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Alzheimer's Disease Reviews: 2004

(331 References)

(2004). "Estrogen and progestogen therapy in postmenopausal women." Fertil Steril 81(1): 231-41.

Abe, K. (2004). "[Possibility of gene and restorative therapies for dementia]." Nippon Rinsho 62 Suppl 4: 229-33.

Agorogiannis, E. I., G. I. Agorogiannis, et al. (2004). "Protein misfolding in neurodegenerative diseases." Neuropathol Appl Neurobiol 30(3): 215-24.

            A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone-specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins.

Algotsson, A. and B. Winblad (2004). "Patients with Alzheimer's disease may be particularly susceptible to adverse effects of statins." Dement Geriatr Cogn Disord 17(3): 109-16.

            In epidemiological, cross-sectional studies, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) prevented to a large extent the development of Alzheimer's disease (AD), but the results of randomized, placebo-controlled studies, focused on statin therapy in patients with ischemic heart disease (IHD), are at variance. Nonetheless, data from epidemiological, longitudinal studies in humans as well as studies on transgenic mouse models and cultured neuronal cell lines indicate that cholesterol may contribute to the pathogenesis of AD. Statins have proven therapeutic and preventive effects in IHD and other vascular diseases in man. They generally are well tolerated, but some adverse effects, probably due to antiproliferative and proapoptotic properties of the statins, are matters of concern. AD patients may be extrasusceptible to adverse effects of statins due to preexisting aberrations in signal transduction and energy metabolism in the neurons and a perturbed cholesterol metabolism in the brain. This problem might be addressed in randomized, double-blind studies with statins in AD. The statins differ from each other in several aspects, and they are not considered to be therapeutically interchangeable. It could be fruitful to use both a placebo and two different types of statins, i.e. an essentially hydrophilic statin and a lipophilic statin, in a double-blinded fashion, and to compare the effects on the cognitive decline in AD.

Alonso, M. and A. Martinez (2004). "GSK-3 inhibitors: discoveries and developments." Curr Med Chem 11(6): 755-63.

            Glycogen synthase kinase 3 (GSK-3) in the 21(st) century emerged as one of the most attractive therapeutic target for the development of selective inhibitors as new promising drugs for unmet pathologies including Alzheimer's disease, stroke, bipolar disorders, chronic inflammatory processes, cancer and diabetes type II. The full potential of GSK-3 inhibitors is just starting to be realized but the number of candidates in development provided by both academic centres and pharmaceutical companies have increased exponentially in the last two years. This review discloses recent discoveries and developments on peptides and small molecules targeting GSK-3. Focusing attention on this exciting target could thus reap considerable clinical and economic rewards.

Alperovitch, A., M. Schwarzinger, et al. (2004). "[Towards a prevention of dementia?]." Rev Neurol (Paris) 160(2): 256-60.

            Many studies have shown that high blood pressure and, to a lesser extent, other vascular risk factors could be the target of interventions aiming to reduce the incidence of dementia. Two large controlled trials have demonstrated that blood pressure lowering drugs have a significant effect on the risk of dementia including Alzheimer's disease. On another hand, large epidemiological studies have shown associations between different vascular factors and dementia. Overall, these data suggest that interventions aiming to reduce the level of vascular risk factors might prevent dementia. The expected benefit of these interventions could be estimated from data provided by epidemiological studies, but large population-based controlled studies are needed to demonstrate the efficacy of preventive interventions.

Amieva, H., L. H. Phillips, et al. (2004). "Inhibitory functioning in Alzheimer's disease." Brain 127(Pt 5): 949-64.

            We present a comprehensive review of studies assessing inhibitory functioning in Alzheimer's disease. The objectives of this review are: (i) to establish whether Alzheimer's disease affects all inhibitory mechanisms equally, and (ii) where possible, to assess whether any effects of Alzheimer's disease on inhibition tasks might be caused by other cognitive deficits, such as slowed processing. We review inhibitory mechanisms considered to play a crucial role in various domains of cognition, such as inhibition involved in working memory, selective attention and shifting abilities, and the inhibition of motor and verbal responses. It was found that whilst most inhibitory mechanisms are affected by the disorder, some are relatively preserved, suggesting that inhibitory deficits in Alzheimer's disease may not be the result of a general inhibitory breakdown. In particular, the experimental results reviewed showed that Alzheimer's disease has a strong effect on tasks requiring controlled inhibition processes, such as the Stroop task. However, the presence of the disease appears to have relatively little effect on tasks requiring more automatic inhibition, such as the inhibition of return task. Thus, the distinction between automatic, reflexive inhibitory mechanisms and controlled inhibitory mechanisms may be critical when predicting the integrity of inhibitory mechanisms in Alzheimer's disease. Substantial effects of Alzheimer's disease on tasks such as negative priming, which are not cognitively complex but do require some degree of controlled inhibition, support this hypothesis. A meta-analytic review of seven studies on the Stroop paradigm revealed substantially larger effects of Alzheimer's disease on the inhibition condition relative to the baseline condition, suggesting that these deficits do not simply reflect general slowing.

Ando, K. (2004). "[Neuropsychopharmacological profile of nicotine]." Nihon Shinkei Seishin Yakurigaku Zasshi 24(2): 55-9.

            The reinforcing effects of nicotine have been investigated by intravenous self-administration methods using mice, rats, dogs, squirrel monkeys, rhesus monkeys, baboons, and humans. Based on accumulated data related to these effects, it is clear that subjects show moderate self-administration of nicotine with no marked manifestation in contrast to excessive self-administration of cocaine with hyperactivity and of morphine with withdrawal syndrome. The magnitude of reinforcing effects of nicotine was judged to be lower than that of cocaine and other abused drugs by the progressive ratio schedule method although persistent self-administration behavior for nicotine was maintained under the second-order schedule with conditioned stimulus in monkeys. The brain mechanism producing the reinforcing effects of nicotine is considered to involve nicotinic receptors at the nucleus accumbens, prefrontal cortex or other regions, as well as the mesolimbic dopaminergic system. It has been demonstrated by brain imaging techniques such as PET and fMRI that the relevant brain sites for producing craving for abused drugs such as cocaine include the amygdala, dorsolateral frontal cortex and anterior cingulated cortex. Further studies should elucidate the mechanism of craving for cigarettes by these imaging techniques. The actions of nicotine and its analogs have been studied for the purpose of developing therapeutic drugs for Alzheimer's disease, Parkinson's disease, Tourrette's syndrome and so on. Thus, studies on nicotine and its analogs with a wide variety of pharmacological profiles are interesting and important in the field of neuropsychopharmacology.

Ansari, R. R. (2004). "Ocular static and dynamic light scattering: a noninvasive diagnostic tool for eye research and clinical practice." J Biomed Opt 9(1): 22-37.

            The noninvasive techniques of static and dynamic light scattering are emerging as valuable diagnostic tools for the early detection of ocular and systemic diseases. These include corneal abnormalities, pigmentary dispersion syndrome, glaucoma, cataract, diabetic vitreopathy, and possibly macular degeneration. Systemic conditions such as diabetes and possibly Alzheimer's disease can potentially be detected early via ocular tissues. The current state of development of these techniques for application to ophthalmic research and ultimately clinical practice is reviewed.

Asada, T. (2004). "[Non-pharmacological therapy for Alzheimer's disease]." Nippon Rinsho 62 Suppl: 72-5.

Asanuma, M., I. Miyazaki, et al. (2004). "Neuroprotective effects of nonsteroidal anti-inflammatory drugs on neurodegenerative diseases." Curr Pharm Des 10(6): 695-700.

            It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, analgesic and antipyretic properties by inhibiting cyclooxygenase (COX), a prostaglandin-synthesizing enzyme. It has also been revealed that NSAIDs exert inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors which are related to inflammatory reactions including cytokine expression. Recently, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs, since it has been reported that inflammatory processes are associated with the pathogenesis of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In the experimental model of Parkinson's disease, NSAIDs have also exerted neuroprotective effects which are based not only on their COX-inhibiting effects but also on other properties: inhibitory effects on nitric oxide synthesis, action as agonists for peroxisome proliferator-activated receptor gamma, and some unknown pharmacological effects. In this article, various pharmacological effects of NSAIDs except their inhibitory action on COX are reviewed, and possible neuroprotective effects of NSAIDs have been discussed on neurodegenerative diseases, especially Parkinson's disease.

Ashford, J. W. (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology." J Mol Neurosci 23(3): 157-65.

            The risk of developing Alzheimer's disease (AD) is tied most closely to age and appears to follow Gompertzian kinetics. However, specific genetic factors are also linked closely to AD, and the apolipoprotein E (APOE) genotype accounts for as much of 50% of the attributable risk for AD in many populations. This paper reviews the onset, diagnosis, and epidemiology of AD, specifically with regard to the APOE genotype and the interaction of the genotype with age.

Avila, J., J. J. Lucas, et al. (2004). "Role of tau protein in both physiological and pathological conditions." Physiol Rev 84(2): 361-84.

            The morphology of a neuron is determined by its cytoskeletal scaffolding. Thus proteins that associate with the principal cytoskeletal components such as the microtubules have a strong influence on both the morphology and physiology of neurons. Tau is a microtubule-associated protein that stabilizes neuronal microtubules under normal physiological conditions. However, in certain pathological situations, tau protein may undergo modifications, mainly through phosphorylation, that can result in the generation of aberrant aggregates that are toxic to neurons. This process occurs in a number of neurological disorders collectively known as tauopathies, the most commonly recognized of which is Alzheimer's disease. The purpose of this review is to define the role of tau protein under normal physiological conditions and to highlight the role of the protein in different tauopathies.

Avila, C., M. A. Parcet, et al. (2004). "[Memory evaluation using functional magnetic resonance: applications in preoperative patients and in Alzheimer s disease]." Rev Neurol 38(3): 284-91.

            The assessment of memory functions related to medial temporal lobe has become one of the most important issues on current neuropsychology. On this communication, we review the results which our research group has achieved using two functional magnetic resonance Image procedures to assess memory function: Hometown walking task and an encoding/retrieval task using complex images. Nine patients with tumoural temporal lesions performed the hometown walking task. The results of these patients showed either a bilateral or contralesional representation of memory function. These results confirm those obtained by Jokeit, Okujava y Woermann (2001), and they seem to prove that this protocol is useful to determine the preservation of memory function in the non damaged hemisphere. On the other hand, the images encoding/retrieval task has been run by two groups of four patients diagnosed as Alzheimer disease and mild cognitive impairment, and another group of five patients who participated as a control group. According to our hypothesis, the results have shown a lower activation at the left parahippocampal gyrus in mild cognitive impairment and Alzheimer disease patients than controls, just as a lower bilateral activation in the same structure for the Alzheimer group than the control group. As a whole, our results show how important may become functional magnetic resonance image for neuropsychological assessment of memory, and as a diagnostic tool for CNS diseases.

Baghdasarian, S. B., H. Jneid, et al. (2004). "Association of dyslipidemia and effects of statins on nonmacrovascular diseases." Clin Ther 26(3): 337-51.

            BACKGROUND: Statins have mechanisms of action that expand their effects beyond cholesterol lowering and atherosclerotic medical conditions. OBJECTIVE: This review summarizes clinical evidence for the association of dyslipidemia and the effects of statin use on aortic stenosis, Alzheimer's dementia (AD), osteoporosis, prevention of diabetes mellitus (DM), diabetic retinopathy, age-related macular degeneration, and diabetic/nondiabetic nephropathy. METHODS: An English-language literature search was conducted using MEDLINE (1966-June 2003). Bibliographies of retrieved articles were reviewed. Search terms included statin, HMG-CoA reductase inhibitors, aortic stenosis, Alzheimer's dementia, osteoporosis, prevention of diabetis, diabetic retinopathy, age-related macular degeneration, diabetic nephropathy, and nondiabetic nephropathy. RESULTS: Three retrospective cohort trials have shown an association between statin use and the progression of aortic stenosis; one of these trials observed a 45% decrease in aortic valve area in 1 year. In AD, one cross-sectional analysis found 60% to 73% lower AD rates in lovastatin or pravastatin recipients ( P<0.001 ). Of the multiple observational studies on the effect of statins on fracture risk, some have shown a decreased risk, with an odds ratio as low as 0.50 (95% CI, 0.33-0.76); others have demonstrated no association. A post hoc analysis of the West of Scotland Coronary Prevention Study found a 30% reduction in the development of DM ( P=0.042 ), but this was not duplicated in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. A small clinical trial of 6 patients (11 eyes) demonstrated improved retinal hard exudates with pravastatin treatment in patients with diabetic retinopathy. In a cross-sectional analysis, age-related macular degeneration was found to be less common among statin users than nonusers (4% [ 1/27 ] vs 22% [ 76/352 ]; P=0.02. Multiple small clinical trials of 19 to 56 patients with diabetic and nondiabetic nephropathy at various stages generated inconsistent results for an association between statin use and decreased albumin excretion rate and decreased rate of decline in glomerular filtration. CONCLUSION: Data of variable quantity and quality support the use of statins as adjuncts in the treatment of nonmacrovascular diseases.

Balardy, L., P. J. Ousset, et al. (2004). "[Clinical aspects of dementia and specificity of Alzheimer's disease]." Soins(685): 30-5.

Ballard, C. G. (2004). "Definition and diagnosis of dementia with Lewy bodies." Dement Geriatr Cogn Disord 17 Suppl 1: 15-24.

            Significant advances have been made in neuropathologic identification procedures for dementia with Lewy bodies (DLB), but difficulties remain in clinical diagnosis. Consensus criteria state that the core features of DLB are fluctuating cognition with pronounced variation in attention and alertness, recurrent visual hallucinations and spontaneous motor features of parkinsonism. At least two of these features must be present for the diagnosis of probable DLB. Assessments of the validity of the consensus criteria against autopsy generally indicate high specificity but varying sensitivity. More detailed assessments of core diagnostic features or better operationalization, particularly of fluctuating cognition, may help improve the diagnostic guidelines. Greater utilization of some features described as supporting the diagnosis (such as auditory hallucinations) and the potential inclusion of additional symptoms (such as REM sleep behavioral disorder) also may be useful. In addition, the potential role of more detailed neuropsychology and neuroimaging in the diagnostic process needs to be evaluated, although it is important that changes to the diagnostic criteria are based on empirical evidence. Other key issues pertain to the classification of DLB patients with concurrent Alzheimer's disease and the differentiation of DLB and Parkinson's disease dementia based on less than a 1-year history of parkinsonism preceding the dementia.

Barnham, K. J., C. L. Masters, et al. (2004). "Neurodegenerative diseases and oxidative stress." Nat Rev Drug Discov 3(3): 205-14.

            Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

Bartzokis, G. (2004). "Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease." Neurobiol Aging 25(1): 5-18; author reply 49-62.

            A hypothetical model of Alzheimer's disease (AD) as a uniquely human brain disorder rooted in its exceptional process of myelination is presented. Cortical regions with the most protracted development are most vulnerable to AD pathology, and this protracted development is driven by oligodendrocytes, which continue to differentiate into myelin producing cells late into the fifth decade of life. The unique metabolic demands of producing and maintaining their vast myelin sheaths and synthesizing the brain's cholesterol supply make oligodendrocytes especially susceptible to a variety of insults. Their vulnerability increases with increasing age at differentiation as later-differentiating cells myelinate increasing numbers of axonal segments. These vulnerable late-differentiating cells drive the protracted process of intracortical myelination and by increasing local cholesterol and iron levels, progressively increase the toxicity of the intracortical environment forming the basis for the age risk factor for AD. At older ages, the roughly bilaterally symmetrical continuum of oligodendrocyte vulnerability manifests as a progressive pattern of myelin breakdown that recapitulates the developmental process of myelination in reverse. The ensuing homeostatic responses to myelin breakdown further increase intracortical toxicity and results in the relentless progression and non-random anatomical distribution of AD lesions that eventually cause neuronal dysfunction and degeneration. This process causes a slowly progressive disruption of neural impulse transmission that degrades the temporal synchrony of widely distributed neural networks underlying normal brain function. The resulting network "disconnections" first impact functions that are most dependent on large-scale synchronization including higher cognitive functions and formation of new memories. Multiple genetic and environmental risk factors (e.g. amyloid beta-peptide and free radical toxicity, head trauma, anoxia, cholesterol levels, etc.) can contribute to the cognitive deficits observed in aging and AD through their impact on the life-long trajectory of myelin development and breakdown. This development-to-degeneration model is testable through imaging and post mortem methods and highlights the vital role of myelin in impulse transmission and synchronous brain function. The model offers a framework that explains the anatomical distribution and progressive course of AD pathology, some of the failures of promising therapeutic interventions, and suggests further testable hypotheses as well as novel approaches for intervention efforts.

Baskys, A. (2004). "Lewy body dementia: the litmus test for neuroleptic sensitivity and extrapyramidal symptoms." J Clin Psychiatry 65 Suppl 11: 16-22.

            Lewy body dementia, also referred to as dementia with Lewy bodies (DLB), is a neurodegenerative disorder now considered to be the second most common cause of dementia after Alzheimer's disease. Postmortem findings suggest that DLB accounts for 20% to 34% of all dementia cases and is often underdiagnosed. Salient features of DLB include fluctuations in cognition, perceptual abnormalities (e.g., visual hallucinations), and mild parkinsonism. Other symptoms include frequent falls, nighttime agitation, and depression. DLB symptomatology can be partly explained by the extensive destruction of dopaminergic and acetylcholinergic pathways caused by neurodegeneration. For this reason, DLB patients are especially vulnerable to the antidopaminergic and anticholinergic actions of most conventional antipsychotics, which makes treatment of the psychotic symptoms of DLB extremely difficult. Patients are particularly sensitive to developing extrapyramidal symptoms (EPS) and also to the potentially fatal complication of neuroleptic sensitivity, which affects approximately 50% of DLB patients. Therefore, a need exists for antipsychotic drugs with less propensity to induce EPS and reduced affinity for dopamine and acetylcholine receptors. Here we review studies evaluating the efficacy and tolerability of atypical antipsychotics for the treatment of psychoses associated with DLB. Olanzapine appears to be poorly tolerated, and risperidone has been associated with high risk of neuroleptic malignant syndrome. Clozapine use remains controversial because of its potent anticholinergic action and risk of agranulocytosis. Quetiapine has been shown to reduce psychiatric manifestations of DLB without causing neuroleptic sensitivity or increasing EPS. Hence, quetiapine is an attractive candidate for the treatment of psychoses in DLB and other dementias.

Bateman, D. A. and A. Chakrabartty (2004). "Interactions of Alzheimer amyloid peptides with cultured cells and brain tissue, and their biological consequences." Biopolymers 76(1): 4-14.

            The Alzheimer amyloid peptides are the main constituent of the diagnostic hallmark of Alzheimer disease, the senile plaque. A halo of neurodegeneration surrounds the senile plaques observed in the brains of Alzheimer patients. Significant efforts are under way to determine whether the Alzheimer peptides are the causal agents of this neurodegeneration. We review the developments in identifying the putative interaction sites of Alzheimer amyloid peptides on cells and intact brain tissue. We focus on the specificity of this interaction and on the molecular nature of potential receptors. These studies form the bases for developing therapeutics that target potential interaction sites and inhibit Alzheimer amyloid peptide deposition.

Benveniste, E. N., V. T. Nguyen, et al. (2004). "Molecular regulation of CD40 gene expression in macrophages and microglia." Brain Behav Immun 18(1): 7-12.

            Inflammatory events in the central nervous system (CNS) contribute to the disease process in a variety of neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's Disease (AD), and cerebral ischemia, and activated macrophages/microglia are central to this response. Immunological activation of these cells leads to the production of a wide array of cytokines, chemokines, matrix metalloproteinases and neurotoxins, and ultimately to glial/neuronal injury and death. The CD40 molecule has an important role in promoting inflammatory responses by macrophages/microglia, since interaction with its cognate ligand, CD154, leads to secretion of cytokines and neurotoxins. Aberrant CD40 expression by macrophages/microglia, induced by cytokines such as IFN-gamma and TNF-alpha, contributes to neuroimmunologic cascades in the CNS. Strategies to suppress CD40 expression may attenuate inflammation and neuronal damage within the CNS, which will ultimately be of benefit in neuroinflammatory diseases. The mediators that regulate expression of CD40 in macrophages/microglia (both induction and inhibition) function at the level of gene transcription. In this review, we present an overview of the molecular basis of CD40 expression in macrophages/microglia. The signal transduction pathways and transcription factors employed by IFN-gamma and TNF-alpha to induce CD40 expression are described, as are the cis-elements in the CD40 promoter that are critical for CD40 transcription. Information is provided on the mechanism(s) underlying suppression of CD40 in macrophages/microglia by immunomodulatory agents such as IL-4, TGF-beta, neuropeptides, neurotrophins, and statins. A comprehensive assessment of CD40 production and function in macrophages/microglia will establish the foundation for future therapeutic manipulation of this critical immunoregulatory protein.

Bertoli-Avella, A. M., B. A. Oostra, et al. (2004). "Chasing genes in Alzheimer's and Parkinson's disease." Hum Genet 114(5): 413-38.

            Alzheimer's disease (AD), the most common type of dementia, and Parkinson's disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on "special" isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of "gene hunting" have evolved during the last few years and the significance of finding genes such as the presenilins, alpha- synuclein, parkin and DJ- 1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.

Bhat, R. V., S. L. Budd Haeberlein, et al. (2004). "Glycogen synthase kinase 3: a drug target for CNS therapies." J Neurochem 89(6): 1313-7.

            Abstract Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used drug for affective disorders, inhibits GSK3 at therapeutically relevant concentrations. Thus while the rationale remains testable, pharmaceutical companies are investing in finding a selective inhibitor of GSK3. In the present review, we summarize the properties of GSK3, and discuss the potential for such a therapy in AD, and other CNS disorders.

Birks, J. and G. G. Wilcock (2004). "Velnacrine for Alzheimer's disease." Cochrane Database Syst Rev(2): CD004748.

            BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Velnacrine is a derivative of tacrine. OBJECTIVES: To determine the clinical efficacy and safety of velnacrine for patients with dementia of Alzheimer's type. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2004 using the terms velnacr* and 'HP 029'. The CDCIG SR is regularly updated and contains records from all major health care databases and a great many ongoing trial databases. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with velnacrine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: Four trials, involving 899 participants, were included. Cutler 1990 reported only the adverse events, and omitted the results for the placebo group. Medication was stopped for all in the highest dose group after the fourth day because one member suffered a tonic seizure. It is not possible to report any comparisons with placebo. Antuono 1995 reported benefit for velnacrine at endpoint for the CGI-C, and the Physical Self-maintenance Scale (PGIR), but not for the Carers Assessment of Time Activity (CATS). These results could not be checked because the relevant information was not reported, and we cannot assess the effect on the results of the higher number of non-completers from the velnacrine group. Treatment was discontinued because of safety reasons in 135 patients, mostly due to an abnormal liver function tests. There was a significant difference in favour of placebo compared with the combined treatment group for the number with an abnormal liver function test before the end of treatment at 24 weeks [105/297 vs 4/152, OR =20.23, 95% CI 7.29 to 56.18, p<0.00001]. There was a significant difference in favour of placebo compared with the combined treatment group for the number of withdrawals before the end of treatment at 24 weeks [130/297 vs 39/152, OR =2.26, 95% CI 1.47 to 3.47, p=0.0002].Results are available for the dose replication phases of Zemlan 1996a and Zemlan 1996b. All the patients had taken velnacrine within two weeks prior to this phase and were identified as responders to velnacrine defined by improvement on the ADAS-Cog. Both studies reported a significant benefit for velnacrine compared with placebo for the ADAS-cog, but the results could not be checked because the relevant information was not reported. Neither study reported any benefit for velnacrine for the other efficacy measures. There was a significant difference in favour of placebo compared with the treatment group for the number with elevated liver transaminases before the end of treatment at 6 weeks [45/153 vs 29/156, OR =1.82, 95% CI 1.07 to 3.11, p=0.03]. There was a significant difference in favour of placebo compared with the treatment group for the number of withdrawals before the end of treatment at 6 weeks [68/211 vs 47/215, OR =1.70, 95% CI 1.10 to 2.62, p=0.02]. REVIEWERS' CONCLUSIONS: There has been no research into the use of velnacrine as a cognitive enhancer in the treatment of Alzheimer's disease since 1994. The FDA peripheral and CNS drug advisory board voted unanimously against recommending approval. This review shows the toxic nature of velnacrine, and provides no evidence of efficacy. There are no grounds for further research into velnacrine.

Birnbaum, S. G., A. W. Varga, et al. (2004). "Structure and function of Kv4-family transient potassium channels." Physiol Rev 84(3): 803-33.

            Shal-type (Kv4.x) K(+) channels are expressed in a variety of tissue, with particularly high levels in the brain and heart. These channels are the primary subunits that contribute to transient, voltage-dependent K(+) currents in the nervous system (A currents) and the heart (transient outward current). Recent studies have revealed an enormous degree of complexity in the regulation of these channels. In this review, we describe the surprisingly large number of ancillary subunits and scaffolding proteins that can interact with the primary subunits, resulting in alterations in channel trafficking and kinetic properties. Furthermore, we discuss posttranslational modification of Kv4.x channel function with an emphasis on the role of kinase modulation of these channels in regulating membrane properties. This concept is especially intriguing as Kv4.2 channels may integrate a variety of intracellular signaling cascades into a coordinated output that dynamically modulates membrane excitability. Finally, the pathophysiology that may arise from dysregulation of these channels is also reviewed.

Blake, A. D., A. C. Badway, et al. (2004). "Delineating somatostatin's neuronal actions." Curr Drug Targets CNS Neurol Disord 3(2): 153-60.

            Somatostatin (somatotropin release inhibitory factor; SRIF) initiates its biological activity by interacting with a family of highly homologous integral membrane receptors (sst(1) -sst(5)). SRIF neuronal actions regulate protein phosphorylation levels, control second messenger production and modulate neuronal membrane potential. Recently, our understanding of SRIF neurobiology has been driven by new pharmacological and molecular biological tools. SRIF receptor subtype specific antibodies have identified a distinctive, yet overlapping, expression pattern for this receptor family, with multiple subtypes co-localizing in the central and peripheral nervous system. This complex expression profile has confounded efforts to establish each receptor's role in the nervous system in part by the possible homo- and heteroligomerization of the receptor proteins. However, the recent discovery of SRIF receptor subtype selective ligands, supplemented by in vitro and in vivo models with inactivated SRIF receptor genes, now provides opportunities to clearly delineate each receptor's neuronal role. The convergence of these pharmacologic, immunologic and molecular biologic approaches extend our understanding of SRIF neurobiology while promising new therapeutic avenues for SRIF research.

Bleich, S., D. Degner, et al. (2004). "Homocysteine as a neurotoxin in chronic alcoholism." Prog Neuropsychopharmacol Biol Psychiatry 28(3): 453-64.

            There is evidence from in vitro and in vivo studies that homocysteine induces neuronal damage and cell loss by both excitotoxicity and different apoptotic processes. Clinical evidence suggest a strong relationship between higher plasma homocysteine levels and brain atrophy in healthy elderly subjects as well as in elderly at risk of and with Alzheimer's disease. Chronic alcoholism leads to elevated plasma homocysteine levels, as shown by clinical investigations and animal experiments. In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of alcoholism-associated brain atrophy. Furthermore, taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anticonvulsive therapy could prevent this severe complication. Homocysteine plays a role in a shared biochemical cascade involving overstimulation of N-methyl-D-aspartate (NMDA) receptors, oxidative stress, activation of caspases, DNA damage, endoplasmic reticulum and mitochondrial dysfunction. These mechanisms are believed to be important in the pathogenesis of both excitotoxicity and apoptotic neurotoxicity. Prospective intervention studies may show whether the incidence of complications of alcohol withdrawal or alcoholism-associated disorders can be reduced by therapeutic measures with early lowering of elevated homocysteine levels (e.g. folate administration). The most important pathophysiological and pathobiochemical features of glutamatergic neurotransmission and of ethanol-induced hyperhomocysteinaemia are reviewed in relation to their excitotoxic and apoptotic potential.

Blesch, A. and M. H. Tuszynski (2004). "Gene therapy and cell transplantation for Alzheimer's disease and spinal cord injury." Yonsei Med J 45 Suppl: 28-31.

            The targeted delivery of genes and the transplantation of suitable cell types into the adult nervous system have received considerable interest over the last years. The development of improved vector systems for in vivo gene delivery and the discovery of neural stem cells in the adult nervous system have opened new venues for potential therapeutic intervention in progressive neurodegenerative disease and nervous system injury. Thus, strategies have evolved for the delivery of potentially neuroprotective molecules, such as neurotrophic factors, and the replacement of cells and tissue lost due to CNS injury and degeneration.

Bliwise, D. L. (2004). "Sleep disorders in Alzheimer's disease and other dementias." Clin Cornerstone 6 Suppl 1A: S16-28.

            Patients with dementias, such as Alzheimer's disease (AD), often have nocturnally disrupted sleep. Clinically, this may present as agitation during the nighttime hours, which may affect as many as a quarter of AD patients during some stage of their illness. Sleep disturbance in AD may be multifactorial and involve sleep-disordered breathing and disrupted chronobiology, both often characterized by excessive daytime napping. Polysomnographically, AD patients show decreased rapid eye movement (REM) sleep in proportion to the extent of their dementia; some evidence suggests that cholinesterase inhibitors, commonly used pharmacologic agents for cognitive loss in AD, may increase REM sleep measures. Unfortunately, such agents may also induce insomnia and vivid dreams. There have been no randomized clinical trials of sedative-hypnotic medications specifically targeted at AD patients with sleep problems. Evidence suggests that sedative-hypnotics, such as benzodiazepine site-specific agonists, may have a role in some cases, whereas atypical antipsychotics may be necessary in other cases. There are also reports of successful interventions with nonpharmacologic options (eg, exercise, illumination). The utility of melatonin as a hypnotic in this population appears equivocal.

Boje, K. M. (2004). "Nitric oxide neurotoxicity in neurodegenerative diseases." Front Biosci 9: 763-76.

            Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"

Bonfils, P., D. Malinvaud, et al. (2004). "[Olfactory disorders]." Ann Otolaryngol Chir Cervicofac 121(2): 67-74.

            Smell and taste problems are of major importance to those who suffer from olfactory disorders. The inability to determine the presence of odors in the home and the markedly reduced capacity or incapacity to appreciate food flavors are key reasons given for limited social interaction. Patients experiencing distorted smells and tastes may avoid food, which results in weight loss and possible malnutrition. We present an overview of smell disorders, based on physiological considerations, with specific attention to clinical characteristics of conditions most commonly causing smell disorders.

Bourre, J. M. (2004). "Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing." J Nutr Health Aging 8(3): 163-74.

            Among various organs, in the brain, the fatty acids most extensively studied are omega-3 fatty acids. Alpha-linolenic acid (18:3omega3) deficiency alters the structure and function of membranes and induces minor cerebral dysfunctions, as demonstrated in animal models and subsequently in human infants. Even though the brain is materially an organ like any other, that is to say elaborated from substances present in the diet (sometimes exclusively), for long it was not accepted that food can have an influence on brain structure, and thus on its function. Lipids, and especially omega-3 fatty acids, provided the first coherent experimental demonstration of the effect of diet (nutrients) on the structure and function of the brain. In fact the brain, after adipose tissue, is the organ richest in lipids, whose only role is to participate in membrane structure. First it was shown that the differentiation and functioning of cultured brain cells requires not only alpha-linolenic acid (the major component of the omega-3, omega3 family), but also the very long omega-3 and omega-6 carbon chains (1). It was then demonstrated that alpha-linolenic acid deficiency alters the course of brain development, perturbs the composition and physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes (2).This leads to physicochemical modifications, induces biochemical and physiological perturbations, and results in neurosensory and behavioural upset (3). Consequently, the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (premature and term) conditions the visual and cerebral abilities, including intellectual. Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects of cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's disease. Recent results have shown that dietary alpha-linolenic acid deficiency induces more marked abnormalities in certain cerebral structures than in others, as the frontal cortex and pituitary gland are more severely affected. These selective lesions are accompanied by behavioural disorders more particularly affecting certain tests (habituation, adaptation to new situations). Biochemical and behavioural abnormalities are partially reversed by a dietary phospholipid supplement, especially omega-3-rich egg yolk extracts or pig brain. A dose-effect study showed that animal phospholipids are more effective than plant phospholipids to reverse the consequences of alpha-linolenic acid deficiency, partly because they provide very long preformed chains. Alpha-linolenic acid deficiency decreases the perception of pleasure, by slightly altering the efficacy of sensory organs and by affecting certain cerebral structures. Age-related impairment of hearing, vision and smell is due to both decreased efficacy of the parts of the brain concerned and disorders of sensory receptors, particularly of the inner ear or retina. For example, a given level of perception of a sweet taste requires a larger quantity of sugar in subjects with alpha-linolenic acid deficiency. In view of occidental eating habits, as omega-6 fatty acid deficiency has never been observed, its impact on the brain has not been studied. In contrast, omega-9 fatty acid deficiency, specifically oleic acid deficiency, induces a reduction of this fatty acid in many tissues, except the brain (but the sciatic nerve is affected). This fatty acid is therefore not synthesized in sufficient quantities, at least during pregnancy-lactation, implying a need for dietary intake. It must be remembered that organization of the neurons is almost complete several weeks before birth, and that these neurons remain for the subject's life time. Consequently, any disturbance of these neurons, an alteration of their connections, and impaired turnover of their constituents at any stage of life, will tend to accelerate ageing. The enzymatic activities of sytivities of synthesis of long-chain polyunsaturated fatty acids from linoleic and alpha-linolenic acids are very limited in the brain: this organ therefore depends on an exogenous supply. Consequently, fatty acids that are essential for the brain are arachidonic acid and cervonic acid, derived from the diet, unless they are synthesized by the liver from linoleic acid and alpha-linolenic acid. The age-related reduction of hepatic desaturase activities (which participate in the synthesis of long chains, together with elongases) can impair turnover of cerebral membranes. In many structures, especially in the frontal cortex, a reduction of cervonic and arachidonic acids is observed during ageing, predominantly associated with a reduction of phosphatidylethanolamines (mainly in the form of plasmalogens). Peroxisomal oxidation of polyunsaturated fatty acids decreases in the brain during ageing, participating in decreased turnover of membrane fatty acids, which are also less effectively protected against peroxidation by free radicals.

Boyle, P. A. (2004). "Assessing and predicting functional impairment in Alzheimer's disease: the emerging role of frontal system dysfunction." Curr Psychiatry Rep 6(1): 20-4.

            Alzheimer's disease (AD) is associated with neuropsychologic and neuropsychiatric dysfunction and is a leading cause of disability among the elderly. Impairments in activities of daily living (ADL) contribute significantly to the disability reported among patients with AD and diminish quality of life for patients and their families. ADL assessment represents an important component of the diagnosis, tracking, and management of AD. Further, an understanding of the determinants of ADL dysfunction is critical for the early identification of individuals at risk for functional disability and for improved patient care. This manuscript reviews methods for assessing ADL in patients with AD and summarizes the available literature on the neuropsychologic and neuropsychiatric correlates of functional impairment in AD. The emerging role of frontal system dysfunction as an important determinant of ADL impairment is discussed, and recommendations for clinical practice and future research are provided.

Boyle, P. A. and P. F. Malloy (2004). "Treating apathy in Alzheimer's disease." Dement Geriatr Cogn Disord 17(1-2): 91-9.

            Apathy, a syndrome of decreased initiation and motivation, affects over 70% of individuals with Alzheimer's disease (AD) and is the most common neuropsychiatric symptom reported in AD patients. The syndrome of apathy is associated with functional impairment among patients and elevated stress among their caregivers. Apathy is one of the primary neuropsychiatric manifestations of frontal system dysfunction, and AD-related apathy is thought to reflect the interaction between cholinergic deficiency and neuropathological changes in frontal brain regions. This article reviews the assessment and treatment of apathy in AD, with emphasis on the utility of acetylcholinesterase inhibitors for reducing apathy in AD. The potential benefits of other pharmacologic agents and combined pharmacologic-behavioral interventions are also discussed, and recommendations for future research are provided.

Braekhus, A. and K. Engedal (2004). "[Vascular dementia--an ill-defined concept]." Tidsskr Nor Laegeforen 124(8): 1097-9.

            BACKGROUND: Vascular dementia is defined as dementia caused by cerebrovascular disease and is seen as the most common cause of dementia after Alzheimer's disease. In our opinion, vascular dementia is an ill-defined term; this proposition is discussed in this article. MATERIAL AND METHODS: The concept of vascular dementia is discussed based on the literature and our own clinical experience. RESULTS: The prevalence of vascular dementia varies markedly across different studies and several clinical diagnostic criteria are used. There has been an ongoing debate as to which radiological changes are associated with vascular dementia; we question the use of neuropathological changes as a diagnostic gold standard. Several studies have shown similarities between dementia of the Alzheimer type and vascular dementia regarding risk factors and symptomatology. INTERPRETATION: We conclude that the concept of vascular dementia should be re-evaluated. It is important to establish valid and reliable criteria for vascular dementia, especially in the light of the therapeutic consequences.

Brew, B. J. (2004). "Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex." Aids 18 Suppl 1: S75-8.

            This review will discuss emerging evidence for the possibility that AIDS dementia complex (ADC) has changed in the era of highly active antiretroviral therapy (HAART). The consequences of not considering these possibilities at the patient level and at the level of research are considerable. Data will be discussed that are derived from epidemiological studies, neuropsychological and positron emission tomography studies, as well as analyses from the abacavir ADC trial. These will then be assessed to develop the concept that there are now different forms of ADC: an inactive form, a chronic variety and a 'transformed' variant. Whereas the latter relates to the compounding influence of a number of other processes on ADC, such as hepatitis C, particular discussion will focus upon Alzheimer's disease and whether HIV may lead to Alzheimer-like changes. It is certainly recognized that some of the concepts discussed here are highly speculative.

Brinton, R. D. (2004). "Impact of estrogen therapy on Alzheimer's disease: a fork in the road?" CNS Drugs 18(7): 405-22.

            The results of recent clinical studies have challenged our previously held view that estrogen therapy promotes neurological health and prevents or ameliorates Alzheimer's disease. A major question emerging from these studies is: how can there be such disparity between the basic science and epidemiological data that show that estrogen can protect neurons against degenerative insults and reduce the risk of Alzheimer's disease and the recent data (from the Women's Health Initiative Memory Study [WHIMS] trial and the trial of estrogen treatment for Alzheimer's disease), which show that hormone replacement therapy (HRT) showed no benefit and even a potential deleterious effect? Which set of data is correct? The proposition put forth in this review is that both sets of data are correct and that two major factors determine the efficacy of estrogen or HRT. First is the time at which estrogen therapy is initiated. The data indicate that initiation of therapy early in menopause and when neurons are in a healthy state, reduces the risk of Alzheimer's disease; whereas, estrogen therapy initiated after the disease has developed or decades following menopause is without benefit. Second, estrogen therapy is not the same as HRT and the type of progestogen used determines the outcome of the therapeutic intervention. Insights into the mechanisms of action of estrogen and progestogen in the brain provide a framework for understanding the paradox of the benefit of estrogen in the prevention of Alzheimer's disease versus the lack of benefit in treatment trials and in trials when HRT is instituted many years after menopause. Based on estrogen-inducible mechanisms, which have been elucidated in healthy neuron model systems, it would be predicted that estrogen therapy could be highly effective in preventing neurodegenerative disease by promoting neuronal defence and memory mechanisms. The mechanisms of action of estrogen also predict that estrogen therapy would be an ineffective strategy for reversing the pathology of Alzheimer's disease. In summary, the time at which estrogen therapy is initiated, the neurological status of the brain at the time of estrogen therapy initiation and the type of progestogen used all contribute to the efficacy of estrogen in preventing neurodegenerative disease and to sustaining neurological health and function. An estrogen advantage hypothesis is put forth that provides a unifying mechanism of estrogen action with implications for both the benefits and risks of estrogen therapy.

Broytman, O. and J. S. Malter (2004). "Anti-Abeta: The good, the bad, and the unforeseen." J Neurosci Res 75(3): 301-6.

            Alzheimer's disease (AD) is characterized in part by the deposition of amyloid beta protein (Abeta) in compact fibrillar plaques. These structures can induce an innate immune response in the brain, which triggers progressive inflammation, neuronal loss, and further acceleration of Abeta plaque formation. Compared with the case in normal individuals, the T and B lymphocytes in AD patients and murine models are hyporesponsive to Abeta. However, depending on the route of delivery, tolerance can be overcome by vaccination, with the induction of an anti-Abeta-mediated immune response. Through mechanisms that are incompletely understood, immunized APP transgenic animals show markedly reduced Abeta deposition, preservation of normal neuronal architecture, and improved performance in memory and spatial learning tasks. In human trials, Abeta vaccination stabilized cognition and slowed the progression of dementia. Neuropathologic examination of a vaccinated subject showed reduced cortical Abeta without changes in other AD-associated pathology. However, in some patients, vaccination induced severe meningoencephalitis, causing the trial to be terminated. Thus, vaccination appears to activate both beneficial and deleterious anti-Abeta immunity, suggesting that the vaccine can have potent clinical utility if an appropriate immunologic response can be generated.

Bsoul, S. A. and G. T. Terezhalmy (2004). "Vitamin C in health and disease." J Contemp Dent Pract 5(2): 1-13.

            Vitamins are essential to maintain normal metabolic processes and homeostasis within the body. The amount of a specific vitamin required by an individual varies considerably and it is influenced by such factors as body size, growth rate, physical activity, and pregnancy. Most vitamins are stored minimally in human cells, but some are stored in liver cells to a greater extent. Vitamins A and D, for example, may be stored in sufficient amounts to maintain an individual without any intake for 5 to 10 months and 2 to 4 months, respectively. However, a deficiency of vitamin B compounds (except vitamin B12) may be noted within days, and the lack of vitamin C will manifest within weeks and may result in death in 5 to 6 months. The current recommended dietary allowance (RDA) of vitamin C is 75 mg for woman and 90 mg for men, based on the vitamin's role as an antioxidant as well as protection from deficiency. High intakes of the vitamin are generally well tolerated, however, a Tolerable Upper Level (TUL) was recently set at 2 g based on gastrointestinal upset that sometimes accompanies excessive dosages. Several populations warrant special attention with respect to vitamin C requirements. These include patients with periodontal disease, smokers, pregnant and lactating women, and the elderly.

Bugiani, O. (2004). "A beta-related cerebral amyloid angiopathy." Neurol Sci 25 Suppl 1: S1-2.

            Cerebral amyloid angiopathy is due to beta-protein accumulation in the vessel walls and occurs in normal aging, Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis. It causes intraparenchimal and subarachnoid bleeding with hemosiderin deposits and multiple infarcts presenting with headache, stroke and epilepsy. Such lesions may contribute to cognitive impairment. So far, no therapy is available. In future, amyloid in the vessel wall might be addressed by amyloid disaggregating drugs and amyloid antibodies.

Bullock, R. (2004). "Future directions in the treatment of Alzheimer's disease." Expert Opin Investig Drugs 13(4): 303-14.

            Alzheimer's disease (AD) remains the most common of the neurodegenerative disorders. In the elderly, it represents the most frequently occurring form of dementia, especially if considered alongside concomitant cerebrovascular disease. Current treatment involves the use of acetylcholinesterase inhibitors, which have shown symptomatic benefits in the recognised domains of cognition, function and behaviour. While they may have intrinsic disease-modifying activity, this is yet to be proven, and strategies to alter the fundamental neuropathological changes in AD continue to be sought. Much of the evidence suggests that the accumulation of amyloid-beta may play a pivotal role, therefore the bulk of current research is focused on possible intervention along the amyloid pathways. However, the abnormal phosphorylation of tau is also a reasonable target and as the molecular basis of AD is better delineated, more targeted treatment approaches are being proposed. This paper reports on the current data that is setting the future directions for research into AD.

Bullock, R. (2004). "Cholinesterase inhibitors and vascular dementia: another string to their bow?" CNS Drugs 18(2): 79-92.

            Two of the four licensed cholinesterase inhibitors, galantamine and donepezil, have recently featured in published work showing how they act in dementia associated with cerebrovascular disease (CVD). It is timely to review this new evidence and place it within the current consensus understanding of what makes up a clearly heterogeneous dementia population. To do this, the current review explores the relationship between Alzheimer's disease, for which this group of compounds originally received licensing approval, and vascular pathology within the brain, highlighting the significant overlap in risk factors and the frequent coexistence of the two conditions in the patients that are studied. Whether they are inter-related or separate entities is discussed, followed by a description of the current classifications of Alzheimer's disease with CVD, and the three subtypes of 'pure' vascular dementia - subcortical, cortical and strategic infarct. Understanding these entities allows more accurate diagnostic and prognostic information to be given to patients, and leads towards matching the published clinical evidence discussed with more predictable clinical syndromes. This distinction is particularly relevant in terms of the studies conducted thus far.Galantamine has been studied in a placebo-controlled study of patients with Alzheimer's disease and CVD as well as patients with vascular dementia, whereas donepezil was studied exclusively in patients with vascular dementia. Differences in the way the placebo groups acted in these studies confirmed the fact that these actually are two distinct groups. Galantamine showed efficacy across the combined groups studied, with placebo deterioration similar to previous Alzheimer's disease studies, while donepezil produced a positive effect in vascular dementia - with this placebo group relatively unchanged. The symptomatic improvements seen were not really surprising, as cholinergic deficits are a common factor across all of these syndromes. Wherever this is the predominant biological finding, it would be expected that cholinesterase inhibitors would have a similar effect, whatever the condition causing it.

Burke, W. J., S. W. Li, et al. (2004). "Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases." Neurotoxicology 25(1-2): 101-15.

            The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.

Bush, A. I. and D. Strozyk (2004). "Serum copper: a biomarker for Alzheimer disease?" Arch Neurol 61(5): 631-2.

Bush, A. and N. Beail (2004). "Risk factors for dementia in people with down syndrome: issues in assessment and diagnosis." Am J Ment Retard 109(2): 83-97.

            It has been clearly established that there is an increased incidence of early onset dementia of the Alzheimer type (DAT) in people who have Down syndrome. There are variations in the age of onset of the clinical signs of DAT, which may be accounted for by different risk factors. In this review we examined the evidence that different biological and psychological factors may influence the risk for DAT. Limitations in design of early studies, the need for consistent diagnostic criteria for DAT in individuals with Down syndrome, and the lack of adequate psychometric tools to detect cognitive change are highlighted. Implications for research and clinical practice are considered in order to assess potential risk factors.

Butterfield, D. A. and A. I. Bush (2004). "Alzheimer's amyloid beta-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide." Neurobiol Aging 25(5): 563-8.

            In the interesting debate entitled "Challenging Views of Alzheimer's Disease II," we defended the position that factors such as oxygen, the single methionine residue of amyloid beta-peptide(1-42) [Abeta(1-42)], and redox metal ions were important for the oxidative stress and neurotoxic properties of this peptide that is critically involved in the pathogenesis of Alzheimer's disease. This brief review summarizes some of our findings relevant to the role of the single methionine residue of Abeta(1-42) in the oxidative stress and neurotoxic properties of this peptide.

Butterfield, D. A. (2004). "Proteomics: a new approach to investigate oxidative stress in Alzheimer's disease brain." Brain Res 1000(1-2): 1-7.

            In Alzheimer's disease (AD) brain oxidative stress is observed indexed by several markers, among which are protein carbonyls and 3-nitrotyrosine, markers for protein oxidation. We hypothesized that identity of these oxidatively modified proteins would lead to greater understanding of some of the potential molecular mechanisms involved in neurodegeneration in this dementing disorder. Proteomics is an emerging method for identification of proteins, and its application to neurodegenerative disorders, especially AD, is just beginning. Posttranslational modification of brain proteins, particularly that due of oxidation of proteins, provides an effective means of screening a subset of proteins within the brain proteome that likely reflects the extensive oxidative stress under which the AD brain exists, and this new methodology provides insights into mechanisms of neurodegeneration in and new therapeutic targets for AD. In this review, the use of proteomics to identify specifically oxidized proteins in AD brain is presented, from which new insights into mechanisms of neurodegeneration and synapse loss in this dementing disorder that is associated with oxidative stress have emerged.

Candore, G., C. R. Balistreri, et al. (2004). "Major histocompatibility complex and sporadic Alzheimer's disease: a critical reappraisal." Exp Gerontol 39(4): 645-52.

            Epidemiological data suggest that some genetic determinants of Alzheimer's disease (AD) might reside in those polymorphisms for the immune system genes that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, MHC polymorphisms have been the focus of a large number of AD association studies. Class Ia, Ib (hemochromatosis gene (HFE)), class II and class III (complement, tumour necrosis factor and heat shock proteins) alleles have been studied. Nearly every positive result has been followed by several studies that have failed to replicate it or that have contradicted it. Several factors, including methodological biases, might explain these discordant results. However, the discordant results obtained with the same alleles in the various populations might also indicate linkage with another nearby locus, different in the diverse populations. In fact, the non-random assortment of alleles at neighbouring loci, i.e. ancestral haplotypes (AH), has been claimed to be maintained as the result of directional selection, i.e. molecular cooperation during the immune response. Thus, AH studies might contribute to explaining why discordant results are obtained with the same alleles in different populations. Hence, it has been suggested that the overall chance of a subject to develop AD might be profoundly affected by a 'susceptibility profile' reflecting the combined influence of inheriting multiple high-risk alleles. Discordant results may be due to other genetic factors not determined in these MHC studies and multivariate analysis in large patient cohorts considering both MHC and non-MHC genes are therefore necessary.

Canevari, L., A. Y. Abramov, et al. (2004). "Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress." Neurochem Res 29(3): 637-50.

            Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Abeta) peptides. Although the disease undoubtedly reflects the interaction of complex multifactorial processes, Abeta itself is toxic to neurons in vitro and the load of Abeta in vivo correlates well with the degree of cognitive impairment. There has therefore been considerable interest in the mechanism(s) of Abeta neurotoxicity. We here review the basic biology of Abeta processing and consider some of the major areas of focus of this research. It is clear that both AD and Abeta toxicity are characterized by oxidative stress, alterations in the activity of enzymes of intermediary metabolism, and mitochondrial dysfunction, especially impaired activity of cytochrome c oxidase. Studies in vitro also show alterations in cellular calcium signaling. We consider the mechanisms proposed to mediate cell injury and explore evidence to indicate which of these many changes in function are primary and which secondary.

Carini, M., G. Aldini, et al. (2004). "Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins." Mass Spectrom Rev 23(4): 281-305.

            Despite the great technical advancement of mass spectrometry, this technique has contributed in a limited way to the discovery and quantitation of specific/precocious markers linked to free radical-mediated diseases. Unsaturated aldehydes generated by free radical-induced lipid peroxidation of polyunsaturated fatty acids, and in particular 4-hydroxy-trans-2 nonenal (HNE), are involved in the onset and progression of many pathologies such as cardiovascular (atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and cerebral ischemia). Most of the biological effects of HNE are attributed to the capacity of HNE to react with the nucleophilic sites of proteins and peptides (other than nucleic acids), to form covalently modified biomolecules that can disrupt important cellular functions and induce mutations. By considering the emerging role of HNE in several human diseases, an unequivocal analytical approach as mass spectrometry to detect/elucidate the structure of protein-HNE adducts in biological matrices is strictly needed not only to understand the reaction mechanism of HNE, but also to gain a deeper insight into the pathological role of HNE. This with the aim to provide intermediate diagnostic biomarkers for human diseases. This review sheds focus on the "state-of-the-art" of mass spectrometric applications in the field of HNE-protein adducts characterization, starting from the fundamental early studies and discussing the different MS-based approaches that can provide detailed information on the mechanistic aspects of HNE-protein interaction. In the last decade, the increases in the accessible mass ranges of modern instruments and advances in ionization methods have made possible a fundamental improvement in the analysis of protein-HNE adducts by mass spectrometry, and in particular by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) tandem mass spectrometry. The recent developments and uses of combined analytical approaches to detect and characterize the type/site of interaction have been highlighted, and several other aspects, including sample preparation methodologies, structure elucidation, and data analysis have also been considered.

Casanova Sotolongo, P., P. Casanova Carrillo, et al. (2004). "[Memory. An introduction to the study of the cognitive disorders in normal and pathological aging]." Rev Neurol 38(5): 469-72.

            INTRODUCTION: As the life expectancy of the population rises, there is also an increase in the frequency of the diseases that appear in the elderly. Aging can be healthy or pathological, but the borderline between the two is still a bit fuzzy. DEVELOPMENT: With the increase in the longevity of the population, Alzheimer's Disease (AD) and other illnesses linked to the aging process have become more common, above all in people between 65 and 85 years of age. The cognitive aspects that, in clinical practice, are most frequently seen to be involved are memory, attention, executive functions and the speed at which information is processed; these are the most common in these patients but the most severe and insidious as well as the first to appear are problems affecting memory. The physiological mechanism behind memory has still not been wholly explained. The modulation of many of the cognitive processes given by the cerebellum expands the borders in the study of the different mnemonic processes. The prefrontal cortex plays an essential role in controlling attention and in the mnemonic filing system required to supervise and modulate sensory motor processing and the basic complex actions of cognition, emotion and human behaviour. CONCLUSIONS: The neuroanatomical, psychological and neurophysiological foundations of memory are very complex and involve the intervention of a number of structures that, within a single integrated context, each contribute to the overall functioning.

Casserly, I. and E. Topol (2004). "Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins." Lancet 363(9415): 1139-46.

            Late-onset sporadic Alzheimer's disease is a heterogeneous disorder. In elderly patients, increasing evidence suggests a link between this neurodegenerative disease, and vascular risk factors and atherosclerosis. The nature of this link remains speculative. Some investigators have suggested that the disease arises as a secondary event related to atherosclerosis of extracranial or intracranial vessels. A toxic effect of vascular factors on the microvasculature of susceptible brain regions has also been argued. An alternative explanation is that atherosclerosis and Alzheimer's disease are independent but convergent disease processes. This hypothesis is lent support by observations of shared epidemiology, pathophysiological elements, and response to treatment in both disorders. It provides a potential framework for an improved understanding of the pathogenesis of Alzheimer's disease, especially in elderly patients with vascular risk factors, and offers some promise toward the search for preventive and therapeutic treatments.

Castellani, R. J., G. Perry, et al. (2004). "Prion disease and Alzheimer's disease: pathogenic overlap." Acta Neurobiol Exp (Wars) 64(1): 11-7.

            Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns over the transmission of animal forms of prion disease, such as bovine spongiform encephalopathy and chronic wasting disease, to humans has only augmented the notion that prion diseases are primarily infectious. Yet within the spectrum of human prion diseases, often overlooked is the fact that the overwhelming majority of cases are age-dependent sporadic, or inherited processes. Closer examination of the pathophysiological processes involved in prion disease further indicates a neurodegenerative, rather than infectious disease. Indeed, the age requirement, the numerous kindreds carrying point mutations in an amyloidogenic protein, the copper binding properties of the amyloidogenic protein, the evidence of free radical damage, the presence of polymorphisms that influence disease susceptibility, the formation of amyloid plaques, and in some cases the presence of neurofibrillary pathology, are features common to both prion disease and Alzheimer's disease. Therefore, while transmissibility will continue to be a major subject of prion disease research, we suspect that further characterization of its pathophysiological mechanisms will only substantiate the notion that prion disease is fundamentally a neurodegenerative process.

Castellani, R. J., M. A. Smith, et al. (2004). "Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer's disease pathogenesis." Neurobiol Aging 25(5): 599-602; discussion 603-4.

            Amyloid deposition within cerebral vessels, or cerebral amyloid angiopathy (CAA), is common in advanced age and even more common in Alzheimer's disease. CAA may be complicated by lobar intracerebral hemorrhage, while rare kindreds of autosomal dominant CAA also show propensity for intracerebral hemorrhage, due to germline mutations in specific amyloidogenic precursor proteins and apparent compromise of structural integrity of the blood vessel wall due to marked amyloid deposition. The relationship between cerebral amyloid angiopathy and cognitive dysfunction, however, is less clear. While cognitive dysfunction in familial CAA is likely related to prodigious amyloid deposits and vascular luminal compromise (e.g., hereditary cerebral hemorrhage with angiopathy-Dutch type (HCHWA-D)), cerebral amyloid angiopathy with intracerebral hemorrhage often presents sporadically in cognitively intact elderly patients. Moreover, while about 80% of subjects with Alzheimer's disease have demonstrable amyloid beta within blood vessel walls at autopsy, the vast majority of these fail to suffer clinically relevant intracerebral hemorrhage during life. The remaining 20% manage to progress and die of their disease with virtual no amyloid within blood vessels. Thus, the role of amyloid beta deposits in cerebral vessels as regards cognitive function on the one hand, and tendency for hemorrhage on the other, remain to be resolved for sporadic late onset Alzheimer's disease and CAA. Recent studies on transgenic APP23 mice suggest a relationship between passive immunization and amyloid angiopathy-associated cerebral hemorrhage, although the mechanism of hemorrhage was unclear from the data presented. We suggest that amyloid accumulation represents a response to chronic stress, and that the neurodegenerative process occurs at the neuronal level, encompassing oxidative stress and aberrant cell cycle activation. As such, CAA represents tissue homeostasis, such that an abrupt perturbation of this balance (e.g., amyloid beta immunization) is deleterious.

Chang, C. Y. and D. H. Silverman (2004). "Accuracy of early diagnosis and its impact on the management and course of Alzheimer's disease." Expert Rev Mol Diagn 4(1): 63-9.

            Alzheimer's disease is the most common form of dementia in the elderly and its prevalence is rapidly rising. Although there is no cure for Alzheimer's disease, treatment can be administered to slow progression or delay the onset of symptoms. A major challenge is the early identification of patients who will develop Alzheimer's disease. As disease-modifying treatments become available, enhancing our ability to identify Alzheimer's early and accurately would allow intervention to slow, halt or even prevent disease progression or onset. Early recognition and intervention facilitates optimal care of Alzheimer's patients and delays the morbidity associated with this progressive illness.

Chartier-Harlin, M. C., L. Araria-Goumidi, et al. (2004). "[Genetic complexity of Alzheimer's disease]." Rev Neurol (Paris) 160(2): 251-5.

            The discovery of pathogenic mutations in the amyloid precursor protein (APP) gene and the presenilin (PS1, PS2) genes, causing familial early-onset AD has lead to the hypothesis of the amyloid cascade. The epsilon4 allele of the apolipoprotein E (APOE) gene, the only recognized genetic risk factor for AD, may be involved in the mechanism. However, to date, search for new genetic determinants has been hampered by methodological limitations. Some loci, for instance on chromosome 12, have been characterized by linkage studies performed in familial cases, but the regions of interest are very large and contain numerous genes. Furthermore, search for polymorphisms implicated in the development of AD, should not be limited to the coding part of the genes, but should also involve the non-translated sequences of the genes, for instance in the regions regulating gene expression. Indeed, these genetic variations may have important impact on key proteins of the pathologic process. Although this task is difficult, the identification of new susceptibility genes should lead to a better understanding of the development of AD.

Citron, M. (2004). "Beta-secretase inhibition for the treatment of Alzheimer's disease--promise and challenge." Trends Pharmacol Sci 25(2): 92-7.

            As the number of cases of Alzheimer's disease (AD) rises in all developed countries, the unmet medical need for disease-modifying pharmacotherapy continues to grow. Much of AD research has been focused on the amyloid cascade hypothesis, which states that amyloid-beta-42 (A beta 42), a proteolytic derivative of the large transmembrane protein amyloid precursor protein (APP), plays an early and crucial role in all cases of AD. Consequently, blocking the production of A beta 42 by specific inhibition of the key proteases required for A beta 42 generation is a major focus of research into AD therapy. The identification of beta-secretase, the aspartic protease that generates the N-terminus of A beta 42, has triggered a race to develop drug-like inhibitors of this enzyme, which has become one of the major AD targets. Although the biology of beta-secretase holds great promise, it will be challenging to generate drug-like inhibitors of this unusual enzyme.

Collins, S. J., V. A. Lawson, et al. (2004). "Transmissible spongiform encephalopathies." Lancet 363(9402): 51-61.

            Nosologically, transmissible spongiform encephalopathies (TSE or prion diseases) should be grouped with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, which are all caused by toxic gain of function of an aberrant form of a constitutively expressed protein. Failure to clear these proteins from the brain induces neuronal dysfunction. Transmissibility is the property that separates TSE from other neurodegenerative diseases, and this property seems to reside within the structure of the abnormal protein. The human phenotypic range of these encephalopathies includes Creutzfeldt-Jakob disease and its variant form, kuru, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. Notwithstanding the generally low incidence of TSE and their limited infectiousness, major epidemics such as bovine spongiform encephalopathy and kuru arise in situations where intraspecies recycling of the abnormal protein is sustained. Moreover, evidence of chronic subclinical infection in animals offers insights into pathogenesis and prompts re-evaluation of the notion of species barriers and present infection control measures. Since case-to-case transmission is the only known mechanism underlying epidemics of TSE, potential reservoirs of infectivity in the tails of epidemics need continued vigilance.

Conant, R. and A. G. Schauss (2004). "Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature." Altern Med Rev 9(1): 17-31.

            Citicoline (CDP-choline; cytidine 5'-diphosphocholine), a form of the essential nutrient choline, shows promise of clinical efficacy in elderly patients with cognitive deficits, inefficient memory, and early-stage Alzheimer's disease. Citicoline has also been investigated as a therapy in stroke patients, although the results of trials to date are inconclusive. Produced endogenously, citicoline serves as a choline donor in the metabolic pathways for biosynthesis of acetylcholine and neuronal membrane phospholipids, chiefly phosphatidylcholine. The principal components of citicoline, choline and cytidine, are readily absorbed in the GI tract and easily cross the blood-brain barrier. Exogenous citicoline, as the sodium salt, has been researched in animal experiments and human clinical trials that provide evidence of its cholinergic and neuroprotective actions. As a dietary supplement, citicoline appears useful for improving both the structural integrity and functionality of the neuronal membrane that may assist in membrane repair. This review, while not intended to be exhaustive, highlights the published, peer-reviewed research on citicoline with brief discussions on toxicology and safety, mechanisms of action, and pharmacokinetics.

Coruzzi, G., A. Menozzi, et al. (2004). "Novel non-steroidal anti-inflammatory drugs: what we have learned from animal studies." Curr Drug Targets Inflamm Allergy 3(1): 43-61.

            The use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently associated with serious adverse effects related to the inhibition of cyclooxygenase (COX) in tissues where prostanoids exert physiological effects, such as gastric mucosal defence, renal homeostasis and platelet aggregation. The discovery of a second COX isoform (COX-2) specifically induced in pathological tissues led to the development of selective COX-2 inhibitors, believed to have an improved safety profile compared to traditional NSAIDs. Animal studies, however, have revealed a protective role for the COX-2 enzyme in the stomach, kidney, heart, vasculature and reproductive system, and therefore, the safety of COX-2 selective inhibitors needs to be reassessed. On the other hand, new therapeutic indications have emerged as a result of the role played by COX-2 overexpression in cancer or Alzheimer's disease. A second approach aimed at obtaining safer NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional NSAIDs chemically linked to NO-releasing moieties retain the therapeutic efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional therapeutic applications in cardiovascular diseases, Alzheimer's disease and cancer have been suggested. Animal data, however, need to be confirmed in large clinical trials. Finally, the increase in endogenous NO via a selective increase in inducible NO synthase in the gastric mucosa is the mechanism underlying the good gastric tolerability and the gastroprotective effects of the non-selective NSAID amtolmetin guacyl, documented to date in the rat.

Craft, S. and G. S. Watson (2004). "Insulin and neurodegenerative disease: shared and specific mechanisms." Lancet Neurol 3(3): 169-78.

            Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

Cribbs, D. H., W. W. Poon, et al. (2004). "Caspase-mediated degeneration in Alzheimer's disease." Am J Pathol 165(2): 353-5.

Crutcher, K. A. (2004). "Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer's disease." J Mol Neurosci 23(3): 181-8.

            There is now a large body of evidence suggesting that apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer's disease. Yet in proportion to the total number of investigations in this field, relatively few groups are studying the contribution of this cholesterol-binding protein to disease risk and severity. Of those that are, a major focus is on the impact of apoE on amyloid-related mechanisms of disease. I argue here that apoE should be considered a major culprit in its own right, not simply in a supporting role. The argument is based on several lines of evidence, including the fact that apoE is associated with both plaques and tangles, the overwhelming evidence for genetic risk of the disease attributed to apoE, increasing evidence that apoE might also modify risk of other nonamyloidogenic neurological diseases, neurotoxicity attributed to apoE and/or proteolytic fragments of apoE, negative consequences of transgenic expression of apoE4 in mice, and genetic evidence for polymorphisms that increase both apoE expression and disease risk, regardless of isoform.

Cummings, J. L. (2004). "Alzheimer's disease." N Engl J Med 351(1): 56-67.

D'Andrea, M. R., G. M. Cole, et al. (2004). "The microglial phagocytic role with specific plaque types in the Alzheimer disease brain." Neurobiol Aging 25(5): 675-83.

            Alzheimer disease (AD) involves glial inflammation associated with amyloid plaques. The role of the microglial cells in the AD brain is controversial, as it remains unclear if the microglia form the amyloid fibrils of plaques or react to them in a macrophage-phagocytic role. Also, it is not known why microglia are preferentially associated with some amyloid plaque types. This review will provide substantial evidence to support the phagocytic role of microglia in the brain as well as explain why microglia are generally associated with specific plaque types that may be explained through their unique mechanisms of formation. In summary, the data presented suggests that plaque associated microglial activation is typically subsequent to specific amyloid plaque formations in the AD brain.

Davis, H. S. and K. Rockwood (2004). "Conceptualization of mild cognitive impairment: a review." Int J Geriatr Psychiatry 19(4): 313-9.

            BACKGROUND: Several factors have prompted renewed interest in the concept of declines in cognitive function that occur in association with aging, in particular the area between normal cognition and dementia. We review the changing conceptualization of what has come to be known as mild cognitive impairment (MCI) in an effort to identify recent developments and highlight areas of controversy. METHODS: Standard MEDLINE search for relevant English-language publications on mild cognitive impairment and its associated terms, supplemented by hand searches of pertinent reference lists. RESULTS: Many conditions cause cognitive impairment which does not meet current criteria for dementia. Within this heterogenous group, termed 'Cognitive Impairment, No Dementia' (CIND), there are disorders associated with an increased risk of progression to dementia. Still, the conceptualization of these latter disorders remains in flux, with variability around assumptions about aging, the relationship between impairment and disease, and how concomitant functional impairment is classified. Amongst patients with MCI, especially its amnestic form, many will progress to Alzheimer's disease (AD). In contrast with clinic-based studies, where progression is more uniform, population-based studies suggest that the MCI classification is unstable in that context. In addition to Amnestic Mild Cognitive Impairment (AMCI), other syndromes exist and can progress to dementia. For example, an identifiable group with vascular cognitive impairment without dementia shows a higher risk of progression to vascular dementia, Alzheimer's disease and mixed dementia. CONCLUSIONS: Recent attempts to profile patients at an increased risk of dementia suggest that this can be done in skilled hands, especially in people whose symptoms prompt them to seek medical attention. Whether these people actually have early AD remains to be determined. The more narrowly defined MCI profiles need to be understood in a population context of CIND.

de la Torre, J. C. (2004). "Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics." Lancet Neurol 3(3): 184-90.

            The cause of Alzheimer's disease (AD) is unknown. This gap in knowledge has created a stumbling block in the search for a genuinely effective treatment or cure for this dementia. This article summarises the arguments for a causal role for either amyloid deposition or cerebrovascular pathology as the primary trigger in the development of non-genetic AD. A bare-bones survey of the published research reveals no compelling evidence that amyloid deposition is neurotoxic in human beings or that it results in neurodegenerative changes involving synaptic, metabolic, or neuronal loss in human or transgenic-mouse brains. By contrast, the data supporting AD as a primary vascular disorder are more convincing. Findings suggesting a vascular cause of AD come from epidemiological, neuroimaging, pathological, pharmacotherapeutic, and clinical studies. The consensus of these studies indicates that chronic brain hypoperfusion is linked to AD risk factors, AD preclinical detection and pharmacotherapeutic action of AD symptoms.

de Leeuw, F. E. and J. van Gijn (2004). "[Vascular dementia]." Ned Tijdschr Geneeskd 148(24): 1181-6.

            Vascular dementia is one of the most frequently occurring dementia syndromes. Its prevalence is about 5% among subjects above 85 years of age. Elevated blood pressure and atherosclerosis are the most important risk factors. According to international criteria, vascular dementia usually occurs within three months after having a stroke. However, the diagnosis can be difficult as some strokes are clinically 'silent' and may go unnoticed. Other factors may also contribute to the dementia syndrome, and concomitant depression may mask its clinical picture. In population studies, treatment of vascular risk factors is associated with a relatively low incidence of vascular dementia, but this effect has not been investigated in a randomized clinical trial. The value of acetylsalicylic acid in attenuating cognitive deterioration in patients with vascular dementia is uncertain. Acetylcholinesterase inhibitors may slow down cognitive decline not only in some patients with Alzheimer's disease but also in patients with vascular dementia.

Dejaegere, T. and B. de Strooper (2004). "[Secretases as therapeutic targets for the treatment of Alzheimer's disease]." Verh K Acad Geneeskd Belg 66(1): 29-58; discussion 58-9.

            Alzheimer's disease is the most frequent degenerative disorder of the central nervous system. A focus on the familial, monogenetic disease subtypes has put researchers on the trail of the primary pathogenetic agent, the Abeta-peptide. The production of this peptide is being controlled by a number of proteolytic enzymes commonly known as the "secretases". An intensive study of the molecular and cell biological functions of these secretases is undertaken with the aim of generating drugs to cure Alzheimer's disease.

DeMattos, R. B. (2004). "Apolipoprotein E dose-dependent modulation of beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease." J Mol Neurosci 23(3): 255-62.

            Susceptibility to the development of Alzheimer's disease (AD) is increased for individuals harboring one or more apolipoprotein E4 (apoE4) alleles. Even though several isoform-specific effects of apoE have been identified, the relationship between biochemical function and risk factor assessment remains unknown. Our previous studies have demonstrated that there is an equilibrium between cerebral spinal fluid (CSF) and plasma beta-amyloid (Abeta) and that amyloid plaques can modify this equilibrium. Trafficking of soluble central nervous system (CNS) Abeta is a very dynamic system that almost certainly is modulated by Abeta-binding proteins. Alt