Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aß) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE-Aß interaction inhibitors produced positive results in transgenic AD mouse models.

Apolipoprotein E genotype, inflammatory biomarkers, and non-psychiatric multimorbidity contribute to the suicidal ideation phenotype in older age. The Salus in Apulia Study.

BACKGROUND: Possible relationships between suicidal ideation and biopsychosocial predictors in older age are unclear. In the population-based Salus in Apulia Study, we investigated the relationships among biomarkers, socio-demographic, psychopathological, inflammatory and metabolic characteristics and suicidal ideation in 1252 older subjects. METHODS: Suicidal ideation was evaluated with the brief version of the Columbia-Suicide Severity Rating Scale. Apolipoprotein E (APOE) genotype and inflammatory profile [interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] were evaluated. A machine learning algorithm, the Random Forest (RF), selected potential biopsychosocial factors associated to suicidal ideation. RESULTS: Suicidal ideators accounted for 2.32 % of subjects, were female, smokers, and obese with multimorbidity. After adjusting for age, gender, education and social dysfunction, logistic regression analyses revealed that suicidal ideation was associated to late-life depression (LLD) (odds ratio:21.71,95 % confidence interval:9.22-51.14). In the full RF model, asthma was the most important contributor to suicidal ideation. In the final RF model, education, age, and mild cognitive impairment followed by gender and global cognition were considered the most important contributors. Among biomarkers, in the final RF model, IL-6 followed by TNF-α, APOE ε4 allele presence, CRP and high-density lipoprotein cholesterol contributed most to suicidal ideation. LIMITATIONS: A relatively small number of older subjects with suicidal ideation (2.3 %); we did not distinguish between active and passive suicidal ideation. CONCLUSIONS: Although LLD is a strong determinant of suicidal ideation, other non-psychiatric factors, i.e., serum inflammation biomarkers, APOE ε4 allele, and multimorbidity, should be taken into account when evaluating a suicidal ideation phenotype in older age.

Efficacy and safety of netupitant/palonosetron combination (NEPA) in preventing nausea and vomiting in non-Hodgkin's lymphoma patients undergoing to chemomobilization before autologous stem cell transplantation.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is particularly challenging for patients receiving highly emetogenic preparative regimens before autologous stem cell transplantation (ASCT) due to the daily and continuous emetogenic stimulus of the multiple day chemotherapy. While studies have shown effective prevention of CINV during the conditioning phase with NK1 receptor antagonist (NK1RA)-containing regimens, there have been no studies evaluating antiemetic use during chemomobilization prior to ASCT. METHODS: This multicenter, open-label, phase IIa study evaluated the efficacy of every-other-day dosing of NEPA administered during chemomobilization in patients with relapsed-refractory aggressive non-Hodgkin's lymphoma. Eighty-one patients participated. RESULTS: Response rates were 77.8% for complete response (no emesis and no rescue use), 72.8% for complete control (complete response and no more than mild nausea), 86.4% for no emesis, and 82.7% for no rescue use during the overall phase (duration of chemomobilization through 48 h after). NEPA was well tolerated with no treatment-related adverse events reported. CONCLUSION: NEPA, administered with a simplified every-other-day schedule, show to be very effective in preventing CINV in patients at high risk of CINV undergoing to chemomobilization of hematopoietic stem cells prior to ASCT.

Association Between Central and Peripheral Age-Related Hearing Loss and Different Frailty Phenotypes in an Older Population in Southern Italy.

Importance: The association between age-related hearing loss (ARHL) and physical or cognitive frailty has been poorly explored. These associations could define new perspectives for delaying frailty-related processes in older age. Objective: To examine whether peripheral ARHL and age-related central auditory processing disorder (CAPD) are independently associated with physical or cognitive frailty. Design, Setting, and Participants: This cross-sectional study analyzed registry data from December 31, 2014, on 1929 older (≥65 years) participants of the Salus in Apulia Study (Southern Italy) who underwent audiologic, physical, and neuropsychological assessment. Data analysis was performed from December 12, 2019, to January 4, 2020. Main Outcomes and Measures: Prevalence of peripheral ARHL in older individuals with physical and/or cognitive frailty and those without frailty assessed using the Fried criteria (physical) and the Mini-Mental State Examination (cognitive). Multivariable logistic regression models were used to assess associations of audiologic variables with frailty phenotype. Results: Data from 1929 participants (mean [SD] age, 73.6 [6.3] years; 974 male [50.5%]) were eligible for the analyses. The prevalence of peripheral ARHL was higher in the physical frailty group (96 [26.6%]) than in the nonfrail group (329 [21.0%]) (difference, 5.61 percentage points; 95% CI, 0.63-10.59 percentage points) and in the cognitive frailty group (40 [38.8%]) than in the nonfrail group (385 [21.1%]) (difference, 17.75 percentage points; 95% CI, 8.2-27.3 percentage points). Age-related CAPD was more prevalent in the physical frailty group (62 [17.2%]) than in the nonfrail group (219 [14.0%]) (difference, 3.21 percentage points; 95% CI, -1.04 to 7.46 percentage points) and in the cognitive frailty group (28 [27.2%]) than in the nonfrail group (253 [13.9%]) (difference, 13.33 percentage points; 95% CI, 4.10-22.21 percentage points). In the multivariable models, age-related CAPD was associated with cognitive frailty in the fully adjusted model (odds ratio [OR], 1.889; 95% CI, 1.094-3.311). There was also an inverse association between the unitary increase in Synthetic Sentence Identification With the Ipsilateral Competitive Message scores, indicating a lower likelihood of this disorder, and cognitive frailty (OR, 0.989; 95% CI, 0.988-0.999). Peripheral ARHL was associated with cognitive frailty only in the partially adjusted model (OR, 1.725; 95% CI, 1.008-2.937). Conclusions and Relevance: In this cross-sectional study of 1929 participants, age-related CAPD was independently associated with cognitive frailty. Whether the management of ARHL may help prevent the development of different frailty phenotypes or improve their clinical consequences should be addressed in longitudinal studies and, eventually, well-designed randomized clinical trials.

Age-Related Central Auditory Processing Disorder, MCI, and Dementia in an Older Population of Southern Italy.

OBJECTIVE: We explored the associations of age-related central auditory processing disorder (CAPD) with mild cognitive impairment (MCI) and dementia in an older population-based cohort in Apulia, Southern Italy (GreatAGE Study). STUDY DESIGN: Cross-sectional data from a population-based study. SETTING: Castellana Grotte, Bari, Italy. SUBJECTS AND METHODS: Between 2013 and 2018, MCI, dementia, age-related CAPD (no disabling hearing loss and <50% score on the SSI-ICM test [Synthetic Sentence Identification-Ipsilateral Competing Message]), neurologic and neuropsychological examinations, and serum metabolic biomarkers assays were investigated on 1647 healthy volunteers aged >65 years. RESULTS: The prevalences of age-related CAPD, MCI, and dementia were 14.15%, 15.79%, and 3.58%, respectively. Among the subjects with MCI and dementia, 19.61% and 42.37% had age-related CAPD. In the regressive models, age-related CAPD was associated with MCI (odds ratio, 1.50; 95% CI, 1.01-2.21) and dementia (odds ratio, 2.23; 95% CI, 1.12-4.42). Global cognition scores were positively associated with increasing SSI-ICM scores in linear models. All models were adjusted for demographics and metabolic serum biomarkers. CONCLUSION: The tight association of age-related CAPD with MCI and dementia suggests the involvement of central auditory pathways in neurodegeneration, but it is not clear which is the real direction of this association. However, CAPD is a possible diagnostic marker of cognitive dysfunction in older patients.

Development of disease-modifying drugs for frontotemporal dementia spectrum disorders.

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau - this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.

Relationship between Inflammatory Food Consumption and Age-Related Hearing Loss in a Prospective Observational Cohort: Results from the Salus in Apulia Study.

Age related hearing loss (ARHL) affects about one third of the elderly population. It is suggested that the senescence of the hair cells could be modulated by inflammation. Thus, intake of anti- and pro-inflammatory foods is of high interest. METHODS: From the MICOL study population, 734 participants were selected that participated in the 2013 to 2018 examination including hearing ability and from which past data collected in 2005/2008 was available. ARHL status was determined and compared cross-sectionally and retrospectively according to clinical and lifestyle data including food and micronutrient intake. RESULTS: ARHL status was associated with higher age but not with education, smoking, relative weight (BMI), and clinical-chemical blood markers in the crossectional and retrospective analyses. Higher intake of fruit juices among ARHL-participants was seen cross-sectionally, and of sugary foods, high-caloric drinks, beer, and spirits retrospectively. No difference was found for the other 26 food groups and for dietary micronutrients with the exception of past vitamin A, which was higher among normal hearing subjects. CONCLUSIONS: Pro-inflammatory foods with a high-sugar content and also beer and spirits were found to be assocated with positive ARHL-status, but not anti-inflammatory foods. Diet could be a candidate for lifestyle advice for the prevention of ARHL.

Understanding the Amyloid Hypothesis in Alzheimer's Disease.

The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-ß (Aß) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aß peptides act as neurotoxic molecules, but only above a critical concentration [Aß]c. A threshold mechanism triggers IAD/NIAD onset only when [Aß]≥[Aß]c. In this process, APOE modifies [Aß]c threshold in an isoform-specific way. Consequently, all factors influencing Aß anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aß catabolism/clearance could contribute to exceed the threshold [Aß]c, being characteristic of each individual. In this model, AP formation does not depend on [Aß]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review.

The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014-2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect on cognitive function. For fatty acid supplementation, mainly long-chain polyunsaturated fatty acids, there was emerging evidence suggesting an impact of this approach in improving specific cognitive domains, magnetic resonance imaging (MRI) findings, and/or cognitive-related biomarkers also in selected subgroups of older subjects, although some results were conflicting. There was convincing evidence of an impact of non-flavonoid polyphenol and flavonoid supplementations in improving specific cognitive domains and/or MRI findings. Finally, there was only low evidence suggesting efficacy of intervention with homocysteine-related and antioxidant vitamins in improving cognitive functions, dementia incidence, or cognitive-related biomarkers in cognitively healthy older subjects.

Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases.

Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.

Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia.

Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease.

Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.

Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

INTRODUCTION: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations. Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND. Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient's life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

Emerging biomarkers and screening for cognitive frailty.

Physical frailty and cognitive frailty are two important targets of secondary intervention in aging research to narrow the gap between life and health span. The objective of the present narrative review was to examine clinical and epidemiological studies investigating the recently proposed construct of cognitive frailty and its subtypes, with a focus on operational definitions, clinical criteria, and emerging biomarkers potentially useful for the screening of this novel entity. Both physical frailty and frailty indexes with a multidimensional nature were associated with late-life cognitive impairment/decline, incident dementia, Alzheimer's disease (AD), mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology proposing cognitive frailty as a clinical entity with cognitive impairment related to physical causes with a potential reversibility. The new clinical and research AD criteria established by the National Institute on Aging-Alzheimer's Association and the American Psychiatric Association could improve the differential diagnosis of cognitive impairment within the cognitive frailty construct. The emerging biomarkers of sarcopenia, physical frailty, and cognitive impairment will provide the basis to establish more reliable clinical and research criteria for cognitive frailty, using different operational definitions for frailty and cognitive impairment and useful clinical, biological, and imaging markers for this novel clinical construct.

Genetic Profile, Environmental Exposure, and Their Interaction in Parkinson's Disease.

The discovery of causative mutations for Parkinson's disease (PD) as well as their functional characterization in cellular and animal models has provided crucial insight into the pathogenesis of this disorder. Today, we know that PD pathogenesis involves multiple related processes including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation of α-synuclein and impaired autophagy. However, with the exception of a few families with Mendelian inheritance, the cause of PD in most individuals is yet unknown and the identified genetic susceptibility factors have only small effect size. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, organic solvents, metals, and air pollutants, while reduced risk of PD associated with smoking cigarettes and coffee consumption. The role of environmental exposure, as well as the contribution of single genetic risk factors, is still controversial. In most of PD cases, disease onset is probably triggered by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. This review summarizes the current knowledge on causal mutation for PD, susceptibility factors increasing disease risk, and the genetic factors that modify the impact of environmental exposure.

Role of CYP2D6 Polymorphisms in the Outcome of Postoperative Pain Treatment.

OBJECTIVE: To investigate the role of CYP2D6 phenotype in the outcome of postoperative (PO) pain (POP) treatment. DESIGN: Longitudinal cohort study. Open-label trial with post hoc analysis. SETTING: General Hospital Surgery and Recovery Units. PATIENTS: Ninety unrelated Caucasians submitted to abdominal/thoracic surgery. INTERVENTIONS: Standard multimodal POP treatment including opioids (tramadol) and nonsteroidal anti-inflammatory drugs (ketoprofen) at different dosages and infusion rates according to the predicted mild, moderate, or severe POP. OUTCOME MEASURES: Pain (Numeric Rating Scale-NRS) and sedation (Ramsay Sedation Scale-RSS) up to 24 hours after surgery. By genotyping 16 CYP2D6 alleles, the four CYP2D6 phenotypes poor metabolizer (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM) were predicted. RESULTS: As compared with the CYP2D6-EM phenotype, in the early PO time (30 min) a higher RSS mean score in IM was observed (P = 0.035). A suggestion towards higher mean score in PM (P = 0.091) and a minor mean score in UM (P = 0.091) was also detected. No difference in the outcome of pain across the CYP2D6 phenotypes was observed. CONCLUSIONS: In respect to the normal CYP2D6 phenotype, our results suggested that slowly metabolizers (IMs and PMs) might have a major sedation, whereas more rapid metabolizers (UM) a minor sedation, in the early time after surgery. A minor role of CYP2D6 phenotype in PO analgesia may be suggested.

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer's disease.

OBJECTIVE: Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer's disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. METHODS: In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. RESULTS: A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510-70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. CONCLUSION: FOXO1 may influence the clinical response to AChEIs in AD patients.

Systemic oxidative stress and conversion to dementia of elderly patients with mild cognitive impairment.

Mild cognitive impairment (MCI) is regarded as a prodromal phase of late onset Alzheimer's disease (LOAD). It has been proposed that oxidative stress (OxS) might be implicated in the pathogenesis of LOAD. The aim of this study was to investigate whether a redox imbalance measured as serum level of hydroperoxides (i.e., by-products of lipid peroxidation) and/or serum antioxidant capacity might be predictive of the clinical progression of MCI to LOAD. The levels of these two markers were measured in 111 patients with MCI (follow-up: 2.0 ± 0.6 years), 105 patients with LOAD, and 118 nondemented healthy controls. Multivariate analysis adjusted for potential confounding factors, including age, gender, smoking, and comorbidities, showed a significant increase (P < 0.05) in baseline levels of OxS in MCI and LOAD as compared to cognitive healthy controls. No differences in either of OxS markers were found by comparing MCI patients who converted (n = 29) or not converted (n = 82) to LOAD. Overall, these results suggest that systemic OxS might be a precocious feature of MCI and LOAD. However, the role of OxS as an early prognostic marker of progression to LOAD needs further investigations.

[Forkhead-box-O1 locus and metabolic markers in the elderly: an association study]. / Forkhead-box-O1 locus y marcadores metabólicos en los ancianos: estudio de asociación.

INTRODUCTION: Mutations of forkhead-box-O1 (FOXO1) gene at locus 13q14.1 cause changes in biochemical parameters leading to premature aging. Protein FoxO1 participates in the regulation of biochemical pathways, including those influencing the regulation of lipid profile and glucose metabolism. These parameters are a risk factor for all-cause mortality in the elderly population. The aim of this study was to investigate the relationship between FOXO1 locus and metabolic-nutritional markers. MATERIAL AND METHODS: Single-nucleotide polymorphisms (SNP) rs2721069, rs4943794 and rs7981045 were determined in 594 hospitalized elderly (65-99 years), patients consecutively admitted to a geriatric ward, and tested the association of FOXO1 variants with biological markers by the analyses of co-variance (ANCOVA) and by Genotype Score Model statistic. RESULTS: The ANCOVA analysis, under different genetic models, revealed significant associations. In particular, assuming a dominant genetic model, a significant association with serum levels of fasting glucose was observed for rs2721069 (P=.034) and rs4943794 (P=.012). For rs4943794 a significant association assuming a free genetic model (P=.039) and an additive one (P=.012) was also observed. No significant relationship was observed between rs7981045 and the analyzed markers. The Genotype Score Model analysis confirmed a significant association between FOXO1 SNP and fasting glucose, taking the SNP rs2721069 and rs4943794 together (P=.048; ß=3.198). CONCLUSIONS: Aging is a complex process, resulting from the interaction between several factors, including environmental and genetic ones. Our findings suggest that FOXO1 locus may influence blood glucose levels in hospitalized older patients, thus being one of the genetic factors contributing to healthy aging.