necrosis was associated with mitotic index ≥5/10HPF. Patients with BRAF V600E mutant tumors had significantly longer OS compared to those without BRAF V600E mutation (p=0.02). PXA-AF patients, regardless of age, had significantly shorter OS compared to those without (p=0.0003). Recurrence-free survival was significantly shorter for adult PXA-AF patients (p=0.047) only. Patients who either recurred or died ≤3 years from diagnosis were more likely to have had either PXA-AF at first diagnosis (p=0.008) or undergone a non-gross total resection procedure (p=0.004) as compared to patients who did not. This study provides further evidence that PXA-AF behaves more aggressively than PXA and may qualify for WHO grade III “anaplastic” designation.
    Brain Pathology 10/2014;
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    ABSTRACT: LGI1 mutations lead to an autosomal dominant form of epilepsy. Lgi1 mutant null mice develop seizures and show abnormal neuronal excitability. A fine structure analysis of the cortex in these mice demonstrated a subtle cortical dysplasia, preferentially affecting layers II-IV, associated with increased Foxp2 and Cux1-expressing neurons leading to blurring of the cortical layers. The hypercellularity observed in the null cortex resulted from an admixture of highly branched mature pyramidal neurons with short and poorly aligned axons as revealed by Golgi staining and immature small neurons with branched disoriented dendrites with reduced spine density and undersized, morphologically altered, and round-headed spines. In vitro, hippocampal neurons revealed poor neurite outgrowth in null mice as well as reduced synapse formation. Electron microscopy demonstrated reduced spine-localized asymmetric (axo-spinous) synapses with post-synaptic densities and vesicle-loaded synapses in the mutant null cortex. The overall pathology in the null mice suggested cortical dyslamination most likely due to mislocalization of late born neurons, with an admixture of those carrying suboptimally developed axons and dendrites with reduced functional synapses with normal neurons. Our study suggests that LGI1 has a role in regulating cortical development, which is becoming increasing recognized as one of the causes of idiopathic epilepsy.
    Brain Pathology 10/2014;
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    ABSTRACT: Olfactory dysfunction is common in multiple sclerosis (MS). Olfactory bulb and tract pathology in MS and other demyelinating disease remains unexplored. A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (MS; n=17), neuromyelitis optica (NMO); n=3), and acute disseminated encephalomyelitis (ADEM); n=7)) was compared to neuroinflammatory (herpes simplex virus encephalitis (HSE); n=3), neurodegenerative (Alzheimer's disease (AD); n=4), and non-neurologic (n=8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons, and inflammation. Inferofrontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases. Olfactory bulb/tract demyelination was frequent in all demyelinating diseases (MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)) but was absent in HSE, AD, and non-neurologic controls. Inflammation was greater in the demyelinating diseases compared to non-neurologic controls. Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination (r=0.610, P=0.009) and parenchymal inflammation (r=0.681, P=0.003). The extent of olfactory bulb/tract demyelination correlated with that found in the subjacent adjacent inferofrontal cortex but not hippocampus. We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and be highly inflammatory, and is specific to demyelinating disease.
    Brain Pathology 09/2014;