Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?

There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer's disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic beta-amyloid (Abeta) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Abeta antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients' neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease.

P3b versus P3a: an event-related potential investigation of the glucose facilitation effect.

The ingestion of a glucose containing drink has been shown to improve performance on a variety of cognitive tasks. There is debate, however, as to whether glucose especially benefits hippocampal memory functioning or whether it has a more global effect on attentional systems. The present study used event related potential methodology (ERPs) to investigate further glucose-mediated cognitive processes. Each participant acted as his/her own control in a repeated measures design, receiving one of two possible treatments (25 g glucose vs. placebo) in a counterbalanced order. After a two hour fasting period participants completed a visual three-stimulus oddball task. This paradigm involves an individual detecting an infrequent target stimulus randomly embedded in a train of repetitive background or standard stimuli. Detection of the target results in a large P3b ERP component (memory updating effect). The infrequent presentation of a novel and irrelevant stimulus, randomly interspersed with the target and standard stimuli, generates a P3a response (orientation of attention effect). These components were used as markers to establish whether the glucose enhancement effect was restricted to the neuro-cognitive processes related to memory. Consistent with behavioural work, glucose moderated the magnitude and latency of the P3b ERP component. However, glucose also interacted with attentional systems (P3a and an earlier P2), although this effect was non-significant. This work converges with recent fMRI findings indicating the sensitivity of the medial-temporal lobes and the pre-frontal cortex to glucose administration.

Predictors of cognitive impairment and dementia in older people with diabetes.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of dementia but the reasons for this association are unclear because there are many potential mechanisms. We explored the relative contribution of diabetes-related variables as predictors of dementia in older individuals with diabetes. METHODS: Survivors, aged > or =70 or more, were recruited from an existing observational cohort study 7.6 +/- 1.0 years after baseline, when they underwent a comprehensive assessment of diabetes, complications and cardiovascular risk factors. Dementia, probable Alzheimer's disease and cognitive impairment without dementia were diagnosed clinically. Logistic regression modelling determined independent predictors of cognitive diagnoses. RESULTS: Of 302 participants, aged 75.7 +/- 4.6 years, 28 (9.3%) had dementia (16 with probable Alzheimer's disease) and 60 (19.9%) had cognitive impairment without dementia. The major independent longitudinal predictors of dementia were older age (per decade; odds ratio 4.0, 95% CI 1.59-10.10), diabetes duration (for each 5 years; odds ratio 1.69, 95% CI 1.24-2.32), peripheral arterial disease (odds ratio 5.35, 95% CI 2.08-13.72) and exercise (which was protective; odds ratio 0.26, 95% CI 0.09-0.73). For Alzheimer's disease, diabetes duration was an independent predictor in addition to age and diastolic blood pressure. The results of the cross-sectional analyses were similar with respect to diabetes duration and peripheral arterial disease. CONCLUSIONS/INTERPRETATION: Peripheral arterial disease is a strong independent risk factor for dementia in diabetes. After adjustment for a wide range of potential risk factors, diabetes duration remains independently associated with dementia and probable Alzheimer's disease, indicating that factors not measured in this study may be important in the pathogenesis of dementia in diabetes.

Vascular depression in older people with diabetes.

AIMS/HYPOTHESIS: Cerebrovascular disease may be causal or a vulnerability factor in late-onset depression and may explain the high rate of depression in older adults with diabetes. We explored a wide range of potential explanatory variables of depression in a longitudinal study of older diabetic subjects to investigate the vascular depression hypothesis in these patients. METHODS: We recruited 207 subjects with diabetes selected for potential cognitive deficits from an existing observational cohort study (average age 75.7 +/- 4.6 years, 52.2% men) for an assessment of depression using a standardised diagnostic instrument (Cambridge Examination for Mental Disorders of the Elderly -- Revised). All subjects underwent a detailed clinical assessment at baseline and at follow-up (after 7.5 +/- 1.1 years). RESULTS: Major depression was present in 45 subjects (21.7%) and minor depression in ten (4.8%). A positive history of strokes and the presence of peripheral arterial disease were significantly associated with depression at the time of diagnosis. In a subsample of 93 cases who underwent structural neuroimaging, the presence of cerebral infarcts was also significantly associated with depression. Treatment with glucose-lowering therapy, higher serum cholesterol levels and difficulties with activities of daily living at baseline were significant predictors of depression at follow-up. CONCLUSIONS/INTERPRETATION: A history of cerebrovascular disease was strongly associated with depression and cerebrovascular risk factors were significant predictors of depression in older diabetic patients. Our findings are consistent with the hypothesis that the excess risk of depression in older diabetic patients is related to underlying cerebrovascular disease.

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease.

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E epsilon4 (APOE epsilon4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Abeta clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE epsilon4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE epsilon4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.

Quantitative MR imaging R2 relaxometry in elderly participants reporting memory loss.

BACKGROUND AND PURPOSE: In Alzheimer disease (AD), elevated brain iron concentrations in gray matter suggest a disruption in iron homeostasis, while demyelination processes in white matter increase the water content. Our aim was to assess whether the transverse proton relaxation rate, or R2, an MR imaging parameter affected by changes in brain iron concentration and water content, was different in elderly participants with mild to severe levels of cognitive impairment compared with healthy controls. METHODS: Twelve elderly participants reporting memory problems and 11 healthy volunteers underwent single-spin-echo MR imaging in a 1.5T scanner, with subsequent neuropsychological testing. R2 data were collected from 14 brain regions in cortical and subcortical gray and white matter. Those with memory complaints were separated into 2 further subgroups: MC1 (no objective cognitive impairment) and MC2 (mild to severe objective cognitive impairment). RESULTS: Mean brain R2 values from the 11 controls correlated strongly (r = 0.94, P < .0001) with reference brain iron concentrations for healthy adults. R2 values in the MC1 and MC2 subgroups were significantly higher in the right temporal cortex and significantly lower in the left internal capsule, compared with healthy controls. R2 values in the MC2 subgroup were significantly lower in the left temporal and frontal white matter, compared with healthy controls. CONCLUSIONS: R2 differences between both subgroups and the healthy controls suggest iron has increased in the temporal cortex, and myelin has been lost from several white matter regions in those with memory complaints, consistent with incipient AD pathogenesis and biochemical data.

Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4.

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an epsilon4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 +/- 6.34); ERT non-users (n = 80, mean age 67.03 +/- 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE epsilon4 allele. APOEepsilon4 carriers receiving ERT performed no better on episodic memory testing than APOE epsilon4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE epsilon4 allele.

Glucose facilitation of cognitive performance in healthy young adults: examination of the influence of fast-duration, time of day and pre-consumption plasma glucose levels.

RATIONALE: Previous investigations have demonstrated increased performance after the administration of a glucose-load on certain aspects of cognitive functioning in healthy young adults. Generally these studies have used a procedure where participants were tested in the morning after an overnight fast. OBJECTIVE: The aim of the present study was, for the first time, to investigate the glucose cognitive facilitation effect under more natural testing times and with shorter duration of the previous fast. METHODS: Measures of verbal and non-verbal memory performance were compared under different fasting intervals (2-h fast versus overnight fast), times (morning versus afternoon) and glycaemic conditions (glucose versus aspartame drinks) in healthy young participants. RESULTS: There was a significant glucose facilitation effect on long-term verbal memory performance. In addition, glucose significantly enhanced long-term spatial memory performance. The effect of glucose was essentially equivalent whether it was given after an overnight fast or a 2-h fast following breakfast or lunch. There was no effect of drink and time of day on working memory performance. CONCLUSIONS: The results of this study further support the hypothesis that glucose administration can enhance certain aspects of memory performance in healthy young adults. More significantly, the findings indicate that this cognitive facilitation effect persists under more naturalistic conditions of glucose administration and is not restricted to long fast durations or morning administration.

Selective attention in Alzheimer's disease.

This chapter presents a review of selective attention functioning in Alzheimer's disease (AD). The primary focus is on work conducted into this complex topic within the author and colleagues' laboratories (i.e. studies of simple and conjoined visual search). Findings obtained by the author and colleagues investigating simple and conjoined feature visual search in AD are related to findings obtained in the same laboratories in the healthy elderly and in patients with Parkinson's disease. Selective attention is a complex, multifactorial entity. Impairment of selective attention may be an early feature of AD and a prominent clinical characteristic of some patients. However, there are currently few reliable clinical measures of attentional dysfunction in AD. The experimental literature implicates some aspects of selective attention more reliably in AD than others. With respect to our own empirical studies, more effortful or controlled aspects of selective attention (as characterized by conjoined feature visual search) are impaired in AD. Furthermore, on the basis of our experimental observations, these aspects of selective attention appear to be disproportionately impaired relative to deficits in other cognitive domains that have previously been reported in the AD literature. By contrast, conjoined feature visual search deficits were not observed in our studies in patients with Parkinson's disease. The selective attention deficits that we have noted in AD patients represent an extension of the types of impairments that we have also observed in healthy aging; that is, compared with the healthy elderly, AD patients were quantitatively but not qualitatively more impaired on conjoined feature visual search. This is an important observation. The ways in which these findings relate to the wider AD selective attention literature are also considered, drawing out several common theoretical strands across a range of empirical studies.

Slowing of reaction time in Parkinson's disease: the involvement of the frontal lobes.

This study investigated the possibility that the previously mixed findings relating to cognitive deficits in Parkinson's disease might be attributable to inhomogeneity within the patients sampled, with attentional deficits occurring only for those Parkinson's patients who also have additional frontal lobe impairment. Twenty-five patients with idiopathic Parkinson's disease were classified as showing frontal dysfunction, or not, on the basis of their performance on the Wisconsin Card Sorting Test and the picture arrangement subtest of the WAIS. The two groups, and a control group of normal elderly subjects matched for age and IQ, undertook tests of visual attention designed to dissociate baseline response speed from central information processing speed. Error rates did not differ between the groups. Performance of the non-frontally impaired Parkinson's group was indistinguishable from that of the controls. By contrast, the 'frontally impaired' Parkinson's group responded significantly more slowly than the controls. Further analyses indicated that for the frontally-impaired Parkinson's group, information processing and automatic functions were unimpaired but there was a generalised slowing (as reflected by increased baseline response time) which may represent a non-specific global cognitive impairment. These findings suggest that the frontal lobes may be implicated in slowed response speed in Parkinson's disease.

Visual attention deficits in Alzheimer's disease: simple versus conjoined feature search.

The authors investigated selective attention in patients with Alzheimer's disease (AD), using a well-known visual search procedure. In simple feature search, the deficit observed in AD patients represented a baseline shift in the median hit reaction time (RT). On the conjoined feature search task, the median hit RT for AD patients increased disproportionately with increasing array size, indicating an additional cognitive impairment on this task. Of particular importance, the cognitive deficit observed in conjunction search was more profound than that predicted on the basis of previous reports of global cognitive slowing in AD. There was some evidence that the performance of AD patients improved more than the performance of controls over the duration of the experimental test session. Patients also had more difficulty in detecting targets on the right side of hemispace and in more peripheral locations.

The hippocampus and delayed recall: bigger is not necessarily better?

Healthy young female participants were tested on a measure of delayed verbal recall and then received volumetric Magnetic Resonance Imaging (MRI) scans. The analysis of the MRI scans focused on the volume of the hippocampus. Left hippocampal volume was negatively associated with the level of delayed verbal recall performance. This relationship was confirmed in further testing. This finding is consistent with a previous report of a similar relationship in healthy elderly individuals, but not in patients with Alzheimer's disease, in whom the opposite relationship was observed. An explanation of these findings in terms of impaired neural pruning of the hippocampus is advanced, whereby insufficient pruning of the hippocampus during childhood and adolescence (following adequate growth) may lead to reduced mnemonic efficiency.

Memory impairments associated with hippocampal versus parahippocampal-gyrus atrophy: an MR volumetry study in Alzheimer's disease.

Delayed memory impairments and medial temporal-lobe atrophy are considered to be cardinal features of Alzheimer's disease (AD). The goal of the present magnetic resonance (MR) volumetry study was to investigate the relationship between both features. We determined MR-derived estimates of hippocampal and parahippocampal volume in a sample of 27 AD patients and in a group of 26 healthy control subjects (NCs) of comparable age and education. We examined the performance of the two groups on immediate and delayed recall trials of an auditory-verbal list-learning task (CVLT), a visual non-verbal memory task (Visual Reproduction of the WMS-R), and a screening procedure that provides an estimate of overall cognitive functioning (DRS). Volumes of the hippocampus and the parahippocampal gyrus were significantly smaller in AD patients than in NCs. AD patients were impaired in their overall level of cognitive functioning and showed memory deficits under immediate and delayed recall conditions. The association between medial temporal-lobe atrophy and cognitive impairments in AD was found to be highly specific: Hippocampal volume correlated positively with delayed but not immediate recall of the verbal auditory list learning task. In contrast, parahippocampal gyrus volume, specifically in the right hemisphere, was positively related to delayed but not immediate recall of the non-verbal visual memory task. In NCs, there was a trend towards a negative association between hippocampal volumes and delayed verbal recall. Our results suggest that hippocampal and parahippocampal gyrus atrophy in AD are related to distinct aspects of the patients' memory impairments. Our findings have implications for current discussions regarding contributions of the hippocampus and the parahippocampal gyrus to memory in the intact human brain.

Glucose and memory: fractionation of enhancement effects?

Recent research findings indicate that glucose administration enhances some aspects of cognitive functioning. To date, those studies which have investigated the effects of glucose on memory in human participants have concentrated on its apparent ability to attenuate memory impairment. Relatively little research has been done in humans investigating the effects of glucose on memory performance in young healthy participants in whom no memory deficits exist. Moreover, the work which has been conducted in this population has produced somewhat equivocal findings. In this study, after overnight fasting the influence of a 25 g oral dosage of glucose on a range of measures of memory performance was investigated in healthy young female participants. Two control treatments (saccharin and water) were also administered. There was a significant glucose facilitation effect upon performance of long-term verbal free and cued recall tasks which did not vary with test delay. Performance on these free and cued verbal recall measures correlated significantly with blood glucose levels across all participants. No glucose-related facilitation was observed on either a test of short-term verbal memory (forwards/backwards digit recall) or a test of long-term non-verbal memory (complex figure reproduction). However, the significant glucose-related effects observed with long-term free and cued recall remained after controlling for participants' differential baseline blood glucose levels and individual levels of immediate memory performance. Therefore, memory improvement after glucose ingestion was not merely a consequence of lower baseline blood glucose or lower immediate memory performance in the glucose treatment group. These findings indicate that there may be some fractionation in the memory facilitation effects of glucose: the memory enhancing effect of glucose administration in healthy young adults may be greatest on tests of long-term verbal recall. The results suggest that glucose may enhance retention in and/or retrieval from long-term verbal memory.

Hippocampal aspiration lesions fail to impair performance of a delayed alternation GO/NO-GO task.

Rats with hippocampal aspiration lesions (HIPP), cortical control lesions (CORT) or sham operations (SHAM) were trained on a delayed alternation GO/NO-GO task, in which responding was reinforced on odd-numbered GO trials but was not reinforced on even-numbered NO-GO trials. The number of responses required to obtain reinforcement, and the length of the inter-trial intervals (ITIs), were varied in different stages of the experiment. These systematic parametric manipulations were conducted in order to compare the roles of intra- and inter-trial information and the temporal spans which could be bridged in performing the task across the three different lesion groups. In addition, at a later stage of testing interference was introduced during the ITI to investigate its effect on task performance. The differences observed between the HIPP, CORT and SHAM groups were generally non-specific for trial type, with HIPP animals responding more overall on both NO-GO and, to a lesser extent, GO trials following each of the ITIs used. The results were consistent with the behavioural inhibition theory of hippocampal function, but not with the temporal discontiguity or working memory models. These surprising findings contrast sharply with those observed following an electrolytic lesion of the hippocampus, which has been reported to produce a delay-dependent impairment of performance on the GO/NO-GO task in rats using a very similar procedure. It is speculated that differences in performance following aspiration and electrolytic lesions may be at least partially attributable to rats adopting different response strategies induced by ITI differences in the two tasks. However, the results also raise an important question concerning the assumed equivalence of aspiration and electrolytic lesions of the hippocampus. The possibility that an interaction between procedural and lesion differences may contribute to the discrepant findings is also considered. The findings illustrate the sensitivity of the hippocampal mnemonic effect on what has become an established testing procedure in the hippocampal literature.

Comparison of in vitro activity of quinolone antibiotics and vancomycin against gentamicin- and methicillin-resistant Staphylococcus aureus by time-kill kinetic studies.

Quinolone antibiotics have been proposed as possible alternatives to vancomycin for methicillin-resistant Staphylococcus aureus infections. We investigated the activities of amifloxacin, ciprofloxacin, norfloxacin, and vancomycin by time-kill kinetic studies. Antibiotic concentrations of 0, 1.0, and 4.0 times the MIC were used against four strains of gentamicin- and methicillin-resistant S. aureus. Staphylococci were plated onto ciprofloxacin-containing agar at all time points, in repeat time-kill kinetic studies. Macrobroth dilution MICs and MBCs were determined. Ciprofloxacin levels were measured by bioassay. Replica plating was performed from the original susceptible inoculum (MIC, 0.125 micrograms/ml) onto ciprofloxacin-supplemented agar. At 4.0 times the MIC, only with ciprofloxacin was there regrowth at 24 and 48 h. All four strains of staphylococci grew on agar supplemented with 1 microgram of ciprofloxacin per ml; three of four grew on agar supplemented with 2 micrograms of ciprofloxacin per ml. MICs and MBCs for these resistant clones ranged from 8 to 32 micrograms/ml. No degradation in activity or amount of ciprofloxacin could be detected in the bioassay. Replica-plated staphylococci grew on agar containing 1 microgram/ml but not higher concentrations of ciprofloxacin at 48 h. Amifloxacin and norfloxacin sustained bactericidal activity comparable to that of vancomycin. We conclude that heteroresistant subpopulations of gentamicin- and methicillin-resistant S. aureus can emerge under antibiotic selection pressure. Such resistant clones may then mutate in the presence of subinhibitory concentrations of antibiotic to higher levels of ciprofloxacin resistance.