A 1-year randomized controlled trial of a nutritional blend to improve nutritional biomarkers and prevent cognitive decline among community-dwelling older adults: The Nolan Study.

Introduction: This study aimed to test the efficacy of a nutritional blend (NB) in improving nutritional biomarkers and preventing cognitive decline among older adults. Methods: A 1-year randomized, double-blind, multicenter, placebo-controlled trial with 362 adults (58.6% female, mean 78.3 years, SD = 4.8) receiving an NB or placebo. Erythrocyte ω-3 index and homocysteine concentrations were primary outcomes. Other outcomes included Patient-Reported Outcomes Measurement Information System (PROMIS) Applied Cognition-Abilities, composite cognitive score (CCS), Cognitive Function Instrument (CFI) self-assessment and study partner, hippocampal volume (HV), and Alzheimer's disease signature cortical thickness (CT). Results: A total of 305 subjects completed the follow-up. Supplementation increased ω-3 index and decreased homocysteine, but did not affect CCS, CFI self-assessment, HV, and CT. Placebo improved and treatment did not change PROMIS at 1 month. Intervention showed a positive effect on CFI study partner. Discussion: Although improving nutritional biomarkers, this 1-year trial with a multi-nutrient novel approach was not able to show effects on cognitive outcomes among older adults.

Effect of short-duration lipid supplementation on fat oxidation during exercise and cycling performance.

The effect of intramyocellular lipids (IMCLs) on endurance performance with high skeletal muscle glycogen availability remains unclear. Previous work has shown that a lipid-supplemented high-carbohydrate (CHO) diet increases IMCLs while permitting normal glycogen loading. The aim of this study was to assess the effect of fat supplementation on fat oxidation (Fox) and endurance performance. Twenty-two trained male cyclists performed 2 simulated time trials (TT) in a randomized crossover design. Subjects cycled at ∼53% maximal voluntary external power for 2 h and then followed 1 of 2 diets for 2.5 days: a high-CHO low-fat (HC) diet, consisting of CHO 7.4 g·kg(-1)·day(-1) and fat 0.5 g·kg(-1)·day(-1); or a high-CHO fat-supplemented (HCF) diet, which was a replication of the HC diet with ∼240 g surplus fat (30% saturation) distributed over the last 4 meals of the diet period. On trial morning, fasting blood was sampled and Fox was measured during an incremental exercise; a ∼1-h TT followed. Breath volatile compounds (VOCs) were measured at 3 time points. Mental fatigue, measured as reaction time, was evaluated during the TT. Plasma free fatty acid concentration was 50% lower after the HCF diet (p < 0.0001), and breath acetone was reduced (p < 0.05) "at rest". Fox peaked (∼0.35 g·kg(-1)) at ∼42% peak oxygen consumption, and was not influenced by diet. Performance was not significantly different between the HCF and HC diets (3369 ± 46 s vs 3398 ± 48 s; p = 0.39), nor were reaction times to the attention task and VOCs (p = NS for both). In conclusion, the short-term intake of a lipid supplement in combination with a glycogen-loading diet designed to boost intramyocellular lipids while avoiding fat adaptation did not alter substrate oxidation during exercise or 1-hour cycling performance.

Nutrition and cognition: meeting the challenge to obtain credible and evidence-based facts.

Nutrition provides a practical and appealing approach to cognitive enhancement, including the modulation of long-term cognitive processes such as neurodevelopment and neurodegeneration. An abundance of promising nutritional influences on cognition have been identified, but many long-term effects remain to be confirmed by data from randomized controlled trials (RCTs). The current article provides a general outline of various factors that hamper the demonstration of causal long-term nutritional effects on cognition by RCTs and advocates the development of methodological solutions to enable substantiation in future RCTs.

Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies.

Acute tryptophan depletion (ATD) studies have shown that serotonin plays a role in learning and memory processes. In this study, we performed a pooled analysis of nine ATD studies in order to examine the nature of the memory-impairing effects of ATD and mediating factors, such as gender, age and vulnerability for disease in which disturbed serotonin was hypothesized to play a role. All studies that were used in this pooled analysis assessed declarative episodic memory using a verbal learning task paradigm. Immediate recall, delayed recall, and delayed recognition scores were examined. A total of 211 participants were included in the analysis. The analysis revealed that ATD impaired not only delayed recall, but also immediate recall. The ATD-induced impairments were larger in females than in males. Furthermore, ATD did not interact with any other serotonergic vulnerability and age. This suggests that the only factor that actually has the properties of a serotonergic vulnerability factor for declarative memory performance is female gender. The findings provide further support for a critical role of serotonin in declarative episodic memory.

Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression.

The present study examined the effects of acute tryptophan (Trp) depletion (ATD), a well-recognized method to lower central serotonin (5-HT) metabolism, on brain activation during a facial emotion perception task. Brain activation was measured using fMRI, and healthy female volunteers with a positive family history of unipolar depression (FH+) were compared to healthy female volunteers without such a history (FH-). Participants viewed two morphed faces and were instructed to choose between the faces based either on the intensity of the emotional expression (direct task) or the gender of the face (incidental task). In the FH+ group, depletion led to the expected lowering of mood, which partly determined the effect of depletion on performance and brain activation. A stronger mood lowering effect was associated with less accurate performance on faces expressing a negative emotion in the incidental task and a stronger right amygdala response to fearful faces in comparison to happy faces. These results were explained in terms of a mood-induced bias leading to a stronger impact of the expressed negative emotion which subsequently leads to more interference in the incidental task and a stronger amygdala response. It was concluded that the effects of ATD on mood, performance, and brain activation in a facial emotion perception task depend on family history of depression. Performance and brain activation partly depend on the effect of ATD on mood.

Driving impairment in depressed patients receiving long-term antidepressant treatment.

BACKGROUND: Depression is a common mental disorder with cognitive deficits, but little information is available on the effects of antidepressant treatment on driving performance in depressed patients. AIMS: Assessing actual driving performance and cognition of depressed patients receiving long-term antidepressant treatment. MATERIALS AND METHODS: Performance was assessed in depressed patients receiving selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenalin reuptake inhibitor (SNRI) treatment for 6-52 weeks and in matched healthy controls by means of two standardised on-the-road driving tests and laboratory tests of cognition. RESULTS: Data showed poorer driving performance as indicated by a higher standard deviation of lateral position or 'weaving motion' in medicated patients relative to controls. Time to speed adaptation and critical flicker fusion threshold were also impaired in medicated patients. The Hamilton Depression Rating Scale scores in medicated patients were significantly higher as compared to that of controls. No other significant results between the two groups were demonstrated on the variables of the driving tests and laboratory tests of cognition. CONCLUSIONS: The depressed patients receiving long-term treatment with SSRI- and SNRI-type antidepressants show impaired driving performance. This impairment in driving performance can probably be attributed to residual depressive symptoms instead of the antidepressant treatment.

The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers.

RATIONALE: Serotonin (5-HT) was implicated in both clinical and experimental studies in flexible, goal-directed behavior. However, the way in which 5-HT manipulations affect brain activation patterns underlying different subprocesses of cognitive flexibility remains largely unknown. OBJECTIVES: The aim of this study was to investigate the effect of a transient lowering of 5-HT on brain activation during performance monitoring and response inhibition. MATERIALS AND METHODS: We used acute tryptophan depletion (ATD), a well-known method to reduce central 5-HT, to investigate the effect of a transient lowering of 5-HT on the blood-oxygen-level dependent (BOLD) response in an event-related functional MRI study. Thirteen healthy male volunteers performed a modified Go/NoGo task in a counterbalanced, placebo-controlled, within-subject design. RESULTS: ATD significantly lowered plasma tryptophan but did not affect mood and cognitive performance. ATD decreased the BOLD response in the dorsomedial prefrontal cortex (BA 8) during performance monitoring. ATD did not affect the BOLD response during response inhibition. CONCLUSIONS: This study provides more evidence for the suggested role of 5-HT in performance monitoring. Because ATD studies have revealed inconsistent effects of ATD on performance and on brain activation, it was suggested that gender and personality traits are important variables to take into account for future research.

Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task.

Acute tryptophan depletion (ATD), a well-recognized method to lower central serotonin levels, was used to examine the effects of lower central serotonin levels on memory function in healthy males. Functional Magnetic Resonance Imaging (fMRI) was used to examine changes in brain activation during the encoding and the retrieval phase of a visual verbal episodic memory task. ATD led to more positively rated words in the encoding phase and to poorer recognition of these positively rated words in the retrieval phase. Furthermore, encoding was accompanied by enhanced brain activation in occipital, middle and superior frontal, anterior and posterior cingulate and striatal areas. Retrieval attempt was accompanied by enhanced activation in the cuneus, inferior occipital gyrus and inferior and middle frontal areas. Retrieval success was accompanied by activation in an extensive network including frontal, parietal, temporal, cingulate, striatal and cerebellar areas. In the encoding phase ATD attenuated activation in the right hippocampus and ATD did not affect brain activity in the retrieval phase. These results show that serotonin is important in long term memory processes, and that serotonin acts on the encoding phase and not on the retrieval phase.

Effects of 5-HT on memory and the hippocampus: model and data.

5-Hydroxytryptamine (5-HT) transmission has been implicated in memory and in depression. Both 5-HT depletion and specific 5-HT agonists lower memory performance, while depression is also associated with memory deficits. The precise neuropharmacology and neural mechanisms underlying these effects are unknown. We used neural network simulations to elucidate the neuropharmacology and network mechanisms underlying 5-HT effects on memory. The model predicts that these effects are largely dependent on transmission over the 5-HT1A and 5-HT3 receptors, which regulate the selectivity of retrieval. It also predicts differential memory deficit profiles for 5-HT depletion and overactivation. The latter predictions were confirmed in studies with healthy and depressed participants undergoing acute tryptophan depletion or ipsipirone challenge. The results suggest that the memory impairments in depressed subjects may be related to 5-HT undertransmission, and support the notion that 5-HT1A agonists ameliorate memory deficits in depression.

General methodological considerations for the assessment of nutritional influences on human cognitive functions.

The premise that cognitive functioning can be influenced through dietary means has gained widespread interest. The assessment of cognitive functioning is a key method to scientifically substantiate such nutritional effects on cognition. The current paper provides a basic overview of the main concepts, issues and pitfalls of human cognitive research. General methods of cognitive assessment, selection of appropriate tests, factors that may mediate task performance and issues pertaining to the interpretation of the results are discussed.

Attention, psychomotor functions and age.

Nutrition might play an important role to ameliorate or to buffer age-related declines in attention and psychomotor functions. The assessment of nutritional effects in aged subjects has to take into account that attention and psychomotor functions can be subdivided in different functions that are differentially affected by age. This paper gives an overview of changes in different facets of attention and psychomotor functions beyond fifty as well as assessment methods for attention and psychomotor performance. It also provides a review of models to explain the pattern of changes with increasing age, and discusses the problems of high performance variance and of age related confounding variables like health status. Two different approaches are discussed that analyse a performance profile and an experimentally oriented functional microanalysis of changes in performance with respect to the effects of nutrition on attention and psychomotor functions. Addressed are examples of missing age-related deficits or even age-related superiority. Caffeine and Ginseng are considered as examples to enhance performance in older persons. Results are in accordance with data on the positive role of physical fitness for mental performance in older persons. Performance of older persons can well be enhanced by functional food components or nutritional supplementation. The effects are comparable to the effects obtained in younger groups, while there is only weak evidence for specific compensatory effects in aged persons. Finally the role of nutrition for the processes of healthy aging is discussed.

How should we measure nutrition-induced improvements in memory?

There is a basic distinction between declarative memories, which can be stated verbally, and non-declarative memory, such as how to ride a bicycle, which cannot be expressed in words. With age it is the performance of declarative memory, particularly episodic memory that requires recall of events placed in time, that declines. As memory is not a unitary phenomenon, it should be ideally monitored using a range of tests that reflect theoretical conceptions of the topic. If circumstances demand the use of a single test then a measure of episodic memory is suggested. When it proves only possible to use a rating scale it should be ensured that memory is distinguished from other aspects of cognition and that different types of memory are not confused. The tests used, and the form in which they are used, need to be chosen to be of appropriate difficulty for the sample studied. A major conclusion is that the selection of the measure of memory used in the study of a dietary intervention should never be routine. It is inevitable that the form of the test used will need to be chosen carefully for the population being studied.

Memory function in women with premenstrual complaints and the effect of serotonergic stimulation by acute administration of an alpha-lactalbumin protein.

Serotonergic hypofunction may underlie at least part of the symptoms that are experienced by women with premenstrual complaints, including memory deficits. In the current study we investigated changes in memory functions in the premenstrual phase compared to the early postmenstrual phase in 16 women with premenstrual complaints. In addition, the effect of an acute serotonergic stimulation by administration of an alpha-lactalbumin protein on premenstrual memory performance was assessed using a double-blind placebo-controlled crossover design. It was found that both short-term and long-term memory for words (30-word learning task) and abstract figures (abstract visual learning task) were mildly impaired in the premenstrual phase. Administration of alpha-lactalbumin during the premenstrual phase could only partially attenuate the memory performance decrements that are seen in the premenstrual phase. Specifically, alphalactalbumin improved long-term memory for abstract figures, but not for words. There were no effects of menstrual phase or alpha-lactalbumin on planning functions (computerized Tower of London). The data suggest that serotonergic hypofunction may play a role in premenstrual memory decline, but serotonergic mechanisms cannot fully account for observed cognitive changes in the premenstrual phase.

Specific serotonergic reuptake inhibition impairs vigilance performance acutely and after subchronic treatment.

Subchronic treatment with the selective serotonergic reuptake inhibitors (SSRIs) fluoxetine, venlafaxine and paroxetine, but not sertraline, were previously shown to specifically impair vigilance performance. The current study was designed to compare the vigilance effects of subchronic treatment with the SSRIs sertraline and citalopram in healthy volunteers, according to a placebo-controlled, double-blind, three-way cross-over design. Twenty-four healthy subjects, aged 30-50 years, of whom 21 completed the study, underwent three treatment periods of 2 weeks in which they received sertraline (50 mg on days 1-8, 100 mg on days 8-15), citalopram (20 mg on days 1-8, 40 mg on days 8-15) and placebo. Treatment periods were separated by 14 days washout periods. Vigilance performance was assessed through a 45-min Mackworth Clock Test at days 1, 8 and 15 of each treatment period. It was found that citalopram impaired vigilance performance acutely after the first 20 mg dose and subchronically after 40 mg daily doses. By contrast, no vigilance impairment was found during sertraline treatment. Sertraline is the only SSRI studied so far with no detrimental effects on vigilance. This may be due to the affinity of sertraline for the dopamine reuptake site. Because citalopram is the most specific SSRI showing this effect, it is concluded that the SSRI-induced decrement of vigilance performance is specifically associated with serotonergic reuptake inhibition.

Tryptophan modulation and cognition.

The interest in the function of the serotonergic system in relation to cognition stems from three sources: (1) the association of depression, cognitive dysfunction and 5-HT dysregulation; (2) the association of drug-induced 5-HT dysregulation and cognitive dysfunction; and (3) the association of cognitive performance and serotonergic function per se. We performed several experiments in subjects at risk for cognitive impairment and in healthy volunteers, in which 5-HT was manipulated by means of either tryptophan depletion or tryptophan loading. The results show that tryptophan and cognitive performance are associated in a complex non-linear fashion. Dissociations are observed between cognitive functions: tryptophan depletion impairs memory consolidation but improves focussed attention; as well as between subject groups: tryptophan depletion impairs problem solving in healthy 1st degree relatives of bipolar depressed patients but improves it in healthy volunteers without such a family history. It was demonstrated that the mood- and memory effects of tryptophan-depletion were specifically mediated by the depletion of tryptophan and also that the observed memory and cognitive deficits were emotionally biased in a manner consistent with depressive symptoms. We conclude that experimental manipulations of tryptophan mediate temporal and frontal cognitive functions such as memory consolidation and working memory respectively, in an opposite manner.

Tryptophan, mood, and cognitive function.

In separate experiments we investigated the duration of the effects of acute tryptophan depletion (ATD) on mood and cognition. The results showed that ATD's effects consist of lowering of mood only in subjects with a family history of unipolar depression. A specific impairment of memory consolidation was seen in all subjects. In subjects without any vulnerability for mood disorders, performance on so-called 'frontal tasks,' measuring higher attentional functions tended to improve after ATD. The effects of ATD on mood and cognition were manifest as long as biochemical indices of low tryptophan remained low. In conclusion, ATD is a model for impairment of memory, next to being a model of mood disorders in vulnerable subjects. Moreover, ATD could be used as a challenge to demonstrate individual vulnerability of the serotonergic system.

Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man.

There is evidence for a specific impairment of human vigilance following enhancement of serotonergic activity by antidepressant drugs. In the present study, we investigated the putative role of serotonergic-dopaminergic interactions in diminished vigilance by comparing the attentional effects of sertraline, a selective serotonin reuptake inhibitor (SSRI) with additional mild dopamine stimulating effects, with those of paroxetine, a SSRI without dopamine activity, using a placebo-controlled, double-blind, three-way cross-over design. Twenty-one (of 24) healthy middle-aged subjects completed the three treatment periods of 2 weeks in which sertraline (50 mg, days 1-7; 100 mg, days 8-14), paroxetine (20 mg, days 1-7; 40 mg, days 8-14) and placebo were administered. Vigilance (Mackworth Clock Test), selective (Stroop, Dichotic Listening) and divided attention (Dichotic Listening) were assessed at baseline and on days 7 and 14 of each treatment period. Selective and divided attention were unaffected by SSRI treatment. Subchronic administration of paroxetine impaired vigilance performance at each investigated dose. Sertraline did not produce a significant decline in vigilance performance, presumably due to its concomitant effects on dopamine activity, counteracting the negative effects of serotonin on dopamine neurotransmission. It is concluded that a serotonergically mediated reduction of dopamine activity plays an important role in the reduction of human vigilance following SSRI administration.

Modulation of the critical flicker fusion effects of serotonin reuptake inhibitors by concomitant pupillary changes.

RATIONALE: Serotonin reuptake inhibitors (SSRIs) have been attributed CNS-activating properties based on their ability to elevate the Critical Flicker Fusion (CFF) threshold. However, such an interpretation may be questioned since CFF elevations may also be due to SSRI-induced increases in pupil diameter. OBJECTIVES: The effect of pupillary changes on CFF assessment following SSRI administration was investigated in a double blind, crossover study. METHODS: During three periods of 15 days, 21 healthy men and women (30-50 years) received sertraline (50 mg on days 1-8, 100 mg on days 9-15), citalopram (20 mg on days 1-8, 40 mg on days 9-15) and placebo. Assessments were done on days 1, 8 and 15 and consisted of pupillary measurements and CFF assessments with and without pupillary control (a 2-mm artificial pupil) using the Leeds Psychomotor Tester. RESULTS: Both SSRIs induced an acute and steady increase in pupil diameters. CFF thresholds were depressed following acute administration of sertraline and citalopram, but this was only apparent when a control was made for the pupillary changes. No CFF effects were seen at day 8, but CFF was again reduced at day 15, with and without control for pupil size. CONCLUSIONS: Mydriasis masked the detrimental effects of both SSRIs on CFF during the acute assessments. Our results raise questions regarding the validity of the assessment of the behavioural toxicity of SSRIs based on CFF measurements without ample control for pupil size, especially when these concern acute measurements.