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Alzheimer's Disease Reviews: 2005

Zlokovic, B. V., R. Deane, et al. (2005). "Neurovascular pathways and Alzheimer amyloid beta-peptide." Brain Pathol 15(1): 78-83.

            According to the prevailing amyloid cascade hypothesis, the onset and progression of a chronic neurodegenerative condition in Alzheimer disease (AD) is initiated by the amyloid beta-peptide (Abeta) accumulation in brain and consequent neuronal toxicity. Recent emphasis on co-morbidity of AD and cerebrovascular disease and the recognition that cerebrovascular dysregulation is an important feature of AD, has shed new light on neurovascular dysfunction as a possible contributor to cognitive decline and Alzheimer neurodegeneration. In the same time, this association has raised a question as to whether there is a causal relationship between cerebrovascular dysregulation and Abeta-initiated pathology, and whether influencing targets in the neurovasculature may prevent different forms of Abeta brain accumulation and/or lower pre-existing accumulates in a later stage of the disease. Pathogenic cascades which operate to dissociate normal transport exchanges between central and peripheral pools of Abeta, and decreased vascular competence leading to brain hypoperfusion and impaired Abeta clearance are discussed. We suggest that there is a link between neurovascular dysfunction and elevated brain Abeta which provides a new scenario for therapeutic interventions to control Alzheimer mental deterioration.

Zlokovic, B. V. (2005). "Neurovascular mechanisms of Alzheimer's neurodegeneration." Trends Neurosci 28(4): 202-8.

            In contrast to traditional neuroncentric views of Alzheimer's disease (AD), recent findings indicate that neurovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Here, I propose the neurovascular hypothesis of AD, suggesting that faulty clearance of amyloid beta peptide (A beta) across the blood-brain barrier (BBB), aberrant angiogenesis and senescence of the cerebrovascular system could initiate neurovascular uncoupling, vessel regression, brain hypoperfusion and neurovascular inflammation. Ultimately, this would lead to BBB compromise, to chemical imbalance in the neuronal environment and to synaptic and neuronal dysfunction, injury and loss. Based on the neurovascular hypothesis, I suggest an array of new potential therapeutic approaches that could be developed for AD, to enhance A beta clearance and neurovascular repair, and to protect the neurovascular unit from divergent inducers of injury and apoptosis.

Zimmermann, M., F. Gardoni, et al. (2005). "Molecular rationale for the pharmacological treatment of Alzheimer's disease." Drugs Aging 22 Suppl 1: 27-37.

            Cerebral deposition of amyloid plaques containing amyloid beta-peptide (Abeta) has traditionally been considered the central feature of Alzheimer's disease (AD). Abeta is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: alpha-, beta- and gamma-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of alpha-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-D-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-D-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated alpha-secretase and they reduced Abeta generation and amyloid accumulation in a transgenic mouse model. beta-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for beta-secretase inhibitors. gamma-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Abeta directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway.

Zimecki, M. and J. Artym (2005). "[Therapeutic properties of proteins and peptides from colostrum and milk]." Postepy Hig Med Dosw (Online) 59: 309-23.

            Colostrum and milk are rich in proteins and peptides which play a crucial role in innate immunity when transferred to the offspring and may accelerate maturation of the immune system in neonates. The immunotropic properties of these proteins prompted investigators research their potential application in prevention and therapy. Lactoferrin (LF) exhibits antibacterial, antifungal, antiviral, antiparasitice, and antitumoral activities. It is protective with regard to intestinal epithelium, promotes bone growth, and accelerates the recovery of immune system function in immunocompromised animals. LF was tried in the treatment of hepatitis C infection and the intestinal form of graft-versus-host disease (GvHD). A proline-rich polypeptide (PRP) demonstrated a variety of immunotropic functions, including the promotion of T-cell maturation and inhibition of autoimmune disorders. PRP, in the form of chewable tablets (Colostrinin) was recently found to improve or stabilize the health status of Alzheimer's disease patients. Casein and casein-derived peptides showed protective activities in enamel demineralization and as caries-preventing agents. The protein hydrolyzates were also protective in diabetic animals, reduced tumor growth, had antihypertensive activity and diminished colicky symptoms in infants. Glycomacropeptide (GMP), a peptide derived from kappa-casein, exhibited various antibacterial and antithrombotic activities. Alpha-lactalbumin (LA) demonstrated antiviral, antitumoral and anti-stress properties. LA-enriched diets were anxiolytic, lowered blood pressure in rats, prevented diarrhea, and led to a better weight gain in malnourished children. HAMLET, a complex of LA and oleic acid, was effective in patients with cutaneous papillomas. Lysozyme found application in infant formulas, the treatment of periodentitis, and the prevention of tooth decay. Milk enriched in lysozyme was used in feeding premature infants suffering from concomitant diseases. Interesting, antibacterial properties were exhibited by lactoperoxidase. Both lysozyme and lactoperoxidase required cooperative action with LF in combating bacteria. In conclusion, preparations derived from milk and colostrum are effective, easily bioaccessible, and safe, finding wide application in prevention and therapy for newborns and adults.

Zijdenbos, A. P., J. P. Lerch, et al. (2005). "Brain imaging in drug R&D." Biomarkers 10 Suppl 1: S58-68.

            Magnetic resonance imaging (MRI), used as a clinical diagnostic tool since the early 1980s, is rapidly gaining traction as an integral part of the drug development process. Brain imaging research spans a wide area, covering both structure and function, and ranging from the physics and physiology associated with novel acquisition techniques, to the development of sophisticated image processing algorithms. This paper briefly describes two methods on either end of this spectrum: the "pipeline" framework for the fully automated morphometric analysis of brain imaging data, and molecular MRI, which holds promise for the non-invasive detection of molecular targets of new pharmacological compounds. The potential use of these technologies is illustrated by examples of their applications in multiple sclerosis, Alzheimer's disease, and oncology.

Zhu, X., G. Perry, et al. (2005). "Insulin signaling, diabetes mellitus and risk of Alzheimer disease." J Alzheimers Dis 7(1): 81-4.

Zhu, X., H. G. Lee, et al. (2005). "Oxidative imbalance in Alzheimer's disease." Mol Neurobiol 31(1-3): 205-17.

            Oxidative stress is a striking feature of susceptible neurons in the Alzheimer's disease brain. Importantly, because oxidative stress is an early event in Alzheimer's disease, proximal to the development of hallmark pathologies, it likely plays an important role in the pathogenesis of the disease. Investigations into the cause of such oxidative stress show that interactions between abnormal mitochondria and disturbed metal metabolism are, at least in part, responsible for cytoplasmic oxidative damage observed in these susceptible neurons, which could ultimately lead to their demise. Oxidative stress not only temporally precedes the pathological lesions of the disease but could also contribute to their formation, which, in turn, could provide some protective mechanism to reduce oxidative stress and ensure that neurons do not rapidly succumb to oxidative insults. In this review, we present the evidence for oxidative stress in Alzheimer's disease and its likely sources and consequence in relation to other pathological changes.

Zhang, H. Y. (2005). "One-compound-multiple-targets strategy to combat Alzheimer's disease." FEBS Lett 579(24): 5260-4.

            The present one-drug-one-target paradigm in drug discovery has been considered partially responsible for the more-funding-less-drug predicament in modern pharmaceutical industry. To hit the multiple targets implicated in complex diseases, two strategies, based on multicomponent or single-ingredient, are conceivable. Although the latter is more difficult to be fulfilled than the former, the recent progress made in the fight against Alzheimer's disease (AD) has brought us the first light of success of the latter strategy. In this review, both synthetic and natural multipotent agents are described, which hit two or more targets implicated in AD, e.g., acetylcholinesterase, monoamine oxidase, amyloid-beta, tau protein, metal ions and reactive oxygen species. Nevertheless, due to the potential risks in safety, absorbability and pharmacokinetics of synthetic multipotent agents, natural counterparts seem more promising in the future development.

Zerbinatti, C. V. and G. Bu (2005). "LRP and Alzheimer's disease." Rev Neurosci 16(2): 123-35.

            The low-density lipoprotein receptor (LDLR)-related protein, LRP, is a unique member of the LDLR family. Frequently referred to as a scavenger receptor, LRP is a large transmembrane endocytic receptor that can bind and internalize many functionally distinct ligands. Besides its role as a cargo-receptor, LRP has also been implicated in many signaling pathways. LRP knockout mice die at early embryonic age, which strongly suggests that LRP's functions are essential for normal development. Within the CNS, LRP is highly expressed in neuronal cell bodies and dendritic processes. In vitro, neurite outgrowth is stimulated by apolipoprotein E (apoE)-containing lipoprotein particles via binding to LRP. ApoE is the major cholesterol transporter in the brain and human carriers of one or two copies of the e4 allele of apoE are at a higher risk of developing Alzheimer's disease (AD). LRP also binds the amyloid precursor protein (APP) and its proteolytic fragment, the amyloid-beta peptide (Abeta), which are major players in the pathogenesis of AD. Finally, LRP has been linked to AD by genetic evidence. In this review we discuss the potential mechanisms by which LRP can affect APP and Abeta metabolism, and therefore contribute to the pathogenesis of AD.

Zekry, D., C. Duyckaerts, et al. (2005). "[Mixed dementia: a neuropathologic point od view]." Psychol Neuropsychiatr Vieil 3(4): 251-9.

            Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of dementia in the elderly. Although AD can be diagnosed with a very high degree of accuracy, the distinction between pure AD, VaD and mixed dementia (MD), where both pathologies co-exist in the same patient, remains a controversial issue and one of the most difficult diagnostic challenges. MD represents a very frequent pathology, especially in the elderly, as underlined by the neuropathological studies. However, the respective importance of degenerative and vascular lesions, their interaction in the genesis of dementia and the mere existence of mixed dementia are still debated. Accurate diagnosis of MD is of crucial significance for epidemiologic purposes and for preventive and therapeutic strategies. Until recently, pharmacological studies have generally focused on pure diseases, either AD or VaD, and have provided little data on the best therapeutic approach to MD. This review will provide an overview of neuropathological aspects of MD in the elderly, which appears to be one of the most common forms of dementia.

Zawia, N. H. and M. R. Basha (2005). "Environmental risk factors and the developmental basis for Alzheimer's disease." Rev Neurosci 16(4): 325-37.

            Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The hallmark pathological features of AD (amyloid plaques and associated proteins) are present in normal aging indivduals, suggesting that AD may result from the acceleration of normal age-related processes in the brain. The sporadic nature of most AD cases strongly argues for an environmental link that may drive AD pathogenesis; however, it is unclear when this environmental stress may occur. Therefore it is important to identify an environmental trigger(s) and to pinpoint the period during which such factors pose the greatest risk. Recently, we reported that developmental exposure of rats to the xenobiotic metal lead (Pb) resulted in a delayed overexpression (20 months later) of the amyloid precursor protein (APP) and its amyloidogenic Abeta product. Similarly, aged monkeys exposed to Pb as infants also responded in the same way. These data suggest that environmental influences occurring during brain development predetermine the expression and regulation of APP later in life, potentially influencing the course of amyloidogenesis, and argue for both an environmental trigger and a developmental origin of AD. In this review, we present evidence for the developmental basis of neurodegeneration and discuss mechanisms that may explain how perturbations during development can have long-term or delayed consequences in the aging brain.

Zatz, M. and A. Starling (2005). "Calpains and disease." N Engl J Med 352(23): 2413-23.

Zarros, A., K. S. Kalopita, et al. (2005). "Serotoninergic impairment and aggressive behavior in Alzheimer's disease." Acta Neurobiol Exp (Wars) 65(3): 277-86.

            The overall goal of all therapeutic interventions in Alzheimer's disease (AD) is to: (a) optimize the impaired functions and (b) restore an affordable quality of life for both the patient and his surroundings. AD has been characterized by a significant serotoninergic impairment. It is well known that impaired serotoninergic function is related to aggressive behavior. We, herein, review the past and recent evidence that seems to link the serotoninergic system with aggressive manifestations in AD patients. Managing the aggressive behavior of these patients might be of significant medical, social and economical importance. However, there is still a long way to go until we verify the exact pathophysiological mechanism(s) involved in the induction of aggression in AD patients. The current data underlines a complex relationship between the observed serotoninergic impairment in AD patients and the (a) cholinergic system, (b) the endocrine (hormonal) state, (c) the nutritional habits, (d) the genetic background and (e) the caregiving environment.

Zadikoff, C. and A. E. Lang (2005). "Apraxia in movement disorders." Brain 128(Pt 7): 1480-97.

            The definition of apraxia specifies that the disturbance of performed skilled movements cannot be explained by the more elemental motor disorders typical of patients with movement disorders. Generally this does not present a significant diagnostic problem when dealing with 'higher-level' praxic disturbances (e.g. ideational apraxia), but it can be a major confound in establishing the presence of limb-kinetic apraxia. Most motor disturbances characteristic of extrapyramidal disorders, particularly bradykinesia and dystonia, will compromise the ability to establish the presence of loss of dexterity and deftness that constitutes this subtype. The term 'apraxia' has also been applied to other motor disturbances, such as 'gait apraxia' and 'apraxia of eyelid opening', that perhaps are misnomers, demonstrating the lack of a coherent nomenclature in this field. Apraxia is a hallmark of corticobasal degeneration (CBD) and historically this has received the most attention among the movement disorders. Corticobasal degeneration is characterized by various forms of apraxia affecting limb function, particularly ideomotor apraxia and limb-kinetic apraxia, although buccofacial and oculomotor apraxia can be present as well. The syndrome of parkinsonism and prominent apraxia, designated the 'corticobasal syndrome' (CBS), may be caused by a variety of other central nervous system pathologies including progressive supranuclear palsy (PSP), Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementias. Distinct from the CBS, PSP and Parkinson's disease can demonstrate varying degrees of apraxia on selected tests, especially in those patients with more severe cognitive dysfunction. Diseases that cause the combination of apraxia and a primary movement disorder most often involve a variety of cerebral cortical sites as well as basal ganglia structures. Clinical-pathological correlates and functional imaging studies are compromised by both this diffuse involvement and the confusion experienced in the clinical evaluation of apraxia in the face of the additional elemental movement disorders. Finally, although apraxia results in clear disability in patients with the CBS, it is not clear how milder ideomotor apraxia found on specific testing contributes to patients' overall day-to-day motor disability.

Young, G. and J. Conquer (2005). "Omega-3 fatty acids and neuropsychiatric disorders." Reprod Nutr Dev 45(1): 1-28.

            Epidemiological evidence suggests that dietary consumption of the long chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish or fish oil, may modify the risk for certain neuropsychiatric disorders. As evidence, decreased blood levels of omega-3 fatty acids have been associated with several neuropsychiatric conditions, including Attention Deficit (Hyperactivity) Disorder, Alzheimer's Disease, Schizophrenia and Depression. Supplementation studies, using individual or combination omega-3 fatty acids, suggest the possibility for decreased symptoms associated with some of these conditions. Thus far, however, the benefits of supplementation, in terms of decreasing disease risk and/or aiding in symptom management, are not clear and more research is needed. The reasons for blood fatty acid alterations in these disorders are not known, nor are the potential mechanisms by which omega-3 fatty acids may function in normal neuronal activity and neuropsychiatric disease prevention and/or treatment. It is clear, however, that DHA is the predominant n-3 fatty acid found in the brain and that EPA plays an important role as an anti-inflammatory precursor. Both DHA and EPA can be linked with many aspects of neural function, including neurotransmission, membrane fluidity, ion channel and enzyme regulation and gene expression. This review summarizes the knowledge in terms of dietary omega-3 fatty acid intake and metabolism, as well as evidence pointing to potential mechanisms of omega-3 fatty acids in normal brain functioning, development of neuropsychiatric disorders and efficacy of omega-3 fatty acid supplementation in terms of symptom management.

Youdim, M. B. and J. J. Buccafusco (2005). "CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases." J Neural Transm 112(4): 519-37.

            Patients with mild forms of dementia and age-related memory impairment have just begun to benefit from pharmacotherapy developed over the last several years. However, current approaches do not significantly modify the course of neurodegeneration or of the aging process, and they offer limited and transient benefit to many patients. The goal of this review is to summarize new potential approaches in which molecules have been developed expressly to target multiple brain systems for the treatment of memory and cognition impairment. Some of these approaches include the development of single molecular entities that combine activity as cholinesterase inhibitors, muscarinic cholinergic M2 receptor antagonists, nicotinic acetylcholine receptor agonists, alpha(2)-adrenergic agonists, or monoamine oxidase inhibitors. Many of the bi-functional compounds discussed have improved efficacy as cognitive enhancing agents and/or they offer potential for neuroprotection and disease modification. It is likely that syndromes such as Alzheimer's disease will require multiple drug therapy to address the varied pathological aspects of the disease. Even if the strategy of combining drugs with different therapeutic targets is workable, the development of multi-functional compounds will obviate the challenge of administering multiple single drug entities with potentially different degrees of bioavailability, pharmacokinetics, and metabolism. Also, the simplification of the therapeutic regimen for individuals with AD who have difficulty with compliance is important.

Yoneda, M. and H. Sanada (2005). "[3-methoxy-4-hydroxyphenylglycol (MHPG)]." Nippon Rinsho 63 Suppl 8: 404-6.

Yang, S. Y., X. Y. He, et al. (2005). "Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase." Trends Endocrinol Metab 16(4): 167-75.

            Human 17beta-hydroxysteroid dehydrogenase type 10 (17beta-HSD10) is a mitochondrial enzyme encoded by the SCHAD gene, which escapes chromosome X inactivation. 17Beta-HSD10/SCHAD mutations cause a spectrum of clinical conditions, from mild mental retardation to progressive infantile neurodegeneration. 17Beta-HSD10/SCHAD is essential for the metabolism of isoleucine and branched-chain fatty acids. It can inactivate 17beta-estradiol and steroid modulators of GABA(A) receptors, and convert 5alpha-androstanediol into 5alpha-dihydrotestosterone (DHT). Certain malignant prostatic epithelial cells contain high levels of 17beta-HSD10, generating 5alpha-DHT in the absence of testosterone. 17Beta-HSD10 has an affinity for amyloid-beta peptide, and might be linked to the mitochondrial dysfunction seen in Alzheimer's disease. This versatile enzyme might provide a new drug target for neuronal excitability control and for intervention in Alzheimer's disease and certain cancers.

Yang, S. Y., X. Y. He, et al. (2005). "3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease." Febs J 272(19): 4874-83.

            3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. HAD has a preference for medium chain substrates, whereas short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs. Therefore, HAD should not be referred to as SCHAD. SCHAD is not a member of the HAD family, but instead, belongs to the short chain dehydrogenase/reductase superfamily. Previously reported cases of SCHAD deficiency are due to an inherited HAD deficiency. SCHAD, also known as 17beta-hydroxysteroid dehydrogenase type 10, is important in brain development and aging. Abnormal levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product, SCHAD, are potential targets for intervention in conditions, such as Alzheimer's disease, Parkinson's disease, and an X-linked mental retardation, that may arise from the impaired degradation of branched chain fatty acid and isoleucine.

Yanagisawa, K. (2005). "Cholesterol and amyloid beta fibrillogenesis." Subcell Biochem 38: 179-202.

            Evidence is accumulating to suggest that cholesterol is a potent risk factor for the development of Alzheimer's disease. An increase in cholesterol level in neuronal membranes may facilitate the generation and aggregation of the amyloid beta-protein (Abeta). Our results and those of other groups suggest that cholesterol has both direct and indirect effects of acceleration of Abeta fibrillogenesis. A novel concept of cholesterol neurobiology is necessary to elucidate the mechanism underlying cholesterol-dependent Abeta pathology.

Yanagisawa, K. (2005). "GM1 ganglioside and the seeding of amyloid in Alzheimer's disease: endogenous seed for Alzheimer amyloid." Neuroscientist 11(3): 250-60.

            A fundamental question about the pathogenesis of Alzheimer's disease (AD) is how monomeric, nontoxic amyloid beta-protein (Abeta) is converted to its toxic aggregates in the brain. The author previously identified a unique Abeta species in the AD brain, which is characterized by its binding to GM1 ganglioside (GM1). On the basis of the molecular characteristics of GM1-bound Abeta (GAbeta), the author hypothesized that GM1 plays a critical role in the process. The author recently examined this possibility using a novel monoclonal antibody raised against purified GAbeta and validated that GAbeta is endogenously generated in the brain and accelerates Abeta assembly by acting as a seed. Furthermore, the author provided a possibility that aging and the expression of apolipoprotein E4 facilitate Abeta assembly in the brain through an increase in the GM1 content in the neuronal membranes, which likely induces GAbeta generation. The author's results imply a mechanism underlying the onset of AD and also provide a new insight into development of novel therapeutic strategy.

Yan, S. D. and D. M. Stern (2005). "Mitochondrial dysfunction and Alzheimer's disease: role of amyloid-beta peptide alcohol dehydrogenase (ABAD)." Int J Exp Pathol 86(3): 161-71.

            An important means of determining how amyloid-beta peptide (Abeta) affects cells is to identify specific macromolecular targets and assess how Abeta interaction with such targets impacts on cellular functions. On the one hand, cell surface receptors interacting with extracellular Abeta have been identified, and their engagement by amyloid peptide can trigger intracellular signaling cascades. Recent evidence has indicated a potentially significant role for deposition of intracellular Abeta in cell stress associated with amyloidosis. Thus, specific intracellular targets of Abeta might also be of interest. Our review evaluates the potential significance of Abeta interaction with a mitochondrial enzyme termed Abeta-binding alcohol dehydrogenase (ABAD), a member of the short-chain dehydrogenase-reductase family concentrated in mitochondria of neurones. Binding of Abeta to ABAD distorts the enzyme's structure, rendering it inactive with respect to its metabolic properties, and promotes mitochondrial generation of free radicals. Double transgenic mice in which increased levels of ABAD are expressed in an Abeta-rich environment, the latter provided by a mutant amyloid precursor protein transgene, demonstrate accelerated decline in spatial learning/memory and pathologic changes. These data suggest that mitochondria ABAD, ordinarily a contributor to metabolic homeostasis, has the capacity to become a pathogenic factor in an Abeta-rich environment.

Yamamoto, H. (2005). "[Regulation of phosphorylation of tau by insulin and Ca2+ signals]." Nippon Yakurigaku Zasshi 125(3): 129-35.

Yamaguchi, H. (2005). "Illustration of dynamic changes in Alzheimer pathology: from mild cognitive impairment to terminal stage." Neuropathology 25(4): 285-7.

            It is quite important to examine the neuropathology of large numbers of brains from non-demented as well as demented subjects to elucidate the pathogenesis of dementia. Such a study, "power neuropathology" reveals the temporal profile of the disease, and results in the development of the treatment and the prevention of dementia.

Xiong, G. and P. M. Doraiswamy (2005). "Combination drug therapy for Alzheimer's disease: what is evidence-based, and what is not?" Geriatrics 60(6): 22-6.

            Although FDA-approved Alzheimer's disease (AD) treatment strategies (cholinesterase inhibitors and memantine) offer proven benefits, providers recognize unmet needs beyond what is currently available. Consequently there is a significant use of anecdotal yet unproven combinations for treating AD in practice. Based on the best evidence, combination drug therapy is the standard of care for treating other medical conditions such as malignancies, human immunodeficiency virus (HIV), and hypertension. We review recent combination drug therapy studies in AD. To date, the best evidence-based combination strategy is for moderate-to-severe AD, in which the addition of memantine to stable donepezil therapy was found to benefit cognition, behavior, and function. In milder stages of AD, the benefit of combination drug therapy has not been demonstrated. This review highlights the urgent need to systematically test additional rational drug combinations and the need for future trials to enroll adequate sample sizes and utilize relevant and sensitive outcome measures.

Xiong, G. L., A. Benson, et al. (2005). "Statins and cognition: what can we learn from existing randomized trials?" CNS Spectr 10(11): 867-74.

            BACKGROUND: Statins are being developed as treatments for Alzheimer's dementia based on evidence from preclinical and observational studies. However, cholesterol plays an integral role in cell membrane signal transduction and suboptimal cholesterol level could potentially impair neuronal function. Additionally, results of observational nonrandomized studies may have been affected by treatment bias. METHODS: We performed a systematic literature review in MEDLINE from January 1966 to July 2004 and included published prospective, randomized, and placebo-controlled human studies that examined the cognitive effects of statins. RESULTS: Nine studies with sample sizes ranging from 22 to 20,000 and duration of 3 weeks to 5 years, met criteria for review. Study populations and cognitive outcomes varied. Four studies were >6 months or longer. Overall, none of these studies reported finding a positive benefit for any statin on cognition in non-demented subjects although there was inconsistent evidence for acute cognitive worsening in some studies. CONCLUSION: While statins intuitively have appeal for the prevention or treatment of dementia, any conclusions about their efficacy should await more definitive evidence from on-going prospective clinical trials.

Xiao, Z., D. Prieto, et al. (2005). "Proteomic patterns: their potential for disease diagnosis." Mol Cell Endocrinol 230(1-2): 95-106.

            Alterations in proteins abundance, structure, or function, act as useful indicators of pathological abnormalities prior to development of clinical symptoms and as such are often useful diagnostic and prognostic biomarkers. The underlying mechanism of diseases such as cancer are, however, quite complicated in that often multiple dysregulated proteins are involved. It is for this reason that recent hypotheses suggest that detection of panels of biomarkers may provide higher sensitivities and specificities for disease diagnosis than is afforded with single markers. Recently, a novel approach based on the analysis of protein patterns has emerged that may provide a more effective means to diagnose diseases, such as ovarian and prostate cancer. The method is based on the use of surface-enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry (TOF-MS) to detect differentially captured proteins from clinical samples, such as serum and plasma. This analysis results in the detection of "proteomic" patterns that have been shown in recent investigations to distinguish diseased and unaffected subjects to varying degrees. This review will discuss the basics of SELDI protein chip technology and highlight its recent applications in disease biomarker discovery with emphasis on cancer diagnosis.

Wulf, G., G. Finn, et al. (2005). "Phosphorylation-specific prolyl isomerization: is there an underlying theme?" Nat Cell Biol 7(5): 435-41.

            The prolyl isomerase Pin1 is a conserved enzyme that is intimately involved in diverse biological processes and pathological conditions such as cancer and Alzheimer's disease. By catalysing cis-trans interconversion of certain motifs containing phosphorylated serine or threonine residues followed by a proline residue (pSer/Thr-Pro), Pin1 can have profound effects on phosphorylation signalling. The structural and functional differences that result from cis-trans isomerization of specific pSer/Thr-Pro motifs probably underlie most, if not all, Pin1-dependent actions. Phosphorylation-dependent prolyl isomerization by Pin1 remains a unique mode for the modulation of signal transduction. Here, we provide an overview of the plethora of regulatory events that involve this unique enzyme, with a particular focus on oncogenic signalling and neurodegeneration.

Wu, Y. H. and D. F. Swaab (2005). "The human pineal gland and melatonin in aging and Alzheimer's disease." J Pineal Res 38(3): 145-52.

            The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep-wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I-II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.

Wu, Y. and Y. Luo (2005). "Transgenic C. elegans as a model in Alzheimer's research." Curr Alzheimer Res 2(1): 37-45.

            Alzheimer's disease (AD) has been associated with aggregation of beta-amyloid peptide (Abeta) and cell death in the brain. Using various models, such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the mouse Mus musculus, investigators have attempted to imitate the pathology process of AD for better understanding of the cellular mechanisms and for possible therapeutic intervention. Among many in vitro and in vivo models of AD, transgenic C. elegans expressing human Abeta has shown its own advantages. The transgenic C. elegans model have been used in studying AD due to its short life span, facility to maintain, ability to develop muscle-associated deposits reactive to amyloid-specific dyes and the concomitant progressive paralysis phenotype. Moreover, the transgenic C. elegans exhibits increased levels of reactive oxygen species (ROS) and protein carbonyls, similar to those observed in AD patients, supporting the current theory on Abeta-induced oxidative stress and subsequent neurodegeneration in AD. DNA microarray assays of the worm demonstrated several stress-related genes being upregulated, particularly two genes homologous to human alphaB-crystallin and tumor necrosis factor-related protein, which were also upregulated in postmortem AD brain. Studies in our laboratory along with others suggest that the transgenic C. elegans model is a suitable in vivo model to relate Abeta-expression with its toxicity, which may underlie AD pathology. It may also be used as a tool for pharmacological evaluation of novel therapeutic agents.

Wright, A. F. (2005). "Neurogenetics II: complex disorders." J Neurol Neurosurg Psychiatry 76(5): 623-31.

            The genetic analysis of common neurological disorders will be a difficult and protracted endeavour. Genetics is only one of many disciplines that will be required but it has already thrown considerable light on the aetiology of several major neurological disorders through the analysis of rare inherited subgroups. The identification of individual susceptibility genes with variants of smaller effect will be more difficult but there is no sharp demarcation between large and small genetic effects, so that many new and important insights will emerge using existing and new technologies. The availability of improved neuroimaging, better animal models of disease and new genetic tools, such as high-throughput gene chips, expression microarrays and proteomics, are extending the range of traditional genetic mapping tools. Finally, an understanding of the genetic and epigenetic mechanisms that restrain the differentiation and integration of human neural stem cells into mature neuronal networks could have a major impact on clinical practice. These approaches will be illustrated in the context of Alzheimer disease, Parkinson disease and synucleinopathies, tauopathies, amyotrophic lateral sclerosis and stroke.

Wood, W. G., U. Igbavboa, et al. (2005). "Is hypercholesterolemia a risk factor for Alzheimer's disease?" Mol Neurobiol 31(1-3): 185-92.

            There is considerable attention being given to the association of Alzheimer's disease and cholesterol homeostasis. To that end, some have suggested that elevated cholesterol levels are a risk factor for Alzheimer's disease. If elevated cholesterol is a risk factor for Alzheimer's disease, then it would be expected that patients with Alzheimer's disease would have elevated serum and brain cholesterol levels. Studies were reviewed that have examined cholesterol levels in Alzheimer's patients and control subjects, including prospective studies, and based on that review, the conclusion is reached that the majority of studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer's disease. Alternative hypotheses are discussed, including cholesterol domains and subgroups of individuals with hypercholesteremia.

Wong, P. C. (2005). "Alzheimer disease: therapeutic targets for clinical trials." Retina 25(8 Suppl): S80-S81.

Wojtera, M., B. Sikorska, et al. (2005). "Microglial cells in neurodegenerative disorders." Folia Neuropathol 43(4): 311-21.

            Microglia are resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. It is widely accepted that microglia contribute to the neurodegeneration through a release of a variety of proinflammatory substances. In fact, they are not the only cells which contribute to immunological processes inside the nervous system. The CNS is composed of different cell populations that answer to pathological factors and influence each other and modulate their reactions. These complex interactions are responsible for the development of brain pathology. This paper reviews the available information on microglial cells contribution to AD, PD and prion diseases development.

Wisniewski, T. and B. Frangione (2005). "Immunological and anti-chaperone therapeutic approaches for Alzheimer disease." Brain Pathol 15(1): 72-7.

            Alzheimer disease (AD) is the most common cause of dementia. Currently available therapies only provide symptomatic relief. A number of therapeutic approaches are under development that aim to increase the clearance of brain Abeta peptides. These include immune mediated clearance of Abeta and the inhibition of the interaction between Abeta and its pathological chaperones. Both active and passive immunization has been shown to have robust effects in transgenic mouse models of AD on amyloid reduction and behavioral improvements. However, a human trial of active immunization has been associated with significant toxicity in a minority of patients. New generation vaccines are being developed which likely will reduce the potential for cell-mediated toxicity. In addition, the recent development of anti-chaperone therapy opens a new therapeutic avenue which is unlikely to be associated with toxicity.

Winnicka, K., M. Tomasiak, et al. (2005). "Piracetam--an old drug with novel properties?" Acta Pol Pharm 62(5): 405-9.

            Piracetam (2-oxo-1-pyrrolidine-acetamide), the most common of the nootropic drugs, is a cyclic derivative of gamma-aminobutyric acid. The treatment with piracetam improves learning, memory, brain metabolism, and capacity. Piracetam has been shown to alter the physical properties of the plasma membrane by increasing its fluidity and by protecting the cell against hypoxia. It increases red cell deformability and normalizes aggregation of hyperactive platelets. Piracetam is an agent with antithrombotic, neuroprotective and rheological properties. The interaction of this molecule with the membrane phospholipids restores membrane fluidity and could explain the efficacy of piracetam in various disorders ranging from dementia and vertigo to myoclonus and stroke.

Wiltfang, J., P. Lewczuk, et al. (2005). "Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia." World J Biol Psychiatry 6(2): 69-84.

            Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Wilkinson, D. (2005). "Is there a double standard when it comes to dementia care?" Int J Clin Pract Suppl(146): 3-7.

            Dementia, a diagnostic syndrome that includes Alzheimer's disease (AD) and vascular dementia, affects more than 4 million Europeans. Its prevalence will increase as the population ages, even though half of cases remain undiagnosed. Dementia has a marked impact on the general health economy. The direct costs of caring for persons with AD alone exceed the cost of heart disease, cancer and stroke combined, primarily because of the need for expensive care in the later stages of the disease. Yet research spending for AD remains disproportionately small. Effective planning for the public health issues posed by AD mandates reduction of either the dependency or the prevalence of the disease. Some drug treatments have alleviated the symptoms of AD and improved the quality of life for patients and their families. However, many countries have introduced inappropriately stringent regulations for the use of medical therapy. These and related issues were addressed during the recent Facing Dementia Forum, in which 175 experts in dementia care discussed results of an extensive international survey. The experts identified three main barriers to effective care: (i) dementia is not considered a health care priority; (ii) there is a mistaken belief that nothing can be done about dementia; and (iii) early dementia is difficult to recognise. These observations provided a basis for the Agenda for Change, a series of strategies to overcome these barriers. The specific findings of the survey, as well as the Agenda for Change, will be reviewed in subsequent articles in this supplement.

Widelitz, R. (2005). "Wnt signaling through canonical and non-canonical pathways: recent progress." Growth Factors 23(2): 111-6.

            The Wnt-beta-catenin pathway regulates cell adhesion, morphology, proliferation, migration and structural remodeling. The aspects of the canonical and non-canonical pathways are reviewed here. The major components of this network are the Wnt ligands which bind to frizzled receptors at the cell surface. Activation of Wnt signaling down regulates the intracellular beta-catenin degradation component, allowing beta-catenin levels to accumulate within the cell. At normal levels, beta-catenin associates at the intracellular side of the membrane with cadherins to promote cell adhesion and with the actin microfilament cytoskeletal network to control cell shape. If beta-catenin levels become elevated, it can begin to accumulate within the cell nucleus and activate transcription in conjunction with co-transcription factors Lefs/Tcfs.Cell populations can regulate neighboring populations via the paracrine action of growth factors and through the action of cell adhesion molecules. Many examples of these interactions exist. The major players in Wnt signaling and its downstream canonical and non-canonical partners are reviewed here. For more details visit the World Wide Web Wnt Homepage (http://www.stanford.edu/~rnusse/wntwindow.html).

Whitwell, J. L. and C. R. Jack, Jr. (2005). "Comparisons between Alzheimer disease, frontotemporal lobar degeneration, and normal aging with brain mapping." Top Magn Reson Imaging 16(6): 409-25.

            Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are both common degenerative dementias in the under 65 age group. Although clinical criteria have been defined for both diseases, there is considerable overlap in clinical features, and hence, diagnosis still can be very difficult particularly in the early stages of the disease. As a result, there has been increasing interest in using magnetic resonance imaging to better characterize these diseases and to aid in diagnosis. Voxel-based morphometry (VBM) is an automated technique that assesses patterns of regional gray matter atrophy on magnetic resonance imaging between 2 groups of subjects. It is unbiased in that it looks throughout the whole brain and does not require any a priori assumptions concerning which structures to assess, giving it a significant advantage over traditional region of interest-based methods. Voxel-based morphometry has been widely used to assess patterns of regional atrophy in subjects with AD and FTLD. These studies have demonstrated specific patterns of regional loss in both diseases, compared the 2 diseases to look for differences that could be diagnostically useful, and have correlated regions of gray matter loss to cognitive and behavioral deficits in these subjects. This article will review the findings of these studies and discuss the role of VBM in these neurodegenerative diseases.

White, H. K. (2005). "Nutrition in advanced Alzheimer's disease." N C Med J 66(4): 307-12.

Wheldon, M. (2005). "Untangling the confusion. Alzheimer's management today." Adv Nurse Pract 13(5): 47-8, 50, 52.

Werner, P. (2005). "Lay perceptions about mental health: where is age and where is Alzheimer's disease?" Int Psychogeriatr 17(3): 371-82.

            Studies on laypersons' beliefs and knowledge about mental disorders have proliferated in recent years. However, attention has been focused mainly on depression and schizophrenia and on young adults. The aim of this paper is to summarize research in the area, and to discuss the need to expand research in the elderly population. The unique characteristics of older persons in terms of the prevalence and type of mental disorders, especially Alzheimer's disease (AD) and other dementias, as well as in terms of their being victims of "double jeopardy" require special attention and research. The present review has three main objectives. First, it summarizes the findings of studies examining different aspects of mental health literacy. Second, the importance of age in the study of mental health literacy is discussed. Third, findings of the few studies examining laypersons' beliefs in the area of AD are presented. Finally, research directions are suggested with special emphasis on the importance of geriatric mental health and mental health literacy.

Weksler, M. E., G. Gouras, et al. (2005). "The immune system, amyloid-beta peptide, and Alzheimer's disease." Immunol Rev 205: 244-56.

            In this review, the case is made that amyloid-beta peptide in the brain of patients with Alzheimer's disease is a primary cause of the disease and that immunotherapy directed against this peptide has the potential to halt and/or reverse disease progression. This supposition is supported by the capacity of anti-beta-amyloid peptide antibodies to prevent or reverse the disease in mouse models of Alzheimer's disease. Furthermore, preliminary results obtained in a small number of patients with Alzheimer's disease are consistent with the observations made in the mouse model of this disease. We review the relationship between the immune system, amyloid-beta peptide, and Alzheimer's disease and the progress made in applying immunotherapy to patients with Alzheimer's disease.

Weintraub, D. and M. B. Stern (2005). "Psychiatric complications in Parkinson disease." Am J Geriatr Psychiatry 13(10): 844-51.

            Although Parkinson disease (PD) is primarily considered a movement disorder, the high prevalence of psychiatric complications suggests that it is more accurately conceptualized as a neuropsychiatric disease. Affective disorders, cognitive impairment, and psychosis are particularly common in PD and are associated with excess disability, worse quality of life, poorer outcomes, and caregiver distress. Yet, in spite of this and their frequent occurrence, there is incomplete understanding of the epidemiology, phenomenology, risk factors, neuropathophysiology, and optimal treatment strategies for these disorders. Psychiatric complications are typically comorbid, and there is great intra- and inter-individual variability in presentation. The hallmark neuropathophysiological changes that occur in PD plus the association between exposure to dopaminergic medications and certain psychiatric disorders suggest a neurobiological basis for most psychiatric symptoms, although psychological factors are probably involved in the development of affective disorders. Although antidepressants, antipsychotics, and cognition-enhancing agents are commonly prescribed in PD, controlled studies demonstrating efficacy and tolerability of these drugs are virtually nonexistent. Because of the high prevalence and complexity of psychiatric complications in PD, geriatric psychiatrists are in a position to offer valuable consultation and clinical care to this population. This article provides an overview of the epidemiology, pathophysiology, clinical presentation, and management of the most common psychiatric complications in PD.

Weiner, M. F., L. S. Hynan, et al. (2005). "Early behavioral symptoms and course of Alzheimer's disease." Acta Psychiatr Scand 111(5): 367-71.

            OBJECTIVE: To determine if behavioral symptoms detected at initial evaluation relate to cognitive or functional status or survival time in Alzheimer's disease (AD) patients. method: Review, in 100 cases of autopsy-proven AD, of the relationship of behavioral symptoms detected at initial evaluation to cognitive and global function measures and survival time. RESULTS: Behavioral symptoms had occurred in 74% of patients, including apathy (51%), hallucinations (25%), delusions (20%) and depressed mood (6.6%). Verbal aggression was common (36.8%); physical aggression less so (17%). The symptomatic group was more functionally (but not cognitively) impaired and had shorter median survival time (8 years: 95% CI: 7-9 years vs. 10 years: 95% CI: 8-12 years; P = 0.002) than the asymptomatic group. The presence of any one symptom at initial evaluation accounted for 6.1% of the variance in duration of illness. CONCLUSION: Presence of behavioral symptoms at initial evaluation of AD patients is associated with greater functional impairment and shorter survival time.

Wehr, H. and M. Bednarska-Makaruk (2005). "[Will statins be used in dementia treatment?]." Neurol Neurochir Pol 39(4): 318-23.

            The paper presents current opinions on the mechanism of beta-amyloid accumulation, the role of cholesterol in the pathogenesis of dementia and observations of the role of statins in its development. Most of the observations were done on Alzheimer's disease, some of them concerned also dementia of a vascular origin and cognition. Statins are inhibitors of the cholesterol synthesis pathway. The mechanism of their action concerns not only their influence on the cholesterol level but also their influence on prenylation of various proteins and in consequence inhibition of inflammatory reactions. They exert also antioxidative activity. As the number of prospective studies is still insufficient the question whether statins could be used as drugs against dementia remains still unsolved.

Webber, K. M., A. K. Raina, et al. (2005). "The cell cycle in Alzheimer disease: a unique target for neuropharmacology." Mech Ageing Dev 126(10): 1019-25.

            Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease including, among others, theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. While there is strong evidence suggesting that each one of these proposed mechanisms contributes to disease pathogenesis, none of these mechanisms are able to account for all the physiological changes that occur during the course of the disease. For this reason, we and others have begun the search for a causative factor that predates known features found in Alzheimer disease, and that might therefore be a fundamental initiator of the pathophysiological cascade. We propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during Alzheimer disease is a potential causative factor that, together with oxidative stress, would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of Alzheimer disease include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Such mitotic alterations are not only one of the earliest neuronal abnormalities in the disease, but as discussed herein, are also intimately linked to all of the other pathological hallmarks of Alzheimer disease including tau protein, amyloid beta protein precursor and oxidative stress, and even risk factors such as mutations in the presenilin genes. Therefore, therapeutic interventions targeted toward ameliorating mitotic changes would be predicted to have a profound and positive impact on Alzheimer disease progression.

Webber, K. M., G. Casadesus, et al. (2005). "Gender differences in Alzheimer disease: the role of luteinizing hormone in disease pathogenesis." Alzheimer Dis Assoc Disord 19(2): 95-9.

            Epidemiological data reporting the predisposition of women to Alzheimer disease has provided researchers with an important clue as to the identity of the driving pathogenic force and lead many to question the potential role of sex steroids, namely estrogen, in disease pathogenesis. However, while estrogen has become the primary focus of research in the field, inconclusive data regarding estrogen replacement therapy has lead some researchers to begin investigating the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. Recently, we proposed that an increase in gonadotropin concentrations, not the decrease in steroid hormone (eg, estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease. Based on this, we suggest that therapeutic interventions targeted at gonadotropins may both prevent disease in those patients currently asymptomatic or may halt, and even reverse, disease in those currently afflicted.

Webber, K. M., G. Casadesus, et al. (2005). "Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis." Ann N Y Acad Sci 1052: 201-9.

            Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.

Watson, D., E. Castano, et al. (2005). "Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease." Neurol Res 27(8): 869-81.

            Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation. Amyloid accumulation may indirectly exert the greatest pathologic effect on the brain vasculature by destroying smooth muscle cells and creating a cascade of negative impacts on cerebral blood flow. The most visible manifestation of amyloid dis-equilibrium could actually be a defense mechanism employed to avoid serious vascular wall degradation while the major toxic effects to the gray and white matter neurons are mediated by soluble oligomeric Abeta peptides with high beta-sheet content. The recognition that dynamic soluble oligomeric Abeta pools exist in AD and are correlated to disease severity led to neurotoxicity and physical conformation studies. It is now recognized that the most basic soluble Abeta peptides are stable dimers with hydrophobic regions sequestered from the aqueous environment and are capable of higher order aggregations. Time course experiments employing a modified ELISA method able to detect Abeta oligomers revealed dynamic intermolecular interactions and additional experiments physically confirmed the presence of stable amyloid multimers. Amyloid peptides that are rich in beta-sheet structure are capable of creating toxic membrane ion channels and a capacity to self-assemble as annular structures was confirmed in vitro using atomic force microscopy. Biochemical studies have established that soluble Abeta peptides perturb metabolic processes, provoke release of deleterious reactive compounds, reduce blood flow, induce mitochondrial apoptotic toxicity and inhibit angiogenesis. While there is no question that gross amyloid deposition does contribute to AD pathology, the destructive potential now associated with soluble Abeta suggests that treatment strategies that target these molecules may be efficacious in preventing some of the devastating effects of AD.

Warren, J. D., J. M. Schott, et al. (2005). "Brain biopsy in dementia." Brain 128(Pt 9): 2016-25.

            Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Warner, J., R. Butler, et al. (2005). "Dementia." Clin Evid(14): 1198-220.

Wang, S. H., J. Li, et al. (2005). "[Inflammatory pathology and the anti-inflammation of saccharide substances in Alzheimer's disease]." Sheng Li Ke Xue Jin Zhan 36(1): 67-70.

Wang, R. and X. C. Tang (2005). "Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer's disease." Neurosignals 14(1-2): 71-82.

            Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer's disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.

Walsh, D. M., I. Klyubin, et al. (2005). "The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention." Biochem Soc Trans 33(Pt 5): 1087-90.

            Burgeoning evidence suggests that soluble oligomers of Abeta (amyloid beta-protein) are the earliest effectors of synaptic compromise in Alzheimer's disease. Whereas most other investigators have employed synthetic Abeta peptides, we have taken advantage of a beta-amyloid precursor protein-overexpressing cell line (referred to as 7PA2) that secretes sub-nanomolar levels of low-n oligomers of Abeta. These are composed of heterogeneous Abeta peptides that migrate on SDS/PAGE as dimers, trimers and tetramers. When injected into the lateral ventricle of rats in vivo, these soluble oligomers inhibit hippocampal long-term potentiation and alter the memory of a complex learned behaviour. Biochemical manipulation of 7PA2 medium including immunodepletion with Abeta-specific antibodies and fractionation by size-exclusion chromatography allowed us to unambiguously attribute these effects to low-n oligomers. Using this paradigm we have tested compounds directed at three prominent amyloid-based therapeutic targets: inhibition of the secretases responsible for Abeta production, inhibition of Abeta aggregation and immunization against Abeta. In each case, compounds capable of reducing oligomer production or antibodies that avidly bind Abeta oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers.

Walker, L. C., C. C. Ibegbu, et al. (2005). "Emerging prospects for the disease-modifying treatment of Alzheimer's disease." Biochem Pharmacol 69(7): 1001-8.

            The currently approved therapies for Alzheimer's disease (AD) in the US are designed to modify the function of specific neurotransmitter systems in the brain. While these palliative treatments can benefit some patients for a period of time, they do not halt the relentless cognitive and behavioral deterioration that characterize this neurodegenerative disorder. Consequently, much current research on AD is directed toward illuminating the disease process itself, particularly the abnormal accumulation of certain proteins in brain: the amyloid-beta protein (Abeta) in senile plaques and cerebral blood vessels, and the tau protein in neurofibrillary tangles. Genetic, biochemical and pathologic evidence now favors a primary role of Abeta aggregation in the Alzheimer proteopathic cascade, and studies in mice indicate that lowering the amount of this protein in brain can be beneficial. Recently, Abeta-immunization therapy has emerged as a particularly promising therapeutic option for treating Alzheimer's disease, but unexpected treatment-related side-effects are an overriding issue. These adverse events were not anticipated from preclinical studies with rodents; hence, more biologically relevant models, such as nonhuman primates, are needed to test the safety and efficacy of novel therapies for Alzheimer's disease.

Walker, D. G. and L. F. Lue (2005). "Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases." J Neurosci Res 81(3): 412-25.

            Inflammation-mediated mechanisms for human neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have evolved from being on the fringe of medical hypotheses to mainstream thinking. Pioneering immunopathology studies with human brain tissues identified microglia associated with neuropathologic hallmarks of these diseases. As activated macrophages were known to produce many potential toxic products, this gave rise to the hypothesis that activated microglia (brain resident macrophages) could be contributing to the degeneration of key target neurons in these diseases, as well as potential vascular dysfunction. Studies with microglia derived from different sources, including human brains, have confirmed that activated microglia can mediate neuronal cell death. Based on these theories, a number of human clinical trials with antiinflammatory agents have been carried out on AD patients. Results to date have indicated a lack of effectiveness at slowing disease progression and have begun to cast doubt on the significance of inflammation in AD. It has been shown recently that activating microglia through immunization of amyloid plaque-developing mice with amyloid beta peptide (Abeta) has promise as a therapeutic strategy and despite some setbacks, has potential as a treatment for AD patients. This article will consider experimental data with microglia to determine whether the additional targets need to be investigated. The use of human microglia cultures, in particular those derived from elderly diseased human brains, offers an experimental system that can closely model the cell type activated in human neurodegenerative diseases. Experimental data produced by our laboratory and others is reviewed to determine the contribution of this unique experimental model to understanding disease mechanisms and possibly discovering new therapeutic targets.

Wahlund, L. O., O. Almkvist, et al. (2005). "Evidence-based evaluation of magnetic resonance imaging as a diagnostic tool in dementia workup." Top Magn Reson Imaging 16(6): 427-37.

            BACKGROUND: The diagnostic utility of magnetic resonance imaging in dementia workups has increased recently. The basic use is to exclude space-occupying processes in the brain. However, magnetic resonance imaging offers major opportunities for studying atrophy of specific brain areas. A great interest has been put in whether atrophy in the medial temporal lobe can serve as an early diagnostic marker for Alzheimer disease. METHODS AND RESULTS: In this evaluation, we used evidence-based techniques and reviewed more than 400 articles that address this issue. Our main finding is that a variety of methods in studying brain areas were used, and this made it difficult to extract conclusive information in a systematic way. CONCLUSION: However, we were able to conclude that atrophy of the hippocampus can distinguish patients with Alzheimer disease from healthy subjects, but there was a lack of evidence because of insufficient studies concerning the usefulness of medial temporal lobe atrophy as a diagnostic marker in a more general setting.

Vogel, T., R. Verreault, et al. (2005). "[Hypertension and Alzheimer's disease]." Presse Med 34(11): 809-12.

            Case-control transversal studies have suggested the existence of an association between low blood pressure and Alzheimer's disease, although there is some doubt on the cause to effect relationship. A drop in blood pressure preceding the onset of dementia has been evoked but never confirmed. Longitudinal studies, with long term follow-up on the existence of hypertension during middle-age, have demonstrated a significant increase in the risk of developing Alzheimer's disease in cohorts of hypertensive patients compared to normotensive subjects. The potential benefit of preventive treatment with antihypertensive drugs in decreasing the risk of Alzheimer's disease has not been confirmed in clinical trials. The hypothesis of the formation of a cerebrovascular disease that would combine with the neuropathological lesions has been evoked, raising doubts on the diagnostic criteria used to define Alzheimer's disease. The novel concept that vascular risk factors could directly induce the formation of neuropathological lesions is interesting but warrants confirmation.

Villemagne, V. L., C. C. Rowe, et al. (2005). "Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer's disease." J Clin Neurosci 12(3): 221-30.

            Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are A beta amyloid plaques, neurofibrillary tangles, and reactive gliosis. Current diagnosis of AD is made by clinical, neuropsychologic, and neuroimaging assessments. Routine structural neuroimaging evaluation is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of AD. Functional neuroimaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) could prove to be valuable in the differential diagnosis of AD, as well as in assessing prognosis. With the advent of new therapeutic strategies aimed at reducing the A beta amyloid burden in the brain, there is increasing interest in the development of PET and SPECT radioligands that will permit the assessment of A beta amyloid burden in vivo. From this, the prospect of specific preclinical diagnosis arises, possibly in conjunction with other related A beta biomarkers in plasma and CSF.

Viegas, C., Jr., S. Bolzani Vda, et al. (2005). "New anti-Alzheimer drugs from biodiversity: the role of the natural acetylcholinesterase inhibitors." Mini Rev Med Chem 5(10): 915-26.

            Alzheimer's disease (AD) is a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays, drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only four commercial medicines approved for treatment of AD, and natural products have played an important alternative role in the research for new acetylcholinesterase inhibitors, as exemplified through the discovery of galantamine. This profile conducts us to give in this paper an overview relating the several classes of natural products with anti-cholinesterasic activity as potential templates to the design of new selective and powerful anti-Alzheimer drugs.

Verhoeff, N. P. (2005). "Acetylcholinergic neurotransmission and the beta-amyloid cascade: implications for Alzheimer's disease." Expert Rev Neurother 5(2): 277-84.

            Alzheimer's disease is characterized by both decreases in acetylcholinergic neurotransmission and increases in beta-amyloid accumulation. Currently, available clinical psychopharmacologic treatment is focused on increasing acetylcholinergic neurotransmission, whereas no clinical treatments to directly reduce beta-amyloid accumulation are available. Cholinesterase inhibitors improve cognition, certain neuropsychiatric symptoms and functional impairment in patients with mild-to-moderate Alzheimer's disease, and it is believed that this is mainly symptomatic treatment. However, this review discusses various levels of interaction between acetylcholinergic neurotransmission and the beta-amyloid cascade, which suggest that some specific acetylcholinergic treatments may reduce beta-amyloid accumulation, and therefore may slow disease progression over the long term. Various suggestions are made on how such potential disease-modifying effects could be studied in the future.

Vellas, B., S. Gauthier, et al. (2005). "Consensus statement on dementia of Alzheimer type in the severe stage." J Nutr Health Aging 9(5): 330-8.

Veerhuis, R., R. S. Boshuizen, et al. (2005). "Amyloid associated proteins in Alzheimer's and prion disease." Curr Drug Targets CNS Neurol Disord 4(3): 235-48.

            Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

Vassar, R. (2005). "beta-Secretase, APP and Abeta in Alzheimer's disease." Subcell Biochem 38: 79-103.

            Amyloid plaques, hallmark neuropathological lesions in Alzheimer's disease (AD) brain, are composed of the beta-amyloid peptide (Abeta). A large body of evidence suggests Abeta is central to the pathophysiology of AD and is likely to start this intractable neurodegenerative disorder. Mutations in three genes (amyloid precursor protein/APP, presenilin1, presenilin2) cause early on-set familial AD by increasing synthesis of the toxic 42 amino acid species of Abeta (Abeta42). Fibrillar Abeta in amyloid plaques appears to cause neurodegeneration, although recent studies suggest soluble Abeta oligomers may also be neurotoxic. Regardless, given the strong correlation between Abeta and AD, therapeutic strategies to lower cerebral Abeta levels should prove beneficial for the treatment of AD. Abeta is derived from APP via cleavage by two proteases, beta- and gamma-secretase. beta-secretase, recently identified as the novel aspartic protease BACEI, initiates the formation of Abeta. Consequently, BACE1 in principle is an excellent therapeutic target for strategies to reduce the production of Abeta in AD. However, the discovery of the homologue BACE2 raised the question of whether it too may be a beta-secretase. To settle this issue, our group and others have used gene targeting to generate BACE1 deficient (knockout) mice. These BACEI knockout mice have been instrumental in validating BACEI as the authentic beta-secretase in vivo. Here, I review the roles of BACE1, APP, and Abeta in AD and discuss the implications of therapeutic approaches that target BACE1 for the treatment of AD.

Vardy, E. R., A. J. Catto, et al. (2005). "Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease." Trends Mol Med 11(10): 464-72.

            The accumulation of the amyloid-beta peptide, the main constituent of the "amyloid plaque", is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amyloid precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme alpha-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's disease. A more complex knowledge of these proteases takes us one step closer to developing "disease-modifying" therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimer's disease become a reality.

Vandenberghe, R. and J. Tournoy (2005). "Cognitive aging and Alzheimer's disease." Postgrad Med J 81(956): 343-52.

            Cognitive aging and clinically probable Alzheimer's disease can be discriminated by means of clinical and neuropsychological testing, and structural and functional imaging techniques. Research at the level of cognitive brain systems and at the molecular level provides exciting new insights into the relation between aging and neurodegeneration. The advances at the clinical and at the basic research levels are necessary if we wish to meet the formidable challenge that the increasing prevalence of Alzheimer's disease poses to the medical community.

Vance, J. E., H. Hayashi, et al. (2005). "Cholesterol homeostasis in neurons and glial cells." Semin Cell Dev Biol 16(2): 193-212.

            Cholesterol is highly enriched in the brain compared to other tissues. Essentially all cholesterol in the brain is synthesized endogenously since plasma lipoproteins are unable to cross the blood-brain barrier. Cholesterol is transported within the central nervous system in the form of apolipoprotein E-containing lipoprotein particles that are secreted mainly by glial cells. Cholesterol is excreted from the brain in the form of 24-hydroxycholesterol. Apolipoprotein E and cholesterol have been implicated in the formation of amyloid plaques in Alzheimer's disease. In addition, the progressive neurodegenerative disorder Niemann-Pick C disease is characterized by defects in intracellular trafficking of cholesterol.

van Muiswinkel, F. L. and H. B. Kuiperij (2005). "The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders." Curr Drug Targets CNS Neurol Disord 4(3): 267-81.

            A large body of evidence indicates that oxidative stress is a salient pathological feature in many neurodegenerative diseases, including Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In addition to signs of systemic oxidative stress, at the biochemical and neuropathological level, neuronal degeneration in these disorders has been shown to coincide with several markers of oxidative damage to lipids, nucleic acids, and proteins in affected brain regions. Neuroinflammatory processes, often associated with the induction of free radical generating enzymes and the accumulation of reactive astrocytes and microglial cells, are considered as a major source of oxidative stress. Given the pathogenic impact of oxidative stress and neuroinflammation, therapeutic strategies aimed to blunt these processes are considered an effective way to confer neuroprotection. Recently, the nuclear transcription factor Nrf2, that binds to the antioxidant response element (ARE) in gene promoters, has been reported to constitute a key regulatory factor in the co-ordinate induction of a battery of endogenous cytoprotective genes, including those encoding for both antioxidant- and anti-inflammatory proteins. In the present review, besides discussing recent evidence underscoring the thesis that the Nrf2-ARE signalling pathway is an attractive therapeutic target for neurodegenerative diseases, we advocate the view that chemopreventive agents might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.

van Dooren, T., I. Dewachter, et al. (2005). "Transgenic mouse models for APP processing and Alzheimer's disease: early and late defects." Subcell Biochem 38: 45-63.

            Transgenic mice with neuronal expression of human AD-mutant APP[V7171] in their brain recapitulate robustly the amyloid pathology as seen in Alzheimer's disease (AD) patients. The AD related pathological phenotype consisting of amyloid plaques and vascular amyloid pathology, develop progressively and relative late in ageing APP transgenic mice, between 10 and 15 months of age. In contrast to the late - and clinically irrelevant - amyloid plaque-pathology, the early cognitive defects and behavioural features are clinically more interesting. This review discusses the generation and in depth phenotypic characterization of both aspects of the APP[V7171] transgenic mice. Attention is focussed on the relation of biochemical data of the different APP fragments and amyloid peptides to the formation of the typical early defects and the late parenchymal and vascular amyloid depositions. The APP[V7171] transgenic mice are a perfect model to characterize and investigate early biochemical and cognitive aspects and a potential resource to define pathological interactions of different factors known to be involved in AD. Finally, any therapeutic intervention can be directly tested and explored in these transgenic mice as excellent pre-clinical models.

van den Bussche, H. (2005). "[Questions and theses of pharmacological therapeutic options of Alzheimer's dementia with acetylcholinesterase inhibitors]." Z Gerontol Geriatr 38 Suppl 1: I18-20.

            The paper reviews the evidence for the recommendation of cholinesterase inhibitors and asks critical questions concerning the reasons for the discrepancy between the weak evidence and the recommendation of these drugs in therapy guidelines. Furthermore, the argument of the severe underuse of these drugs is examined.

Van Dam, D., E. Vloeberghs, et al. (2005). "APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder." CNS Spectr 10(3): 207-22.

            Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.

Uzun, S., O. Kozumplik, et al. (2005). "Aripiprazole: an overview of a novel antipsychotic." Psychiatr Danub 17(1-2): 67-75.

            Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydroaripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. At least 1 to 2 weeks, and sometimes up to 4 weeks, may pass before aripiprazole reaches its full effect. The efficacy of aripiprazole was investigated in the treatment of schizophrenia, in the treatment of acute manic episode associated with Bipolar I Disorder, and in the treatment of psychosis associated with Alzheimer's dementia. Aripiprazole has demonstrated superiority to placebo in clinical studies of the treatment of both schizophrenia and acute bipolar mania. Aripiprazole has been evaluated for safety in 5592 patients who participated in multiple dose, premarketing trials in schizophrenia, bipolar mania, and dementia of the Alzheimer's type. The recommended starting and target dose for aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day. Dosage increases should not be made before 2 weeks of continuous therapy, the time needed to achieve steady state. At least 1 to 2 weeks, and sometimes up to 4 weeks, may pass before aripiprazole reaches its full effect. In this presentation was given an overview of novel antipsychotic aripiprazole.

Urso, C. (2005). "North Carolina's support of family caregivers." N C Med J 66(1): 43-7.

Urakami, K., Y. Wakutani, et al. (2005). "[Epidemiology of dementia of the aged]." Nippon Naika Gakkai Zasshi 94(8): 1467-72.

Ulrey, C. L., L. Liu, et al. (2005). "The impact of metabolism on DNA methylation." Hum Mol Genet 14 Spec No 1: R139-47.

            Methylation of genomic cytosines is one of the best characterized epigenetic mechanisms, and investigation of its relationship with other biochemical pathways represents a critical stage in the elucidation of biological information processing. The field also has immense potentia