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A strong perception exists that elderly people are at risk for persistent cognitive deterioration lasting longer than six months following major surgery, particularly heart surgery. Furthermore, based on laboratory evidence, investigators hypothesize that surgery or anesthesia might precipitate incident dementia. Recent clinical studies have found that cognition might frequently be impaired within the first few months postoperatively, and that such impairment may be associated with death or debility. Unsurprisingly, the specter of cognitive decline or dementia following surgery is a source of consternation to elderly people and their families. However, there are methodological concerns relating to the investigation of postoperative cognitive decline. Studies have been hampered by lack of standard diagnostic criteria for cognitive decline, by the use of statistical rather than clinical definitions, by poorly matched controls or even the absence of controls, and by inadequate detection of preexisting mild dementia. For these reasons, there are ongoing controversies surrounding the time course, the severity, and even the clinical relevance of persistent postoperative cognitive deterioration. There is evidence that most patients recover cognition in the long-term, and that for those who experience persistent decline, this is probably attributable to underlying undiagnosed neurological disease or other co-morbidities rather than to surgery or to anesthesia. There is currently minimal clinical evidence linking surgery or anesthesia to incident dementia. Rigorous clinical research is needed to resolve the controversy whether anesthesia or surgery is likely to cause persistent neurological decline or to precipitate dementia. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a degenerative disorder characterized by a decreased regional cerebral blood flow (CBF). It is most likely that a reduction in CBF could displace a pathway leading to AD genesis, in so far neuron death explains a sustained reduction in the supply of oxygen, glucose, and nutrients. Nevertheless, the concept of secondary CBF deficiency cannot explain the critical stages of early memory loss while, on the other hand, the picture of progressive ischemia due to primary CBF decline sheds light on the course of AD in a most persuasive manner. The concept of primary CBF deficiency is even more strengthened by the lack of correlation between degree of dementia and amount of CBF. Vascular abnormalities, frequently observed to co-occur with AD, might play a critical role in the initiation and aggravation of AD pathology given that the elimination of amyloid-β (Aβ) through a vascular route is an important brain Aβ clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. The goal of this review is to provide scientists comprehensive knowledge of the state-of the art influence vascular damage and reduced perfusion have on the final development of AD and to hopefully stimulate more research in this area of neuroscience. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that general anesthesia may initiate or accelerate cognitive impairment and Alzheimer's disease (AD). To understand the possible underlying mechanisms, several studies have been carried out in animal models. In this review, we first briefly discuss the mechanisms leading to neurodegeneration and cognitive impairment in AD, with an emphasis on tau abnormalities in this pathological process. Subsequently, we review the role of anesthesia in inducing tau abnormalities and the possible mechanisms. Recent studies suggest that anesthesia may accelerate the development of AD by promoting abnormal hyperphosphorylation of tau. Further studies are certainly needed to understand the molecular mechanism by which anesthesia may initiate or accelerate cognitive impairment and AD. An understanding of the mechanism will help develop strategies for preventing or eliminating this adverse effect of anesthesia. [ABSTRACT FROM AUTHOR]

Cerebrovascular hypoperfusion occurs prior to the clinical symptoms of Alzheimer's disease (AD) and represents the most accurate indicator predicting whether an individual develops AD at a future time. To study how cerebrovascular hypoperfusion contributes to AD, we induced cerebrovascular hypoperfusion by bilateral carotid occlusion surgery in adult rats and investigated its impacts on spatial memory, synapses, and accumulation of oligomeric amyloid-β. We found progressive spatial memory deficits, as tested by Morris water maze, starting 30 days after occlusion surgery. The memory deficits were accompanied with decrease in synaptic density and alterations of synaptic ultrastructure in the CA1 area of the hippocampus, as evaluated by electron microscopy. By using immunoelectron microscopy, we also found time-dependent accumulation of oligomeric amyloid-β in the hippocampus, especially in the axonal terminals after chronic cerebrovascular hypoperfusion. Western blot analysis revealed decreased levels of postsynaptic density-95 (PSD-95) and synaptophysin in rat brains after chronic cerebrovascular hypoperfusion. Our findings provide novel insight into the mechanism by which chronic cerebrovascular hypoperfusion contributes to the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

There is a great interest in the environmental and genetic factors which modify the risk of Alzheimer's disease since the manipulation of these factors could help to change the prevalence and natural course of this disease. Among the first group, anesthesia and surgery have been considered as risk enhancers, based mostly on "in vitro" experiments and epidemiological studies. We have investigated the effects of repetitive anesthesia, twice a week, for 3 months, from 7 to 10 months of age, with isoflurane on survival, behavior, apoptosis in hippocampal cells, amyloid-β (Aβ) peptide and tau patterns, chaperones and autophagy in WT and AβPP{swe} mice. We have found that AβPP{swe} mice treated with isoflurane have increased mortality, less responsiveness after anesthesia, long lasting reduced exploratory behavior, increased number of TUNEL{+} apoptotic cells, and increased ratio of pro-apoptotic proteins in hippocampus, reduced astroglial and increased microglial responses, increased Aβ aggregates and high molecular weight peptides, abnormal chaperone responses and reduced autophagy. These effects were not present in WT mice, suggesting that the deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with increased susceptibility but does not affect normal subjects. [ABSTRACT FROM AUTHOR]

We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-β polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on paired helical filaments from brains of AD patients and surface plasmon resonance studies confirm these findings. The capacity of these drugs to penetrate the blood-brain barrier was evaluated: i) in vitro by parallel artificial membrane permeability assay followed by experimental Log P determinations; and ii) in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain of mice using HPLC/UV. Importantly, our studies indicate that the brain/blood concentration ratios for these compounds were suitable for their use as PET radiotracers. Since neurofibrillary tangles are positively correlated with cognitive impairment, we concluded that LNS and AST have a great potential in PET neuroimaing for in vivo early detection of AD and in reducing the formation of neurofibrillary tangles. [ABSTRACT FROM AUTHOR]

The occurrence of neuropsychiatric symptoms in patients with Alzheimer's disease hampers the clinical management and exacerbates the burden for caregivers. To what extent psychotic symptoms are genetically determined and which are the genes involved has to be established. We tested the hypothesis that the occurrence of delusions and hallucinations in AD is associated with variations in the G72/DAOA gene, which is supposed to play a key role in the glutamate pathway regulated through the NMDA receptors. A panel of single nucleotide polymorphisms were genotyped in a cohort of 185 Alzheimer's disease patients. The analysis demonstrated a nominally significant association (p< 0.05) with one single nucleotide polymorphism (rs2153674). In addition, multivariate regression showed that the rs2153674 genotype accounts for up to 15% of the variance in delusions severity, as assessed by using the Neuropsychiatric Inventory. If the results from the present study will be replicated, the glutamate hypothesis could be invoked to explain the occurrence of psychosis in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The processes underlying the pathogenesis of Alzheimer's disease involve several factors including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. This review is mainly devoted to discuss evidence supporting the notion that mitochondrial dysfunction and oxidative stress are interconnected and intimately associated with the development and progression of Alzheimer's disease. Furthermore, the review explores the role of insulin signaling in the pathophysiology of the disease. Indeed, several studies have begun to find links between insulin and mechanisms with clear pathogenic implications for this disorder. Understanding the key mechanisms involved in the etiopathogenesis of Alzheimer's disease may provide opportunities for the design of efficacious preventive and therapeutic strategies. [ABSTRACT FROM AUTHOR]

The authors comment on studies indicating a possible link between anesthetics and cognitive deficits, meeting clinical criteria of amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD). One study found an association between early-life exposure to anesthesia and an earlier onset of AD. Conducting comprehensive research to review anesthesia protocols is recommended to help limit the impact of anesthesia on patients with, or at risk of AD.

The article discusses various reports published within the issue, including one on long-term postoperative cognitive dysfunction in older people, and another on incidence of postoperative cognitive dysfunction.