Brain Pathology

The new edition of the World Health Organization (WHO) book on ‘Histological Typing of Tumours of the Central Nervous System’ reflects the progress in brain tumour classification which has been achieved since publication of the first edition in 1979. Several new tumour entities have been added, including the pleomorphic xanthoastrocytoma, central neurocytoma, the infantile desmoplastic astrocytoma/ganglioglioma, and the dysembryoplastic neuroepithelial tumour. The list of histological variants has also been expanded. In line with recent morphological and molecular data on glioma progression, the glioblastoma is now grouped together with astrocytic tumours. The classification of childhood tumours has been largely retained, the diagnosis primitive neuroectodermal tumour (PNET) only being recommended as a generic term for cerebellar meduiloblastomas and neoplasms that are histologically indistinguishable from medulloblastoma but located in the CNS at sites other than the cerebellum. The WHO grading scheme was revised and adapted to new entities but its use, as before, remains optional.

Multiple sclerosis (MS) is characterized by synthesis of oligoclonal immunoglobulins and the presence of B‐cell clonal expansions in the central nervous system (CNS). Because ectopic lymphoid tissue generated at sites of chronic inflammation is thought to be important in sustaining immunopathological processes, we have investigated whether structures resembling lymphoid follicles could be identified in the CNS of MS patients. Sections from post‐mortem MS brains and spinal cords were screened using immunohistochemistry for the presence of CD20⁺ B‐cells, CD3⁺ T‐cells, CD 138⁺ plasma cells and CD21⁺, CD35⁺ follicular dendritic cells, and for the expression of lymphoid chemokines (CXCL13, CCL21) and peripheral node addressin (PNAd). Lymphoid follicle‐like structures containing B‐cells, T‐cells and plasma cells, and a network of follicular dendritic cells producing CXCL13 were observed in the cerebral meninges of 2 out of 3 patients with secondary progressive MS, but not in relapsing remitting and primary progressive MS. We also show that proliferating B‐cells are present in intrameningeal follicles, a finding which is suggestive of germinal center formation. No follicle‐like structures were detected in parenchymal lesions. The formation of ectopic lymphoid follicles in the meninges of patients with MS could represent a critical step in maintaining humoral autoimmunity and in disease exacerbation.

Multiple sclerosis (MS) is traditionally seen as an inflammatory demyelinating disease, characterized by the formation of focal demyelinated plaques in the white matter of the central nervous system. In this review we describe recent evidence that the spectrum of MS pathology is much broader. This includes demyelination in the cortex and deep gray matter nuclei, as well as diffuse injury of the normal‐appearing white matter. The mechanisms responsible for the formation of focal lesions in different patients and in different stages of the disease as well as those involved in the induction of diffuse brain damage are complex and heterogeneous. This heterogeneity is reflected by different clinical manifestations of the disease, such as relapsing or progressive MS, and also explains at least in part the relation of MS to other inflammatory demyelinating diseases.

Một trong những đặc điểm đáng chú ý nhất của tế bào thần kinh đệm sao (astrocytes) là phản ứng mạnh mẽ của chúng trước những chấn thương thần kinh khác nhau, một đặc điểm được bảo tồn tốt ở nhiều loài khác nhau. Phản ứng của tế bào đệm sao xảy ra nhanh chóng và có thể được phát hiện trong vòng một giờ sau khi có chấn thương cơ học tại chỗ (Mucke et al., 1991). Sự tăng sinh đáng chú ý của tế bào đệm sao phản ứng được quan sát thấy trong chứng mất trí do AIDS; một loạt các bệnh nhiễm virus khác; các bệnh não dạng bọt liên quan đến prion; các bệnh viêm dẫn đến mất myelin; chấn thương não cấp tính; và các bệnh thoái hóa thần kinh như bệnh Alzheimer. Sự nổi bật của phản ứng tế bào đệm sao trong các bệnh khác nhau, tốc độ của phản ứng tế bào đệm sao và sự bảo tồn tiến hóa của phản ứng astroglial cho thấy rằng các tế bào đệm sao phản ứng thực hiện những chức năng quan trọng của hệ thần kinh trung ương (CNS). Tuy nhiên, vai trò chính xác của các tế bào đệm sao phản ứng trong CNS bị tổn thương vẫn chưa được làm rõ. Chương này tổng hợp các mô hình thực nghiệm khác nhau và các bệnh biểu hiện sự tăng sinh tế bào đệm sao và gia tăng protein axit fibrillary thần kinh đệm (GFAP). Những nghiên cứu in vitro gần đây nhằm ức chế tổng hợp GFAP cũng được trình bày.

Vai trò của các quá trình viêm của tế bào đĩa trong bệnh Alzheimer đã được nêu bật bởi các nghiên cứu dịch tễ học gần đây xác lập chấn thương đầu là một yếu tố rủi ro quan trọng, và việc sử dụng các tác nhân chống viêm là một yếu tố cải thiện quan trọng, trong bệnh này. Bài tổng quan này đang tiến xa giả thuyết rằng sự kích hoạt mãn tính của các quá trình viêm tế bào đĩa, phát sinh từ các tổn thương di truyền hoặc môi trường đến tế bào thần kinh và đi kèm với sự phân giải mãn tính của các cytokine và protein khác do tế bào đĩa mang lại, kích hoạt một chu trình cytokine của các sự kiện tế bào và phân tử với những hậu quả thoái hóa thần kinh. Trong chu trình này, interleukin-1 là tác nhân khởi đầu và điều phối chính. Interleukin-1 thúc đẩy tổng hợp và xử lý protein tiền thân β-amyloid của tế bào thần kinh, do đó tạo điều kiện cho sự lắng đọng liên tục của β-amyloid, và kích hoạt tế bào đĩa đồng thời thúc đẩy sự tổng hợp và giải phóng một số phân tử viêm và hoạt động thần kinh. Một trong số này, S100β, là một cytokine thúc đẩy sự phát triển của neurite, gây căng thẳng cho tế bào thần kinh thông qua các hành động dinh dưỡng và thúc đẩy sự rối loạn chức năng và chết tế bào thần kinh bằng cách làm tăng nồng độ canxi tự do trong tế bào thần kinh. Tổn thương tế bào thần kinh phát sinh từ các tổn thương tế bào thần kinh do cytokine này có thể kích hoạt viêm màng não với sự biểu hiện quá mức của interleukin-1, do đó sản xuất sự khuếch đại và tự duy trì chu trình cytokine này. Sự khuếch đại phản hồi bổ sung được cung cấp thông qua các yếu tố khác của chu trình. Sự phát triển mãn tính của chu trình cytokine này đại diện cho một cơ chế khả thi cho sự tiến triển của các thay đổi thoái hóa thần kinh dẫn đến bệnh Alzheimer.

Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water‐ and lipid‐soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca²⁺‐dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca²⁺. The up‐regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca²⁺‐dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mito‐chondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic an ion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably depends on the severity and precise nature of the ischemie injury. Recent studies have emphasized the role of peroxynitrite in causing singlestand breaks in DNA, which activate the DNA repair protein poly(ADP‐ribose) polymerase (PARP). This catalyzes the cleavage and thereby the consumption of NAD⁺, the source of energy for many vital cellular processes. Over‐activation of PARP, with resulting depletion of NAD⁺, has been shown to make a major contribution to brain damage after transient focal ischemia in experimental animals. Neuronal accumulation of poly(ADP‐ribose), the end‐product of PARP activity has been demonstrated after brain ischemia in man. Several therapeutic strategies have been used to try to prevent oxidative damage and its consequences after brain ischemia in man. Although some of the drugs used in early studies were ineffective or had unacceptable side effects, other trials with antioxidant drugs have proven highly encouraging. The findings in recent animal studies are likely to lead to a range of further pharmacological strategies to limit brain injury in stroke patients.

Antibodies to α‐synuclein (AS) now provide a sensitive and specific method for the detection of Lewy bodies (LBs) and their use will allow a more accurate determination of the prevalence of LBs in Alzheimer's Disease (AD). Studies using AS immunohistochemistry (IHC) have found LBs in the amygdala of over 60% early onset familial AD and in 50% of Down's syndrome patients with AD, however, no studies have reported the use of AS IHC to detect LBs in a large cohort of sporadic AD. This study examined 145 sporadic AD cases diagnosed using CERAD criteria from 1995–1999 for the presence of LBs using AS IHC. AS IHC detected LBs in 88/145 (60.7%) of sporadic AD cases. Similarly, LBs were found in 56.8% of the 95 cases fulfilling the more stringent NIA‐RI criteria for the diagnosis of AD (Braak stage 5–6). In all cases with LBs, the amygdala was involved and LBs were always most numerous in this area, however, in some cases LBs in the substantia nigra were rare or not present. In conclusion, this study found that AS IHC detects LBs in the majority of sporadic AD cases and that the amygdala is the most commonly affected region.

Ischemic stroke is a leading cause of death and disability in developed countries. Yet, in spite of substantial research and development efforts, no specific therapy for stroke is available. Several mechnism for neuroprotection have been explored including ionchannels, excitatory amino acids and oxygen raicals yet none has culminated in an effective therapeutic effect. The review article on “inflammation and stroke” summarizes key data in support for the possibility that inflammatory cells and mediators are important contributing and confounding factors in ischemic brain injury. In particular, the role of cytokines, endothelial cells and leukocyte adhesion molecules, nitric oxide and cyclooxygenase (COX‐2) products are discussed. Furthermore, the potential role for certain cytokines in modulation of brain vulnerability to ischemia is also reviewed.The data suggest that novel therapeutic strategies may evolve from detailed research on some specific inflammatory factors that act in spatial and temporal relationships with traditionally recognized neurotoxic factors. The dual nature of some mediators in reformatting of brain cells for resistance or sensitivity to injury demonstrate the delicate balance needed in interventions based on anti‐inflammatory strategies.

This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain‐Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stress in vitro than are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore result in vivo in selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A₂. Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosine (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced

Major discoveries in the biology of nervous system tumors have raised the question of how non‐histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro‐oncological specialties. The present “white paper” catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided “ISN‐Haarlem” guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be “layered” with histologic classification, WHO grade and molecular information listed below an “integrated diagnosis”; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro‐oncology; and (iv) entity‐specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.