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.

/pdf/astrocytes-biology-and-pathology-2hq13zf0bo.pdf

Astrocytes: biology and pathology

Neuropathologic examination of autopsy brain tissue of 100 subjects with human immunodeficiency virus (HIV) infection revealed in 38 brains lesions attributable to HIV, in 17 brains without other pathologies.’ These lesions were characterized as multifocal giant cell encephalitis2 (MGCE) and /or progressive diffuse leukoencephalopathy ’ (PDL), both featuring multinucleated giant cells as evidence of the local presence and cytopathic action of HIV2 on monohistiocytes (as confirmed by electron microscopic detection of retroviral particles in four MGCE cases and immunocytochemical detection of HIV proteins in two MGCE brains’). Gray matter changes were found as diffuse glial/glioneuronal poliodystrophy in 5 1 brains.’ HIV-associated brain tissue lesions represent a novel syndrome in which opportunistic agents can be excluded and which can be differentiated from hitherto established brain lesions found in the immunocompromised host, such as progressive multifocal leukoencephalopathy (PML) and nodular (subacute) encephalitis (in most cases cytomegalovirus [ CMV] or toxoplasma detectable). Features that are important in the evaluation of the pathogenesis of HIV-associated lesions (MGCE and PDL) comprise: 1. Monohistiocytes/macrophages, including multinucleated giant cells and “rod cells,” all of which were labeled by an antimacrophage antibody, are the predominant cells in the lesions (FIGS. lA, lB, and 2B). 2. Parenchymal damage is usually seen as demyelination (FIG. 2A); close attachment of macrophages to damaged myelin is suggestive of myelin stripping. However, neurons, axons, and oligodendroglia remain intact even in the proximity of macrophages (FIG. 1B). 3. Focal lesions of MGCE have a perivascular site (FIGS. 1A and 1B); occasionally, fibrinous streaks are seen extending from the vessel wall, somewhat similar to vasculitis. These morphologic characteristics do not seem to support a hypothesis of primary neurocytopathy by HIV. Rather, they suggest secondary events related to the predominant cell in the lesion, the monohistiocyte/macrophage, which appears to be attracted to areas of focal vascular damage, possibly by endothelial HIV infection.

Pathogenesis of human immunodeficiency virus (HIV)-associated brain lesions. A neuropathologic evaluation.

In this and a companion paper we present immunohistochemical and ultrastructural data on hamsters
infected with the Echigo-1 strain of Creutzfeldt-Jakob disease. Ultrastructurally, two types of vacuoles were
readily discriminated in the brain: the grey matter vacuoles of spongiform change and intramyelin vacuoles.
The vacuoles were always membrane-bound; the membranes were single or double. The axons were
entirely missing from the plane of the sections or, if visible, were shrunken and attached to the innermost
layer of the myelin. It was noteworthy that some vacuoles indented cell bodies or processes and thus were
reminiscent of the intraneuronal vacuoles typical for natural scrapie, BSE and CWD in ungulates and
cervids but not of the vacuoles encountered in rodent models of scrapie and CJD. We also noticed vacuoles
distending myelinated fibres in which the axons had become dystrophic. Some axons underwent
Wallerian degeneration while others met the criteria for dystrophic neuritis. Both alterations existed in the
same areas. Typical dystrophic neurites contained abnormal subcellular organelles, mainly electron-dense
lysosomal inclusions. Other neurites contained numerous multi-vesicular bodies and autophagic vacuoles.
Nuclear paracrystalline rod-like inclusions were occasionally visible in neurons while other inclusions comprised
spiroplasma-like inclusions in synaptic boutons. The robust cellular reactions consisted of reactive
astrocytes and macrophages filled with cellular debris. It is of note that complex autophagic vacuoles were
observed in the cytoplasm of neurons.

Morphometry of synaptophysin immunoreactive ganglion cells in Auerbach plexus in patients with colorectal cancer. Is this a new prognostic factor

Human genetic prion diseases have invariably been linked to alterations of the prion protein (PrP) gene PRNP. Two sisters died from probable Creutzfeldt-Jakob disease (CJD) in Switzerland within 14 y. At autopsy, both patients had typical spongiform change in their brains accompanied by punctuate deposits of PrP. Biochemical analyses demonstrated proteinase K-resistant PrP. Sequencing of PRNP showed 2 wild-type alleles in both siblings. Retrospectively, clinical data revealed a history of dural transplantation in the initially deceased sister, compatible with a diagnosis of iatrogenic CJD. Clinical and familial histories provided no evidence for potential horizontal transmission. This observation of 2 siblings suffering from CJD without mutations in the PRNP gene suggests potential involvement of non-PRNP genes in prion disease etiology.

Iatrogenic and sporadic Creutzfeldt-Jakob disease in 2 sisters without mutation in the prion protein gene

A new Austrian family with fatal familial insomnia: Brain pathology without detectable PrPres

Despite decades of research, much intensified in recent years, transmissible spongiform encephalopathies (TSEs) or prion diseases have remained enigmatic in many aspects. Among these, the intricate connection between infectivity and genetics, genotype-phenotype correlation, and pathogenesis of brain damage are major problems in need of clarification. Fatal familial insomnia (FFI) appears as an ideal model situation for answering some of these problems: it has been understood to have a distinctive clinicopathological phenotype based on a specific genotype as well as transmissibility. However, as always with good science, new data prompts more questions than it is able to answer. The following survey of FFI cases in Europe and around the world is no exception from this rule.

Herbert Budka

Papers

Pathogenesis of human immunodeficiency virus (HIV)-associated brain lesions. A neuropathologic evaluation.

Morphometry of synaptophysin immunoreactive ganglion cells in Auerbach plexus in patients with colorectal cancer. Is this a new prognostic factor

Iatrogenic and sporadic Creutzfeldt-Jakob disease in 2 sisters without mutation in the prion protein gene

A new Austrian family with fatal familial insomnia: Brain pathology without detectable PrPres

Fatal familial insomnia around the world. Introduction.