Molecular characterization of monoamine oxidases
A and Bi.
Abell CW, Kwan SW. Prog Nucleic Acid Res Mol Biol. 2001; 65:129-56. Monoamine oxidase A and B (MAO A and B) are the major neurotransmitter-degrading enzymes in the central nervous system and in peripheral tissues. MAO A and B cDNAs from human, rat, and bovine species have been cloned and their deduced amino acid sequences compared. Comparison of A and B forms of the enzyme shows approximately 70% sequence identity, whereas comparison of the A or B forms across species reveals a higher sequence identity of 87%. Within these sequences, several functional regions have been identified that contain crucial amino acid residues participating in flavin adenine dinucleotide (FAD) or substrate binding. These include a dinucleotide-binding site, a second FAD-binding site, a fingerprint site, the FAD covalent-binding site, an active site, and the membrane-anchoring site. The specific residues that play a role in FAD or substrate binding were identified by comparing sequences in wild-type and variants of MAO with those in soluble flavoproteins of known structures. The genes that encode MAO A and B are closely aligned on the X chromosome (Xp11.23), and have identical exon-intron organization. Immunocytochemical localization studies of MAO A and B in primate brain showed distribution in distinct neurons with diverse physiological functions. A defective MAO A gene has been reported to associate with abnormal aggressive behavior. A deleterious role played by MAO B is the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a proneurotoxin that can cause a parkinsonian syndrome in mammals. Deprenyl, an inhibitor of MAO B, has been used for the treatment of early-stage Parkinson's disease and provides protection of neurons from age-related decay
The biology of folate in depression: implications for nutritional hypotheses of the psychoses. Abou-Saleh MT, Coppen A. J Psychiatr Res. 1986; 20(2):91-101. Folate deficiency is a common occurrence in psychiatric disorders, whether organic or functional, particularly in depressive illness. We have shown that folate deficiency is a common association of depressive symptoms in a variety of settings including primary endogenous or non-endogenous depression, and in alcoholic, lithium-treated and anorexic patients. Possible pathogenetic mediating mechanisms for this association are methylation and hydroxylation and the implications for nutritional hypotheses of the psychoses are discussed. We suggest that folate deficiency, with or without deficiencies of other nutritional factors such as monoamine precursors, vitamins B6, B12 and C, may predispose to or aggravate psychiatric disturbances, particularly depression and a model for these interactions is proposed
The effect of meclofenoxate with ginkgo biloba extract or zinc on lipid peroxide, some free radical scavengers and the cardiovascular system of aged rats. al Zuhair H, Abd el-Fattah A, el Sayed MI. Pharmacol Res. 1998 Jul; 38(1):65-72. Aged rats are highly prone to many physiological changes such as blood pressure and heart rate. These changes could be due to modification in membrane phospholipid composition of their blood vessels. Lipid peroxide in vivo has been identified as a basic deteriorative reaction in cellular mechanisms of aging in human. The effect of a nootropic drug, meclofenoxate (MF) or its combination with extract of ginkgo biloba (EGb-761) or zinc (Zn) on malondialdehyde (MDA) product as an index of endogenous lipid peroxidation; phospholipid; glutathione (GSH) and protein thiols (PrSHs) contents as well as superoxide dismutase (SOD) activity in blood, brain, heart and liver of 24-month-old male rats was investigated. Aged rats were treated with MF once daily at oral doses of 100 mg kg-1 body wt. alone or with either EGb at a dose of 150 mg kg-1 body wt. or Zn at 10.5 mg kg-1 body wt. for 4 weeks. This study showed that aging caused a higher increment in MDA level of brain and heart than liver and plasma accompanied with reduction in brain and heart phospholipid contents as well as alteration of the antioxidant systems as compared to 4-month-old rats. Treatment of aged rats with MF alone or combined with either EGb or Zn caused improvement in the measured free radical scavengers especially in brain and heart tissues. Our results also showed that both EGb and Zn induced a significant potential effect of MF action on blood pressure and heart rate. The results were explained in the light of the antioxidant properties of EGb and Zn. Thus it is concluded that EGb and Zn have a beneficial role with MF in diminishing cumulative oxidative changes in aging
Selegiline treatment and the extent of degenerative changes in brain tissue of patients with Alzheimer's disease. Alafuzoff I, Helisalmi S, Heinonen EH, et al. Eur J Clin Pharmacol. 2000 Feb; 55(11-12):815-9. BACKGROUND: A beneficial effect of selegiline (L-deprenyl) in Alzheimer's disease (AD) has been reported in several clinical studies. METHODS: The brain tissue from 17 deceased patients, members of a double-blind clinical trial to assess the potential benefit of selegiline in AD, were analysed. FINDINGS: In our study, the decrease in the Mini-Mental State Examination (MMSE) scores during the progress of the disease had been significantly influenced by selegiline treatment. Prior to death, the MMSE scores were significantly higher in those patients receiving selegiline than in those receiving placebo. However, according to our results, none of the lesions critical for AD diagnosis, such as counts of senile/neuritic plaques, neurofibrillary tangles or beta-A4 load, were influenced by the selegiline treatment. INTERPRETATION: In conclusion, according to our study, mechanisms other than neuronal degeneration seen as lesions critical for AD diagnosis are influenced by selegiline treatment, leading to the functional benefit found in AD
Effects of long-term Hydergine administration on lipofuscin accumulation in senescent rat brain. Amenta D, Ferrante F, Franch F, et al. Gerontology. 1988; 34(5-6):250-6. The effects of ageing and of 6 months of Hydergine treatment on lipofuscin deposition within the cytoplasma of pyramidal neurons of rat prefrontal cortex, hippocampus (fields CA1 and CA3) and of Purkinje neurons were assessed microfluorimetrically. No lipofuscin autofluorescence was detected in the nerve cell populations of 3-month-old rats, but lipopigment had accumulated in nerve cell bodies of 16-month-old animals and increased significantly thereafter in rats of 22 months of age. In 22-month-old rats, Hydergine administration (0.6 and 1 mg/kg p.o.) started at 16 months caused a significant dose-related decrease in lipofuscin accumulation within the cytoplasm of the various kinds of nerve cells examined
Effect of long-term feeding with acetyl-L-carnitine on the age-related changes in rat brain lipid composition: a study by 31P NMR spectroscopy. Aureli T, Di Cocco ME, Capuani G, et al. Neurochem Res. 2000 Mar; 25(3):395-9. Changes in brain lipid composition have been determined in 24 months-old Fischer rats with respect to 6 months-old ones. The cerebral levels of sphingomyelin and cholesterol were found to be significantly increased in aged rats, whereas the amount of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid appear to be unaffected by aging. Long-term feeding with acetyl-L-carnitine was able to reduce the age-dependent increase of both sphingomyelin and cholesterol cerebral levels with no effect on the other measured phospholipids. These findings shown that changes in membrane lipid metabolism and/or composition represent one of the alterations occurring in rat brain with aging, and that long-term feeding with acetyl-L-carnitine can be useful in normalizing these age-dependent disturbances
A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. Balestreri R, Fontana L, Astengo F. J Am Geriatr Soc. 1987 May; 35(5):425-30. In a double-blind clinical trial, vinpocetine, a synthetic ethyl ester of apovincamine, was shown to effect significant improvement in elderly patients with chronic cerebral dysfunction. Forty-two patients received 10 mg vinpocetine three times a day (tid) for 30 days, then 5 mg tid for 60 days. Matching placebo tablets were given to another 42 patients for the 90 day trial period. Patients on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment including measurements on the Clinical Global Impression (CGI) scale, the Sandoz Clinical Assessment-Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to the treatment drug
Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Bartus RT, Dean RL, III, Sherman KA, et al. Neurobiol Aging. 1981; 2(2):105-11. In an attempt to gain some insight into possible approaches to reducing age-related memory disturbances, aged Fischer 344 rats were administered either vehicle, choline, piracetam or a combination of choline or piracetam. Animals in each group were tested behaviorally for retention of a one trial passive avoidance task, and biochemically to determine changes in choline and acetylcholine levels in hippocampus, cortex and striatum. Previous research has shown that rats of this strain suffer severe age-related deficits on this passive avoidance task and that memory disturbances are at least partially responsible. Those subjects given only choline (100 mg/kg) did not differ on the behavioral task from control animals administered vehicle. Rats given piracetam (100 mg/kg) performed slightly better than control rats (p less than 0.05), but rats given the piracetam/choline combination (100 mg/kg of each) exhibited retention scores several times better than those given piracetam alone. In a second study, it was shown that twice the dose of piracetam (200 mg/kg) or choline (200 mg/kg) alone, still did not enhance retention nearly as well as when piracetam and choline (100 mg/kg of each) were administered together. Further, repeated administration (1 week) of the piracetam/choline combination was superior to acute injections. Regional determinations of choline and acetylcholine revealed interesting differences between treatments and brain area. Although choline administration raised choline content about 50% in striatum and cortex, changes in acetylcholine levels were much more subtle (only 6-10%). No significant changes following choline administration were observed in the hippocampus. However, piracetam alone markedly increased choline content in hippocampus (88%) and tended to decrease acetylcholine levels (19%). No measurable changes in striatum or cortex were observed following piracetam administration. The combination of choline and piracetam did not potentiate the effects seen with either drug alone, and in certain cases the effects were much less pronounced under the drug combination. These data are discussed as they relate to possible effects of choline and piracetam on cholinergic transmission and other neuronal function, and how these effects may reduce specific memory disturbances in aged subjects. The results of these studies demonstrate that the effects of combining choline and piracetam are quite different than those obtained with either drug alone and support the notion that in order to achieve substantial efficacy in aged subjects it may be necessary to reduce multiple, interactive neurochemical dysfunctions in the brain, or affect activity in more than one parameter of a deficient metabolic pathway
[Effectiveness of the preparation Gavinton in preventing motion sickness]. Bodo D, Kotovskaia AR, Galle RR, et al. Kosm Biol Aviakosm Med. 1982 May; 16(3):49-51. The effectiveness of the Hungarian drug kavinton used to prevent motion sickness was assessed. During the study 8 motion sickness susceptible test subjects were kept in a chamber rotating at a rate of 6 rpm for 5 hours. The effectiveness of the drug taken regularly during the exposure was compared with that of scopolamine and placebo taken as a single dose. The results obtained are suggestive of a positive effect of kavinton as an antimotion drug
Biochemical and behavioural effects of hypoxic hypoxia in rats: study of the protection afforded by ergot alkaloids. Boismare F, Le Poncin M, Lefrancois J. Gerontology. 1978; 24 Suppl 1:6-13. The conditioned avoidance response and the cerebral levels of dopamine and noradrenaline have been studied in control rats and in rats submitted to a hypobaric hypoxia. A protection against the effects of hypoxia was induced by both dihydroergocornine (20 microgram/kg) and dihydroergocryptine (100 microgram/kg), and the noradrenaline level did not decrease. This stabilization of cerebral noradrenaline level seems to be the main protection factor observed
Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Bonoczk P, Gulyas B, Adam-Vizi V, et al. Brain Res Bull. 2000 Oct; 53(3):245-54. Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients
Acetyl L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Brooks JO, III, Yesavage JA, Carta A, et al. Int Psychogeriatr. 1998 Jun; 10(2):193-203. OBJECTIVES: To assess the longitudinal effects of acety-L-carnitine (ALC) on patients diagnosed with Alzheimer's disease. DESIGN: Longitudinal, double-blind, parallel-group, placebo-controlled. SETTING: Twenty-four outpatient sites across the United States. PARTICIPANTS: A total of 334 subjects diagnosed with probable Alzheimer's disease by NINCDS-ADRDA criteria. These data were originally reported by Thal and colleagues (1996). MEASUREMENTS: Cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) given every 3 months for 1 year. RESULTS: The average rate of change was estimated using the trilinear approach, which allows for periods of both change and stability. Both the ALC group and the placebo group exhibited the same mean rate of change on the ADAS (0.68 points/month). However, a multiple regression analysis revealed a statistically significant Age x Drug interaction characterized by younger subjects benefiting more from ALC, significant, cutpoint for ALC benefit was 61 years of age. CONCLUSIONS: ALC slows the progression of Alzheimer's disease in younger subjects, and the use of the trilinear approach to estimate the average rate of change may prove valuable in pharmacological trials
Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study. Buchman AL, Sohel M, Brown M, et al. JPEN J Parenter Enteral Nutr. 2001 Jan; 25(1):30-5. BACKGROUND: Previous investigations have demonstrated that choline deficiency, manifested in low plasma-free choline concentration and hepatic injury, may develop in patients who require long-term total parenteral nutrition (TPN). Preliminary studies have suggested lecithin or choline supplementation might lead to improved visual memory in the elderly and reverse abnormal neuropsychological development in children. We sought to determine if choline-supplemented TPN would lead to improvement in neuropsychological test scores in a group of adult, choline-deficient outpatients receiving TPN. METHODS: Eleven subjects (8 males, 3 females) who received nightly TPN for more than 80% of their nutritional needs for at least 12 weeks before entry in the study were enrolled. Exclusion criteria included active drug abuse, mental retardation, cerebral vascular accident, head trauma, hemodialysis or peritoneal dialysis, (prothrombin time [PT] >2x control), or acquired immune deficiency syndrome (AIDS). Patients were randomly assigned to receive their usual TPN regimen (n = 6, aged 34.0 +/- 12.6 years) over a 12-hour nightly infusion or their usual TPN regimen plus choline chloride (2 g) (n = 5, aged 37.3 +/- 7.3 years). The following neuropsychological tests were administered at baseline and after 24 weeks of choline supplementation (or placebo): Weschler Adult Intelligence Scale-Revised (WAIS-R, intellectual functioning), Weschler Memory Scale-Revised (WMS-R, two subtests, verbal and visual memory), Rey-Osterrieth Complex Figure Test (visuospatial functioning and perceptual organization), Controlled Oral Word Association Test (verbal fluency), Grooved Pegboard (manual dexterity and motor speed), California Verbal Learning Test (CVLT, rote verbal learning ability), and Trail Making Parts A & B (visual scanning, psychomotor speed and set shifting). Scores were reported in terms of standard scores including z scores and percentile ranks. Mean absolute changes in raw scores were compared between groups using the Wilcoxon rank sum test, where p values < .05 constituted statistical significance. RESULTS: Significant improvements were found in the delayed visual recall of the WMS-R (7.0 +/- 2.7 vs -.33 +/- 5.7, p = ".028)," and borderline improvements in the List B subset of the CVLT (1.0 +/- 0.8 vs -2.0 +/- 2.4, p = ".06)" and the Trails A test (-3.8 +/- 8.1 vs 3.7 +/- 4.5 seconds, p = ".067)." No other statistically significant changes were seen. CONCLUSIONS: This pilot study indicates both verbal and visual memory may be impaired in patients who require long-term TPN and both may be improved with choline supplementation
[Etiopathogenesis and curative treatment of skin ulcer in intermediate beta-thalassemia]. Cacace E, Manconi E, Binaghi F, et al. Ann Ital Med Int. 1986 Mar; 1(1):47-53.
[Cerebral blood flow and metabolism, and neurologic deficit in an experimental infarction. Application to the study of an ergot derivative]. Cahn J, Borzeix MG. Presse Med. 1983 Dec 29; 12(48):3058-60. Both age and hypertension are risk factors for the brain. In the presence of a multiple cerebral infarction as obtained by the intra-carotid injection of sodium arachidonate, Hydergine is capable, in the young and old, hypertensive or normotensive rat, of limiting the extent of the edematous reaction, to prevent the intra-cerebral accumulation of Ca++ ions, and limit the fall in cerebral blood flow, all of these facts resulting in a significant improvement in neuromotor behaviour
Repeated injections of piracetam improve spatial learning and increase the stimulation of inositol phospholipid hydrolysis by excitatory amino acids in aged rats. Canonico PL, Aronica E, Aleppo G, et al. Funct Neurol. 1991 Apr; 6(2):107-11. Repeated injections of piracetam (400 mg/kg, i.p. once a day for 15 days) to 16-month old rats led to an improved performance on an 8-arm radial maze, used as a test for spatial learning. This effect was accompanied by a greater ability of excitatory amino acids (ibotenate and glutamate) to stimulate [3H]inositol-monophosphate formation in hippocampal slices incubated in the presence of 10 mM Li+. Repeated administration of piracetam did not induce changes in excitatory amino acid-stimulated polyphosphoinositide hydrolysis in hippocampal slices prepared from 2-month old animals
Levodopa or dopamine agonists or Deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study. Caracena TMM. Parkinsonism Rel Disord. 2001 7(2):107-14.
Subtle cobalamin deficiency. Carmel R. Ann Intern Med. 1996 Feb 1; 124(3):338-40.
Testosterone supplementation improves spatial and verbal memory in healthy older men. Cherrier MM, Asthana S, Plymate S, et al. Neurology. 2001 Jul 10; 57(1):80-8. OBJECTIVE: To determine the relationship between exogenous testosterone administration and cognitive abilities in a population of healthy older men. BACKGROUND: Serum levels of total and bioavailable testosterone gradually decrease with age in men and are associated with reductions in muscle mass, osteoporosis, decreased sexual activity, and changes in cognition. METHODS: Twenty-five healthy, community-dwelling volunteers, aged 50 to 80 years, completed a randomized, double-blind, placebo-controlled study. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Cognitive evaluations were conducted at baseline, week 3, and week 6 of treatment by use of a battery of neuropsychologic tests. RESULTS: Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Because of aromatization of testosterone, estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. Significant improvements in cognition were observed for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) in older men treated with testosterone compared with baseline and the placebo group, although improvements were not evident for all measures. CONCLUSIONS: The results suggest that short-term testosterone administration enhances cognitive function in healthy older men. However, it remains unclear whether these improvements in cognition are attributable to increased testosterone or estradiol levels, or both. The potential role of testosterone vs its metabolites on cognition requires further research
Memory decline in healthy older people: implications for identifying mild cognitive impairment. Collie A, Maruff P, Shafiq-Antonacci R, et al. Neurology. 2001 Jun 12; 56(11):1533-8. BACKGROUND: Criteria for mild cognitive impairment require objective evidence of a memory deficit but do not require objective evidence of memory decline. Application of these criteria may therefore result in the misclassification of older patients with memory decline as normal because their neuropsychological test performance at a single point in time may be within normal limits. This study aimed to identify and characterize older people with memory decline. METHOD: Word list delayed recall (WLDR) test performance was assessed on five occasions during a 2-year period in a cohort of healthy older individuals. Older people with declining (n = 35) and nondeclining (n = 66) WLDR scores were identified. Both subgroups were then compared on apoE genotype, Clinical Dementia Rating, and neuropsychological test performance at the fifth assessment. RESULTS: Thirty-four percent of the group with declining memory recorded a Clinical Dementia Rating of 0.5, compared with 5% of the nondeclining memory group. No between-group differences were observed in cognitive domains other than memory, self-reported cognitive failures, or the proportion of each group carrying the apoE epsilon 4 allele. CONCLUSIONS: A large proportion of healthy older individuals show memory decline, which may represent the early stages of a potentially more severe cognitive impairment. Further investigation is necessary to determine the relationship between apoE genotype, self-reported cognitive impairment, and memory decline in older people
Pregnenolone sulfate increases hippocampal acetylcholine release and spatial recognition. Darnaudery M, Koehl M, Piazza PV, et al. Brain Res. 2000 Jan 3; 852(1):173-9. The pregnenolone sulfate is a neurosteroid with promnesic properties. Recently, a correlation between endogenous levels of pregnenolone sulfate in the hippocampus and performance in a spatial memory task has been reported in aged rats. Cholinergic transmission is known to modulate memory processes and to be altered with age. In the present experiment we investigated the effect of increasing doses of pregnenolone sulfate on hippocampal acetylcholine release. Our results show that intracerebroventricular administrations of this neurosteroid induced a dose-dependent increase in acetylcholine release. Administration of 12 and 48 nmol of pregnenolone sulfate induced a short lasting (20 min) enhancement of acetylcholine output with a maximum around 120% over baseline and the administration of 96 and 192 nmol doses induced a long-lasting (80 min) increase that peaked around 300% over baseline. In a second experiment we have observed that the 12 nmol dose enhanced spatial memory performance, whereas the 192 nmol dose was inefficient. These results are consistent with previous work suggesting that, a modest increase in acetylcholine release facilitates memory processes, while elevation beyond an optimal level is ineffective. Nevertheless, neurosteroids may be of value for reinforcing depressed cholinergic transmission in certain age-related memory disorders
Predictors of brain morphology for the men of the NHLBI twin study. DeCarli C, Miller BL, Swan GE, et al. Stroke. 1999 Mar; 30(3):529-36. BACKGROUND AND PURPOSE: Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy, accumulation of abnormal cerebral white matter signals, and clinically silent stroke. We extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy, amount of abnormal white matter, and stroke on MRI. METHODS: Subjects were the 414 surviving members of the prospective National Heart, Lung, and Blood Institute Twin Study, who have been examined on 4 separate occasions, spanning the 25 years between 1969-1973 and 1995-1997. Quantitative measures of brain volume, volume of abnormal white matter signal (WMHI), and volume of stroke, when present, were obtained from those participating in the fourth examination. RESULTS: The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72. 5+/-2.9 years at final examination. Average blood pressure (BP) levels were normal, although 32% of the subjects had received or were currently taking antihypertensive medications. As a group, 31% had symptomatic cardiovascular disease, 11% had symptomatic cerebrovascular disease, and 8% had symptomatic peripheral vascular disease. Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume. Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes. In addition, the magnitude of orthostatic BP change was significantly associated with WMHI volume. Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease, without significant differences in the prevalence of hypertension treatment. CONCLUSIONS: Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease. Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease, extensive WMHI may be a subclinical expression of cerebrovascular disease. Careful treatment of midlife BP elevations may diminish these later-life brain changes
Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. DeFeudis FV, Drieu K. Curr Drug Targets. 2000 Jul; 1(1):25-58. The effects of EGb 761 on the CNS underlie one of its major therapeutic indications; i.e., individuals suffering from deteriorating cerebral mechanisms related to age-associated impairments of memory, attention and other cognitive functions. EGb 761 is currently used as symptomatic treatment for cerebral insufficiency that occurs during normal ageing or which may be due to degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory disturbances. Depressive symptoms of patients with Alzheimer's disease (AD) and aged non-Alzheimer patients may also respond to treatment with EGb 761 since this extract has an "anti-stress" effect. Basic and clinical studies, conducted both in vitro and in vivo, support these beneficial neuroprotective effects of EGb 761. EGb 761 has several major actions; it enhances cognition, improves blood rheology and tissue metabolism, and opposes the detrimental effects of ischaemia. Several mechanisms of action are useful in explaining how EGb 761 benefits patients with AD and other age-related, neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and free radical-scavenging activities, it reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A and muscarinic receptors, protects against ischaemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity, and counteracts the cognitive deficits that follow stress or traumatic brain injury. Identified chemical constituents of EGb 761 have been associated with certain actions. Both flavonoid and ginkgolide constituents are involved in the free radical-scavenging and antioxidant effects of EGb 761 which decrease tissue levels of reactive oxygen species (ROS) and inhibit membrane lipid peroxidation. Regarding EGb 761-induced regulation of cerebral glucose utilization, bilobalide increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels, a result that is supported by the finding that bilobalide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase. With regard to its "anti-stress" effect, EGb 761 acts via its ginkgolide constituents to decrease the expression of the peripheral benzodiazepine receptor (PBR) of the adrenal cortex
Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Deijen JB, van der Beek EJ, Orlebeke JF, et al. Psychopharmacology (Berl). 1992; 109(4):489-96. This study evaluates the effects of vitamin B-6 supplementation (20 mg pyridoxine HCL daily for 3 months) on mood and performance in 38 self-supporting healthy men, aged between 70-79 years. Effects were compared with 38 controls who received placebo and were matched for age, plasma pyridoxal-5'-phosphate (PLP) concentration and intelligence score. Before and after drug intervention vitamin B-6 status was determined, and mood and performance were measured by means of a computerized testing system. In addition, the phasic pupil response was measured in order to assess mental effort. Positive effects of vitamin B-6 supplementation were only found with respect to memory, especially concerning long-term memory. In view of the finding that mental performance improvement and delta PLP values were most strongly correlated within an intermediate range of delta PLP, it is suggested that cognitive effects are primarily associated with a certain range of vitamin B-6 status increment. The general conclusion is that vitamin B-6 supplementation improves storage of information modestly but significantly
An ergot preparation (hydergine) in the treatment of cerebrovascular disorders in the geriatric patient: double-blind study. Ditch M, Kelly FJ, Resnick O. J Am Geriatr Soc. 1971 Mar; 19(3):208-17.
Effect of selegiline on cognitive functions in Parkinson's disease. Dixit SN, Behari M, Ahuja GK. J Assoc Physicians India. 1999 Aug; 47(8):784-6. BACKGROUND: Selegiline hydrochloride, a selective MAO-B inhibitor is known to improve motor functions in Parkinson's disease (PD). The present study was undertaken to study the effect of selegiline on memory and intelligence of PD patients. MATERIAL AND METHOD: Thirty two patients of PD were divided in two groups: selegiline group (n = 17) received 10 mg selegiline per day and control group (n = 15) did not receive selegiline. Patients receiving trihexyphenidyl and selegiline were excluded. All other treatment remained unchanged. All patients were examined at baseline and after three months for change in UPDRS score, WAIS score, memory test and P300. RESULTS: Patients in selegiline group had less severe disease (UPDRS score 24.11 +/- 14.07) as compared to controls (UPDRS score 40.53 +/- 18.52). There was significant improvement in UPDRS score (p < 0.05), WAIS (p < 0.001) and memory (p < 0.001) in selegiline group. In the control group there was a significant prolongation of P300 latency (p < 0.05). CONCLUSION: The study suggests that selegiline improves memory functions and intelligence in PD patients in addition to motor functions. It also prevents prolongation of P300 latency which is a marker of cognitive function
SPECT monitoring of improved cerebral blood flow during long-term treatment of elderly patients with nootropic drugs. Dormehl IC, Jordaan B, Oliver DW, et al. Clin Nucl Med. 1999 Jan; 24(1):29-34. PURPOSE: In normal aging persons, oxygen and glucose consumption progressively decreases with reduced cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A data processing model with the use of Tc-99m SPECT of the human brain has been developed and found to be sensitive for monitoring the effects of drugs that increase CBF. In this study, the effect of two vasodilator drugs (the combination of pentifylline and nicotinic acid versus piracetam) was compared with the effect of placebo on CBF. MATERIALS AND METHODS: Thirty elderly volunteers had three different procedures using the Peelproc method to spatially standardize and compare CBF patterns by SPECT before and after drug intervention. The 30 patients were divided into five groups of six persons each who were randomly assigned in a 1:1 ratio to the treatment sequences consisting of three phases: the combination of pentifylline and nicotinic acid (C), piracetam (N), and placebo (P), or C-N-P; P-N-C; P-C-N; N-C-P; C-P-N; or N-P-C. Phases 1 to 3 each consisted of a baseline recording of parameters (day 0), treatment for 60 days (days 1 to 60), and recording of parameters after treatment (day 61). RESULTS: In elderly human volunteers (ages, 52 to 70 years), after 2 months of oral treatment with a combination of pentifylline and nicotinic acid (800 mg pentifylline, 200 mg nicotinic acid daily), SPECT results for the Peel-proc program indicated a statistically significant improvement in CBF of the total brain, with a more pronounced improvement in the cerebellum and frontal regions, where a definite shift from abnormal to normal blood flow was detected. Spontaneous communication from most of the volunteers suggested that they experienced an improvement in memory and general well-being from the combination treatment. After 2 months of oral treatment with piracetam (2.4 g daily) in elderly human volunteers, SPECT results indicated a regional improvement in CBF, particularly in the cerebellum. However, no beneficial effects with this drug were spontaneously reported. CONCLUSION: The in vivo method to quantitatively monitor the progress of long-term drug therapy on CBF described here could be useful to assess and even direct changes in therapy
[Cavinton in the prevention of the convulsive syndrome in children after birth injury]. Dutov AA, Gal'tvanitsa GA, Volkova VA, et al. Zh Nevropatol Psikhiatr Im S S Korsakova. 1991; 91(8):21-2. The authors studied the efficacy of cavinton as an agent helpful in preventing neurologic disorders in the newborn with hypoxic ischemic encephalopathy due to intracranial birth trauma. The short-term results of the treatment were elucidated in 61 children. In group I including 20 persons given conventional therapy, the disappearance of seizures was recorded in 6 patients; out of 41 children (group II) given additionally cavinton, in 27. Twenty-nine children were followed up for a year. In group I, convulsive paroxysms recurred in 4 patients, whereas in the group II children, no convulsive syndrome was recorded on the follow-up. The group II children also showed a decrease of the phenomena of intracranial hypertension and normalization of the psychomotor development. The preventive effect of cavinton seen in children with a history of birth trauma may be accounted for by its capacity of normalizing cerebrovascular disorders and by its own anticonvulsive properties
The actions of Hydergine on the brain. A histochemical, circulatory and neurophysiological study. Emmenegger H, Meier-Ruge W. Pharmacology. 1968; 1(1):65-78.
Enhancement of brain choline levels by nicotinamide: mechanism of action. Erb C, Klein J. Neurosci Lett. 1998 Jun 19; 249(2-3):111-4. Following the subcutaneous (s.c.) administration of nicotinamide (10 mmol/kg), the brain and CSF levels of nicotinamide were increased to millimolar concentrations, but the concentrations of N-methylnicotinamide (NMN) in the CSF, and of NMN and NAD+ in brain tissue were not significantly altered. Concomitantly, nicotinamide caused increases of the choline levels in the venous brain blood. In hippocampal slices, nicotinamide (1-10 mM) induced choline release in a calcium- and mepacrine-sensitive manner and, in [3H]choline-labelled slices, increased the levels of [3H]lyso-phosphatidylcholine and [3H]glycerophosphocholine. We conclude that nicotinamide enhances brain choline concentrations by mobilising choline from choline-containing phospholipids, presumably via activation of phospholipase A2, while the formation of NMN does not contribute to this effect
Vinpocetin protects against excitotoxic cell death in primary cultures of rat cerebral cortex. Erdo SL, Cai NS, Wolff JR, et al. Eur J Pharmacol. 1990 Oct 23; 187(3):551-3. The protective effect of vinpocetin, a drug clinically useful in brain hypoxia/ischemia, was examined in vitro on cerebrocortical cultures treated with glutamate and related excitotoxins. The extent of cell death was quantified by measuring lactic dehydrogenase activity released from damaged cells into the culture medium. Vinpocetin partially protected the cortical cells against cell death induced by N-methyl-D-aspartate, quisqualate and kainate, indicating that the drug exerts a direct protective action on cerebrocortical cells bearing excitatory amino acid receptors
Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus. Farr SA, Banks WA, Morley JE. Brain Res. 2000 May 12; 864(2):263-9. There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by enhancing cholinergic and glutamatergic activity. In the present studies, we examined the effects of administration into the hippocampus of 17 beta-estradiol and estrone on retention of T-maze footshock avoidance in female ovariectomized mice. Both 17 beta-estradiol and estrone improved retention on an equimolar basis in a dose-dependent fashion. We then used the T-maze footshock paradigm to test whether a dose of 17 beta-estradiol ineffective as a single injection (subthreshold) could potentiate the effects of arecoline, a cholinergic agonist, or L-glutamate, a glutamatergic agonist, on retention. The dose of either arecoline or L-glutamate needed to improve retention was reduced at least ten-fold by the low dose of 17 beta-estradiol. These findings support the concept that estrogen improves memory by potentiating the activity of the cholinergic and glutamatergic systems
Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits. Fioravanti MFE. Arch Gerontol Geriatr. 1997; 26(1):1-13.
Effect of vinpocetine on noradrenergic neurons in rat locus coeruleus. Gaal L, Molnar P. Eur J Pharmacol. 1990 Oct 23; 187(3):537-9. Conventional extracellular single unit recordings were used to investigate the effect of vinpocetine on locus coeruleus noradrenergic neurons in chloral hydrate-anesthetized rats. Vinpocetine produced a significant and dose-dependent increase in the firing rate of locus coeruleus neurons (ED30 = 0.75 mg/kg i.v.) up to 1 mg/kg i.v., followed by a complete blockade of spiking activity at doses higher than this. The effective dose range was in very good agreement with the dose range corresponding to the memory-enhancing effects of the compound. Our results supplied direct electrophysiological evidence that vinpocetine increases the activity of ascending noradrenergic pathways. This effect can be related to the cognitive-enhancing characteristics of the compound
A clinical and neurophysiological trial on nootropic drugs in patients with mental decline. Gallai V, Mazzotta G, Del Gatto F, et al. Acta Neurol (Napoli). 1991 Feb; 13(1):1-12. The different expressions of mental decline in elderly people, from simple senile benign forgetfulness to SDAT, can be evaluated by psychometric and neurophysiological tests. In the present study, the effects of oxiracetam, piracetam and placebo were compared in a group of elderly subjects. The results of the trial, structured as single blind, clearly showed that nootropics positively effect both clinical and neurophysiological performances and that oxiracetam produces a more pronounced effect when compared to piracetam. In fact, oxiracetam was found more effective in improving psychometric scales such as GDS (clinical performances) as well as the amplitude and the latency of the P300 (neurophysiological performances), which reflect a functional recovery of the cerebral pathways related to attention and memory
Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Gamoh S, Hashimoto M, Sugioka K, et al. Neuroscience. 1999; 93(1):237-41. Wistar rats were fed a fish oil-deficient diet through three generations. The young (five-week-old) male rats of the third generation were randomly divided into two groups. Over 10 weeks, one group was perorally administered docosahexaenoic acid dissolved in 5% gum Arabic solution at 300 mg/kg/day; the other group received a similar volume of vehicle alone. Five weeks after starting the administration, the rats were tested for learning ability related to two types of memory, reference memory and working memory, with the partially (four of eight) baited eight-arm radial maze. Reference memory is information that should be retained until the next trial. Working memory is information that disappears in a short time. Entries into unbaited arms and repeated entries into visited arms were defined as reference memory errors and working memory errors, respectively. Docosahexaenoic acid administration over 10 weeks significantly reduced the number of reference memory errors, without affecting the number of working memory errors, and significantly increased the docosahexaenoic acid content and the docosahexaenoic acid/arachidonic acid ratio in both the hippocampus and the cerebral cortex. In addition, the ratio demonstrated a significantly negative correlation with the number of reference memory errors. These results suggest that chronic administration of docosahexaenoic acid is conducive to the improvement of reference memory-related learning ability, and that the docosahexaenoic acid/arachidonic acid ratio in the hippocampus or the cerebral cortex, or both, may be an indicator of learning ability
Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats. Gamoh S, Hashimoto M, Hossain S, et al. Clin Exp Pharmacol Physiol. 2001 Apr; 28(4):266-70. 1. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on spatial memory related learning ability in aged (100 weeks) male Wistar rats. 2. Rats were fed a fish oil-deficient diet through three generations and were then randomly divided into two groups. Over 10 weeks, one group was per orally administered 300 mg/kg per day DHA dissolved in 5% gum Arabic solution and the other group was administered the vehicle alone. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to estimate two types of spatial memory related learning ability displayed by reference memory error and working memory error. 3. Chronic administration of DHA significantly decreased the number of reference memory errors and working memory errors. 4. The level of lipid peroxide (LPO) in the hippocampus tended to decrease with chronic DHA administration and demonstrated a positive correlation with the number of reference memory errors. 5. These results suggest that the accumulation of hippocampal LPO reduces spatial memory related learning ability in aged rats. Moreover, chronic administration of DHA was effective in decreasing the level of hippocampal LPO, then improving learning ability
Inhibition of glutamine synthetase activity prevents memory consolidation. Gibbs ME, O'Dowd BS, Hertz L, et al. Brain Res Cogn Brain Res. 1996 Jul; 4(1):57-64. Methionine sulfoximine, a specific inhibitor of the exclusively glial enzyme glutamine synthetase, was shown, at a concentration of 3.5-4.5 mM, to prevent consolidation of memory for a passive avoidance task in day-old chicks. Provided the drug was administered 5-20 min before the learning task, significant retention loss was observed from the normal time of onset of the second of three postulated stages in the memory formation sequence but the drug had to be administered considerably earlier. The amnestic effect of methionine sulfoximine was successfully counteracted by L-glutamine (10 mM) and monosodium glutamate (4 mM), and also by a cocktail of alpha-ketoglutarate (5 mM) and alanine (5 mM). This effect of methionine sulfoximine is attributed to its blockade of the production of glutamine via the glutamate-glutamine cycle, leading to a reduced capacity of neurons to replenish their transmitter glutamate
Absence of cognitive impairment or decline in preclinical Alzheimer's disease. Goldman WP, Price JL, Storandt M, et al. Neurology. 2001 Feb 13; 56(3):361-7. OBJECTIVE: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. METHODS: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. RESULTS: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). CONCLUSIONS: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT
Evidence that age-associated memory impairment is not a normal variant of aging. Goldman WP, Morris JC. Alzheimer Dis Assoc Disord. 2001 Apr; 15(2):72-9. The concept of age-associated memory impairment (AAMI) suggests that clinically recognized memory dysfunction can be a feature of normal aging. To determine whether AAMI represents a variant of normal aging, we longitudinally studied individuals meeting AAMI criteria for development of dementia. Two hundred two community-living individuals (mean age, 77 years) with or without mild memory impairment were assessed annually for an average of 3 years at the Washington University Alzheimer's Disease Research Center. At baseline, no individual was unequivocally demented, as defined by a Clinical Dementia Rating (CDR) score of 1 or greater. Modified National Institute of Mental Health criteria were used to identify individuals with AAMI who otherwise met a criterion for cognitive normality. The Short Blessed Test (SBT) was used as a measure of general cognitive function; conservative (SBT = 5) and permissive (SBT = 10) cutoff scores were used as indicators of cognitive normality. With the more permissive measure of cognitive normality, 59 (29%) of the 202 individuals met AAMI criteria. Progression to dementia by 3 years occurred in 42% of AAMI individuals versus 16% of the individuals who did not meet AAMI criteria. With the more restrictive SBT cutoff of 5, 22% of individuals met AAMI criteria; progression to dementia occurred in 31% of these individuals versus 9% of the individuals without AAMI. Survival times to dementia differed significantly between AAMI and non-AAMI groups defined by either cutoff score. Our findings indicate that individuals with AAMI have a three-fold greater risk for development of dementia than individuals who do not meet AAMI criteria. Hence, AAMI may represent a dementia prodrome rather than a benign variant of aging
Cognitive and neurobehavioral functioning after mild versus moderate traumatic brain injury in older adults. Goldstein FC, Levin HS, Goldman WP, et al. J Int Neuropsychol Soc. 2001 Mar; 7(3):373-83. This study evaluated the early cognitive and neurobehavioral outcomes of older adults with mild versus moderate traumatic brain injury (TBI). Thirty-five patients who were age 50 years and older and sustained mild or moderate TBI were prospectively recruited from acute care hospitals. Patients were administered cognitive and neurobehavioral measures up to 2 months post-injury. Demographically comparable control participants received the same measures. Patients and controls did not have previous histories of substance abuse, neuropsychiatric disturbance, dementia, or neurologic illness. Moderate TBI patients performed significantly poorer than mild TBI patients and controls on most cognitive measures, whereas the mild patients performed comparably to controls. In contrast, both mild and moderate patients exhibited significantly greater depression and anxiety/somatic concern than controls. The results indicate that the classification of TBI as mild versus moderate is prognostically meaningful as applied to older adults. The findings extend previous investigations in young adults by demonstrating a relatively good cognitive outcome on objective measures, but subjective complaints after a single, uncomplicated mild TBI in older persons
Memory impairment on free and cued selective reminding predicts dementia. Grober E, Lipton RB, Hall C, et al. Neurology. 2000 Feb 22; 54(4):827-32. OBJECTIVE: To estimate the relative rates of dementia in initially nondemented subjects with and without memory impairment defined by baseline free recall from the Free and Cued Selective Reminding (FCSR) test. BACKGROUND: Our approach to identifying persons at high risk for future dementia is to show the presence of memory impairment not caused by other cognitive deficits by using a memory test that controls attention and cognitive processing. When the conditions of testing are not adequately controlled, prediction is reduced because age-associated memory deficits due to other cognitive deficits are confused with dementia-associated memory deficits. METHODS: Longitudinal evaluation of 264 initially nondemented, elderly community volunteers from the Einstein Aging Study with clinical and psychometric examinations every 12 to 18 months for up to 10 years. MAIN OUTCOME MEASURES: Dementia was defined by an algorithmic definition that required a Blessed Information Memory and Concentration score >8 and clinical evidence of functional decline. RESULTS: Thirty-two incident cases of dementia developed during follow-up. Survival analyses indicated that subjects with impaired free recall at baseline had dementia develop (relative risk = 75.2, 95% CI = 9.9 to 567) over 5 years of follow-up at dramatically higher rates than subjects with intact free recall after adjusting for age, gender, and education. CONCLUSION: Poor performance on free recall from FCSR predicts future dementia. These findings support the existence of a preclinical phase of dementia characterized by memory impairment, which is present for at least 5 years before diagnosis
Rheoencephalographic and psychological studies with ethyl apovincaminate in cerebral vascular insufficiency. Hadjiev D, Yancheva S. Arzneimittelforschung. 1976; 26(10a):1947-50. The effect of ethyl apovincaminate (RGH-4405, Cavinton) on the rheoencephalogram and memory functions was studied in 50 patients with ischaemic disturbances of cerebral circulation. The drug was administered in a single i.v. dose of 10 mg and orally three times daily 5 mg for a month. Improvement of cerebral circulation was observed after i.v. and oral medication. Blood flow was most markedly increased in the gray matter. The effect on arterial pressure was negligible. Improvement of memorizing capacity evaluated by psychological tests was recorded after one month of Cavinton treatment, associated with alleviation or complete disappearance of symptoms. No side-effects attributable to the drug were observed. It is pointed out that Cavinton is indicated in the treatment of ischaemic disorders of the cerebral circulation, particularly in chronic insufficiency
Piracetam in the treatment of post-concussional syndrome. A double-blind study. Hakkarainen H, Hakamies L. Eur Neurol. 1978; 17(1):50-5. The effect of piracetam, a cyclical derivative of GABA, was compared with that of a placebo in a double-blind study of 60 patients with post-concussional syndrome of 2-12 months' duration. The daily dose of piracetam was 4,800 mg. After 8 weeks of treatment piracetam significantly reduced the occurrence and severity of the following symptoms: vertigo, headache, tiredness, decresed alertness, increased sweating and neurasthenic symptoms. No significant effect was observed on the following symptoms: tremor, orthostatic symptoms, and memory disorders. Side effect were reported by 64% of the patients under piracetam and by 32% under placebo. In the author's opinion, piracetam seems to be a promising new drug for the treatment of post-concussional syndrome
Age-associated memory impairment. Normal aging or warning of dementia? Hanninen T, Soininen H. Drugs Aging. 1997 Dec; 11(6):480-9. Aging causes deterioration in various aspects of memory performance in healthy adults. Different diagnostic classifications have been proposed for use in the characterisation of mild cognitive disorders associated with aging. One of the best established of these classifications is age-associated memory impairment (AAMI). Epidemiological data suggest that AAMI is a phenomenon of normal aging rather than a sign of progression from normal aging to a pathological state such as Alzheimer's disease. A number of studies that have combined neuropsychological, neuroradiological and neurophysiological data have provided evidence of distinct characteristics in individuals with AAMI. At present, however, AAMI does not appear to describe any homogeneous group of individuals. Moreover, the neuropsychological methods used to diagnose AAMI appear to be ambiguous. Thus, AAMI appears to occur in a highly heterogeneous group of individuals, and is of questionable clinical or theoretical significance. More reliable diagnostic approaches are needed for use in studies that are attempting to identify the risk factors for dementia or to find a treatment for very early dementia
Effect of piracetam on cerebral glucose metabolism in Alzheimer's disease as measured by positron emission tomography. Heiss WD, Hebold I, Klinkhammer P, et al. J Cereb Blood Flow Metab. 1988 Aug; 8(4):613-7. The effect of piracetam (a putative enhancer of cerebral metabolism) on regional CMRGlu was studied by positron emission tomography of 2[18F]-fluoro-2-deoxy-D-glucose in nine patients with Alzheimer's disease, and in seven cases with multiinfarct dementia or unclassified dementia. In Alzheimer's disease, i.v. administration of piracetam, 6 g b.i.d. for 2 weeks, significantly improved rCMRGlu in most cortical areas, whereas no effect on CMRGlu of the drug was observed in the multiinfarct dementia/unclassified dementia groups. These results lend further support to the notion that adjuvant piracetam treatment is of benefit in Alzheimer's disease. They may also indicate that the typical metabolic depression in Alzheimer's disease is caused by complex interaction of disturbed transmitter and cellular function rather than by a specific deficit in the cholinergic system alone
Abnormalities of energy metabolism in Alzheimer's disease studied with PET. Heiss WD, Szelies B, Kessler J, et al. Ann N Y Acad Sci. 1991; 640:65-71. Positron emission tomography (PET) is currently the only technology affording three-dimensional measurement of the brain's energy metabolism which is closely coupled to brain function. Studies of glucose metabolism by PET of (18F)-2-fluoro-2-deoxy-D-glucose are therefore widely applied to show the contribution of various brain structures in the performance of a variety of tasks or their participation in functional deficits associated with various diseases. Although glucose metabolism decreases slightly with age to a regionally different degree, most types of dementia show severe changes in glucose metabolism. Alzheimer's disease (AD) is characterized by metabolic disturbances most prominent in the parietotemporal association cortex and later in the frontal lobe, whereas primary cortical areas, basal ganglia, thalamus, brainstem, and cerebellum are not affected. It is this typical pattern that distinguishes AD from other dementia syndromes. A ratio calculated from the metabolic rates of glucose of "affected" and "nonaffected" brain regions was able to separate patients with AD from age-matched controls and permitted the discrimination of patients with cognitive impairment of other origin in 85%. The discriminative power can be further improved by activation studies. A continuous visual recognition task increased the metabolic rate in normal subjects by 21% and in patients with AD by 6% on average, with significant regional differences. During activation the significant relation between severity of disease and temporoparietal metabolic rate became even stronger. In the assessment of effects of treatment on disturbed metabolism, PET studies demonstrated an equalization of metabolic heterogeneities in patients responding to a muscarinergic cholinagonist, whereas general increases in glucose utilization were observed with piracetam, pyritinol, and phosphatidyl-serine. The therapeutic relevance of such metabolic effects, however, must be proved in controlled clinical trials
Pharmacological properties of piracetam: rationale for use in stroke patients. Hitzenberger GRH. CNS Drugs. 1998;(1):19-27.
Estrogen use and verbal memory in healthy postmenopausal women. Kampen DL, Sherwin BB. Obstet Gynecol. 1994 Jun; 83(6):979-83. OBJECTIVE: To assess whether differences in verbal memory might be related to estrogen use in a group of healthy, well-functioning, postmenopausal community-residing women from a broad socioeconomic range. METHODS: Healthy postmenopausal women drawn from the general population were given tests of verbal and spatial memory, language, attention, and general spatial skills. The performance of women taking estrogen was compared to that of women from the same population who were not taking any form of estrogen replacement therapy. RESULTS: There were no differences between the estrogen users and non-users on any sociodemographic variables. However, the scores of women taking estrogen were significantly higher on tests of immediate and delayed paragraph recall compared to the scores of non-users. No differences were apparent on other tests of cognitive functioning, including tests of spatial memory. CONCLUSION: Estrogen appears to have a specific effect on verbal memory skills in healthy postmenopausal women. The clinical relevance of these findings for healthy older women remains to be determined
Ginkgo biloba for cerebral insufficiency. Kleijnen J, Knipschild P. Br J Clin Pharmacol. 1992 Oct; 34(4):352-8. 1. By means of a critical review we tried to establish whether there is evidence from controlled trials in humans on the efficacy of Ginkgo biloba extracts in cerebral insufficiency. 2. The methodological quality of 40 trials on Ginkgo and cerebral insufficiency was assessed using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. A comparison of the quality was made with trials of co-dergocrine, which is registered for the same indication. 3. There were eight well performed trials out of a total of 40. Shortcomings were limited numbers of patients included, and incomplete description of randomization procedures, patient characteristics, effect measurement and data presentation. In no trial was double-blindness checked. Virtually all trials reported positive results, in most trials the dosage was 120 mg Ginkgo extract a day, given for at least 4-6 weeks. For the best trials, there were no marked differences in the quality of the evidence of the efficacy of Ginkgo in cerebral insufficiency compared with co-dergocrine. The results of the review may be complicated by a combination of publication bias and other biases, because there were no negative results reported in many trials of low methodological quality. 4. Positive results have been reported for Ginkgo biloba extracts in the treatment of cerebral insufficiency. The clinical evidence is similar to that of a registered product which is prescribed for the same indication. However, further studies should be conducted for a more detailed assessment of the efficacy
Effects of nicotinamide on central cholinergic transmission and on spatial learning in rats. Koppen A, Klein J, Schmidt BH, et al. Pharmacol Biochem Behav. 1996 Apr; 53(4):783-90. High-dose nicotinamide (1000 mg/kg) leads to a minor increase of plasma choline but to a major increase of the choline concentrations in the intra- and extracellular spaces of the brain. In the hippocampus, the nicotinamide-induced increase in choline was associated with an increase in the release of acetylcholine under stimulated conditions. In young rats, nicotinamide in doses between 10 and 1000 mg/kg did not influence spatial learning, as tested in the Morris water maze. In old rats, low doses of nicotinamide were ineffective whereas the high dose of 1000 mg/kg even impaired spatial learning. The combined administration of choline and nicotinamide had a synergistic effect on brain choline levels but had similar effects as nicotinamide given alone in the behavioral experiments. Additional tests for spontaneous behaviour and locomotion revealed procholinergic and sedative effects of the compound. We conclude that the ineffectiveness of the putative cognition enhancer nicotinamide in the learning task may be due to the observed sedative effect. Therefore, the development of nonsedative nicotinamide derivatives is recommended
Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment. La Rue A, Koehler KM, Wayne SJ, et al. Am J Clin Nutr. 1997 Jan; 65(1):20-9. Associations between nutritional status and cognitive performance were examined in 137 elderly (aged 66-90 y) community residents. Participants were well-educated, adequately nourished, and free of significant cognitive impairment. Performance on cognitive tests in 1986 was related to both past (1980) and concurrent (1986) nutritional status. Several significant associations (P < 0.05) were observed between cognition and concurrent vitamin status, including better abstraction performance with higher biochemical status and dietary intake of thiamine, riboflavin, niacin, and folate (rs = "0.19-0.29)" and better visuospatial performance with higher plasma ascorbate (r = "0.22)." Concurrent dietary protein in 1986 correlated significantly (rs = "0.25-0.26)" with memory scores, and serum albumin or transferrin with memory, visuospatial, or abstraction scores (rs = "0.18-0.22)." Higher past intake of vitamins E, A, B-6, and B-12 was related to better performance on visuospatial recall and/or abstraction tests (rs = "0.19-0.28)." Use of self-selected vitamin supplements was associated with better performance on a difficult visuospatial test and an abstraction test. Although associations were relatively weak in this well-nourished and cognitively intact sample, the pattern of outcomes suggests some direction for further research on cognition-nutrition associations in aging
Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson's disease. Parkinson's Disease Research Group of the United Kingdom. Lees AJ. BMJ. 1995 Dec 16; 311(7020):1602-7. OBJECTIVE: To compare effectiveness of levodopa and levodopa combined with selegiline in treating early, mild Parkinson's disease. DESIGN: Open, long term, prospective randomised trial. SETTING: 93 hospitals throughout United Kingdom. SUBJECTS: 520 patients with early Parkinson's disease who were not receiving dopaminergic treatment. INTERVENTIONS: Treatment with levodopa and dopa decarboxylase inhibitor (arm 1) or levodopa and decarboxylase inhibitor in combination with selegiline (arm 2). MAIN OUTCOME MEASURES: Assessments of serial disability, frequency and severity of adverse events, and deaths from all causes. RESULTS: After average of 5-6 years' follow up, mortality ratio in arm 2 compared with arm 1 was 1.57 (95% confidence interval 1.09 to 2.30), and difference in survival between the two arms was significant (log rank test, P = 0.015). Hazard ratio adjusted for age and sex was 1.49 (1.02 to 2.16), and after adjustment for other baseline factors it increased to 1.57 (1.07 to 2.31). Patients in arm 1 had slightly worse disability scores than those in arm 2, but differences were not significant. Functionally disabling peak dose dyskinesias and on/off fluctuations were more frequent in arm 2 than arm 1. During the trial the dose of levodopa required to produce optimum motor control steadily increased in arm 1 (median daily dose 375 mg at 1 year and 625 mg at 4 years), but median dose in arm 2 did not change (375 mg). CONCLUSIONS: Levodopa in combination with selegiline seemed to confer no clinical benefit over levodopa alone in treating early, mild Parkinson's disease. Moreover mortality was significantly higher with combination treatment, casting doubts on its chronic use in Parkinson's disease
Deprenyl's effect at slowing progression of parkinsonian disability: the DATATOP study. The Parkinson Study Group. LeWitt PA. Acta Neurol Scand Suppl. 1991; 136:79-86. Studying a cohort of 800 mildly-affected parkinsonians, the North American DATATOP* project has concluded that progression in disability can be attenuated by the use of deprenyl, 10 mg/day. Interim results of this controlled clinical trial were reported after participants received treatment for an average of 12 months. The study found that deprenyl treatment almost halved the risk of reaching a stage of Parkinsonism at which the start of levodopa treatment becomes imperative for lessening disability. In addition to this study end-point, other ratings supported an improved clinical outcome from the chronic deprenyl (DP) regimen. The 34 investigators conducted clinical evaluations both while subjects received medication and after a 4-week wash-out. Though some subjects experienced mild symptomatic improvements of Parkinsonism from DP, these effects were insufficient to account for the DP-treated group's delay at reaching the study end-point. In addition to DP, this placebo-controlled double-blind study also assessed the possibility of protective effects from another antioxidative strategy, a 2,000 I.U./day regimen of alpha-tocopherol. To date, results of the latter trial have not been reported. Monoamine oxidase type-B (MAO-B) metabolism of dopamine generates hydrogen peroxide and, thereby, an oxidative stress on the nigrostriatal dopaminergic neuron. The inhibition of MAO-B by DP may have been the means by which progression of Parkinsonism was attenuated, although other mechanisms are also tenable. DATATOP has pointed to the potential for arresting the progression of Parkinson's disease, and has provided an unparalleled opportunity to study the clinical course and neurochemical indices of untreated Parkinsonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. Lindenbaum J, Healton EB, Savage DG, et al. N Engl J Med. 1988 Jun 30; 318(26):1720-8. Among 141 consecutive patients with neuro-psychiatric abnormalities due to cobalamin deficiency, we found that 40 (28 percent) had no anemia or macrocytosis. The hematocrit was normal in 34, the mean cell volume was normal in 25, and both tests were normal in 19. Characteristic features in such patients included paresthesia, sensory loss, ataxia, dementia, and psychiatric disorders; longstanding neurologic symptoms without anemia; normal white-cell and platelet counts and serum bilirubin and lactate dehydrogenase levels; and markedly elevated serum concentrations of methylmalonic acid and total homocysteine. Serum cobalamin levels were above 150 pmol per liter (200 pg per milliliter) in 2 patients, between 75 and 150 pmol per liter (100 and 200 pg per milliliter) in 16, and below 75 pmol per liter (100 pg per milliliter) in only 22. Except for one patient who died during the first week of treatment, every patient in this group benefited from cobalamin therapy. Responses included improvement in neuropsychiatric abnormalities (39 of 39), improvement (often within the normal range) in one or more hematologic findings (36 of 39), and a decrease of more than 50 percent in levels of serum methylmalonic acid, total homocysteine, or both (31 of 31). We conclude that neuropsychiatric disorders due to cobalamin deficiency occur commonly in the absence of anemia or an elevated mean cell volume and that measurements of serum methylmalonic acid and total homocysteine both before and after treatment are useful in the diagnosis of these patients
Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Liu J, Head E, Gharib AM, et al. Proc Natl Acad Sci U S A. 2002 Feb 19; 99(4):2356-61. Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (P < 0.05; P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function
Alterations of the intracellular water and ion concentrations in brain and liver cells during aging as revealed by energy dispersive X-ray microanalysis of bulk specimens. Lustyik G, Nagy I. Scan Electron Microsc. 1985;(Pt 1):323-37. Age dependence of the intracellular concentrations of monovalent ions (Na+, K+ and Cl-) was examined in 1, 11 and 25-month-old rat brain and liver cells by using energy dispersive X-ray microanalysis. The in vivo concentrations of Na+, K+ and Cl- ions were calculated from two different measurements: The elemental concentrations were measured in freeze-dried tissue pieces, and the intracellular water content was determined by means of a recently developed X-ray microanalytic method, using frozen-hydrated and fractured bulk specimens as well as subsequent freeze-drying. All the single monovalent ion concentrations and consequently, also the total monovalent ion content showed statistically significant increases during aging in brain cortical neurons. A 3-6% loss of the intracellular water content was accompanied by a 25-45% increase of the monovalent ionic strengths by the age of 25 months. A membrane protective OH radical scavenger (centrophenoxine) reversed the dehydration in the nerve cells of old animals, resulting in a decrease of the intracellular ion concentrations. Aging has a less prominent effect on the water and ion contents of the hepatocytes. The degree of water loss of cytoplasm exceeds that of the nuclei in the liver, suggesting that dominantly the translational steps can be involved in the general age altered slowing down of the protein synthetic machinery, predicted by the membrane hypothesis of aging (Zs.-Nagy, 1978)
Hydergine: interaction with the neurotransmitter systems in the central nervous system. Markstein R. J Pharmacol. 1985; 16 Suppl 3:1-17. Hydergine (co-dergocrine, ergoloid mesylates, dihydroergotoxine) is an ergot preparation which has been shown to be of value in the treatment of senile mental impairment. Results from biochemical in vitro investigations suggest that Hydergine interacts directly with subtypes of alpha-adrenoceptors, dopamine and serotonin receptors. For instance, in slices of rat cerebral cortex, it blocked noradrenaline-induced increase of cyclic AMP content and facilitated electrically evoked noradrenaline release which is consistent with antagonistic properties at postsynaptic alpha 1- and presynaptic alpha 2-adrenoceptors. Furthermore, Hydergine had mixed agonist/antagonist properties at postsynaptic D1 receptors mediating stimulation of adenylate cyclase, and at pre- and postsynaptic D2 receptors mediating inhibition of evoked dopamine and acetylcholine release in the rat striatum, respectively. Hydergine had also mixed agonist/antagonist properties at the serotonin-sensitive adenylate cyclase in the rat hippocampus and the presynaptic serotonin autoreceptors present on nerve terminals in the rat cortex. Based on these in vitro data, it is suggested that Hydergine influences central monoaminergic systems in a dualistic manner. On the one hand, it can compensate for a transmitter deficit in dopaminergic and serotoninergic systems, but at the same time, counteract a possible hyperactivity in the same transmitter systems. The noradrenergic systems may be affected in a similar way but by a different mechanism. In this latter system, Hydergine increased evoked noradrenaline release by blocking presynaptic alpha-adrenergic autoreceptors, but by a simultaneous blockade of postsynaptic alpha 1-adrenoceptors sets a ceiling effect to the noradrenergic stimulation. Thus, Hydergine might be able to counteract and prevent disturbances in the interplay between monoaminergic and other transmitter systems in the central nervous system. It is proposed that these multiple effects of Hydergine are in part responsible for its beneficial effects in senile mental impairment
Experimental assessment of selected antimotion drugs. Matsnev EI, Bodo D. Aviat Space Environ Med. 1984 Apr; 55(4):281-6. Space motion sickness (SMS) has been a perplexing problem in both the Soviet and U.S. manned space programs. Both the sensory conflict theory (neuronal signal mismatch) and the cephalad fluid shift concept explain the mechanism. This paper reviews the mechanism of action of various drugs that primarily affect brain blood flow or brain metabolism. In particular, Cavinton (apovincamic acid ethyl ester) has been used successfully in offsetting SMS in experimental test subjects
Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Matthews RT, Yang L, Browne S, et al. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8892-7. Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases
Antioxidants protect against glutamate-induced cytotoxicity in a neuronal cell line. Miyamoto M, Murphy TH, Schnaar RL, et al. J Pharmacol Exp Ther. 1989 Sep; 250(3):1132-40. The effects of reducing agents and antioxidants on L-Glutamate (Glu)-induced cytotoxicity were examined in the N18-RE-105 neuronal cell line. The cytotoxicity by Glu (1 and 10mM) was potentiated by exposure to growth medium containing a low concentration of cystine (5-100 microM), instead of the normal medium containing 200 microM cystine. In contrast, the toxicity was suppressed by increasing the cystine concentration to 500 to 1000 microM. Reducing agents, cysteine (30-1000 microM), dithiothreitol (10-250 microM) and glutathione (GSH, 10-1000 microM) also protected the cells against the cytotoxicity of 10 mM Glu in a concentration-dependent manner. The antioxidants vitamin E (10-100 microM), idebenone (0.1-3 microM) and vinpocetine (10-100 microM) also provided marked protection against the cytotoxicity of Glu (10 mM) or quisqualate (1 mM). Antioxidants also prevented the delayed cell death caused by lowering the concentration of cystine in the medium to 5 microM. Incubation of the cells with 10 mM Glu caused a marked decrease in cellular GSH levels. Although cysteine and dithiothreitol prevented the GSH reduction caused by Glu, antioxidants did not. The cellular levels of oxidants were assessed using 2,7-dichlorofluorescin, a probe that accumulates within cells and is converted to a fluorescent product by oxidation. Glu (10 mM) caused a marked increase in such fluorescence, whereas vitamin E and idebenone reduced markedly the number of fluorescent cells to control levels even added with 10 mM Glu. These results indicate that oxidative stress due to loss of cellular levels of GSH is one mechanism whereby Glu/quisqualate exert cytotoxicity and suggest that centrally active antioxidants may reduce neuronal damage in pathologic conditions associated with excessive Glu release
Deprenyl stimulates the efflux of monoamines from the rat hypothalamus in vitro. MohanKumar PS, MohanKumar SM, Quadri SK. Brain Res Bull. 2001 Apr; 54(6):675-80. The direct effects of L-deprenyl, a monoamine oxidase inhibitor, on the hypothalamus of male Sprague-Dawley rats was investigated by measuring the efflux of norepinephrine (NE), dopamine (DA), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) using a combination of high performance liquid chromatography with electrochemical detection and an in vitro incubation system. After measuring basal efflux by incubating the hypothalami with Krebs-Ringers Henseleit (KRH) alone during the first incubation period, hypothalami were incubated either with the medium, KRH alone (0 mM), or KRH containing 0.1, 1, and 10 mM L-deprenyl. During the third incubation period, hypothalami were again incubated with KRH alone to measure the residual effects if any. During the final incubation period, the hypothalami were stimulated with high K(+) KRH. Deprenyl produced a dose-dependent increase in the efflux of NE, DA, and 5-HT from the hypothalami. Neurotransmitter efflux returned to pretreatment levels when L-deprenyl was removed from the medium. In contrast to NE, DA, and 5-HT, the efflux of the metabolites DOPAC and 5-HIAA was inhibited in a dose-dependent fashion after incubation with L-deprenyl. Results from this study demonstrate that L-deprenyl is capable of stimulating the efflux of neurotransmitters in vitro by a direct action on the hypothalamus
Effects of meclofenoxate and citicholine on learning and memory in aged rats. Mosharrof AH, Petkov VD, Petkov VV. Acta Physiol Pharmacol Bulg. 1987; 13(4):17-24. The maze method for active avoidance with punishment reinforcement and the step-through method for passive avoidance with negative reinforcement were used to study the processes of learning and memory in 22-month-old rats, as well as the effects of meclofenoxate (Mf) and citicholine (CCh) on these processes. Meclofenoxate, administered in a dose of 50 mg/kg twice daily for 7 days using the maze-training method, increased the number of responses to the conditioned stimulus, when retention tests were made 24 hours and 7 days after training, whereas citicholine, applied in the same way in a dose of 10 mg/kg, shortened the latency of the responses with reinforcement during the training and increased the number of correct responses to the conditioned stimulus in retention tests 7 days after the training. With the same pattern of administration, both Mf and CCh strongly prolonged the time spent by the animals in the light chamber (i.e., improved retention) in tests using the step-through method 24 hours and 7 days after the training. Both drugs prevented the occurrence of scopolamine-induced (2 mg/kg i.p.) amnesia. A comparison of the results obtained for 22-month-old rats with the results obtained in earlier experiments on 5-month-old rats under fully identical experimental conditions showed that the age-dependent differences in the memory process and in the effects on it of the psychotropic agents meclofenoxate and citicholine were not unidirectional in character
Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography. Nagasawa H, Kogure K, Kawashima K, et al. Tohoku J Exp Med. 1990 Nov; 162(3):225-33. Three female patients aged from 74 to 79 with multi-infarct dementia were studied using positron emission tomography (PET) to assess the effect of co-dergocrine mesylate (Hydergine) on cerebral glucose metabolism. The cerebral glucose utilization (CMRGlc) of each patient was evaluated by PET scan using 2-deoxy-[18F]-2-fluoro-D-glucose (FDG). Following the first PET study, 0.04 mg/kg of co-dergocrine mesylate was injected intravenously with 250 ml saline solution, and then the second PET study was performed. The CMRGlc was determined from the images of the PET scan and the radioactivity of 18F in the plasma. After the administration of co-dergocrine mesylate, the value of CMRGlc increased significantly in the cerebral cortex (p less than 0.01 and p less than 0.05) and basal ganglia (p less than 0.05) compared with values before the administration, but no significant increase was found in the centrum semiovale. These results suggest that co-dergocrine mesylate stimulates glucose metabolism of neurons in the human brain
Anti-apoptotic function of L-(-)deprenyl (Selegiline) and related compounds. Naoi M, Maruyama W, Yagi K, et al. Neurobiology (Bp). 2000; 8(1):69-80. (-)Deprenyl has been proposed to be neuroprotective to dopamine neurons in the parkinsonian brains. To clarify the mechanism, the effects of (-)deprenyl and structurally related compounds on apoptosis induced by a neurotoxin, N-methyl(R)-salsolinol, and reactive oxygen species, nitric oxide and peroxynitrite, were examined in dopaminergic SH-SY5Y cells. DNA damage was quantified by the single cell gel electrophoresis (comet) assay. (-)-Deprenyl protected the cells from apoptosis in a dose-dependent way, which required pre-treatment at least for 20 min. The effect was confirmed even after washing out of (-)deprenyl, indicating that (-)-deprenyl initiates the intracellular process to antagonize the apoptotic death program. The studies on the structure-activity relationship reveal that N-propargyl residue with hydrophobic structure is essential for the anti-apoptotic function. These results suggest that (-)deprenyl and related compounds may be applicable as neuroprotective agents in neurodegenerative diseases
Protective action of vinpocetine against experimentally induced gastric damage in rats. Nosalova V, Machova J, Babulova A. Arzneimittelforschung. 1993 Sep; 43(9):981-5. The efficacy of vinpocetine (CAS 42971-09-5) to prevent gastric mucosal damage induced by several noxious agents and its antisecretory effect were studied in rats. Vinpocetine administered orally or intraperitoneally inhibited the development of gastric lesions induced by 96% ethanol in a dose-dependent way. The highest protective activity was observed when vinpocetine was given intraperitoneally 30 min before ethanol, and its effect was still significant when administered 120 min before ethanol exposure. Oral administration of vincamine also displayed gastroprotective action in this model. Pretreatment with indometacin counteracted the protective action of vinpocetine against ethanol-induced damage, suggesting the involvement of a prostaglandin-mediated mechanism. The protective effect of vinpocetine was compared with that of prostaglandin E2, sucralfate, and tripotassium dicitrate bismuthate. The antiulcer activity of vinpocetine was demonstrated also in gastric injury induced by phenylbulazone and in chronic gastric ulcer induced by acetic acid. Histamine-stimulated gastric acid secretion in pylorus-ligated rats was partially inhibited by vinpocetine administered intraduodenally. The activity of vinpocetine established in these experiments is indicative of its potential clinical value as a gastroprotective agent
Piracetam in the treatment of acute stroke. Orgogozo JM. Pharmacopsychiatry. 1999 Mar; 32 Suppl 1:25-32. The neuroprotective properties of the nootropic agent piracetam together with reported hemorrheologic and antithrombotic effects provided the rationale for the evaluation of piracetam in acute stroke. Pilot studies showed an increase in compromised regional cerebral blood flow and improvement in motor function, aphasia and level of consciousness. Subsequently the Piracetam in Acute Stroke Study (PASS) was performed and the chief results have recently been reported (Stroke 28 (1997) 2347-2352). This was a multicenter double-blind trial in 927 patients to determine whether, compared with placebo, piracetam improved outcome when given within 12 hours of the onset of acute ischemic stroke, confirmed by computed tomography within 24 hours of admission (but not necessarily prior to treatment). Patients received an initial iv bolus of placebo or 12g piracetam, 12g piracetam daily for 4 weeks and maintenance treatment for a further 8 weeks. Neurologic status at 4 weeks was the primary end point; secondary outcome measures were functional outcome and aphasia at 12 weeks. Results in aphasic patients have not previously been reported. Analysis was planned both in all patients (n = 927) and an early treatment subgroup (n = 460) treated within 6 hours of stroke onset. This period was subsequently redefined as 7 hours. Intention-to-treat analyses in the total population showed a significant (P = 0.04) increase compared with placebo in the number of patients recovered from aphasia but no significant neurologic or functional improvement. Post hoc analysis in the early treatment subgroup showed improved neurologic outcome (P = 0.07), better function (P = 0.02) and a greater recovery rate from aphasia (P = 0.02). Additional analysis in this early treatment subgroup confined to 360 patients with moderate and severe stroke showed significant improvement in all 3 outcomes. There was no significant difference in mortality between treatment groups after 12 weeks. There were fewer deaths in piracetam-treated patients in those patients in the intention-to-treat population admitted with primary hemorrhagic stroke
Association of monoamine oxidase B alleles with age at onset in amyotrophic lateral sclerosis. Orru S, Mascia V, Casula M, et al. Neuromuscul Disord. 1999 Dec; 9(8):593-7. An active role of monoamine oxidase B (MAO-B) in the pathogenesis of neurodegenerative disorders such as Parkinson's disease has been proposed as the enzyme is known to be a generator of free radicals which seem to be responsible for neuron oxidative damage. We evaluated the influence of MAO-B in the pathogenesis of the sporadic forms of Amyotrophic lateral sclerosis (ALS) by studying the MAO-B allele distribution in 51 patients and 71 healthy controls. MAO-B did not directly result in a risk factor for ALS but seemed to strongly influence age at onset. The mean ALS onset age was significantly higher in individuals carrying allele 5 compared to individuals without this allele (60.4 +/- 8.1 vs. 52.1 +/- 10.3 years; P = 0.004). These results, in agreement with findings in the literature, suggest an increased MAO-B expression in ALS and support the hypothesis that neuronal cell death in neurodegenerative diseases is triggered by astroglial reaction
The Scandinavian Multi-Infarct Dementia Trial: a double-blind, placebo-controlled trial on nimodipine in multi-infarct dementia. Pantoni L, Bianchi C, Beneke M, et al. J Neurol Sci. 2000 Apr 15; 175(2):116-23. Vascular dementia is a major cause of mental and physical disability in Western countries. Treatment of vascular dementia is currently based on the recognition and control of vascular risk factors, while specific drugs have not been approved yet. The aim of the present multinational, double-blind, placebo-controlled study was to evaluate the safety and efficacy of nimodipine administered for as long as 26 weeks in improving cognition or slowing cognitive deterioration in patients defined as having multi-infarct dementia (DSM-III-R criteria). Two hundred and fifty-nine patients were included (128 nimodipine, 131 placebo), and 251 were available for the intention-to-treat analysis. No significant difference between drug-treated and placebo patients was noted on the Gottfries-Brane-Steen scale score (primary efficacy criterion), the remaining neuropsychological tests (Zahlen-Verbindungs-Test, Fuld-Object-Memory Evaluation, Word Fluency Test, Digit Span, Mini-Mental State Examination), and the functional scales (index of Activity of Daily Living, Instrumental Activity of Daily Living, Rapid Disability Scale, Clinical Dementia Rating), although the majority of changes were in favor of the active drug group. A lower incidence of cerebrovascular and cardiac events was observed in the nimodipine-treated patients in comparison with the placebo group. This study failed to show a significant effect of nimodipine on cognitive, social or global assessments in patients defined as affected by multi-infarct dementia according to the DSM-III-R criteria. A post-hoc analysis (presented in an accompanying paper) suggests that nimodipine may have a favorable effect in the subgroup of patients defined as affected by subcortical (small vessel) vascular dementia
Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial. Pantoni L, Rossi R, Inzitari D, et al. J Neurol Sci. 2000 Apr 15; 175(2):124-34. In Western countries, vascular dementia (VaD) is the most common form of cognitive deterioration after Alzheimer's disease. Therapeutic trials in VaD have so far failed to yield satisfactory results. One explanation of this failure may be the etiological and clinical heterogeneity of the included patients. Patients with subcortical VaD, defined on a clinical and radiological basis, may constitute a more homogeneous group. Thus, we conducted a post-hoc subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial that evaluated the efficacy and safety of oral nimodipine administered for 6 months in 259 patients. The original patients sample was divided on the basis of head CT in those with subcortical VaD (n=92, 45 nimodipine, 47 placebo) and those with multi-infarct dementia (n=167, 83 nimodipine, 84 placebo). While in the total trial population a treatment effect could not be proved, in this subgroup analysis, the subcortical VaD patients treated with nimodipine performed better on the majority of neuropsychological tests and functional scales in comparison with patients on placebo. No trend could be evidenced in the multi-infarct dementia patients. Treatment efficacy was in particular suggested for the Zahlen-Verbindungs-Test, Fuld-Object-Memory Evaluation, Word Fluency, and for the Instrumental Activities of Daily Living scale. The results did not reach statistical significance in this small sample. Our study preliminarily indicates that nimodipine could be effective in patients with small vessel subcortical VaD and supports the rationale for a further controlled and adequately powered trial to test nimodipine in patients with subcortical VaD
Lipofuscin accumulation in ageing myocardium & its removal by meclophenoxate. Patro N, Sharma SP, Patro IK. Indian J Med Res. 1992 Jun; 96:192-8. A study was undertaken on the age-associated histochemical changes in the ventricular myocardium and the influence of meclophenoxate hydrochloride (MPH) on the age pigment lipofuscin. Sixty Wistar albino rats in three age-groups (3, 15 and 30 months old) were treated with meclophenoxate hydrochloride (100 mg/kg body wt/day, ip) for a period of 2-8 wk. Five animals each from the three age-groups served as controls. Various histochemical and micromorphometric studies were carried out on the myocardial tissue. A linear increase in the myocardial volume occupied by the pigment was observed with advancing age. As a result of meclophenoxate treatment, a gradual decrease in the myocardial volume occupied by the pigment was noted. After 4-6 wk treatment, the pigment bodies were found lodged into the capillary endothelium and the lumen, facilitating the removal of the pigment via blood stream. Histochemical and micromorphometric analyses of ventricular myocardium of albino rats have shown thus that deposition of the age-pigment, lipofuscin, can be accepted as an index of cellular ageing
The effects of piracetam on lipofuscin of the rat cerebellar and hippocampal neurons after long-term alcohol treatment and withdrawal: a quantitative study. Paula-Barbosa MM, Brandao F, Pinho MC, et al. Alcohol Clin Exp Res. 1991 Oct; 15(5):834-8. There is a growing body of evidence indicating that chronic alcohol consumption induces morphological changes in the central nervous system (CNS) similar to those observed during brain senescence, including an increased formation of lipofuscin. In addition, it was also found that alcohol withdrawal does not reverse these changes. On the contrary, most of the alterations observed during alcohol consumption worsen as happens with the increased lipofuscin formation. Thus, using our model of alcohol feeding and withdrawal, we decided to examine the effects of different drugs said to offer neuronal protection during CNS degenerative processes. The action of piracetam, a cyclic derivate of GABA and commonly used as a nootropic agent, was tested by studying the lipofuscin accumulation on the cerebellar Purkinje and hippocampal CA3 pyramidal cells in alcohol-treated and withdrawn rats. Piracetam was found to markedly decrease the formation of neuronal lipofuscin. Whatever the functional implications of this pigment, its reduction in piracetam-treated animals might be related either to a protective effect on the intraneuronal membranous system or to an antioxidant property of this molecule
Gerontopsychological studies using NAI ('Nurnberger Alters-Inventar') on patients with organic psychosyndrome (DSM III, Category 1) treated with centrophenoxine in a double blind, comparative, randomized clinical trial. Pek G, Fulop T, Zs-Nagy I. Arch Gerontol Geriatr. 1989 Jul; 9(1):17-30. A double blind clinical trial was performed on 50 persons (25 men, 25 women) over the age 60 (average age: 77 years). They suffered from dementias of medium level (DSM III, Category 1, ICD No. 299), and had been residents in an old age home longer than 3 months at the start of the trial. The patients were treated first for 2 weeks by placebo tablets and their initial performance was recorded during this period by using the Nuremberg Gerontopsychological Inventory (NAI). This was then followed by a treatment for 8 weeks with the nootropic drug, centrophenoxine (CPH), the dose of which was 2 g/day distributed in 2 x 2 tablets of Helfergin500 (Promonta, Hamburg, FRG), or with placebo tablets of identical size, then the NAI test was repeated again. Verum or placebo treatment was selected randomly and the code was revealed only after having elaborated all the results of the trial. During the treatment period four drop-outs occurred for intercurrent diseases. Evaluation was based on a semi-quantitative, intra-individual comparison of the performance before and after treatment. The results obtained suggest that CPH treatment may be useful in dementias of medium level in quite old groups of patients, since 48% of the verum group displayed improvements in the memory functions against 28% of the placebo group. CPH seems to be a useful and harmless drug in the treatment and most probably also in prevention of the dementias
Vinpocetine attenuates the metabolic dysfunction induced by amyloid beta-peptides in PC12 cells. Pereira C, Agostinho P, Oliveira CR. Free Radic Res. 2000 Nov; 33(5):497-506. The cytoprotective effect of vinpocetine [14-ethoxycarbonyl-(3alpha, 16alpha-ethyl)-14,15-eburnamine] was investigated on PC12 cells treated with the amyloid beta-peptides (Abeta) for 24 hours. Vinpocetine was shown to protect cells from the inhibition in redox status induced by exposure to Abeta25-35 and Abeta1-40, the maximal protection being achieved at a vinpocetine concentration of 40 microM. At this concentration, vinpocetine blocked the inhibition of the mitochondrial respiratory chain complexes II-III and IV and completely abolished the depletion of pyruvate levels induced by toxic concentrations of Abeta peptides. Furthermore, the accumulation of ROS in cells exposed to Abeta25-35 and Abeta1-40 evaluated using the fluorescent probe 2',7'-dichlorofluorescin (DCF), was reduced in the presence of 40 microM vinpocetine. Taken together, the data presented herein demonstrate that vinpocetine protects cells from Abeta toxicity, preventing the generation of oxidative stress due to the excessive accumulation of ROS. This study suggests that vinpocetine can exert neuroprotective properties which might be of importance and contribute to its clinical efficacy in the treatment of Alzheimer's disease or other neurodegenerative disorders in which oxidative stress is involved
The relation between antioxidants and memory performance in the old and very old. Perrig WJ, Perrig P, Stahelin HB. J Am Geriatr Soc. 1997 Jun; 45(6):718-24. OBJECTIVES: Aging processes, and among them brain aging, are thought to be associated with free radical action. It is hypothesized that plasma antioxidant vitamin levels correlate with cognitive performance in healthy older subjects. DESIGN: Longitudinal and cross-sectional comparisons. SETTING: The city of Basle, considered representative of the older urban population in Switzerland. PARTICIPANTS: A total of 442 subjects aged 65 to 94 years (mean: 75 years; 312 male, 132 female) was selected from a random sample. MEASUREMENTS: In 1993, participants were tested for memory, and plasma vitamin levels were measured for the three antioxidants alpha-tocopherol, ascorbic acid, and beta-carotene. These vitamin parameters, measured previously in 1971 in the same sample, were integrated in our analyses. In addition, plasma cholesterol, ferritin, and systolic blood pressure were taken into account. Memory variables were priming, working-memory, free recall, recognition and the WAIS-R vocabulary test (semantic memory). RESULTS: Correlations showed significant stability of the plasma antioxidants over the time lag of 22 years (alpha-tocopherol: r = .47, P < or = ".001;" beta-carotene: r = ".43," P < .001; ascorbic acid: r = ".22," P < .001). Free recall, recognition, and vocabulary (but not priming and working-memory) correlated significantly with ascorbic acid and beta-carotene in the cross-sectional 1993 data as well as in the longitudinal 1971-1993 analysis. These two antioxidants remained significant predictors, especially of semantic memory, after controlling for possible confounding variables like age, education, and gender using multiple regression analyses and ANOVAs. CONCLUSION: Among people aged 65 and older, higher ascorbic acid and beta-carotene plasma level are associated with better memory performance. These results indicate the important role played by antioxidants in brain aging and may have implications for prevention of progressive cognitive impairments
Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Petersen RC, Stevens JC, Ganguli M, et al. Neurology. 2001 May 8; 56(9):1133-42. OBJECTIVE: The goal of this project was to determine whether screening different groups of elderly individuals in a general or specialty practice would be beneficial in dete |