Michael Valenzuela

Brain reserve and dementia: a systematic review.

BACKGROUND Behavioural brain reserve is a property of the central nervous system related to sustained and complex mental activity which can lead to differential expression of brain injury. Behavioural brain reserve has been assessed using autobiographical data such as education levels, occupational complexity and mentally stimulating lifestyle pursuits. So far there have been several epidemiological reports but no systematic review to put conflicting results into context. Our aim was to quantitatively review evidence for the effect of brain reserve on incident dementia. METHOD Cohort studies of the effects of education, occupation, premorbid IQ and mental activities on dementia risk were of interest. Abstracts were identified in MEDLINE (1966-September 2004), CURRENT CONTENTS (to September, 2004), PsychINFO (1984-September 2004), Cochrane Library Databases and reference lists from relevant articles. Twenty-two studies met inclusion criteria. Key information was extracted by both reviewers onto a standard template with a high level of agreement. Studies were combined through a quantitative random-effects meta-analysis. RESULTS Higher brain reserve was associated with a lowered risk for incident dementia (summary odds ratio, 0.54; 95% confidence interval, 0.49-0.59). This effect was found over a median of 7.1 years follow-up and resulted from integrating data across more than 29000 individuals. Notably, increased complex mental activity in late life was associated with lower dementia rates independent of other predictors; a dose-response relationship was also evident between extent of complex mental activities in late life and dementia risk. CONCLUSIONS This study demonstrates robust evidence that complex patterns of mental activity in the early, mid- and late-life stages is associated with a significant reduction in dementia incidence. Randomized control trials based on brain-reserve principles are now required.

The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients.

Objective: To characterize the neuropsychological profile of vascular cognitive impairment (VCI) and vascular dementia (VaD). Methods: The authors examined 170 patients with stroke or TIA at 3 to 6 months after the vascular event, and 96 age-matched healthy controls, with detailed neuropsychological and medical-psychiatric assessments, with a majority (66.7%) undergoing MRI brain scans. The subjects were diagnosed as having VaD, VCI, or no cognitive impairment by consensus. The neuropsychological tests were classified into cognitive domains, and composite z-scores adjusted for age and education. Results: VaD subjects had disturbance in all cognitive domains, with verbal memory, especially retention, being less affected. VCI subjects had similar but less severe disturbance. The domains that best discriminated cognitively impaired from unimpaired patients were abstraction, mental flexibility, information processing speed, and working memory. Cognitive impairment had a significant correlation with deep white matter hyperintensities, but not with volume and number of infarctions, even though the VaD subjects had larger infarct volumes than VCI subjects. The MRI variables did not provide additional discrimination between subgroups. Conclusions: The cognitive deficits in VaD and VCI are characterized by disturbance of frontal functions, with less verbal memory impairment. VaD and VCI differ in severity but not pattern of disturbance. The brain lesions that best account for these deficits are noninfarct subcortical white matter and gray matter changes due to ischemia. The picture of VaD/VCI presented shows subcortical deficits embellished by cognitive deficits from cortical infarctions.

Can cognitive exercise prevent the onset of dementia? Systematic review of randomized clinical trials with longitudinal follow-up.

OBJECTIVES Epidemiological and preclinical studies suggest that mental activity levels may alter dementia risk. Clinical trials are now beginning to address the key issues of persistence of effect over extended follow-up and transfer of effect to nontrained domains. The aim of this report was to therefore systematically review results from clinical trials, which have examined the effect of cognitive exercise on longitudinal cognitive performance in healthy elderly individuals. METHODS MEDLINE, PubMed, and key references were used to generate an initial list of relevant studies (N = 54). These were reviewed to identify randomized controlled trials, which tested the effect of a discrete cognitive exercise training regime on longitudinal (>3 months) posttraining neuropsychological performance in healthy older adults. Seven RCTs met entry criteria. Prechange and postchange scores were integrated using a random effects weighted mean difference (WMD) meta-analytic approach (Review Manager Version 4.2). RESULTS A strong effect size was observed for cognitive exercise interventions compared with wait-and-see control conditions (WMD = 1.07, CI: 0.32-1.83, z = 2.78, N = 7, p = 0.006, N = 3,194). RCTs with follow-up greater than 2 years did not appear to produce lower effect size estimates than those with less extended follow-up. Quality of reporting of trials was in general low. CONCLUSION Cognitive exercise training in healthy older individuals produces strong and persistent protective effects on longitudinal neuropsychological performance. Transfer of these effects to dementia-relevant domains such as general cognition and daily functioning has also been reported in some studies. Importantly, cognitive exercise has yet to be shown to prevent incident dementia in an appropriately designed trial and this is now an international priority.

Magnetic resonance spectroscopy in AD

Proton MR spectroscopy (MRS) studies have found both decreased N-acetylaspartate (NAA) and increased myo-inositol in the occipital, temporal, parietal, and frontal regions of patients with AD, even at the early stages of the disease. This diffuse NAA decline is independent of regional atrophy and probably reflects a decrease in neurocellular viability. Reports of such metabolite changes are now emerging in the mild cognitive impairment prodrome and in investigation of the medial temporal lobe. In vivo quantitation of neural choline in AD has been inconclusive because of poor test–retest repeatability. Less robust evidence using phosphorous MRS has shown significant phosphocreatine decline and increments in the cell membrane phosphomonoesters in the early, and possibly asymptomatic, stages of the disease. These phosphorous metabolite disturbances normalize with disease progression. Phosphodiester concentration has been found to correlate strongly with AD plaque counts. MRS of AD has therefore introduced new pathophysiologic speculations. Studies of automated MRS for AD diagnosis have reported high sensitivity and moderate specificity, but are yet to test prospective samples and should be extended to include at least two MRS regions of interest. MRS has promise for predicting cognitive status and monitoring pharmacologic efficacy, and can assess cortical and subcortical neurochemical change. Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 13 issue to find the title link for this article.

Brain reserve and cognitive decline : a non-parametric systematic review

BACKGROUND A previous companion paper to this report (Valenzuela and Sachdev, Psychological Medicine 2006, 36, 441-454) suggests a link between behavioural brain reserve and incident dementia; however, the issues of covariate control and ascertainment bias were not directly addressed. Our aim was to quantitatively review an independent set of longitudinal studies of cognitive change in order to clarify these factors. METHOD Cohort studies of the effects of education, occupation, and mental activities on cognitive decline were of interest. Abstracts were identified in MEDLINE (1966-September 2004), CURRENT CONTENTS (to September 2004), PsychINFO (1984-September 2004), Cochrane Library Databases and reference lists from relevant articles. Eighteen studies met inclusion criteria. Key information was extracted by both reviewers onto a standard template with a high level of agreement. Cognitive decline studies were integrated using a non-parametric method after converting outcome data onto a common effect size metric. RESULTS Higher behavioural brain reserve was related to decreased longitudinal cognitive decline after control for covariates in source studies (phi=1.70, p<0.001). This effect was robust to correction for both multiple predictors and multiple outcome measures and was the result of integrating data derived from more than 47000 individuals. CONCLUSIONS This study affirms that the link between behavioural brain reserve and incident dementia is most likely due to fundamentally different cognitive trajectories rather than confound factors.

Lifespan Mental Activity Predicts Diminished Rate of Hippocampal Atrophy

Objective Epidemiological studies suggest that complex mental activity may reduce the risk for dementia, however an underlying mechanism remains unclear. Our objective was to determine whether individual differences in lifespan complex mental activity are linked to altered rates of hippocampal atrophy independent of global measures of neurodegeneration. Methods Thirty seven healthy older individuals had their complex mental activity levels estimated using the Lifetime of Experiences Questionnaire (LEQ) and completed serial MRI investigations at baseline and three years follow-up. Hippocampal volume and semi-automatic quantitation of whole brain volume (WBV) and white matter hyperintensities (WMHs) were compared at both time points. Results Higher LEQ scores were correlated with hippocampal volume independent of covariates at the three year follow-up stage (r = 0.43, p = 0.012). Moreover, those with higher LEQ scores experienced less hippocampal atrophy over the follow-up period (r = 0.41, p = 0.02). High LEQ individuals had less than half the hippocampal volume decline of low LEQ individuals in a multivariate analysis (F = 4.47, p = 0.042). No parallel changes were found in measures of WBV and WMHs. Conclusions High level of complex mental activity across the lifespan was correlated with a reduced rate of hippocampal atrophy. This finding could not be explained by general differences in intracranial volume, larger hippocampi at baseline, presence of hypertensive disease, gender or low mood. Our results suggest that neuroprotection in medial temporal lobe may be one mechanism underlying the link between mental activity and lower rates of dementia observed in population-based studies. Additional studies are required to further explore this novel finding.

Cognitive and memory training in adults at risk of dementia: A Systematic Review

BackgroundEffective non-pharmacological cognitive interventions to prevent Alzheimers dementia or slow its progression are an urgent international priority. The aim of this review was to evaluate cognitive training trials in individuals with mild cognitive impairment (MCI), and evaluate the efficacy of training in memory strategies or cognitive exercises to determine if cognitive training could benefit individuals at risk of developing dementia.MethodsA systematic review of eligible trials was undertaken, followed by effect size analysis. Cognitive training was differentiated from other cognitive interventions not meeting generally accepted definitions, and included both cognitive exercises and memory strategies.ResultsTen studies enrolling a total of 305 subjects met criteria for cognitive training in MCI. Only five of the studies were randomized controlled trials. Meta-analysis was not considered appropriate due to the heterogeneity of interventions. Moderate effects on memory outcomes were identified in seven trials. Cognitive exercises (relative effect sizes ranged from .10 to 1.21) may lead to greater benefits than memory strategies (.88 to -1.18) on memory.ConclusionsPrevious conclusions of a lack of efficacy for cognitive training in MCI may have been influenced by not clearly defining the intervention. Our systematic review found that cognitive exercises can produce moderate-to-large beneficial effects on memory-related outcomes. However, the number of high quality RCTs remains low, and so further trials must be a priority. Several suggestions for the better design of cognitive training trials are provided.

The effect of exercise training on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials.

OBJECTIVES Investigations of exercise and cognition have primarily focused on healthy or demented older adults, and results have been equivocal in individuals with mild cognitive impairment (MCI). Our aim was to evaluate efficacy of exercise on cognition in older adults with MCI. DESIGN We conducted a meta-analysis of random controlled trials (RCTs) of exercise effects on cognitive outcomes in adults with MCI. Searches were conducted in Medline, EMBASE, CINAHL, PEDro, SPORTSDICUS, PsychInfo, and PubMed. PARTICIPANTS Adults aged over 65 years with MCI or Mini-Mental State Exam mean score 24-28 inclusive. MEASUREMENTS Study quality was assessed using the PEDro scale; data on participant and intervention characteristics and outcomes were extracted, followed by meta-analysis. RESULTS Fourteen RCTs (1,695 participants; age 65-95 years) met inclusion criteria. Quality was modest and under-powering for small effects prevalent. Overall, 42% of effect sizes (ESs) were potentially clinically relevant (ES >0.20) with only 8% of cognitive outcomes statistically significant. Meta-analysis revealed negligible but significant effects of exercise on verbal fluency (ES: 0.17 [0.04, 0.30]). No significant benefit was found for additional executive measures, memory, or information processing. Overall results were inconsistent with benefits varying across exercise types and cognitive domains. CONCLUSIONS There is very limited evidence that exercise improves cognitive function in individuals with MCI, although published research is of moderate quality and inconclusive due to low statistical power. Questions remain regarding the magnitude, generalization, persistence, and mechanisms of benefits. Large-scale, high-quality RCTs are required to determine if exercise improves cognition or reduces dementia incidence in those with MCI.

Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke -the Sydney Stroke Study

BACKGROUND The frequency and clinical, neuropsychological and neuroimaging correlates of apathy in patients who have had a stroke are inadequately defined. METHOD A total of 167 consecutive patients admitted to the stroke units of two university hospitals after an ischaemic stroke and 109 controls received extensive medical, psychiatric and neuropsychological assessments; a subset received a magnetic resonance imaging (MRI) scan. The groups were matched for sex and age. Patients were assessed 3-6 months after their stroke. The sample for this study comprised 135 patients and 92 controls who completed the Apathy Evaluation Scale (AES). RESULTS Apathy was present in 26.7% of stroke patients compared to 5.4% of controls. Apathetic stroke patients were older, more functionally dependent and had lower Mini-Mental State Examination (MMSE) scores than those without apathy. Apathy was not associated with risk factors for cerebrovascular disease or stroke severity. There was a weak but significant correlation between apathy and self-reported depression but not with clinician-rated depression. Neuropsychologically, after correction for age, premorbid intelligence (IQ) and depression, apathy was associated with reduced attention and speed of information processing. On neuroimaging there were trends for associations of apathy with the extent of hyperintensities in the right hemisphere and right fronto-subcortical circuit, but not with total stroke volume or number of strokes. CONCLUSIONS Apathy is common following a cerebrovascular event. Presence of apathy may be related to older age and right fronto-subcortical pathway pathology, rather than stroke severity. It is associated with functional impairment and cognitive deficits.

Brain reserve and the prevention of dementia.

Purpose of review To evaluate and synthesize recent evidence linking mental activity and dementia risk, which commonly invokes ‘brain reserve’ as the mediating construct. Recent findings Brain reserve has acquired several interpretations; however, the most reliable and practical definition focuses at the behavioural level by assessing frequency and range of participation in complex mental activities. Epidemiological research suggests a clear and consistent link of high brain reserve with reduced dementia risk. Furthermore, emerging clinical trials of cognitive exercise suggest that it may be effective for the prevention of longitudinal cognitive and functional decline. Recent animal studies implicate several mechanisms, including disease-dependent and disease-independent compensatory pathways. Summary Given the precipitous forecasts for dementia over the coming decades, effective preventive strategies are of utmost importance. Findings from brain reserve studies now meet many of the formal criteria for causal agency between complex mental activity and reduced dementia risk. Key clinical trials are therefore under way to test these claims and results are keenly awaited.