Affective problems and decline in cognitive state in older adults: a systematic review and meta-analysis.

Evidence suggests that affective problems, such as depression and anxiety, increase risk for late-life dementia. However, the extent to which affective problems influence cognitive decline, even many years prior to clinical diagnosis of dementia, is not clear. The present study systematically reviews and synthesises the evidence for the association between affective problems and decline in cognitive state (i.e., decline in non-specific cognitive function) in older adults. An electronic search of PubMed, PsycInfo, Cochrane, and ScienceDirect was conducted to identify studies of the association between depression and anxiety separately and decline in cognitive state. Key inclusion criteria were prospective, longitudinal designs with a minimum follow-up period of 1 year. Data extraction and methodological quality assessment using the STROBE checklist were conducted independently by two raters. A total of 34 studies (n = 71 244) met eligibility criteria, with 32 studies measuring depression (n = 68 793), and five measuring anxiety (n = 4698). A multi-level meta-analysis revealed that depression assessed as a binary predictor (OR 1.36, 95% CI 1.05-1.76, p = 0.02) or a continuous predictor (B = -0.008, 95% CI -0.015 to -0.002, p = 0.012; OR 0.992, 95% CI 0.985-0.998) was significantly associated with decline in cognitive state. The number of anxiety studies was insufficient for meta-analysis, and they are described in a narrative review. Results of the present study improve current understanding of the temporal nature of the association between affective problems and decline in cognitive state. They also suggest that cognitive function may need to be monitored closely in individuals with affective disorders, as these individuals may be at particular risk of greater cognitive decline.

Effect of varenicline on aspects of inhibitory control in smokers.

RATIONALE: Varenicline, a partial agonist at α4ß2 nicotinic receptors (nAChRs) aids smoking cessation by reducing craving. Successful quitting may be associated with greater inhibitory control but the effectiveness of varenicline in this regard is unknown. OBJECTIVES: This study aimed to investigate the effect of varenicline on aspects of inhibitory control in smokers. METHODS: A double-blind, placebo-controlled study investigating the effect of varenicline 1 mg (or matched placebo) in satiated and abstinent smokers. Tests included Rapid Visual Information Processing (RVIP), Stop-Signal (SS), Prospective Memory (PM) and the Cambridge Gambling Task (CGT). RESULTS: Smoking enhanced RVIP accuracy and latency to respond. Varenicline did not alter RVIP performance, nor the effect of smoking, suggesting that these effects were unrelated to α4ß2 nAChRs. Smoking increased the number of errors during SS and increased the stop latency, indicating that smoking decreased inhibitory control. Varenicline partially mimicked this effect of smoking but also reduced the smoking-induced increase, indicating a role for α4ß2 nAChRs. Likewise, smoking increased the number of points bet following a win during CGT and varenicline blocked this effect. There was no effect of smoking or varenicline on PM target detection per se. However, smoking protected the target detection rate in the ongoing task when a concurrent intention was introduced. Varenicline improved response speed in both satiated and abstinent smokers. CONCLUSIONS: Some aspects of inhibitory control may be mediated by α4ß2-related mechanisms and blockade of smoking-induced disinhibition may contribute towards the action of varenicline as an aid to smoking cessation.

APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures.

The APOE e4 allele, which confers an increased risk of developing dementia in older adulthood, has been associated with enhanced cognitive performance in younger adults. An objective of the current study was to compare task-related behavioural and neural signatures for e4 carriers (e4+) and non-e4 carriers (e4-) to help elucidate potential mechanisms behind such cognitive differences. On two measures of attention, we recorded clear behavioural advantages in young adult e4+ relative to e4-, suggesting that e4+ performed these tasks with a wider field of attention. Behavioural advantages were associated with increased task-related brain activations detected by fMRI (BOLD). In addition, behavioural measures correlated with structural measures derived from a former DTI analysis of white matter integrity in our cohort. These data provide clear support for an antagonistic pleiotropy hypothesis--that the e4 allele confers some cognitive advantage in early life despite adverse consequences in old age. The data implicate differences in both structural and functional signatures as complementary mediators of the behavioural advantage.

A role for glutamate in subjective response to smoking and its action on inhibitory control.

RATIONALE: Our previous study using memantine in smokers suggests that there may be a differential role for N-methyl-D-aspartate (NMDA) receptors in the subjective and cognitive effects of smoking. OBJECTIVES: This study was designed to investigate if D-cycloserine (DCS) would modulate the subjective and cognitive effects of limited smoking. METHODS: Forty-eight habitual smokers abstinent for a minimum of 2 h were randomly allocated to receive either placebo or 50 mg DCS (double-blind) and were subsequently required either to smoke half of one cigarette or to remain abstinent. Subjective and physiological effects of DCS were measured at baseline, 90 min postcapsule, and again after the partial-smoking manipulation, while the effects on sustained attention (rapid visual information processing test--RVIP) and cognitive flexibility (intra-extra dimensional set-shift test--IED) were evaluated only after the partial-smoking manipulation. RESULTS: DCS alone did not produce significant subjective effects other than an increase in ratings of "Stimulated". In combination with partial smoking, however, DCS blocked the smoking-induced increase in "Stimulated" and the decrease in "Relaxed" ratings. Furthermore, in combination with smoking, DCS reduced the number of false alarms during the RVIP test (an index of inhibitory control) and produced a small increase in diastolic blood pressure. DCS failed to modulate IED performance. CONCLUSIONS: These findings provide further evidence of a role for glutamate release in the subjective effects of smoking but not the effects on attention and cognitive flexibility. Furthermore, our results indicate that glutamate release may also be involved in the effect of smoking on inhibitory control.

Degree of dependence influences the effect of smoking on cognitive flexibility.

Pre-frontal cortical (PFC) dysfunction has been put forward as the basis for development and maintenance of addiction. To explore this relationship, the present study investigated the effects of smoking on PFC-mediated cognitive flexibility and subjective states in low- (LD) and high-dependent (HD) smokers. Twenty-four LD and 24 HD smokers (Fagerström dependence scores ≤ 4 and ≥ 5, respectively) were randomly allocated to non-smoking or smoking condition (12 LD and 12 HD participants per condition). After abstaining from smoking for a minimum of two hours volunteers completed a battery of questionnaires [nicotine-specific Visual Analogue Scales (Nic-VAS), Questionnaire of Smoking Urges (QSU) and Profile of Mood States (POMS)] at baseline [T1] and again after smoking one cigarette or remaining abstinent [T2]. Cognitive flexibility was evaluated at T2 using the Intra-Extra Dimensional Set-Shift test. The Rapid Visual Information Processing test was performed as a control nicotine-sensitive task at several time points during the experiment. Compared to LD smokers, HD smokers had higher salivary cotinine and breath CO levels at baseline and reported more craving (QSU) and felt less stimulated (Nic-VAS), vigorous, friendly and elated (POMS) throughout the experiment. Smoking increased Nic-VAS ratings of 'Buzzed' and 'Dizzy' and decreased craving in all participants. Smoking selectively impaired cognitive flexibility in HD smokers since HD smokers allocated to the smoking condition made significantly more errors with the intra-dimensional set-shift than their counterparts in the abstinent condition. No effect of smoking on RVIP test was observed, most likely due to the practice effect which was significant in both groups of smokers. The practice effect, however, was more pronounced in LD smokers. This study demonstrates that PFC-mediated cognitive effects of smoking as well as subjective reports vary according to the degree of nicotine dependence.

Acute effects of donepezil in healthy young adults underline the fractionation of executive functioning.

The cholinergic system is involved in the modulation of both bottom-up and top-down attentional control. Top-down attention engages multiple executive control processes, but few studies have investigated whether all or selective elements of executive functions are modulated by the cholinergic system. To investigate the acute effects of the pro-cholinergic donepezil in young, healthy volunteers on distinct components of executive functions we conducted a double-blind, placebo-controlled, independent-groups design study including 42 young healthy male participants who were randomly assigned to one of three oral treatments: glucose (placebo), donepezil 5 mg or donepezil 7.5 mg. The test battery included measures of different executive components (shifting, updating, inhibition, dual-task performance, planning, access to long-term memory), tasks that evaluated arousal/vigilance/visuomotor performance, as well as functioning of working memory subsidiary systems. Donepezil improved sustained attention, reaction times, dual-task performance and the executive component of digit span. The positive effects in these executive tasks did not correlate with arousal/visuomotor/vigilance measures. Among the various executive domains investigated donepezil selectively increased dual-task performance in a manner that could not be ascribed to improvement in arousal/vigilance/visuomotor performance nor working memory slave systems. Other executive tasks that rely heavily on visuospatial processing may also be modulated by the cholinergic system.

The eyes have it: an exploration of eye movements in action disorganisation syndrome.

We examined eye movements in a patient, FK, who has action disorganisation syndrome (ADS), as he performed the everyday task of making a cup of tea. We compared his eye movements with those of a person with Alzheimer's disease and with healthy volunteers. Despite showing very disorganised behaviour many aspects of FK's eye movements were relatively normal. However, unlike normal participants FK made no advance glances to objects that were about to be used, and he made increased numbers of fixations to irrelevant objects during the task. There were also differences in the durations of his eye movements during correct actions and during his perseverative and task-addition responses. We discuss the implications for understanding ADS and the cognitive processes required for correctly performing everyday tasks.

Differential involvement of glutamatergic mechanisms in the cognitive and subjective effects of smoking.

There is growing preclinical evidence for the involvement of glutamate in the behavioral actions of nicotine. The aim of this study, was to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the cognitive and subjective effects of smoking in humans. Sixty regular smokers took part in this double-blind placebo controlled study, that investigated the effect of the NMDA-antagonist memantine (40 mg) and the nicotinic-receptor antagonist mecamylamine (10 mg) on smoking-induced improvement in performance of a task of sustained attention and on smoking-induced changes in subjective effects and craving. Increases in subjective ratings of 'buzzed' following smoking were reversed by memantine, but not by mecamylamine. In contrast, improvement on a Rapid Visual Information Processing task by smoking was opposed by mecamylamine, but not by memantine. Smoking reduced craving for cigarettes, but neither drug altered this effect. Our results suggest that glutamatergic mechanisms may have differential involvement in the subjective and cognitive actions of smoking. Further investigations using different ligands are warranted to fully characterize the role of glutamate underlying the consequences of smoking behavior.

Positive effects of nicotine on cognition: the deployment of attention for prospective memory.

RATIONALE: Human and animal studies over the last two decades report that nicotine can improve cognitive performance. Prospective memory (PM), the retrieval and implementation of a previously encoded intention, is also improved by pre-administration of nicotine. As with other nicotine effects, however, predicting precisely how and when nicotine improves the processes engaged by PM has proved less straightforward. OBJECTIVE: We present two studies that explore the source of nicotine's enhancement of PM. Experiment 1 tests for effects of nicotine on preparatory attention (PA) for PM target detection. Experiment 2 asks whether nicotine enhances processing of the perceptual attributes of the PM targets. MATERIALS AND METHODS: Young adult non-smokers matched on baseline performance measures received either 1 mg nicotine or matched placebo via nasal spray. Volunteers completed novel PM tasks at 15 min post-administration. RESULTS: Experiment 1 confirmed that pre-administration of nicotine to non-smokers improved detection rate for prospective memory targets presented during an attention-demanding ongoing task. There was no relationship between PM performance and measures of preparatory attention. In experiment 2, salient targets were more likely to be detected than non-salient targets, but nicotine did not confer any additional advantage to salient targets. CONCLUSION: The present study suggests that nicotinic stimulation does not work to enhance perceptual salience of target stimuli (experiment 2), nor does it work through better deployment of preparatory working attention (experiment 1). An alternative explanation that nicotine promotes PM detection by facilitating disengagement from the ongoing task is suggested as a future line of investigation.

Nicotine effects on retrieval-induced forgetting are not attributable to changes in arousal.

BACKGROUND: There is emerging evidence from behavioural studies in humans for nicotinic modulation of inhibitory control. Administration of nicotine, however, also increases general arousal, and this may be responsible for the cognitive enhancing effects of nicotine. DISCUSSION: To test an arousal explanation of nicotine's effects on cognitive inhibition, this study compared the separate and combined effects of an acute dose of nicotine and an arousal manipulation on inhibitory processes associated with the retrieval-induced forgetting (RIF) paradigm. RESULTS: In a double blind placebo controlled design, 1.0 mg of nicotine delivered via nasal spray to non-smoking healthy young adults significantly increased the retrieval-induced forgetting observed in episodic list learning, relative to the placebo condition. In contrast, negative arousal evoked by an unsolvable anagram task had no effect either separately or in combination with nicotine. CONCLUSION: This result argues against the attribution of nicotine-induced changes in RIF performance to non-specific arousal effects. It suggests, furthermore, that pharmacological manipulation of the RIF produces effects that are qualitatively distinct from mood-induced effects. We consider these changes to relate to the direct modulation of information processing by nicotine.

Non-cholinergic modulation of antisaccade performance: a modafinil-nicotine comparison.

INTRODUCTION: The antisaccade task provides a powerful tool with which to investigate the cognitive and neural systems underlying goal-directed behaviour, particularly in situations when the correct behavioural response requires the suppression of a prepotent response. Antisaccade errors (failures to suppress reflexive prosaccades towards sudden-onset targets) are increased in patients with damage to the dorsolateral prefrontal cortex, and in patients with schizophrenia. Nicotine has been found to improve antisaccade performance in patients with schizophrenia and healthy controls. This performance enhancing effect may be due to direct effects on the cholinergic system, but there has been no test of this hypothesis. MATERIALS AND METHODS: In a double blind, double dummy, placebo-controlled design, we compared the effect of nicotine and modafinil, a putative indirect noradrenergic agonist, on antisaccade performance in healthy non-smokers. RESULTS AND DISCUSSION: Both compounds reduced latency for correct antisaccades, although neither reduced antisaccade errors. These findings are discussed with reference to the pharmacological route of performance enhancement on the antisaccade task and current models of antisaccade performance.

Nicotine improves memory for delayed intentions.

RATIONALE: The present paper asked first whether the cholinergic agonist nicotine improves memory for delayed intentions (prospective memory, ProM) and second whether pharmacological dissociation would support the psychological distinction that is made between strategic (effortful) and automatic (non-effortful) intention activation in prospective memory. OBJECTIVES: To use nicotine as a pharmacological tool with which to examine the neurochemical bases of prospective memory and to dissociate strategic from automatic components of ProM retrieval. METHODS: In three experiments, minimally deprived (2 h) smokers either smoked or abstained prior to completing a standard prospective memory study. This involved participants in the simultaneous processing of a ProM task and a cover task (ongoing between the setting and the recall of the intention). Here, the ongoing task involved lexical decision (LDT), while the ProM task required a response to pre-specified target items occurring within the LDT stimuli. Variations in task instructions were used to manipulate the processing requirements of the ProM task, the attention allocated to the ProM task and the balance of importance assigned to the ongoing and ProM tasks. RESULTS: In experiment 1, where the ProM processing was automatic, nicotine did not improve ProM accuracy. In experiment 2, where the ProM task involved strategic processing, positive effects of nicotine were observed. In experiment 3, we covaried ProM task instructions, assigned task importance and nicotine conditions. We observed a main effect of nicotine on ProM accuracy, a main effect of task on ProM accuracy and a main effect of assigned task importance on ProM accuracy. There were no interactions between the factors. CONCLUSIONS: Employing both direct and indirect manipulations of strategic engagement, we demonstrated nicotine-induced enhancement of performance on the ProM task. The results are consistent with the view that relatively small changes in instruction and in task variables engage strategic processing in a ProM task and that when these conditions stretch cognitive resources, nicotine may significantly improve performance.

Verbal fluency facilitated by the cholinergic blocker, scopolamine.

This study was designed to explore putative facilitatory effects of low doses of scopolamine (SP) on phonemic (letter) and semantic (category) verbal fluency. A double-blind, parallel-group design was used with 36 subjects who completed a test battery before and 2 h after 0.6 mg or 1.2 mg of SP or placebo. Fluency measures included total number of words generated, clustering (the production of words within semantic or phonemic subcategories) and switching (the ability to shift efficiently to new subcategories). Low doses of scopolamine increased phonemic fluency, as has been shown previously. Semantic fluency was not increased by SP, although subjects treated with 1.2 mg of SP generated higher-frequency words. SP did not affect clustering or switching. It is suggested that phonemic and semantic fluency reflect distinct cognitive processes.

Do people with Alzheimer's disease have a disproportionate deficit in functional knowledge? Verbal versus motoric access to semantic memory.

Healthy elderly and Alzheimer's disease (AD) volunteers participated in four conditions in which they were asked to demonstrate the function and category of a series of objects either verbally or non-verbally. When responding verbally to category judgement questions, volunteers with mild-moderate AD showed levels of performance comparable with age and IQ-matched healthy elderly, but when responding verbally to questions about an item's function, they show marked deficits. This deficit was substantially reduced, however, when they were encouraged to provide the information motorically. Healthy elderly were able to use either mode of access without difficulty. The results of this study suggest that functional semantic knowledge may not be disproportionately degraded, but that when cognitive resources are compromised, retrieval may depend more critically upon mode of access. Functional information, for example, is usually acquired by actually using the object. Verbalizing such functions would require suppressing the direct (motoric) route and accessing information in a less familiar (verbal) form. In short, for people with AD, apparent deficits in semantic knowledge may reflect deficient use of unfamiliar routes of access to the information rather than degradation of semantic knowledge per se.

People with dementia use schemata to support episodic memory.

This paper describes two experiments which examine whether people with dementia use schemata, established knowledge stores associated with specific scenarios, to aid episodic memory. On all tests of memory, volunteers with dementia remembered less than their age-matched controls. There was evidence for an age-related decline in cognitive resources available for effortful memorizing. For people with dementia, errors of commission in free recall, false recognition scores and reconstruction data were consistent with the use of schema to guide retrieval of items from memory. We conclude that retrieval support improves memory performance for both the healthy and dementing elderly. More importantly, pre-established schemata remain intact well into the course of dementia and can support recall of newly acquired episodic information.

Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease.

Nicotinic systems play an important role in the neural basis of working memory and attention. Recent progress in understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors and their pharmacology has opened up new possibilities for novel CNS therapeutics with nicotinic agents. In this paper, we review the theoretical justification and the experimental evidence supporting these developments. We focus on the applications of nicotinic agonists in CNS disorders that are degenerative in nature, namely Parkinson's disease and Alzheimer's disease. We suggest that there is considerable potential for therapeutic applications in the near future. Clinically, two major issues remain: (a) the selectivity of effects, that is, developing compounds which are selective in producing improvement in cognition, motor function, attention, or pain without significant side-effects; and (b) the realistic likelihood of long-term improvements in everyday functioning in people who have degenerative diseases.

Moving out of the laboratory: does nicotine improve everyday attention?

The most robust demonstrations of the nicotine-related performance effects on human cognitive processes are seen in tasks that measure attention. If nicotine does have some potential for enhancing attention, the obvious question to ask is whether the effects demonstrated in the laboratory hold any significance for real-life performance. This paper describes three studies that compare the effects in smokers of a single own brand cigarette on laboratory tests of attention and on everyday analogues of these laboratory tasks. In the laboratory measures of sustained attention and in the everyday analogue, performance advantages were registered in the smoking condition. These benefits were observed in smokers who abstained for a self-determined period of not less than 2 h. The studies were unable to replicate previous research reporting positive effects of smoking on a laboratory task of selective attention, the Stroop task. Small but significant improvements in performance were registered in the everyday analogues, which involved sustaining attention in a dual task situation, a telephone directory search task and a map search task. In addition, smokers showed a significant colour-naming decrement for smoking-related stimuli in the Stroop task. This attentional bias towards smoking-related words occurred independent of whether they had abstained or recently smoked an own brand cigarette. The effect is discussed in terms of the two-component model of processing bias for emotionally valenced stimuli.

The roles of vision and eye movements in the control of activities of daily living.

The aim of this study was to determine the pattern of fixations during the performance of a well-learned task in a natural setting (making tea), and to classify the types of monitoring action that the eyes perform. We used a head-mounted eye-movement video camera, which provided a continuous view of the scene ahead, with a dot indicating foveal direction with an accuracy of about 1 deg. A second video camera recorded the subject's activities from across the room. The videos were linked and analysed frame by frame. Foveal direction was always close to the object being manipulated, and very few fixations were irrelevant to the task. The first object-related fixation typically led the first indication of manipulation by 0.56 s, and vision moved to the next object about 0.61 s before manipulation of the previous object was complete. Each object-related act that did not involve a waiting period lasted an average of 3.3 s and involved about 7 fixations. Roughly a third of all fixations on objects could be definitely identified with one of four monitoring functions: locating objects used later in the process, directing the hand or object in the hand to a new location, guiding the approach of one object to another (e.g. kettle and lid), and checking the state of some variable (e.g. water level). We conclude that although the actions of tea-making are 'automated' and proceed with little conscious involvement, the eyes closely monitor every step of the process. This type of unconscious attention must be a common phenomenon in everyday life.

Effortful processing is a requirement for nicotine-induced improvements in memory.

We report two studies examining the effects of nicotine on memory in minimally deprived smokers. In experiment 1, semantically related words were recalled significantly better than unrelated words following nicotine, even when volunteers were explicitly instructed to target the unrelated word set for recall. Experiment 2 examined the effect of nicotine on two different types of lexical association: association by joint category membership (semantically related items), and association by derived meaning ("encapsulated" word pairs). Nicotine-induced improvements in recall were observed only for category associates and not for encapsulated word pairs. This implies that explicit, effortful processing of material in the presence of nicotine is necessary for improved recall performance to be observed.

Deprivation state but not nicotine content of the cigarette affects responding by smokers on a progressive ratio task.

In two experiments, we used a progressive ratio schedule to explore factors associated with smoking motivation. In study 1, smokers who had abstained for more than 8 h bar-pressed for longer to obtain puffs on a cigarette than did non-deprived smokers. Neither group, however, showed nicotine-induced improvements in performance on an attention-demanding task. In the second study, two groups of minimally deprived smokers worked on the progressive ratio task for puffs of either a standard or an ultralow nicotine cigarette. The amount of work expended for puffs was the same for both cigarettes. The groups were also indistinguishable in terms of their subjective experience of the impact of smoking. These results suggest that the addition of nicotine to the cigarette may not have an immediate impact on the effort expended for a puff on that cigarette, and that short term changes in craving may be observed independent of satiety effects associated with nicotine ingestion. We conclude that the progressive ratio task is a useful and sensitive measure of desire to smoke, although the two experiments highlight the complexity of the relationship between subjective, objective and behavioural measures of smoking and nicotine ingestion in humans.