Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease

Oxidative stress has been shown to be a triggering event in the pathogenesis of Alzheimer's disease (AD). However, little evidence exists on the role of oxidative imbalance in Mild Cognitive Impairment (MCI), a group with a high risk of progression to AD. We therefore assessed the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species in 85 MCI patients, 42 mild AD patients and 37 age-matched controls. In mild AD patients, the plasma levels of vitamin E were significantly decreased, while the plasma concentration of oxidized glutathione was increased in both MCI and mild AD patients. An increase in plasmatic and erythrocytes oxidative markers was also observed in MCI and mild AD patients as compared to controls. In both patients groups, increased levels of plasma antioxidants were found in females, whereas apolipoprotein E epsilon4 allele carriers showed higher indices of intracellular oxidative markers. Moreover, in MCI patients, cognitive function positively correlates with antioxidant levels. This study shows that most of the oxidative changes found in mild AD patients are already present in the MCI group, and that progression to AD might be accompanied by antioxidant depletion.     

Performance of aβ1-40, aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.     

CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease

Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.     

Vitamin E and enzymatic/oxidative stress-driven oxysterols in amnestic mild cognitive impairment subtypes and Alzheimer's disease

Oxidative stress,which contributes to neuronal damage, is thought to be a pathophysiologicalmechanism of Alzheimer's disease (AD). Markers of oxidative stress may appear early in the preclinical, mild cognitive impairment (MCI) phase of AD.We investigated the interaction among enzymatic-derived oxysterols (24S-hydroxycholesterol and 27-hydroxycholesterol), markers of oxidative stress, including free radical-related oxysterols (7 hydroxycholesterol and 7-ketocholesterol), and vitamin E in AD patients and two amnestic MCI subtypes, amnestic single-domain MCI (a-MCI) subjects, and multidomain MCI (md-MCI) subjects, compared to healthy control subjects (HC). The study included 37 patients with AD, 24 with a-MCI, 29 with md-MCI, and 24 HC. Plasma assessments were made using isotope dilution-mass spectrometry. Although we found no significant change in free radical- or enzymatic-derived oxysterol concentrations in AD or MCI patients, vitamin E levels corrected for cholesterol were reduced in AD patients compared to HC. Results suggest that AD patients have upregulated cerebral oxidative stress or a nutritional deficit of vitamin E. The oxysterols investigated here are not useful markers for diagnosing AD or MCI.     

Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease

Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = -0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders.     

Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease

Alzheimer's disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42, APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia.     

Peripheral antioxidant markers in mild cognitive impairment and its progression to dementia

Mild cognitive impairment (MCI) is recognized as a prodromal phase of dementing disorders, and it has been suggested that oxidative stress may play a role in the pathogenesis of Alzheimer's disease (AD), and in predicting progression of MCI to AD. In the present article, on the basis of an increasing body of evidence from cross-sectional and longitudinal studies, we discussed the issue of the possible impact of antioxidant compounds from diet and supplementation on MCI and its progression to AD.     

The new Alzheimer’s criteria in a naturalistic series of patients with mild cognitive impairment

To test the validity of the new diagnostic criteria for Alzheimer’s disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren’s cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz’s t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70–0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.     

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.     

Cognitive Decline in Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease: A Prospective Cohort Study

ObjectiveWe explored whether the mild cognitive impairment (MCI) stages of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) differ in their cognitive profiles, and longitudinal progression.DesignA prospective, longitudinal design was utilized with annual follow-up (Max 5 years, Mean 1.9, standard deviation 1.1) after diagnosis. Participants underwent repeated cognitive testing, and review of their clinical diagnosis and symptoms, including evaluation of core features of DLB.SettingThis was an observational study of independently living individuals, recruited from local healthcare trusts in North East England, UK.ParticipantsAn MCI cohort (n = 76) aged ≥60 years was utilized, differentially diagnosed with MCI due to AD (MCI-AD), or possible/probable MCI with Lewy bodies (MCI-LB).MeasurementsA comprehensive clinical and neuropsychological testing battery was administered, including ACE-R, trailmaking tests, FAS verbal fluency, and computerized battery of attention and perception tasks.ResultsProbable MCI-LB presented with less impaired recognition memory than MCI-AD, greater initial impairments in verbal fluency and perception of line orientation, and thereafter demonstrated an expedited decline in visuo-constructional functions in the ACE-R compared to MCI-AD. No clear diagnostic group differences were found in deterioration speeds for global cognition, language, overall memory, attention or other executive functions.ConclusionThese findings provide further evidence for differences in severity and decline of visuospatial dysfunctions in DLB compared with AD; further exploration is required to clarify when and how differences in attention, executive, and memory functions emerge, as well as speed of decline to dementia.     

Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer’s disease

Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.     

Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer's disease

Numerous investigations point to the importance of oxidative imbalance in mediating AD pathogenesis. Accumulated evidence indicates that lipid peroxidation is an early event during the evolution of the disease and occurs in patients with mild cognitive impairment (MCI). Because MCI represents a condition of increased risk for Alzheimer's disease (AD), early detection of disease markers is under investigation. Previously we showed that HNE-modified proteins, markers of lipid peroxidation, are elevated in MCI hippocampus and inferior parietal lobule compared to controls. Using a redox proteomic approach, we now report the identity of 11 HNE-modified proteins that had significantly elevated HNE levels in MCI patients compared with controls that span both brain regions: Neuropolypeptide h3, carbonyl reductase (NADPH), alpha-enolase, lactate dehydrogenase B, phosphoglycerate kinase, heat shock protein 70, ATP synthase alpha chain, pyruvate kinase, actin, elongation factor Tu, and translation initiation factor alpha. The enzyme activities of lactate dehydrogenase, ATP synthase, and pyruvate kinase were decreased in MCI subjects compared with controls, suggesting a direct correlation between oxidative damage and impaired enzyme activity. We suggest that impairment of target proteins through the production of HNE adducts leads to protein dysfunction and eventually neuronal death, thus contributing to the biological events that may lead MCI patients to progress to AD.     

Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment

Abstract

Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2±210.5; 581.9±379.4; and 777.5±467.8 pg/l respectively; P<0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8±463.0; stable MCI, 724.0±343.4; P=0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR=3.0 CI_95% [1.2–7.8], P=0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR=4.4 CI_95% [1.6–12.1], P=0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.     

Longitudinal changes of CSF biomarkers in Alzheimer's disease

Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF amyloid-β (Aβ)(42), tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ(42), highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ(42) level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease.     

Cognitive profiles in Alzheimer's disease and in mild cognitive impairment of different etiologies

There has been increasing interest in determining whether amnestic, nonamnestic and multiple-domain subtypes of mild cognitive impairment (MCI) reflect different disease etiologies. In this study, we examined the extent to which cognitive profiles of nondemented patients with MCI diagnosed with prodromal Alzheimer's disease (AD) differed from those MCI patients diagnosed with vascular disease. We also compared these diagnostic groups to mildly demented patients diagnosed with AD and normal elderly controls. Results indicate that a majority of both MCI-AD and MCI-vascular patients experienced amnestic features and that multiple-domain was the most common presentation. MCI-AD and MCI-vascular groups did not differ on neuropsychological measures tapping memory, language, visuospatial skills/praxis or executive function. Further both MCI groups could be distinguished from dementia patients with regards to performance on measures of memory but not on non-memory measures. Considerable variability was observed in the degree of memory impairment among MCI patients with scores as much as 6 standard deviations below expected mean values. MCI-AD and MCI-vascular patients frequently exhibit both common and overlapping amnestic and nonamnestic features. The implication of these findings for future clinical research is discussed.     

Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment

Cerebrospinal fluid (CSF) measurements of amyloid-β42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau) may be used to predict future Alzheimer's disease (AD) dementia in patients with mild cognitive impairment (MCI). The precise temporal development of these biomarkers in relation to clinical progression is unclear. Earlier studies have been hampered by short follow-up. In an MCI cohort, we selected 15 patients who developed AD (MCI-AD) and 15 who remained cognitively stable during 4 years of follow-up. CSF was sampled at three serial occasions from each patient and analyzed for Aβ peptides, the soluble amyloid-β protein precursor protein fragments sAβPPα and sAβPPβ, T-tau, P-tau, and chromogranin B, which is a protein linked to regulated neuronal secretion. We also measured, for the first time in MCI patients, an extended panel of Aβ peptides by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry (MS). Most biomarkers were surprisingly stable over the four years with coefficients of variation below or close to 10%. However, MCI-AD patients decreased in CSF AβX??? and chromogranin B concentrations, which may indicate a reduced number of functional neurons or synapses with disease progression. The MS Aβ peptide panel was more useful than any single Aβ peptide to identify MCI-AD patients already at baseline. Knowledge on these biomarkers and their trajectories may facilitate early diagnosis of AD and be useful in future clinical trials to track effects of disease modifying drugs.     

Diffusion tensor imaging based white matter changes and antioxidant enzymes status for early identification of mild cognitive impairment

Mild cognitive impairment (MCI) is an early stage of dementia. The changes in white matter integrity and antioxidant enzymes levels are crucial in onset and progression to Alzheimer’s disease (AD). To elucidate the changes in cognitive performance, white matter integrity, oxidative stress marker, for early detection of prodromal state of AD. Fifty cases of MCI and controls (55-75 years) were subjected to Mini Mental State Examination (MMSE), diffusion tensor imaging (DTI) followed by estimation of superoxide dismutase, glutathione peroxidase and lipid peroxidation in serum of MCI and control population. The MMSE scores of MCI subjects were (28±2 - 22.6±1) as compared with controls (28±1- 29±1). DTI metrics fractional anisotropy (FA) values in right and left frontal lobe, fornix, corpus callosum, while apparent diffusion coefficient (ADC) values in right temporal lobe, hippocampus head, corpus callosum right, and forcep major were significantly altered in MCI as compared with controls. Superoxide dismutase, glutathione peroxidase level were lower while lipid peroxidation marker malondialdehyde (MDA) was increased in patients with MCI as compared with controls. The study emphasized that changes in neuro-psychological performance, white matter integrity and antioxidant enzymes level provide early signature for diagnosis of MCI.     

Reduced platelet amyloid precursor protein ratio (APP ratio) predicts conversion from mild cognitive impairment to Alzheimer’s disease

Studies have shown that platelet APP ratio (representing the percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein) is reduced in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we sought to determine if baseline APP ratio predicts the conversion from MCI to AD dementia after 4 years of longitudinal assessment. Fifty-five older adults with varying degrees of cognitive impairment (34 with MCI and 21 with AD) were assessed at baseline and after 4 years. MCI patients were re-classified according to the conversion status upon follow-up: 25 individuals retained the diagnostic status of MCI and were considered as stable cases (MCI-MCI); conversely, in nine cases the diagnosis of dementia due to AD was ascertained. The APP ratio (APPr) was determined by the Western blot method in samples of platelets collected at baseline. We found a significant reduction of APPr in MCI patients who converted to dementia upon follow-up. These individuals had baseline APPr values similar to those of demented AD patients. The overall accuracy of APPr to identify subjects with MCI who will progress to AD was 0.74 ± 0.10, p = 0.05. The cut-off of 1.12 yielded a sensitivity of 75 % and a specificity of 75 %. Platelet APPr may be a surrogate marker of the disease process in AD, with potential implications for the assessment of abnormalities in the APP metabolism in patients with and at risk for dementia. However, diagnostic accuracy was relatively low. Therefore, studies in larger samples are needed to determine whether APPr may warrant its use as a biomarker to support the early diagnosis of AD.     

Vitamin C restores behavioral deficits and amyloid-β oligomerization without affecting plaque formation in a mouse model of Alzheimer's disease

Oxidative stress is related to the pathogenesis of Alzheimer's disease (AD) characterized by progressive memory impairment. Soluble amyloid-β (Aβ) oligomers cause cognitive loss and synaptic dysfunction rather than senile plaques in AD. The decline of the antioxidant status is associated with dementia in AD patients, especially low levels of vitamin C. Our group previously reported a relationship between anti-aging and supplementation of vitamin C derivatives. Here we report that vitamin C mitigated Aβ oligomer formation and behavioral decline in an AD mouse model treated with a vitamin C solution for 6 months. The attenuation of Aβ oligomerization was accompanied with a marked decrease in brain oxidative damage and in the ratio of soluble Aβ?? to Aβ??, a typical indicator of AD progression. Furthermore, the intake of vitamin C restored the declined synaptophysin and the phosphorylation of tau at Ser396. On the other hand, brain plaque deposition was not altered by the dietary intake of vitamin C. These results support that vitamin C is a useful functional nutrient for the prevention of AD.     

Vitamin E as an antioxidant/free radical scavenger against amyloid beta-peptide-induced oxidative stress in neocortical synaptosomal membranes and hippocampal neurons in culture: insights into Alzheimer's disease

Amyloid beta-peptide (Abeta), the major constituent in senile plaques in Alzheimer's disease (AD) brain, is thought by many researchers to be central to neurotoxicity in AD brain. Increasing evidence from many laboratories indicates that AD brain is under oxidative stress, with strong evidence of protein oxidation, lipid peroxidation, and peroxynitrite damage. A link between the central role of Abeta and oxidative stress in AD brain may be Abeta-associated free radical oxidative stress. If so, antioxidants such as vitamin E should modulate Abeta-induced oxidative damage and neurotoxicity in brain cells. This review summarizes studies of Abeta-associated free radical oxidative stress and its inhibition by vitamin E in cortical synaptosomal membranes and hippocampal neuronal cells in culture. Taken together with the recent report that vitamin E slows the progression of AD, this review strongly supports a central role of Abeta-associated free radical oxidative stress in neurotoxicity in AD brain.