The medical director, JAMDA, and the twenty-first century.
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Editorial Policies↗
Biomedical subjects
John E Morley
Publications and source records attributed to John E Morley.
The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation?
Leptin is a pluripotent regulatory protein secreted by fat and exerts many effects through the CNS. Interpretation of the characteristics by which it crosses the blood-brain barrier (BBB) supports the view that leptin most potently signals the brain at serum levels well below those associated with the current definition of ideal body weight. This fits with the perspective that low serum levels of leptin are a signal to brain that a sufficient store of calories are available for the organism to expend energy for efforts unrelated to acquisition of calories. This would explain why low serum levels of leptin are permissive in many of the non-feeding actions of leptin, such as enhancing CNS-mediated immune function, memory, bone growth, reproduction, breathing, and neurogenesis. Triglycerides inhibit the transport of leptin across the BBB and so could be key in the onset of the peripheral leptin resistance, which is a hallmark of obesity. These results explain the paradox of why obesity should induce resistance to an anorectic: hypertriglyceridemia also occurs with starvation and we postulate that triglyceride-induced resistance to leptin transport across the BBB initially evolved to limit the signal of an anorectic to the brain during starvation.
Adaptation, Physiological↗
The relationship between libido and testosterone levels in aging men.
CONTEXT: Although it is known that serum testosterone (T) concentrations are related to libido, the strength of that relationship in community-dwelling men has not yet been determined. OBJECTIVE: Our objective was to assess the strength and significance of the association between aging men's self-reports of libido and serum T concentrations. DESIGN: Our study was a community-based evaluation of men's health and aging, including three data collection waves: baseline (T1, 1987-1989) and follow-ups (T2, 1995-1997; T3, 2002-2004). Libido was measured on a 14-point scale assessing self-reported frequency of desire and thoughts/fantasies; low libido was defined as a score of less than 7 of 14. SETTING: We conducted an epidemiological study in greater Boston, Massachusetts. PARTICIPANTS: There were 1632 men aged 40-70 yr at baseline, with follow-up on 922 (56%) at 9 yr (T2) and 623 (38%) at 15 yr (T3). MAIN OUTCOME MEASURES: We assessed total and calculated bioavailable T . RESULTS: Three hundred eighteen (19%) subjects reported low libido at baseline. Libido and T displayed a significant association. However, the difference in mean T levels between those subjects with low libido and those without was small; analyses indicated a 3.4 ng/dl (0.12 nmol/liter) increase in total T per unit increase in libido. Subjects reporting low libido exhibited an increased but modest probability of exhibiting low T. Dividing T concentrations by the number of androgen receptor gene cytosine, adenine, guanine repeats did not enhance associations. CONCLUSIONS: Libido and T concentrations are strongly related at the population level. However, the value of individual patient reports of reduced libido as indicators of low T levels is open to question.
Adenine↗
Ghrelin controls hippocampal spine synapse density and memory performance.
The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.
Animals↗
Office management of weight loss in older persons.
Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, decreasing immune function, decreased functional status, and death. There are 4 major causes of weight loss: anorexia, sarcopenia, cachexia, and dehydration. Many of the reasons for the development of these conditions are treatable. For example, depression is the most common cause of weight loss in the elderly. Early screening for anorexia can be undertaken in the physician's office utilizing the Simplified Nutritional Assessment Questionnaire. An algorithmic approach to the office management of weight loss is provided.
Aged↗
Cognitive impairment.
As populations continue to age, the prevalence of dementia is expected to increase. AD is by far the most common cause of dementia. The clinical course of dementia represents the challenges that this disease presents. There are no truly effective therapies for treating dementia, and the cost effectiveness of ChEIs has been challenged; however, there has been an explosion of information about AD. Evidence-based practice parameters for diagnosis and management of dementia have been developed. There has been an increased interest in the possible prodromal states of dementia, such as MCI. The concept of MCI has risen in prominence in recent years; it is speculated that initiation of therapies early in the course of disease may be needed for them to be effective. Considering the enormous burdens that AD places on individuals and society, disease-modifying treatments for AD are needed desperately. There are promising avenues for the development of potentially disease-modifying therapies for this devastating disease.
Aged↗
Frailty.
Frailty is a common condition in older people. It now can be objectively defined by the Fried criteria. When recognized, early intervention should begin with the institution of endurance, resistance, and balance exercises. In men with testosterone deficiency a trial of testosterone replacement should be considered. Vitamin D deficiency needs to be recognized and treated. Appropriate treatment of underlying diseases, such as anemia, diabetes mellitus, and congestive heart failure, are a key management principle. In people who have frailty aggressive health promotion and disease prevention techniques can lead to an inhibition of the downward spiral to disability.
Aged↗
Andropause: a quality-of-life issue in older males.
Testosterone deficiency occurs commonly in men as they grow older. This deficiency often is associated with a decline in sexual activity and a loss of muscle mass. Testosterone replacement can reverse many of these effects. At present, no ideal form of testosterone replacement is available. Like the phosphodiesterase-5 inhibitors, testosterone replacement in older men is a quality of life issue.
Aged↗
Leptin and adiponectin levels in middle-aged postmenopausal women: associations with lifestyle habits, hormones, and inflammatory markers--a cross-sectional study.
To investigate the relationships between blood levels of leptin or adiponectin and lifestyle habits, hormones, and inflammatory markers, we measured parameters of alcohol intake, smoking, physical activity, and blood levels of leptin, adiponectin, testosterone, estrone, estradiol, cortisol, dihydroepiandrostenedione, luteinizing hormone, thyroxin, C-reactive protein (CRP), and interleukin 6 and interleukin 2 receptor in 76 healthy middle-aged postmenopausal women. Anthropometric measures and body composition (evaluated by dual-energy x-ray absorptiometry) and lipid profiles were also assessed. By simple regression, leptin correlated positively with fat and lean masses, glucose, triglycerides, low-density lipoprotein cholesterol, and total cholesterol, and negatively with high-density lipoprotein cholesterol. Adioponectin correlated negatively with fat and lean masses and low-density lipoprotein cholesterol, and positively with high-density lipoprotein cholesterol. Leptin concentration was correlated inversely with adiponectin (r = -0.26, P < .05) and positively with CRP (r = 0.56, P < .01). Adiponectin concentration was negatively correlated with time since last alcoholic drink (r = -0.24, P < .05) and CRP (r = -0.27, P < .05) and positively with testosterone level (r = 0.23, P < .05). By multiple regression analysis, leptin concentration was predicted by age (P < .05), testosterone (P < .05), adiponectin (P < .05), CRP (P < .01), and interleukin 6 receptor (P < .01). Adiponectin concentration was predicted by the time since last alcoholic drink (P < .05), testosterone (P < .05), leptin (P < .05), and C-reactive protein (P = .05). Similar results were found when leptin or adiponectin concentration was adjusted for fat mass. These results suggested that levels of leptin and adiponectin in middle-aged postmenopausal women are partially determined by sexual hormones and inflammatory marker levels, and both predicted one another. Moreover, adiponectin level may be modulated by alcohol intake.
Adiponectin↗
Validation of salivary testosterone as a screening test for male hypogonadism.
BACKGROUND: Saliva collection is an easy, non-invasive method to measure hormones. METHODS: Two studies were performed. In the first, a convenience sample of 1,454 males who had submitted saliva for salivary testosterone measurements were studied. In the second study, we intensively studied symptoms and measurements of total testosterone, free testosterone symptoms and measurements of total testosterone, free testosterone and bioavailable testosterone in relationship to salivary testosterone in 127 men. A secondary endpoint was to examine the relationship of salivary testosterone to hypogonadal symptoms in the ADAM and AMS questionnaires. RESULTS: In the first study, we have shown that salivary testosterone, measured in 1,454 males aged 20 to 89 years, declines by 47% over the lifespan. In the second study, salivary testosterone was strongly correlated with bioavailable testosterone (p < 0.000001) calculated free testosterone (p < 0.00001) and total testosterone (p < 0.002). Salivary testosterone was significantly related to hypogonadal symptoms on the St. Louis University ADAM questionnaire and the Aging Male Survey. CONCLUSIONS: These studies support the use of salivary testosterone as an acceptable assay for screening for hypogonadism. Salivary testosterone is not a better assay than other measures to diagnose hypogonadism.
Adult↗
Cachexia: pathophysiology and clinical relevance.
Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.
Aging↗
Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder--a pilot study.
CONTEXT: The Mini-Mental State Examination (MMSE) is commonly used as a screening tool to detect dementia. However, it performs poorly in identifying persons with mild neurocognitive disorder. The Saint Louis University Mental Status (SLUMS) examination is a 30-point screening questionnaire that tests for orientation, memory, attention, and executive functions. OBJECTIVE: The objective of this study was to compare SLUMS and the MMSE for detecting dementia and mild neurocognitive disorder (MNCD) using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. METHODS: Patients at the Veterans' Affairs Geriatric Research, Education and Clinical Center, St. Louis, MO (N = 702) were clinically classified as having normal cognitive functioning, MNCD, or dementia based on DSM-IV criteria. The SLUMS and MMSE were administered for comparison. RESULTS: Mean age was 75.3 years (standard deviation: 5.5). Regarding education, 62.4% of the sample had at least completed high school and 30.6% had not. Sensitivity and specificity were calculated and receiver operator curves (ROCs) generated for SLUMS and MMSE as a function of diagnosis (MCND versus dementia) and education. Both the SLUMS and MMSE produced acceptable ROCs for the diagnosis of dementia, but the ROCs for SLUMS were better than the MMSE for the diagnosis of MNCD in both education groups. CONCLUSION: These results suggest that the SLUMS and MMSE have comparable sensitivities, specificities, and area under the curve in detecting dementia. Although the definition of MNCD is controversial, the authors believe that the SLUMS is possibly better at detecting mild neurocognitive disorder, which the MMSE failed to detect, but this needs to be further investigated.
Aged↗
The use of games to improve patient outcomes.
In gerontology and geriatrics, learning often requires both the acquisition of new facts and a change in attitude towards elderly persons. Games, in addition to stimulating a desire to learn, are powerful instruments to change attitudes. This paper introduces games currently being used by the Gateway Geriatric Education Center to teach gerontological and geriatric principles to healthcare providers. It summarizes assessments that have been used to measure the effectiveness of those games to promote learning. Arguments are made that more rigorous methodologies of evaluation for games should be adopted in order to demonstrate the effects of that learning on improved patient outcomes.
Aged↗
Effects of leptin on memory processing.
Leptin is a peptide hormone secreted by adipose tissue. Studies have shown that leptin crosses the blood-brain barrier (BBB) by a saturable transport system where it acts within the hypothalamus to regulate food intake and energy expenditure. Leptin also acts in the hippocampus where it facilitates the induction of long-term potentiation and enhances NMDA receptor-mediated transmission. This suggests that leptin plays a role in learning and memory. Obese mice and rats, which have leptin receptor deficiency, have impaired spatial learning. In disease states such as diabetes, humans and animals develop leptin resistance at the BBB. This suggests that low leptin levels in the brain may be involved in cognitive deficits associated with diabetes. In the current study, the effects of leptin on post-training memory processing in CD-1 mice were examined. Mice were trained in T-maze footshock avoidance and step down inhibitory avoidance. Immediately after training, mice received bilateral injections of leptin into the hippocampus. Retention was tested 1 week later in the T-maze and 1 day later in step down inhibitory avoidance. Leptin administration improved retention of T-maze footshock avoidance and step down inhibitory avoidance. Leptin administered 24 h after T-maze training did not improve retention when tested 1 week after training. SAMP8 mice at 12 months of age have elevated amyloid-beta protein and impaired learning and memory. We examined the effect of leptin on memory processing in the hippocampus of 4 and 12 months old SAMP8 mice. Leptin improved retention in both 4 and 12 months old SAMP8 mice; 12 month SAMP8 mice required a lower dose to improve memory compared to 4 months SAMP8 mice. The current results indicate that leptin in the hippocampus is involved in memory processing and suggests that low levels of leptin may be involved in cognitive deficits seen in disease states where leptin transport into the CNS is compromised.
Animals↗
Preproenkephalin targeted antisenses cross the blood-brain barrier to reduce brain methionine enkephalin levels and increase voluntary ethanol drinking.
Antisense potentially can manipulate target gene expression in the brain if it can cross the blood-brain barrier (BBB). We designed three (10mer, 17mer, and 19mer) phosphorothioated antisenses (PS-ODNs) directed against the precursor molecule of methionine enkephalin (Met-Enk), an opiate peptide which suppresses voluntary ethanol drinking. We measured the ability of the antisenses to cross the BBB, accumulate in the brain and CSF, decrease levels of Met-Enk in brain and blood, and affect voluntary ethanol drinking. Each antisense readily crossed the BBB, with 0.07-0.16% of the i.v. dose accumulating per gram of brain. Capillary depletion and CSF sampling each confirmed that the antisenses entered the CNS. Gel electrophoresis of radioactivity recovered from brain and serum showed intact antisense and a higher molecular weight form likely representing antisense bound to protein, but no degradation products. Each antisense molecule and a cocktail of all three reduced Met-Enk levels in brain and serum. Met-Enk levels in the brain were reduced more rapidly and for a longer duration than Met-Enk levels in the serum, indicating a degree of selective targeting to the CNS. Additionally, administration of the cocktail was more effective in reducing Met-Enk levels than any of the individual antisenses. Each antisense increased voluntary ethanol drinking by about 20% and the cocktail increased it by about 80%. Taken together, these results used pharmacokinetic, immunochemical, and behavioral methods to show that PS-ODN antisenses that readily cross the BBB can decrease brain levels of Met-Enk and increase voluntary ethanol drinking.
Animals↗
Comparison of screening questionnaires for the diagnosis of hypogonadism.
Three questionnaires, the St. Louis University Androgen Deficiency in Aging Male (ADAM), the Aging Male Survey (AMS) and the Massachusetts Male Aging Study (MMAS), have been developed as potential screening tools for hypogonadism in older males. We compared these questionnaires in 148 males aged 23-80 years using bioavailable testosterone as the "biochemical gold standard" for diagnosis of hypogonadism. The sensitivity for the ADAM was 97%, for the AMS 83% and the MMAS 60%. Specificity was 30% for the ADAM, 59% for the MMAS and 39% for AMS. Both bioavailable testosterone and the calculated free testosterone correlated significantly with a number of the individual questions. Total testosterone correlated poorly with most of the questions. In conclusion, the ADAM and AMS may be useful screening tools for hypogonadism across the adult lifespan, but both are relatively nonspecific.
Adult↗
Proteomic identification of less oxidized brain proteins in aged senescence-accelerated mice following administration of antisense oligonucleotide directed at the Abeta region of amyloid precursor protein.
Amyloid beta-peptide (Abeta) is the major constituent of senile plaques, a pathological hallmark of Alzheimer's disease (AD) brain. It is generally accepted that Abeta plays a central role in the pathophysiology of AD. Abeta is released from cells under entirely normal cellular conditions during the internalization and endosomal processing of amyloid precursor protein (APP). However, accumulation of Abeta can induce neurotoxicity. Our previous reports showed that decreasing the production of Abeta by giving an intracerebroventricular injection of a 42-mer phosphorothiolated antisense oligonucleotide (AO) directed at the Abeta region of the APP gene reduces lipid peroxidation and protein oxidation and improves cognitive deficits in aged senescence-accelerated mice prone 8 (SAMP8) mice. In order to investigate how Abeta level reduction improves learning and memory performance of SAMP8 mice through reduction of oxidative stress in brains, we used proteomics to identify the proteins that are less oxidized in 12-month-old SAMP8 mice brains treated with AO against the Abeta region of APP (12 mA) compared to that of the age-control SAMP8 mice. We found that the specific protein carbonyl levels of aldoase 3 (Aldo3), coronin 1a (Coro1a) and peroxiredoxin 2 (Prdx2) are significantly decreased in the brains of 12 mA SAMP8 mice compared to the age-controlled SAMP8 treated with random AO (12 mR). We also found that the expression level of alpha-ATP synthase (Atp5a1) was significantly decreased, whereas the expression of profilin 2 (Pro-2) was significantly increased in brains from 12 mA SAMP8 mice. Our results suggest that decreasing Abeta levels in aged brain in aged accelerated mice may contribute to the mechanism of restoring the learning and memory improvement in aged SAMP8 mice and may provide insight into the role of Abeta in the memory and cognitive deficits in AD.
Acetaldehyde↗
Effect of testosterone on functional recovery in a castrate male rat stroke model.
Both increased and decreased testosterone levels have been reported to correlate with poor outcome after acute ischemic stroke. The present study focused on the role of testosterone during recovery from neurological deficits in a rat focal ischemia model. Castrate male rats were subjected to behavioral tests after 90 min of middle cerebral artery occlusion (MCAO). On day 7 post-MCAO, neurological deficit-matched rats were assigned to a treatment group implanted with subcutaneous testosterone pellets or a control group implanted with sham cholesterol pellets. After 4 weeks post-MCAO, the average infarct volume was not significantly different between the two groups. Rats in the testosterone group demonstrated significantly earlier improvement in neurological deficits and shortened latency of adhesive tape removal compared with the control group as analyzed by Wilcoxon signed ranks test. Walking on parallel bars improved in both groups with a trend towards early recovery observed in the testosterone group. Biased left body swings persisted during the test period in both groups post-MCAO. Serum testosterone was within physiological levels in the treatment group but was not detectable in the control group by radioimmunoassay. GAP-43 and synaptophysin expression did not differ between groups. Less GFAP expression and reactive astrocyte hypertrophy were found around the infarct area in testosterone-treated rats compared with control rats. In conclusion, testosterone replacement post-MCAO accelerated functional recovery in castrate rats, suggesting a potential therapeutic role for testosterone replacement in stroke recovery.
Androgens↗