Recomendaciones generales de los tratamientos antipsicóticos

Study I of this project shows that the plasma concentrations of different vitamin E forms are related to the diagnosis of AD and MCI in older adults. All previous cross-sectional clinical studies examined only α-tocopherol in subjects with dementia/AD, reporting either reduced plasma/serum levels in diseased individuals compared to controls138-149 or no association.148,150-155 Some studies showed decreased plasma α-tocopherol also in subjects with MCI,138,147 while other studies did not confirm this finding.115,136 Cross-sectional analyses in population-based studies have also shown conflicting results, and only one study (CSBA) analyzed all tocopherol forms.115,156,157 In the CSBA cohort plasma tocopherols were assessed in a population of older adults (age 65+ years) with normal cognition, MCI, or dementia, and higher δ-tocopherol levels were found in subjects with dementia (compared to MCI and CN) when analyzing vitamin E/cholesterol ratio. No differences were found among the three groups when tocopherols levels were analyzed as absolute values.115

In the AddNeuroMed cohort, both cases of AD and MCI had lower plasma levels of different vitamin E forms, and reduced values for indices representing total vitamin E amounts, compared to CN subjects. This pattern was evident both when considering vitamin E values standardized by cholesterol and when evaluating absolute values of vitamin E. Further, both clinical diagnosis of AD and MCI were characterized by increased plasma indices of vitamin E oxidative/nitrosative damage.

Within the AddNeuroMed cohort, it has also been shown that the combined analysis of vitamin E plasma levels and automated MRI measures can accurately distinguish AD and MCI cases from CN individuals. Additionally, it can prospectively identify MCI cases that will progress to a clinical diagnosis of AD after one year (Study II).

The development of biomarkers for AD is an active area of research. To date, neuroimaging- and CSF-based markers have been the most widely studied. Structural MRI, PET, and CSF parameters have been included in the new diagnostic criteria for AD, MCI due to AD and preclinical AD. However, many clinical settings do not have the ability to implement some of these techniques, and further validation and standardization of the

67 proposed biomarkers would be advantageous.66,67 Brain atrophy evidenced by MRI is an indicator of neuronal injury, and combined assessment of different brain regions can highlight regional patterns of abnormalities more specific for AD compared to the evaluation of single structures.69 For example hippocampal atrophy is not specific to AD; it can also be present in hippocampal sclerosis and frontal lobe dementia.

Blood based markers can represent inexpensive and minimally-invasive tools for early identification and monitoring of AD progression. Obtaining blood samples can easily be implemented in large scale screening and prevention studies, and for repeated measures. Several studies suggest that plasma levels of different proteins and metabolites might be related to AD pathology, including indices of OS/NS and inflammation.43,44,73,74,76,86,147,247 Such plasma markers could be a systemic metabolic hallmark of AD or reflect a change in plasma secondary to a disease-specific process in the brain. A recent study of healthy older adults concluded that pattern of nutrient biomarkers detected in plasma correlated with cognitive functioning and MRI brain volumes. The plasma profile high in α-tocopherol was associated with better global cognition and reduced total brain atrophy.161 Plasma indices of vitamin E status could be indicators reflecting biochemical changes associated with AD pathophysiology. However, the challenge for blood-based biomarkers is still considerable. The main difficulty when studying blood is due to the variability of plasma components in response to non-AD influences (i.e., drugs, time of sampling, environmental factors). The combination of different methods, such as MRI, CSF parameters, blood measures, and neuropsychological data allow for the evaluation of different aspects of AD, increasing their diagnostic and prognostic value through a multimodality markers approach. A recent study within the ADNI project reported that combinations of neuropsychological data, CSF, and MRI measures attained an accuracy of 67.1% in predicting MCI conversion to AD after two years, outperforming the evaluation of the single modality markers.75 In another survey, the combination of MRI, CSF, and FDG-PET separated MCI converters from non-converters with a sensitivity of 91.5% and a specificity of 73.4%.71 However, CSF and FDG-PET are not easy to implement in large scale studies or for repeated measures. In Study II, the joint evaluation of plasma vitamin E and MRI measures increased the accuracy in separating AD and MCI from CN subjects to 98% and 91%, respectively. This combination of parameters was also able to classify 85% of the MCI converters as AD-like and 67% of the stable MCI as CN-like subjects. In a previous study using data from AddNeuroMed and ADNI cohorts, MRI data were able to identify 71% of the MCI converters and 60% of the stable MCI subjects. Thus the joint evaluation of MRI and plasma vitamin E indices seems to provide a more robust predictive tool.69

Other antioxidant micronutrients

Vitamin E is the main lipid-soluble, non-enzymatic antioxidant in the human body, in which other non-enzymatic antioxidants are also available. Those are a combination of hydrophilic and lipophilic compounds, which interact with each other and with enzymatic

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antioxidants for a fine tuning of the redox status. In the AddNeuroMed population (Study I) β-carotene and retinol (non-enzymatic, lipophilic antioxidants) were also analysed, to provide a broader picture of the antioxidant micronutrients status in cognitive impairment. Both β-carotene and retinol (vitamin A) plasma levels were reduced in AD and MCI cases compared to CN individuals, supporting the presence of an altered antioxidant micronutrient status in these disorders.

High plasma levels or high dietary intake of carotenoids/β-carotene have been associated with better cognitive performance160,248 and reduced risk of cognitive decline and AD in some,249 but not all, studies.180 Two RCTs reported protective benefits for cognition in subjects supplemented with β-carotene.250,251 In some population-based studies plasma vitamin A was not related to dementia diagnosis.157,164 while other studies reported reduced levels in subjects with dementia or MCI.139,147 Carotenoids and retinol are present in the brain,112 and evidence of their antioxidant and anti-amyloidogenic properties warrant further investigation of their role in neurodegeneration.252

6.2 Vitamin E, Alzheimer’s disease and mild cognitive impairment: general