Late-Onset Depression but not Early-Onset Depression may Increase the Risk of All-Cause Mortality in Older Age: 8-Year Follow-Up of the Salus in Apulia Study.

OBJECTIVES: Individuals with late-life depression (LLD) may have shorter survival, but there is a lack of findings in population-based settings about health-related outcomes of LLD and its subtypes: early-onset depression (EOD) and late-onset depression (LOD). We aimed to evaluate the risk of all-cause mortality of individuals with LLD and its subtypes in an older population-based cohort. Moreover, we investigated whether inflammatory, cognitive, genetic features and multimorbidity could modify the effect of this association. DESIGN: Longitudinal population-based study with 8-year follow-up. SETTING AND PARTICIPANTS: We analyzed data on a sample of 1479 participants, all aged >65 years, in the Salus in Apulia Study. METHODS: LLD was diagnosed through DSM-IV-TR criteria and LOD and EOD according to the age of onset. Multimorbidity status was defined as the copresence of 2 or more chronic diseases. RESULTS: The overall prevalence of LLD in this older sample from Southern Italy was 10.2%, subdivided into 3.4% EOD and 6.8% LOD. In multivariable Cox models adjusted for age, gender, education, global cognition, apolipoprotein E ε4 allele, physical frailty, interleukin-6, and multimorbidity, LLD showed a greater risk of all-cause mortality. LOD differed from EOD regarding gender, education, cognitive dysfunctions, and diabetes mellitus. There was a significantly increased risk of all-cause mortality for participants with LOD (hazard ratio:1.99; 95% CI 1.33-2.97) in the time of observation between enrollment date and death date (7.31 ± 2.17 months). CONCLUSIONS AND IMPLICATION: In older age, individuals with LOD but not with EOD had a significantly decreased survival, probably related to increased inflammation, multimorbidity, and cognitive impairments.

Vitamin D in the development and progression of alzheimer's disease: implications for clinical management.

INTRODUCTION: Although the pathophysiological bases of Alzheimer's disease (AD) remain incompletely understood and disease-modifying therapies are not available, intervention on modifiable risk factors is warranted. Research on nutrition and dietary components is challenging and controversies still persist about the role of micro- and macronutrients and health outcomes in dementia. Importantly, results of preclinical investigations have shown that vitamin D triggers different neural pathways that may be protective against these neurodegenerative mechanisms, including the deposition of amyloid plaques, inflammatory processes, neurofibrillary degeneration, glutamatergic excitotoxicity, excessive intraneuronal calcium influx, and oxidative stress, although its relationship with AD still needs to be fully understood. AREAS COVERED: The authors analyzed the recent evidence about the effects of vitamin D insufficiency on AD and the role of supplementation. EXPERT OPINION: Both insufficient (25-49.9 ng/ml) and deficient levels (<25 ng/ml) of vitamin D may contribute to an increased susceptibility to AD. However, further well-designed prospective studies are needed for a better understanding of the involvement of low vitamin D concentrations in the AD natural history. Randomized clinical trials will also be necessary to address the issue of causality and determine whether vitamin D supplementation may be effective for the prevention or treatment of AD.

Social Frailty in the COVID-19 Pandemic Era.

Special attention and efforts to protect from or reduce health-related outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus triggering coronavirus disease 2019 (COVID-19), should be applied in susceptible populations, including frail older people. In particular, the early death cases occurred primarily in older people with a frailty status, possibly due to a weaker immune system fostering faster progression of the viral infection. Frailty is an age-related multidimensional clinical condition defined as a non-specific state of vulnerability, identifying older people at increased risk of falls, institutionalization, hospitalization, disability, dementia, and death. Among frailty phenotypes, social frailty has been least studied. It considers the role of socioeconomic context as a vulnerability status later in life. COVID-19 does not affect all populations equally, and social inequalities contribute to drive the spread of infections. It was known that the perception of social isolation, e.g., loneliness, affects mental and physical health, but the implicated molecular mechanisms, also related to the immune system, and its associated cognitive and health-related sequelae, are poorly understood. The increasing psychological distress derived by prolonged exposure to stress due to the lockdown scenario, and the reduced sources of support, contributed to making heavy demands on personal resources, i.e., self-efficacy and interpersonal variables. So, perceived loneliness may be a factor associated with psychological distress and an outcome in itself. In the COVID-19 pandemic era, a correct assessment of social frailty may be essential in terms of the prevention of late-life neuropsychiatric disorders.

The Challenge of Antidepressant Therapeutics in Alzheimer's Disease.

The link between depression and Alzheimer's disease (AD) is controversial, because it is not clear if depression is an independent risk factor for the disease or a prodromal symptom in the older population. Cerebral amyloid-ß (Aß) peptide deposition is associated with both cognitive symptoms and neuropsychiatric symptoms (NPS), which may be a biological mechanism of compensation. Despite the widespread use of antidepressant therapeutics (30-50% of patients with AD/dementia are on antidepressants), there is mixed evidence regarding the benefits from their use in AD depression. Monoaminergic antidepressant drugs have shown only modest or no clinical benefits. Therefore, it is important to understand the reason of this drug-resistance and the relationship between antidepressant drugs and the Aß peptide. The goal of the present review is to highlight the etiology of depression in patients affected by AD in comparison to depressive disorders without AD, and to speculate on more appropriate and alternative therapeutics.

When basal cell carcinomas became giant: an Italian multicenter study.

BACKGROUND: Giant basal cell carcinoma (GBCC) is a basal cell carcinoma (BCC) enlarged in a diameter more than 5 cm. Since GBCCs are a highly infrequent entity and the occurrence rate is approximately 0.5-1% out of all BCC types, only anecdotal cases are reported, and causes and characteristics inducing development of this tumor are not defined. OBJECTIVES: Evaluate causative factors and clinico-histological characteristics of GBCCs. METHODS: The study is a 6-month, hospital-based case series study performed in 12 Italian dermatologic centers. RESULTS: A total of 59 cases and 458 control BCCs were collected. No significant differences existed between the two groups if we take into account social or cultural factors. The average duration of GBCCs is considerably longer than controls. GBCCs are located on unexposed areas while BCCs are on areas not usually covered by clothes. Superficial histological subtype was more frequent in the BCCs group, while infiltrative in GBCCs. GBCCs showed significantly higher local invasiveness, and greater metastatic capacity. More than half of GBCCs had been previously treated with one or more treatments. CONCLUSIONS: Patients with GBCCs appear to belong to two categories: (i) those who present with GBCC due to delay in accessing medical attention, and (ii) those who have BCCs previously treated with inappropriate strategies. Only very few cases can be carried out with intrinsic biological features of tumor aggressiveness. Social and cultural conditions do not appear to be involved in the development of GBCCS. These observations may help clinicians in selecting correct therapeutic strategies in the treatment of BCCs, which give rise to GBCC.

Sensorial frailty: age-related hearing loss and the risk of cognitive impairment and dementia in later life.

The peripheral hearing alterations and central auditory processing disorder (CAPD) associated with age-related hearing loss (ARHL), may impact cognitive disorders in older age. In older age, ARHL is also a significant marker for frailty, another age-related multidimensional clinical condition with a nonspecific state of vulnerability, reduced multisystem physiological reserve, and decreased resistance to different stressors (i.e. sensorial impairments, psychosocial stress, diseases, injuries). The multidimensional nature of frailty required an approach based on different pathogeneses because this clinical condition may include sensorial, physical, social, nutritional, cognitive, and psychological phenotypes. In the present narrative review, the cumulative epidemiological evidence coming from several longitudinal population-based studies, suggested convincing links between peripheral ARHL and incident cognitive decline and dementia. Moreover, a few longitudinal case-control and population-based studies also suggested that age-related CAPD in ARHL, may be central in determining an increased risk of incident cognitive decline, dementia, and Alzheimer's disease (AD). Cumulative meta-analytic evidence confirmed cross-sectional and longitudinal association of both peripheral ARHL and age-related CAPD with different domains of cognitive functions, mild cognitive impairment, and dementia, while the association with dementia subtypes such as AD and vascular dementia remained unclear. However, ARHL may represent a modifiable condition and a possible target for secondary prevention of cognitive impairment in older age, social isolation, late-life depression, and frailty. Further research is required to determine whether broader hearing rehabilitative interventions including coordinated counseling and environmental accommodations could delay or halt cognitive and global decline in the oldest old with both ARHL and dementia.

The Role of Biomarkers in Psychiatry.

Psychiatric illnesses are cognitive and behavioral disorders of the brain. At present, psychiatric diagnosis is based on DSM-5 criteria. Even if endophenotype specificity for psychiatric disorders is discussed, it is difficult to study and identify psychiatric biomarkers to support diagnosis, prognosis, or clinical response to treatment. This chapter investigates the innovative biomarkers of psychiatric diseases for diagnosis and personalized treatment, in particular post-genomic data and proteomic analyses.

CYP2D6 genotypes in revolving door patients with bipolar disorders: A case series.

RATIONALE: In psychiatric disorders, interindividual differences in cytochrome P450 (CYP)2D6 (CYP2D6) enzymatic activity could be responsible of adverse drug reactions (ADRs) and therapeutic failures (TFs) for CYP2D6-metabolized drugs, contributing to the periodical hospital readmissions of the revolving door (RD) condition. PATIENT CONCERNS: We investigated CYP2D6 genotypes in a controlled series of 5 consecutive RD patients with Bipolar Disorder (BD). DIAGNOSES: Psychiatric patients affected by Bipolar Disorder. INTERVENTIONS: We defined TFs as a difference at the Brief Psychiatric Rating Scale score ΔBPRS < 25% at each 1-week of stable treatment, and ADRs as the onset of extrapyramidal symptoms and/or metabolic impairment with weight gain. OUTCOMES: At 3 months, a mean number of 2.75 ±â€Š1.26 ADR and a mean ΔBPRS score of 16.07 ±â€Š0.05% were observed. At 6 months of follow-up, compared to the only patient without BD (ΔBPRS < 32.10%), BD patients (n = 4) showed TFs (ΔBPRS < 25%). CYP2D6 genotyping revealed intermediate metabolizer phenotypes for BD patients and an extensive metabolizer phenotype for the patient without BD. In BD patients, the ratio of drugs maintained/discontinued for TFs or ADRs was 1.75 for non-CYP2D6 versus 0.33 for CYP2D6 interacting drugs, while the proportion of ADR:TF was 0:4 versus 6:3. LESSONS: Our findings may suggest that CYP2D6 clinically relevant genotypes may be involved in the unwanted outcomes observed in RD patients with BD.

Pharmacotherapy for the treatment of depression in patients with alzheimer's disease: a treatment-resistant depressive disorder.

INTRODUCTION: Pharmacotherapy for the treatment of depressive disorders in Alzheimer's Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8-12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects. AREAS COVERED: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine. EXPERT OPINION: The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.

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.

Innovative biomarkers in psychiatric disorders: a major clinical challenge in psychiatry.

INTRODUCTION: Currently, the diagnosis of psychiatric illnesses is based upon DSM-5 criteria. Although endophenotype-specificity for a particular disorder is discussed, the identification of objective biomarkers is ongoing for aiding diagnosis, prognosis, or clinical response to treatment. We need to improve the understanding of the biological abnormalities in psychiatric illnesses across conventional diagnostic boundaries. The present review investigates the innovative post-genomic knowledge used for psychiatric illness diagnostics and treatment response, with a particular focus on proteomics. Areas covered: This review underlines the contribution that psychiatric innovative biomarkers have reached in relation to diagnosis and theragnosis of psychiatric illnesses. Furthermore, it encompasses a reliable representation of their involvement in disease through proteomics, metabolomics/pharmacometabolomics and lipidomics techniques, including the possible role that gut microbiota and CYP2D6 polimorphisms may play in psychiatric illnesses. Expert opinion: Etiologic heterogeneity, variable expressivity, and epigenetics may impact clinical manifestations, making it difficult for a single measurement to be pathognomonic for multifaceted psychiatric disorders. Academic, industry, or government's partnerships may successfully identify and validate new biomarkers so that unfailing clinical tests can be developed. Proteomics, metabolomics, and lipidomics techniques are considered to be helpful tools beyond neuroimaging and neuropsychology for the phenotypic characterization of brain diseases.

Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review.

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

Ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis.

This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of neurological complications. In this review, different aspects of ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis are examined: clinical features, genetic defect, mutation spectrum, pathogenesis, and neurobiological basis; indications for clinical practice are also provided to the readers. The aim of this review is to stress the importance of cooperation among dermatologists, neurologists and psychiatrists, in order to provide patients suffering from these diseases with timely diagnosis and targeted treatments.

Adolescence: psychopathological discomfort, distress or psychiatric disorder? Clinical experience, description and analysis of a sample.

BACKGROUND: The aim of this study was to highlight how many psychopathological disorders emerging during adolescence are not easily detectable and interpretable. METHODS: We investigated the social, emotional and demographic factors related to psychopathological distress, measuring the overall functioning of the child/adolescent and the consequent impact on academic and social functioning, along with its implications on the emergence of feelings of discomfort and anxiety. RESULTS: Many psychopathological disorders are easily detectable and diagnosable in this particular stage of life, and although they are rooted in adolescent distress, they can generate real psychiatric disorders. CONCLUSIONS: The data emerging from clinical practice stress the need for a comprehensive in order to identify possible subclinical symptoms for onset of mental illness, so as to be able to implement more targeted and less invasive therapeutic strategies.