Psychogeriatric Research: A Conceptual Introduction to Aging and Geriatric Neuroscience

Abstract

Psychogeriatrics (PG) is a multidisciplinary specialty in clinical neuroscience dealing with brain disorders in the elderly population. As any other biomedical field PG has to establish an educational and practical framework in epidemiology, etiopathogenesis, diagnosis, treatment, and social, ethical, and legal issues associated with brain aging and age-related central nervous system disorders. Understanding the molecular basis of aging will help to characterize and differentiate the fundamentals of pathological aging and psychogeriatric ailments. Modern epidemiology of age-related brain disorders have to incorporate novel diagnostic criteria, biological markers, and genetic epidemiology to its methodological armamentarium to avoid bias. Molecular genetics will help to conceptually redefine many psychogeriatric disorders depending upon its genetic component and those interacting environmental factors leading to the phenotypic expression of given diseases. Genetic testing for monogenic and complex/polygenic/multifactorials disorders has to be included in diagnostic protocols since approximately 60 to 80% of major psychogeriatric disorders are genetically driven. It is also important to distinguish mutational genetics from susceptibility genetics in order to establish novel therapeutic strategies and preventive programmes. Genomics, proteomics, and pharmacogenomics are novel fields from which PG can benefit in the areas of etiopathogenesis, diagnosis, and treatment. Drug development in PG requires updated regulations in developed countries. New pharmacological treatments for aging brain disorders are needed. Pharmacogenomics will become an optimal strategy for drug development, contributing to design a molecular psychopharmacology for the elderly, individualizing drug therapy, optimizing efficacy and safety, and reducing unnecessary costs. ing. In this regard, geriatric neuroscience would integrate the following disciplines: geriatric psychiatry, psychogeriatrics, neuropsychiatry, geriatric neurology, behavioural neurology, neurogeriatrics, neuropsychology, geriatric psychology, neuropsychopharmacology, neuroimaging, basic neuroscience, and neurogeneti~s.',~,~) At the clinical setting, in CNS disorders of the elderly, there are no definitional boundaries between neurology and psychiatry from a practical perspective; the so far established differences are the result of habits and traditional training rather than practical distinctions. Diagnostic procedures and therapeutic alternatives are also common and complementary in CNS disorders of the elderly when applying a neurological or psychiatric approach. The elucidation, prevention, and treatment of most CNS disorders will depend largely on advances in neuro~cience.~)Although the early beginnings of neuroscience are linked to Santiago Ramon y Cajal and Charles Sherrington at the turn of the past century, followed by the pioneering work of

Pharmacogenetic Aspects of Therapy with Cholinesterase Inhibitors: The Role of CYP2D6 in Alzheimers Disease Pharmacogenetics

“…Few studies with combination treatments have been reported and most of them are poorly designed. We have also to realize that the vast majority of dementia cases in people older than 75-80% are of a mixed type, in which the cerebrovascular component associated with neurodegeneration can not be therapeutically neglected [8,9,14,26,32,44,128].…”

“…Mutations in the APP, PS1, PS2, and MAPT genes give rise to well-characterized differential neuropathological and clinical phenotypes of dementia [2,28]. The analysis of genotype-phenotype correlations has also revealed that the presence of the APOE-4 allele in AD, in conjunction with other genes, influences disease onset, brain atrophy, cerebrovascular perfusion, blood pressure, -amyloid deposition, ApoE secretion, lipid metabolism, brain bioelectrical activity, cognition, apoptosis, and treatment outcome [2][3][4][5][6]16,26,32,[43][44][45]. The characterization of phenotypic profiles according to age, cognitive performance (MMSE and ADAS-Cog score), serum ApoE levels, serum lipid levels including cholesterol (CHO), HDL-CHO, LDL-CHO, VLDL-CHO, and triglyceride (TG) levels, as well as serum nitric oxide (NO), -amyloid, and histamine levels, reveals sex-related differences in 25% of the biological parameters and almost no differences (0.24%) when patients are classified as APOE-4(-) and APOE-4(+) carriers, probably indicating that gender-related factors may influence these parametric variables more powerfully than the presence or absence of the APOE-4 allele; in contrast, when patients are classified according to their APOE genotype, dramatic differences emerge among APOE genotypes (>45%), with a clear biological disadvantage in APOE-4/4 carriers who exhibit (i) earlier age of onset, (ii) low ApoE levels, (iii) high CHO and LDL-CHO levels, and (iv) low NO, -amyloid, and histamine levels in blood.…”

“…Among these genes of susceptibility, the apolipoprotein E (APOE) gene (19q13.2) is the most prevalent as a risk factor for AD, especially in those subjects harbouring the APOE-4 allele, whereas carriers of the APOE-2 allele might be protected against dementia. APOE-related pathogenic mechanisms are also associated with brain aging and with the neuropathological hallmarks of AD [2,14,16,26]. (c) Diverse mutations located in mitochondrial DNA (mtDNA) through heteroplasmic transmission can influence aging and oxidative stress conditions, conferring phenotypic heterogeneity [30,31].…”

“…These pathogenic events may exert an additive effect, converging in final pathways leading to premature neuronal death. Some of these mechanisms are common to several neurodegenerative disorders which differ depending upon the gene(s) affected and the involvement of specific genetic networks, together with cerebrovascular factors, epigenetic factors (DNA methylation) and environmental conditions (nutrition, toxicity, social factors, etc) [2,16,26,[32][33][34][35][36][37]. The higher the number of genes involved in AD pathogenesis, the earliest the onset of the disease, the faster its clinical course, and the poorer its therapeutic outcome [2].…”

“…These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system, this interaction eliciting liver toxicity and other adverse drug reactions (ADRs) [8,9] (Tables 1 & 2). Under these circumstances, therapeutics optimization is a major goal in the elderly population, and novel pharmacogenetic and pharmacogenomic procedures may help in this endeavour [3][4][5][6]26,27].…”