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Huntington's Disease Reviews: 2002

(62 References)


Alberch, J., E. Perez-Navarro, et al. (2002). "Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease." Brain Res Bull 57(6): 817-22.

            Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Neuroprotective therapy could be achieved with the knowledge of the specific trophic requirements of these neuronal populations. Thus, the induction of endogenous trophic response or the exogenous administration of neurotrophic factors may help to prevent or stop the progression of the illness. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults. Transplantation of cells genetically engineered to release neurotrophic factors in the striatum has been used to study the neuroprotective effects of neurotrophin and GDNF family members in the excitotoxic model of Huntington's disease. Neurotrophins (brain-derived neurotrophic factor [BDNF], neurotrophin-3, and neurotrophin-4) protected striatal projection neurons against quinolinic or kainic acid treatment. However, GDNF family members showed a more specific action. Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus. In conclusion, the trophic requirements of each population of striatal projection neurons are due to a complex interaction between several neurotrophic factors, such as neurotrophins and GDNF family members, which can be modified, in different pathological conditions. Moreover, these neurotrophic factors may be able to provide selective protection for basal ganglia circuits, which are affected in striatonigral degenerative disorders, such as Huntington's disease or multisystem atrophy.


Albers, D. S. and M. F. Beal (2002). "Mitochondrial dysfunction in progressive supranuclear palsy." Neurochem Int 40(6): 559-64.

            A progressive impairment of mitochondrial function has been suggested to play a critical role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. Mitochondrial dysfunction can lead to number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition pore and secondary excitotoxicity. Progressive supranuclear palsy (PSP) is a rare neurological disorder characterized by the appearance of supranuclear gaze palsy and extrapyramidal symptoms [Arch. Neurol. 10 (1964) 333]. Although the etiological basis of PSP is unknown, compelling evidence from spectroscopy studies in PSP patients, biochemical studies in post-mortem PSP brain tissue and PSP cybrids has emerged that supports a contributory role of bio-energetic defects in the pathogenesis of PSP.


Bahr, B. A. and J. Bendiske (2002). "The neuropathogenic contributions of lysosomal dysfunction." J Neurochem 83(3): 481-9.

            Multiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre-adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age-related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of alpha-synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age-related diseases including the link between protein deposition and synaptic loss.


Barkhatova, V. P. (2002). "[Huntington's chorea: pathogenesis and new treatment approaches]." Zh Nevrol Psikhiatr Im S S Korsakova 102(3): 72-5.


Beal, M. F. (2002). "Coenzyme Q10 as a possible treatment for neurodegenerative diseases." Free Radic Res 36(4): 455-60.

            Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.


Bing, O. H., C. H. Conrad, et al. (2002). "Studies of prevention, treatment and mechanisms of heart failure in the aging spontaneously hypertensive rat." Heart Fail Rev 7(1): 71-88.

            The spontaneously hypertensive rat (SHR) is an animal model of genetic hypertension which develops heart failure with aging, similar to man. The consistent pattern of a long period of stable hypertrophy followed by a transition to failure provides a useful model to study mechanisms of heart failure with aging and test treatments at differing phases of the disease process. The transition from compensated hypertrophy to failure is accompanied by changes in cardiac function which are associated with altered active and passive mechanical properties of myocardial tissue; these events define the physiologic basis for cardiac decompensation. In examining the mechanism for myocardial tissue dysfunction, studies have demonstrated a central role for neurohormonal activation, and specifically the renin-angiotensin-aldosterone system. Pharmacologic attenuation of this system at differing points in the course of the process suggests that prevention but not reversal of myocardial tissue dysfunction is possible. The roles of the extracellular matrix, apoptosis, intracellular calcium, beta-adrenergic stimulation, microtubules, and oxygen supply-demand relationships in ultimately mediating myocardial tissue dysfunction are reviewed. Studies suggest that while considerable progress has been made in understanding and treating the transition to failure, our current state of knowledge is limited in scope and we are not yet able to define specific mechanisms responsible for tissue dysfunction. It will be necessary to integrate information on the roles of newly discovered, and as yet undiscovered, genes and pathways to provide a clearer understanding of maladaptive remodeling seen with heart failure. Understanding the mechanism for tissue dysfunction is likely to result in more effective treatments for the prevention and reversal of heart failure with aging. It is anticipated that the SHR model will assist us in reaching these important goals.


Bodemer, W. and F. J. Kaup (2002). "[Basic research on BSE transmission to people]." Dtsch Tierarztl Wochenschr 109(8): 338-41.

            Prion diseases of animal and man belong to neurological diseases with amyloidal deposition of the respective proteins. As to prion disease, the cellular prionprotein is in its abnormal isoform(s) an essential component of prionprotein aggregates found in affected tissue. In contrast to all neurodegenerative diseases like Morbus Alzheimer or Huntington's disease, prion diseases are transmissible. Therefore, prion diseases were designated Transmissible Spongiform Encephalopathies (TSE). The diseases are well known since decades. Scrapie was first described around 1750, a BSE case was reported in the 1850, most likely a misdiagnosis, and in 1920/1930 the human Creutzfeldt-Jakob disease (CJD) had been described. Transmission of CJD i.e. Kuru had been suspected in the early 1950s and erronously classified as slow virus disease. The CJD transmission posed a problem to humans when transplants from CJD cases were used for treatment. Fortunately, these iatrogenic transmissions remained limited. But with the advent of BSE and appearance of variant CJD cases in the UK and some places in Europe scientists suspected that transmission from cattle to man could have happened. From animal models we know of successful transmission via several routes. Species barriers do not completely prevent transmission. Rather transmission barriers might exist controlling individual susceptibility against prions. Modes of transmission, susceptibility for transmission, identification of receptor molecules as well as molecular mechanisms of the transmission process are intensely investigated. Current knowledge let us to assume that inapparent stages of prion infection pretend a (not existing) species barrier. This inapparent infection preceeds overt disease and, thus, most re-search focuses on the development of highly sensitive assay systems for detection of minute amounts of pathological prionprotein in suspected cases. Inapparence also should warn us to underestimate BSE or human vCJD cases; at present, 124 in Europe and one probable case in Hongkong (7 March 2002). Whether BSE had spread to other parts of the world by animal nutrition components or meat can neither be excluded nor confirmed at this time. New data on transmission and consequences of BSE for the human population are summarized in this review.


Bonelli, R. M., A. Aschoff, et al. (2002). "Cerebrospinal fluid tissue transglutaminase in vascular dementia." J Neurol Sci 203-204: 207-9.

            The enzyme tissue transglutaminase (tTG), an indicator of acute cell death, is found in brains of Alzheimer's and Huntington's disease patients. tTG, as a specific marker for apoptosis, may therefore be a powerful biochemical marker of the acute degenerating process in vivo and may be useful in discrimination between vascular dementia (VaD) and Alzheimer's disease (AD). It may serve as completion of CSF analysis in diagnosis of dementing disorders and be a simple way of assessing the efficacy of possible new anti-apoptotic drugs.


Bonini, N. M. (2002). "Chaperoning brain degeneration." Proc Natl Acad Sci U S A 99 Suppl 4: 16407-11.

            Drosophila has emerged as a premiere model system for the study of human neurodegenerative disease. Genes associated with neurodegeneration can be expressed in flies, causing phenotypes remarkably similar to those of the counterpart human diseases. Because human neurodegenerative diseases, including Huntington's and Parkinson's diseases, are disorders for which few cures or treatments are available, Drosophila brings to bear powerful genetics to the problem of these diseases. The molecular chaperones were the first modifiers defined that interfere in the progression of such disease phenotypes in Drosophila. Hsp70 is a potent suppressor of both polyglutamine disease and Parkinson's disease in Drosophila. These studies provide the promise of treatments for human neurodegeneration through the up-regulation of stress and chaperone pathways.


Butterfield, D. A., A. Castegna, et al. (2002). "Vitamin E and neurodegenerative disorders associated with oxidative stress." Nutr Neurosci 5(4): 229-39.

            Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.


Cantello, R. (2002). "Applications of transcranial magnetic stimulation in movement disorders." J Clin Neurophysiol 19(4): 272-93.

            The author reviews the applications of transcranial magnetic stimulation (TMS) in a series of movement disorders--namely, Parkinson's disease, corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, essential tremor, dystonia, Huntington's chorea, myoclonus, the ataxias, Tourette's syndrome, restless legs syndrome, Wilson's disease, Rett syndrome, and stiff-person syndrome. Single- and paired-pulse TMS studies have been done mainly for pathophysiologic purposes. Repetitive TMS has been used largely for therapy. Many TMS abnormalities are seen in the different diseases. They concur to show that motor cortical areas and their projections are the main target of the basal ganglia dysfunction typical of movement disorders. Interpretation has not always been clear, and sometimes there were discrepancies and contradictions. Largely, this may be the result of the extreme heterogeneity of the methods used and of the patients studied. It is premature to give repetitive TMS a role in treatment. Overall, however, TMS gives rise to a new, outstanding enthusiasm in the neurophysiology of movement disorders. There is reason to predict that TMS, with its continuous technical refinement, will prove even more helpful in the near future. Then, research achievements are reasonably expected to spill over into clinical practice.


Cersosimo, R. J. (2002). "Lung cancer: a review." Am J Health Syst Pharm 59(7): 611-42.

            The frequency, risk factors, pathophysiology, diagnosis, and management of lung cancer are reviewed. An estimated 157,400 Americans died of lung cancer in 2001. Lung cancer is the second most frequent cancer in both men and women. The major risk factor for lung cancer is smoking, which accounts for 75-80% of lung cancer-related deaths. Lung cancers can be broadly classified into two forms, small-cell carcinomas and non-small-cell carcinomas. Non-small-cell lung cancer is more common, accounting for up to 75% of lung cancers. Lung cancer is diagnosed by chest radiography, sputum cytology, bronchoscopy, needle biopsy, and other techniques. Surgery plays a major role in managing stage I and stage II non-small-cell lung cancer and may be used for stage III disease. Patients with stage IIIa disease may be surgical candidates, but involvement of mediastinal lymph nodes reduces the probability of survival. Adjuvant irradiation may reduce the rate of local recurrence but does not increase survival time. Adjuvant chemotherapy may confer a small survival-time advantage if the regimen includes cisplatin. Chemotherapy combined with radiation therapy may produce a survival advantage over irradiation alone. Patients with advanced non-small-cell lung cancer should receive combination chemotherapy. Several regimens have shown a survival advantage over best supportive care. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan have activity both as single agents and in combination. Surgery has only a limited role in the management of small-cell lung cancer. Patients with limited disease should receive a platinum-based chemotherapy regimen plus radiation therapy. Combination chemotherapy should be offered to patients with extensive disease. The most active regimens contain cisplatin or carboplatin. Paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan combinations have shown some promise. Lung cancer, although highly preventable, is usually diagnosed at an incurable stage. Chemotherapy is playing an increasingly important role alongside surgery and radiation therapy in the management of this disease.


Christen, Y. (2002). "[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases]." J Soc Biol 196(1): 85-94.

            Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.


Chuang, D. M., R. W. Chen, et al. (2002). "Neuroprotective effects of lithium in cultured cells and animal models of diseases." Bipolar Disord 4(2): 129-36.

            Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.


Cooper, A. J., T. M. Jeitner, et al. (2002). "Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological-length repeats: does transglutaminase activity play a role in (CAG)(n)/Q(n)-expansion diseases?" Neurochem Int 40(1): 53-67.

            Protein aggregates are a hallmark of Huntington's disease (HD) and other inherited neurodegenerative diseases caused by an elongated (CAG)(n) repeat in the genome and to a corresponding increase in the size of the Q(n) domain in the expressed protein. When the protein associated with HD (huntingtin) contains <35 Q repeats disease does not occur. However, an n>/=40 leads to disease. Some investigators have proposed that aggregates in the nuclei of affected cells are toxic, but other workers have suggested that the aggregates may be neutral or even protective. Whether or not they are toxic, an understanding of the processes whereby the aggregates develop may shed light on the neuropathological processes involved in the (CAG)(n)/Q(n)-expansion disorders. Q(n) domains have a tendency to non-covalently self align as 'polar zippers' rendering them less soluble, but evidence that such polar zippers occur in the aggregates in intact HD brain has so far been limited. The human brain contains at least three Ca(2+)-dependent enzymes (transglutaminases, TGases) that catalyze protein cross-linking reactions, namely TGase 1, TGase 2 (tissue transglutaminase, tTGase) and TGase 3. Q(n) aggregates have been found by several groups to be excellent substrates of tTGase. Moreover, the activity toward the Q(n) domains increases greatly as n is increased to 40 or beyond. tTGase mRNA and total TGase activity are elevated in HD brain. Moreover, some evidence suggests that Ca(2+) homeostasis is disrupted in HD brain. We propose that the combination of increased huntingtin (or huntingtin fragment containing the Q(n) domain) in the nucleus, increased the ability of the Q(n) domains to act as substrate, increased Ca(2+) levels and increased inherent TGase activity all contribute to increased cross-linking of proteins in HD brain. At first the proteasome machinery can recognize and degrade the cross-linked proteins, but over time the proteasome machinery may be overwhelmed and protein aggregates will accumulate.


Crowther, D. C. (2002). "Familial conformational diseases and dementias." Hum Mutat 20(1): 1-14.

            Familial conformational diseases occur when a mutation alters the conformation of a protein resulting in abnormal intermolecular interactions, protein aggregation, and consequent tissue damage. The molecular mechanisms of conformational disease are best understood for the serine protease inhibitor (serpin) superfamily of proteins. The serpinopathies include alpha(1)-antitrypsin (SERPINA1) deficiency and the newly characterized familial encephalopathy with neuroserpin inclusion bodies (FENIB) resulting from mutations in the neuroserpin (SERPINI1) gene. This review discusses how insights gained from the study of the serpins may be used to guide our research into other common diseases such as Alzheimer disease, Huntington disease, and Parkinson disease.


Deglon, N. and P. Aebischer (2002). "Lentiviruses as vectors for CNS diseases." Curr Top Microbiol Immunol 261: 191-209.


Domanska-Janik, K. (2002). "[Stem cells--potential therapeutic use in neurological diseases]." Neurol Neurochir Pol 36 Suppl 1: 107-17.

            There is a growing interest in medical potential of stem cells which may be used someday to create new tissue. Suggested applications involve a board spectrum ranging from the replacement for cells destroyed by diseases to even organ transplants. As ethical and legal controversy makes uncertain the future of embryonic stem cells research, attention has been recently turned to adult stem cells to discover whether they also can serve to transplantation. In this article we present data indicating that adult stem cells found in areas of the body like blood, skin, lymph and nervous systems, may be more versatile than previously assumed and in certain conditions can broke tissue barriers for differentiation. Thus, in this respect they can behave like their own pluripotent ancestors, although underlying mechanisms for this phenomena are still not clear. Furthermore, the following issues are shortly discussed: What are the characteristics of the different stem cells and where they can be found. What are experimental evidences that stem cells can be used for brain repair. What are the main problems must be solved before their clinical application and the risk-benefit assessment. The possible strategies and targets for stem cell therapies of neurological diseases.


Feigin, A. and D. Zgaljardic (2002). "Recent advances in Huntington's disease: implications for experimental therapeutics." Curr Opin Neurol 15(4): 483-9.

            PURPOSE OF REVIEW: In this article we have set out to critically review recent advances in the basic and clinical understanding of Huntington's disease, with specific emphasis on those findings that are most relevant to the planning, design, and conduct of future clinical trials for this devastating disorder. RECENT FINDINGS: The exact mechanisms underlying neuronal death in Huntington's disease remain unknown. Over the past 10 years, the leading models of neurodegeneration in the disease have involved mitochondrial dysfunction and subsequent excitotoxic injury, oxidative stress, and apoptosis. Recent studies have lent support to these models, but additional theories involving abnormalities of protein metabolism and transcriptional dysregulation have emerged as well. As progress is made toward clarifying the pathophysiological mechanisms leading to Huntington's disease, and new therapies are proposed, investigators have begun to develop improved outcome measures for potential use in future clinical trials aimed at slowing the progression of the disorder. SUMMARY: Recent advances in the understanding of the molecular biology and pathophysiology of Huntington's disease have suggested new therapeutic strategies aimed at slowing progression or forestalling onset of this neurodegenerative disease. In preparation for future clinical trials, clinical studies have begun to provide more quantitative measures of disease onset and progression. This progress in both the basic science and clinical realms raises real hope for effective therapies in the near future.


Fernandez-Ruiz, J., I. Lastres-Becker, et al. (2002). "Endocannabinoids and basal ganglia functionality." Prostaglandins Leukot Essent Fatty Acids 66(2-3): 257-67.

            In recent years, our knowledge on the cannabinoid pharmacology has shown a significant rise in terms of both quantity (more compounds and more targets) and quality (more selective compounds). This allows to consider cannabinoids and related compounds as a promising new line of research for therapeutic treatment of a variety of conditions, such as brain injury, chronic pain, glaucoma, asthma, cancer and AIDS-associated effects and other pathologies. Motor disorders are another promising field for the therapeutic application of cannabinoid-related compounds, since the control of movement is one of the more relevant physiological roles of the endocannabinoid transmission in the brain. There are two pathologies, Parkinson's disease and Huntington's chorea, which are particularly interesting from a clinical point of view due to the direct relationship of endocannabinoids and their receptors with neurons that degenerate in those disorders. However, other neurological pathologies, such as Alzheimer's disease or multiple sclerosis, which are not motor disorders in origin, but present a strong alteration in the control of movement, have also been a subject of interesting research for a cannabinoid therapy. This review will summarize our current knowledge on the role of these endogenous substances in the control of movement and, in particular, on the possible therapeutic usefulness of these compounds in the treatment of motor pathologies.


Flashman, L. A. (2002). "Disorders of awareness in neuropsychiatric syndromes: an update." Curr Psychiatry Rep 4(5): 346-53.

            Impaired awareness has been reported in a number of neuropsychiatric disorders. The purpose of this review is to provide an update on the current understanding of impaired awareness in neuropsychiatric syndromes, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), traumatic brain injury (TBI), schizophrenia, mood disorders, and obsessive-compulsive disorder (OCD). Unawareness of illness or deficits can have important diagnostic, treatment, and functional implications, and further understanding of its clinical and neural correlates will be extremely helpful in mediating its impact. Nevertheless, the area of unawareness has received relatively little attention as compared with other manifestations of neuropsychiatric illness. Evidence supporting a role for the involvement of frontal and parietal lobes across disorders is presented. Although most research has used neuropsychologic measures to assess brain functioning, more recent, limited literature in AD and schizophrenia has begun to examine neural correlates of unawareness using structural and functional imaging.


Herrero, M. T., C. Barcia, et al. (2002). "Functional anatomy of thalamus and basal ganglia." Childs Nerv Syst 18(8): 386-404.

            THALAMUS: The human thalamus is a nuclear complex located in the diencephalon and comprising of four parts (the hypothalamus, the epythalamus, the ventral thalamus, and the dorsal thalamus). The thalamus is a relay centre subserving both sensory and motor mechanisms. Thalamic nuclei (50-60 nuclei) project to one or a few well-defined cortical areas. Multiple cortical areas receive afferents from a single thalamic nucleus and send back information to different thalamic nuclei. The corticofugal projection provides positive feedback to the "correct" input, while at the same time suppressing irrelevant information. Topographical organisation of the thalamic afferents and efferents is contralateral, and the lateralisation of the thalamic functions affects both sensory and motoric aspects. Symptoms of lesions located in the thalamus are closely related to the function of the areas involved. An infarction or haemorrhage thalamic lesion can develop somatosensory disturbances and/or central pain in the opposite hemibody, analgesic or purely algesic thalamic syndrome characterised by contralateral anaesthesia (or hypaesthesia), contralateral weakness, ataxia and, often, persistent spontaneous pain. BASAL GANGLIA: Basal ganglia form a major centre in the complex extrapyramidal motor system, as opposed to the pyramidal motor system (corticobulbar and corticospinal pathways). Basal ganglia are involved in many neuronal pathways having emotional, motivational, associative and cognitive functions as well. The striatum (caudate nucleus, putamen and nucleus accumbens) receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas (prefrontal, premotor and supplementary motor areas) which are concerned with motor planning. These circuits: (i) have an important regulatory influence on cortex, providing information for both automatic and voluntary motor responses to the pyramidal system; (ii) play a role in predicting future events, reinforcing wanted behaviour and suppressing unwanted behaviour, and (iii) are involved in shifting attentional sets and in both high-order processes of movement initiation and spatial working memory. Basal ganglia-thalamo-cortical circuits maintain somatotopic organisation of movement-related neurons throughout the circuit. These circuits reveal functional subdivisions of the oculomotor, prefrontal and cingulate circuits, which play an important role in attention, learning and potentiating behaviour-guiding rules. Involvement of the basal ganglia is related to involuntary and stereotyped movements or paucity of movements without involvement of voluntary motor functions, as in Parkinson's disease, Wilson's disease, progressive supranuclear palsy or Huntington's disease. The symptoms differ with the location of the lesion. The commonest disturbances in basal ganglia lesions are abulia (apathy with loss of initiative and of spontaneous thought and emotional responses) and dystonia, which become manifest as behavioural and motor disturbances, respectively.


Hu, F. B. and W. C. Willett (2002). "Optimal diets for prevention of coronary heart disease." Jama 288(20): 2569-78.

            CONTEXT: Coronary heart disease (CHD) remains the leading cause of mortality in industrialized countries and is rapidly becoming a primary cause of death worldwide. Thus, identification of the dietary changes that most effectively prevent CHD is critical. OBJECTIVE: To review metabolic, epidemiologic, and clinical trial evidence regarding diet and CHD prevention. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE through May 2002 for epidemiologic and clinical investigations of major dietary factors (fat, cholesterol, omega-3 fatty acids, trans-fatty acids, carbohydrates, glycemic index, fiber, folate, specific foods, and dietary patterns) and CHD. We selected 147 original investigations and reviews of metabolic studies, epidemiologic studies, and dietary intervention trials of diet and CHD. DATA EXTRACTION: Data were examined for relevance and quality and extracted by 1 of the authors. DATA SYNTHESIS: Compelling evidence from metabolic studies, prospective cohort studies, and clinical trials in the past several decades indicates that at least 3 dietary strategies are effective in preventing CHD: substitute nonhydrogenated unsaturated fats for saturated and trans-fats; increase consumption of omega-3 fatty acids from fish, fish oil supplements, or plant sources; and consume a diet high in fruits, vegetables, nuts, and whole grains and low in refined grain products. However, simply lowering the percentage of energy from total fat in the diet is unlikely to improve lipid profile or reduce CHD incidence. Many issues remain unsettled, including the optimal amounts of monounsaturated and polyunsaturated fats, the optimal balance between omega-3 and omega-6 polyunsaturated fats, the amount and sources of protein, and the effects of individual phytochemicals, antioxidant vitamins, and minerals. CONCLUSIONS: Substantial evidence indicates that diets using nonhydrogenated unsaturated fats as the predominant form of dietary fat, whole grains as the main form of carbohydrates, an abundance of fruits and vegetables, and adequate omega-3 fatty acids can offer significant protection against CHD. Such diets, together with regular physical activity, avoidance of smoking, and maintenance of a healthy body weight, may prevent the majority of cardiovascular disease in Western populations.


Hughes, R. E. (2002). "Polyglutamine disease: acetyltransferases awry." Curr Biol 12(4): R141-3.

            Recent evidence indicates that inhibition of histone acetyltransferases may be a primary cause of cellular pathogenesis in polyglutamine diseases such as Huntington disease; the results raise the possibility that pharmacologic manipulation of protein acetylation levels could be of therapeutic benefit.


Humbert, S. and F. Saudou (2002). "Toward cell specificity in SCA1." Neuron 34(5): 669-70.

            Transcriptional dysregulation appears as an emerging and unifying pathogenic mechanism in polyQ neurodegenerative disorders such as Spinocerebellar ataxias and Huntington's disease. It is unclear how cell death specificity occurs in these diseases. In this issue of Neuron, link polymerase II, a general component of the transcriptional machinery, to PQBP-1, a cerebellar enriched protein, thus providing insight into the selectivity of neuronal death in SCA1.


Jankowsky, J. L., A. Savonenko, et al. (2002). "Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development." Curr Neurol Neurosci Rep 2(5): 457-64.

            Neurodegenerative diseases present an extraordinary challenge for medicine due to the grave nature of these illnesses, their prevalence, and their impact on individuals and caregivers. The most common of these age-associated chronic illnesses are Alzheimer's disease (AD) and Parkinson's disease (PD); other examples include the prion disorders, amyotrophic lateral sclerosis (ALS), and the trinucleotide (CAG) repeat diseases. All of these diseases are characterized by well-defined clinical syndromes with progressive courses that reflect the dysfunction and eventual loss of specific neuronal populations. Current therapies provide only symptomatic relief; none significantly alter the course of disease. We describe here how transgenic mice designed to model these diseases have substantially contributed to the identification and validation of many promising new therapies, and conversely how they have quickly and cost effectively eliminated several targets with unrealized expectations.


Jucaite, A. (2002). "[Dopaminergic modulation of cerebral activity and cognitive functions]." Medicina (Kaunas) 38(4): 357-62.

            Alterations in dopaminergic system are known to lie in the basis of such diseases as Parkinson's disease, Huntington's disease, Attention Deficit/Hyperactivity Disorder, Tourette syndrome, schizophrenia and drug abuse. This induced broad investigations of dopaminergic system in nearly all the areas of neuroscience. New insights into the pathogenesis of neuropsychiatric diseases have emerged. Research in the field of dopaminergic neurotransmission and memory was awarded Nobel prize in the year 2000. New avenues for the development of more selective drugs have been opened. In their daily practice clinicians are often prescribing medications acting on presynaptic or postsynaptic sites of dopaminergic units. Thus the aim of this review was to renew some knowledge on the architecture of dopaminergic system and also to glance through some of the studies implying its modulating effect on cognitive functions.


Karpuj, M. V., M. W. Becher, et al. (2002). "Evidence for a role for transglutaminase in Huntington's disease and the potential therapeutic implications." Neurochem Int 40(1): 31-6.

            Transglutaminase (TGase) activity is increased in affected regions of brains from patients with Huntington's disease (HD). TGase activity is particularly elevated in the nucleus compared with the cytoplasm from these brains. Gamma-glutaminyl-lysyl cross-links have been detected in nuclear inclusions in HD brain, indicating that TGase may play a prominent role in the aggregation of huntingtin (htt). Attempts to ameliorate experimental disease, via inhibition of TGase in transgenic models of HD in mice, are under investigation.


Kim, S. Y., T. M. Jeitner, et al. (2002). "Transglutaminases in disease." Neurochem Int 40(1): 85-103.

            Transglutaminases (TGases) are enzymes that are widely used in many biological systems for generic tissue stabilization purposes. Mutations resulting in lost activity underlie several serious disorders. In addition, new evidence documents that they may also be aberrantly activated in tissues and cells and contribute to a variety of diseases, including neurodegenerative diseases such as Alzheimer's and Huntington's diseases. In these cases, the TGases appear to be a factor in the formation of inappropriate proteinaceous aggregates that may be cytotoxic. In other cases such as celiac disease, however, TGases are involved in the generation of autoantibodies. Further, in diseases such as progressive supranuclear palsy, Huntington's, Alzheimer's and Parkinson's diseases, the aberrant activation of TGases may be caused by oxidative stress and inflammation. This review will examine the role and activation of TGases in a variety of diseases.


Kuran, W. (2002). "[Current perspectives in the treatment of Huntington's chorea]." Neurol Neurochir Pol 36(4): 757-65.

            Huntington's chorea (HD) is a degenerative condition of the central nervous system of genetic origin, inherited as an autosomal dominant trait. The mechanism of the genetic defect is already known, it is a dynamic mutation in the ITI5 gene situated on chromosome 4 p 16.3 coding the protein huntington. The disease is progressive and leading to lethal outcome and effective treatment is unknown. Methods of treatment of various disturbances developing in this disease are described with stress laid on neuroprotective methods which could perhaps give better results in not so far future.


Kwak, S. (2002). "[Huntington disease]." Nippon Rinsho 60 Suppl 4: 417-21.


Lesort, M., W. Chun, et al. (2002). "Does tissue transglutaminase play a role in Huntington's disease?" Neurochem Int 40(1): 37-52.

            Tissue transglutaminase (tTG) likely plays a role in numerous processes in the nervous system. tTG posttranslationally modifies proteins by transamidation of specific polypeptide bound glutamines (Glns). This reaction results in the incorporation of polyamines into substrate proteins or the formation of protein crosslinks, modifications that likely have significant effects on neural function. Huntington's disease is a genetic disorder caused by an expansion of the polyglutamine domain in the huntingtin protein. Because a polypeptide bound Gln is the determining factor for a tTG substrate, and mutant huntingtin aggregates have been found in Huntington's disease brain, it has been hypothesized that tTG may contribute to the pathogenesis of Huntington's disease. In vitro, polyglutamine constructs and huntingtin are substrates of tTG. Further, the levels of tTG and TG activity are elevated in Huntington's disease brain and immunohistochemical studies have demonstrated that there is an increase in tTG reactivity in affected neurons in Huntington's disease. These findings suggest that tTG may play a role in Huntington's disease. However in situ, neither wild type nor mutant huntingtin is modified by tTG. Further, immunocytochemical analysis revealed that tTG is totally excluded from the huntingtin aggregates, and modulation of the expression level of tTG had no effect on the frequency of the aggregates in the cells. Therefore, tTG is not required for the formation of huntingtin aggregates, and likely does not play a role in this process in Huntington's disease brain. However, tTG interacts with truncated huntingtin, and selectively polyaminates proteins that are associated with mutant truncated huntingtin. Given the fact that the levels of polyamines in cells is in the millimolar range and the crosslinking and polyaminating reactions catalyzed by tTG are competing reactions, intracellularly polyamination is likely to be the predominant reaction. Polyamination of proteins is likely to effect their function, and therefore it can be hypothesized that tTG may play a role in the pathogenesis of Huntington's disease by modifying specific proteins and altering their function and/or localization. Further research is required to define the specific role of tTG in Huntington's disease.


Lieberman, J. and F. R. Frankel (2002). "Engineered Listeria monocytogenes as an AIDS vaccine." Vaccine 20(15): 2007-10.

            Listeria monocytogenes (Lm) is an attractive vector to elicit T cell immunity because it infects antigen-presenting cells and because infection originates at the mucosa. Lm expressing HIV gag elicits sustained high levels of gag-specific CTL in mice. Since Lm causes disease in immunocompromised hosts, a highly attenuated strain of Lm that requires D-Ala for viability was produced. Attenuated bacteria expressing HIV-1 gag (Lmdd-gag) are as efficient as wild-type recombinants at stimulating gag-specific murine CTL when administered with D-Ala and at boosting human CTL in vitro. Lmdd-gag immunization protects mice from vaccinia-gag challenge and induces mucosal CTL, even after systemic immunization.


Lieberman, J., N. Manjunath, et al. (2002). "Avoiding the kiss of death: how HIV and other chronic viruses survive." Curr Opin Immunol 14(4): 478-86.

            Virus-specific CD8 T cells during chronic infection often exceed in numbers virus-replicating infected cells. Why then do antiviral CD8 T cells not do a better job of controlling infection? Although viral strategies for immune evasion are well known, this review will focus on changes in the CD8 T cell that interfere with cytolytic function. Most antiviral CD8 T cells in chronic infection do not express perforin, a molecule that is required for cytolysis. IL-2 and other costimulatory signals can restore cytotoxicity that has been impaired, suggesting a role for CD4 T cell anergy. The chance to eradicate an infection by T cell mediated lysis is undermined after an infection becomes established, in part because the effector immune response is impaired in the setting of chronic antigen.


Maier, C. M. and P. H. Chan (2002). "Role of superoxide dismutases in oxidative damage and neurodegenerative disorders." Neuroscientist 8(4): 323-34.

            In recent years, oxidative stress has been implicated in a variety of degenerative processes, diseases, and syndromes. Some of these include atherosclerosis, myocardial infarction, stroke, and ischemia/reperfusion injury; chronic and acute inflammatory conditions such as wound healing; central nervous system disorders such as forms of familial amyotrophic lateral sclerosis (ALS) and glutathione peroxidase-linked adolescent seizures; Parkinson's disease and Alzheimer's dementia; and a variety of other age-related disorders. Among the various biochemical events associated with these conditions, emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger, superoxide dismutase (SOD), as a common denominator. This review summarizes the function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities. Experimental evidence from laboratory animals that either overexpress (transgenics) or are deficient (knockouts) in antioxidant enzyme/protein levels and the genetic SOD mutations observed in some familial cases of ALS are also discussed.


Mattson, M. P., W. Duan, et al. (2002). "Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior." Neurobiol Aging 23(5): 695-705.

            Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.


Mazzola, J. L. and M. A. Sirover (2002). "Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders?" Neurotoxicology 23(4-5): 603-9.

            Recent evidence reveals that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is not simply a classical glycolytic protein of little interest. Instead, it is a multifunctional protein with diverse cytoplasmic, membrane and nuclear activities. Significantly, each activity is separate and distinctfrom its role in energy production. Its nuclear activities include its emerging role in apoptosis especially in neuronal cells. GAPDH translocates into the nucleus during programmed cell death. Introduction of antisense GAPDH sequences reduces apoptosis and prevents its nuclear translocation. Independent analyses demonstrate that GAPDH may be involved in the cellular phenotype of age-related neurodegenerative disorders. GAPDH binds uniquely in vitro to the beta-amyloid precursor protein (betaAPP), to huntingtin as well as to other triplet repeat neuronal disorder proteins. In Parkinson's disease (PD) cells, immunofluorescent data suggests the co-l localization of GAPDH and alpha-synuclein in Lewy bodies. Drugs used to treat PD bind specifically to GAPDH. Our recent findings (Mazzola and Sirover, 2001) demonstrate a subcellular reduction in GAPDH glycolytic activity in Alzheimer's disease (AD) and in Huntington's disease (HD) cells. The latter may be due to intracellular alteration of GAPDH structure (Mazzola and Sirover 2002). We discuss the hypothesis that the intracellularformation of GAPDH: neuronal protein complexes may represent an emerging cellular phenotype of neurodegenerative disorders. The cytoplasmic binding of neuronal proteins to GAPDH could affect energy production. Nuclear interactions could affect its apoptotic activity. Other functions of this multidimensional protein may also be inhibited. Experimental paradigms to test this hypothesis are considered.


McMahon, P. M. and G. S. Gazelle (2002). "Colorectal cancer screening issues: a role for CT colonography?" Abdom Imaging 27(3): 235-43.

            Colorectal cancer is the third most common cancer in the United States and will cause 56,700 deaths in 2001, despite the availability of screening tests capable of detecting the disease at earlier stages and reducing mortality. This article reviews the natural history of colorectal cancer, common risk factors and prevention strategies, and the strengths, limitations, and cost effectiveness of available screening tests. Although reminders to undergo colorectal cancer screening have become commonplace in the popular media, compliance with screening guidelines remains poor. Although still an unproven technology for widespread screening, computed tomographic (CT) colonography has several attractive characteristics for a screening test. For example, CT scanners are widely available, in contrast to limited numbers of gastroenterologists and radiologists' declining skill and interest in barium enema examinations. Also, patients may be less reluctant to undergo CT colonography than screening colonoscopy. Development of virtual bowel cleansing could further increase compliance and thereby reduce mortality from colorectal cancer. Other articles in this Feature Section discuss technical details of CT colonography and its methodologic challenges.


Menalled, L. B. and M. F. Chesselet (2002). "Mouse models of Huntington's disease." Trends Pharmacol Sci 23(1): 32-9.

            Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In 1993 the mutation that causes HD was identified as an unstable expansion of CAG repeats in the IT15 gene. Since then one of the most important advances in HD research has been the generation of various mouse models that enable the exploration of early pathological, molecular and cellular abnormalities produced by the mutation. In addition, these models have made it possible to test different pharmacological approaches to delay the onset or slow the progression of HD. In this article, insights gained from mouse models towards the understanding of HD and the design of new therapeutic strategies are discussed.


Mezzina, M. and O. Danos (2002). "Five years of vector service for gene therapy." Trends Genet 18(3): 118-9.


Muchowski, P. J. (2002). "Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones?" Neuron 35(1): 9-12.

            The most conspicuous feature of many neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, is the occurrence of protein aggregates in ordered fibrillar structures known as amyloid found inside and outside of brain cells. The appearance of aggregates in diseased brains implies an underlying incapacity in the cellular machinery of molecular chaperones that normally functions to prevent the accumulation of misfolded proteins. Here we review recent studies that have revealed a critical role for molecular chaperones in several neurodegenerative disorders.


Murphy, R. M. (2002). "Peptide aggregation in neurodegenerative disease." Annu Rev Biomed Eng 4: 155-74.

            In the not-so-distant past, insoluble aggregated protein was considered as uninteresting and bothersome as yesterday's trash. More recently, protein aggregates have enjoyed considerable scientific interest, as it has become clear that these aggregates play key roles in many diseases. In this review, we focus attention on three polypeptides: beta-amyloid, prion, and huntingtin, which are linked to three feared neurodegenerative diseases: Alzheimer's, "mad cow," and Huntington's disease, respectively. These proteins lack any significant primary sequence homology, yet their aggregates possess very similar features, specifically, high beta-sheet content, fibrillar morphology, relative insolubility, and protease resistance. Because the aggregates are noncrystalline, secrets of their structure at nanometer resolution are only slowly yielding to X-ray diffraction, solid-state NMR, and other techniques. Besides structure, the aggregates may possess similar pathways of assembly. Two alternative assembly pathways have been proposed: the nucleation-elongation and the template-assisted mode. These two modes may be complementary, not mutually exclusive. Strategies for interfering with aggregation, which may provide novel therapeutic approaches, are under development. The structural similarities between protein aggregates of dissimilar origin suggest that therapeutic strategies successful against one disease may have broad utility in others.


Nguimfack Mbodie, P. C. (2002). "[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?]." Encephale 28(2): 147-53.

            The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.


Niu, T., X. Chen, et al. (2002). "Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications." Drugs 62(7): 977-93.

            Cardiovascular disease is the major cause of morbidity and mortality in Westernised societies. It is well known that the aetiology of this devastating disorder involves both genetic and environmental factors. Sequence variants of the components of the renin-angiotensin-aldosterone system and the kallikrein-kinin system are suggested to have significant influences on cardiovascular homeostasis. Both gene targeting and transgenic studies in mice have clearly suggested a critical role of the angiotensin converting enzyme (ACE) gene in blood pressure regulation. Furthermore, an up-regulation of myocardial ACE gene expression has been observed in patients with heart failure. Thus, the ACE gene has been recognised as a top candidate gene for cardiovascular research. Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has attracted significant attention and has been extensively investigated in a spectrum of cardiovascular phenotypes, because of its correlation with serum ACE activity. A large majority of previous studies have shown a positive association between the DD genotype and an increased risk of myocardial infarction, but results in hypertension, left ventricular hypertrophy, cardiomyopathy and restenosis after percutaneous transluminal coronary angioplasty remain quite controversial. Since ACE inhibitors are widely used in hypertension and congestive heart failure, we also review the literature on the relationship of ACE I/D polymorphism with ACE inhibitor response. It appears that this polymorphism has some moderate impact on the cardiovascular response to ACE inhibitors but there is no consensus as to which allele confers a more pronounced effect. In addition, previous data are suggestive of an association between the ACE I allele and a greater risk of increased occurrence of ACE inhibitor-induced cough, but such a relationship needs further confirmation. Overall, since ACE I/D is only an intronic marker, the true locus that controls the ACE enzyme activity remains to be identified, and could be located within either the ACE gene or another nearby gene such as the human growth hormone gene. We note that since associations tend to vary across different gender or ethnic groups, or across different socio-ecological settings, consideration of potential gene-gene and gene-environment interactions should be made. Furthermore, the dissection of the genetic underpinning of cardiovascular disease needs delineation of all molecular variants of the key physiological pathways that influence cardiovascular function.


Orr, H. T. (2002). "Microarrays and polyglutamine disorders: reports from the Hereditary Disease Array Group." Hum Mol Genet 11(17): 1909-10.


Pasacreta, J. V., L. Jacobs, et al. (2002). "Genetic testing for breast and ovarian cancer risk: the psychosocial issues." Am J Nurs 102(12): 40-7; quiz 48.


Ranum, L. P. and J. W. Day (2002). "Dominantly inherited, non-coding microsatellite expansion disorders." Curr Opin Genet Dev 12(3): 266-71.

            Dominantly inherited diseases are generally caused by mutations resulting in gain of function protein alterations. However, a CTG expansion located in the 3' untranslated portion of a kinase gene was found to cause myotonic dystrophy type 1, a multisystemic dominantly inherited disorder. The recent discovery that an untranslated CCTG expansion causes the same constellation of clinical features in myotonic dystrophy type 2 (DM2), along with other recent discoveries on DM1 pathogenesis, have led to the understanding that both DM1 and DM2 mutations are pathogenic at the RNA level. These findings indicate the existence of a new category of disease wherein repeat expansions in RNA alter cellular function. Pathogenic repeat expansions in RNA may also be involved in spinocerebellar ataxia types 8, 10 and 12, and Huntington's disease-like type 2.


Ross, C. A. (2002). "Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders." Neuron 35(5): 819-22.

            The mechanisms of neurodegeneration in the CAG repeat polyglutamine diseases, including Spinal and Bulbar Muscular Atrophy (SBMA), Huntington's disease (HD), DentatoRubral and PallidoLuysian Atrophy (DRPLA), and Spino-Cerebellar Ataxia (SCA), have been controversial. Issues have included the role of polyglutamine aggregation and possible amyloid formation, localization in the cell nucleus, and possible proteolytic processing. Proposed mechanisms have included activation of caspases or other triggers of apoptosis, mitochondrial or metabolic toxicity, and interference with gene transcription. Recent studies using transgenic mouse and Drosophila models have helped resolve some of these issues and raise hopes for development of therapeutic targets.


Royall, D. R., E. C. Lauterbach, et al. (2002). "Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association." J Neuropsychiatry Clin Neurosci 14(4): 377-405.

            This report reviews the state of the literature and opportunities for research related to "executive control function" (ECF). ECF has recently been separated from the specific cognitive domains (memory, language, and praxis) traditionally used to assess patients. ECF impairment has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. No single putative ECF measure can yet serve as a "gold standard." This and other obstacles to assessment of ECF are reviewed. ECF impairment and related frontal system lesions and metabolic disturbances have been detected in many psychiatric and medical disorders and are strongly associated with functional outcomes, disability, and specific problem behaviors. The prevalence and severity of ECF deficits in many disorders remain to be determined, and treatment has been attempted in only a few disorders. Much more research in these areas is necessary.


Rubinsztein, D. C. (2002). "Lessons from animal models of Huntington's disease." Trends Genet 18(4): 202-9.

            Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product, huntingtin. Studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis. These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens.


Schapira, A. H. (2002). "Primary and secondary defects of the mitochondrial respiratory chain." J Inherit Metab Dis 25(3): 207-14.

            Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.


Seemanova, E. (2002). "[Syndromes and diseases caused by mutations of trinucleotide expansions]." Cas Lek Cesk 141(16): 503-7.

            A novel type of mutation--due to expansion of DNA trinucleotide repeats--has been discovered about 10 years ago. Nowadays 15 genetic syndromes and diseases caused by these mutations are known such as FRA X A syndrome, FRA X E syndrome, Kennedy syndrome spinobulbare muscle atrophy, Curschmann-Steinert syndrome of myotonic dystrophia, Huntington disease, Friedreich ataxia, spinocerebellare ataxias types I., II., III., VI., VII., VIII., XII. and Taylor's oculopharyngeal muscle dystrophy. The mutations of instable trinucleotids represent some exceptions from the regular monogenic transmission such as premutation, genomic imprinting, generation anticipation (acceleration, accentuation), somatic mosaicism. A good understanding of their special properties is necessary for efficient interdisciplinar collaboration of medical teams taking care for these patients and their families.


Sharma, N. and D. G. Standaert (2002). "Inherited movement disorders." Neurol Clin 20(3): 759-78, vii.

            The inherited movement disorders comprise a rapidly growing category of human disease. Advances in genetics have led to the identification of the gene mutation in Huntington's disease and three different gene mutations, which may lead to Parkinson's disease. In addition, gene mutations have been identified in less common movement disorders including Wilson's disease, Hallervorden-Spatz syndrome, paroxysmal kinesogenic choreoathetosis, neuroacanthocytosis, and some forms of dystonia. This article summarizes what is known about the genetic mutations that cause these movement disorders, as well as the clinical features of each disease and the symptomatic treatments currently available.


Sil'kis, I. G. (2002). "[Possible mechanism of cannabinoid-mediated modulation of signal transduction through the basal ganglia]." Ross Fiziol Zh Im I M Sechenova 88(2): 144-57.

            A possible mechanism of cannabinoid-mediated akinesia is suggested. This effect is proposed to be the consequence of a decrease in LTD/LTP in cortical inputs to striatopallidal/striatonigral cells in the matrix due to CB1 receptor activation. In addition, cannabinoids can attenuate locomotor activity due to a reducing of glutamate/GABA release from axon terminals of subthalamic nucleus/striatonigral cells of matrix and subsequent decrease/increase in the activity of neurons of globus pallidus/substantia nigra pars reticulata. Cannabinoid-mediated rise of dopamine release might be a result of a decrease of dopamine neuron inhibition by striatonigral cells of striosomes. It follows from the suggested mechanism that an inactivation (activation) of CB1 receptors leading to rise (lowering) of the motor activity can be useful for treatment of Parkinson (Huntington) disease.


Stevenson, D. A. and V. C. Strasburger (2002). "Advise or consent? Issues in genetic testing of adolescents." Adolesc Med 13(2): 213-21, v.

            Medical genetics is a rapidly advancing field, and genetic testing is becoming readily accessible as well as more sophisticated. Genetic testing has the potential to be both harmful and beneficial in terms of physical, psychosocial, and reproductive health. Ethical and legal implications of genetic testing are profound and particularly confounding in children and adolescents. This chapter discusses points to consider in evaluating the potential benefit and harm of the decision to undergo testing in adolescence.


Syed, V. and N. B. Hecht (2002). "Disruption of germ cell-Sertoli cell interactions leads to spermatogenic defects." Mol Cell Endocrinol 186(2): 155-7.

            In the aging human testis, partially regressed tubules contain Sertoli cells with an altered appearance and reduced numbers of germ cells. Investigating the effects of aging on Sertoli cell-germ cell interactions from Brown Norway rats, we have found that a selective breakdown in germ cell-Sertoli interactions could lead to severe reductions in male fertility. Previous studies have identified two specific inducible germ cell markers (a von Ebner's-like protein and the Huntington disease protein) and two specific inducible Sertoli cell markers (a sertonin receptor and a novel gene) that are expressed in Sertoli cell-germ cell cocultures and in vivo [Endocrinology 140 (1999a) 5754; J. Biol. Chem. 27 (1999b) 10737]. We find that germ cells from aged regressed testes are unable to respond to selective signals from Sertoli cells, although germ cells from aged normal sized testes respond well. Similarly, Sertoli cells from aged regressed testes fail to respond to certain signals from young germ cells. We propose that selective disruptions in communication between Sertoli cells and germ cells contribute to germ cell loss during aging.


Tarsy, D., R. J. Baldessarini, et al. (2002). "Effects of newer antipsychotics on extrapyramidal function." CNS Drugs 16(1): 23-45.

            Following acceptance of clozapine as a superior antipsychotic agent with low risk of adverse extrapyramidal syndromes (EPS), such as dystonia, parkinsonism, akathisia or tardive dyskinesia, several novel antipsychotic drugs have been developed with properties modelled on those of clozapine. Though generally considered 'atypical' in their relatively low risk of inducing EPS, these agents vary considerably in their pharmacology and impact on neurological functioning. Although few comparative data are available, the atypical antipsychotics can be tentatively ranked by EPS risk (excluding akathisia and neuroleptic malignant syndrome) in the following order: clozapine < quetiapine < olanzapine = ziprasidone. At higher doses, risperidone is ranked with a higher EPS risk than olanzapine and ziprasidone, but its risk of EPS is lower with lower doses. In general, this ranking is inversely related to antidopaminergic (D2 receptor) potency. The high antiserotonergic (5-HT2A receptor) potency of risperidone, clozapine, ziprasidone and olanzapine, but not quetiapine, as well as the antimuscarinic activity of olanzapine and clozapine may also limit EPS. For the treatment of psychotic reactions to dopamine agonist therapy in Parkinson's disease, clozapine is both effective and relatively well tolerated; quetiapine may be tolerated, olanzapine is not well tolerated, risperidone is poorly tolerated, and amisulpride and ziprasidone have not been well evaluated. Clozapine, perhaps because of its anticholinergic activity, can reduce parkinsonian tremor. It is useful for ongoing psychosis with tardive dyskinesia, especially for dystonic features. No atypical antipsychotic is clearly effective for motor abnormalities in Huntington's disease or Tourette's syndrome, and the effect of these drugs on other neurological disorders have been well evaluated in only small numbers of patients. In summary, with the exception of clozapine, and perhaps quetiapine, atypical antipsychotics have brought only relative avoidance of EPS, strongly encouraging continued searches for novel antipsychotic agents.


Thompson, P. D. (2002). "Neurodegenerative causes of myoclonus." Adv Neurol 89: 31-4.


Tsuang, D. W. and T. D. Bird (2002). "Genetics of dementia." Med Clin North Am 86(3): 591-614.

            Many neurodegenerative diseases are exceedingly complex disorders (Fig. 6). In the past decade, we have made tremendous advances in our understanding [figure: see text] of the genetic basis of these disorders. One common characteristic of these disorders is the existence of rare families in which a given disease is inherited as a Mendelian trait. In this article, we have reviewed the genetics of several common neurodegenerative disorders that are associated with cognitive disturbances and for which causative genes have been identified. Further genetic analysis should clarify the roles of known genes in the pathogenesis of common sporadic forms of these various diseases. Investigation of the normal and aberrant functions of these genes should provide insight into the underlying mechanisms of these disorders. Such research should facilitate new strategies for therapeutic interventions. Although molecular genetics has helped to clarify the etiology of these disorders, clinicians have played a critical role in the careful identification and classification of many families who were involved in the eventual mapping and cloning of causative mutations. The role of the clinician should not be underestimated. Future clinical and molecular genetics findings hold many clinical implications. It is likely that new diagnostic and therapeutic strategies for dementing disorders are just on the horizon.


Wenstrom, K. D. (2002). "Fragile X and other trinucleotide repeat diseases." Obstet Gynecol Clin North Am 29(2): 367-88, vii.

            Hereditary unstable DNA is composed of strings of trinucleotide repeats, in which three nucleotides are repeated over and over (ie CAGCAGCAGCAG). These repeats are found in several sites within genes; depending on their location, the number of triplet repeats in a string can change as it is passed on to offspring. When the number of repeats increases to a critical size, it can have a variety of affects on gene function. The repeats may cause a loss in gene function (as in Fragile X) or may result in the gain of a new, abnormal protein and thus a new function (as in myotonic dystrophy and Huntington disease). Although a variety of trinucleotide repeat diseases have been reported and merit consideration, this discussion will focus primarily on Fragile X syndrome, myotonic dystrophy, and Huntington disease.


Wyss, M. and A. Schulze (2002). "Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?" Neuroscience 112(2): 243-60.

            Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity.Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease.Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.


Yu, H. and N. E. Head (2002). "Persistent infections and immunity in cystic fibrosis." Front Biosci 7: d442-57.

            Cystic fibrosis (CF) is the most common autosomal recessive lethal disease in the Caucasian population. Chronic respiratory infections with Pseudomonas aeruginosa, neutrophil-dominated airway inflammation and progressive lung damage are the major causes of morbidity and mortality in CF. Two persistent infection phenotypes expressed by this bacterium are biofilm and mucoidy. Biofilm, also called the microcolony mode of growth is the surface-associated adherent bacterial community, while mucoidy refers to a phenotype conducive to copious amounts of mucoid exopolysaccharide (MEP)/alginate that provides a matrix for mature biofilms conferring resistance to host defenses and antibiotics. Recent completion of the whole genomic sequence of the standard reference strain P. aeruginosa PAO1 has led to discoveries that many clinical isolates of this species possess unique genomic sequences (genomic islands) due to horizontal gene transfer. We propose this type of genetic exchange may play an important role in causing intrinsic genomic diversity of this organism. Therefore, the diversity, as revealed through profiles of restriction fragment length polymorphism (RFLP), may be linked to an array of novel and unexplored pathogenic mechanisms in P. aeruginosa. CF mouse models, while displaying many clinical similarities to human CF, have yet to demonstrate a chronic pulmonary disease phenotype. This review is intended to provide an overview of P. aeruginosa persistent infection phenotypes (biofilm and mucoidy) and an aerosol infection mouse model for CF. Genomic diversity of P. aeruginosa and its implications in the pathogenesis in CF will also be discussed.


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