2011, Vol 11, No 4
Chemokines and their receptors on neurons in neurodegeneration and neuroprotection
AKTUALN NEUROL 2011, 11 (4), p. 210-215
ABSTRACT

The first studies on expression of chemokines and their receptors in the central nervous system (CNS) appeared several years ago and since that time many papers were published increasing our knowledge in that field. Recent studies are concentrated mostly on involvement of chemokines and chemokine receptors in neurodegeneration and neuroprotection. There are evidences that chemokines may directly initiate neurodegeneration through activation of their receptors on the surface of neurons or indirectly through activation of microglia which in turn may secrete neurotoxic mediators damaging neuronal cells. There are also evidences suggesting that chemokines and chemokine receptors are also involved in neuroprotection. So far only two chemokines, CX3CL1 (fractalkine) and CXCL12 (SDF-1 – stromal cell-derived factor- 1) have been shown to be expressed constitutively in the CNS. However, expression of many chemokine receptors including CXCR2, CXCR4, CCR1, CCR3, CCR4, CCR5, CCR9/10, CX3CR1 i DARC has been detected on the surface of neuronal cell. Based on presented in this review studies it may be concluded that direct interaction between some chemokine receptors and chemokines or other chemokine receptor ligands may be important for development of neurodegeneration and/or neuroprotection. The detailed mechanisms of those processes are still not well known. This is confirmed by the high number of inconsistent results in current scientific literature so the further studies are necessary in that field.

Keywords: chemokines, chemokine receptors, neurodegeneration, neuroregeneration, inflammation
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CADASIL – clinical picture, diagnostic process and treatment
AKTUALN NEUROL 2011, 11 (4), p. 216-226
ABSTRACT

Despite of its name, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a systemic vascular disease related to mutations in the NOTCH 3 gene located on chromosome 19. The clinical course of CADASIL is highly variable, even within families and carriers of the same mutation. The onset of the disease is usually in 4-5 decade of life. CADASIL manifests clinically as migraine with aura, recurrent ischaemic strokes, mood disorders, and progressing dementia. Early presence of abnormalities in autoregulation of the cerebral blood flow is characteristic for the disorder. On T2-weighted MRI scans diffused hyperintensities in the cerebral white matter are visible. Involvement of the anterior temporal lobe and external capsule on brain MRI is considered as radiological feature for the disease. The pathologic hallmarks of CADASIL are degeneration and loss of vascular smooth muscle cells in resistant middle- and small-sized arteries, and presence of granular osmiophilic material (GOM) in wall of small vessels. Diagnostic criteria which allow to diagnose the disorder involve positive result of genetic examination and the presence of GOM deposits in vessel wall in skin or muscle biopsy. Since pathomechanism of CADASIL is unknown, treatment of the disease is only symptomatic. This review focuses on an update of CADASIL clinical picture, diagnosis and management based on the recent basic and clinical evidences.

Keywords: CADASIL, cerebral small vessel disease, GOM, leukoencephalopathy, Notch 3
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CADASIL – morphological changes and their pathomechanism
AKTUALN NEUROL 2011, 11 (4), p. 227-236
ABSTRACT

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic vessel disease related to mutations in the NOTCH 3 gene located on chromosome 19. Pathological process in CADASIL selectively damages to small blood vessels: mainly arterioles and small arteries, but also capillary vessels and, in relatively lesser extend, venules. Characteristic morphological features are degeneration and loss of cells in vessel wall: vascular smooth muscle cells in arteries and pericytes in capillaries, as well as intramural accumulation of extracellular domain of Notch 3 receptor and granular osmiophilic material (GOM), the latter visible only at the level of electron microscopy. Histopathological changes are the most pronounced in cerebral vessels that lead to diffuse white matter damage, recurrent lacunar ischaemic strokes and microbleeds. In spite of intensive investigations the mechanism connecting NOTCH 3 mutations with morphological changes in CADASIL is poorly understood. The paper, summarizing current data from the literature and our own investigations, is an attempt to answer for the questions concerning: 1) the pathomechanism of the observed in CADASIL histopathological changes, especially loss of vascular smooth muscle cells and contribution of anoikis phenomenon in that process, 2) the cause of so selective character of pathological process in CADASIL, and 3) the reason for that clinical symptoms of the genetically determined disease appear so late.

Keywords: CADASIL, cerebral small vessel disease, GOM, leukoencephalopathy, Notch 3
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CADASIL – role of Notch 3 signaling system in pathomechanism of the disease
AKTUALN NEUROL 2011, 11 (4), p. 237-243
ABSTRACT

Notch signaling is a very conservative system of cell-cell communications playing an essential role in vascular development and human vascular diseases. One of such diseases is a hereditary vascular degenerative disorder known as cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL). The disorder is caused by mutations in the NOTCH 3 gene encoding a transmembrane receptor of the same name present in vessels only on vascular smooth muscle cells and pericytes. The disease involves mainly small arteries and capillaries in which degeneration and loss of cells expressing Notch 3 receptor is observed. In the affected vessels accumulation of Notch 3 extracellular domain (N3-ECD) and granular osmiophilic material (GOM) containing N3-ECD are also found. Although pathogenesis of CADASIL is still unknown there are two main distinct hypotheses concerning its development. The first of them assumes that the disease is caused by dysfunction of the mutated Notch 3 receptor which acquires a new properties. According to the second hypothesis, CADASIL – as many other neurodegenerative diseases – is a proteinopathy due to accumulation of proteinaceous aggregates in vessel wall. This paper is an overview of recent findings concerning the role of Notch 3 in vascular biology and hypothetical participation of that signaling system in CADASIL pathogenesis.

Keywords: CADASIL, CADASIL, cerebral small vessel disease, GOM, leukoencephalopathy, Notch 3
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Correlation between MRI, neuropathology and clinics in multiple sclerosis
AKTUALN NEUROL 2011, 11 (4), p. 244-250
ABSTRACT

Magnetic resonance imaging (MRI) of the central nervous system (CNS) is currently the most important imaging tool for diagnosis and monitoring of multiple sclerosis (MS). Recently several studies were published looking for the correlation between neuroimaging, clinics and pathology in the CNS during MS. These efforts are focused on seeking correlation between changes in MRI scans and inflammation, demyelination, neurodegeneration and gliosis in CNS. T1-weighted hypointensive lesions in MS correlate mostly with demyelination and neuronal loss. Moreover many trials indicate that the volume of T1-hypointense lesions correlate well with clinical disability in MS patients. Gadolinium enhancement in T1-weighted images reflects blood-brain barrier (BBB) breakdown and histologically correlates with the inflammatory phase of lesion development. Most MS lesions are hyperintense on T2-weighted MRI scans. The appearance of MRI changes in MS is not typical for any kind of tissue destruction. There are some trials suggesting that in clinically isolated syndromes (CIS) the number of cerebral T2-lesions is predictive for the development of definite MS in the future. All of data presented above indicate that there are still many problems with correlating CNS neuroimaging data from MS patients with their clinical status as well as with CNS histopathology. However, there is some progress in that field lately because of development of the new MRI techniques.

Keywords: multiple sclerosis, magnetic resonance imaging, inflammation, demyelination, neurodegeneration, gliosis
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Changes in motor cortex activation after botulinum toxin treatment in MS patients with leg spasticity
AKTUALN NEUROL 2011, 11 (4), p. 251-256
ABSTRACT

Local administration of botulinum neurotoxin type A (BoNT-A) is becoming the preferred treatment for focal spasticity, a movement disorder commonly occurring in multiple sclerosis (MS). In this study, 4 out of 10 enrolled MS patients with leg spasticity and 5 healthy controls (HCs) were included. In the patient group, the fMRI examination was performed three times: before the BoNT-A administration and at the week 4 and week 12 visits after injection. During all the examinations, subjects performed blocks of repeated knee extension-flexion alternating with rest blocks, each 15 seconds long. The patient group mean images at the week 0 examination showed significant compensatory spatial enlargement of bilateral frontoparietal sensorimotor cortices when compared to controls, whereas the results of the second examination showed significant contraction of previously activated areas with no significant difference from HCs. At the final examination, the activation areas expanded back close to their original volume, in association with the disappearance of the BoNT-A effect on spasticity. Conclusion: We conclude that motor cortex engagement reflects the BoNT-A treatment- related changes in the periphery, likely indirectly mediated by altered afferentation. This is a novel observation, although consistent with the conclusions of other studies using different methods and paradigms.

Keywords: fMRI, motor cortex, multiple sclerosis, muscle spasticity, botulinum A toxin
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Relation of regional mortality and female-to-male ratio in multiple sclerosis to the past long-term meteorological factors in Poland
AKTUALN NEUROL 2011, 11 (4), p. 257-264
ABSTRACT

Background: Regional average crude or sex-adjusted mortality rates (CMR, S-AMR) and female-to-male ratio (FTMR) in multiple sclerosis (MS) may correlate to the past long-term meteorological factors (MF) in Poland. Objective: To analyse association between regional MR or FTMR in MS and the past long-term MF. Method: The study was based on death certificates of 2172 MS patients (M – 878, F – 1294) who died in Poland in the years 2004-2008. Demographic data were derived from the General Registry Office and meteorological data (1931-1970) from the Meteorological Institute. Correlational investigation was carried out using Spearman’s rank test. Results: Higher CMR in northeastern Poland was 1.45/100 000 individuals and accompanied by minimal solar insolation (SI) in December (16 h) and the lowest air temperature (AT) in January (-5.6°C). CMR was inversely correlated to mean minimal SI in December (r=-0.518; p=0.04), mean annual or January AT (r=-0.539; p=0.03; r=-0.611; p=0.01). CMR was not correlated to annual SI, degree of cloudiness, the annual number of frosty days or sum of precipitation. S-AMR in M and in F were not associated with MF. Higher FTMR (2.72) occurred in northwestern Poland with warmest AT in January (-1.4°C) and the low number of frosty days (65). Mean FTMR (1.55) correlated to annual or January AT (r=+0.638; p=0.01; r=+0.726; p=0.004). Conclusions: CMR in MS was inversely correlated in Poland to the past SI and annual or minimal AT in January. The past SI and AT might influence vitamin D3 level, immunosuppressive cytokines, immune dysregulation and higher mortality especially in northeastern Poland. Greater FTMR in MS correlated to annual or January AT and the annual number of frosty days. AT might facilitate particularly in women more frequent respiratory tract infections.

Keywords: multiple sclerosis, mortality rates, female-to-male ratio, meteorological factors, Poland, provinces of Poland
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Pathogenesis of development of atheromatous plaque in carotid arteries
AKTUALN NEUROL 2011, 11 (4), p. 265-273
ABSTRACT

It is scientifically confirmed that atherosclerosis simultaneously develops in the whole arterial system. The mechanism and character of atherosclerotic plaque formation is similar in different regions of the vascular system. The essence of atherosclerosis pathogenesis appears to be an excessive inflammatory and fibroproliferative response to various forms of arterial wall injury. The development of unstable atheromatous plaques is closely related to the inflammatory process involving the arterial wall. Immunological factors seem to play an important role in the development of atherosclerotic plaques and their destabilization. Unstable plaque is characterized by higher blood supply, thinner and more fragile fibrous layer and higher number of inflammatory cells. Lipid core of plaque is bigger and more rich in liquid cholesterol esters. Pathological and growing vessels are the main source of bleeding to plaque what leads to its rupture. Cytokines and growth factors have a strong impact on activation of atheromatous plaque. Finding of inflammatory markers of plaque destabilisation in blood serum may be an additional diagnostic tool useful for diagnosis and monitoring of stroke management. It should be stressed that a closer look at participation of the immune system in pathogenesis of artherosclerosis may contribute to a development of the new therapies of this pathology and its complications like ischaemic stroke.

Keywords: artherosclerosis, atheromatous plaque, inflammation, inflammatory mediators, ischaemic stroke
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Exertional heat stroke in a marathon runner – case report
AKTUALN NEUROL 2011, 11 (4), p. 274-279
ABSTRACT

Heat stroke is a life-threatening and often fatal medical emergency. Key symptoms include fever exceeding 40°C and neurological deficits. In heat stroke thermoregulation mechanisms become inefficient and the body is unable to maintain its normal temperature. Ineffective thermoregulation results in elevation of body temperature to extreme values, leading to multiorgan failure and sometimes even to death. Most at-risk of developing heat stroke are infants and the elderly. Other risk factors include intense physical exertion at high ambient temperature and humidity, dehydration and some drugs. Heat stroke occurring in adolescents and adults as a result of intense physical effort is classified as exertional heat stroke. The incidence of exertional heat stroke during long-distance running mass events is estimated at 1 per 1000. Taking into account increasing popularity of long-distance running in Poland, the chance of facing such events by health professionals will be increasing. Timely diagnosis and effective management of heat stroke are paramount for the patients’ survival and long-term prognosis. Standard treatment of heat stroke includes rapid cooling in order to reduce deep temperature below critical threshold value of 40°C and correction of water-electrolyte disturbances. Medical services supporting mass events should be adequately prepared to deal with such cases. This paper presents a case of a 39-year-old marathon runner,who developed an exertional heat stroke with associated focal neurological deficits and indices of multiorgan failure persisting for several days after onset of heat stroke. Clinical picture of exertional heat stroke, associated risk factors and recommended management are discussed.

Keywords: heat stroke, exertional heat stroke, risk factors, treatment, management
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