Naji Tabet

Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study

BACKGROUND Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimers disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand (123)I-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included. METHODS We did a phase III study in which we used a (123)I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0.80) and specificity (0.85) targets and prespecified lower thresholds (sensitivity 0.65, specificity 0.73) using one-sided binomial tests with a significance level of alpha=0.025. FINDINGS Abnormal scans had a mean sensitivity of 77.7% for detecting clinical probable DLB, with specificity of 90.4% for excluding non-DLB dementia, which was predominantly due to Alzheimers disease. A mean value of 85.7% was achieved for overall diagnostic accuracy, 82.4% for positive predictive value, and 87.5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohens kappa=0.87). The procedure was well tolerated with few adverse events. INTERPRETATION A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimers disease.

Microbes and Alzheimer's Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even thoug ...

Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers.

The potential of putative cognitive-enhancing compounds to improve mental processing both in healthy and vulnerable populations is an area of growing interest to scientific and clinical communities. The possible influence of individual genetic differences on efficacy of these compounds has yet to be considered. We sought to investigate the profile of young-adult apolipoprotein E (APOE) ɛ4 carriers across cognitive domains given that possession of this gene variant increases risk of developing dementia in later life. We also explored whether APOE genotype interacts with the cognitive enhancer, nicotine. A total of 1 mg of the cholinergic agonist nicotine was administered through nasal spray to healthy non-smoking young adults (aged 18–30) with either ɛ3/ɛ3 (N=29) or ɛ4 (at least one ɛ4 allele, N=27) genotype. Participants were matched on age, sex, and IQ in a placebo-controlled, double-blind 2 (drug: placebo, nicotine) × 2 (genotype: ɛ3, ɛ4) between subjects design. Here, we show that, paradoxically, possession of the ɛ4 allele confers a cognitive advantage on tasks mediated by the frontal lobe, and that young carriers of the ɛ4 allele show larger cognitive benefit from procholinergic nicotinic stimulation. These results are the first to show that genetic differences influence the efficacy of a cognitive enhancer.

The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review

BACKGROUND Non-pharmacological interventions may have a role in both the prevention and slowing down of disease progression in Alzheimers disease (AD). The role of exercise in disease prevention, for example, has been extensively evaluated in large epidemiological studies. Much less is known about the potential benefit of exercise in patients already diagnosed with AD. It was therefore the aim of this systematic review to assess the effectiveness of exercise in attenuating cognitive decline within AD. METHOD A systematic review was conducted statistically accompanied by a meta-analysis. Publications between January 1991 and October 2012 were identified by searching the electronic databases PubMed, Science Direct, Web of Knowledge, and PsychINFO. Selected studies required AD patients to take part in an exercise-based randomized controlled trial (RCT) and have a cognitive outcome measure. RESULTS Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32-1.17). CONCLUSIONS From the six studies reviewed, the evidence suggests that exercise can have a positive effect on rate of cognitive decline in AD. However, the variation between study designs makes conclusions regarding the optimum intervention on cognitive outcome in AD difficult. Well-designed and powered RCTs are still needed to ascertain the efficacy of exercise in slowing down cognitive impairment in AD patients. However, a positive initial indication for exercise efficacy justifies such efforts.

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.

Cognitive and neural signatures of the APOE E4 allele in mid-aged adults

The apolipoprotein E (APOE) e4 allele is strongly associated with increased risk of cognitive impairments in older adulthood. There is also a possible link to enhanced cognitive performance in younger adults, and the APOE e4 allele may constitute an example of antagonistic pleiotropy. The aim of this work was to investigate the cognitive and neural (functional) effects of the APOE e4 allele during mid-age (45–55 years), where a transition toward cognitive deficit might be expected. APOE e4 carriers (e4+) were compared with non-e4 carriers (e4−) on tasks of sustained and covert attention and prospective memory, and functional magnetic resonance imaging data acquired. Performance by e4+ was equivalent or better than e4− on all 3 tasks, although performance benefits were less pronounced than in youth. Neurally, e4+ showed less task-related recruitment of extrastriate and parietal areas. This became more evident when neural activation data were compared with that of young adults acquired in a parallel study. As expected, mid-age participants showed more diffuse neural activation. Notable was the fact that e4+ showed a relative inability to recruit parietal regions as they aged. This was coupled with a tendency to show greater recruitment of frontal regions, and underactivation of extrastriate visual regions. Thus, mid-age e4+ show a pattern of neural recruitment usually seen later in life, possibly reflecting the source of an accelerated aging profile that describes the e4 genotype.

Non-pharmacological interventions in the prevention of delirium

Delirium is a serious and common disorder especially among older people on inpatients units. Numerous modifiable or manageable delirium risk factors have been identified. As a result, there is now a widespread notion that many cases of delirium can be prevented. In this review, published data evaluating non-pharmacological interventions for delirium prevention were assessed in relation to their efficacy. Currently, most published studies are based on direct targeting of risk factors and/or introduction of educational programmes to increase staff knowledge and awareness. However, there continues to be a dearth of randomised controlled trials evaluating non-pharmacological interventions, partly because of the inherent difficulties associated with delirium research in general and with the evaluation of non-pharmacological interventions in particular. Instead, many of the available studies have been observational or non-randomised in nature. Nevertheless, the majority of these support a role for non-pharmacological interventions in delirium prevention. While more research is certainly needed, the majority of available data are based on best practice protocols, guidelines and interventions. Hence, a consistent and concerted effort is now justified to introduce non-pharmacological prevention strategies across units to help tackle the increasingly prevalent delirium among older people.

Clinical usefulness of dopamine transporter SPECT imaging with 123I-FP-CIT in patients with possible dementia with Lewy bodies: randomised study

BACKGROUND Dementia with Lewy bodies (DLB) is underrecognised in clinical settings. AIMS To investigate whether performing a (123)I-ioflupane injection ((123)I-FP-CIT also called DaTSCAN™) single photon emission computed tomography (SPECT) scan in patients with possible DLB would lead to a more certain diagnosis (probable DLB or non-DLB dementia). METHOD We randomised 187 patients with possible DLB 2:1 to have a scan or not (control group). The outcome measure was a change in diagnosis to probable DLB or non-DLB. RESULTS There were 56 controls and 114 scanned patients, of whom 43% had an abnormal scan. More patients in the imaging group had a change in diagnosis compared with controls at 8 and 24 weeks (61% (n = 70) v. 4% (n = 2) and 71% (n = 77) v. 16% (n = 9); both P<0.0001). Clinicians were more likely to change the diagnosis if the scan was abnormal (82%) than if it was normal (46%). CONCLUSIONS Imaging significantly contributed to a more certain diagnosis, proving to be a useful adjunct in the work-up of patients with possible DLB.

Slowing the progression of Alzheimer’s disease; what works?

Alzheimers disease (AD) is an age-related progressive dementia, which is increasing in prevalence world-wide. Typically affecting short-term memory at onset, this devastating illness advances to impair all aspects of cognition, as well as non-cognitive domains. Although much effort has been made in recent years to develop disease-modifying treatments, medications which provided promising results in pre-clinical research have so far faltered in human clinical trials. Attention has recently shifted into trying to identify preventative measures that may delay the onset of the illness. Preventative factors include physical activity, proper diet, cognitive stimulation and the management of conditions such as hypertension, diabetes and obesity. However, it remains imperative to identify approaches that may help patients already diagnosed with the illness. Alongside pharmacological research, much work has been done on uncovering strategies which may slow down the progression of AD. This review aims to summarize evidence supporting or refuting methods impacting on the progression of the disease. AD remains a chronic and serious condition, therefore any intervention delaying the onset of moderate/severe symptoms will have a significant impact on patients and their families.

Vitamins, trace elements, and antioxidant status in dementia disorders

Antioxidants, such as vitamins C and E, have been proposed for the treatment of dementia disorders. Although other vitamins and trace elements may also have antioxidant-enhancing activities, it is not known whether the overall antioxidant status in dementia patients is associated with the intake level of these vitamins and trace elements. In this study, we assessed the levels of vitamins and trace elements in the diet of patients with Alzheimers disease (AD), vascular dementia (VaD), and dementia with Lewy bodies (DLB) and a group of carers, along with blood levels of total antioxidant capacity (TAC). Results show that the dietary intake was decreased for most measured vitamins and trace elements in severe AD, but not in other dementia groups. In addition, we found no significant difference in the levels of TAC between any of the dementia groups. There was, however, a significant correlationbetween intake of vitamin B1, vitamin B12, zinc, and selenium and blood levels of TAC in the VaD group, but not in the AD and DLB groups. Furthermore, no association was observed in any of the dementia groups between zinc and copper intake and Cu/Zn superoxide dismutase activity, or between dietary selenium intake and glutathione peroxidase activity. The activities of these two endogenous antioxidant enzymes do not seem to be influenced by intake levels of relevant substances. The data indicate that the influence of dietary vitamins and metal ions on the overall antioxidant status is limited to VaD patients only. Clinical trials are needed to ascertain the value of antioxidant supplementation in VaD patients.