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.

Pro-inflammatory cytokines IL-1ß and TNF-α are not associated with blood homocysteine concentration in Alzheimer's disease.

Increased concentrations of pro-inflammatory blood cytokines and plasma homocysteine (Hcy) are frequently reported in Alzheimer's disease (AD). Hcy appears to have immunomodulating and pro-inflammatory activities. Further, emerging evidence from animal and non-AD human studies implicates Hcy in potentiating the activities of pro-inflammatory cytokines; Hcy toxicity may also, in part, be mediated by these cytokines. As little is known about the potential relationship between these inflammatory markers specific to AD, the aim of this study was to assess potential impact of Hcy on the widely reported increases in cytokine concentrations in AD. Blood concentrations of two pro-inflammatory cytokines, IL-1ß and TNF-α, along with Hcy were assessed in 40 AD patients and 30 cognitively intact controls. Mean blood concentrations of IL-1ß and TNF-α differed significantly between the AD and control groups (p=0.001 and p<0.001 resp). This difference survived adjustment for age and gender on logistic regression. Hcy was significantly correlated with age only in the patient (rs=0.38, p=0.02) but not the control group. There was no significant correlation between IL-1ß and Hcy, and between TNF-α, and Hcy in either the AD or the control group. Hence, our AD data did not replicate results obtained from animal and non-AD human studies which have linked pro-inflammatory cytokines concentrations to Hcy. A different inflammatory focus may exist in AD which may be influenced at least in a significant part by non-vascular pathogenesis. However, these results indirectly support the notion that the observed mild hyperhocysteinemia in AD may be due to non-inflammatory factors.

Impact of cerebrovascular pathology on behavioural and neuropsychiatric symptoms in patients with Alzheimer's dementia: findings from a retrospective, naturalistic study.

AIM: Cerebrovascular disease (CVD) has been associated with depression and a host of neuropsychiatric conditions including dementia. This study assessed the relationship between cerebrovascular findings reported on MRI brain scans and neuropsychiatric symptoms (NPS) and behavioural problems in patients with Alzheimer's disease (AD). METHODS: Medical notes were retrospectively reviewed in patients undergoing brain MRI following referral for cognitive impairment to a memory clinic between January 2004 and June 2008. Patients with AD were graded into four categories of CVD severity based on neuroradiology reports and assessed for behavioural and NPS and activities of daily living using Neuropsychiatric Inventory (NPI), Geriatric Depression Scale (GDS) and Bristol Activities of Daily Living (BADL). Frontal lobe symptoms and parkinsonian features were also evaluated. RESULTS: Of the initial 232 patients who underwent MRI 72% were diagnosed with AD. 89% of AD patients had CVD findings reported on MRI. Moderate-to-severe CVD was present in 47% of patients. None of the AD patients satisfied a diagnosis of vascular dementia. There was no significant relationship observed between level of MRI CVD findings and scores on NPI (p = 0.57), GDS (p = 0.26) and BADL (p = 0.46). The level of CVD severity did not appear to influence frontal lobe and parkinsonian assessments (p = 0.60). CONCLUSION: The contribution of CVD to the pathogenesis of various NPS is still debated. Our study, based on patients diagnosed with AD in a memory clinic setting, suggests that there is no relationship between the extent of CVD pathology and neuropsychiatric and behavioural measures in AD patients. Further prospective quantitative studies are needed to assess the role of CVD, if any, in neuropsychiatric and behavioural symptoms in AD. It is possible that the relatively small pathological contribution of CVD to the development of these symptoms is obscured by the effect of the wider neurodegeneration encountered in AD.

Prevalence and cognitive impact of cerebrovascular findings in Alzheimer's disease: a retrospective, naturalistic study.

AIMS: Cerebrovascular disease (CVD) is a major risk factor for cognitive decline associated with progression to Alzheimer's disease (AD) and dementia. The objective of this study was to retrospectively assess the prevalence of CVD and its cognitive impact in patients with AD in everyday clinical practice. METHODS: Medical notes were retrospectively reviewed for all individuals who presented at East Sussex Memory Clinic (2004-2008) for investigation of cognitive impairment and had brain magnetic resonance imaging (MRI) as part of their clinical work-up. Global cognitive status was assessed with Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination. The extent of cerebrovascular abnormalities was qualitatively evaluated with MRI. RESULTS: Notes were reviewed for 232 patients (109 males, 123 females), mean age 76 years (range 62-93), who underwent MRI. Of these, 167 (72%) patients were diagnosed with AD. CVD was present in 89% of AD patients and 47% of patients had moderate to severe cerebrovascular abnormalities. The majority of patients (57%) had MMSE scores in the 21-26 range, indicative of mild AD. There was a trend towards worse cognitive status in patients with more severe CVD, which did not reach significance. Hachinski Ischaemic score indicated these patients did not have vascular dementia (VaD) (mean +/- standard deviation 1.1 +/- 1.3). CONCLUSION: These findings, based on qualitative MRI, indicate that cerebrovascular pathology is a very common associated feature in patients with mild to moderate AD, without VaD. Although the study suggests that CVD does not contribute to cognitive decline, and is not associated with the development of VaD, a non-significant trend was observed towards worsening cognitive status with increasing severity of CVD. The finding of this trend suggests a need for additional research, especially a prospective quantitative method of assessing CVD, to improve our understanding of how CVD contributes to cognitive impairment in AD.

Ultra-fast Microwave Synthesis of ZnO Nanowires and their Dynamic Response Toward Hydrogen Gas.

Ultra-fast and large-quantity (grams) synthesis of one-dimensional ZnO nanowires has been carried out by a novel microwave-assisted method. High purity Zinc (Zn) metal was used as source material and placed on microwave absorber. The evaporation/oxidation process occurs under exposure to microwave in less than 100 s. Field effect scanning electron microscopy analysis reveals the formation of high aspect-ratio and high density ZnO nanowires with diameter ranging from 70 to 80 nm. Comprehensive structural analysis showed that these ZnO nanowires are single crystal in nature with excellent crystal quality. The gas sensor made of these ZnO nanowires exhibited excellent sensitivity, fast response, and good reproducibility. Furthermore, the method can be extended for the synthesis of other oxide nanowires that will be the building block of future nanoscale devices.

Behavioural and psychological symptoms of Alzheimer type dementia are not correlated with plasma homocysteine concentration.

BACKGROUND/AIMS: Vitamin B12 and folate deficiencies have been associated with cognitive impairment and various psychiatric symptoms but not specifically with behavioural and psychological symptoms of dementia (BPSD). A limitation of previous studies in dementia was lack of concurrent homocysteine measurement especially as it may provide a better indicator of tissue activities of these vitamins. This study was designed to clarify whether a relationship exists between plasma homocysteine concentration and BPSD. METHODS: Plasma homocysteine, serum vitamin B12 and folate were measured in 23 Alzheimer's disease (AD) patients with BPSD and 27 AD patients without BPSD as determined through the use of the Neuropsychiatric Inventory (NPI). Blood levels of measured substances were also correlated with individual NPI scores and with cumulative NPI scores for different cluster of symptoms. RESULTS: There was no significant difference (p = 0.956) in the mean plasma homocysteine levels between AD patients with BPSD (17.48 micromol/l) and AD patients without BPSD (17.34 micromol/l). Similarly, there was no significant difference between the two groups in the mean serum B12 (382.61 and 391.60 pg/ml, respectively) and folate (7.95 and 10.02 ng/ml, respectively). Mean levels for both vitamins were well within the laboratory reference range. Neither individual nor cluster NPI scores correlated significantly with plasma homocysteine. CONCLUSION: This study shows for the first time that BPSD are not associated with hyperhomocysteinaemia in Alzheimer dementia. Although previous studies have identified homocysteine as an independent risk factor in AD, the results reported here do not lend weight to an aetiological role for homocysteine specifically in BPSD.

Acetylcholinesterase inhibitors for Alzheimer's disease: anti-inflammatories in acetylcholine clothing!

The pathogenesis of Alzheimer's disease (AD) has been linked to a deficiency in the brain neurotransmitter acetylcholine. Subsequently, acetylcholinesterase inhibitors (AChEIs) were introduced for the symptomatic treatment of AD. The prevailing view has been that the efficacy of AChEIs is attained through their augmentation of acetylcholine-medicated neuron to neuron transmission. However, AChEIs also protect cells from free radical toxicity and beta-amyloid-induced injury, and increased production of antioxidants. In addition, it has been reported that AChEIs directly inhibit the release of cytokines from microglia and monocytes. These observations are supported by evidence showing a role for acetylcholine in suppression of cytokine release through a 'cholinergic anti-inflammatory pathway'. Based on the accumulating research data so far, it is no longer appropriate to consider that the sole action of AChEIs in AD is through direct acetylcholine-medicated enhancement of neuronal transmission. Evidence points to a possible anti-inflammatory role for these agents as well.

Alpha lipoic acid for dementia.

BACKGROUND: Oxidative processes have been implicated in the pathogenesis of neurodegenerative dementias including Alzheimer's disease. Protecting the central nervous system against these damaging mechanisms may be a useful therapeutic approach. Alpha lipoic acid (ALA) is an endogenous antioxidant that interrupts cellular oxidative processes in both its oxidized and reduced forms. These properties might qualify ALA for a modulatory role in the treatment of people with dementia. OBJECTIVES: To assess the role and clinical efficacy of alpha lipoic acid in the treatment of dementia. SEARCH STRATEGY: A search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG) on 3 February 2003 using the terms 'alpha lipoic acid' and 'thioctic'. The CDCIG Specialized register is updated regularly and contains records from all major health care databases (MEDLINE, EMBASE, PsycInfo, CINAHL) as well as from many trials databases. SELECTION CRITERIA: All double-blind randomized placebo-controlled trials examining the efficacy of alpha lipoic acid in dementia DATA COLLECTION AND ANALYSIS: No trials were found that met the selection criteria MAIN RESULTS: No meta-analysis could be performed. A systematic search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, as well as registers of ongoing and unpublished trials could not identify any studies investigating the use of ALA for dementia. REVIEWER'S CONCLUSIONS: In the absence of randomized double-blind placebo-controlled trials investigating ALA for dementia, no evidence exists to explore any potential effects. Until data from trials become available for analysis, ALA cannot be recommended for people with dementia.

Acetyl-L-carnitine for dementia.

BACKGROUND: Dementia is a common mental health problem affecting 5% of those over 65. Various pathological processes are linked to memory impairment in dementia, particularly those affecting the cholinergic neurotransmitter system. Acetyl-l-carnitine (ALC) is derived from carnitine and is described as having several properties which may be beneficial in dementia. This includes activity at cholinergic neurons, membrane stabilization and enhancing mitochondrial function. Work on the effects of ALC has been ongoing since the 1980s yet the efficacy of ALC in cognitive decline remains unclear. Early studies suggested a beneficial effect of ALC on cognition and behaviour in aging subjects. However, later, larger studies have not supported these findings. Some of the difficulties lie in the early and later studies differing widely in methodology and assessment tools used, and are therefore difficult to compare. ALC is not currently in routine clinical use. OBJECTIVES: The objective of this review is to establish whether Acetyl-l-carnitine is clinically effective in the treatment of people with dementia. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2003 using the terms acetyl-l-carnitine, l-carnitine acetyl ester, acetylcarnitine. SELECTION CRITERIA: All double-blind, randomized, trials involving people with dementia in which treatment with ALC was compared with a placebo group DATA COLLECTION AND ANALYSIS: Data were extracted by a reviewer (SH) and entered into Revman 4.1 software. Where possible intention-to-treat data were used, but most of the analyses were of completers (people who completed the study). MAIN RESULTS: There are 11 included trials, all of which had restricted the participants to people with Alzheimer's disease. All trials assessed the cognitive effects of ALC and in addition six considered severity of dementia, six considered functional ability and six considered clinical global impression. There were statistically significant treatment effects in favour of ALC at 12 and 24 weeks for the numbers showing improvement as determined by Clinical Global Impression, [OR 2.33, 95% CI 1.25 to 4.35, P<0.01] and [OR 3.91, 95% CI 1.32 to 11.54, P=0.01] but not as determined by the CIGIC at 52 weeks. There was no evidence of benefit for ALC in the areas of cognition, severity of dementia, functional ability or Clinical Global Impression as a continuous measure. Various adverse events were reported, but from the meta-analyses there were no statistically significant differences between treated and placebo groups. REVIEWER'S CONCLUSIONS: There is evidence for benefit of ALC on clinical global impression, but there was no evidence using objective assessments in any other area of outcome. Given the large number of comparisons made, the statistically significant result may be due to chance. At present there is no evidence to recommend its routine use in clinical practice. Although the intention of the review was to access ALC for the treatment of all dementias, the included trials had confined themselves to participants with Alzheimer's disease. Individual patient data may add to the findings, as would trials including other types of dementia and other outcomes (e.g. mood and caregiver quality of life). However, the evidence does not suggest that ALC is likely to prove an important therapeutic agent. More work on the pharmacokinetics of ALC in humans is also required.

Ibuprofen for Alzheimer's disease.

BACKGROUND: Non-steroidal antiinflammatory drugs such as ibuprofen may have a role in the treatment of conditions characterized by inflammatory processes. Ibuprofen may attenuate the effects of modulators of inflammation that have been implicated in the pathogenesis of Alzheimer's disease. OBJECTIVES: To investigate the efficacy of ibuprofen treatment for people with Alzheimer's disease. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 December 2002 using the (many) terms listed in the main text of the review. The CDCIG Register is updated regularly and contains records from all major health care databases and many ongoing trials databases. In addition computerized databases and Internet sites pertaining to ibuprofen and Alzheimer's disease were systematically examined by two reviewers independently. Data on ongoing trials of ibuprofen for the treatment of people with AD were also sought. SELECTION CRITERIA: Eligibility for this review included all single or multi centre placebo-controlled randomized trials examining the efficacy of ibuprofen in the treatment of people diagnosed with Alzheimer's disease according to internationally accepted criteria. Inclusion and exclusion criteria were specified to ensure lack of bias in selection and methodological quality of selected trials. DATA COLLECTION AND ANALYSIS: The aim was for the two reviewers NT and HF to collect data independently. The data selected would reflect cognitive, behavioural, physical and psychological domains of AD. MAIN RESULTS: A systematic search of all available databases and other sources failed to identify any completed randomized, double-blind and placebo-controlled trials, assessing the efficacy of ibuprofen in AD eligible for inclusion in the review. One double-blind placebo-controlled trial investigating ibuprofen treatment for age-associated memory impairment has been identified, but is yet unfinished and no data are yet available. Other trials assessing the effect of ibuprofen on CSF beta amyloid in cognitively unimpaired individuals and the effect of other NSAIDs such as naproxen and rofecoxib for people with AD are currently under way. REVIEWER'S CONCLUSIONS: No evidence yet exists from randomized double-blind and placebo-controlled trials on whether ibuprofen is efficacious for patients diagnosed as having Alzheimer's disease. Ibuprofen, like other NSAIDs, has an identifiable and in some instances a significant side-effect profile which may include gastrointestinal bleeding. Therefore, it needs to be shown that the benefits of such a treatment outweighs the risk of side effects before ibuprofen can be recommended for people with Alzheimer's disease.

Indomethacin for the treatment of Alzheimer's disease patients.

BACKGROUND: Inflammatory processes involving cytokines, prostaglandins, free radicals and glial cells have been implicated in the pathogenesis of Alzheimer's disease. Non-steroidal anti-inflammatory drugs such as indomethacin attenuate inflammatory reactions. Hence, there may be a role for some of these drugs in the treatment of Alzheimer's disease. OBJECTIVES: To examine the efficacy of indomethacin in the treatment of patients suffering from Alzheimer's disease. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (which contains records from many different medical and trials databases) on 14 June 2001 using the terms indomethacin and indome* and NSAIDS. In addition two independent reviewers systematically searched relevant computerized databases and Internet sites. This was supplemented by hand searching and additional references sought from selected papers. SELECTION CRITERIA: Single or multi-centre placebo-controlled randomized trials examining the efficacy of indomethacin in patients diagnosed with Alzheimer's disease were eligible for selection for this review. Using a standard extraction form, inclusion/exclusion criteria were set to ensure design quality and lack of bias of all trials included. DATA COLLECTION AND ANALYSIS: Data were collected independently by two reviewers and any discrepancies were subject to discussion. Corresponding authors were contacted for any missing data needed for statistical analysis. MAIN RESULTS: Only one study was selected for this review (~~Rogers 1993~~). We detected no statistically significant difference between indomethacin treatment and placebo for the individual cognitive tests, Mini Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale ( ADAS), Boston Naming Test (BNT) and Token Test (TK). Dropouts and death rate were the only reported results that were amenable to evaluation. The dropout rate was higher in the indomethacin group (10/24) than in the control group (6/20). Gastrointestinal adverse events were more prevalent in the treatment group (5/24 compared with 1/20 in control group). There was no statistically significant difference in death rate between the two groups (p=0.9). REVIEWER'S CONCLUSIONS: On the basis of this one trial and subsequent analysis of data as reported by the authors, indomethacin cannot be recommended for the treatment of mild to moderate severity Alzheimer's disease. At doses of 100-150 mg daily, serious side effects will limit its use.

To tell or not to tell-comparison of older patients' reaction to their diagnosis of dementia and depression.

OBJECTIVE: Investigation of the reaction of elderly patients to the disclosure of their diagnosis of dementia compared with depression. DESIGN: Elderly patients suffering from dementia and depression were asked to complete a questionnaire about the diagnosis and other aspects of their clinical summary sent to them by post. Demographic data included age, gender, marital status and occupation; degree of dementia or depression was established by administering the mini-mental state examination and the geriatric depression scale, respectively. SETTING: Patients were consecutive attendees of outpatient clinics (old age psychiatry) located in two suburban areas near London. MEASURES: Demographic data included age, gender, marital status and occupation; degree of dementia or depression was established by administering the mini-mental state examination and the geriatric depression scale, respectively. RESULTS: One hundred cases were recruited, 53 with dementia and 47 with depression. Most depressed and dementia patients ( > 75%) liked the idea of reading their diagnosis but 25% of dementia cases felt upset. Within the dementia group, the majority of patients with mild or severe dementia welcomed the idea of knowing their diagnosis; and 13 (100%) of the patients with vascular dementia wished to know (compared with 68% cases with Alzheimer's disease). None felt upset, and only 39% of them felt pessimistic after reading their own clinical summary. However, among dementia patients who also happened to be depressed, a higher proportion (60%) expressed an unfavourable view towards knowing their diagnosis, but only a minority (40%) of them were actually upset. Most older married females, especially those with depression and Alzheimer's disease, felt pessimistic afterwards. CONCLUSIONS: There was no significant difference between patients with dementia or depression in their wish to know their diagnosis. Patients with severe dementia, even if they felt upset, preferred to be told their diagnosis. Patients with vascular dementia tended to express a more favourable view.

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 Alzheimer's 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.

Vitamin E for Alzheimer's disease.

BACKGROUND: Vitamin E is a dietary compound that functions as an antioxidant scavenging toxic free radicals. Evidence that free radicals may contribute to the pathological processes in Alzheimer's disease has led to interest in the use of vitamin E in the treatment of this disorder. OBJECTIVES: To examine the effects of vitamin E treatment for people with Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched with the following terms: vitamin E, Alzheimer's disease, dementia, alpha-tocopherol, cognitive impairment, cognitive function and controlled trials. The latest search was carried out in July 2000. SELECTION CRITERIA: All unconfounded, double blind, randomized trials in which treatment with vitamin E at any dose was compared with placebo for patients with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the selection criteria an assessed study quality. One reviewer extracted and analysed the data. For each outcome measure data were sought on every patient randomized. Where such data were not available an analysis of patients who completed treatment was conducted. MAIN RESULTS: Only one study was identified which met the inclusion criteria (Sano 1997). The primary outcome used in this study of 341 participants was survival time to the first of 4 endpoints, death, institutionalisation, loss of 2 out of 3 basic activities of daily living, or severe dementia, defined as a global Clinical Dementia Rating of 3. The investigators reported the total numbers in each group who reached the primary endpoint within two years for participants completing the study ("completers"). There appeared to be some benefit from vitamin E with fewer participants reaching endpoint - 58% (45/77) of completers compared with 74% (58/78) - a Peto odds ratio of 0.49, 95% confidence interval 0.25 to 0.96. However, more participants taking vitamin E suffered a fall (12/77 compared with 4/78; odds ratio 3.07, 95% CI 1.09 to 8.62). It was not possible to interpret the reported results for specific endpoints or for secondary outcomes of cognition, dependence, behavioural disturbance and activities of daily living. REVIEWER'S CONCLUSIONS: There is insufficient evidence of efficacy of vitamin E in the treatment of people with with Alzheimer's disease. The one published trial of acceptable methodology (Sano 1997) was restricted to patients with moderate disease, and the published results are difficult to interpret. There is sufficient evidence of possible benefit to justify further studies. There was an excess of falls in the vitamin E group compared with placebo which requires further evaluation.

Free radicals as mediators of toxicity in Alzheimer's disease: a review and hypothesis.

Recent research has increasingly suggested a central role for free radical induced tissue damage in the pathogenesis of Alzheimer's disease (AD). In this paper we review evidence for the interaction between free radicals and other major factors/metabolic areas which have also been implicated in AD, including beta-amyloidosis, inflammatory cytokines, mitochondrial dysfunction and metal ions/homocysteine. We hypothesize that free radicals and antioxidants should not be considered in isolation in the aetiology and treatment of AD. It is the reciprocal induction and self-amplifying interplay between all of the above factors which is important in the pathogenesis of this disorder, and to which multi-pharmacological therapeutic strategies should be directed.