The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book’, the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.

https://link.springer.com/content/pdf/10.1007%2Fs00401-007-0243-4.pdf

The 2007 WHO Classification of Tumours of the Central Nervous System

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

Nobel Lecture: Prions

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Astrocytes: biology and pathology

Prion diseases are rare neurological disorders that may be of genetic or infectious origin, but most frequently occur sporadically in humans. Their outcome is invariably fatal. As the responsible pathogen, prions have been implicated. Prions are considered to be infectious particles that represent mainly, if not solely, an abnormal, protease-resistant isoform of a cellular protein, the prion protein or PrPC. As in other neurodegenerative diseases, aggregates of misfolded protein conformers are deposited in the CNS of affected individuals. Pathogenesis of prion diseases comprises mainly two equally important, albeit essentially distinct, topics: first, the mode, spread, and amplification of infectivity in acquired disease, designated as peripheral pathogenesis. In this field, significant advances have implicated an essential role of lymphoid tissues for peripheral prion replication, before a likely neural spread to the CNS. The second is the central pathogenesis, dealing, in addition to spread and replication of prions within the CNS, with the mechanisms of nerve cell damage and death. Although important roles for microglial neurotoxicity, oxidative stress, and complement activation have been identified, we are far from complete understanding, and therapeutic applications in prion diseases still need to be developed.

Pathogenesis of prion diseases.

Aims : NeuN is considered to be a marker of neuronal differentiation in brain tumours. Our aim was to perform, for the first time, a systematic and comparative analysis of NeuN expression in all major brain tumour subtypes to provide guidance for the rational use of NeuN immunohistochemistry in diagnostic histopathology.

Methods and results : Anti-NeuN immunohistochemistry was performed on paraffin-embedded biopsy specimens of 106 diffuse astrocytomas, 100 pilocytic astrocytomas, 107 ependymomas, 59 1p-aberrant oligodendroglial neoplasms, 115 glioblastomas, 115 medulloblastomas, 14 gangliogliomas/gangliocytomas and 10 central neurocytomas. We found no NeuN expression in pilocytic astrocytoma, whereas all other investigated tumour subtypes showed focal or widespread expression in varying proportions of cases. Comparing NeuN expression in clear cell tumours, widespread NeuN expression had a positive predictive value of 76.9% (95% confidence interval 46.2, 95.0) for central neurocytoma. Lack of NeuN expression had a positive predictive value of 87.3% (76.5, 94.4) for oligodendroglioma.

Conclusions : Immunohistochemistry can detect NeuN expression in all major brain tumour subtypes except pilocytic astrocytoma. In the individual case, assessment of NeuN expression may be helpful in the differential diagnosis of clear cell primary brain tumours but does not seem to be useful for the differential diagnosis of other brain tumour subtypes.

Comparative analysis of NeuN immunoreactivity in primary brain tumours: conclusions for rational use in diagnostic histopathology.

Multiple sclerosis (MS) is an idiopathic chronic inflammatory demyelinating disease of the central nervous system with variable extent of remyelination. Remyelination originates from oligodendrocyte (OG) precursor cells, which migrate and differentiate into mature OG. Tubulin polymerization promoting protein (TPPP/p25) is located in mature OG and aggregates in oligodendroglial cytoplasmic inclusions in multiple system atrophy. We developed a novel monoclonal anti-TPPP/p25 antibody to quantify OG in different subtypes and disease stages of MS, and possible degenerative changes in OG. We evaluated autopsy material from 25 MS cases, including acute, primary progressive, secondary progressive, relapsing remitting MS, and five controls. Demyelinated lesions revealed loss of TPPP/p25-positive OG within the plaques. In remyelination, TPPP/p25 was first expressed in OG cytoplasms and later became positive in myelin sheaths. We observed increased numbers of TPPP/p25 immunoreactive OG in the normal appearing white matter (NAWM) in MS patients. In MS cases, the cytoplasmic area of TPPP/p25 immunoreactivity in the OG was higher in the periplaque area when compared with NAWM and the plaque, and TPPP/p25 immunoreactive OG cytoplasmic area inversely correlated with the disease duration. There was a lack of phospho-TDP-43, phospho-tau, α-synuclein, and ubiquitin immunoreactivity in OG with enlarged cytoplasm. Our data suggest impaired differentiation, migration, and activation capacity of OG in later disease stages of MS. Upregulation of TPPP/p25 in the periplaque white matter OG without evidence for inclusion body formation might reflect an activation state. Distinct and increased expression of TPPP/p25 in MS renders it a potential prognostic and diagnostic marker of MS.

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Tubulin polymerization promoting protein (TPPP/p25) as a marker for oligodendroglial changes in multiple sclerosis

Thirteen autopsy cases of patients with clinical criteria of the Guillain-Barre syndrome were investigated for pathological changes and cellular composition of inflammatory infiltrates in the CNS and PNS. The survival times from the onset of neurological symptoms until death ranged from 1 day to 12 months. In the CNS, degeneration of spinal posterior tracts was seen in three cases. Mononuclear infiltrates consisted of evenly proportioned lymphocytes and macrophages in cases with survival of 1 and 2 days, whereas macrophages predominated in cases with survival of 5 days and longer. Infiltrates presented as nodular clusters around blood vessels and neurons, or were scattered diffusely. They were found within the spinal cord in eight out of 13 cases, within the medulla oblongata in eight out of 12 cases, within the pons in five out of nine cases, and in one out of four midbrains. Activation of microglia, either focal or diffuse, was found in various degrees in 11 out of 13 cases, involving the spinal cord (six out of 13 cases), the medulla oblongata (10 out of 12 cases), the pons (five out of nine cases) or as subependymal rims along the walls of the ventricular system and the central canal of the spinal cord (seven out of 13 cases). In the PNS, myelin loss (12 out of 13 cases), axonal degeneration (six out of 13 cases) and mononuclear cell infiltrates (13 out of 13 cases) were seen in segmental and cranial nerves, spinal ganglia and spinal roots in varying distribution and severity. Mononuclear cell infiltrates were composed of macrophages and T lymphocytes, with even distribution in cases with short survival (1 and 2 days), and predominance of macrophages in cases with protracted clinical course. T lymphocytes were equally composed of OPD4+ and CD8+ cells without obvious differences between cases of short and long duration, or between PNS and CNS infiltrates in 11 out of 12 cases, whilst two cases had a dominant OPD4+ subset. We conclude that CNS pathology is frequent in patients with Guillain-Barre syndrome. It involves axons with secondary myelin impairment, microglial activation and inflammatory infiltration. In this series, primary demyelination is not found in the CNS. Changes such as degeneration of spinal posterior tracts are secondary to pathology in the PNS. Inflammatory cell reactions in the CNS are similar to those in the PNS and to CNS pathology in experimental allergic neuritis. This inflammation might reflect CNS immune activation in the absence of the relevant antigen, in addition to cellular reactions accompanying secondary CNS changes. The presence of distinct pathology in the CNS is in contrast with other recent studies on the pathology of Guillain-Barre syndrome which, unlike this study, may have been influenced by recently introduced treatments.

Central nervous system pathology in patients with the Guillain-Barré syndrome.

Definitive diagnosis of neurodegenerative diseases (NDDs) relies on the neuropathological evaluation. NDDs are defined as disorders with progressive loss of neurons showing distinct anatomical distribution, and accordingly different clinical phenotypes. Recent research has identified a spectrum of immunohistochemically detectable proteins deposited in the central nervous system which serve as a basis for protein-based disease classification. Accordingly, diagnostic criteria and disease staging have been updated. Furthermore, it has become evident that there is considerable overlap between deposited proteins and pathologies. This review summarizes recent achievements in neuropathological diagnosis and classification of NDDs and recommends approaches to be used during the diagnostic procedure in practice, thus to serve as guideline for a common level of diagnostic quality.

Herbert Budka

Papers

Pathogenesis of prion diseases.

Comparative analysis of NeuN immunoreactivity in primary brain tumours: conclusions for rational use in diagnostic histopathology.

Tubulin polymerization promoting protein (TPPP/p25) as a marker for oligodendroglial changes in multiple sclerosis

Central nervous system pathology in patients with the Guillain-Barré syndrome.

Current concepts of neuropathological diagnostics in practice: neurodegenerative diseases.