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LE Magazine July 2008

Cognitive impairment

Conversion of mild cognitive impairment to dementia in elderly subjects: a preliminary study in a memory and cognitive disorder unit.

Prevalence and incidence of predementia syndromes vary as a result of different diagnostic criteria, as well as different sampling and assessment procedures. Mild cognitive impairment (MCI) is thought to be a prodromal phase of dementia and therefore highly predictive of subsequent conversion. The aim of our study was to investigate the risk of conversion to dementia for different MCI subtypes diagnosed according to standardized and recently revised criteria (amnestic; impairment of memory plus other cognitive domains; nonamnestic). Participants were recruited among the 2,866 patients referring to the Memory and Cognitive Disorders Unit of the Local Health Unit of Bologna, Maggiore Hospital, between October 2000 and February 2006. In this preliminary study we analyzed data from 52 elderly outpatients with a diagnosis of MCI and a mean follow-up of 1.21+/-0.61 years (range 0.23-3.10 years). Mean age was 72.8+/-6.6 years, males were 61.5%. Mean baseline mini mental state examination (MMSE) score was 27.1+/-1.5. There were 15 incident cases of dementia (28.8%), with Alzheimer’s disease (AD) accounting for 53.3% of all cases, AD with cerebrovascular disease for 33.4% and fronto-temporal dementia for 13.3%. Overall rate of conversion was 23.8 per 100 person-years. During the same follow-up period, 53.8% of participants remained stable and 17.3% reverted to normal. Rates of conversion for the specific MCI subtypes were 38 per 100 person-years for amnestic MCI, 20 per 100 person- years for non-amnestic MCI, and 16 per 100 person-years for memory plus other cognitive domains MCI. With respect to non-converters, converters were generally older (76.1+/-4.2 vs. 71.5+/-7.0 years, p=0.021), had a lower MMSE score (26.4+/-1.66 vs. 27.4+/-1.4, p=0.035) and a higher prevalence of atrophy at neuroimaging (73.7% vs. 42.4%, p=0.047). Moreover, with respect to non-converters, converters tended to have higher serum high density lipoprotein (HDL) levels, and lower serum folate levels. No difference was observed for the other study variables, included MCI subtype. Our findings suggest that the current definitions for MCI subtypes, particularly those referring to individuals with multiple or non-amnestic cognitive impairment, include a substantial number of individuals who may not progress to dementia. The possible role of cortical atrophy and low folate in the conversion from MCI to dementia could have important implications, because both conditions are easily identifiable. Moreover, low folate status is potentially amenable to therapeutic options. Although discouraging with respect to the clinical usefulness of currently available MCI criteria, our results raise the possibility that defining a protocol of multiple clinical risk factors may be useful in identifying MCI individuals at increased risk of conversion.

Arch Gerontol Geriatr. 2007;44 Suppl 1:233-41

Evidence of increased oxidative damage in subjects with mild cognitive impairment.

OBJECTIVE: To determine if increased levels of oxidative damage are present in the brains of persons with mild cognitive impairment (MCI), a condition that often precedes Alzheimer disease (AD). METHODS: The authors assessed the amount of protein carbonyls, thiobarbituric acid-reactive substances (TBARS), and malondialdehyde in the superior and middle temporal gyri (SMTG) and cerebellum of short postmortem interval and longitudinally evaluated normal subjects and those with MCI and early AD. RESULTS: Elevated levels of protein carbonyls (approximately 25%), malondialdehyde (approximately 60%), and TBARS (approximately 210%) were observed in the SMTG of individuals with MCI and early AD vs normal control subjects. The elevation in TBARS was associated with the numbers of neuritic but not diffuse plaques. Levels of protein carbonyls increased as delayed verbal memory performance declined. CONCLUSION: Oxidative damage occurs in the brain of subjects with mild cognitive impairment, suggesting that oxidative damage may be one of the earliest events in the onset and progression of Alzheimer disease.

Neurology. 2005 Apr 12;64(7):1152-6

Oxidative damage in mild cognitive impairment and early Alzheimer’s disease.

Increasing evidence supports a role for oxidative damage in the pathogenesis of Alzheimer’s disease (AD). Multiple studies show significantly increased levels of lipid peroxidation and protein, DNA, and RNA oxidation in vulnerable regions of the brain of patients with late-stage AD (LAD). More recent studies of patients with amnestic mild cognitive impairment (MCI), the earliest clinical manifestation of AD, show similar patterns of oxidative damage. These observations suggest that oxidative damage to critical biomolecules occurs early in the pathogenesis of AD and precedes pronounced neuropathologic alterations. Because oxidative damage begins early in the progress of the disease, it represents a potential therapeutic target for slowing the onset and progression of AD.

J Neurosci Res. 2007 Nov 1;85(14):3036-40

(R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis.

Age-related depletion of GSH levels and perturbations in its redox state may be especially deleterious to metabolically active tissues, such as the heart and brain. We examined the extent and the mechanisms underlying the potential age-related changes in cerebral and myocardial GSH status in young and old F344 rats and whether administration of (R)-alpha-lipoic acid (LA) can reverse these changes. Our results show that GSH/GSSG ratios in the aging heart and the brain declined by 58 and 66% relative to young controls, respectively (p < 0.001). Despite a consistent loss in GSH redox status in both tissues, only cerebral GSH levels declined with age (p < 0.001). To discern the potential mechanisms underlying this differential loss, the levels and the activities of gamma-glutamylcysteine ligase (GCL) and cysteine availability were determined. There were no significant age-related changes in substrate or enzyme levels, or GCL activity when saturating amounts of substrates were provided. However, kinetic analysis of GCL in brains of old rats displayed a significant increase (p < 0.05) in the apparent [Km] for cysteine (Km cys) vs. young rats (84.3+/-25.4 vs. 179.0+/-49.0; young and old, respectively), resulting in a 40% loss in apparent catalytic turnover of the enzyme. Thus, the age-related decline in total GSH appears to be mediated, in part, by a general decrement in GCL catalytic efficiency. Treating old rats with LA (40 mg/kg body wt; by i.p.) markedly increased tissue cysteine levels by 54% 12 h following treatment and subsequently restored the cerebral GSH levels. Moreover, LA improved the age-related changes in the tissue GSH/GSSG ratios in both heart and the brain. These results demonstrate that LA is an effective agent to restore both the age-associated decline in thiol redox ratio as well as increase cerebral GSH levels that otherwise decline with age.

Arch Biochem Biophys. 2004 Mar 1;423(1):126-35

L-carnitine and DL-alpha-lipoic acid reverse the age-related deficit in glutathione redox state in skeletal muscle and heart tissues.

In the present study, the glutathione redox system was evaluated as a function of age in rat heart and muscle. A decline in reduced glutathione (GSH) levels is associated with aging and many age-related diseases. The objective of this study was to determine whether L-carnitine and DL-alpha-lipoic acid could compensate for GSH depletion in protection against oxidative insults. In this study we determined reduced glutathione, oxidized glutathione (GSSG), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) in skeletal muscle and heart of young and aged rats. We also calculated GSH/GSSG molar ratio and glutathione redox system. GSH levels were significantly lowered in aged rats than young rats. Conversely, GSSG levels were significantly high in aged rats. GSH/GSSG molar ratio and redox index were found to decreased in aged rats. The activities of GPx, GR, and G6PDH were found to be decreased in aged rats when compared with young rats. Supplementation of carnitine and lipoic acid to aged rats significantly increased the GSH levels thereby increasing the activity of GPx, GR, and G6PDH in skeletal muscle and heart of aged rats. In conclusion, our study suggests that supplementation of carnitine and lipoic acid to aged rats improves the glutathione redox system.

Mech Ageing Dev. 2004 Jul;125(7):507-12

Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites.

Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. Some of this decay can be reversed in aged animals by feeding them the mitochondrial metabolites acetylcarnitine and lipoic acid. In this review, we summarize our recent studies on the effects of these mitochondrial metabolites and mitochondrial antioxidants (alpha-phenyl-N-t-butyl nitrone and N-t-butyl hydroxylamine) on the age-associated mitochondrial decay of the brain of old rats, neuronal cells, and human diploid fibroblast cells. In feeding studies in old rats, these mitochondrial metabolites and antioxidants improve the age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age-associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltransferase. These mitochondrial metabolites and antioxidants protect neuronal cells from neurotoxin- and oxidant-induced toxicity and oxidative damage; delay the normal senescence of human diploid fibroblast cells, and inhibit oxidant-induced acceleration of senescence. These results suggest a plausible mechanism: with age, increased oxidative damage to proteins and lipid membranes, particularly in mitochondria, causes a deformation of structure of enzymes, with a consequent decrease of enzyme activity as well as substrate binding affinity for their substrates; an increased level of substrate restores the velocity of the reaction and restores mitochondrial function, thus delaying mitochondrial decay and aging. This loss of activity due to coenzyme or substrate binding appears to be true for a number of other enzymes as well, including mitochondrial complex III and IV.

Ann N Y Acad Sci. 2002 Apr;959:133-66

Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease.

The efficacy of acetyl-L-carnitine (gamma-trimethyl- beta-acetylbutyrobetaine (Alcar) in mild cognitive impairment (MCI) and mild (early) Alzheimer’s disease (AD) was investigated with a meta-analysis of double-blind, placebo-controlled prospective, parallel group comparison studies of at least 3 months duration. The duration of the studies was 3, 6 or 12 months and the daily dose varied between studies from 1.5-3.0 g/day. An effect size was calculated to reflect the results of the variety of measures used in the studies grouped into the categories of clinical tests and psychometric tests. The effect sizes from the categories were integrated into an overall summary effect size. The effect size for the Clinical Global Impression of Change (CGI-CH) was calculated separately. Meta-analysis showed a significant advantage for Alcar compared to placebo for the integrated summary effect [ES =0.201, 95% confidence interval (CI)=0.107-0.295] and CGI-CH (ES =0.32, 95% CI=0.18-0.47). The beneficial effects were seen on both the clinical scales and the psychometric tests. The advantage for Alcar was seen by the time of the first assessment at 3 months and increased over time. Alcar was well tolerated in all studies.

Int Clin Psychopharmacol. 2003 Mar;18(2):61-71

Dendritic spine loss in hippocampus of aged rats. Effect of brain phosphatidylserine administration.

Dendritic spine density of pyramidal cells in region CA1 of the hippocampus has been evaluated in young (3 months), old (27 months) and old phosphatidylserine (BC-PS)-treated rats. BC-PS (50 mg/kg, suspended in tap water) was administered daily, starting at the age of 3 months until 27 months. Spine density was analyzed on Golgi-stained pyramidal neurons by a computerized analysis system. In 27-month-old rats, spine density showed with respect to 3-month-old animals, a significant decrease in both basal and apical dendrites (p less than 0.01; one-way ANOVA), with a mean loss of 12.11% in the basal dendrites and of 10.64% in the apical ones. In 27-month-old rats treated with BC-PS, values of spine density were not statistically different when compared to those of 3-month-old animals. The mechanisms underlying the beneficial effect of BC-PS treatment on neuronal connectivity might be explained on the basis of its pharmacological actions on neuronal membranes [9], neurotransmission [43] and/or interaction with NGF [7].

Neurobiol Aging. 1987 Nov-Dec;8(6):501-10

Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration.

This double-blind study assesses the therapeutic efficacy and the safety of oral treatment with phosphatidylserine (BC-PS) vs placebo (300 mg/day for 6 months) in a group of geriatric patients with cognitive impairment. A total of 494 elderly patients (age between 65 and 93 years), with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global Deterioration Scale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty-nine patients dropped out within the 6-month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine-treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. In addition, clinical evaluation and laboratory tests demonstrated that BC-PS was well tolerated. These results are clinically important since the patients were representative of the geriatric population commonly met in clinical practice.

Aging (Milano). 1993 Apr;5(2):123-33

Glutathione metabolism during aging and in Alzheimer disease.

The concentration of glutathione (GSH), the most abundant intracellular nonprotein thiol and important antioxidant, declines with age and in some age-related diseases. The underlying mechanism, however, is not clear. The previous studies from our laboratory showed that the age-dependent decline in GSH content in Fisher 344 rats was associated with a downregulation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH synthesis. Our recent studies further indicated that the activity and mRNA content of glutathione synthase (GS), which catalyzes the second reaction in de novo GSH synthesis, were also decreased with age in some tissues. No age-associated change was observed in glutathione reductase or gamma-glutamyl transpeptidase activities. Also, although GSH content declined with age in both male and female mice, male mice experienced more dramatic age-associated decline in many tissues/organs than female mice. Furthermore, we found that GSH content was significantly decreased in the red blood cells from male Alzheimer disease patients, which was associated with decreases in GCL and GS activities. Finally, we showed that estrogen increased GSH content, GS and GR activities, and GCL gene expression in the liver of both male and female mice. Taken together, our results suggest that (1) GCL plays a critical role in maintaining GSH homeostasis under both physiological and pathological conditions; (2) decreased GSH content may be involved in AD pathology in humans; and (3) estrogen increases GSH content in mice by multiple mechanisms.

Ann N Y Acad Sci. 2004 Jun;1019:346-9

Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death.

Beta-amyloid peptide is considered to be responsible for the formation of senile plaques that accumulate in the brains of patients with Alzheimer’s disease. There has been compelling evidence supporting the idea that beta-amyloid-induced cytotoxicity is mediated through the generation of reactive oxygen intermediates (ROIs). Considerable attention has been focused on identifying phytochemicals that are able to scavenge excess ROIs, thereby protecting against oxidative stress and cell death. Resveratrol (3,5,4’-trihydroxy-trans-stilbene), a phytoalexin found in the skin of grapes, has strong antioxidative properties that have been associated with the protective effects of red wine consumption against coronary heart disease (“the French paradox”). In this study, we have investigated the effects of resveratrol on beta-amyloid-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with beta-amyloid exhibited increased accumulation of intracellular ROI and underwent apoptotic death as determined by characteristic morphological alterations and positive in situ terminal end-labeling (TUNEL staining). Beta-amyloid treatment also led to the decreased mitochondrial membrane potential, the cleavage of poly(ADP-ribose)polymerase, an increase in the Bax/Bcl-X(L) ratio, and activation of c-Jun N-terminal kinase. Resveratrol attenuated beta-amyloid-induced cytotoxicity, apoptotic features, and intracellular ROI accumulation. Beta-amyloid transiently induced activation of NF-kappaB in PC12 cells, which was suppressed by resveratrol pretreatment.

Free Radic Biol Med. 2003 Apr 15;34(8):1100-10

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