Age-associated Memory Impairment Research Articles

Research on the mechanism of buyang huanwu decoction in the amelioration of age-associated memory impairment based on the “co-occurrence network regulation of intestinal microecology-host metabolism-immune function”

Ethnopharmacological relevanceBrain aging can promote neuronal damage, contributing to aging-related diseases like memory dysfunction. Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine formula known for tonifying qi and activating blood circulation, shows neuroprotective properties. Despite this, the specific mechanism by which BYHWD improves age-associated memory impairment (AAMI) has not been explored in existing literature. Aim of the studyThis study aimed to investigate the mechanism of BYHWD in the improvement of AAMI based on the “co-occurrence network regulation of intestinal microecology-host metabolism-immune function”. Materials and methodsFirstly, D-galactose was performed to induce a rat model of AAMI. Learning and memory deficits was assessed by the Morris water maze test. H&E and Nissl staining were used to observe the pathological changes in neurons in the hippocampus of rats. Meanwhile, the levels of pro-inflammatory cytokines and the activation of antioxidant enzymes in rat serum were measured using ELISA. Finally, an integrated pharmacological approach was applied to explore the potential mechanism of BYHWD in improving AAMI. ResultsOur results indicated that BYHWD significantly mitigated the pathological structure of the hippocampus, reversed the levels of IL-6, TNF-α, GSH, and CAT in the serum, and improved learning and memory in aging rats. Transcriptomics combined with network pharmacology showed that energy metabolism and the inflammatory response were the key biological pathways for BYHWD to ameliorate AAMI. Integrative analysis of the microbiome and metabolomics revealed that BYHWD has the potential to restore the balance of abundance between probiotics and harmful bacteria, and ameliorate the reprogramming of energy metabolism caused by aging in the brain. The co-occurrence network analysis demonstrated that a strong correlation between the treatment of AAMI and the stability of intestinal microecology, host metabolism, and immune network. ConclusionThe findings of this study collectively support the notion that BYHWD has a superior therapeutic effect in an AAMI rat model. The mechanism involves regulating the “intestinal microecology-metabolism-immune function co-occurrence network” system to restore the composition of gut microbiota and metabolites. This further improves the metabolic phenotype of brain tissue and maintains the homeostasis of central nervous system's immunity, leading to an improvement in AAMI. Consequently, this study offers a unique perspective on the prevention and treatment of AAMI. And, BYHWD is also considered to be a promising preclinical treatment for improving AAMI.

Unveiling citicoline's mechanisms and clinical relevance in the treatment of neuroinflammatory disorders.

Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti-inflammatory effects. This review aims to elucidate citicoline's anti-inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age-associated memory impairment. Citicoline's anti-inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate-a pro-inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF-κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age-related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti-inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration.

'Citicoline' and support of the memory function: Evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006.

Following an application from Egde Pharma Sp. z o.o, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Poland, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to citicoline and memory. The Panel considers that the food, citicoline (cytidine 5-diphosphocholine, CDP-Choline) inner salt, is sufficiently characterised. Improvement, maintenance or reduced loss of memory is a beneficial physiological effect for middle-aged or elderly adults encountering age-associated subjective memory impairment. The applicant identified three pertinent human intervention studies in healthy individuals that investigated the effect of citicoline on memory. In weighing the evidence, the Panel took into account that only one randomised controlled trial in healthy participants showed a beneficial effect of citicoline on episodic memory when consumed at doses of 500 mg/day for 12 weeks, whereas this effect has not been observed in another study using citicoline at doses of 1 g/day for 3 months or supported by data obtained in patients with dementia using doses of 1 g/day for 12 weeks and 12 months. No convincing evidence of a plausible mechanism by which citicoline or any of its components (in addition to their endogenous synthesis) could exert an effect on memory in humans has been provided. The Panel concludes that a cause-and-effect relationship has not been established between the consumption of citicoline (CDP-Choline) inner salt and improvement, maintenance or reduced loss of memory in middle-aged or elderly adults encountering age-associated subjective memory impairment.

The effects of GPER on age-associated memory impairment induced by decreased estrogen levels.

Estrogen, as a pleiotropic endocrine hormone, not only regulates the physiological functions of peripheral tissues but also exerts vital neuroregulatory effects in the central nervous system (CNS), such as the development of neurons and the formation of neural network connections, wherein rapid estrogen-mediated reactions positively stimulate spinogenesis and regulate synaptic plasticity and synaptic transmission to facilitate cognitive and memory performance. These fast non-genomic effects can be initiated by membrane-bound estrogen receptors (ERs), three best known of which are ERα, ERβ, and G protein-coupled estrogen receptor (GPER). To date, the effects of ERα and ERβ have been well studied in age-associated memory impairment, whereas there is still a lack of attention to the role of GPER in age-associated memory impairment, and there are still disputes about whether GPER indeed functions as an ER to enhance learning and memory. In this review, we provide a systematic overview of the role of GPER in age-associated memory impairment based on its expression, distribution, and signaling pathways, which might bring some inspiration for translational drugs targeting GPER for age-related diseases and update knowledge on the role of estrogen and its receptor system in the brain.

Principal component analysis suggests multiple dimensions of memory inhibition that are differentially affected by age.

Cognitive inhibition is among the executive functions that decline early in the course of normal aging. Failures to be able to inhibit irrelevant information from memory may represent an essential factor of age-associated memory impairment. While a variety of elaborate behavioral tasks have been developed that presumably all index memory inhibition, the extent to which these different tasks measure the same underlying cognitive construct that declines with age has not been well explored. In the current study, 100 and 75 cognitively healthy younger (n = 71; age = 30.7 ± 5.4 years, 56.7% female) and older (n = 104, age = 69.3 ± 5.9 years, 66.2% female) adults with equivalent educational attainment performed three computer-based memory inhibition tasks: the Retrieval Induced Forgetting task, the Suppress task, and the Directed Forgetting task. We conducted a principal component analysis using scores derived from different components of these tasks to explore whether and how the tasks relate to one another. We further investigated how age, sex and education, along with, in a subsample of the participants, a neuropsychological measure of episodic memory, impacted both the task scores individually, and the principal components derived from the exploratory analysis. We identified 3 distinct sources of variability which represent potentially independent cognitive processes: memory retrieval facilitation, and two memory inhibition processes that distinguished themselves by the degree of volitional initiation of memory suppression. Only the memory retrieval component correlated with a neuropsychologically-derived episodic memory score, and both memory inhibition principal components were age dependent. Our findings provide support for a distinction in memory suppression processes between those 'instructed' to be performed and those which happen without explicit instruction. This distinction adds nuance to the dichotomous classification of controlled vs. automatic inhibitory mechanisms, which have been shown in previous work to vary as a function of the degree of frontal involvement. Our findings further demonstrate that while both of these measures of inhibition were affected by age, the episodic memory component was not, suggesting that inhibitory impairments may precede memory deficits in healthy aging.

P2Y6 receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging.

Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y6 receptor (P2Y6 R) on the surface of microglia, inducing microglial phagocytosis of neurons. However, whether the activation of P2Y6 R affects microglial phagocytosis of synapses is unknown. We show here that inactivation of P2Y6 R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal-glial co-cultures. In vivo, wild-type mice aged from 4 to 17 months exhibited reduced synaptic density in cortical and hippocampal regions, which correlated with increased internalization of synaptic material within microglia. However, this aging-induced synaptic loss and internalization were absent in P2Y6 R knockout mice, and these mice also lacked any aging-induced memory loss. Thus, P2Y6 R appears to mediate aging-induced loss of synapses and memory by increasing microglial phagocytosis of synapses. Consequently, blocking P2Y6 R has the potential to prevent age-associated memory impairment.

Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

ABSTRACTBackgroundSupplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations.ObjectiveThe objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI).MethodsA total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons.ResultsA total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052).ConclusionsDietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was registered at clinicaltrials.gov as NCT03369925.

Effect of Citicoline on Memory Function in Healthy Order Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract Objectives Subtle deficits in memory in healthy elderly adults are considered to be a normal consequence of aging [i.e., age-associated memory impairment (AAMI)]. The prevalence of cognitive impairment without dementia in the elderly is estimated at 5.4 million, and every year roughly 12% of these individuals go on to develop dementia. Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. Unfortunately, few studies have investigated the effects of citicoline supplementation on memory in healthy elderly adults with memory loss due to aging. Thus, the objective of this study was to investigate the effects of Cognizin®, a citicoline supplement, on memory in healthy elderly populations with AAMI. Methods A total of 100 healthy men and women between 50 to 85 years of age with AAMI participated in this randomized, double-blind, placebo-controlled trial. Subjects were randomized to receive placebo (n = 51) or Cognizin® (n = 49; 500 mg/day) for 12 weeks. Memory functions were assessed at baseline and end of the intervention (12 weeks) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, hematology and clinical chemistry. Results A total of 99 out of 100 subjects completed the study in its entirety. After the 12 week intervention, subjects supplemented with Cognizin® showed significantly greater improvements in episodic memory (assessed by the Paired Associate test) compared to those on placebo. Scores for composite memory, calculated using the scores of four memory tests (Spatial Span, Monkey Ladder, Paired Associate, and Digit Span) also improved to a greater extent following Cognizin® supplementation compared to placebo. There were no adverse events related to a study product and hematology and clinical chemistry were stable throughout the intervention. Conclusions Dietary supplement of Cognizin® for 12 weeks improved overall memory performance, especially episodic memory, in healthy males and females with AAMI. The findings suggest that regular consumption of Cognizin® may be safe and potentially beneficial against memory loss due to aging. Funding Sources Kyowa Hakko Bio Co., Ltd.

Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice.

The mechanisms of age-associated memory impairment may be associated with glutamate receptor function and chromatin modification. To observe the effect of an enriched environment on the cognitive function of mice with age-associated memory impairment, 3-month-old C57BL/6 male mice ("young" mice) were raised in a standard environment, while 24-month-old C57BL/6 male mice with memory impairment ("age-associated memory impairment" mice) were raised in either a standard environment or an enriched environment. The enriched environment included a variety of stimuli involving movement and sensation. A water maze test was then used to measure cognitive function in the mice. Furthermore, quantitative real-time polymerase chain reaction and western blot assays were used to detect right hippocampal GluN2B mRNA as well as protein expression of GluN2B and CREB binding protein in all mice. In addition, chromatin immunoprecipitation was used to measure the extent of histone acetylation of the hippocampal GluN2B gene promoters. Compared with the young mice, the water maze performance of age-associated memory impairment mice in the standard environment was significantly decreased. In addition, there were significantly lower levels of total histone acetylation and expression of CREB binding protein in the hippocampus of age-associated memory impairment mice in the standard environment compared with the young mice. There were also significantly lower levels of histone acetylation, protein expression, and mRNA expression of GluN2B in the hippocampus of these mice. In contrast, in the age-associated memory impairment mice with the enriched environment intervention, the water maze performance and molecular biological indexes were significantly improved. These data confirm that an enriched environment can improve cognitive dysfunction in age-associated memory impairment mice, and suggest that the mechanisms may be related to the increased expression of CREB binding protein and the increased degree of total histone acetylation in the hippocampus of age-associated memory impairment mice, which may cause the increase of histone acetylation of GluN2B gene promoter and the enhancement of GluN2B mRNA transcription and protein expression in hippocampus. The animal experiment was approved by the Animal Ethics Committee of Yangzhou University, China (approval No. 20170312001) in March 2017.

The Neurocognitive Function and Neuroimaging Characteristics between Age-Associated Memory Impairment and Mild Cognitive Impairment

The Neurocognitive Function and Neuroimaging Characteristics between Age-Associated Memory Impairment and Mild Cognitive Impairment

Spearmint Extract Improves Working Memory in Men and Women with Age-Associated Memory Impairment.

Objective: The purpose of this study was to investigate the effects of supplementation with a spearmint (Mentha spicata L.) extract, high in polyphenols including rosmarinic acid, on cognitive performance, sleep, and mood in individuals with age-associated memory impairment (AAMI).Design: Subjects with AAMI (N = 90; 67% female; age = 59.4 ± 0.6 years) were randomly assigned (n = 30/group) to consume 900, 600, or 0 mg/day (two capsules, once daily) spearmint extract for 90 days, in this double-blind, placebo-controlled trial. Assessments were completed for cognition (days 0, 45, and 90), sleep (days 0 and 90), and mood (days 0 and 90) by using the Cognitive Drug Research (CDR) System™, Leeds Sleep Evaluation Questionnaire (LSEQ), and Profile of Mood States (POMS™), respectively.Results: Quality of working memory and spatial working memory accuracy improved after supplementation with 900 mg/day spearmint extract by 15% (p = 0.0469) and 9% (p = 0.0456), respectively, versus placebo. Subjects consuming 900 mg/day spearmint extract reported improvement in their ability to fall asleep, relative to subjects consuming placebo (p = 0.0046). Overall treatment effects were evident for vigor-activity (p = 0.0399), total mood disturbance (p = 0.0374), and alertness and behavior following wakefulness (p = 0.0415), with trends observed for improvements after spearmint supplementation relative to placebo.Conclusions: These results suggest that the distinct spearmint extract may be a beneficial nutritional intervention for cognitive health in older subjects with AAMI.

Using Fuzzy Systems to Infer Memory Impairment from MRI

Alzheimer’s disease (AD) is a common form of dementia, which mostly affects elderly people. Gradual loss in memory and declining cognitive functions are core symptoms associated with AD. Conventional brain images do not provide sufficient information to diagnose AD at an early stage. To delay the progression of memory impairment, there is a dire need to develop systems capable of early AD diagnosis. This paper describes a proposed fuzzy method for inferring the risk of dementia using the brain cortical thickness and hippocampus thickness. The aim is to develop a reliable index that allows the evaluation of brain health. The dementia index poses potential to become a biologically based biomarker for the clinical assessment of patient’s dementia. Results show that the inference value of patient with mild cognitive impairment is significantly higher than that of healthy (control) or schizophrenia (SCZ) patients. Our results suggest that a higher inference value indicates that the patient is at higher risk and is more likely to eventually progress to AD. The system is also tested with age-associated memory impairment patients. The results confirm that our model is able to distinguish between these four patient groups.

Ageing and integrative care: examining a multidisciplinary memory clinic in an Irish setting

Introduction : St Patrick’s Mental Health Service (SPMHS) memory clinic is a multidisciplinary memory assessment service established in 2003. SPMHS is the largest not-for-profit provider of mental health services in the Republic of Ireland. Up to 40% of patients admitted to inpatient care at St Patrick’s University Hospital are aged 65 and over. As a result a memory assessment service was felt to be a crucial part of the development of older adult services at SPMHS. As dementia prevalence increases, (1) it is important to accurately define the dementia subtype, as this has treatment implications, and to screen for other causes of cognitive impairment including depression and age associated memory impairment. Practice change and innovation : The memory clinic was initially based on the Cambridge model of memory assessment by John Hodges. (2)This model describes a system in which multidisciplinary assessment is completed within the same day by a psychiatrist, neuropsychologist and neurologist. SPMHS memory clinic initially followed this model but has developed into a unique service through a number of adaptations. A two day admission involving comprehensive testing is now arranged. All costs are reimbursed by private insurers. Primary care is integrated into the service model and a reversible dementia screen is performed by the General Practitioner prior to admission. The memory clinic administrator arranges an MRI Brain scan in advance. The rationale behind this change was to blend appropriate observation of the patient over a two day period with the various elements of the cognitive assessment. Comprehensive and holistic assessment of memory and cognitive function requires a multidisciplinary approach. Disciplines that conduct joint and separate assessments include neuropsychology, psychiatry, occupational therapy and gerontological nursing. Input from neurology and social work are available. A driving assessment may be arranged on request. This is conducted by a senior occupational therapist and driving instructor and the primary impetus for this development was provided by the memory clinic. A detailed blended multidisciplinary report is created and feedback is given to the patient and their family one week after testing. The report is also sent to the primary care physician. Outcomes : The benefits of this model are that it allows for a comprehensive assessment involving all relevant members of the team. The two day admission allows for recovery time between assessments. This gives the service user the best chance of maximising their performance and minimises the anxiety induced by memory testing. However, while reducing anxiety during assessment an unfamiliar environment can often expose problems with orientation, flexibility and many other cognitive domains and this in itself is useful diagnostically. We will present a summary of the 252 cases seen in the memory clinic since its foundation in 2003, focusing on diagnoses and treatment. Although further improvements will be implemented in the future, this model has proven to be sustainable and comprehensive. With appropriate funding this model could be transferred onto other private and public settings. This will likely be necessary in the future given the growing population over the age of 65 and increasing prevalence of dementia. References : 1. Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. World Alzheimer Report 2015: The Global Impact of Dementia. London: Alzheimer’s Disease International; 2015. 2. Kipps C M, Hodges J R. Cognitive assessment for clinicians. J Neurol, neurosurg and psychiatry. 2005; 76(1):22-30.

Temporal binding function of dorsal CA1 is critical for declarative memory formation

Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment.

In older men with low testosterone levels and age-associated memory impairment, testosterone did not improve memory.

Source Citation Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA. 20...

Journal Digest

Journal Digest

Safety and tolerability of a dried aqueous spearmint extract

Spearmint (Mentha spicata L.) and spearmint extracts are Generally Recognized as Safe (GRAS) for use as flavoring in beverages, pharmaceuticals, and confectionaries. Studies of spearmint extracts in humans and animals have reported conflicting results with respect to toxicity. Since the chemical composition of these extracts was not reported and the spearmint source material was different, the relevance of these existing data to evaluating the risks associated with ingestion of a dried aqueous spearmint extract standardized to rosmarinic acid is not clear. Hence, the safety and tolerability of the dried aqueous spearmint extract was evaluated as part of a double-blind, randomized, placebo-controlled trial in healthy adults with age-associated memory impairment. Ingestion of both 600 and 900 mg/day for 90 days had no effect on plasma levels of follicular stimulating hormone, luteinizing hormone, or thyroid stimulating hormone, or other safety parameters including vital signs, plasma chemistry or whole blood hematology values. Additionally, there were no reported severe adverse events, no significant between-group differences in the number of subjects reporting adverse effects and the adverse events reported could not be attributed to ingestion of the extract. These results therefore show that ingestion of the aqueous dried spearmint extract is safe and well-tolerated.

Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment

Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89). Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. clinicaltrials.gov Identifier: NCT00799617.

The Mild Cognitive Impairment (MCI) in Searching for its Clinical Identity, Comment of the NEDICES Cohort Data

Elderly cognitive decline is a well-known disorder that affects many people. One of the first medical definitions for this clinical reality was Kral’s “benign and malignant senescent forgetfulness”. After Kral, many authors proposed other entities of memory impairment or cognitive decline in the elderly: “Age-associated memory impairment”, “Agerelated memory decline”, “Ageing-associated cognitive decline”, Mild Cognitive Impairment (MCI) and “Cognitive Impairment Non-Dementia” (CIND) of the Canadian Study. And very recently, the DSM-V defined the elderly cognitive decline as a “Minor Neurocognitive Disorder”. By large, MCI had far more citations than any other predementia state in MEDLINE (more than 8,000 reviews in this medical database). This success in the medical literature is rather the expression of a controversy than a well-defined clinical disorder. In fact, its medical birth, near 30 years ago, was as a research entity that precludes dementia. The theoretical definition of MCI is quite clear (A cognitive decline with an increased dementia risk); the problem is the operational definition of this cognitive decline in many elderly that have produced, along the time many definitions and subtypes. In summary, MCI is defined as cognitive decline (of one or more cognitive domains, mainly memory) with normal or near normal functional activities of the patient, and obviously, no dementia. According to the type and extension of the affected cognitive domain, MCI has received several subtyping: Amnestic- only memory affected, non-amnestic- deficit in another cognitive domain different from the memory, such as executive capacities. Both of them could be shown alone or in combination (only amnestic MCI, only non-amnestic, or amnestic o non-amnestic plus other cognitive domain affected. There are several well-known characteristics of this entity. First, it is prevalent in the elderly, more prevalent (about 10-15%) that the dementia states (5-10%). Obviously, in both conditions, its prevalence oscillates with the operational definitions used and with the population demographic characteristics studied: age, sex and education. Second, MCI involves an increased risk of dementia and mortality in relation to the normal cognition elders. Third, it is an unstable disorder, many MCI cases do not evolve to dementia, and many others change to normal cognition in a period of 2-3 years. Fourth, MCI is a heterogeneous entity with many risk factors and aetiologies; it is not always the predementia state of the main neurodegenerative disorders of the elderly: Alzheimer disease (AD), Parkinson disease (PD) and others; cerebral vascular diseases, depression and elderly co-morbidities underpinning many MCI cases. From an epidemiological point of view, it is interesting to comment the MCI definition in three different scenarios: the clinical setting, the population-based surveys, and the trial studies because in these three scenarios, MCI had different characteristics and evolution.

Why an M1 Antagonist Could Be a More Selective Model for Memory Impairment than Scopolamine.

Since the early studies of Deutsch (1), the non-selective muscarinic receptor antagonist scopolamine has been used as a drug that impairs memory performance in man. The notion that scopolamine could be used as a pharmacological model of age-associated memory impairment and dementia further strengthened the cholinergic hypothesis of geriatric memory dysfunction by Bartus et al. (2). Since then, a vast amount of studies applied this model to induce memory impairments in young healthy subjects to model age-related memory disorders. At present, scopolamine is still considered to be the best model for inducing cognitive impairments in healthy subjects (3). Scopolamine is therefore used as a pharmacological model to test novel cognition-enhancing drugs in animals [e.g., Ref. (4–6)] and in humans [e.g., Ref. (7, 8)]. In clinical trials, scopolamine is in particular being used as a model for AD in which novel cognition-enhancing drugs are tested (see https://ClinicalTrials.gov).