The development of cerebral amyloid angiopathy in cerebral vessels. A review with illustrations based upon own investigated post mortem cases.

The process of ß-amyloid accumulation in cerebral vessels is presented. Cerebral amyloid angiopathy (CAA) was confirmed during an autopsy. It was diagnosed according to the Boston criteria. Cerebral amyloid angiopathy can involve all kinds of cerebral vessels (cortical and leptomeningeal arterioles, capillaries and veins). The development of CAA is a progressive process. ß-amyloid appears first in the tunica media, surrounding smooth muscle cells, and in the adventitia. ß-amyloid is progressively accumulated, causing a gradual loss of smooth muscle cells in the vessel wall and finally replacing them. Then, the detachment and delamination of the outer part of the tunica media results in the "double barrel" appearance, fibrinoid necrosis, and microaneurysm formation. Microbleeding with perivascular deposition of erythrocytes and blood breakdown products can also occur. ß-amyloid can also be deposited in the surrounding of the affected vessels of the brain parenchyma, known as "dysphoric CAA". Ultrastructurally, when deposits of amyloid fibers were localized in or outside the arteriolar wall, the degenerating vascular smooth muscle cells were observed. In the Institute of Psychiatry and Neurology the study was carried out in a group of 48 patients who died due to intracerebral hemorrhage caused by sporadic CAA.

Morphological changes in the corpus callosum in chronic alcoholism.

In a group of 66 patients (age 24 to 78 years) with the clinical diagnosis of chronic alcoholism the changes in the corpus callosum were evaluated. The period of alcohol abuse varied from 3 to over 30 years. In 57 cases atrophy of the corpus callosum was noted. The trunk was involved most frequently. Myelin sheaths exhibited abnormalities from slight pallor to total destruction. In 19 cases the damage of myelin sheaths was restricted to disseminated, perivascular, spongy degenerations. The vessels were sclerotic, especially periventricular ones exhibited degenerative changes. Perivascular gliosis was also seen. Conclusions from the present study indicate that the structural changes observed in the corpus callosum during chronic alcohol abuse are connected with CNS involution and with degenerative changes within vessels walls. The damage of myelin sheaths localized in our material similarly as Marchiafava-Bignami disease, differs from the later by less advanced changes, perivascular spreading of demyelination, and frequent destruction of axons.

Brain vascular changes in the case of primary antiphospholipid syndrome.

Morphological picture of arterial fibromuscular dysplasia (FMD) of carotid and cerebral arteries associated with intracranial aneurysm and thrombotic small vessel vasculopathy in a 34-year-old woman with primary antiphospholipid syndrome (PAPS) is presented. The patient died because of hemorrhage caused by aneurysm rupture. In the walls of the aneurysm and aneurysmal dilatation of middle cerebral artery dysplastic changes of FMD type were found. The case fulfills the clinical and serological criteria of antiphospholipid syndrome (APS). Microscopic examination of the brain showed occlusion of small cerebral vessels, characteristic for antiphospholipid syndrome. It was caused by fibrin thrombi and endothelial proliferation or fibrous webs in the vessel lumen. Neither features of systemic lupus erythematosus (SLE) nor related autoimmune diseases were observed in the morphological examination of the brain, skin and internal organs. Therefore, it was feasible to confirm the diagnosis of PAPS in the patient with FMD of the large cephalic arteries.

Ultrastructural changes in neuronal and glial cells in subacute sclerosing panencephalitis: correlation with disease duration.

This paper presents ultrastructural changes in neuronal and glial cells with special reference to intranuclear inclusion bodies in subacute sclerosing panencephalitis (SSPE) with different duration (from several weeks to seven years). Brain autopsy at ultrastructural level revealed the nucleocapsids of paramyxovirus in neuronal and oligodendroglial nuclei in 4 of 6 SSPE cases under study. Nucleocapsids of measles virus were present in two cases of disease lasting several weeks and in two cases with disease duration of two years, while abundant nuclear bodies and granulofilamentous inclusions in astrocytic nuclei were found in all cases. Occasionally, both granulofilamentous inclusions and complex nuclear bodies occurred in the same astrocytic nucleus. Only in the case lasting seven years they were not observed. It is likely that there is a structural and morphological relationship between these two types of inclusions present in astrocytic nuclei. Nuclear bodies and granulofilamentous inclusions were common and independent of the presence or absence of virus nucleocapsids. In the case of SSPE with a seven-year duration but without viral nucleocapsids in neuronal and oligodendroglial nuclei, neuronal tangles were observed.

Quantitative evaluation of intranuclear inclusions in SSPE: correlation with disease duration.

Three types of intranuclear inclusions in neurones, oligodendrocytes and astrocytes were quantitatively evaluated by electron microscopy in the autopsy material derived from six cases of subacute sclerosing panencephalitis (SSPE) with different duration of disease. Viral nucleocapsids were found in neurones and oligodendrocytes with the highest incidence (about 38% of nuclei) in two acute cases (adolescent), whereas in two subacute cases only 10% of nuclei of these cells contained nucleocapsids. However, in one acute case (child) and one chronic case, no nucleocapsids were detected at all, despite very intensive study. Two other types of intranuclear inclusions--nuclear bodies (NBs) and granulofilamentous inclusions (GFs) were present in astrocytic nuclei in all cases. Nuclear bodies were found the most frequently (about 66%) in cases of a several-week-long duration, and their incidence decreased with the extended duration of the disease. In the case of a seven-year-long duration, about 31% of nuclei contained NBs. The incidence of certain types of NBs varied also in individual groups of cases, and the same applied to the occurrence of cellular nuclei with different numbers of NBs. Nuclear bodies types IVand V occurred with similar frequency, regardless of the disease duration. The highest incidence of nucleocapsids and NBs was accompanied by the highest (about 25%) frequency of GF in astrocytic nuclei. The incidence of the latter declined with the prolonged duration of the disease, and in the chronic case it was about 16 times lower than in acute cases. In some acute and subacute cases, GF occurred together with NBs. Astrocytic nuclei with both types of inclusions occurred with a similar frequency (about 1.6-1.8%).

Changes in dopaminergic neurons of the mesocorticolimbic system in Parkinson's disease.

The qualitative analysis of changes in major nuclei (n. paranigralis left and right, n. interfascicularis) of the mesocorticolimbic system (ventral tegmental area-VTA) was carried out on 25 cases with Parkinson's disease (PD). The cellular depletion with insignificant gliosis without the presence of macrophages was found. In addition, numerous extracellular melanin nodules being the remnants of broken dopaminergic neurons were found. The presence of Lewy bodies observed in all cases confirms the diagnosis of idiopathic Parkinson's disease. The morphometric analysis performed on selected long-lasting 7 PD cases and 6 controls showed that cellular depletion in n. paranigralis and in n. interfascicularis accounts for 42% and 62%, respectively in relation to controls. The number of melanin nodules grows with the age in the control group. While in the group of PD cases the number of nodules in VTA declines with the disease duration. It may indicate that the factor which damages melanin neurons also exerts a destructive effect on extracellular melanin.

Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease.

The analysis of qualitative changes in the locus coeruleus (LC) was performed on brains from 21 cases of Parkinson's disease. Eleven cases were selected for quantitative analysis of the loss of LC noradrenergic pigmented neurons. The qualitative studies revealed uneven dissemination of the noradrenergic cells loss of overall structure of the LC. Few preserved neurons showed degenerative changes. Extracellular neuromelanine granules, traces of dying neurons, were also observed. A weak astro- and microglia proliferation corresponded with neuronal loss. Lewy bodies were found in the LC in all cases. The quantitative analysis revealed that the average loss of adrenergic neurons in the LC accounts for about 70% in relation to the control group. The degenerative changes were observed in the whole LC, but they were most intensive in its caudal and next in the middle segment. The results suggest also that the degenerative process began in the middle segment and then it spread towards caudal segment of the LC as the stages of disease advanced.

Primary malignant lymphoma of the brain.

A primary lymphoma in the left temporal lobe of the brain in a 66-year old man is presented. The brain tumor was diagnosed on the basis of clinical symptoms (temporary dizziness, mixed aphasia and right hemiparesis) and repeated CT scanning of the brain. The patient with diagnosed malignant, non-operative brain tumor underwent a series of radiotherapy and steroidtherapy. The patient died twelve months after the first signs and symptoms had occurred. A general autopsy did not reveal any neoplasmatic changes. A macroscopic neuropathological examination showed large tumor's mass in the left temporal lobe which was not separated clearly from its surrounding. A microscopic examination included histopathological (HE, Kanzler-Arendt, Perdrau, PATH, PAS) and immunocytochemical techniques (GFAP, anti-galactocerebroside, LCA, CD45RO, OPD4, CD20). It was found that the examined brain tumor was B-cell malignant lymphoma with the presence of T-cells. Since no changes were revealed in internal organs, the tumor was diagnosed as a primary brain lymphoma.

Primitive neuroectodermal tumor (PNET). A case report.

The authors present a case of relatively rare tumor of the central nervous system (CNS) in a 19-year-old female, who died 18 months after the first manifestation of meningismus, increased intracranial pressure and secondary hydrocephalus. Brain autopsy revealed abundant neoplastic infiltrations, which spread through the subarachnoid space. Neoplastic infiltrations were also present in the third ventricle and in a form of small subependymal nodules along the whole ventricular system. The microscopical examination showed that neoplasm consisted of small cells, which formed neuroblastic Homer Wright rosettes. Immunohistochemical studies (for synaptophysin, chromogranin A, GFAP, vimentin) together with morphology and localization of neoplasm suggested diagnosis of primitive neuroectodermal tumor (PNET) that spread mainly in the leptomeninges and caused obliteration of subarachnoid space.

Border zone neovascularization in cerebral ischemic infarct.

Immunocytochemical and quantitative studies on vascular reaction (angiogenesis) in cortical border zone of infarct were undertaken. Intensity and temporal profile of angiogenesis was assessed in 60 patients aged between 48 and 69 (younger group), and between 70 and 92 (older group), with cerebral infarct in the area of middle cerebral artery vascularization, who died during the first six weeks following the stroke. We have found that angiogenesis was a multistage process in which four stages were distinguished: phase of primary activation of endothelial cells, two consecutive phases of active angiogenesis and final phase of only sporadic proliferation of vessels. The distinction of phases in a multiphase angiogenic cascade helped us to evaluate the correlation with survival time and the age of patients. The most pronounced intensification of angiogenesis and increased density of CD 31 positive capillaries in penumbra were observed in the second phase, especially in younger patients. The duration of the penumbral neovascularization decreased in the older age patient. Our results indicate that sprouting angiogenesis is a quantitatively significant source of vessels in the cerebral infarct border zone. However, non-therapeutically stimulated angiogenesis developed only 3-4 days after the stroke, that is beyond the period of reversible changes in ischemic penumbra recognized as a "therapeutical window" in the human brain. The angiogenic therapy opens a new way towards the revascularization of ischemic brain infarct.

Quantitative study of pathological forms of astroglia in Wilson's disease.

The number and distribution of Alzheimer type I and II cells (Alz I and II) as well as Opalski cells (Opl) were estimated in chosen brain regions of seven autopsied cases with Wilson's disease (WD). The authors of this study focused especially on the question whether the kind and intensity of astrocytes is linked to the clinical form of the disease and to the intensity of brain damage. Alz I and II cells were counted by the use of the HE method, whereas the number of Opl cells was calculated using the PAS method. The study revealed that among the three types of cells the number of Alz II cells was the highest and that of Alz I cells was the lowest. The distributional patterns of these three types of cells were different. Alz I cells were found mainly in the putamen. Alz II cells were observed diffusely, although they occurred in different numbers in the whole brain. The highest number of Opl cells was found in the putamen. Alz I cells were found only in the neurological type of the disease. The highest number of Alz II cells was seen in the hepatic type of the disease, whereas the highest number of Opl cells was observed in the neurological "mixed" forms. Moreover, intensity of tissue damage with presence of necroses was greatest in neurological WD. In the hepatic type dispersed areas of status spongiosus were observed, without presence of necroses. Our study revealed that the type and amount of the pathological astroglia may correlate both with the clinical form of WD and intensity of tissue damage. Alz II cells seem to be a characteristic feature of the early stage of astroglial response to the pathogenic factor whereas Alz I and Opl cells occur in WD only in the advanced stage of tissue damage.

Neuropathological analysis of pathological forms of astroglia in Wilson's disease.

A neuropathological study of Alzheimer type I (Alz I) and Alzheimer type II (Alz II) as well as Opalski (Opl) cells was performed serially on brain tissue from nine autopsied Wilson's disease (WD) cases. Conventional staining methods (Kluver-Barrera, HE, PAS) and immunocytochemical techniques (anti-GFAP and anti-Metallothionein-MT) were used. On conventional staining, each of the studied abnormal cell types retained common morphological characteristics of astroglia, and concurrently demonstrated its own distinctive features, specific only for a given cell type. Anti-GFAP staining revealed positive immunoreactivity of Alz I and Opl cells, and its absence in Alz II cells. On anti-MT staining both the cytoplasm and nucleus of Alz I and Opl cells showed positivity whereas in Alz II cells the cytoplasm was positive in contrast to the negative nucleus. The results of our study confirm the hypothesis of the astroglial origin of all three types of cells. The lack of immunoreactivity for GFAP and similar immunocytochemical staining patterns for MT in Alz II cells and protoplasmic astrocytes may suggest that Alz II cells originate from the protoplasmic type of astroglia. The fact that Alz I and Opl cells resemble fibrous astrocytes in their immunoreactive positivity for GFAP may lead to a supposition that they originate from the fibrous type of astroglia. MT-positive expression by the three abnormal cell types suggests that they may be involved in the process of copper detoxification in WD.

Dysembryoplastic neuroepithelial tumor. A case report.

Dysembryoplastic neuroepithelial tumor (DNT) is a rare, benign tumor encountered in the cortex. It is characterized by the presence of cells of different histogenesis. Due to its mixed nature (glial-neuronal), WHO histological classification of brain tumors included it into the group of neuronal and glial-neuronal mixed tumors. Case of tumor in a 19-year-old woman experiencing for three years seizure of temporal lobe epilepsy is presented. A cranial magnetic resonance imaging (MRI) showed "pseudocystic" tumor in temporal lobe. Histological and immunocytochemical examinations of the tumor fragment removed during surgery revealed large numbers of neuronalglial nodules occurring in the cerebral cortex. Columns of glial-neuronal structures crossing parallely to the cortex surface, surrounded by oligodendrocyte-like cells (OLC) were a characteristic feature of the tumor texture. In the tumor interstitium, "floating" maturated, dysplastic-free ganglionic cells were visible in numerous bright spaces. In addition, numerous lobuliform--structured areas consisted of oligodendrocyte-like cells. Oligodendrocyte-like cells were characterized by positive immunoreaction to the presence of S-100 protein and synaptophysin. Basing on clinical manifestation and histopathological findings dysembryoplastic neuroepithelial tumor was diagnosed.

Neurones and microglia in central nervous system immune response to degenerative processes. Part 1: Alzheimer's disease and Lewy body variant of Alzheimer's disease. Quantitative study.

The quantitative correlation between neurone loss and brain immune response, assessed by intensity of microglia inflammatory reaction in cortical association area and limbic cortex, was investigated and compared in previously immunohistochemistry (IHC) and ultrastructural confirmed 11 cases of Alzheimer's disease (AD), 7 cases mixed form of Dementia with AD findings and Lewy bodies (AD/DLB) reported, in accordance with Consortium on Dementia, as Lewy body variant of AD (LBV) and 6 non-demented autopsy control cases from 63 to 86 years old. In the present work we investigated association and limbic cortical areas linked with memory mechanisms; there are regions characterised by early distribution of IHC confirmed AD and DLB/AD (LBV) markers, as well as a substantial physiological stability of neurone pool regardless of age. The results indicated that AD and LBV differ in their neurone loss intensity and inflammatory reaction, with much higher intensity in AD. In Alzheimer's disease, neurone loss in association temporal cortex made up 51% of control values with simultaneous 8-fold increase in the density of MHC II-positive activated microglia, whereas in LBV, both the loss of neurone density and the increase in activated microglia density, was not so high (up to 41% and 4-5-fold, respectively). Changes in the limbic cortex were less pronounced. A strong correlation in the clinical material between neurone loss and microglia activation in both processes, especially in AD (r = 0.73), speaks in favour of the hypothesis on the neuronal immune surveillance and arousal of immune brain response in conditions of declining control, due to significant neurone loss in the neurodegenerative process. The inflammatory reaction of MHC II-immunoreactive microglia, concomitant with neurodegenerative process, seems to be a consequence of increased immune response due to loss of neurones and weakening of their control upon immunosurveillance in central nervous system.

Adult schizophrenic-like variant of adrenoleukodystrophy.

A 35-year-old man died after 30 months following the onset of the disease. There was a history of changes in his mental condition, including disturbances of behavior as well as the evidence of progressing dementia. The patient revealed gait disturbances and finally became bed ridden. Bizarre behavior and changes of mood with concurrent growing irritability which predominated during the course of disease, may explain the initial diagnosis of schizophrenia. Then cerebellar and spastic movement disorders leading to paraparesis and sphincters disturbances developed. Clinical symptoms of adrenal failure were not found apart from episodes of arterial pressure fall. After two years a magnetic resonance imaging (MRI) revealed an extensive diffuse demyelinative process in white matter of cerebral and cerebellar hemispheres. Activity of lysosomal enzymes was normal. A general autopsy revealed atrophy of adrenal cortex and the presence of ballooned cells with striated cytoplasm in the reticular and fasciculate zones. Neuropathological examination revealed an extensive demyelination of white matter in cerebral and cerebellar hemispheres and of the long paths of the brain stem, corresponding to changes in MRI examination. Within demyelination areas damage of axons and diffuse cellular and fibrous gliosis were found as well as perivascular lymphocytic infiltrations with the presence of strong PAS (+) and Sudan (+) macrophages. Immunocytochemical reactions with HAM-56 and RCA1 in macrophages were positive. Electron microscopy examination revealed lamellar inclusions in cytoplasm of macrophages. Similar structures were present in the lysosomes of astrocytes. Morphological examination of adrenal glands as well as morphological and ultrastructural study of the brain allowed us to diagnose the cerebral form of adrenoleukodystrophy (ALD). Topography and character of the brain changes seems to be in keeping with a rare schizophrenic-like variant of ALD with progressive dementia. Abnormal plasma profile and increased VLCFA concentration in the patient's 13-year-old daughter confirm the ALD diagnosis.

Central nervous system infection caused by Borrelia burgdorferi. Clinico-pathological correlation of three post-mortem cases.

The spirochete Borrelia burgdorferi (B. burgdorferi) may cause severe meningoencephalomyelitis as the sole manifestation of Lyme borreliosis. We would like to present three such cases, where definite neuroborreliosis was clinically diagnosed in two cases and possible neuroborreliosis was recognized in one case. Alive spirochetes were isolated and cultured from blood and cerebrospinal fluid (CSF) in both definite cases. B. burgdorferi as the causative agent of the infection was confirmed in CSF by polymerase chain reaction (PCR) in one definite case. In the possible case spirochetes were cultured from blood and CSF. Alive spirochetes were not isolated, however anti-B. burgdorferi antibody value in serum was significantly elevated. On necropsy gross examination brain edema without focal changes was detected in two cases. Cerebral atrophy was seen in Case 3. Microscopically, lymphocytic infiltrates, microglial diffuse and nodular activation, spongiform changes, diffuse demyelination of the cerebral and cerebellar white matter, and diffuse astrocytosis, were characteristic pathological features in all presented cases. Multifocal, perivascular degenerative changes in the cerebral and cerebellar white matter were observed in the first case. Inflammatory changes in the nuclei and roots of cranial nerves were present in the third case.

Lewy body variant of Alzheimer's disease and Alzheimer's disease: a comparative immunohistochemical study.

Immunohistochemistry (IHC) and ultrastructural study were performed on 19 demented autopsy cases of sporadic Alzheimer's disease (AD). Semiquantitative IHC assessment of the pathological changes, according to the criteria of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) and the Consortium on Dementia with Lewy Bodies, showed morphological hallmarks of AD in 18 demented patients. It was found that 11 of these cases fulfilled criteria for "pure" AD, whereas the remaining 7 cases, with mixed findings, Lewy bodies (LBs) and Lewy-related dystrophic neurites, neuritic plaques (NP) and sometimes neurofibrillary tangles (NFT), met the criteria for Lewy body variant of Alzheimer's disease (LBV). One case with brain stem and cortical LBs but without NP and NFT was finally diagnosed as a pure form of dementia with Lewy bodies (DLB). Regional distribution and semiquantitative assessment frequency of alpha-synuclein-immunoreactive LBs, tau-immunoreactive NFT and beta-amyloid immunoreactive senile plaques, were compared between LBVand AD. Ultrastructural examination confirmed the filamental structure of cortical LBs. In conclusion, IHC study including antibody to alpha-synuclein, the sensitive marker for Lewy bodies, revealed the coexistence of brain stem and cortical LBs and pathological features of AD in a great part of dementia cases. Patients with mixed, LBs, NP and sometimes NFT pathology, fulfilled neuropathological CERAD criteria for LBV. Semiquantitative comparative IHC study, according to LBs- and NFT-scores and CERAD NP-scores showed in the LBV group a significantly lower frequency of NFT coexisting with neocortical LBs than in the group with pure form of AD.

[Current views on the mechanisms of dopaminergic neuron death of the nigrostriatal system in Parkinson's disease]. / Obecne poglady na mechanizmy smierci neuronów dopaminergicznych ukladu nigrostriatalnego w chorobie Parkinsona.

Current views on the pathogenesis of Parkinson's disease are presented. Studies, particularly those carried out during the last decade, highlight the significance of endogenic processes responsible for a cumulative production of neurotoxic substances, especially free oxygen radicals which exert chronic effect on neurons. In Parkinson's disease, overproduction of free radicals and concomitant failure of protective mechanisms are most likely. An excess of free radicals is cytotoxic because of their very high chemical activity and uncontrolled chain reactions with numerous organic compounds, especially those which are mostly responsible for vital functions of cells. Oxidative stress disturbs metabolism of the cell what finally leads to its death most probably due to damage of cell membrane. That results in increased plasma membrane permeability for calcium ions which activate several subcellular mechanisms and initiate the final phase of cell death. Nonprotein-bound "free" iron ions are the strongest and most dangerous generators of free oxygen radicals. It is thought that ferric (Fe-3+" iron bound to neuromelanin may play a profound role in the overproduction of especially cytotoxic hydroxyl radicals, derivatives of molecular oxygen. Both, oxygen stress inducing factor and the sequence of related biochemical disorders remain still unknown. However, the synergy of the excess of reactive oxygen metabolites (mainly free radicals), nitric oxide, "free" iron ions and neuromelanin may contribute considerably to the generation of oxygen stress.

[Morphometric assessment of lesions in the dopaminergic nigrostriatal system in Parkinson disease]. / Morfometryczna ocena zmian w nigrostriatlnym ukladzie dopaminergicznym w chorobie Parkinsona.

The qualitative changes in substantia nigra were analysed in the material of 25 cases of Parkinson's disease. A morphometric quantitative study of depletion of pigmented dopaminergic cells of substantia nigra was performed in six long-term cases of the disease. In addition, the number of melanin nodules was assessed as a marker of cell disintegration. The results obtained were compared with the morphometric evaluation of neuronal depletion in the mesocorticolimbic system (ventral tegmental area-VTA). The qualitative study indicated that melanin depletion in dopaminergic cells of substantia nigra in Parkinson's disease is diffuse and it is located mainly in the lateral alfa layer. Neuronal depletion with concomitant numerous extracellular neuromelanin nodules and granules was observed. A slight astrocytic gliosis free of macrophages accompanied cellular changes. The qualitative changes in substantia nigra are similar to those observed in VTA. The morphometric evaluation revealed that depletion of dopaminergic neurons in substantia nigra in Parkinson's disease is 73%, on average, while in VTA it remains under 5%. Hence, depletion in substantia nigra is much more intense. The analysis of the relationship between the number of neurons in substantia nigra and the age of subjects in the control group indicated that the number of neurons decreased proportionally to the age. In the group under study no significant relationship between neurons depletion and duration of disease or patients age was found. In the studied group of patients with Parkinson's disease, the number of melanin nodules in substantia nigra was significantly higher than in controls.

[Modern views on the pathogenesis of Wilson's disease]. / Aktualne poglady na patogeneze choroby Wilsona.

Wilson's disease is a rare, multiorganic genetically coded disorder, induced by impaired copper transport. The recent identification of the disease gene and the discovery of gene product--copper transporting P-type ATPase that is integrate membranous protein has contributed greatly to better understanding of the pathogenesis. This protein is probably essential for incorporation of copper into ceruloplasmin and for its biliary excretion. Multiple mutations of Wilson's disease gene are responsible for the excess of so called "free" copper which is toxic to tissues. Copper toxicity involves first of all, functional disorders of many enzymatic systems, particularly those of respiratory chain enzymes. In the central nervous system, a special kind of copper toxicity is medicated by astroglia, so that a direct, harmful effect of both copper and ammonia on the brain is observed. The authors present a current review on biochemical mechanisms of copper toxicity and physiopathological significance of the CNS astroglia in Wilson's disease.