HDV RNA Levels and Progression of Hepatitis Delta Infection: A 14 Year Follow Up Experience in Italy.

BACKGROUND: Identification of outcome predictors is one of the unmet needs in chronic HDV infection. Until recently, no reliable quantitative assays for HDV RNA were available. AIMS: To evaluate the impact of baseline viremia on natural history of HDV infection in a cohort of patients whose serum samples were stored at their first visit 15 years ago. METHODS: Quantitative HBsAg, HBeAg, HBeAb, HBV DNA, HDV RNA, genotypes, and liver disease severity were assessed at baseline. Patients who were no longer on active follow-up were recalled and re-evaluated in August 2022. RESULTS: The majority of patients were male (64.9%); the median age was 50.1 years; and all patients were Italian, with only three born in Romania. All were HBeAg negative with HBV genotype D infection. Patients were subdivided three groups: 23 were in active follow-up (Group 1), 21 were recalled due to no longer being in follow-up (Group 2), and 11 died (Group 3). Liver cirrhosis was diagnosed in 28 subjects at the first visit; 39.3% of diagnosed patients were in Group 3, 32.1% were in Group 1 and 28.6% were in Group 2 (p = 0.001). Baseline HBV DNA IU/mL Log10 were 1.6 (1.0-5.9) in Group 1, 1.3 (1.0-4.5) in Group 2, and 4.1 (1.5-4.5) in Group 3; median baseline HDV RNA Log10 levels were 4.1 (0.7-6.7) in Group 1, 3.2 (0.7-6.2) in Group 2, and 5.2 (0.7-6.7) in Group 3, resulting significantly higher rates among patients in Group 3 compared to the other groups (p = 0.038). Eighteen patients in Group 2, as compared to 7 in Group 1, had undetectable HDV RNA at the follow-up evaluation (p = 0.001). CONCLUSIONS: HDV chronic infection is a heterogeneous disease. It may not only progress but also improve over time in patients, who eventually become HDV RNA-undetectable. HDV RNA levels may help identify the subgroup of patients with less progressive liver disease.

High Rates of Hidden HCV Infections among Hospitalized Patients Aged 55-85.

BACKGROUND AND AIMS: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a hospital-wide project focusing on inpatients born from 1935 to 1985 and conducted it in our institution. METHOD: All inpatients aged 35 to 85, admitted from 10 February 2020 to 9 February 2021 for many different diseases and conditions underwent HCV antibody (HCVAb) testing by third-generation ELISA. When positive, reflex HCV RNA testing and genotyping were performed. Clinical history, fibrosis diagnosis, laboratory data and concomitant medications were available for all. RESULTS: The HCV screening rate of inpatients was 100%. In total, 11,748 participants were enrolled, of whom 53.50% were male. The HCVAb positivity rate was 3.03%. The HCVAb rate increased with age and was higher for patients born between 1935 and 1944 (4.81%). The rate of HCV RNA positivity was 0.97%. The vast majority (80.70%) of HCV RNA-positive participants were 55 or older; in about 40% of cases, HCV RNA-positive patients were unaware of their infection. Although 16 patients died after HCV chronic infection diagnosis (two due COVID-19) or HCV treatment prescription (one due to COVID-19), 74.56% of patient HCV diagnoses were linked to HCV treatment, despite their co-morbidities. All patients older than 65 who died had an active HCV infection. CONCLUSION: The present study revealed a rate of active HCV infections among inpatients lower than what has been reported in the past in the general population; this appears to be a result of the widespread use of pangenotypic direct-acting antiviral agents (DAAs). The overall rate of active infection was lower than the rate observed in the 1935-1954 cohort. The high rate of inpatients unaware of HCV infections and the high number of deaths among subjects with an active HCV infection born from 1935 to 1954, suggest that, at least in southern Italy, targeted screening of this birth cohort may be required to reduce the number of undiagnosed cases and hidden infections.

Examining the association between genetic liability for schizophrenia and psychotic symptoms in Alzheimer's disease.

Psychosis (delusions or hallucinations) in Alzheimer's disease (AD + P) occurs in up to 50% of individuals and is associated with significantly worse clinical outcomes. Atypical antipsychotics, first developed for schizophrenia, are commonly used in AD + P, suggesting shared mechanisms. Despite this implication, little empirical research has been conducted to examine whether there are mechanistic similarities between AD + P and schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with AD + P. Schizophrenia PRS was calculated using Psychiatric Genomics Consortium data at ten GWAS p value thresholds (PT) in 3111 AD cases from 11 cohort studies characterized for psychosis using validated, standardized tools. Association between PRS and AD + P status was tested by logistic regression in each cohort individually and the results meta-analyzed. The schizophrenia PRS was associated with AD + P at an optimum PT of 0.01. The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.18-fold increased risk (95% CI: 1.06-1.3; p = 0.001). These new findings point towards psychosis in AD-and particularly delusions-sharing some genetic liability with schizophrenia and support a transdiagnostic view of psychotic symptoms across the lifespan.

Pharmacogenetics in the clinical analysis laboratory: clinical practice, research, and drug development pipeline.

Introduction: Over the last decade, the spread of next-generation sequencing technology along with the rising cost in health management in national health systems has led to widespread use/abuse of pharmacogenetic tests (PGx) in the practice of many clinical disciplines. However, given their clinical significance, it is important to standardize these tests for having an interaction with the clinical analysis laboratory (CAL), in which a PGx service can meet these requirements. Areas covered: A diagnostic test must meet the criteria of reproducibility and validity for its utility in the clinical routine. This present review mainly describes the utility of introducing PGx tests in the CAL routine to produce correct results useful for setting up personalized drug treatments. Expert opinion: With a PGx service, CALs can provide the right tool to help clinicians to make better choices about different categories of drugs and their dosage and to manage the economic impact both in hospital-based settings and in National Health Services, throughout electronic health records. Advances in PGx also allow a new approach for pharmaceutical companies in order to improve drug development and clinical trials. As a result, CALs can achieve a powerful source of epidemiological, clinical, and research findings from PGx tests.

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.

Hydroxytryptamine transporter gene-linked polymorphic region (5HTTLPR) is associated with delusions in Alzheimer's disease.

BACKGROUND: Serotoninergic pathways underlying delusion symptoms in Alzheimer's disease (AD) have not been fully clarified. 5-Hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats in the promoter region of serotonin transporter encoding-gene affecting transcription. METHODS: We investigated the association of 5-HTTLPR with delusions in a total of 257 consecutive patients clinically diagnosed as AD according to the National Institute on Aging-Alzheimer's Association criteria. All participants underwent a comprehensive evaluation with a standardized comprehensive geriatric assessment and Neuropsychiatric Inventory. RESULTS: Delusion symptoms were observed in 171 patients (66.54%). In respect to AD patients without delusions, AD patients with delusions showed a low prevalence of S-plus carriers (5-HTTLPR-L/S + 5-HTTLPR-S/S genotypes) [p < 0.001; odds ratio (OR) = 0.240, 95% confidence interval (CI) = 0.121-0.471]. Logistic regression analysis adjusted for the apolipoprotein E polymorphism showed that in AD patients with delusions the presence of an 5-HTTLPR-S allele may reduce disease duration (p = 0.005; OR = 0.680, 95% CI = 0.522-0.886) and increase aberrant motor activity (p = 0.013; OR = 2.257, 95% CI = 1.195-4.260). The present findings suggested that 5-HTTLPR might be associated with delusions in AD. S-plus carriers might be associated with protective effect against delusions in AD. CONCLUSIONS: More studies on wider samples of high selected demented patients are needed to confirm our results. However, the present findings suggested that a genetic factor related to serotonin metabolism might exert a protective role on the clinical expression of neuropsychiatric clusters in AD with important implications regarding mechanisms underlying delusions and their possible treatment across the AD and dementia spectrum.

Klotho at the Edge of Alzheimer's Disease and Senile Depression.

Klotho, encoded by the KL gene, is a single-pass transmembrane protein and a circulating factor that plays a key role in cellular metabolism and body homeostasis and has been associated with age-related diseases. Alterations of this protein seem to influence the development of serotonergic neurons and could play a role in major depression in the elderly. Pretreatment of neurons with Klotho protein can avoid neuronal injury related to the toxic amyloid-ß and glutamate, centrally related to the pathogenesis of Alzheimer's disease (AD), in order that Klotho protein could play a neuroprotective role in AD patients. Late-life depression, mild cognitive impairment, and dementia are different nosological entities but share common neurobiological facets and could represent a clinical continuum. Enhancement of Klotho levels in the early stages of the disease could represent a therapeutic strategy to prevent further deterioration and to ameliorate the outcome of elderly AD patients with or without major depression.

Late-Life Depression versus Amnestic Mild Cognitive Impairment: Alzheimer's Disease Incidence in 4 Years of Follow-Up.

BACKGROUND/AIM: The aim of the study was to evaluate the prognostic power of late-life depression (LLD) compared with amnestic mild cognitive impairment (aMCI) for the onset of Alzheimer's disease (AD) within 4 years of follow-up. METHODS: We estimated the incidence of AD in 60 patients presenting with aMCI, 115 patients suffering of LLD treated with antidepressants with good compliance, and 66 healthy control (HC) patients, followed for 4 years. RESULTS: The risk to develop AD, within 4 years, was 68.33% for aMCI and 49.57% for LLD. In AD patients 5.60% deteriorated without depression, and 72.20% deteriorated with depression after 4 years of follow-up (p < 0.0001). No HC patients deteriorated to AD or any other dementia type. CONCLUSION: In our results, aMCI was the first predictive condition that increased the risk to develop AD. Depression is a potentially preventable medical condition across the lifespan and may be a modifiable risk factor.

Neurocognitive Disorders and Dehydration in Older Patients: Clinical Experience Supports the Hydromolecular Hypothesis of Dementia.

Abnormalities of water homeostasis can be early expressions of neuronal dysfunction, brain atrophy, chronic cerebrovasculopathy and neurodegenerative disease. The aim of this study was to analyze the serum osmolality of subjects with cognitive impairment. One thousand and ninety-one consecutive patients attending the Alzheimer’s Evaluation Unit were evaluated with the Mini-Mental State Examination (MMSE), 21-Item Hamilton Depression Rating Scale (HDRS-21), Activities of Daily Living (ADL), Instrumental-ADL (IADL), Mini Nutritional Assessment (MNA), Exton-Smith Scale (ESS), and Cumulative Illness Rating Scale (CIRS). For each patient, the equation for serum osmolality developed by Khajuria and Krahn was applied. Five hundred and seventy-one patients had cognitive decline and/or depression mood (CD-DM) and 520 did not have CD-DM (control group). Patients with CD-DM were less likely to be male (p < 0.001), and were more likely to be older (p < 0.001), have a significant clear cognitive impairment (MMSE: p < 0.001), show the presence of a depressive mood (HDRS-21: p < 0.001) and have major impairments in ADL (p < 0.001), IADL (p < 0.001), MNA (p < 0.001), and ESS (p < 0.001), compared to the control group. CD-DM patients had a higher electrolyte concentration (Na⁺: p < 0.001; K⁺: p < 0.001; Cl−: p < 0.001), risk of dehydration (osmolality p < 0.001), and kidney damage (eGFR: p = 0.021), than the control group. Alzheimer’s disease (AD) patients showed a major risk for current dehydration (p ≤ 0.001), and dehydration was associated with the risk of developing a type of dementia, like AD or vascular dementia (VaD) (OR = 2.016, p < 0.001). In the multivariate analysis, the presence of dehydration state was associated with ADL (p < 0.001) and IADL (p < 0.001), but independently associated with age (r² = 0.0046, p = 0.77), ESS (r² = 0.0052, p = 0.54) and MNA (r² = 0.0004, p = 0.48). Moreover, younger patients with dementia were significantly more dehydrated than patients without dementia (65⁻75 years, p = 0.001; 76⁻85 years, p = 0.001; ≥86 years, p = 0.293). The hydromolecular hypothesis intends to explain the relationship between dehydration and cognitive impairment in older patients as the result of protein misfolding and aggregation, in the presence of a low interstitial fluid volume, which is a defect of the microcirculation. Defective proteins were shown to impair the amount of information in brain biomolecular mechanisms, with consequent neuronal and synaptic damage.

Erythrocyte Associated Amyloid-ß as Potential Biomarker to Diagnose Dementia.

BACKGROUND: Although it is known that Alzheimer's disease (AD) is associated with the progressive accumulation of amyloid ß-peptide (Aß) in the human brain, its pathogenic role has to be completely clarified. Aß moves from the bloodbrain barrier to the plasma and an increased Aß production in brain could be associated with higher Aß concentrations in blood. A recent study has evaluated Aß40 and Aß42 levels in human red blood cells (RBCs) with evidence of agedependent higher Aß concentration in RBCs. OBJECTIVE: The aim of the study was to investigate if erythrocyte associated Aß (iAß) levels could be different in subjects affected by dementia in comparison with controls and according to the patient's cognitive impairment or different dementia subtypes. METHOD: To answer these questions we assessed iAß40 and iAß42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD. RESULTS: In this population we found significant differences in iAß42 between controls and cognitive impaired patients. Moreover, iAß42 significantly differed between dementia vs MCI. AD also showed different iAß42 levels as compared to VaD. Conversely, no differences were found for iAß40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAß42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found. CONCLUSION: Our findings support the evidence that iAß42 could be an instrument to early recognize dementia and predict cognitive impairment.

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.

Analysis of MTNR1B gene polymorphisms in relationship with IRS2 gene variants, epicardial fat thickness, glucose homeostasis and cognitive performance in the elderly.

ABSTARCT Genome-wide association studies pinpointed common variants in or near the MTNR1B gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. IRS2 gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between MTNR1B and IRS2 gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of IRS2 gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that MTNR1B and IRS2 gene variants impacted EF thickness, lipid profile and glucose homeostasis. IRS2 but not MTNR1B variants impacted MMSE scores. In conclusion, MTNR1B SNPs interact with IRS2 gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk.

Role of the APOE polymorphism in carotid and lower limb revascularization: A prospective study from Southern Italy.

BACKGROUND: Atherosclerosis is a complex multifactorial disease and the apolipoprotein E (APOE) polymorphism has been associated to vascular complications of atherosclerosis. OBJECTIVES: To investigate the relationship between the APOE genotypes and advanced peripheral vascular disease. MATERIALS AND METHODS: 258 consecutive patients (201 males and 57 females, mean age 70.83 ± 7.89 years) with severe PVD were enrolled in a 42-months longitudinal study (mean 31.65 ± 21.11 months) for major adverse cardiovascular events. At follow-up genotypes of the APOE polymorphism were investigated in blinded fashion. RESULTS: As compared with ε3/ε3, in ε4-carriers a significant higher incidence of major adverse cardiovascular events (35.58% vs. 20.79%; p = 0.025) and total peripheral revascularization (22.64% vs. 5.06%; p < 0.001) was observed. Prospective analysis, showed that ε4-carriers have an increased hazard ratio for major adverse cardiovascular events (adjusted HR 1.829, 95% CI 1.017-3.287; p = 0.044) and total peripheral revascularization (adjusted HR = 5.916, 95% CI 2.405-14.554, p <0.001). CONCLUSIONS: The ε4 allele seems to be risk factor for major adverse cardiovascular events, and in particular for total peripheral revascularization in patients with advanced atherosclerotic vascular disease.

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder.

Klotho protein, encoded by the Klotho gene (KL) at locus 13q12, is an antiaging hormone-like protein playing a pivotal role in cell metabolism homeostasis and associated to longevity and age-related diseases. In particular, altered cell metabolism in central nervous system may influence the behavior of serotoninergic neurons. The role of KL in the response to treatment with selective serotonin reuptake inhibitors (SSRIs) in late-life depressive syndromes and late-life major depressive disorder (MDD) is unclear. We genotyped three single-nucleotide polymorphisms (SNPs) of KL in 329 older patients with diagnosis of late-life MDD, treated with SSRIs and evaluated with the Hamilton Rating Scale for Depression 21-items (HRSD-21) at baseline and after 6 months. A reduction ≥50 and <10 % in HDRS-21 score was considered as response or nonresponse to therapy, respectively, and the values of reduction between 10 and 49 % as poor responders. After 6 months of SSRI treatment, 176 patients responded, 54 patients did not respond and 99 patients showed a poor response. Ordinal logistic models showed a significant association between mutation of SNP rs1207568 and responders and, similarly, for each unitary risk allele increase overlapping results were found. Conversely, a significantly higher frequency of the minor genotype of SNP rs9536314 was found in nonresponders. Considering the pre-post differences of HRSD-21 scores as a continue variable, we confirmed a significant improvement of depressive symptoms after treatment in patients carrying at least one minor allele at rs1207568 and a worse response in patients homozygous for the minor allele at rs9536314. Our results were the first that suggested a possible role of KL in the complex pathway of SSRI response in late-life MDD.

Gastrointestinal Microbiota and Their Contribution to Healthy Aging.

Studies on populations at different ages have shown that after birth, the gastrointestinal (GI) microbiota composition keeps evolving, and this seems to occur especially in old age. Significant changes in GI microbiota composition in older subjects have been reported in relation to diet, drug use and the settings where the older subjects are living, that is, in community nursing homes or in a hospital. Moreover, changes in microbiota composition in the old age have been related to immunosenescence and inflammatory processes that are pathophysiological mechanisms involved in the pathways of frailty. Frailty is an age-related condition of increased vulnerability to stresses due to the impairment in multiple inter-related physiologic systems that are associated with an increased risk of adverse outcomes, such as falls, delirium, institutionalization, hospitalization and death. Preliminary data suggest that changes in microbiota composition may contribute to the variations in the biological, clinical, functional and psycho-social domains that occur in the frail older subjects. Multidimensional evaluation tools based on a Comprehensive Geriatric Assessment (CGA) have demonstrated to be useful in identifying and measuring the severity of frailty in older subjects. Thus, a CGA approach should be used more widely in clinical practice to evaluate the multidimensional effects potentially related to GI microbiota composition of the older subjects. Probiotics have been shown to be effective in restoring the microbiota changes of older subjects, promoting different aspects of health in elderly people as improving immune function and reducing inflammation. Whether modulation of GI microbiota composition, with multi-targeted interventions, could have an effect on the prevention of frailty remains to be further investigated in the perspective of improving the health status of frail 'high risk' older individuals.

Delusions in Patients with Alzheimer's Disease: A Multidimensional Approach.

In Alzheimer's disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.

Measuring pharmacogenetics in special groups: geriatrics.

INTRODUCTION: The cytochrome P450 (CYP) enzymes oxidize about 80% of the most commonly used drugs. Older patients form a very interesting clinical group in which an increased prevalence of adverse drug reactions (ADRs) and therapeutic failures (TFs) is observed. Might CYP drug metabolism change with age, and justify the differences in drug response observed in a geriatric setting? AREAS COVERED: A complete overview of the CYP pharmacogenetics with a focus on the epigenetic CYP gene regulation by DNA methylation in the context of advancing age, in which DNA methylation might change. EXPERT OPINION: Responder phenotypes consist of a continuum spanning from ADRs to TFs, with the best responders at the midpoint. CYP genetics is the basis of this continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice. Physiological age-related changes in DNA methylation, the main epigenetic mechanisms regulating gene expression in humans, results in a physiological decrease in CYP gene expression with advancing age. This may be one of the physiological changes that, together with increased drug use, contributed to the higher prevalence of ADRs and TFs observed in the geriatric setting, thus, making geriatrics a special group for pharmacogenetics.

Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life.

It has been suggested that the serotonin or 5-hydroxytriptamine (5-HT) transporter (5-HTT) and its gene-linked polymorphic region (5-HTTLPR) are selective serotonin reuptake inhibitor (SSRI) response modulators in late-life depression (LLD), and particularly in late-life major depressive disorder (MDD). Previous studies differed in design and results. Our study aimed to investigate the solute carrier family 6 (neurotransmitter transporter and serotonin) member 4 (SLC6A4) gene locus, encoding 5-HTT and SSRI treatment response in late-life MDD. For a prospective cohort study, we enrolled 234 patients with late-life MDD to be treated with escitalopram, sertraline, paroxetine or citalopram for 6 months. The SLC6A4 polymorphisms rs4795541 (5-HTTLPR), rs140701 and rs3813034 genotypes spanning the SLC6A4 locus were investigated in blinded fashion. No placebo group was included. We assessed responder or non-responder phenotypes according to a reduction in the 21-item version of the Hamilton Depression Rating Scale (HDRS-21) score of ⩾ 50%. At follow-up, 30% of the late-life MDD patients were non-responders to SSRI treatment. No time-course of symptoms and responses was made. A poor response was associated with a higher baseline HDRS-21 score. We observed a significant over-representation of the rs4795541-S allele in the responder patients (0.436 versus 0.321; p = 0.023). The single S-allele dose-additive effect had OR = 1.74 (95% CI 1.12-2.69) in the additive regression model. Our findings suggested a possible influence of 5-HTTLPR on the SSRI response in patients with late-life MDD, which is potentially useful in identifying the subgroups of LLD patients whom need a different pharmacological approach.

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.