Life Extension Magazine February 2003
PURPOSE: To investigate relationships between use of vitamin supplements and the three principal cataract types in a population-based sample. METHODS: We studied 2873 of the 3654 participants (79%) aged 49 to 97 years attending the cross-sectional Blue Mountains Eye Study who completed a detailed food frequency questionnaire, which included type, dose and duration of vitamin supplement use. Masked grading of nuclear, cortical and posterior subcapsular opacities from lens photographs was performed, using the Wisconsin method. RESULTS: Use of multivitamin supplements was associated with reduced prevalence of nuclear cataract, odds ratio 0.6, 95% confidence interval 0.4 to 1.0, P =.05. For both nuclear and cortical cataract, longer duration of multivitamin use was associated with reduced cataract prevalence (nuclear cataract, trend P =.02; cortical cataract, trend P =.03). Use of thiamin supplements was associated with reduced prevalence of nuclear (odds ratio 0.6, confidence interval 0.4 to 1.0, P =.03, dose trend P =.03) and cortical cataract (odds ratio 0.7, confidence interval 0.5 to 0.9, P =.01, dose trend P =.02). Riboflavin (odds ratio 0.8, confidence interval 0.6 to 1.0, P =.05) and niacin (odds ratio 0.7, confidence interval 0.6 to 1.0, P =.04) supplements exerted a weaker protective influence on cortical cataract. Vitamin A supplements were protective against nuclear cataract (odds ratio 0.4, confidence interval 0.2 to 0.8, P =.01, dose trend P =.01). Folate (odds ratio 0.4, confidence interval 0.2 to 0.9, P =.03) appeared protective for nuclear cataract, whereas both folate (odds ratio 0.6, confidence interval 0.3 to 0.9, P =.01, dose trend P =.04) and vitamin B12 supplements (odds ratio 0.7, confidence interval 0.5 to 1.0, P =.03, dose trend P =.02) were strongly protective against cortical cataract. CONCLUSIONS: Long-term use of multivitamins, B group and vitamin A supplements was associated with reduced prevalence of either nuclear or cortical cataract. A strong protective influence on cortical cataract, from use of folate or vitamin B12 supplements, is a new finding.
Am J Ophthalmol 2001 Jul;132(1):19-26
Serum status of carotenoids and tocopherols in patients with age-related cataracts: a case-control study.
BACKGROUND: Cataract is an important health problem that increase with age, causes decreased visual acuity and constitute a major cause of disability in the elderly. Epidemiological studies have shown that elevated serum levels and/or intake of several antioxidants, such as carotenoids, vitamin E and ascorbic acid, are associated with a diminished risk for cataracts. OBJECTIVE: To assess the serum fat-soluble antioxidant status in patients with cataracts and its relationship with visual function. METHODS: One hundred thirty eight patients with senile cataracts, classified according to visual acuity, and 110 age and sex-matched controls were studied for individual carotenoids and tocopherols in serum by a quality-controlled HPLC method. One-way ANOVA analysis and logistic regression analysis were applied. RESULTS: Higher serum levels of lutein and zeaxanthin were associated as risk factors for cataract while b-cryptoxanthin and g-tocopherol appeared as protective variables. Higher levels of zeaxanthin and lower concentrations of b-cryptoxanthin were associated with cataracts in people < 61y whereas only lower levels of g-tocopherol were shown in subjects > 61y. No significant correlations (adjusted for sex and age) were found between visual acuity and serum concentrations of carotenoids or tocopherols. CONCLUSION: Although the relation between carotenoids and cataracts is biologically plausible, serum carotenoid levels are highly dependent on dietary intake and thus may not be clinically relevant biomakers for cataracts risk.
J Nutr Health Aging 2002;6(1):66-8
Antioxidant systems in rat lens as a function of age: effect of chronic administration of vitamin E and ascorbate.
Oxidative damage occurring in the lenses of patients with senile cataract may be due to partially reduced forms of oxygen. We assayed the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Red), and glucose-6-phosphate dehydrogenase (G6PD) in rat lenses at different ages (1, 4 and 24 months), and also evaluated lens glutathione (GSH) levels and the effects of chronic administration of vitamin E and sodium ascorbate. We observed a significant age-related decrease in GSH-Px, GSH-Red and G6PD activities, but no age-related change in SOD activity. Chronic treatment with both vitamin E and sodium ascorbate failed to restore enzymatic activities to the levels of younger rats. An age-related reduction in GSH content was also observed; however, chronic administration of vitamin E, but not of sodium ascorbate, restored GSH levels to those of younger rats.
Aging (Milano) 1999 Feb;11(1):39-43
Experimental evidence for interactive effects of chronic UV irradiation and nutritional deficiencies in the lens.
The eye lens is subjected to many risk factors over time, which contribute to changes in its transparency, finally leading in combination to cataract development. Ultra violet (UV) radiation is regarded as one of the widespread risk factors contributing to cataract formation, for example in combination with nutritional deficiencies. Both factors possibly contribute to the high number of cataracts in the sunbelt region of the world. In this study, two essential nutritional factors were investigated in Brown Norway rats, zinc and vitamin E deficiencies, alone and in combination with UV-A and UV-B irradiation. Young female Brown Norway rats were put on a special diet for 10 weeks, either highly deficient in zinc or in vitamin E. The diet was otherwise identical to the control diet. Two weeks after putting the animals on the diet, UV irradiation was started in some of the groups with mydriatic pupils with three irradiation sessions per week (UV-A 1 J/cm2; UV-B 0.2 J/cm2). Irradiation was continued until the end of the diet treatment period. Body weight and food consumption were established at weekly intervals, as well as slitlamp microscopy to monitor changes in anterior eye segment morphology. In addition changes in transparency of the cornea and lens have been monitored and evaluated with a Scheimpflug camera (Topcon SL-45) at baseline, and after four and eight weeks of irradiation. After sacrifice of the animals, the lens wet weight as well as the activity of superoxide dismutase (SOD) were determined. Zinc deficiency alone led to an almost complete arrest of body weight increase. In the cornea, UV-A in combination with zinc or vitamin E deficiency did not have any interactive effects. The combination of UV-B and zinc deficiency showed subtractive instead of additive effects on corneal transparency and neovascularization. In the lens both deficiencies positively interacted with UV-A and UV-B by increasing the density of the capsular and cortical layers. The lens fresh weight was significantly lower in zinc-deficient animals additionally irradiated with UV-A or UV-B. The activity of SOD was significantly lower in the lenses of zinc- or vitamin E-deficient animals additionally irradiated with UV-B. The experiments presented clearly demonstrate that dietary zinc and vitamin E deficiencies do interact with UV radiation damage in the cornea and lens of Brown Norway rats.
Dev Ophthalmol 2002;35:113-24
Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of Parkinson's disease.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately 1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 184.108.40.206), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 220.127.116.11), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 18.104.22.168), and complex V (ATP synthase, EC 22.214.171.124). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
Biol Signals Recept 2001 May-Aug;10(3-4):224-53
Age-related changes in the lipid compositions of rat and human tissues.
The levels of cholesterol, ubiquinone, dolichol, dolichyl-P, and total phospholipids in human lung, heart, spleen, liver, kidney, pancreas and adrenal from individuals from one-day-old to 81 years of age were investigated and compared with the corresponding organs from two to 300 day-old rats. The amount of cholesterol in human tissues did not change significantly during aging, but the level of this lipid in the rat was moderately elevated in the organs of the oldest animals. In human pancreas and adrenal the ubiquinone content was highest at one year of age, whereas in other organs the corresponding peak value was at 20 years of age, and was followed by a continuous decrease upon further aging. A similar pattern was observed in the rats, with the highest concentration of ubiquinone being observed at 30 days of age. Dolichol levels in human tissues increase with aging, but they increase to very different extents. In the lungs this increase is seven-fold, and in the pancreas it is 150-fold. The elevation in the dolichol contents of rat tissues ranges from 20 to 30-fold in our material. In contrast, the levels of the phosphorylated derivative of dolichol increased to a more limited extent, i.e., two to six-fold in human tissues and even less in the rat. These results demonstrate that the levels of a number of lipids in human and rat organs are modified in a characteristic manner during the life span. This is in contrast to phospholipids, which constitute the bulk of the cellular lipid mass.
Lipids 1989 Jul;24(7):579-84
Age-related decline in dopamine transporters: analysis of striatal subregions, nonlinear effects and hemispheric asymmetries.
Neuroimaging studies have documented an age-related decline in striatal dopamine transporters (DATs) as a marker of dopaminergic neurodegeneration. The authors further elucidated the effects on this neural system in healthy aging, in contrast to Parkinson disease (PD). The effects of age on striatal DAT availability were examined in a large, healthy subject sample (N=126) with [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT) and single photon emission computed tomography (SPECT). Striatal DAT availability (V3") showed a significant inverse correlation with age, declining in a nearly linear manner by 46% over the age range 18 to 88 years, or 6.6% per decade. Rates of decline were comparable for caudate (48%) and putamen (45%), with only minimal increase in left-right asymmetry with age. Hemispheric asymmetries were unrelated to the handedness of subjects. These results demonstrate that aging is associated with a relatively symmetric loss of DATs in the caudate and putamen in both hemispheres. These findings have implications not only for healthy aging but also for neurodegenerative disorders such as PD.
Am J Geriatr Psychiatry 2002 Jan-Feb;10(1):36-43
Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease.
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.
Nature 2002 Jul 4;418(6893):50-6
Results of chronic subthalamic nucleus stimulation for Parkinson's disease: a 1-year follow-up study.
BACKGROUND: Deep brain stimulation (DBS) has been established as an alternative approach for the treatment of advanced Parkinson's disease (PD). Recently, the subthalamic nucleus (STN) has been identified as the optimal target for DBS. METHODS: Thirty-eight patients have undergone surgery for advanced PD since 1996. They include 12 females and 26 males with a mean age of 55.6 years. The mean stage on the Hoehn and Yahr Scale was 3.5 (off condition). Electrodes (Medtronic DBS 31389) were stereotactically implanted into the STN bilaterally. Targeting was performed using computerized tomography (CT) scans and ventriculography (VG). After four days of external stimulation, permanent neurostimulators were implanted. Patients were evaluated preoperatively and 1, 6 and 12 months postoperatively. Evaluations were performed in defined on and off states using the Unified Parkinson's Disease Rating Scale (UPDRS) as well as the Hoehn and Yahr Scale, the dyskinesia scale, and the Activities of Daily Living (ADL) Scale. RESULTS: Significant improvement of all motor symptoms was found in all patients (UPDRS motor score 32/48 preoperatively versus 15/30 at 12-month follow-up, p < 0.001). Daily off-times were reduced by 35%. Dyskinesias also improved markedly (UPDRS IV: 3.2/3.1 [on/off] vs. 0.9/1.3 at 12 months follow-up). Postoperative L-dopa medication was adjusted (mean reduction: 53%). Complications occurred in two patients (5%) who developed infections, leading to system removal. Systems were replaced after six months. Two patients (5%) had a permanent worsening of a previously known depressive state and developed progressive dementia. CONCLUSIONS: TN stimulation is a relatively safe procedure for treating advanced PD. The possibility of readjusting the stimulation parameters postoperatively improves the therapeutic outcome and reduces side effects in comparison to ablative methods.
Surg Neurol 2002 May;57(5):306-11; discussion 311-3
Novel physical treatments for the management of neuropsychiatric disorders.
OBJECTIVE: To briefly describe the novel non-drug physical interventions currently in use in the investigation and treatment of neuropsychiatric disorders regarding their efficacy and potential future applications. METHODS: A systematic review of the literature concerning transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), vagus nerve stimulation (VNS) and neurosurgery for mental disorders (NMD) was conducted using Medline and literature known to the authors. RESULTS: A summary of each procedure is provided giving a succinct overview of efficacy, current applications and possible future indications. CONCLUSION: Novel and innovative physical interventions are currently being used to study brain function in health and disease. In particular, TMS has quickly established itself as a useful investigational tool and is emerging as a possible antidepressant therapy. Similarly, VNS has been applied successfully in the management of intractable epilepsy and is undergoing evaluation in the management of patients with treatment-resistant depression. DBS has shown significant promise in the treatment of Parkinson's disease and may have use in the management of obsessive-compulsive disorder. Finally, neurosurgical procedures for the treatment of mental disorders have been sufficiently refined to stage a comeback, although rigorous scientific study of their efficacy and indications is still necessary.
J Psychosom Res 2002 Aug;53(2):709-19
Subthalamic GAD gene therapy in a Parkinson's disease rat model.
The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.
Science 2002 Oct 11;298(5592):425-9
Distribution of coenzyme Q homologues in brain.
Ubiquinone (coenzyme Q10), in addition to its function as an electron and proton carrier in mitochondrial electron transport coupled to ATP synthesis, acts in its reduced form (ubiquinol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and protecting mitochondrial inner-membrane proteins and DNA against oxidative damage accompanying lipid peroxidation. Tissue ubiquinone levels are subject to regulation by physiological factors that are related to the oxidative activity of the organism: they increase under the influence of oxidative stress, e.g. physical exercise, cold adaptation, thyroid hormone treatment, and decrease during aging. In the present study, coenzyme Q homologues were separated and quantified in the brains of mice, rats, rabbits and chickens using high-performance liquid chromatography. In addition, the coenzyme Q homologues were measured in cells such as NG-108, PC-12, rat fetal brain cells and human SHSY-5Y and monocytes. In general, Q1 content was the lowest among the coenzyme homologues quantified in the brain. Q9 was not detectable in the brains of chickens and rabbits, but was present in the brains of rats and mice. Q9 was also not detected in human cell lines SHSY-5Y and monocytes. Q10 was detected in the brains of mice, rats, rabbits, and chickens and in cell lines. Since both coenzyme Q and vitamin E are antioxidants, and coenzyme Q recycles vitamins E and C, vitamin E was also quantified in mice brain using HPLC-electrochemical detector (ECD). The quantity of vitamin E was lowest in the substantia nigra compared with the other brain regions. This finding is crucial in elucidating ubiquinone function in bioenergetics; in preventing free radical generation, lipid peroxidation, and apoptosis in the brain; and as a potential compound in treating various neurodegenerative disorders.
Neurochem Res 2002 May;27(5):359-68
Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.
BACKGROUND: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. OBJECTIVE: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. DESIGN: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. SETTING: Academic movement disorders clinics. PATIENTS: Eighty subjects with early PD who did not require treatment for their disability. INTERVENTIONS: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12- and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. RESULTS: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04). CONCLUSIONS: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.
Arch Neurol 2002 Oct;59(10):1541-50
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