Perminder S. Sachdev

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.

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimers disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

Differentiation of vascular dementia from AD on neuropsychological tests

Background: The concept of vascular dementia (VaD) is currently in a state of evolution. Memory impairment is emphasized as a primary criterion, reflecting the influence of AD on the concept of dementia. We have systematically reviewed whether the nature of neuropsychological dysfunction is distinct in AD and VaD, and whether similar defining criteria for the concept of dementia in both disorders can be supported. Methods: We searched five bibliographic databases (Medline, Biological Abstracts, EMBASE, PsychINFO, PsychLIT) for research articles in which VaD and AD had been compared using neuropsychological tests and that met criteria for scientific merit. Results: Of the 45 studies, 18 were excluded because of inadequacies, and the remaining 27 were analyzed. There were a number of similarities of dysfunction between VaD and AD. However, when matched for age, education, and severity of dementia, VaD patients had relatively superior function in verbal long-term memory and more impairment in frontal executive functioning compared with AD patients. Interpretation of the results is limited by uncertainty in diagnostic criteria for VaD, possible inclusion bias due to use of clinical diagnosis alone, possible overlap of AD and VaD, and the methodologic shortcomings of some studies. Conclusions: The neuropsychological differentiation of VaD from AD was consistent with the different neuroimaging findings in the two disorders, and argues for differential criteria for the definition of the syndromes. The simple application of Alzheimer’s dementia criteria to VaD, with the inclusion of cerebrovascular disease etiology, may not be sufficient to capture the uniqueness of VaD.

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.

Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial {

BACKGROUND Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. AIMS To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). METHOD Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. RESULTS There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. CONCLUSIONS Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

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.

The Falls Efficacy Scale International (FES-I). A comprehensive longitudinal validation study

OBJECTIVE this study aimed to perform a comprehensive validation of the 16-item and 7-item Falls Efficacy Scale International (FES-I) by investigating the overall structure and measurement properties, convergent and predictive validity and responsiveness to change. METHOD five hundred community-dwelling older people (70-90 years) were assessed on the FES-I in conjunction with demographic, physiological and neuropsychological measures at baseline and at 12 months. Falls were monitored monthly and fear of falling every 3 months. RESULTS the overall structure and measurement properties of both FES-I scales, as evaluated with item response theory, were good. Discriminative ability on physiological and neuropsychological measures indicated excellent validity, both at baseline (n = 500, convergent validity) and at 1-year follow-up (n = 463, predictive validity). The longitudinal follow-up suggested that FES-I scores increased over time regardless of any fall event, with a trend for a stronger increase in FES-I scores when a person suffered multiple falls in a 3-month period. Additionally, using receiver-operating characteristic (ROC) curves, cut-points were defined to differentiate between lower and higher levels of concern. CONCLUSIONS the current study builds on the previously established psychometric properties of the FES-I. Both scales have acceptable structures, good validity and reliability and can be recommended for research and clinical purposes. Future studies should explore the FES-Is responsiveness to change during intervention studies and confirm suggested cut-points in other settings, larger samples and across different cultures.

The topography of white matter hyperintensities on brain MRI in healthy 60- to 64-year-old individuals

We report the topography of brain white matter hyperintensities (WMHs) on T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging in 477 healthy subjects aged 60-64 years selected randomly from the community. WMHs were delineated by using a computer algorithm. We found that all subjects had periventricular WMHs and 96.6% subjects also had deep WMHs. The mean volume of WMHs was 4.9 ml, comprising 0.83% of the white matter, of which 1.2 ml was severe in intensity. The deep WMHs were distributed throughout the cerebral hemispheres, with the occipital and frontal white matter bearing the greatest burden. The territory of the lenticulostriate arteries had the greatest WMHs. A white matter region of 4 mm adjacent to the cortex was not affected by hyperintensities. The mean (SD) number of discrete WMHs was 19.6 (7.1) per subject, of which 6.1 (4.4) were severe in intensity. Nearly half (48.6%) of the subjects had at least one large WMH (>12 mm diameter) and one eighth (12.5%) of the subjects had at least one large WMH that appeared to be severe in MRI. The overall load of WMHs was similar in men and women, but the latter had a higher proportion of their white matter so affected. This study provides the first detailed topographic analysis of WMHs in a large representative middle-aged sample, emphasizes their high prevalence in mid-adult life and raises issues about their etiology and significance.