Cognitive correlates of reduced driving performance in healthy older adults: A meta-analytic review.

AIMS / OBJECTIVES: This meta-analytic review examines the evidence for the relationship between cognitive function and driving performance in older adults. The primary aims of this review were: (a) to identify cognitive correlates of reduced driving performance in older adults and (b) to determine whether such measures reliably predict reductions in driving performance over time. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Peer reviewed studies that examined the (cross-sectional or longitudinal) relationship between standardised neuropsychological test performance measures and driving performance (e.g., via an on-road test, in-vehicle monitoring system, hazard perception test or driving simulator) in healthy adults aged 60 years and older, were included. RESULTS/DISCUSSION: Eighteen studies were eligible for inclusion, of which 12 met requirements for meta-analysis. The results indicated that reaction time and Trail Making Test (TMT) A scores exhibited small-to-moderate correlations with driving performance, with moderate effects identified for block design, TMT B, Useful Field of View (UFOV) 2 and 3 tests. Further, no significant relationships were observed between the Mini-Mental State Examination and UFOV 1 with driving performance. Due to a paucity of data, the longitudinal relationship between such measures and driving could not be identified. The findings highlight (a) the potential of cognitive assessments to identify older adults at risk of driving impairment (as part of a larger diagnostic assessment), and (b) the urgent need for prospective longitudinal studies in investigating the impact of age-related changes in cognition on driving performance over time.

Protein prescription and delivery practices in critically ill adults: A survey of Australian and New Zealand intensive care dietitians.

BACKGROUND: Protein provision is thought to be integral to attenuating muscle wasting in critical illness, yet patients receive half of that prescribed. As international guidelines lack definitive evidence to support recommendations, understanding clinicians' views relating to protein practices is of importance. OBJECTIVES: The objective of this study was to describe Australia and New Zealand intensive care unit (ICU) dietitians' protein prescription and perceived delivery practices in critically ill adults, including common barriers and associations between ICU clinical experience and protein prescriptions for different clinical conditions. METHODS: A 42-item descriptive quantitative survey of Australian and New Zealand intensive care dietitians was disseminated through nutrition and ICU society e-mailing lists. Data were collected on respondent demographics and reported protein practices including questions related to a multitrauma case study. Data were analysed using descriptive and content analysis and reported as n (%). Fisher's exact tests were used to compare experience and protein prescriptions. RESULTS: Of the 67 responses received (one excluded due to >50% missing data), more than 80% of respondents stated they would prescribe 1.2-1.5 g protein/kg bodyweight/day for most critically ill patients, most commonly using European Society of Clinical Nutrition and Metabolism (ESPEN) guidelines to support prescriptions (n = 61/66, 92%). Most respondents (n = 49/66, 74%) thought their practice achieved 61-80% of protein prescriptions, with frequently reported barriers including fasting periods (n = 59/66, 89%), avoiding energy overfeeding (n = 50/66, 76%), and gastrointestinal intolerance (n = 47/66, 71%). No associations between years of ICU experience and protein prescriptions for 14 of the 15 predefined clinical conditions were present. CONCLUSIONS: Australian and New Zealand ICU dietitians use international guidelines to inform protein prescriptions of 1.2-1.5 g/kg/day for most clinical conditions, and protein prescriptions do not appear to be influenced by years of ICU experience. Key perceived barriers to protein delivery including avoidance of energy overfeeding and gastrointestinal intolerance could be explored to improve protein adequacy.

Associations of Later-Life Education, the BDNF Val66Met Polymorphism and Cognitive Change in Older Adults.

In 358 participants of the Tasmanian Healthy Brain Project, we quantified the cognitive consequences of engaging in varying loads of university-level education in later life, and investigated whether or not BDNF Val66Met affected outcomes. Assessment of neuropsychological, health, and psychosocial function was undertaken at baseline, 12-month, and 24-month follow-up. Education load was positively associated with change in language processing performance, but this effect did not reach statistical significance (P = 0.064). The BDNF Val66Met polymorphism significantly moderated the extent to which education load was associated with improved language processing (P = 0.026), with education load having a significant positive relationship with cognitive change in BDNF Met carriers but not in BDNF Val homozygotes. In older adults who carry BDNF Met, engaging in university-level education improves language processing performance in a load-dependent manner.

Association between the serotonin transporter gene polymorphism and verbal learning in older adults is moderated by gender.

The S allele of the functional 5-HTTLPR polymorphism has previously been associated with reductions in memory function. Given the change in function of the serotonergic system in older adults, and the functional consequences of memory decline in this age group, further investigation into the impact of 5-HTTLPR in healthy older adults is required. This investigation examined the effect of 5-HTTLPR variants (S carriers versus L/L homozygotes) on verbal and visual episodic memory in 438 healthy older adults participating in the Tasmanian Healthy Brain Project (age range 50-79 years, M=60.35, s.d.=6.75). Direct effects of 5-HTTLPR on memory processes, in addition to indirect effects through interaction with age and gender, were assessed. Although no direct effects of 5-HTTLPR on memory processes were identified, our results indicated that gender significantly moderated the impact that 5-HTTLPR variants exerted on the relationship between age and verbal episodic memory function as assessed by the Rey Auditory Verbal Learning Test. No significant direct or indirect effects were identified in relation to visual memory performance. Overall, this investigation found evidence to suggest that 5-HTTLPR genotype affects the association of age and verbal episodic memory for males and females differently, with the predicted negative effect of S carriage present in males but not females. Such findings indicate a gender-dependent role for 5-HTTLPR in the verbal episodic memory system of healthy older adults.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients.

BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non-bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid-suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality.

The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function.

The concept of cognitive reserve (CR) has been proposed to account for observed discrepancies between pathology and its clinical manifestation due to underlying differences in brain structure and function. In 433 healthy older adults participating in the Tasmanian Healthy Brain Project, we investigated whether common polymorphic variations in apolipoprotein E (APOE) or brain-derived neurotrophic factor (BDNF) influenced the association between CR contributors and cognitive function in older adults. We show that BDNF Val66Met moderates the association between CR and executive function. CR accounted for 8.5% of the variance in executive function in BDNF Val homozygotes, but CR was a nonsignificant predictor in BDNF Met carriers. APOE polymorphisms were not linked to the influence of CR on cognitive function. This result implicates BDNF in having an important role in capacity for building or accessing CR.

Reducing false positive diagnoses in mild cognitive impairment: the importance of comprehensive neuropsychological assessment.

BACKGROUND AND PURPOSE: Longitudinal studies of mild cognitive impairment (MCI) report that a sizeable proportion of MCI cases revert to normal levels of functioning over time. The rate of recovery from MCI indicates that existing MCI diagnostic criteria result in an unacceptably high rate of false positive diagnoses and lack adequate sensitivity and specificity. METHODS: The aim of the present study was to identify a set of neuropsychological measures able to differentiate between true positive cases of MCI from those who were unimpaired at 11 months' follow-up. RESULTS: A discriminant function analysis identified that a combination of measures of complex sustained attention, semantic memory, working memory, episodic memory and selective attention correctly classified outcome in more than 80% of cases. The rate of false positive diagnoses (5.93%) was considerably lower than is evident in previously published MCI studies. CONCLUSIONS: The results of the present study indicate that the rate of false positive MCI diagnoses can be significantly reduced through the use of sensitive and specific neuropsychological measures of memory and non-memory functions.

Endogenous amylin and glucagon-like peptide-1 concentrations are not associated with gastric emptying in critical illness.

BACKGROUND: In health, the hormones amylin and glucagon-like peptide-1 (GLP-1) slow gastric emptying (GE) and modulate glycaemia. The aims of this study were to determine amylin and GLP-1 concentrations in the critically ill and their relationship with GE, glucose absorption and glycaemia. METHODS: In fasted critically ill and healthy subjects (n = 26 and 23 respectively), liquid nutrient, containing 100 mg (13) C-sodium octanoate and 3 g 3-O-methlyglucose (3-OMG), was administered via a nasogastric tube. Amylin, GLP-1, glucose and 3-OMG concentrations were measured in blood samples taken during fasting, and 30 min and 60 min after the 'meal'. Breath samples were taken to determine gastric emptying coefficient (GEC). Intolerance to intragastric feeding was defined as a gastric residual volume of ≥ 250 ml and/or vomiting within the 24 h prior to the study. RESULTS: Although GE was slower (GEC: critically ill 2.8 ± 0.9 vs. health, 3.4 ± 0.2; P = 0.002), fasting blood glucose was higher (7.0 ± 1.9 vs. 5.7 ± 0.2 mmol/l; P = 0.005) and overall glucose absorption was reduced in critically ill patients (3-OMG: 9.4 ± 8.0 vs. 17.7 ± 4.9 mmol/l.60 min; P < 0.001), there were no differences in fasting or postprandial amylin concentrations. Furthermore, although fasting [1.7 (0.4-7.2) vs. 0.7 (0.3-32.0) pmol/l; P = 0.04] and postprandial [3.0 (0.4-8.5) vs. 0.8 (0.4-34.3) pmol/l; P = 0.02] GLP-1 concentrations were increased in the critically ill and were greater in feed intolerant when compared with those tolerating feed [3.7 (0.4-7.2) vs. 1.2 (0.7-4.6) pmol/l; P = 0.02], there were no relationships between GE and fasting amylin or GLP-1 concentrations. CONCLUSION: In the critically ill, fasting GLP-1, but not amylin, concentrations are elevated and associated with feed intolerance. Neither amylin nor GLP-1 appears to substantially influence the rate of GE.

The learning profile of persistent mild cognitive impairment (MCI): a potential diagnostic marker of persistent amnestic MCI.

BACKGROUND AND PURPOSE: Previous research examining mild cognitive impairment (MCI) has highlighted the heterogeneity of outcome in MCI sufferers. MCI is associated with greater risk of progression to dementia; however, a substantial proportion of those identified with MCI have alternative outcomes including recovery to unimpaired status. This heterogeneity may in part reflect insufficient sensitivity and specificity in identifying subclinical memory impairment. METHOD: The present study examined learning in a sample of 109 adults aged 61-91 years with persistent amnestic MCI, persistent non-amnestic MCI, recovered MCI and healthy controls. At the final assessment point, learning for words recalled across each trial of the Rey Auditory Verbal Learning Test was examined for each group. RESULTS: It was found that persistent amnestic MCI participants displayed significantly lower learning compared with recovered MCI and healthy control groups. DISCUSSION: The results of this study indicated that poor learning across trials may be a defining feature of persistent amnestic MCI. Further research is required to establish the predictive utility of within trial list learning performance to identify individuals with persistent and progressive variants of MCI.

Mesenteric blood flow, glucose absorption and blood pressure responses to small intestinal glucose in critically ill patients older than 65 years.

PURPOSE: To compare nutrient-stimulated changes in superior mesenteric artery (SMA) blood flow, glucose absorption and glycaemia in individuals older than 65 years with, and without, critical illness. METHODS: Following a 1-h 'observation' period (t (0)-t (60)), 0.9 % saline and glucose (1 kcal/ml) were infused directly into the small intestine at 2 ml/min between t (60)-t (120), and t (120)-t (180), respectively. SMA blood flow was measured using Doppler ultrasonography at t (60) (fasting), t (90) and t (150) and is presented as raw values and nutrient-stimulated increment from baseline (Δ). Glucose absorption was evaluated using serum 3-O-methylglucose (3-OMG) concentrations during, and for 1 h after, the glucose infusion (i.e. t (120)-t (180) and t (120)-t (240)). Mean arterial pressure was recorded between t (60)-t (240). Data are presented as median (25th, 75th percentile). RESULTS: Eleven mechanically ventilated critically ill patients [age 75 (69, 79) years] and nine healthy volunteers [70 (68, 77) years] were studied. The magnitude of the nutrient-stimulated increase in SMA flow was markedly less in the critically ill when compared with healthy subjects [Δt (150): patients 115 (-138, 367) versus health 836 (618, 1,054) ml/min; P = 0.001]. In patients, glucose absorption was reduced during, and for 1 h after, the glucose infusion when compared with health [AUC(120-180): 4.571 (2.591, 6.551) versus 11.307 (8.447, 14.167) mmol/l min; P < 0.001 and AUC(120-240): 26.5 (17.7, 35.3) versus 40.6 (31.7, 49.4) mmol/l min; P = 0.031]. A close relationship between the nutrient-stimulated increment in SMA flow and glucose absorption was evident (3-OMG AUC(120-180) and ∆SMA flow at t (150): r (2) = 0.29; P < 0.05). CONCLUSIONS: In critically ill patients aged >65 years, stimulation of SMA flow by small intestinal glucose infusion may be attenuated, which could account for the reduction in glucose absorption.

The effect of occupational exposure to manganese dust and fume on neuropsychological functioning in Australian smelter workers.

Chronic low-level occupational exposure to manganese (Mn) is reportedly associated with the development of Parkinsonian-like symptoms. In a study of 143 manganese smelter workers, inhalable Mn exposure was associated with lower performances on the Digit Symbol Coding and Stroop tests; respirable Mn exposure was associated with improved Digit Symbol Coding test performance and reduced performance on the Trail Making (Part A), Matrix Reasoning, and Stroop tests. While these relationships reached statistical significance, the magnitude of these effects was significantly smaller than the standard error of measurement of the neuropsychological tests, indicating that these differences are not of clinical significance.

Modification of a weak learning experience by memory retrieval in the day-old chick.

Activation of memory retrieval after weak learning (WL), during either the short- or intermediate-term stages of memory in day-old chickens, resulted in the strengthening of the memory to levels normally associated with strong learning. Administration of the calcium channel antagonist lanthanum chloride, the glutamate receptor agonist monosodium glutamate, or the N-methyl-D-aspartate glutamatergic receptor antagonist AP5 prevented strengthening of a WL memory by reminder-activated memory retrieval. The results of this study are discussed in light of our recent findings suggesting two phases of memory retrieval in the day-old chick. The results are consistent with the proposition that a memory undergoing the processes of formation may be modified to include information gleaned at the time of memory retrieval and that a second phase of memory retrieval may be responsible for such modification.

Administration of DL-2-amino-5-phosphonovaleric acid (AP5) induces transient inhibition of reminder-activated memory retrieval in day-old chicks.

DL-2-Amino-5-phosphonovaleric acid (50 microM) administered immediately after a visual reminder presented to day-old chickens between 7.5 min and 24 h following a single trial passive avoidance learning task produced transient losses of memory on retention test, an effect not observed in the absence of a reminder or when the reminder was given 48 h post learning. The duration of the transient deficits decreased with increasing interval between training and the reminder trial. The time of onset of memory loss after the reminder trial appeared to increase with increasing interval between the training and the reminder trials. The results suggest that, for a period of at least up to 24 h after passive avoidance training, retrieval of memory may lead to processes which are sensitive to inhibition by the NMDA receptor antagonist AP5, with the duration of sensitivity post retrieval decreasing as the period of memory consolidation increases. The results extend previously reported findings and suggest the possibility that consolidation of a stable memorial representation of a learning experience may take over several days and may entail the concurrent laying down of a stable retrieval mechanism.

Administration of lanthanum chloride following a reminder induces a transient loss of memory retrieval in day-old chicks.

Lanthanum chloride (5.0 mM) administered immediately after a visual reminder presented to day-old chickens between 7.5 min and 48 h following a single trial passive avoidance learning task produced an immediate but transient loss of memory on retention test, an effect not observed in the absence of a reminder. The duration of the transient deficit was relatively stable with lanthanum chloride consistently inducing a loss of memory that was evident 5 min after the reminder, with recovery by 10-15 min. The results suggest that, for a period of at least up to 48 h after passive avoidance training, the activation of memory retrieval by a reminder stimulus may lead to processes which are sensitive to inhibition by the calcium channel antagonist lanthanum chloride. These results extend previously reported findings implicating the involvement of glutamate-sensitive channels in a transient memory process that is also activated as a result of a reminder stimulus, but that is no longer present 48 h after training. The glutamate-sensitive mechanism appears to be a secondary mechanism activated following memory retrieval and to be dependent on the level of memory consolidation that the memory for the original experience has undergone. The results presented here suggest that lanthanum chloride, a calcium channel antagonist, inhibits memory retrieval in the day-old chick. This effect implicates calcium channel mediated processes in immediate memory recall. Further, the results suggest the lanthanum inhibits a primary mechanism, that precedes that glutamate-sensitive mechanism identified previously and that both are dependent on the activation of memory retrieval by a reminder.

Administration of glutamate following a reminder induces transient memory loss in day-old chicks.

Monosodium glutamate (4.0 mM) administered immediately after a visual reminder presented to day-old chickens between 7.5 min and 24 h following a single trial passive avoidance learning task produced transient losses of memory on retention test, an effect not observed in the absence of a reminder or when the reminder was given 48 h post-learning. The duration of the transient deficit decreased with increasing interval between the training and the reminder trial. The time of onset of memory loss after the reminder trial appeared to increase with increasing interval between the training and the reminder trials. The results suggest that, for a period of at least up to 24 h after passive avoidance training, retrieval of memory may lead to processes which are sensitive to inhibition by glutamate, with the duration of sensitivity post-retrieval decreasing as the period of memory consolidation increases. The results extend previously reported findings with rodents and suggest the possibility that consolidation of a stable memorial representation of a learning experience may take place over several days and may entail the concurrent laying down of a stable retrieval mechanism.

Purification of recombinant human N-acetyltransferase type 1 (NAT1) expressed in E. coli and characterization of its potential role in folate metabolism.

Human arylamine N-acetyltransferase type 1 (NAT1) has been cloned from human genomic DNA, into the vector pET(5a) and expressed in Escherichia coli. The recombinant protein has been purified to apparent homogeneity using anion exchange chromatography. The arylamine acceptor specificity, and the effect of potential NAT1 inhibitors has been investigated using purified recombinant protein. The Km of the recombinant NAT1 protein for the substrates para-aminobenzoate (p-aba) and 4-aminosalicylate are 14.3 and 11.8 microM, respectively. Folate and amethopterin were found to be potent competitive inhibitors of p-aba acetylation, with Ki values of 13.3 and 9.5 microM, respectively. The pteroate moiety of folate, in contrast is a poor inhibitor, with 100 microM pteroate inhibiting only 40% of NAT1 activity. A catabolite of folate para-aminobenzoly-L-glutamate has also been shown to be a NAT1 substrate with a Km value of 263 microM.