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Cortical atrophy in Parkinson disease: correlation between clinical and CT findings with special emphasis on prefrontal atrophy.
Adam P, Fabre N, Guell A, et al.
AJNR Am J Neuroradiol. 1983 May; 4(3):442-5.
Thirty-seven patients with Parkinson disease were evaluated clinically and with computed tomography in order to determine the incidence of prefrontal atrophy. An age-matched healthy control group was also scanned. The computed tomographic criteria used were the width of cortical sulci and ventriculocerebral indices. Parkinsonian patients with frontal cortical atrophy represent only one patient out of three. They are much older than parkinsonian patients with normal computed tomographic scans, and the onset of their illness occurs later. No significant difference was found according to gender, parkinsonian clinical triad, psychomotor study, or mean duration of illness and/or dopatherapy to the time of computed tomography. This work seems to separate two Parkinson diseases: one beginning before 65 years and damaging the nigrostriate system, and another beginning after 65 years and damaging both the nigrostriate system and the cortex, particularly the frontal cortex
Mercury intoxication simulating amyotrophic lateral sclerosis.
Adams CR, Ziegler DK, Lin JT.
JAMA. 1983 Aug 5; 250(5):642-3.
A 54-year-old man had a syndrome resembling amyotrophic lateral sclerosis after a brief but intense exposure to elemental mercury. The syndrome resolved as his urinary mercury levels fell. Mercury toxicity must be considered not only in individuals with recent anterior horn-cell dysfunction but also with otherwise unexplained peripheral neuropathy, tremor, ataxia, and a gamut of psychiatric symptoms including confusion and depression
Slow allotypic variants of the NAT2 gene and susceptibility to early-onset Parkinson's disease.
Agundez JA, Jimenez-Jimenez FJ, Luengo A, et al.
Neurology. 1998 Dec; 51(6):1587-92.
OBJECTIVE: To determine the frequency and the linkage distribution of seven mutations at the polymorphic gene coding for the arylamine N-acetyl transferase (NAT2; EC 2.3.1.5) in 121 unrelated patients with sporadic PD and in 121 unrelated healthy volunteers. METHODS: The study was performed with mutation-specific PCR using genomic DNA obtained from blood of the probands. RESULTS: Comparison of the NAT2 genotypes of the overall PD patients and control subjects did not indicate statistically significant differences. However, patients with early-onset PD (onset before the age of 50 years, n=37) showed a higher frequency of slow-acetylation genotypes (78.4% patients) compared with both healthy control subjects (55.4%) and with late-onset (onset after 51 years of age, n=84) PD patients (54.8%). Such a difference was statistically significant (p < 0.015) and was the result of a homogeneous increase in the frequency of slow-acetylation alleles. All subgroups analyzed in the study were in Hardy-Weinberg equilibrium for mutations at the NAT2 gene. CONCLUSIONS: Slow-acetylation-mutated alleles may be considered low-penetrance genes in early-onset PD pathogenesis, with a relative risk ratio for individuals with slow-acetylation genotype of 2.92 (95% CI, 1.26 to 6.78). This study provides evidence for the interaction of genetic and environmental factors in the etiology of sporadic PD
ADA Statement on Dental Amalgam.
Anderton RM.
2001;2001 May
Protective effect of melatonin in a chronic experimental model of Parkinson's disease.
Antolin I, Mayo JC, Sainz RM, et al.
Brain Res. 2002 Jul 12; 943(2):163-73.
Parkinson's disease is a chronic condition characterized by cell death of dopaminergic neurons mainly in the substantia nigra. Among the several experimental models used in mice for the study of Parkinson's disease 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced parkinsonism is perhaps the most commonly used. This neurotoxin has classically been applied acutely or sub-acutely to animals. In this paper we use a chronic experimental model for the study of Parkinson's disease where a low dose (15 mg/kg bw) of MPTP was administered during 35 days to mice to induce nigral cell death in a non-acute way thus emulating the chronic condition of the disease in humans. Free radical damage has been implicated in the origin of this degeneration. We found that the antioxidant melatonin (500 microg/kg bw) prevents cell death as well as the damage induced by chronic administration of MPTP measured as number of nigral cells, tyrosine hydroxylase levels, and several ultra-structural features. Melatonin, which easily passes the blood-brain barrier and lacks of any relevant side-effect, is proposed as a potential therapy agent to prevent the disease and/or its progression
Parieto-occipital glucose hypometabolism in Parkinson's disease with autonomic failure.
Arahata Y, Hirayama M, Ieda T, et al.
J Neurol Sci. 1999 Mar 1; 163(2):119-26.
To investigate the characteristics of regional cerebral metabolism in a subgroup of patients with Parkinson's disease and autonomic failure, we studied seven patients with Parkinson's disease with autonomic failure (PA group), 11 patients with Parkinson's disease without apparent autonomic failure (PD group), and nine normal controls using fluoro-deoxyglucose positron emission tomography (FDG-PET). To determine differences in metabolic distribution among these groups, regional relative glucose metabolic rates (RGMR), which were normalized with cerebellar values, were calculated and age-adjusted covariance analyses were done. When compared with that of controls. RGMR in the cerebral cortex of the PA group was markedly reduced in the occipital cortex (P<0.001), inferior parietal cortex (P<0.005) and superior parietal cortex (P<0.005), but without a decrease in the sensory motor and medial temporal cortices, putamen and thalamus. In contrast, the PD group did not show significant focal hypometabolic distribution. Our findings raise the possibility that Parkinson's disease with autonomic failure may overlap with the features of dementia with Lewy bodies
Epidemiologic correlates of sporadic amyotrophic lateral sclerosis.
Armon C, Kurland LT, Daube JR, et al.
Neurology. 1991 Jul; 41(7):1077-84.
We evaluated 74 selected patients with amyotrophic lateral sclerosis (ALS) and 201 matched controls for risk factors for ALS by a case-control design and a sequential questionnaire/interview technique to quantitate biographic data. We analyzed occupational and recreational data only for 47 male patients and 47 corresponding patient controls; data for women were insufficient. We used nonparametric analyses to evaluate five primary comparisons of ALS patients with controls: (1) more hard physical labor, p not significant (NS); (2) greater frequency of neurodegenerative disease in family members, p NS; (3) greater exposure to lead, p less than 0.05; (4) more years lived in a rural community, p NS; and (5) more trauma or major surgery, p NS. Men with ALS had worked more frequently at blue-collar jobs (although not a statistically significant difference, p = 0.10) and at welding or soldering (p less than 0.01). These results suggest that there may be an association between ALS in men and exposure to lead vapor. The limited nature of the association favors a multifactorial etiologic mechanism of ALS
ToxFAQs™ for Aluminum. CAS 7429-90-5.
ASTDR.
1999;1999 Jun;
The effect of dehydroepiandrosterone sulfate administration to patients with multi-infarct dementia.
Azuma T, Nagai Y, Saito T, et al.
J Neurol Sci. 1999 Jan 1; 162(1):69-73.
We measured cerebrospinal fluid (CSF) levels of dehydroepiandrosterone sulfate (DHEAS) by radioimmunoassay in seven patients with multi-infarct dementia (MID), fourteen age- and gender-matched non-demented patients with a history of cerebral infarction and fifteen age- and gender-matched patients without neurological disorders. The levels of DHEAS in CSF of patients with MID were significantly lower than those in non-demented patients with a history of cerebral infarction or those in patients without neurological disorders. Daily intravenous administration of 200 mg DHEAS for 4 weeks markedly increased serum and CSF levels of DHEAS in seven MID patients, improved decrease of daily activities and emotional disturbances in three patients and EEG abnormalities in two patients. The DHEAS therapy may provide a beneficial effect on MID patients
Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials.
Backlund EO, Granberg PO, Hamberger B, et al.
J Neurosurg. 1985 Feb; 62(2):169-73.
Autologous adrenal medullary tissue was transplanted to the striatum in two patients with severe parkinsonism. The aim was to provide the striatum with a new cellular source of catecholamines. Some rewarding effects were registered. This is the first time that such tissue has been transplanted in the human brain. The results merit further clinical trials
Association of slow acetylator genotype for N-acetyltransferase 2 with familial Parkinson's disease.
Bandmann O, Vaughan J, Holmans P, et al.
Lancet. 1997 Oct 18; 350(9085):1136-9.
BACKGROUND: Epidemiological studies have identified positive family history and exposure to environmental toxins as risk factors for Parkinson's disease (PD). An inherited defect of xenobiotic metabolism could result in increased susceptibility to such toxins. We investigated the frequency of functionally relevant polymorphisms in six detoxification enzymes among patients with PD to elucidate the relation between these polymorphisms and the disease. METHODS: We obtained brain-tissue samples from 100 patients with apparently sporadic PD and blood samples from 100 living patients with familial PD. For the control group, we extracted DNA from the tissue of 100 pathologically normal brains. The six enzymes analysed in these three groups were: CYP2D6, CYP2E1, NAD(P)H-menadione reductase, glutathione transferases M1 and T1, and N-acetyltransferase 2. We also investigated N-acetyltransferase 2 in 100 blood samples from patients with genetically proven Huntington's disease. We used PCR-based methods and restriction-enzyme analysis to detect polymorphisms. FINDINGS: The slow acetylator genotype for N-acetyltransferase 2 was more common in the familial PD group (69%) than in all controls (37%). Even after correction for multiple comparisons, this result remained highly significant (p = 0.002) for familial PD compared with normal controls (odds ratio 3.79 [95% CI 2.08-6.90]) and compared with Huntington's disease (2.45 [1.37-4.38], p = 0.004). The slow acetylator frequency for N-acetyltransferase 2 for sporadic PD was between that for Huntington's disease and familial PD. The frequencies of all the other polymorphisms were similar in the two study groups and the normal control group. INTERPRETATION: We found an association between the slow acetylator genotype for N-acetyltransferase 2 and familial PD. Further studies are needed to investigate the biological relevance of these findings, but slow acetylation could lead to impaired ability of patients with familial PD to handle neurotoxic substances
Detailed genotyping demonstrates association between the slow acetylator genotype for N-acetyltransferase 2 (NAT2) and familial Parkinson's disease.
Bandmann O, Vaughan JR, Holmans P, et al.
Mov Disord. 2000 Jan; 15(1):30-5.
In a preliminary report we demonstrated an association between the slow acetylator genotype of N-acetyltransferase 2 (NAT2) and familial cases of Parkinson's disease (FPD). Using a considerably more precise NAT2 typing method, which detects all mutant NAT2 alleles with a frequency of >1% in the white population, we have now retyped all the original patients and control subjects to investigate the reliability of our initial findings. The slow acetylator genotype remained considerably more common among FPD (73%) than normal control subjects (NPC, 43%) or the disease (Huntington's disease [HD]) control group (52%) with an odds ratio (OR) of 3.58 (95% confidence interval (CI): 1.96-6.56; p = 0.00003) for FPD versus NPC and an OR of 2.50 (95% CI: 1.37-4.56, p = 0.003) for FPD versus HD. Furthermore, the wild-type allele 4 conferred a protective effect with an OR of 0.39 (95% CI: 0.23-0.64; p = 0.0025) for FPD versus NPC and an OR of 0.50 (95% CI: 0.30-0.85, p = 0.01) for FPD versus HD. The results of this study support an association between the NAT2 slow acetylator genotype and FPD in our population
Case-Control Studies of Liver, Gallbladder and Pancreatic Cancer and Metalworking Fluid Exposure in the Automobile Industry.
Bardin JAEEEWDHKDWSRGRJ.
2000;November 14, 2000;
Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice.
Beal MF, Matthews RT, Tieleman A, et al.
Brain Res. 1998 Feb 2; 783(1):109-14.
We investigated whether oral administration of coenzyme Q10 (CoQ10) could attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in one-year-old mice. Four groups of one-year-old, male C57BL/6 mice received a either standard diet or a diet supplemented with CoQ10 (200 mg/kg/day) for five weeks. After four weeks, one group that had received the standard diet and one group that had received the CoQ10 supplemented diet were treated with MPTP. The four groups continued on their assigned diets for an additional week prior to sacrifice. Striatal dopamine concentrations were reduced in both groups treated with MPTP, but they were significantly higher (37%) in the group treated with CoQ10 and MPTP than in the group treated with MPTP alone. The density of tyrosine hydroxylase immunoreactive (TH-IR) fibers in the caudal striatum was reduced in both MPTP-treated groups, but the density of TH-IR fibers was significantly (62%) greater in the group treated with CoQ10 and MPTP than in the group treated with MPTP alone. Our results indicate that CoQ10 can attenuate the MPTP-induced loss of striatal dopamine and dopaminergic axons in aged mice and suggest that CoQ10 may be useful in the treatment of Parkinson's disease
Mitochondria, NO and neurodegeneration.
Beal MF.
Biochem Soc Symp. 1999; 66:43-54.
A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process
Niacin depletion in Parkinsonian patients treated with L-dopa, benserazide and carbidopa.
Bender DA, Earl CJ, Lees AJ.
Clin Sci (Lond). 1979 Jan; 56(1):89-93.
1. Benserazide and carbidopa, decarboxylase inhibitors used in the treatment of Parkinson's disease, have been shown to inhibit the enzyme kynurenine hydrolase in rat and mouse liver. This results in reduced synthesis of nicotinamide coenzymes from tryptophan, and hence an increased reliance on dietary niacin. 2. Pellagra might be expected as a result of this inhibition of endogenous synthesis of nicotinamide nucleotides, but has not been reported in patients treated with either drug. 3. The urinary excretion of N1-methyl-nicotinamide, a product of nicotinamide nucleotide metabolism, is considerably reduced in patients treated with dopa alone or in combination with an inhibitor of peripheral dopa decarboxylase, to as low as 40% of the control value. This means that many of these patients could be classified as 'at risk' of niacin deficiency, even if not frankly deficient. 4. Patients treated with dopa plus a decarboxylase inhibitor, but not those treated with dopa alone, also show a reduced excretion of xanthurenic acid, and an increased excretion of kynurenine, as would be expected after inhibition of the kynurenine pathway, and possibly indicative of marginal vitamin B6 deficiency
Smoking, alcohol, and coffee consumption preceding Parkinson's disease: a case-control study.
Benedetti MD, Bower JH, Maraganore DM, et al.
Neurology. 2000 Nov 14; 55(9):1350-8.
OBJECTIVE: To study the association of PD with preceding smoking, alcohol, and coffee consumption using a case-control design. METHODS: The authors used the medical records linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, during the years 1976 to 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control subject. The authors reviewed the complete medical records of cases and control subjects to abstract exposure information. RESULTS: For coffee consumption, the authors found an OR of 0.35 (95% CI = 0.16 to 0.78, p = 0.01), a dose-effect trend (p = 0.003), and a later age at PD onset in cases who drank coffee compared with those who never did (median 72 versus 64 years; p = 0.0002). The inverse association with coffee remained significant after adjustment for education, smoking, and alcohol drinking and was restricted to PD cases with onset at age <72 years and to men. The OR for cigarette smoking was 0.69 (95% CI = "0.45" to 1.08, p = "0.1)." The authors found no association between PD and alcohol consumption. Extreme or unusual behaviors such as tobacco chewing or snuff use and a diagnosis of alcoholism were significantly more common in control subjects than cases. CONCLUSIONS: These findings suggest an inverse association between coffee drinking and PD; however, this association does not imply that coffee has a direct protective effect against PD. Alternative explanations for the association should be considered
[Microbial ecology of the colon].
Bergogne-Berezin E.
Ann Gastroenterol Hepatol (Paris). 1985 Dec; 21(6):383-8.
It has been known for a long time that the human gastrointestinal tract contains 10(14) micro-organisms, which are predominantly anaerobic. Recent research has provided a better understanding of the functions and the equilibrium of the intestinal ecosystem in which the intestinal mucosa and the microbial flora which it supports interact. Any modification in one or other of the constituents of this ecosystem is likely to disturb the normal ecological equilibrium, resulting in a variety of gastro-intestinal diseases. Today, the intestinal ecosystem can be considered to be a system of defence and equilibrium or, conversely, as a reservoir of infection, which is confirmed by the study of certain faecal bacterial profiles with a high risk of infection. In gastrointestinal surgery and paediatrics, the correlation between antibiotic therapy, intestinal microbial proliferation and the development of septicaemia confers a fundamental role of the defence barriers of the gastrointestinal tract in the control or potentially pathogenic endogenous micro-organisms
Chronic systemic pesticide exposure reproduces features of Parkinson's disease.
Betarbet R, Sherer TB, MacKenzie G, et al.
Nat Neurosci. 2000 Dec; 3(12):1301-6.
The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD
N-acetyltransferase 2 polymorphism in sporadic Parkinson's disease in a Polish population.
Bialecka M, Gawronska-Szklarz B, Drozdzik M, et al.
Eur J Clin Pharmacol. 2002 Feb; 57(12):857-62.
OBJECTIVE: A genetic background of Parkinson's disease has been suggested, including genes implicated in xenobiotic metabolism. So far, many candidate genes responsible for the occurrence of the disease have been enumerated. This study was carried out to determine the presence of N-acetyltransferase 2 polymorphism in Parkinson's disease patients in a Polish population. METHODS: Fifty-four patients with diagnosed sporadic Parkinson's disease and 81 healthy individuals were enrolled into the study. The N-acetyltransferase 2 alleles (*4, *5, *6 and *7) were identified using polymerase chain reaction-restriction fragment length polymorphism methods with DNA extracted from peripheral blood. RESULTS: A preponderance of slow acetylators in patients with Parkinson's disease was demonstrated. Among 54 subjects with parkinsonism, 64.8% were homozygous for two mutated alleles responsible for the slow-acetylator phenotype. In the control group, a predominance of fast acetylators was noted. Subjects homozygous and heterozygous with genotypes determining fast acetylation constituting 53% of subjects, whereas 47% were slow acetylators. Comparison of the two groups of the study, i.e. Parkinson's disease and healthy individuals, revealed a statistically significant predominance of slow acetylators in Parkinson's disease patients (P < 0.05). The risk of Parkinson's disease development was more than two times greater in slow acetylators than healthy subjects. The frequency of point mutations was similar both in patients with Parkinson's disease and the healthy controls. CONCLUSION: Slow-acetylation genotype may be an important factor of individual susceptibility to Parkinson's disease
Food additive excitotoxins and degenerative brain disorders.
Blaylock RL.
Med Sentinel. 1999; 4(6):212-5.
Motor correlates of occipital glucose hypometabolism in Parkinson's disease without dementia.
Bohnen NI, Minoshima S, Giordani B, et al.
Neurology. 1999 Feb; 52(3):541-6.
OBJECTIVE: To determine whether occipital reduction in regional cerebral glucose metabolism in PD reflects retinal versus nigrostriatal dopaminergic degeneration. We hypothesized that occipital glucose metabolic reduction should be symmetric if parkinsonian retinopathy is responsible for the reduction. METHODS: PD patients without dementia (n = 29; age 63 +/- 10 years) and normal controls (n = 27; age 60 +/- 12 years) underwent [18F]fluorodeoxyglucose PET imaging. Regional cerebral glucose metabolic rates were assessed quantitatively. RESULTS: When compared with normal controls, PD patients showed most severe glucose metabolic reduction in the primary visual cortex (mean -15%, p < 0.001). Occipital glucose metabolic reduction was greater in the hemisphere contralateral to the side of the body affected initially or more severely in PD. There was an inverse correlation between side-to-side asymmetries in finger-tapping performance and occipital glucose metabolic reduction (r = "-0.45," p < 0.05; n = "28)." The correlation was strongest in patients with a relatively early stage of PD with more unilateral motor impairment (Hoehn and Yahr stage I, r = "-0.74," p < 0.01; n = "10)." CONCLUSION: The results indicate a pathophysiologic association between nigrostriatal dysfunction and occipital glucose metabolic reduction in PD
L-tryptophan: a rational anti-depressant and a natural hypnotic?
Boman B.
Aust N Z J Psychiatry. 1988 Mar; 22(1):83-97.
L-tryptophan is an essential amino acid which is the metabolic precursor of serotonin. Because of the evidence that serotonin deficiency may be an aetiological factor in some sorts of affective disorder and that serotonin is important in the biochemistry of sleep, L-tryptophan has been suggested as a "rational" anti-depressant and as a "natural" hypnotic. This paper reviews the biochemistry and pharmacology of L-tryptophan as well as the literature of the clinical trials that have been conducted with it and suggests that, by itself, L-tryptophan may be useful in mild cases of depression accompanied by endogenous features and cases of bipolar disorder resistant to standard treatments. It also potentiates the monoamine oxidase inhibitors and possibly the serotonergic tricyclic drugs. L-tryptophan may improve the depressed mood of Parkinsonian patients and has a clinically useful hypnotic action. There is evidence it may be useful in organic mental disorders induced by levodopa. Dosage schedules, contraindications and complications are discussed
Characterizing Risk at Metal Finishing Facilities.
Brown DJ.
1998;1998 May Report EPA/600/R-97/111.
Environmental antecedents of young-onset Parkinson's disease.
Butterfield PG, Valanis BG, Spencer PS, et al.
Neurology. 1993 Jun; 43(6):1150-8.
We conducted an exploratory study of young-onset Parkinson's disease (YOPD) to examine occupational and environmental factors associated with disease risk. This case-control study included 63 YOPD patients (diagnosis on or before age 50); controls (n = 68) were diagnosed with rheumatoid arthritis. Crude odds ratios (ORs) were computed to identify exposure variables for logistic regression analyses. After controlling for the variables of race, educational level, sex, age, age at diagnosis, and family history of Parkinson's disease (PD), PD was positively associated with insecticide exposure (OR = 5.75, p < 0.001), past residency in a fumigated house (OR = "5.25," p = "0.046)," herbicide exposure (OR = "3.22," p = "0.033)," rural residency at time of diagnosis (OR = "2.72," p = "0.027)," and nuts and seed eating 10 years before diagnosis (OR = "1.49," p = "0.021)." PD was inversely associated with cigarette smoking at 5 years (OR = "0.50," p = "0.027)," 10 years (OR = "0.43," p = "0.012)," and 15 years (OR = "0.37," p = "0.005)" before diagnosis, farm residency (OR = "0.38," p = "0.018)," and exposure to dimethyl sulfoxide (OR = "0.10," p < 0.001). These findings are consistent with hypotheses linking PD to exposure to pesticide agents
Alzheimer's disease, Parkinson's disease, and motoneurone disease: abiotrophic interaction between ageing and environment?
Calne DB, Eisen A, McGeer E, et al.
Lancet. 1986 Nov 8; 2(8515):1067-70.
The hypothesis is that Alzheimer's disease, Parkinson's disease (PD), and motoneurone disease are due to environmental damage to specific regions of the central nervous system and that the damage remains subclinical for several decades but makes those affected especially prone to the consequences of age-related neuronal attrition. This proposal is based on the association between environmental factors and certain neurodegenerative diseases (eg, methylphenyltetra-hydropyridine and parkinsonism, poliovirus infection and post-poliomyelitis syndrome, chickling pea ingestion and lathyrism, an unidentified environmental factor and amyotrophic lateral sclerosis-PD complex of Guam, and trauma and pugilist's encephalopathy) and on the long latent period between exposure to environmental factor and the appearance of symptoms in some of these disorders. The practical implications of this hypothesis are that epidemiological attention should be focussed on the environment in early rather than late life, prevention may be a realistic goal if the cause of subclinical damage can be identified, a search should be undertaken for causal mechanisms linking subclinical neuronal damage due to an environmental factor and the normal ageing process, and (4) better understanding of the regional selective vulnerability of the nervous system to the ageing process might allow a rational approach to treatment
Aging of the nigrostriatal pathway in humans.
Calne DB, Peppard RF.
Can J Neurol Sci. 1987 Aug; 14(3 Suppl):424-7.
Progressive degeneration of functionally related groups of neurons occurs in certain infective, toxic, nutritional and genetically determined neurological diseases. It also takes place in normal aging, and several of the regions that undergo selective decay with the passage of time seem to be the same target regions that are afflicted in degenerative disorders such as Parkinson's disease. Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Infective etiology is relatively easy to exclude by a combination of immunological tests and transfer experiments. Genetic causation can be rendered unlikely when large kindreds are available for study. Nutritional deprivation and acute or subacute toxicity are accessible to explanation by examining the environment. The most difficult mechanism of pathogenesis to refute is chronic toxic damage, where the lesion may derive from long-term exposure to a relatively widespread noxious agent or agents. Variations in involvement of individuals within a population may stem from differing capacities to activate or inactivate a toxin. Inherent in this concept of etiology is recognition that compensatory potential within the central nervous system may contribute to prolonged existence of subclinical lesions so that a latent period may exist for several decades, between causal event and the onset of symptoms. Furthermore, progressive clinical deterioration may take place even though the cause may have been transient, many years before.(ABSTRACT TRUNCATED AT 250 WORDS)
Familial Parkinson's disease: possible role of environmental factors.
Calne S, Schoenberg B, Martin W, et al.
Can J Neurol Sci. 1987 Aug; 14(3):303-5.
We report here six families with Parkinson's disease in whom the onset of symptoms tended to occur at approximately the same time irrespective of the age of the patient. The mean difference in the time of onset in different generations was 4.6 years while the mean difference in age of onset in children and parents was 25.2 years. We construe this pattern of age separation within families as suggestive of an environmental rather than genetic cause. Support for this view derives from the lack of correlation between occurrence of the disease and the degree of consanguinity. We conclude that our findings are in accord with the hypothesis which attributes the cause of some cases of Parkinson's disease to early, subclinical environmental damage followed by age-related attrition of neurons within the central nervous system
Biological and clinical significance of endotoxemia in the course of hepatitis C virus infection.
Caradonna L, Mastronardi ML, Magrone T, et al.
Curr Pharm Des. 2002; 8(11):995-1005.
Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes/ macrophages. In turn, LPS-activated monocytes/ macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12 are the major mediators. Before therapy (To) and at the end of 6-month interferon (IFN)-alpha/Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients. At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg/ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg/ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg/ml). In terms of serum cytokine concentration, at T6 IFN-gamma levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values. The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity. In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration. Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed
Evaluation of leakage of bacteria and endotoxins in teeth treated endodontically by two different techniques.
Carratu P, Amato M, Riccitiello F, et al.
J Endod. 2002 Apr; 28(4):272-5.
Root canal recontamination occurs after contact between oral-bacterial flora and the coronal extremity of the root canal. The aim of this study was to evaluate the time required for endotoxins and bacteria to penetrate through root-canal obturations performed with vertical and lateral gutta-percha condensation techniques. Specimens prepared by the two alternative methods were exposed to contaminated saliva, and leakage into the root was evaluated over time. None of the obturated roots was infiltrated by endotoxins after 31 days. On the contrary, between day 13 and day 37 bacteria had infiltrated all specimens
[Usefulness of olanzapine in the levodopa-induced psychosis in patients with Parkinson's disease].
Chacon JR, Duran E, Duran JA, et al.
Neurologia. 2002 Jan; 17(1):7-11.
BACKGROUND: To evaluate the antipsychotic efficacy of olanzapine (OLZ) in patients with Parkinson's disease (PD) and drug-induced psychosis (DIP) and its repercussion on the motor function. METHODS: Ten patients (5 women and 5 men) diagnosed of PD and DIP, aged 67 years (range: 50-81), with PD duration of 11.1 years (range: 6-23), treated chronically with levodopa per day, received a dose of 2.5 or 5.0 mg OLZ daily. Data concerning improvement of psychosis and worsening of motor function was based on Positive And Negative Symptoms Scale (PANSS) and Unified Parkinsons Disease Rating Scale (UPDRS) motor. RESULTS: Psychotic symptoms were improved in all patients. In most of them the improvement was almost total. Seven patients increased levodopa dose on OLZ, but significant worsening of motor function was reported just in one patient. None of the patients had agranulocytosis in the blood monitoring. Two patients presented weight gain. Seven patients improved their cognitive status. CONCLUSIONS: We conclude that OLZ at the doses studied may have efficacy for DIP which appears in PD and does not induce worsening of motor function in most of the patients
Parkinson's disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake.
Checkoway H, Powers K, Smith-Weller T, et al.
Am J Epidemiol. 2002 Apr 15; 155(8):732-8.
A reduced risk for Parkinson's disease (PD) among cigarette smokers has been observed consistently during the past 30 years. Recent evidence suggests that caffeine may also be protective. Findings are presented regarding associations of PD with smoking, caffeine intake, and alcohol consumption from a case-control study conducted in western Washington State in 1992-2000. Incident PD cases (n = 210) and controls (n = 347), frequency matched on gender and age were identified from enrollees of the Group Health Cooperative health maintenance organization. Exposure data were obtained by in-person questionnaires. Ever having smoked cigarettes was associated with a reduced risk of PD (odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.4, 0.8). A stronger relation was found among current smokers (OR = 0.3, 95% CI: 0.1, 0.7) than among ex-smokers (OR = 0.6, 95% CI: 0.4, 0.9), and there was an inverse gradient with pack-years smoked (trend p < 0.001). No associations were detected for coffee consumption or total caffeine intake or for alcohol consumption. However, reduced risks were observed for consumption of 2 cups/day or more of tea (OR = "0.4," 95% CI: 0.2, 0.9) and two or more cola drinks/day (OR = "0.6," 95% CI: 0.3, 1.4). The associations for tea and cola drinks were not confounded by smoking or coffee consumption
Melatonin attenuates MPP+-induced neurodegeneration and glutathione impairment in the nigrostriatal dopaminergic pathway.
Chen ST, Chuang JI, Hong MH, et al.
J Pineal Res. 2002 May; 32(4):262-9.
In this study we selected a rat model of Parkinson's disease (PD) by using intrastriatal infusion of the 1-methyl-4-phenyl-pyridinium ion (MPP+) to investigate the neuroprotective action of melatonin and its inhibitory activity on MPP+-impaired glutathione (GSH) system in the nigrostriatal system. Results show that MPP+ caused not only a severe neuronal injury in the striatum and in the ipsilateral substantia nigra (SN), but it also induced a significant decrease in GSH levels and an increase in the GSSG/GSH ratio 3 days after intrastriatal MPP+ infusion. Intraperitoneal co-administration of melatonin (10 mg/kg, five times) significantly attenuated MPP+-induced nigrostriatal neurotoxicity and GSH impairment. Depletion of cytosolic GSH by L-buthionine sulfoximine (BSO) did not cause neuronal damage by itself. It, however, when co-administrated with MPP+, potentiated the GSH reduction in the striatum, without aggravating nigrostriatal neurodegeneration induced by MPP+. Moreover, the MPP+-caused neuronal damage was positively correlated with a rising ratio of GSSG/GSH, but not with a drop of GSH. These results suggest that the MPP+-triggered oxidative stress may play a more important role than the loss of the antioxidant GSH in determining neuronal injury. Interestingly, the neuronal damage and oxidative stress elicited by co-treatment of BSO with MPP+ were effectively reduced by melatonin. Our results hence provide direct evidence showing that melatonin attenuates MPP+-induced nigrostriatal dopaminergic injury by its ability to impede the increase of GSSG/GSH ratio; therefore melatonin may have therapeutic implications in PD
The American Medical Association Encyclopedia of Medicine.
Clayman CB.
1989;
Abnormal tissue distribution of lead in amyotrophic lateral sclerosis.
Conradi S, Ronnevi LO, Vesterberg O.
J Neurol Sci. 1976 Oct; 29(2-4):259-65.
The lead content of cerebrospinal fluid (CSF) was found to be significantly elevated in 12 patients with amyotrophic lateral sclerosis, when compared to 28 control subjects having non-degenerative neurological disorders. The difference could not be explained as being merely secondary to blood-CSF barrier damage. A hypothetical model of the pathogenesis of the disease is advanced and the results are discussed in relation to this model
The epidemiology of primary degenerative dementia and related neurological disorders.
Cooper B.
Eur Arch Psychiatry Clin Neurosci. 1991; 240(4-5):223-33.
Observation of cytopathological similarities between the changes of Alzheimer-type dementia, Parkinson's disease and motor neuron disease, as well as of some degree of clinical association between these conditions, has led to the suggestion that all three belong to a common class of degenerative neurological disorders, each of which as a rule first becomes manifest when age-related neuronal attrition is superimposed on subclinical damage caused by environmental noxae earlier in life. The importance of this model lies in its potential relevance to prevention. The epidemiological data reviewed here suggest that, while the three disease groups are all strongly linked with ageing, there may be major differences between their patterns of occurrence in populations, which make it doubtful if the same environmental pathogens are responsible in each instance. The most plausible unifying hypothesis at present is that the predisposing neuronal damage can be caused by a number of widely distributed metallic neurotoxins, each of which has a tendency to pick out specific areas or cell groups within the CNS and thus to give rise to distinct though overlapping clinical syndromes. The evidence bearing on this and other causal hypotheses is, however, still tenuous because of the scarcity of empirical data. Population-based case-control and cohort studies are called for, as part of a co-ordinated research endeavour
Metabolic polymorphisms.
Daly AK, Cholerton S, Gregory W, et al.
Pharmacol Ther. 1993 Feb; 57(2-3):129-60.
Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases
Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility.
Daly AK, Cholerton S, Armstrong M, et al.
Environ Health Perspect. 1994 Nov; 102 Suppl 9:55-61.
Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase MI (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYP1A1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations
Monoamine neurotoxins-induced apoptosis in lymphocytes by a common oxidative stress mechanism: involvement of hydrogen peroxide (H(2)O(2)), caspase-3, and nuclear factor kappa-B (NF-kappaB), p53, c-Jun transcription factors.
del Rio MJ, Velez-Pardo C.
Biochem Pharmacol. 2002 Feb 15; 63(4):677-88.
The destruction of dopaminergic and serotonergic nerve cells by selective 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT), respectively, is a commonly used tool to investigate the mapping of neuronal pathways, elucidation of function and to mimic human neurodegenerative disease such as Parkinson's and Alzheimer's diseases. Despite intense investigations, a complete picture of the precise molecular cascade leading to cell death in a single cellular model is still lacking. In this study, we provide evidence that 6-OHDA, 5,6- and 5,7-DHT toxins-induced apoptosis in peripheral blood lymphocytes cells in a concentration-dependent fashion by a common oxidative mechanism involving: (1) the oxidation of toxins into quinones and production of the by-product hydrogen peroxide, reflected by desipramine-a monoamine uptake blocker-and antioxidants inhibition, (2) activation and/or translocation of nuclear factor-kappaB, p53 and c-Jun transcription factors, showed by immunocytochemical diaminobenzidine-positive stained nuclei, (3) caspase-3 activation, reflected by caspase Ac-DEVD-CHO inhibition, (4) mRNA and protein synthesis de novo according to cycloheximide and actinomycin D cell death inhibition. These results are consistent with the notion that uptake and intracellular autoxidation of those toxins precede the apoptotic process and that once H(2)O(2) is generated, it is able to trigger a specific cell death signalisation. Thus, taken together these results, we present an ordered cascade of the major molecular events leading peripheral blood lymphocytes to apoptosis. These results may contribute to explain the importance of H(2)O(2) as a second messenger of death signal in some degenerative diseases linked to oxidative stress stimuli
Smoking, alcohol, and coffee consumption preceding Parkinson's disease.
Deleu D.
Neurology. 2001 Apr 10; 56(7):984-5.
[L-dopa-induced psychoses and their treatment with L-tryptophan].
Demling J.
Fortschr Med. 1986 Apr 30; 104(17):360-2.
PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study.
DeStefano AL, Lew MF, Golbe LI, et al.
Am J Hum Genet. 2002 May; 70(5):1089-95.
Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD
Excited to death: different ways to lose your neurones.
Dodd PR.
Biogerontology. 2002; 3(1-2):51-6.
The selective loss of neurones in a range of neurodegenerative diseases is widely thought to involve the process of excitotoxicity, in which glutamate-mediated neuronal killing is elaborated through the excessive stimulation of cell-surface receptors. Every such disease exhibits a distinct regional and subregional pattern of neuronal loss, so processes must be locally triggered to different extents to account for this. We have studied several mechanisms which could lead to excitotoxic glutamate pathophysiology and compared them in different diseases. Our data suggest that glutamate can reach toxic extracellular levels in Alzheimer disease by malfunctions in cellular transporters, and that the toxicity may be exacerbated by continued glutamate release from presynaptic neurones acting on hypersensitive postsynaptic receptors. Thus the excitotoxicity is direct. In contrast, alcoholic brain damage arises in regions where GABA-mediated inhibition is deficient, and fails properly to dampen trans-synaptic excitation. Thus the excitotoxicity is indirect. A variety of such mechanisms is possible, which may combine in different ways
Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease.
Duan W, Ladenheim B, Cutler RG, et al.
J Neurochem. 2002 Jan; 80(1):101-10.
Although the cause of Parkinson's disease (PD) is unknown, data suggest roles for environmental factors that may sensitize dopaminergic neurons to age-related dysfunction and death. Based upon epidemiological data suggesting roles for dietary factors in PD and other age-related neurodegenerative disorders, we tested the hypothesis that dietary folate can modify vulnerability of dopaminergic neurons to dysfunction and death in a mouse model of PD. We report that dietary folate deficiency sensitizes mice to MPTP-induced PD-like pathology and motor dysfunction. Mice on a folate-deficient diet exhibit elevated levels of plasma homocysteine. When infused directly into either the substantia nigra or striatum, homocysteine exacerbates MPTP-induced dopamine depletion, neuronal degeneration and motor dysfunction. Homocysteine exacerbates oxidative stress, mitochondrial dysfunction and apoptosis in human dopaminergic cells exposed to the pesticide rotenone or the pro-oxidant Fe(2+). The adverse effects of homocysteine on dopaminergic cells is ameliorated by administration of the antioxidant uric acid and by an inhibitor of poly (ADP-ribose) polymerase. The ability of folate deficiency and elevated homocysteine levels to sensitize dopaminergic neurons to environmental toxins suggests a mechanism whereby dietary folate may influence risk for PD
Gas chromatography applied to the lactulose-mannitol intestinal permeability test.
Dumas F, Aussel C, Pernet P, et al.
J Chromatogr B Biomed Appl. 1994 Apr 1; 654(2):276-81.
Intestinal permeability can be modified by various illnesses, trauma and sepsis. Alterations of the intestinal wall can facilitate the diffusion of potentially harmful substances such as endotoxins, as well as bacterial translocation. We describe the validation of a capillary gas chromatographic method for the determination of mannitol and lactulose, used as intestinal permeability probes. The method is linear up to 3 g/l for mannitol and 300 mg/l for lactulose; recovery from overload samples is between 92 to 110%. Intra-assay coefficients of variation (C.V.s) were 2.7 and 6.8% for mannitol and lactulose, respectively, and inter-assay C.V.s were 8.9 and 9.3%. Normal values for 25 healthy subjects (mean +/- S.D.) were 14.5 +/- 3.1% and 0.27 +/- 0.15% for mannitol and lactulose, respectively. The GC method presented is rapid and precise
Oxidative stress and antioxidant therapy in Parkinson's disease.
Ebadi M, Srinivasan SK, Baxi MD.
Prog Neurobiol. 1996 Jan; 48(1):1-19.
Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease
Increased inorganic mercury in spinal motor neurons following chelating agents.
Ewan KB, Pamphlett R.
Neurotoxicology. 1996; 17(2):343-9.
Heavy metal toxicity has been implicated in the pathogenesis of motor neuron diseases. In an attempt to assess the efficacy of chelating agents to remove mercury from motor neurons, we quantitated the effect of the chelating agents meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3- dimercaptopropane -1-sulphonate (DMPS) on the burden of inorganic mercury in mouse spinal motor neurons. Mice were injected intraperitoneally with 1.0 mg HgCl2/kg body weight and one week later with either 4,400 mg/kg DMPS, 3,600 mg/kg DMSA or 5% NaHCO3 (control) over 4 weeks. Mercury deposits in motor neurons of 50 micron frozen sections of lumbar spinal cord were visualised with an autometallographic technique. Optical sections of silver-enhanced deposits were acquired using a confocal microscope in reflective mode and the volume of the deposits within the perikaryon was estimated. Mercury deposits occupied significantly more volume in motor neurons after both DMPS (7.4%, SD +/- 0.7%) and DMSA (8.0% +/- SD 0.7%) treatment than in controls (4.3%, SD +/- 1.7%). The higher levels of neuronal inorganic mercury may be due to increased entry of mercury into motor axons across the neuromuscular junction as a result of chelator-induced elevated circulating mercury
Normalization of brain serotonin by L-tryptophan in levodopa-treated rats.
Fahn S, Snider S, Prasad AL, et al.
Neurology. 1975 Sep; 25(9):861-5.
To test possible biochemical mechanisms by which L-tryptophan may reverse mental side effects of levodopa therapy in parkinsonism we administered levodopa, 250 mg per kilogram intraperitoneally, alone and with L-tryptophan, 500 mg per kilogram intraperitoneally, to rats pretreated with the peripheral dopa decarboxylase inhibitor, carbidopa (25 mg per kilogram). Rats were decapitated 0.5, 1, and 2 hours following amino acid injection and brain levels of amino acids, amines, and acid metabolites were determined. As expected, levodopa alone reduced tryptophan and serotonin and increased dopa and dopamine at the 1 and 2 hour intervals. Concurrent administration of L-tryptophan did not significantly alter the increased dopa and dopamine but did restore serotonin levels to within normal range at all time points. If similar events occur in parkinsonian patients, normalization of brain serotonin and not competitive reduction of brain dopa and dopamine may be the basis for the improvement in mental status
An open trial of high-dosage antioxidants in early Parkinson's disease.
Fahn S.
Am J Clin Nutr. 1991 Jan; 53(1 Suppl):380S-2S.
High dosages of tocopherol and ascorbate were administered to patients with early Parkinson's disease as a preliminary open-labeled trial for the eventual controlled double-blind study evaluating antioxidants as a test of the endogenous toxin hypothesis of the etiology of Parkinson's disease. The primary endpoint of the trial was the need to treat patients with levodopa. The time when levodopa became necessary in the treated patients was compared with another group of patients followed elsewhere and not taking antioxidants. The time when levodopa became necessary was extended by 2.5 y in the group taking antioxidants. The results of this pilot study suggest that the progression of Parkinson's disease may be slowed by the administration of these antioxidants. A large multicenter, controlled clinical trial currently underway in North America evaluating tocopherol and deprenyl has the potential to confirm these results
A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease.
Fahn S.
Ann Neurol. 1992; 32 Suppl:S128-S132.
High dosages of a combination of alpha-tocopherol and ascorbate were administered to patients with early Parkinson's disease as an open-labeled trial and pilot study to test the endogenous toxic hypothesis of the etiology of Parkinson's disease. Patients receiving concomitant amantadine and anticholinergics were allowed to participate, but those receiving levodopa or dopamine agonists were not. The study was begun prior to the availability of deprenyl. The primary end point of the trial was progression of the disease until patients needed treatment with levodopa or a dopamine agonist. The time when levodopa became necessary in the treated patients was compared to another group of patients followed elsewhere who did not receive antioxidants. The time when levodopa became necessary was extended by 2.5 years in the group receiving alpha-tocopherol and ascorbate. Results of this pilot study suggest that the progression of Parkinson's disease may be slowed by administration of these antioxidants. Controlled clinical trials using double-blind randomization techniques are required to confirm these results
Frontal dysfunction in early Parkinson's disease.
Farina E, Cappa SF, Polimeni M, et al.
Acta Neurol Scand. 1994 Jul; 90(1):34-8.
Recent studies have suggested that patients with Parkinson's disease (PD) share many of the behavioral deficits found following lesions to the pre-frontal cortex. We assessed the performance of a group of 22 mildly impaired, not-demented parkisonians (I or II Hoehn & Yahr stage) in a test of classification and recall of pictures of familiar objects, which has been demonstrated to be sensitive to frontal damage in patients with unilateral cerebral excision. Parkinsonians utilized fewer categories than normal controls for object classification, while no significant difference was found in the immediate and delayed recall scores. These results support the contention that a subclinical dysfunction of frontal type may be present even in the early stages of PD. A subanalysis of the data suggests that this dysfunction could possibly be aggravated by anticholinergic drugs
Significance of the parkin gene and protein in understanding Parkinson's disease.
Fishman PS, Oyler GA.
Curr Neurol Neurosci Rep. 2002 Jul; 2(4):296-302.
Mutations in the parkin gene cause autosomal recessive inherited juvenile parkinsonism (ARJP) and account for the majority of cases of inherited Parkinson's disease (PD) of young onset (<45 years of age). Patients with parkin mutations commonly have atypical clinical features such as dystonia at onset, hyper-reflexia, diurnal fluctuations, and sleep benefit; however, parkin mutation patients with both typical PD symptoms and older age of onset have been identified. Parkin is a ubiquitin protein ligase (E3), a component in the pathway that attaches ubiquitin to specific proteins, designating them for degradation by the proteasome. Several substrates for parkin have been identified (CDCrel-1, o-glycosylated alpha-synuclein, parkin associated endothelin-like cell receptor, and synphilin). The role of these substrates in the pathogenesis of ARJP is under active study. Most patients with parkin mutations lack Lewy bodies, suggesting that functional parkin is involved in the formation of these highly ubiquitinated inclusions. Furthermore, the recognition that parkin mutations can lead to a disorder clinically similar to sporadic PD, but presumably lacking Lewy bodies, calls into question the necessity of Lewy bodies for the diagnosis of PD and nigral cell death. Studies of parkin are increasing the focus on the role of the ubiquitin-proteasome system in the pathogenesis of both familial and sporadic PD
Status and future concerns of clinical and environmental aluminum toxicology.
Flaten TP, Alfrey AC, Birchall JD, et al.
J Toxicol Environ Health. 1996 Aug 30; 48(6):527-41.
A wide range of toxic effects of aluminum (Al) have been demonstrated in plants and aquatic animals in nature, in experimental animals by several routes of exposure, and under different clinical conditions in humans. Aluminum toxicity is a major problem in agriculture, affecting perhaps as much as 40% of arable soils in the world. In fresh waters acidified by acid rain, Al toxicity has led to fish extinction. Aluminum is a very potent neurotoxicant. In humans with chronic renal failure on dialysis, Al causes encephalopathy, osteomalacia, and anemia. There are also reports of such effects in certain patient groups without renal failure. Subtle neurocognitive and psychomotor effects and electroencephalograph (EEG) abnormalities have been reported at plasma Al levels as low as 50 micrograms/L. Infants could be particularly susceptible to Al accumulation and toxicity, reduced renal function being one contributory cause. Recent reports clearly show that Al accumulation occurs in the tissues of workers with long-term occupational exposure to Al dusts or fumes, and also indicate that such exposure may cause subtle neurological effects. Increased efforts should be directed toward defining the full range of potentially harmful effects in humans. To this end, multidisciplinary collaborative research efforts are encouraged, involving scientists from many different specialties. Emphasis should be placed on increasing our understanding of the chemistry of Al in biological systems, and on determining the cellular and molecular mechanisms of Al toxicity
In vivo elevation of extracellular potassium in the rat amygdala increases extracellular glutamate and aspartate and damages neurons.
Fujikawa DG, Kim JS, Daniels AH, et al.
Neuroscience. 1996 Oct; 74(3):695-706.
It is well known that high potassium (K+) solutions introduced by microdialysis into normal brain increase the extracellular concentration of the excitatory amino acid glutamate, and in vitro studies suggest that a high exogenously applied glutamate concentration can produce excitotoxic neuronal death. However, only recently were in vivo studies undertaken to determine whether high-K+ exposure damages neurons. We implanted microdialysis probes into rat amygdalae bilaterally, and after a 2-h baseline period exposed one side to a modified Krebs-Ringer-bicarbonate solution containing 100 mmol/l KCl for 30,50 and 70 min, followed by a 2-h recovery period, and 70 min and 3 h without a recovery period. Of 100.9 +/- 2.0 mmol/l KCl, 12.0 +/- 1.0% was extracted by amygdalar tissue in vivo. Election of the extracellular K+ concentration in the amygdala for 70 min or longer without a recovery period produced extensive neuronal damage and edematous-appearing neuropil in the tissue dialysed, as well as loss of normal neurons. Histological evidence of edema subsided in the groups with a 2-h recovery period. Although the number of damaged neurons was not significantly higher in the group with a 70 min high-K+ exposure and 2-h recovery period, the number of normal neurons was reduced, suggesting cell loss. During 70-min high-K+ exposure, the extracellular glutamate concentration increased to 242-377% of baseline during the first 60 min, and extracellular aspartate rose to 162-213% during the first 50 min; extracellular taurine rose even higher, to 316-567% of baseline, and glutamine fell to 14-27% of baseline. Extracellular serine was decreased at 20, 50 and 70 min of high-K+ exposure; extracellular glycine was unchanged. The elevated extracellular glutamate and aspartate concentrations suggest that exposure of the amygdala to high extracellular K+ may produce cell death through an excitotoxic process, and point the way to future studies to define the specific mechanisms involved
[Levodopa-induced psychosis in patients with idiopathic Parkinson disease].
Garcia-Escrig M, Bermejo PF, Fernandez Ponsati JT.
Med Clin (Barc ). 1999 Feb 27; 112(7):245-50.
BACKGROUND: To identify which clinical factors can modify the probability of the appearance of the psychotic syndromes in patients with idiopathic Parkinson's disease treated with levodopa. PATIENTS AND METHODS: 214 patients were retrospectively studied to evaluate the appearance of hallucinosis, delusions or mental confusion, from the beginning of the treatment with levodopa to a transversal evaluation along the course of the disease. To determine which clinical factors were independent predictors of psychosis, a multivariate logistic regression model was obtained, using the variables for which the univariate studies showed p values under 0.25. RESULTS: The multivariate model showed that the probability of developing psychosis during levodopa treatment was higher for the patients with intermediate or advanced stages of the disease (Hoehn and Yarh scale), at the beginning of the treatment (OR: 4.5; 95% CI: 1.86-11.23), when amantadine was administrated as associated drug (OR: 3.31; 95% CI: 1.19-9.23) and for the patients who presented motor fluctuations (OR: 3.08; 95% CI: 1.32-7.16). Univariate studies showed a significant association between levodopa psychosis and dyskinesias (univariate OR: 2.44; 95% CI: 1.12-5.33). Patients who suffered from psychotic complications had received significantly higher mean levodopa daily dose (p = 0.016) and the punctuation reached in the Folstein's Mini-Mental Scale was significantly lower (p = 0.0001). CONCLUSIONS: Levodopa psychosis appears in a "bad prognostic" group of patients, characterized by a greater motor and cognitive impairment and by the occurrence of other levodopa central adverse effects, higher doses of levodopa and a more frequent administration of other antiparkinsonian drugs
[Influence of chewing gum consumption and dental contact of amalgam fillings to different metal restorations on urine mercury content].
Gebel T, Dunkelberg H.
Zentralbl Hyg Umweltmed. 1996 Nov; 199(1):69-75.
It had been shown previously by various authors that contact of amalgam fillings to metal fillings of different type can increase the electrochemically caused amalgam corrosion in vitro thus leading to an elevated release of mercury. So it was recommended to renounce of a dental contact of amalgam to metal fillings of other type. One aim of the present study was to evaluate possible influences of this contact in vivo on the urinary mercury contents in human volunteers. Neither approximal nor occlusal contacts had any influence on the urinary mercury excretion in comparison to a reference group with similar amalgam status. Furthermore, the influence of gum chewing on urinary mercury levels was taken into account. It could be shown that the consumption of chewing gum resulted in a significantly higher mean urinary mercury content in probands with amalgam fillings in comparison to people with similar amalgam status (gum chewers: 1.36 Hg/24 h vs. non-chewers 0.70 microgram Hg/24 h). Thus, gum chewing has to be considered as important parameter of influence on the urinary mercury levels of people with amalgam fillings
Treatment of levodopa psychosis with L-tryptophan.
Gehlen WMJ.
Dtsch Med Wochenschr. 1974; 99(10):457-63.
Bacterial resistance.
Gentry LO.
Orthop Clin North Am. 1991 Jul; 22(3):379-88.
Pathogenic bacteria remain adaptable to an increasingly hostile environment and a wider variety of more potent antibiotics. Organisms not intrinsically prepared for defense have been able to acquire resistance to newer antimicrobial agents. Chromosomal mutations alone cannot account for the rapid emergence and spread of antibiotic resistance. It has been established that plasmids and transposons are particularly important in the evolution of antibiotic-resistant bacteria. Plasmid- or transposon-mediated resistance provides the bacteria with pre-evolved genes refined to express high-level resistance. In particular, transposons can transfer these resistance determinants in diverse bacterial species, and nature provides in humans and animals large intestinal reservoirs in which such communications are facilitated. Antibiotic therapy exerts selection pressures on bacteria. Eradication or marked reduction in the populations of susceptible organisms promotes the overgrowth of intrinsically resistant strains and favors those resistant as a result of favorable chromosomal mutations or via plasmids or transposons. In our hospitals, where antibiotic consumption continues to increase, the nosocomial flora consists of many resistant bacteria, and infections acquired in the nosocomial setting are now far more severe than their community-acquired counterparts. There is convincing evidence that infection control measures must take into further consideration the contribution of the hospital worker as carrier and mediator of antibiotic resistance
Mosby Medical Encyclopedia.
Glanze WD.
1996;
Dementias: the role of magnesium deficiency and an hypothesis concerning the pathogenesis of Alzheimer's disease.
Glick JL.
Med Hypotheses. 1990 Mar; 31(3):211-25.
Evidence is presented indicating that dementias are associated with a relative insufficiency of Magnesium (Mg) in the brain. Such insufficiency may be attributable to low intake or retention of Mg; high intake of a neurotoxic metal, such as aluminum (Al), which inhibits activity of Mg-requiring enzymes; or impaired transport of Mg and/or enhanced transport of the neurotoxic metal into brain tissue. It is proposed that Alzheimer's disease (AD) involves a defective transport process, characterized by both an abnormally high incorporation of Al and an abnormally low incorporation of Mg into brain neurons. The hypothesis is advanced that an altered serum protein contributes to the progression of AD by having a greater affinity for Al than for Mg, in contrast to the normal protein, which binds Mg better than Al. The altered protein crosses the blood-brain barrier more efficiently than the normal protein and competes with the normal protein in binding to brain neurons. Binding of the altered protein to the target neurons would both facilitate Al uptake and impede Mg uptake. Evidence suggests that albumin is the serum protein that is altered
Case-control study of early life dietary factors in Parkinson's disease.
Golbe LI, Farrell TM, Davis PH.
Arch Neurol. 1988 Dec; 45(12):1350-3.
Studies of the amyotrophic lateral sclerosis parkinsonism dementia complex of Guam direct suspicion to a heat-labile component of vegetables found in greatest concentration in seeds. We therefore surveyed patients with Parkinson's disease (PD) regarding early adult consumption of fruits and vegetables usually eaten raw, with seeds that are swallowed or scraped with the teeth. We administered a pretested questionnaire by telephone to 81 nondemented patients with PD and to a same-sex married sibling without PD. The patients and their siblings were asked whether they or their spouse (as an internal standard) had been more likely to eat each of 17 food items between marrying and age 40 years. No item was associated with the presence of PD. Unexpectedly associated with the absence of PD were preference for nuts (odds ratio, 0.39), salad oil or dressing (pressed from seeds) (odds ratio, 0.30), and plums (odds ratio, 0.24). These three items have higher vitamin E content than the other 14 items in our questionnaire. Our data are consistent with the hypothesis that vitamin E, as an antioxidant, may have prophylactic value against PD
Functions of the hypothalamo-hypophyseal-adrenal system in aging in female monkeys.
Goncharova ND, Oganyan TE, Taranov AG.
Neurosci Behav Physiol. 2000 Nov; 30(6):717-21.
Comparative studies on the functioning of the adrenal cortex in female rhesus macaques (Macaca mulatta) of different ages are reported - animals were aged 6-9 years (young adults; n = 5) and 20-26 years (old adults; n = 5). Corticosteroid concentrations (cortisol (F) and dehydroepiandrosterone sulfate (DHEAS)) were determined by specific radioimmunological and immunoenzyme methods in basal conditions, after acute stress (insulin-induced hypoglycemia, 2-h movement restriction), and after administration of dexamethasone. Basal F levels showed no marked age differences, while DHEAS concentrations in older animals decreased sharply. These animals also demonstrated weakened adrenal cortex responses to movement restriction, giving rise to delays in reaching peak F and DHEAS levels and decreases in the areas under their response curves (AUC) during the 4-h study period. In the dexamethasone test, the hypothalamo-hypophyseal-adrenal system of monkeys aged 20-26 years was relatively resistant to the suppressing effect of glucocorticoids via the negative feedback mechanism. It is suggested that disruption of feedback in the system controlling adrenal cortex function may be at least partially due to the development of peripheral blood steroid dysbalance with aging, this consisting particularly of a decrease in the DHEA (DHEAS) level; this steroid is known for its neurological activity
Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study.
Good PF, Olanow CW, Perl DP.
Brain Res. 1992 Oct 16; 593(2):343-6.
The Laser Microprobe Mass Analyzer (LAMMA) is a sensitive instrument for identifying and localizing trace elements in tissue samples. Using LAMMA, we have examined melanin-containing neurons of the substantia nigra in patients with Parkinson's disease (PD) and controls. We found that iron significantly accumulates within neuromelanin granules of patients with PD compared to controls. Increased aluminum was found in the neuromelanin granules of 2 of 3 PD cases but in no controls. The accumulation of iron and aluminum, which are known to promote oxidant stress, may account for the selective degeneration of neuromelanin-containing neurons in PD
Lipofuscin pigment accumulation in human brain during aging.
Goyal VK.
Exp Gerontol. 1982; 17(6):481-7.
Histopathologic and autofluorescence investigations were carried out to study lipofuscin pigment accumulation in various age groups of human beings died in accidents (in 100 cases ranging from 1-70 years-of-age). Lipofuscin pigment granules were first observed to appear at 9 years of age. Qualitative studies revealed a progressive increase in the intracellular lipofuscin pigment accumulation with advancing age. These pigment granules were found to congregate in mass in nerve cells of old individuals. An increase in the lipofuscin pigment accumulation and decrease of Nissl substance was observed during aging. The percentage of pigmented nerve cells and the percentage of cytoplasmic area occupied by lipofuscin pigment granules increased significantly with the advancement of age
Toxic and essential metal interactions.
Goyer RA.
Annu Rev Nutr. 1997; 17:37-50.
Cadmium, lead, mercury, and aluminum are toxic metals that may interact metabolically with nutritionally essential metals. Iron deficiency increases absorption of cadmium, lead, and aluminum. Lead interacts with calcium in the nervous system to impair cognitive development. Cadmium and aluminum interact with calcium in the skeletal system to produce osteodystrophies. Lead replaces zinc on heme enzymes and cadmium replaces zinc on metallothionein. Selenium protects from mercury and methylmercury toxicity. Aluminum interacts with calcium in bone and kidneys, resulting in aluminum osteodystrophy. Calcium deficiency along with low dietary magnesium may contribute to aluminum-induced degenerative nervous disease
Effects of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease.
Growdon JH, Melamed E, Logue M, et al.
Life Sci. 1982 Mar 8; 30(10):827-32.
To determine whether 1-tyrosine administration can enhance dopamine synthesis in humans as it does in rats, we measured levels of tyrosine and the major dopamine metabolite, homovanillic acid, in lumbar spinal fluids of 23 patients with Parkinson's disease before and during ingestion of 100 mg/kg/day of tyrosine. Nine patients took 100 mg/kg/day of probenecid in six divided doses for 24 hours prior to each spinal tap; 14 patients did not receive probenecid. L-tyrosine administration significantly increased CSF tyrosine levels in both groups of patients (p less than .01) and significantly increased homovanillic acid levels in the group of patients pretreated with probenecid (p less than .02). These data indicate that l-tyrosine administration can increase dopamine turnover in patients with disorders in which physicians wish to enhance dopaminergic neurotransmission
Restorative neurology in movement disorders.
Hagell P.
J Neurosci Nurs. 2000 Oct; 32(5):256-62.
Cell replacement for restoration of neurological functions in patients with movement disorders has been investigated for more than 15 years. Initial attempts used autologous adrenal medulla grafts implanted into the denervated striatum of patients with Parkinson's disease (PD). This approach was soon abandoned in favor of intrastriatal implantation of human embryonic mesencephalic tissue, rich in dopaminergic neurons. Available data from grafted PD patients show long-term (up to 10 years) graft survival and clinical benefits. The pattern and magnitude of symptomatic relief following transplantation, however, are incomplete and the outcome varies among patients. The need for large amounts of human embryonic tissue has to be circumvented and a better understanding of the relationship between graft placement and symptomatic recovery is necessary before this procedure can be offered to larger groups of patients. Clinical trials in Huntington's disease have so far shown inconclusive results. Neural cell replacement therapy is still an experimental procedure, but has the potential to become a future restorative treatment in PD and other movement disorders
N-acetyltransferase-2 polymorphism in Parkinson's disease: the Rotterdam study.
Harhangi BS, Oostra BA, Heutink P, et al.
J Neurol Neurosurg Psychiatry. 1999 Oct; 67(4):518-20.
The N-acetyltransferase-2 gene (NAT-2) has been associated with Parkinson's disease. The genotype associated with slow acetylation has been reported to be increased in patients with Parkinson's disease. Three mutant alleles M1, M2, and M3 of NAT-2 were investigated in 80 patients with idiopathic Parkinson's disease and 161 age matched randomly selected controls from a prospective population based cohort study. The allelic frequencies and genotypic distributions in patients were very similar to those found in controls. In controls the frequency of the wild type allele increased significantly with age suggesting that the mutant alleles are associated with an increased risk of mortality. These findings suggest that NAT-2 polymorphism is not a major genetic determinant of idiopathic Parkinson's disease, but may be a determinant of mortality in the general population
Diet and Parkinson's disease. II: A possible role for the past intake of specific nutrients. Results from a self-administered food-frequency questionnaire in a case-control study.
Hellenbrand W, Boeing H, Robra BP, et al.
Neurology. 1996 Sep; 47(3):644-50.
In a case-control study, we compared the past dietary habits of 342 Parkinson's disease (PD) patients recruited from nine German clinics with those of 342 controls from the same neighborhood or region. Data were gathered with a structured interview and a self-administered food-frequency questionnaire. Nutrient intakes were calculated from the reported food intakes through linkage with the German Federal Food Code and analyzed using multivariate conditional logistic regression to control for total energy intake, educational status, and cigarette smoking. At the macronutrient level, patients reported higher carbohydrate intake than controls after adjustment for total energy intake, smoking, and educational status (OR = 2.74, 95% confidence interval [CI]: 1.30-6.07, for the highest versus lowest quartile, p trend = 0.02). This was reflected in higher monosaccharide and disaccharide intakes at the nutrient level. There was no difference between patients and controls in protein and fat intake after adjustment for energy intake. We found an inverse association between the intakes of beta-carotene (OR = 0.67, 95% CI: 0.37-1.19, p trend = 0.06) and ascorbic acid (OR = 0.60, 95% CI: 0.33-1.09, p trend = 0.04) by patients, although only the trend for ascorbic acid intake reached statistical significance. There was no difference between groups for alpha-tocopherol intake after adjustment for energy intake. We also found that patients reported a significantly lower intake of niacin than controls (OR = 0.15, 95% CI: 0.07-0.33, p trend < 0.00005). Our results suggest that if antioxidants play a protective role in this disease, the amounts provided by diet alone are insufficient. Although the interpretation of the inverse association between niacin intake and PD is complicated by the high niacin content in coffee and alcoholic beverages, which were also inversely associated with PD in this study, the strength of this association and its biologic plausibility warrant further investigation
Unusual pigmented vesical lesion in a middle-aged woman.
Herrera GA, Turbat-Herrera EA, Lockard VG.
Ultrastruct Pathol. 1990 Nov; 14(6):529-35.
Excess lipofuscin deposition in tissues is a phenomenon observed in normal aging. The amount of lipofuscin in myocardium, liver, skeletal muscle, and adnexal skin structures varies considerably with age and increases in older individuals. In addition, lipofuscin deposition occurs in association with specific, non-age-related processes; these include melanosis coli, the so-called brown bowel syndrome, and the black thyroid. Localized lipofuscinosis has also been described in the gallbladder, esophagus, and fallopian tubes. The present article adds lipofuscinosis vesicalis to the list of entities characterized by focal lipofuscin deposition. All cases have a characteristic gross appearance that is somewhat variable from entity to entity and in some cases may suggest clinically an ominous pathologic process
Exogenous glutamate enhances glutamate receptor subunit expression during selective neuronal injury in the ventral arcuate nucleus of postnatal mice.
Hu L, Fernstrom JD, Goldsmith PC.
Neuroendocrinology. 1998 Aug; 68(2):77-88.
Administration of high doses of glutamate (Glu) leads to selective neurodegeneration in discrete brain regions near circumventriclular organs of the early postnatal mouse. The arcuate nucleus-median eminence complex (ARC-ME) appears to be the most Glu-sensitive of these brain regions, perhaps because of the intimate relationships between its neurons and specialized astroglial tanycytes. To investigate the mechanism of Glu-induced neuronal loss, we administered graded doses of the sodium salt of glutamate (MSG) to postnatal mice, measured their plasma Glu concentrations, and performed microscopic analyses of the ARC-ME region 5 h after treatment. Nursing, 7-day-old mouse pups (CD1, Charles River, Hollister, Calif.) were injected subcutaneously with single doses of 0.1-0.5 or 1.0-4.0 mg of MSG per g BW, or with water vehicle alone. Mice were decapitated 5 h later and the brains immediately fixed by immersion in buffered aldehydes. Frontal vibratome tissue sections at comparable levels of the ARC-ME were examined by light microscopy. A dose of 4.0 mg MSG/g BW caused neurodegeneration throughout the ARC region, while 1.0 mg/g MSG resulted in less extensive damage. Injection of 0.2 mg MSG/g BW, which raised plasma Glu concentrations 17-fold after 15 min, was the minimum dose tested at which nuclear and cytoplasmic changes were observed in a small group of subependymal neurons near the lateral recesses of the third ventricle. Higher doses of 0.3-0.5 mg MSG caused injury to additional neurons situated farther laterally, but damage remained confined to the ventral region of the ARC nucleus. Ultrastructural examination showed some subependymal neurons with pyknotic nuclei, reduced cytoplasmic volume, and swollen subcellular organelles, while others had fragmented and condensed nuclear material. Immunostaining for tyrosine hydroxylase indicated that dopamine neurons were spared at the threshold dose, but suffered damage after higher doses of MSG. Immunostaining for Glu receptor subtypes revealed that 0.2 mg MSG/g BW enhanced neuronal expression of NMDAR1 and of GluR2/4, and that higher doses of MSG preferentially increased NMDAR1 expression in injured neurons. These results extend previous reports of Glu sensitivity in the ARC-ME region of 7-day postnatal mice. A dose of 0.2 mg MSG/g BW s.c. causes clear but discrete injury to specific subependymal neurons of undetermined phenotype near the base of the third ventricle. Slightly higher doses of MSG evoke damage of additional neurons confined to the ventral region of the ARC traversed by tanycytes. These same greater amounts of MSG promote dose-related increase in the expression of NMDAR1 more than of GluR2/4 in injured ARC neurons, suggesting that elevated Glu receptor levels may contribute to or be related to neuronal cell death. Taken together with previous findings, the data suggest that Glu responsitivity in the ARC-ME of the postnatal mouse may result from transient developmental conditions involving the numerical ratios and juxtaposition between tanycytes and neurons, expression of Glu receptors, and perhaps other ontogenetic factors which may not persist in the mature adult
[Endotoxin-induced injury to the endothelium].
Iakovlev MI, Likhoded VG, Anikhovskaia IA, et al.
Arkh Patol. 1996 Mar; 58(2):41-5.
Literature and own data on endotoxin- induced injuries to endothelium are reviewed. It is shown that endotoxin can cause, hyperactivation of granulocytes, activation of complements, local endothelial injuries and some increase of vascular cell wall permeability, oxidation of low-density lipoproteins (LDL) and LDL-LPS complexes, binding of LPS with high-density lipoproteins (HDL) and some decrease of HDL ability to bind cholesterol, stimulation of endothelial and smooth muscle cell replication in local injuries to vessel wall. Low doses of endotoxin were found in blood plasma and on granulocytes surface in healthy and sick subjects. It is concluded that intestinal microflora endotoxin may play an essential role in pathogenesis of atherosclerosis
Metals.
International Occupational Safety and Health Information Centre.
1999;1999 Sep;
Impact of nocturnal bruxism on mercury uptake from dental amalgams.
Isacsson G, Barregard L, Selden A, et al.
Eur J Oral Sci. 1997 Jun; 105(3):251-7.
The mercury (Hg) release from dental amalgam fillings increases by mechanical stimulation. The aim of this study was to investigate the possible impact of nocturnal bruxism on Hg exposure from dental amalgams and to evaluate the effect of an occlusal appliance. 88 female patients from an orofacial pain clinic with a complete maxillary and mandibular dentition, a normal frontal vertical overbite with cuspid guidance, and at least 4 occlusal amalgam fillings in contact with antagonists in intercuspidal position, were examined with the Bruxcore bruxism monitoring device to measure the level of on-going nocturnal bruxism. Based on the degree of abrasion recorded, the subjects were divided into a group defined as bruxists, (n = 29), another group defined as non-bruxists, (n = 32), serving as controls, the intermediate group being discarded. The Hg exposure was assessed from the Hg concentration in plasma and urine, corrected for the creatinine content. In a regression model with bruxism as the only explanatory variable, no significant effect of bruxism was found, but when the number of amalgam fillings, chewing gum use, and other background variables were taken into account, there was a limited impact of bruxism on Hg in plasma. The nocturnal use of an occlusal appliance did not, however, significantly change the Hg levels. This study indicates that mechanical wear on amalgams from nocturnal bruxism may increase the Hg uptake, but the magnitude of this effect seems to be less than from the use of chewing gum
Serum levels of coenzyme Q10 in patients with Parkinson's disease.
Jimenez-Jimenez FJ, Molina JA, De Bustos F, et al.
J Neural Transm. 2000; 107(2):177-81.
We compared serum levels of coenzyme Q10 and the coenzyme Q10/cholesterol ratio in 33 patients with Parkinson's disease (PD) and 31 matched controls. The mean serum coenzyme Q10 levels did not differ significantly between the 2 study groups. Coenzyme Q10 levels were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale (UPDRS) or the Hoehn and Yahr staging in the PD group. The coenzyme Q10/cholesterol ratio had a significant correlation (although low) with duration of the disease (r = -0.46), total UPDRS score (r = -0.39), motor examination of the UPDRS (r = 0.45). These values were not influenced significantly by therapy with levodopa or dopamine agonists. The normality of serum coenzyme Q10 and coenzyme Q10/cholesterol ratio suggest that these values are not related with the risk for PD
Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management.
Kidd PM.
Altern Med Rev. 2000 Dec; 5(6):502-29.
Parkinson's disease (PD) is the most common movement pathology, severely afflicting dopaminergic neurons within the substantia nigra (SN) along with non-dopaminergic, extra-nigral projection bundles that control circuits for sensory, associative, premotor, and motor pathways. Clinical, experimental, microanatomic, and biochemical evidence suggests PD involves multifactorial, oxidative neurodegeneration, and that levodopa therapy adds to the oxidative burden. The SN is uniquely vulnerable to oxidative damage, having high content of oxidizable dopamine, neuromelanin, polyunsaturated fatty acids, and iron, and relatively low antioxidant complement with high metabolic rate. Oxidative phosphorylation abnormalities impair energetics in the SN mitochondria, also intensifying oxygen free radical generation. These pro-oxidative factors combine within the SN dopaminergic neurons to create extreme vulnerability to oxidative challenge. Epidemiologic studies and long-term tracking of victims of MPTP (1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine) poisoning, suggest oxidative stress compounded by exogenous toxins may trigger the neurodegenerative progression of PD. Rational, integrative management of PD requires: (1) dietary revision, especially to lower calories; (2) rebalancing of essential fatty acid intake away from pro-inflammatory and toward anti-inflammatory prostaglandins; (3) aggressive repletion of glutathione and other nutrient antioxidants and cofactors; (4) energy nutrients acetyl L-carnitine, coenzyme Q10, NADH, and the membrane phospholipid phosphatidylserine (PS), (5) chelation as necessary for heavy metals; and (6) liver P450 detoxification support
Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease.
Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al.
Nature. 2002 Jul 4; 418(6893):50-6.
Parkinson's disease is a widespread condition caused by the loss of midbrain neurons that synthesize the neurotransmitter dopamine. Cells derived from the fetal midbrain can modify the course of the disease, but they are an inadequate source of dopamine-synthesizing neurons because their ability to generate these neurons is unstable. In contrast, embryonic stem (ES) cells proliferate extensively and can generate dopamine neurons. If ES cells are to become the basis for cell therapies, we must develop methods of enriching for the cell of interest and demonstrate that these cells show functions that will assist in treating the disease. Here we show that a highly enriched population of midbrain neural stem cells can be derived from mouse ES cells. The dopamine neurons generated by these stem cells show electrophysiological and behavioural properties expected of neurons from the midbrain. Our results encourage the use of ES cells in cell-replacement therapy for Parkinson's disease
Structural changes in alpha-synuclein affect its chaperone-like activity in vitro.
Kim TD, Paik SR, Yang CH, et al.
Protein Sci. 2000 Dec; 9(12):2489-96.
Alpha-synuclein, a major constituent of Lewy bodies (LBs) in Parkinson's disease (PD), has been implicated to play a critical role in synaptic events, such as neuronal plasticity during development, learning, and degeneration under pathological conditions, although the physiological function of alpha-synuclein has not yet been established. We here present biochemical evidence that recombinant alpha-synuclein has a chaperone-like function against thermal and chemical stress in vitro. In our experiments, alpha-synuclein protected glutathione S-transferase (GST) and aldolase from heat-induced precipitation, and alpha-lactalbumin and bovine serum albumin from dithiothreitol (DTT)-induced precipitation like other molecular chaperones. Moreover, preheating of alpha-synuclein, which is believed to reorganize the molecular surface of alpha-synuclein, increased the chaperone-like activity. Interestingly, in organic solvents, which promotes the formation of secondary structure, alpha-synuclein aggregated more easily than in its native condition, which eventually might abrogate the chaperone-like function of the protein. In addition, alpha-synuclein was also rapidly and significantly precipitated by heat in the presence of Zn2+ in vitro, whereas it was not affected by the presence of Ca2+ or Mg2+. Circular dichroism spectra confirmed that alpha-synuclein underwent conformational change in the presence of Zn2+. Taken together, our data suggest that alpha-synuclein could act as a molecular chaperone, and that the conformational change of the alpha-synuclein could explain the aggregation kinetics of alpha-synuclein, which may be related to the abolishment of the chaperonic-like activity
Cerebellar norepinephrine in patients with Parkinson's disease and control subjects.
Kish SJ, Shannak KS, Rajput AH, et al.
Arch Neurol. 1984 Jun; 41(6):612-4.
Norepinephrine was measured in postmortem cerebellar cortex of 22 non-neurological control subjects and nine patients with Parkinson's disease, using the high-performance liquid chromatography method with amperometric detection. In all control subjects, substantial amounts of norepinephrine was found in cerebellar cortex. There was a moderate negative correlation between age of control subjects and cerebellar norepinephrine concentration. In the patients with Parkinson's disease, the cerebellar cortical norepinephrine levels were significantly below normal. This is in accord with previously reported reduced norepinephrine levels in locus ceruleus and other regions of the parkinsonian brain. Although the main symptoms of Parkinson's disease are primarily caused by disturbed basal ganglia (dopamine) function, cerebellar dysfunction related to norepinephrine may contribute to some abnormalities of motor performance in this disorder
[Histological study on possibility of senile dementia diagnosis in forensic autopsy cases].
Kubo S, Ogata M, Kitamura O, et al.
Nippon Hoigaku Zasshi. 1990 Feb; 44(1):18-24.
Forensic autopsied brains from 57 cases were examined to establish histopathological criteria for normal aging and senile dementia. Senile plaques, neurofibrillary tangles (NFT), amyloid angiopathy and lipofuscin deposits were quantified in the occipital lobe and in the hippocampus. Histopathological data were analysed by the image analyzer. The primitive senile plaque (SPP) and lipofuscin deposits were observed over age of 50. The senile plaque with core (SPC) and NFT were presented in the cases above 70 year of age. There were close correlation between the individual age in non-demented, and the number, size and occupation ratio of SPC in the occipital lobe and hippocampus. In the dementia cases, the occupation ratio of SPC in the hippocampus and the number of SPP in the occipital cortex were significantly increased against the non-demented group
Oral levodopa/carbidopa solution versus tablets in Parkinson's patients with severe fluctuations: a pilot study.
Kurth MC, Tetrud JW, Irwin I, et al.
Neurology. 1993 May; 43(5):1036-9.
Four patients with Parkinson's disease, optimally treated with levodopa/carbidopa (LD/CD) tablets but experiencing severe motor fluctuations, underwent an open trial of a levodopa/carbidopa/ascorbic acid solution (LCAS) orally at timed intervals. LCAS reduced bradykinesia, decreased dysfunctional dyskinesia, and increased functional "on" time when compared with previous LD/CD tablet therapy. Oral LCAS allowed better titration of levodopa dosage and offered a more predictable response than LD/CD tablets. Preparation and oral consumption of LCAS was easy and inexpensive. LCAS may be a practical alternative for patients whose motor fluctuations fail to respond to optimal therapy with LD/CD tablets
[Drug-induced parkinsonism].
Kuzuhara S.
Nippon Rinsho. 1997 Jan; 55(1):112-7.
Drug-induced parkinsonism(DIP) is at present the second most frequent cause of parkinsonism next to idiopathic Parkinson's disease(PD) in Japan. The ratio of the incidence of DIP to PD has been reported to be between 1:2 and 1:5, which varied at the period surveyed. The most frequent causative drugs were calcium-blocking agents, flunarizine and cinnarizine in 1980s, and they have been replaced in recent years by benzamide derivatives with antipsychotic, antiemetic or prokinetic actions, sulpiride, tiapride and metoclopraramide. The clinical features of DIP are similar to those of PD except for rather rapid progression of the symptoms. Careful neurological examination and check of all drugs the patient has taken are important for correct diagnosis. Most causative drugs act as the dopamine D2 receptor blocker in the brain and discontinuance of the drug(s) is necessary for the treatment. Parkinsonian symptoms begin to improve in several weeks and patients are relieved from the symptoms usually within several months
Thiamin mono- and pyrophosphatase activities from brain homogenate of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia patients.
Laforenza U, Patrini C, Poloni M, et al.
J Neurol Sci. 1992 Jun; 109(2):156-61.
Thiamin-pyrophosphatase (TPPase) and thiamin-monophosphatase (TMPase) were determined using a spectrophotometric method at various pH values (5.5, 7.5, and 9.0) in brain tissue obtained at autopsy from amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) patients from Guam and from Guamanian patients who died from other diseases (controls). TPPase separation by thin-layer polyacrylamide gel isoelectric focusing (IEF) was also performed using both gray and white matter. TPPase content, chemically determined at pH 9.0, was found to be significantly reduced in the frontal cortex of ALS and PD patients compared to controls. TMPase content, on the contrary, was unchanged. IEF analysis showed 9 clear-cut bands with TPPase activity in the pH range 5.4-7.2 and a broad band at pH 4.7-5.2. The enzymatic activity was higher in gray than in white matter. In one patient the pattern was clearly different, with two additional bands observed at pH 7.1 and 6.7, and thought to be due to genetic microheterogeneity
Inhibition of brain glycolysis by aluminum.
Lai JC, Blass JP.
J Neurochem. 1984 Feb; 42(2):438-46.
Aluminum inhibited both the cytosolic and mitochondrial hexokinase activities in rat brain. The IC50 values were between 4 and 9 microM. Aluminum was effective at mildly acidic (pH 6.8) or slightly alkaline (pH 7.2-7.5) pH, in the presence of a physiological level of magnesium (0.5 mM). However, saturating (8 mM) magnesium antagonized the effect of aluminum on both forms of hexokinase activity. Other enzymes examined were considerably less sensitive to inhibition by aluminum. The IC50 of aluminum for phosphofructokinase was 1.8 mM and for lactate dehydrogenase 0.4 mM. At 10-600 microM, aluminum actually stimulated pyruvate kinase. Aluminum also inhibited lactate production by rat brain extracts: this effect was much more marked with glucose as substrate than with glucose-6-phosphate. However, the IC50 for inhibiting lactate production using glucose as substrate was 280 microM, higher than that required to inhibit hexokinase. This concentration of aluminum is comparable to those reportedly found in the brains of patients who had died with dialysis dementia and in the brains of some of the patients who had died with Alzheimer disease. Inhibition of carbohydrate utilization may be one of the mechanisms by which aluminum can act as a neurotoxin
Tryptophan deficiency stupor--a new psychiatric syndrome.
Lehmann J.
Acta Psychiatr Scand Suppl. 1982; 300:1-57.
Dehydroepiandrosterone (DHEA) reduces neuronal injury in a rat model of global cerebral ischemia.
Li H, Klein G, Sun P, et al.
Brain Res. 2001 Jan 12; 888(2):263-6.
Introduction: Many studies report an inverse correlation between levels of DHEA and neurological diseases. Exogenous DHEA protects hippocampal neurons against excitatory amino acid induced neurotoxicity. The purpose of this experiment is to evaluate the effect of DHEA in an animal model of transient but severe forebrain ischemia. Methods: At thirteen days prior to induction of ischemia, male Wistar rats were implanted with various doses of DHEA-placebo, 25 mg, 50 mg or 100 mg. Forebrain ischemia was induced for 10 min using a modified four-vessel occlusion technique, with hippocampal neuronal injury assessed at 7 days post-ischemically and expressed as a percentage of total cells. Results: Both normal and necrotic hippoc |