Parkinson’s disease, the most common neurological disorder in the elderly, is characterized by progressive extrapyramidal motor dysfunction including resting tremors, muscle rigidity, hypolocomotion (bradykinesia and akinesia) and postural instability. Various non-motor features are also seen such as cognitive impairments (deficits in learning and memory) and mood disorders (depression and anxiety). While the 5-HT1A receptor has long been implicated in the pathogenesis and treatment of anxiety and depression, recent research has revealed new therapeutic roles for 5-HT1A receptors in the treatment of Parkinson’s disease. These include the modulation of parkinsonian motor symptoms, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, cognitive impairments and emesis. Thus, 5-HT1A agonists improve the various motor disorders associated with dopaminergic deficits, dyskinesia induced by chronic L-DOPA treatment, mood disturbances (anxiety and depression) and dopamine agonist-induced emesis. In addition, partial 5-HT1A agonists are expected to improve cognitive impairment in Parkinson’s patients. These findings encourage research into new 5-HT1A receptor ligands, which will improve efficacy and/or ameliorate adverse reactions in the treatment of Parkinson’s disease.
5-HT1A receptors; Parkinson’s disease; extrapyramidal motor disorders; cognitive impairment; depression; anxiety
Nutrition is the process in which growth, repair, and maintenance of the body are accomplished by consuming and utilizing food substances. A proper diet must be ingested to ensure the right amount of nutrition is delivered to sustain appropriate physiological mechanisms. Knowledge of the basic constituent of dietary intake is essential for several of health related variables. Poor diet negatively affects overall health which can lead to obesity and can cause many types of diseases including cardiovascular disease, diabetes, metabolic syndrome, etc. Our research group has previously invested in studying the adaptations in body composition following spinal cord injury (SCI) and how regional as well as total adipose tissue distribution may negatively influence the metabolic profile in this population. Little is known about the role of nutrition following SCI and it is unclear how it impacts body composition and the metabolic profile. The purpose of this mini-review is to summarize the available evidence on how macronutrient components (carbohydrate, fat and protein) impact health status after SCI. We hope as an outcome of this work to stimulate further research in this area to expand the knowledge on how to properly design dietary interventions that suit the adaptations following SCI.
Body composition; carbohydrate; energy expenditure; fat; nutrition; protein; spinal cord injury
Tau protein could appear like a family of multiple isoforms rising by alternative splicing of its nuclear RNA or by different posttranslational modifications. The levels (or proportion) of these different tau isoforms could change in different neurons during development, aging or disease (tauopathies) in mammals. It is discussed that in some disorders there is a gain of toxic function of modified tau, due to the phosphorylation or aggregation of tau protein. These phenotypic changes are mainly found in aging organisms. On the other hand, loss of tau function could facilitate the appearance of some defects (related to iron toxicity) in aging animals lacking tau.
Tau isoforms; posttranslational modifications; Alzheimer disease
Voxel-based morphometry (VBM) using structural brain MRI has been widely used for assessment of normal aging and Alzheimer’s disease (AD). VBM of MRI data comprises segmentation into gray matter, white matter, and cerebrospinal fluid partitions, anatomical standardization of all the images to the same stereotactic space using linear affine transformation and further non-linear warping, smoothing, and finally performing a statistical analysis. Two techniques for VBM are commonly used, optimized VBM using statistical parametric mapping (SPM) 2 or SPM5 with non-linear warping based on discrete cosine transforms and SPM8 plus non-linear warping based on diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL). In normal aging, most cortical regions prominently in frontal and insular areas have been reported to show age-related gray matter atrophy. In contrast, specific structures such as amygdala, hippocampus, and thalamus have been reported to be preserved in normal aging. On the other hand, VBM studies have demonstrated progression of atrophy mapping upstream to Braak’s stages of neurofibrillary tangle deposition in AD. The earliest atrophy takes place in medial temporal structures. Stand-alone VBM software using SPM8 plus DARTEL running on Windows has been newly developed as an adjunct to the clinical assessment of AD. This software provides a Z-score map as a consequence of comparison of a patient’s MRI with a normal database.
Neuroradiology; MRI; voxel-based morphometry; aging; Alzheimer’s disease
Aging is a major risk factor for cardiovascular diseases, one of the main world-wide causes of death. Several structural and functional changes occur in the cardiovascular system during the aging process and the mechanisms involved in such alterations are yet to be completely described. BK channels are transmembrane proteins that play a key role in many physiological processes, including regulation of vascular tone. In vascular smooth muscle cells, BK opening and the consequent efflux of potassium (K+) leads to membrane hyperpolarization, which is followed by the closure of voltage-dependent Ca2+ channels, reduction of Ca2+ entry and vasodilatation. BK regulates nitric oxide-mediated vasodilatation and thus is crucial for normal endothelial function. Herein we will briefly review general structural properties of BK and focus on their function in the cardiovascular system emphasizing their role in cardiovascular aging and diseases.
Calcium-activated potassium channels; BK; vascular smooth muscle cells; endothelium; aging; cardiovascular diseases
Nonenzymatic glycation of macromolecules, especially proteins leading to their oxidation is increased in diabetes mellitus due to hyperglycemia and play an important role in associated complications of the disease. The glycation primarily occurs at intrachain lysine residues of proteins and results in the formation of an early stage stable product as Amadori-lysine which undergo further irreversible chemical reactions to form advanced glycation endproducts. This review deals with the role of Amadori modified proteins in pathogenesis of diabetes. We aim to explain immunogenicity of Amadori-glycated proteins, which might be involve in production of serum autoantibodies in the diabetic patients, and effect of inhibitors on the glycation process.
Amadori products; Antibodies; diabetes complications; lysine rich proteins
Telomere shortening is associated with cellular senescence and aging. Dyskeratosis congenita (DC) is a premature aging syndrome caused by mutations in genes for telomerase components or telomere proteins. DC patients have very short telomeres and exhibit aging-associated pathologies including epidermal abnormalities and bone marrow failure. Here, we show that DC skin fibroblasts are defective in their ability to support the clonogenic growth of epidermal keratinocytes. Conditioned media transfer experiments demonstrated that this defect was largely due to lack of a factor or factors secreted from the DC fibroblasts. Compared to early passage normal fibroblasts, DC fibroblasts express significantly lower transcript levels of several genes that code for secreted proteins, including Insulin-like Growth Factor 1 (IGF1) and Hepatocyte Growth Factor (HGF). Aged normal fibroblasts with short telomeres also had reduced levels of IGF1 and HGF, similar to early passage DC fibroblasts. Knockdown of IGF1 or HGF in normal fibroblasts caused a reduction in the capacity of conditioned media from these fibroblasts to support keratinocyte clonogenic growth. Surprisingly, reconstitution of telomerase in DC fibroblasts did not significantly increase transcript levels of IGF1 or HGF or substantially increase the ability of the fibroblasts to support keratinocyte growth, indicating that the gene expression defect is not readily reversible. Our results suggest that telomere shortening in dermal fibroblasts leads to reduction in expression of genes such as IGF1 and HGF and that this may cause a defect in supporting normal epidermal proliferation.
Telomerase; telomeres; IGF1; HGF; dyskeratosis; skin
Many elderly patients suffer from lung cancers, but it is not clear if their lung cancers differ from those of younger patients. In this study, we compared genetic and prognostic characteristics of lung cancers of patients aged ≥75 years with those of patients aged ≤ 64 years. In the genetic analysis, we explored 292 surgically treated non-squamous cell lung cancers with known mutational status of epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK). In the prognostic analysis, we retrospectively analyzed 405 surgically treated non-small cell lung cancers (NSCLCs) before the era of routine clinical application of post-surgical adjuvant chemotherapy. Postsurgical recurrence-free survival (RFS) was compared between elderly patients and younger counterparts. The genetic analysis showed elderly non-squamous cell lung cancer patients to have higher prevalence of EGFR mutations (53.1 % vs 42.0%, P = 0.15) and lower prevalence of the ALK translocation (0 % vs 4.5%, P = 0.23) than their younger counterparts. The prognostic analysis showed postsurgical RFS was similar between the elderly NSCLC patients and the younger patients. However in multivariate analysis, adjusting for gender, smoking status, pathological stage, and histology, elderly patients had significantly worse prognoses (HR 1.57, 95% CI, 1.08–2.29; P = 0.02) compared with younger patients. These results suggest differences in genetic and prognostic aspects between elderly lung cancer patients and younger lung cancer patients.
Oncogenic driver mutation; prognostic factor; recurrence-free survival; epidermal growth factor receptor gene mutation; anaplastic lymphoma kinase translocation
Multiple cues from the environment of our indirect and immediate ancestors, which often
persist throughout the prenatal period and adulthood, are shaping our phenotypes through
either direct, parent-to-child influences, or transgenerational inheritance. These effects
are due to gene-environment interactions, which are intended to be a predictive tool and a
mechanism of quick adaptation to the environment, as compared with genetic variations that
are inherited over many generations. In certain circumstances the influences induced by
the gene-environment interactions can have deleterious effects upon the health status, in
the context of a radical change in the environment that does not fit with the predicted
conditions, via epigenetic alterations. Conversely the best fit to the
expected environment might have a delayed aging process and a longer
life span. This review will touch upon the Developmental Origins of Health and Disease
(DoHAD) concept, while discussing recent advances in the understanding of metabolic and
cognitive disruptions, with a focus on epigenetic factors, their transgenerational
effects, and the consequences they might have upon the onset of chronic disease and
Metabolism; cognition; epigenetic; transgenerational
With advancing age traditional cardiovascular risk factors follow a U-shaped relationship with survival outcomes. This relationship has been described as reverse metabolism. The mechanism of such relationship is unclear. However, it appears that malnutrition, inflammation and functional decline are characteristics shared by populations exhibiting the U-shaped risk. Thus, frailty or decline in functional reserve may be the main confounding factor of the relationship between cardiovascular risk factors and adverse outcomes in older patients. Clinical implication of this is not yet clear but more attention should be focused on optimal management of undernutrition and weight loss by improving feeding and maintaining physical activity.
Frailty; malnutrition; cardiovascular risk
Depression in elderlies is not known quite well and thus cannot be treated adequately. The fact that elderliness is accepted as a property of depressive symptoms both by the relatives of the patients and doctors is one of the factors which make it difficult to recognize depression. Existence of multiple physical diseases in elderlies, use of multiple medicines, occurrence of pharmacokinetic and pharmacodynamics changes depending on the age necessitate to take several factors into account while diagnosing and using medicines. In this study, clinical properties and risk factors of depression in old age period was reviewed and the properties of such depressions were summarized.
Elderly; depression; late-life depression
Up-regulation of kynurenine (KYN) pathway of tryptophan (TRP) was suggested as one of the mechanisms of aging and aging-associated disorders. Genetic and pharmacological impairment of TRP – KYN metabolism resulted in prolongation of life span in Drosophila models. Minocycline, an antibiotic with anti-inflammatory, antioxidant and neuroprotective properties independent of its antibacterial activity, inhibited KYN formation from TRP. Since minocycline is the only FDA approved for human use medication with inhibitory effect on TRP – KYN metabolism, we were interested to study minocycline effect on life- and health-spans in Drosophila model. Minocycline (0.87mM) prolonged mean, median and maximum life span of wild-type Oregon Drosophila melanogaster of both genders. Minocycline (0.87 mM) stimulated vertical climbing in male flies. Minocycline dose-dependently decreased quantity and survivorship of pupae of filial generation. Minocycline might be a promising candidate drug for anti-aging intervention and treatment of aging-associated medical and psychiatric disorders. The role of TRP – KYN metabolism in the mechanisms of minocycline-effect on life- and health-span might be elucidated by the future assessment of minocycline effects in Drosophila mutants naturally or artificially knockout for genes impacting the key enzymes of KYN pathway of TRP metabolism.
Minocycline; life span; Drosophila melanogaster; kynurenine; vertical climbing; health span
Chronic kidney disease (CKD) is rather common in elderly adults who comprise the fastest growing subset of patients with end-stage renal disease (ESRD). At present, there are no specific guidelines and recommendations regarding early identification and management of elderly with CKD and the current CKD classification system may overestimate its exact prevalence. Screening strategies based either in a more accurate formula of estimation of GFR alone, or preferably in combination with proteinuria are urgently needed in order to raise awareness and to promote early diagnosis of CKD in the elderly. The number of elderly dialysis patients is also increasing and may lead to severe socio-economic problems worldwide. Both hemodialysis and peritoneal dialysis can sustain life, but present various disadvantages. There is a trend for home based dialysis therapies but the results are based on a small number of patients. Recent reports indicate that dialysis may not provide a clear benefit over non-dialysis regarding survival and quality of life issues, especially in the presence of extensive comorbidities. Current practices around the world regarding access to dialysis in the elderly are rather controversial, reflecting each country’s health policies and ethical patterns. Although advanced age should not be considered as an absolute contraindication for kidney transplantation, it is not frequently offered in elderly ESRD patients due to the shortage of renal grafts. Global judgment of all physical and mental/psychological issues and full informed consent regarding possible complications are mandatory before listing elderly ESRD patients for kidney transplantation. As scientific evidence is rather scarce, there is an urgent need for prospective studies and an individualized approach for the diagnosis and treatment of the elderly CKD patients, in order to optimize care and improve quality of life in this special population.
Chronic kidney disease; elderly; hemodialysis; peritoneal dialysis; renal transplantation
Numerous studies have now demonstrated that many older women retain an interest in their sexual lives. Yet, how many old age psychiatrists commonly check with older women about whether the depression they are treating, or the SSRIs (Selective Serotonin Re-uptake Inhibitors) they have prescribed, have adversely affected their patient’s sexual lives? We consider the latest evidence regarding cultural, social and medical influences on older women’s sexual lives and some specific issues which affect lesbian and transsexual people. We examine how mental illness and psychotropic medication in particular can adversely affect older women’s sexual functioning and at how difficult it often proves to be for women to seek help. We also focus on why doctors and in particular psychiatrists may not take a sexual history, look for sexual side effects or refer for appropriate treatment, especially when interviewing older women patients. Most published information about psychiatric training and sexual issues focuses on the younger male patient. We therefore aimed to provide a broad-ranging review of the literature regarding female sexual functioning in old age, the difficulties that can arise and the role that old age psychiatrists have an opportunity to fulfil, in this often neglected aspect of their patients’ treatment. From our review it was clear that, in the light of the increasing cultural acceptability of discussions regarding sexuality and older women, the training of student doctors and trainee psychiatrists needs to reflect this change so that old age psychiatrists can enhance the quality of their patient care.
Female; old age; sexuality; chronic disease; help-seeking; psychiatry
In recent years, genome wide association studies have revolutionized the understanding of the genetic architecture of complex disease, particularly in the context of disorders that present in old age, such as type 2 diabetes and cardiovascular disease. This new era is made all the more compelling by the fact that, through extensive validation efforts, there is now very strong consensus among human geneticists on what the key loci are that contribute to the pathogenesis of these traits. However, as these variants have been almost exclusively uncovered in an adult setting, there is the question of when these genetic variants start exerting their effects; indeed many may start setting up an individual’s predisposition to a disease of old age very early on in life. To this end, we review what breakthroughs have been made in elucidating which of these genetic factors are operating in childhood and conversely what discoveries have actually been made in the pediatric setting that have then been found subsequently to increase one’s risk of a late-onset disease. After all, it well known that complex traits like obesity, type 2 diabetes and inflammatory bowel disease are strongly determined by genetic factors, but the isolation of genes in these complex phenotypes in adults has been impeded by interaction with strong environmental factors. Distillation of the genetic component in these complex traits, which will at least partially have origins in childhood, should be easier to determine in a pediatric setting, where the relatively short period of a child’s lifetime limits the impact of environmental exposure.
Disease; late-onset; childhood; genetic; association
Longstanding immunological dogma holds that flexible immune recognition, which forms the mechanistic basis of adaptive immunity, is strictly confined to the lymphocyte lineage. In higher vertebrates, flexible immune recognition is represented by recombinatorial antigen receptors of enormous diversity known as immunoglobulins, expressed by B lymphocytes, and the T cell receptor (TCR), expressed by T lymphocytes. The recent discovery of recombinatorial immune receptors that are structurally based on the TCR (referred to as TCR-like immunoreceptors, “TCRL”) in myeloid phagocytes such as neutrophils and monocytes/macrophages now challenges the lymphocentric paradigm of flexible immunity. Here, we introduce the emerging concept of “extralymphocytic flexible immune recognition” and discuss its implications for inflammation and aging.
TCR; macrophage; neutrophil; immunosenescence
Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly.
Neuroradiology; neuroimaging; aging; cerebrovascular disease; white matter; cerebral infarction
The serotonin receptor 2A gene polymorphism is associated with attentional processes in schizophrenia. However, the specificity of the underlying cognitive constructs affected within this domain requires further elucidation. We carried out the first investigation of whether the TC/CC genotype of the 5-HT2A T102C polymorphism confers impairments in early-onset schizophrenia (EOS; onset of psychotic symptoms before age 18) but not in healthy siblings, the putative mechanism being that serotonergic inhibitory modulation of prefrontal dopamine is impaired in the presence of the C allele which in turn is a genetic risk marker for schizophrenia. Fifty-three EOS outpatients and 46 of their non-psychotic siblings (no current Axis I diagnoses) were genotyped for 5-HT2A T102C polymorphism. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptomatology severity. Diagnostic classification was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Structured Clinical Interview. The Degraded-Stimulus Continuous Performance Test (DS-CPT) was used to measure sustained focused attention. As predicted, EOS probands produced fewer correct responses (hit rate) and demonstrated poorer perceptual sensitivity compared with the healthy siblings. The C allele at codon 102 was associated with fewer correct responses compared with the TT genotype. There was no significant relationship between the polymorphism and clinical parameters, as measured using the PANSS. Our findings suggest that the C allele may be related to sustained attentional impairments in EOS.
adolescence; attention; biological relatives; gene polymorphism; T102C; HTR2A; Schizophrenia
miRNAs have recently been shown to play a key role in cell senescence, by downregulating target genes. Thus, inference of those miRNAs that critically downregulate target genes is important. However, inference of target gene regulation by miRNAs is difficult and is often achieved simply by investigating significant upregulation during cell senescence. Here, we inferred the regulation of target genes by miRNAs, using the recently developed MiRaGE server, together with the change in miRNA expression during fibroblast IMR90 cell senescence. We revealed that the simultaneous consideration of 2 criteria, the up(down)regulation and the down(up) regulatiion of target genes, yields more feasible miRNA, i.e., those that are most frequently reported to be down/upregulated and/or to possess biological backgrounds that induce cell senescence. Thus, when analyzing miRNAs that critically contribute to cell senescence, it is important to consider the level of target gene regulation, simultaneously with the change in miRNA expression.
bioinformatics; mirna; target gene; expression regulation; senescence
Small cerebral bleeds are frequently observed in brains of patients with Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). However, they are also observed in patients with other neurodegenerative dementias and in persons without cognitive impairment. The aim of this survey is to compare the bleeding load in brains with different dementia syndromes and in age-matched controls. Hundred sixty-five brains were examined. The prevalence and the severity of the different cerebrovascular lesions were examined. Quantification of the number of mini-bleeds allowed to determinate the bleeding load in different cerebral regions. Micro-bleeds were considered as small macroscopically visible lesions while mini-bleeds were defined as small perivascular accumulations of red blood cells or siderophages only visible on microscopic examination. Several types of cerebrovascular lesions prevailed in AD brains with CAA, compared to the controls. White matter changes prevailed in frontotemporal lobar degeneration. Mini-bleeds were significantly more frequent in the cerebral cortex of AD and Lewy body dementia brains. They also prevailed around the dentate nucleus of the cerebellum and in the tegmentum pontis of patients with progressive supranuclear palsy. On the other hand the bleeding load in frontotemporal lobar degeneration and in corticobasal degeneration was similar to that in age-matched control brains. Cerebrovascular lesions, including micro-bleeds, predominated in AD brains with CAA. Mini-bleeds, on the other hand, were more related to the neurodegenerative process itself and reflected associated disruption of the blood-brain barrier.
neuropathology; Alzheimer dementia; cerebral amyloid angiopathy; Lewy body dementia; frontotemporal lobar degeneration; progressive supranuclear palsy; corticobasal degeneration; cerebrovascular pathology; micro- and mini-bleeds
This report reviews evidence on disorders related to inadequate vitamin D repletion in older people. Vitamin D is as essential for bone health in adults as in children, preventing osteomalacia and muscle weakness and protecting against falls and low-impact fractures. Vitamin D is provided by skin synthesis by UVB-irradiation from summer sunshine and to a small extent by absorption from food. However, these processes become less efficient with age. Loss of mobility or residential care restricts solar exposure. Reduced appetite and financial problems often add to these problems. Thus, hypovitaminosis D is common world-wide, but is more common and more severe in older people. Non-classical effects of vitamin D, depending on serum circulating 25-hydroxyvitamin D concentrations, are present in most non-bony tissues; disorders associated with hypovitaminosis D include increased risks of sepsis [bacterial, mycobacterial and viral], cardiovascular and metabolic disorders [e.g. hyperlipidemia, type 2 diabetes mellitus, acute vascular events, dementia, stroke and heart failure]. Many cancer risks are associated with vitamin D inadequacy, though causality is accepted only for colo-rectal cancer. Maintenance of repletion in healthy older people requires intakes of ≥800IU/day [20μg], as advised by the Institute of Medicine [IOM], but achieving such intakes usually requires supplementation. Excessive intakes are dangerous, especially in undiagnosed primary hyperparathyroidism or sarcoidosis, but the IOM finds doses <4000 IU/day are safe. Many experts suggest that ≥1000–2000 IU [25–50μg] of vitamin D daily is necessary for older people, especially when independence is lost, or hypovitaminosis D could add to the clinical problem[s]. Much higher doses than these are needed for treatment of established deficiency or insufficiency.
vitamin D; elderly; deficiency; supplementation; aging; pathology
Normal brain aging is associated with depression and cognitive decline. One of the mechanisms of aging-associated emotional and cognitive impairment might be the down-regulation of biosynthesis of N-acetylserotonin (NAS), one of the methoxyindole derivatives of tryptophan (TRP). Aging is associated with decreased NAS production, largely resulting from the down-regulation of beta 1 adrenoreceptors that activate serotonin N-acetyltransferase, the enzyme catalyzing formation of NAS from serotonin. NAS exerts antidepressant-like and cognition-enhancing effects. The NAS role in cognition supported by the discovery that scotophobin, decapeptide extracted from brain and associated with cognition improvement, inhibits NAS conversion into melatonin. Furthermore, NAS (and its derivatives) attenuated cognitive impairment induced by cholinergic neurotoxin and protected against beta-amyloid neurotoxicity. Considering that NAS (but not serotonin or melatonin) is a potent agonist to high-affinity BDNF tyrosine kinase (TrkB) receptors, antidepressant and cognition-enhancing effect of NAS might be mediated by activation of TrkB receptors. NAS and TRkB gradually decreased from 1 postnatal week becoming undetectable in the brains of old rats. Additional mechanisms might include non-receptor mediated anti-inflammatory and anti-oxidative effects of NAS. Therapeutic antidepressant and cognition-improving interventions might include administration of NAS and its analogs; inhibition of tryptophan - kynurenine metabolism to increase serotonin availability as a substrate for NAS biosynthesis; up-regulation of NAS formation from serotonin and down-regulation of NAS conversion into melatonin.
N-acetylserotonin; aging; memory; scotophobin; BDNF; TrkB
With advancing age, the prevalence of both stroke and non valvular atrial fibrillation (NVAF) is increasing. NVAF in old age has a high embolic potential if not anticoagulated. Oral anticoagulation therapy is cost effective in older people with NVAF due to their high base line stroke risk. The current stroke and bleeding risk scoring schemes have been based on complex scoring systems that are difficult to apply in clinical practice. Both scoring schemes include similar risk factors for ischemic and bleeding events which may lead to confusion in clinical decision making to balance the risks of bleeding against the risks of stroke, thereby limiting the applicability of such schemes. The difficulty in application of such schemes combined with physicians’ fear of inducing bleeding complications has resulted in under use of anticoagulation therapy in older people. As older people (≥75 years) with NVAF are all at high risk of stroke, we are suggesting a pragmatic approach based on a yes/no decision rather than a risk scoring stratification which involves an opt out rather an opt in approach unless there is a contraindication for oral anticoagulation. Antiplatelet agents should not be an alternative option for antithrombotic treatment in older people with NVAF due to lack of efficacy and the potential of being used as an excuse of not prescribing anticoagulation. Bleeding risk should be assessed on individual basis and the decision to anticoagulate should include patients’ views.
atrial fibrillation; anticoagulation; older people
Lithium is a mood stabilizer shown to have neuroprotective effects against several chronic and acute neuronal injuries, including stroke. However, it is unknown whether lithium treatment protects against brain injury post-stroke in a rat model of permanent distal middle cerebral artery occlusion (MCAo) combined with transient bilateral common carotid artery occlusion (CCAo), a model that mimics human stroke with partial reperfusion. In addition, whether lithium treatment alters Akt activity as measured by the kinase activity assay has not been reported, although it is known to inhibit GSK3β activity. After stroke, Akt activity contributes to neuronal survival while GSK3β activity causes neuronal death. We report that a bolus of lithium injection at stroke onset robustly reduced infarct size measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 48 h post-stroke and inhibited cell death in the ischemic penumbra, but not in the ischemic core, as shown by TUNEL staining performed 24 h post-stroke. However, lithium treatment did not alter the reduction in Akt activity as measured by Akt kinase assay. We further showed that lithium did not alter phosphorylated GSK3β protein levels, or the degradation of β-catenin, a substrate of GSK3β, which is consistent with previous findings that long-term treatment is required for lithium to alter GSK3β phosphorylation. In summary, we show innovative data that lithium protects against stroke in a focal ischemia model with partial reperfusion, however, our results dispute the importance of Akt activity in the protective effects of lithium.
Lithium; Akt; Cerebral focal ischemia; GSK3β; β-catenin
We have previously demonstrated that aging is associated with prolonged pulmonary inflammation in a murine model of thermal injury. To further investigate these observations, we examined lung congestion, markers of neutrophil chemotaxis and adhesion, and lung endothelia responses in young and aged mice following burn injury. Analysis of lung tissue and bronchoalveolar lavage fluid 24 hours after injury revealed that more neutrophils accumulated in the lungs of aged mice (p<0.05), but did not migrate into the alveoli. We then sought to determine if accumulation of neutrophils in the lungs of aged mice was due to differences in the peripheral neutrophil pool or local changes within the lung. Following burn injury, aged mice developed a pronounced peripheral blood neutrophilia (p<0.05) in comparison to their younger counterparts. In aged animals, there was a reduced frequency and mean fluorescent intensity of neutrophil CXCR2 expression (p<0.05). Interestingly, in uninjured aged mice, peripheral blood neutrophils demonstrated elevated chemokinesis, or hyperchemokinesis, (p<0.05), but showed a minimal chemotatic response to KC. To determine if age impacts neutrophil adhesion molecules, we assessed CD62L and CD11b expression on peripheral blood neutrophils. No age-dependent difference in the frequency or mean fluorescent intensity of CD62L or CD11b was observed post-burn trauma. Examination of pulmonary vasculature adhesion molecules which interact with neutrophil selectins and integrins revealed that intracellular adhesion molecule-1 (ICAM-1) was elevated in aged mice at 24 hours after burn as compared to young mice (p<0.05). Overall, our data suggests that age-associated pulmonary congestion observed following burn injury may be due to differences in lung endothelial adhesion responses that are compounded by elevated numbers of hyperchemokinetic circulating neutrophils in aged mice.
Adhesion; Aging; Chemotaxis; Neutrophils; Lung; Burn injury