Journal of Neural Transmission. Supplement70
Parkinsonís Disease and Related Disorders is a collection of articles on main aspects of pathophysiology, pathomorphology, neurovisualization, experimental models and treatment of parkinsonism. The book has been edited by Prof. P. Riederer, Prof. H. Reichmann, Prof. M.B.H. Youdim and Prof. M. Gerlach and is a supplement to the European Journal of Neural Transmission.
The monograph has 12 chapters, written by acknowledged and world-famous specialists in the field of parkinsonism and other neurodegenerative diseases, accompanied by it, from Europe, Australia, USA, Canada, Israel and the Republic of South Africa.
The first chapter is devoted to parkinsonism pathomorphology and begins with the history of the revolutionary discovery of the L-DOPA curative effect on Parkinsonís disease. It is presented by O. Hornykiewicz, being its discoverer. W. Raab, G. Weber and M. Vogt were the fist to study the role of catecholamines and acetylcholine in Parkinsonís disease. It happened in the 1950s. Their works served the basis for the research of A. Carlsson, carried out in 1958. He proved, that L-DOPA restored the balance of catecholamines and dopamine in experimental animals, subjected to administration of reserpine, exhausting their cerebral reserves. In 1960 O. Hornykiewicz and his colleague H. Ehringer studied postmortem brain of 14 cases with different neurodegenerative diseases and an impaired function of basal ganglia. Only 6 of them had considerable reduction of dopamine in the caudate and putamen. They turned out to be people, who had suffered from parkinsonism during their life. This discovery allowed to make two important conclusions. In the first place, a reduced level of dopamine could be a cause of parkinsonism symptomatology development; in the second place, dopamine was not synthesized in the striatum and was likely to be delivered there from the substantia nigra. Then O. Hornykiewicz asked the neurologist Walter Birkmayer to do clinical trials with i.v. L-DOPA. After a delay of 8 months, i.e. in July 1961, Birkmayer injected 50-150 of L-DOPA intravenously to 20 PD cases. The effect was so startling, that it exceeded all expectations of the researchers. Bed-ridden patients could stand up and walk. However, the disease symptoms returned in 60-120 min and in some hours the cases became as motionless as they had been before. Unfortunately, the author, describing the extremely interesting chronology of these events, did not mention our outstanding compatriot K.N. Tretyakov, who was the first to report lesion of the substantia nigra neurons in Parkinsonís disease in 1919.
The next article of the chapter is written by the American neurophysiologists T. Witchmann and M.R. DeLong. It deals with a modern pathophysiologic model of formation of parkinsonian motor signs. The authors describe the role of the subthalamic nucleus function desynchronization against a background of progressive loss of an inhibiting effect of the indirect striatal-pallidal pathway, caused by a reduced level of dopamine in the striatum. These facts explain that peculiar interest, which is aroused by neurosurgical interventions on the subthalamic nucleus.
The American researcher R.E. Burke presents detailed information on a glial cell line-derived neurotrophic factor (GDNF), which can be regarded as a leading candidate for cellular therapy with growth factors and regeneration of dopaminergic neurons of the substantia nigra. GDNF injection into the striatum has suppressed cell death in neurons by 60%. These experimental results allow to consider this trend to be prospective.
The article by S.M. Smith and M.R. Smidt from the Department of Pharmacology and Anatomy of the Institute of Neuroscience (the Netherlands) is devoted to the role of transcription factors in differentiation of stem cells into mature midbrain dopaminergic neurons. They have demonstrated, that Pitx3 accelerats differentiation of mouse embryonic stem cells into the A9 cell group of midbrain dopaminergic neurons. Taking into account rapid development of cellular technologies, the authors are sure of possible use of stem cells for engineering dopaminergic neurons in vivo in the nearest future.
The German pathomorphologist H. Braak and his colleagues present a new view on stages of a neurodegenerative process in parkinsonism. Studying 301 autopsy cases has revealed, that a pathologic process starts with a lesion of motor nuclei of the ninth-tenth pairs of cranial nerves of medulla oblongata, tegmentum pontis and anterior olfactory nuclei. Structures of the midbrain, including substantia nigra, the blue spot and Meynertís nucleus, and association and primary fields of the neocortex are involved into a degenerative process at the stage of PD clinical manifestation and final stages respectively. Thus, Parkinsonís disease can be regarded as a multi-systemic cerebral disease.
The Australian biologist G.D. Mellick considers the interaction of genetic factors, in particular those, coding the activity of the cytochrome P450 systems, and an effect of the environment. He advances the ecogenetic theory of PD development. It is known, that family history of PD and pesticides increase its risk, while smoking reduces it to a great extent. The activity of CYP2D6, being one of the enzymes of the cytochrome P450, is characterized by phenotypic variability. There are individuals with slow metabolism of this detoxication system. In case of penetration of neurotoxins into the body this mechanism can be a cause of their accumulation and a pathogenic effect on the brain. Smoking, or to be more precise nicotine, activates cerebral detoxication systems and can reduce a risk of PD development. This fact should not be interpreted as a call for smoking. It only allows to think of a possible protective effect of nicotine from the point of view of PD development and progression.
The review of genetic studies is given by Y. Mizuno et al. from Japan, who are the leading specialists in this field. Today there are 11 identified genes, which are known to responsible for development of familial forms of Parkinsonís disease. It appears, that some new genes will be discovered in the nearest future. Familial cases are characterized by a considerably earlier onset. Appearance of reliable means of prevention would allow to treat predisposed individuals at a preclinical stage of the disease.
The chapter, devoted to parkinsonism neurovisualization, contains the article by W. Lok Au et al. from Canada. It describes limitations of methods of structural visualization (MRI) in differential diagnosis of the disease and emphasizes the role of such methods of functional diagnosis as PET and SPECT. However, proton magnetic resonance spectroscopy (MRS), diffusion-weighted and diffusion tensor imaging can be useful in differentiation between atypical parkinsonism (multi-systemic atrophy, progressive supranuclear palsy) and Parkinsonís disease. As for multi-systemic atrophy and progressive supranuclear palsy, diffusion-weighted images are indicative of obvious changes in the putaminal projection, which reflect progressive loss of neurons in this cerebral structure. Use of functional MRI for estimating neuronal activity in different cerebral areas permits to study pathogenesis of formation of PD complications. It has been demonstrated, that working memory disorders are conditioned by dysfunction of the prefrontal cortex, anterior cingulate cortex and parietal cortex. According to the findings, the nigrostriatal system modulates motor functions via thalamic projections to motor cortex, whereas the mesocortical dopaminergic system facilitates cognitive tasks via direct inputs to the prefrontal cortex. PET with radioligands, capable of labeling presynaptic terminals, permits to estimate a tempo of PD progression. It is of peculiar importance in search for means, retarding the disease progression.
The last years are characterized by revival of interest in such an available diagnostic method, as transcranial sonography. Using it, D. Berg discovered increased echogenicity at the substantia nigra in 90% of cases with Parkinsonís disease. It is interesting to mention, that 8-10% of individuals without clinical manifestations of PD had hyperechogenicity at the substamntia nigra as well. PET with 18F-DOPA demonstrated reduction of its striatal uptake in more than 60% of cases, indicating dysfunction of the nigrostriatal system, which reflects possibility of preclinical diagnosis of Parkinsonís disease.
The information, presented in chapter 6, concerns several new clinical aspects of Parkinsonís disease. The article, entitled Parkinsonís Disease: Premotor Clinico-Pathological Correlations and written by E.Ch. Wolters and H. Braak, deals with symptoms, which appear before such typical manifestations of the disease, as hypokinesea, rigidity and tremor. It turned out, that 10% of cases developed hyposmia 1-2 years before motor disorders (it was watched in 90% of patients at advanced stages of the disease); 25% of cases had muscle pain in the neck and extremities; 50 % of cases complained of constipation, impaired urination, depression, sleep disorders, attention disturbances and difficulties, experienced in decision making. The authors emphasize importance of these symptoms for early diagnosis of PD and their considerable effect on life quality.
Peculiarities of gait disorders, watched at various stages of PD and depending on presence of accompanying affective, vegetative and cognitive disturbances, are analyzed in detail in the article by N. Giladi and Y. Balash from Israel. Gait disturbances and postural control abnormalities lead to frequent falls of patients. The so-called freezing of gait has a severe effect on everyday life. This state is closely connected with affective (anxiety and depression) and cognitive disorders. This fact is to be taken into account in planning and carrying out treatment. When frequent ďOffĒ states become a cause of falls and marked disorders of walking and ďOnĒ states are accompanied by severe disabling dyskinesia, the author recommend to perform deep stimulation of the subthalamic nucleus or the internal globus pallidum. One should pay attention, that such interventions are contraindicated in cases with dementia and behavioral disorders. Besides, one should not neglect simple recommendations on use of physiotherapeutic methods, which improve walking. They include walking in a rhythm of music or a metronome, dancing and equilibrium training.
Non-motor manifestations of Parkinsonís disease (a syndrome of progressive vegetative insufficiency, cognitive and psychotic disorders, sleep disturbances), watched at advanced stages, are discussed in detail in the next five articles. One can find information on disorders of cardiac sympathetic innervation, which limit variability of a cardiac rhythm up to a ďfixedĒ one. Orthostatic hypotension is a serious problem, as practically all anti-parkinsonian drugs promote its aggravation. Sleep disturbances are observed in the majority of cases with PD (60-98%). They are mainly represented by impaired nocturnal sleep and excessive daytime sleepiness. Sleep fragmentation is caused by nocturnal exhaustion of dopamine reserves and taking agonists of dopamine receptors and L-DOPA before going to bed allows to improve nocturnal sleep quality. Disorders of nocturnal sleep are closely connected with restless legs syndrome and periodic limb movements in sleep. An opposite problem, the so-called attacks of daytime sleepiness, is a characteristic symptom of late stages of the disease. It is more typical of cases with dementia. L-DOPA and especially agonists of dopamine receptors can aggravate episodes of sudden sleepiness. It should be taken into account in patients with high daytime activity. Modafinil, amantadine and jumex can increase a level of alertness.
Dementia is still one of the most complicated problems in treatment of PD late stages. D.J. Burn from Great Britain presents a review on pathomorphologic aspects of this syndrome. A degenerative process, connected with accumulation of abberant proteins of a-Synuclein and deposition of b-amyloid in subcortical structures, cortex cells and limbic areas of the brain, is the basis for dementia development in PD cases. Neurochemical changes are represented, first of all, by cholinergic deficit, spreading from Meynertís nucleus up to anterior segments of frontal, temporal cortex and posterior parieto-occipital areas of cerebral hemispheres. Thus, central inhibitors of acetylcholinesterase are the main drugs for therapy of dementia in PD. Further studies should be aimed at elucidating mechanisms of formation of a-Synuclein aggregates and protein-protein interaction against a background of existing pathologic changes of tau protein.
There are four articles, devoted to surgical treatment of Parkinsonís disease and written by A.L. Benabid et al. from France, C. Hamani, J. Neimat and A.M. Lozano from Canada and a group of scientists from different countries of Europe. Three main structures, which are traditionally considered to be targets for neurosurgical manipulations, include the subthalamic nucleus, globus pallidus inetrnus and thalamus. At present high-frequency stimulation of these structures is the main method of neurosurgical treatment. The major predictors of its success are cases, meeting all the criteria of Parkinsonís disease, and a quality of response to L-DOPA. Selection of a target is based on a type and predominance of these or those parkinsonian symptoms. In case of marked tremor contralateral stimulation of Vim nuclei of the thalamus leads to its considerable reduction in the absence of any effect on other symptoms, that is why interventions on thalamic nuclei are extremely rare today. As for an effect on the disease symptoms, the results of globus pallidus internus stimulation can vary rather greatly. One can watch reduction of tremor (70-80% of cases), rigidity and hypokinesia (40-60%). Postoperative improvement of walking and a posture is characterized by a gradual exhaustion of an effect, which is observed in approximately 40% and 25% of cases during the first year and 3-4 subsequent years respectively. The most impressive effect is reduced severity of dyskinesia, present in 90% of operated cases. Thus, this way of treatment is a method of choice in severe disabling dyskinesias. The subthalamic nucleus is certain to be the most popular target. It is conditioned by its small size, possibility of exact placement of an electrode with the help of modern stereotaxic devices and an ability to get reproducible results in different neurosurgical clinics. Stimulation of the subthalamic nucleus not only improves all cardinal symptoms (tremor, hypokinesia, rigidity), but also has a positive effect on postural stability and walking. There is an opinion, that reduction of the subthalamic nucleus hyperactivity by implanting electrodes inhibits excessive release of glutamate and, thus, ensures a neuroprotective effect. The leading contraindications to deep brain stimulation are cognitive disorders, accompanying neurological disturbances, coagulopathies and an age of more than 70 years. The most frequent complications (about 30 000 operations) are intracranial hemorrhages due to the electrode penetration (2-3%) and infectious complications (3-4%), which can be treated successfully with antibiotics in a half of cases; however, the second half will require removal of electrodes. Lead replacement is necessary in 5% of cases due to a poor clinical effect or development of postoperative swelling in the region of an internal pulse generator. Neurological and psychiatric side effects, induced by stimulation, include paresthesia, diplopia, dystonia, hypophonia, eyelid apraxia, increased libido, sialorrhea. Perioperative confusion and depression occur in 15% and 5-25% of cases respectively. There are some authors, reporting memory disorders and attempted suicide. However, there is no proof, that they have been caused by surgical interventions.
The concluding sections of the book are devoted to neuroprotection and other treatment strategies. The article by the American neuropharmacologists Z.K. Wszolek and M.J. Zigmond contains the analysis of a modern concept of neuroprotective therapy for Parkinsonís disease. Drugs under discussion include agents, possessing a bioenergetic effect at the mitochondrial level (coenzyme Q10, creatine), chelate compounds, MAO-B inhibitors (rasagiline, selegiline, lazabemide), anti-apoptotic agents (rasagiline, rapamycin, selegiline, caspase inhibitors), NMDA-receptor antagonists (amantadine, memantine), hormones (estrogens), nicotine, caffeine, anti-inflammatory agents (minocycline, aspirin, tetracycline), growth and neurotrophic factors. W. Weinstock et al. present ladistigil, which is one of the latest achievements of neuropharmacology. It inhibits acetyl and butycholinesterase and MAO-A and B selectively in the brain. It is supposed to be effective in treatment of dementia and depression, which usually follow one after another or develop in parallel.
Summarizing the aforesaid, it should be noted, that the present book is a rich source of modern information on pathogenesis, diagnosis, new clinical symptoms, treatment of PD and similar syndromes. It gives a full-value description of achievements of experimental and clinical studies, new trends and prospects of further research. The monograph contains rather interesting articles on neurosurgical treatment of Parkinsonís disease. Thus, it is useful for those, studying neurosurgery, and practicing neurosurgeons, performing interventions on deep brain structures. Besides, the book is undoubtedly important for specialists, dealing with motor disorders or parkinsonism, neurologists and scientists, carrying out research in the field of neurophysiology and neuropharmacology.