A rule-based categorization deficit in Alzheimer's disease?

This study examined the categorization processes that Alzheimer's disease (AD) patients use during assessments of semantic memory. Rule-based categorization involves the careful, analytic processing of strict criteria to determine category membership, particularly for items from graded categories with ambiguous category membership; similarity-based categorization requires an overall comparison of a test stimulus with a prototype or remembered exemplar of the category and is relatively effective for the rapid categorization of items with unambiguous category membership. To assess these processes in AD, patients were asked to decide the category membership of test stimuli for categories with poorly defined or fuzzy boundaries (e.g., VEGETABLE) and for categories with well-defined boundaries (e.g., FEMALE) and then to judge the representativeness of the test stimulus for its chosen category. A subgroup of AD patients demonstrated a typical pattern of impaired semantic memory compared to healthy control subjects; that is, difficulty deciding the category membership of test items from fuzzy categories. Among these patients, we found no deficit in category membership decisions about items taken from well-defined categories. We also found that AD patients and healthy controls do not differ in their representativeness judgments of items within a correctly judged category. These findings are most consistent with the hypothesis that rule-based categorization difficulty limits semantic memory in AD.     

Lifespan brain activity, β-amyloid, and Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of progressive cognitive decline and dementia in adults. While the amyloid cascade hypothesis of AD posits an initiating role for the β-amyloid (Aβ) protein, there is limited understanding of why Aβ is deposited. A growing body of evidence based on in vitro, animal studies and human imaging work suggests that synaptic activity increases Aβ, which is deposited preferentially in multimodal brain regions that show continuous levels of heightened activation and plasticity across the lifespan. Imaging studies of people with genetic predispositions to AD are consistent with these findings, suggesting a mechanism whereby neural efficiency or cognitive reserve may diminish Aβ deposition. The aggregated findings unify observations from cellular and molecular studies with human cognitive neuroscience to reveal potential mechanisms of AD development.     

Inflated and contradictory category naming deficits in Alzheimer's disease?

Although some studies have documented category-specific deficits in patients with Alzheimer's disease, others have not. One possible reason is that where control groups have been used in previous studies, they have performed at ceiling; and this may spuriously affect the incidence and type of deficit reported (especially with common statistical techniques such as z-scores). We examined this issue in 18 Alzheimer's patients and 26 elderly controls, who named two picture sets: a simple set that typically produces ceiling effects (Set 1) and one that produces a normal distribution in controls (Set 2). Sets 1 and 2 produced inconsistent and even contradictory deficits in the same patients. The results also show that ceiling effects may inflate the number of living thing deficits and hence, distort the reported ratio of living to nonliving cases.     

Heterogeneity in verbal memory: a marker of preclinical Alzheimer's disease?

Demonstrations of memory changes in those at risk for Alzheimer's disease by the presence of the APOE e4 allele have been inconsistent to date. The present study went beyond traditional analyses of central tendency (i.e., group differences on mean test scores) and also conducted distribution analyses to search for subtle cognitive differences in subgroups of normal-functioning elderly persons with the APOE e4 genotype. The results of the study revealed that (a) the e4 and non-e4 groups failed to differ in terms of their mean scores on tests of memory and verbal skills; and (b) relative to the non-e4 group, the e4 subjects had significantly greater heterogeneity of variance on the memory measures but not on fundamental verbal skills. Logistic regression analyses indicated that the discrepancy in scores on the memory measures was a significant predictor of genotype group membership (82% correct classification rate). Implications of these findings for the detection of a preclinical phase of AD are discussed.     

Metabolic syndrome and Alzheimer's disease: a link to a vascular hypothesis?

Current evidence from epidemiological, neuroimaging, pathological, pharmacotherapeutic, and clinical studies indicate an association of Alzheimer's disease with risk factors of vascular atherosclerotic disease either in isolation or in aggregate. "Metabolic syndrome" (MetS) is the name for a clustering of risk factors for cardiovascular disease and type 2 diabetes that are of metabolic origin. These include central obesity, elevated plasma glucose, high blood pressure, atherogenic dyslipidemia, a prothrombotic state, and a proinflammatory state. In this article, we provide an overview of the relevant literature with regard to the relationship of Alzheimer's disease with MetS. Accumulating evidence suggests a "vascular hypothesis" to be related to the pathology of Alzheimer's disease. In the light of this evidence, clinician may consider lifestyle interventions toward an early and effective cardiovascular risk-factor management to reduce the cardiometabolic and the cognitive decline risk, while further research of other preventive strategies may be warranted.     

The cholinergic lesion of Alzheimer's disease: pivotal factor or side show?

A profound loss of cortical cholinergic innervation is a nearly invariant feature of advanced Alzheimer's disease (AD). The temporal course of this lesion and its relationship to other aspects of the disease have not yet been fully clarified. Despite assertions to the contrary, a review of the evidence suggests that a perturbation of cholinergic innervation is likely to be present even in the very early stages of AD. This cholinergic lesion is unlikely to be a major determinant of the clinical symptoms or of the neuropathological lesions. Nonetheless, it almost certainly contributes to the severity of the cognitive and behavioral deficits, especially in the areas of memory and attention. The cholinergic lesion may also influence the progression of the neuropathological process through complex interactions with amyloidogenesis, tau phosphorylation and neuroplasticity.     

Do behavioral disturbances in persons with Alzheimer's disease predict caregiver depression over time?

Random effects models were used to examine the association between behavioral disturbances in persons with Alzheimer's disease (N = 90) and caregiver depressive symptoms at 2-month intervals over an 18-month period. There was substantial variability in trajectories of change in caregiver depressive symptoms over time but no systematic increase in distress despite increased severity of dementia symptoms. Total behavioral disturbances were associated with higher levels of caregiver depressive symptoms: this effect was primarily attributable to aggressive behaviors. No consistent departure from linearity was evident in the relationship between behavior and depression over time.     

The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease

Alzheimer's disease (AD) is the 3rd most costly disease and the leading cause of dementia. It can linger for many years, but ultimately is fatal, the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD.     

Memory profiling in mild cognitive impairment: Can we determine risk for Alzheimer's disease?

Mild cognitive impairment (MCI) is considered a transitional stage between normal ageing and Alzheimer's disease (AD), but not all MCI cases progress to AD and there has been limited focus on how to identify who will progress. Given claims for a characteristic kind of memory impairment in AD involving deficits in encoding and consolidation of information, we propose that ‘memory profiling’ of individuals with MCI may help identify which individuals will progress. We initially set out to establish whether the same characteristic memory profile was present prior to the onset of AD (preAD). Very few studies provided data that allowed us to examine this, but results tentatively supported an encoding/consolidation profile in preAD. A single study tested the clinically important contrast of preAD versus non‐preAD MCI cases and found no difference under any condition or in memory profiles, but interpretation of the findings is limited by short duration of follow‐up, ceiling effects, and task limitations in assessing more complex and qualitative aspects of memory. Although existing data lead to equivocal conclusions, we believe that memory profiling is an endeavour worth pursuing, particularly given the increasing number of people with MCI presenting for clinical assessment. We propose that tests designed specifically to measure memory processes should be sensitive to preAD and are required in prospective longitudinal designs to identify these clinically crucial MCI cases.     

Discourse about discourse: what is it and how does it progress in Alzheimer's disease?

Discourse about discourse or a subject's comments about his/her performance during a discourse task can be defined as modalizing discourse (discours modalisateur; [Nespoulous, 1980]; [Nespoulous et al., 1998]). Since it does not convey the expected content of the discourse task (referential discourse), modalizing discourse has often been considered non-informative, and as such, has received little interest. The present study investigated the modalizing aspect of discourse production and its evolution in Alzheimer's disease (AD). Five AD patients produced a picture-induced narrative across five consecutive assessments. Two measures were derived: the modalizing/referential ratio (M/R ratio) and the percentage of repeated ideas. Results revealed that, compared to a group of 27 normal controls matched for age and education, AD patients: (1) obtained higher M/R ratios that tended to diminish as the number of assessments increased, and (2) produced higher percentages of repeated ideas throughout all assessments. These results suggest that modalizing discourse makes up a large proportion of AD patients' discourse and should be included in further studies to accurately describe their discourse behavior. The implications of modalizing discourse on preserved pragmatic abilities and its inclusion in comprehensive management programs of AD patients are discussed.     

Does physical activity reduce risk for Alzheimer's disease through interaction with the stress neuroendocrine system?

Lack of physical activity (PA) is a risk factor for Alzheimer's disease (AD), and PA interventions are believed to provide an effective non-pharmacological approach for attenuating the symptoms of this disease. However, the mechanism of action of these positive effects is currently unknown. It is possible that the benefits may be at least partially mediated by the effects on the neuroendocrine stress system. Chronic stress can lead to dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, leading to aberrant basal and circadian patterns of cortisol secretion and a cascade of negative downstream events. These factors have been linked not only to reduced cognitive function but also increased levels of amyloid-β plaques and protein tau "tangles" (the neuropathological hallmarks of AD) in the non-demented mouse models of this disease. However, there is evidence that PA can have restorative effects on the stress neuroendocrine system and related risk factors relevant to AD. We explore the possibility that PA can positively impact upon AD by restoring normative HPA axis function, with consequent downstream effects upon underlying neuropathology and associated cognitive function. We conclude with suggestions for future research to test this hypothesis in patients with AD.     

Are clinical diagnoses of Alzheimer's disease and other dementias affected by education and self-reported race?

A randomized controlled trial examined whether the diagnostic process for Alzheimer's disease and other dementias may be influenced by knowledge of the patient's education and/or self-reported race. Four conditions were implemented: diagnostic team knows (a) race and education, (b) education only, (c) race only, or (d) neither. Diagnosis and clinical staging was established at baseline, at Wave 2, and for a random sample of Wave 3 respondents by a consensus panel. At study end, a longitudinal, "gold standard" diagnosis was made for patients with follow-up data (71%). Group differences in Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) diagnosis were estimated using logistic regression and generalized estimating equations. Sensitivity and specificity were examined for baseline diagnosis in relation to the gold standard, longitudinal diagnosis. Despite equivalent status on all measured variables across waves, members of the "knows race only" group were less likely than those of other groups to receive a diagnosis of dementia. At final diagnosis, 19% of the "knows race only" group was diagnosed with dementia versus 38% to 40% in the other 3 conditions (p = .038). Examination of sensitivities and specificities of baseline diagnosis in relation to the gold standard diagnosis showed a nonsignificant trend for lower sensitivities in the knowing race conditions (0.3846), as contrasted with knowing education only (0.480) or neither (0.600). The finding that knowledge of race may influence the diagnostic process in some unknown way is timely, given the recent State-of-the-Science conference on Alzheimer's disease prevention, the authors of which called for information about and standardization of the diagnostic process. (PsycINFO Database Record (c) 2012 APA, all rights reserved).     

Can cognitive and behavioural disorders differentiate frontal variant-frontotemporal dementia from Alzheimer's disease at early stages?

Frontal variant-Frontotemporal dementia (fvFTD) and Alzheimer's disease (AD) patients matched for severity of dementia at the Clinical Dementia Rating (CDR) received neuropsychological testing in order to explore if the dysexecutive disorder might characterise fvFTD at early stage, when AD is dominated by the episodic memory defect. We also determined if the behavioural syndrome was more severe in fvFTD than AD, and if specific patterns of behavioural symptoms could differentiate the two types of dementia, using the Neuropsychiatry Inventory (NPI). AD patients performed worse than fvFTD not only in memory but also in executive tasks. Apathy and eating disorders proved to be more severe or frequent in fvFTD even if the two groups did not differ in the total NPI score. CDR score significantly correlated with the NPI score in fvFTD and with the MMSE in AD. Our data confirm that the memory disorders may differentiate the two types of dementia; however, the dysexecutive syndrome is as severe, and even more severe in AD. The severity of the behavioural syndrome is comparable in the two groups but the nature of the behavioural disorders may vary to some extent. We conclude that AD dementia at early stage is a behavioural-cognitive syndrome, while in fvFTD the behavioural disorders appear when the cognitive deficit is still relatively mild.     

The variability of practice hypothesis in motor learning: does it apply to Alzheimer's disease?

Based on Schmidt's (1975) variability of practice hypothesis, this study examined acquisition and transfer of a gross motor skill, namely tossing, in 58 patients with Alzheimer's disease (AD) and 58 healthy older adults under constant, blocked, and random practice conditions. While healthy older adults were able to learn the tossing task equally well under the three practice conditions, only AD patients receiving constant practice showed significant improvements. Tests of intermediate transfer yielded the expected random practice advantage in healthy controls but not AD patients. None of the practice conditions facilitated intermediate transfer in AD patients; however, constant practice did benefit these impaired individuals on tests of near transfer. These results indicate that the variability of practice hypothesis does not extend to AD patients. As motor learning and transfer were clearly a function of constant practice, future attempts to retrain basic activities of daily living in AD patients should emphasize consistency in training.     

Do adapted vignettes improve medical decision‐making capacity for individuals with Alzheimer's disease?

Medical decision‐making capacity (MDC) is known to decline in individuals with Alzheimer's disease (AD). The vignette method uses hypothetical information as a prerequisite for measuring the capacity to make well‐informed decisions to clinical trials. Our aim was to investigate if adapted vignettes can help individuals with mild AD to assimilate information, make decisions and express them in an understandable way, compared to corresponding decisions based on linguistically more demanding vignettes, as measured by the Swedish Linguistic Instrument for Medical Decision‐making (LIMD). Two vignettes from LIMD were altered linguistically with the aim to facilitate understanding for individuals with AD. An experimental within‐subject design was used to study the influence on MDC of readability (original/adapted vignettes) and content (two different clinical trials). We included 24 patients with mild AD in this prospective study, which read all four vignettes along with a few other tests. This allowed us to investigate the association between MDC and cognitive function. Adapted vignettes did not yield significant differences regarding MDC as compared with original vignettes using a two‐way repeated measures analysis of variance. A difference was found between the two clinical trials where LIMD score was significantly higher for Kidney disease than hypertension vignettes. Our results indicate that adapted vignettes may not improve MDC for individuals with mild AD. MDC was affected by which clinical trial the vignettes regarded, which implies that other factors affecting MDC need to be investigated, like length of text and vocabulary used.     

Tool use in left brain damage and Alzheimer's disease: What about function and manipulation knowledge?

Tool use disorders are usually associated with difficulties in retrieving function and manipulation knowledge. Here, we investigate tool use (Real Tool Use, RTU), function (Functional Association, FA) and manipulation knowledge (Gesture Recognition, GR) in 17 left‐brain‐damaged (LBD) patients and 14 AD patients (Alzheimer disease). LBD group exhibited predicted deficit on RTU but not on FA and GR while AD patients showed deficits on GR and FA with preserved tool use skills. These findings question the role played by function and manipulation knowledge in actual tool use.     

Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer's disease

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by increased β-amyloid (Aβ) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10mg/kg) on learning and memory impairments was assessed in intrahippocampal Aβ(1-40)-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of Aβ-lesioned rats. The Aβ-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of Aβ-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates Aβ-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress.