Neuropathology and Applied Neurobiology

Microglia in the central nervous system are usually maintained in a quiescent state. When activated, they can perform many diverse functions which may be either beneficial or harmful depending on the situation. Although microglial activation may be accompanied by changes in morphology, morphological changes cannot accurately predict the function being undertaken by a microglial cell. Studies of peripheral macrophages and in vitro and animal studies of microglia have resulted in the definition of specific activation states: M1 (classical activation) and M2 (sometimes subdivided into alternative activation and acquired deactivation). Some authors have suggested that these might be an overlapping continuum of functions rather than discrete categories. In this review, we consider translational aspects of our knowledge of microglia: specifically, we discuss the question as to what extent different activation states of microglia exist in the human central nervous system, which tools can be used to identify them and emerging evidence for such changes in ageing and in Alzheimer's disease.

Gliomas are the most frequent intrinsic tumours of the central nervous system and encompass two principle subgroups: diffuse gliomas and gliomas showing a more circumscribed growth pattern (‘nondiffuse gliomas’). In the revised fourth edition of the WHO Classification of CNS tumours published in 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time, a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p/19q codeletion. Following this approach, the diagnosis of (anaplastic) oligoastrocytoma can be expected to largely disappear. Furthermore, in the WHO 2016 Classification gliomatosis cerebri is not an entity anymore but is now considered as a growth pattern. The most important changes in the very diverse group of ‘nondiffuse’ gliomas and neuronal‐glial tumours are the introduction of anaplastic pleomorphic xanthoastrocytoma, of diffuse leptomeningeal glioneuronal tumour and of RELA fusion‐positive ependymoma as entities. In the last part of this review, after very briefly touching upon classification of neuronal, choroid plexus and pineal region tumours, some practical implications and challenges associated with the WHO 2016 Classification of gliomas are discussed.

Serial sections of the brains of two cases with Alzheimer's disease were stained with the standard Bodian, modified Bielschowsky (reformed Gros‐Schultze's modification) and thioflavin S methods. The numbers of demonstrated Alzheimer's neurofibrillary tangles (NFTs) were different between the two silver stains: from 15 to 75% more NFTs were shown and more distinctly with the modified Bielschowsky stain than with the Bodian stain. Many of the NFTs in both cases were of eosinophilic and less argentophilic type. Although the NFTs were not counted, the thioflavin S stain seemed to have no apparent advantage over the modified Bielschowsky stain in the demonstration of NFTs.

M. Shioya, S. Obayashi, H. Tabunoki, K. Arima, Y. Saito, T. Ishida and J. Satoh (2010) Neuropathology and Applied Neurobiology36, 320–330
Aberrant microRNA expression in the brains of neurodegenerative diseases: miR‐29a decreased in Alzheimer disease brains targets neurone navigator 3

Aims: MicroRNAs (miRNAs) are small non‐coding RNAs that regulate translational repression of target mRNAs. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled that manner in the brain plays a key role in neuronal development. However, at present, the pathological implication of aberrant miRNA expression in neurodegenerative events remains largely unknown. To identify miRNAs closely associated with neurodegeneration, we performed miRNA expression profiling of brain tissues of various neurodegenerative diseases. Methods: We initially studied the frontal cortex derived from three amyotrophic lateral sclerosis patients by using a microarray of 723 human miRNAs. This was followed by enlargement of study population with quantitative RT‐PCR analysis (n = 21). Results: By microarray analysis, we identified up‐regulation of miR‐29a, miR‐29b and miR‐338‐3p in amyotrophic lateral sclerosis brains, but due to a great interindividual variation, we could not validate these results by quantitative RT‐PCR. However, we found significant down‐regulation of miR‐29a in Alzheimer disease (AD) brains. The database search on TargetScan, PicTar and miRBase Target identified neurone navigator 3 (NAV3), a regulator of axon guidance, as a principal target of miR‐29a, and actually NAV3 mRNA levels were elevated in AD brains. MiR‐29a‐mediated down‐regulation of NAV3 was verified by the luciferase reporter assay. By immunohistochemistry, NAV3 expression was most evidently enhanced in degenerating pyramidal neurones in the cerebral cortex of AD. Conclusions: These observations suggest the hypothesis that underexpression of miR‐29a affects neurodegenerative processes by enhancing neuronal NAV3 expression in AD brains.

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.

P. G. Ince, J. Lowe and P. J. Shaw (1998) Neuropathology and Applied Neurobiology24, 104–117

Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology

The classification of amyotrophic lateral sclerosis (ALS) is reconsidered in the light of developments in the molecular pathogenesis and histopathology of the condition. A current view is encapsulated in the El Escorial World Federation of Neurology criteria for the diagnosis of ALS. While intended for research purposes, use of these criteria for entry into clinical trials may result in the exclusion of some patient groups with related disorders that are likely to share aetiological mechanisms but which are not classified as ‘definite ALS’ or ‘probable ALS’. The relationship between ALS and the more restricted motor disorders of progressive lateral sclerosis and progressive muscular atrophy, together with cerebral degenerations including ALS‐dementia and ALS‐related frontal lobe dementia, are reviewed. The possibility is raised that they all represent syndromic manifestations of a similar pathogenetic cascade whose clinical phenotype depends upon the anatomical selectivity of involvement in each individual. The new evidence regarding the central role of oxidative stress and abnormal glutamatergic neurotransmission in familial and sporadic ALS seem applicable across these disorders. New evidence regarding the molecular pathology of inclusion bodies in these various syndromes, including ubiquitinated inclusions and hyaline conglomerate inclusions, shows striking similarities between them. Marked differences in the anatomical distribution of lesions determine the predominance and type of motor and cognitive features in each syndrome. This concept of a clinicopathological spectrum is potentially of equal relevance to other late onset neurodegenerative disorders including multisystem atrophies, the Lewy body disorders and various manifestations of Alzheimer's disease. It will gain increasing importance as therapies evolve from the symptomatic to those directed at underlying pathogenetic events.

Environmental enrichment (EE) increases levels of novelty and complexity, inducing enhanced sensory, cognitive and motor stimulation. In wild‐type rodents, EE has been found to have a range of effects, such as enhancing experience‐dependent cellular plasticity and cognitive performance, relative to standard‐housed controls. Whilst environmental enrichment is of course a relative term, dependent on the nature of control environmental conditions, epidemiological studies suggest that EE has direct clinical relevance to a range of neurological and psychiatric disorders. EE has been demonstrated to induce beneficial effects in animal models of a wide variety of brain disorders. The first evidence of beneficial effects of EE in a genetically targeted animal model was generated using Huntington's disease transgenic mice. Subsequent studies found that EE was also therapeutic in mouse models of Alzheimer's disease, consistent with epidemiological studies of relevant environmental modifiers. EE has also been found to ameliorate behavioural, cellular and molecular deficits in animal models of various neurological and psychiatric disorders, including Parkinson's disease, stroke, traumatic brain injury, epilepsy, multiple sclerosis, depression, schizophrenia and autism spectrum disorders. This review will focus on the effects of EE observed in animal models of neurodegenerative brain diseases, at molecular, cellular and behavioural levels. The proposal that EE may act synergistically with other approaches, such as drug and cell therapies, to facilitate brain repair will be discussed. I will also discuss the therapeutic potential of ‘enviromimetics’, drugs which mimic or enhance the therapeutic effects of cognitive activity and physical exercise, for both neuroprotection and brain repair.

Abundant neurofibrillary lesions made of hyperphosphorylated microtubule‐associated protein tau constitute one of the defining neuropathological features of Alzheimer’s disease. However, tau containing filamentous inclusions in neurones and/or glial cells also define a number of other neurodegenerative disorders clinically characterized by dementia and/or motor syndromes. All these disorders, therefore, are grouped under the generic term of tauopathies. In the first part of this review we outline the morphological and biochemical features of some major tauopathies, e.g. Alzheimer’s disease, argyrophilic grain disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. The impact of the recent finding of tau gene mutations in familial frontotemporal dementia and parkinsonism linked to chromosome 17 on other tauopathies is discussed in the second part. The review closes with a look towards a new understanding of neurodegenerative disorders characterized by filamentous nerve cell inclusions. The recent identification of the major protein component of their respective inclusions led to a surprising convergence of seemingly unrelated disorders. The new findings now allow us to classify neurodegenerative disorders with filamentous nerve cell inclusions into four main categories: (i) the tauopathies; (ii) the α‐synucleinopathies; (iii) the polyglutamine disorders; and (iv) the iquitin disorders’. Within the proposed classification scheme, tauopathies constitute the most frequent type of disorder.

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in the tauopathies, which include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17), progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Tau isoform composition and cellular and regional distribution as well as morphology of these inclusions vary in each disorder. Recently, several pathological missense and exon 10 splice‐donor site mutations of the tau gene were iden‐tified in FTDP‐17. Exon 10 codes for the second of four microtubule‐binding repeat domains. The splice‐site mutations result in increased inclusion of exon 10 which causes a relative increase in tau isoforms containing four microtubule‐binding repeat domains over those containing three repeat domains. This could be a central aetiological mechanism in FTDP‐17 and, perhaps, other related tauopathies. We have investigated changes in the ratio and distribution of three‐repeat and four‐repeat tau in the different tauopathies as a basis of the phenotypic range of these disorders and the selective vulnerability of different subsets of neurones. In this study, we have developed two monoclonal antibodies, RD3 and RD4 that effectively distinguish these closely related tau isoforms. These new isoform‐specific antibodies are useful tools for analysing tau isoform expression and distribution as well as pathological changes in the human brain.