Alzheimer Disease: Maryland

Sun MK, Alkon DL. · Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Academic & Research Building, The 3rd floor, Rockville, MD 20850, USA. · Recent Pat CNS Drug Discov. · Pubmed #18221200 No free full text.

Abstract: Activity of protein kinase C (PKC) isozymes plays a critical role in various types of learning and memory. In addition, abnormal functions of PKC signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and dementia related to ischemic/stroke events. In preclinical studies, inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes has been found to enhance learning and memory and/or to produce antidementic effects. The PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of cognitive therapeutics and agents against dementia in the future.

Castellani RJ, Perry G, Smith MA. · Department of Pathology, University of Maryland, Baltimore, MD 21201, USA. · Neurotox Res. · Pubmed #18201954 No free full text.

Abstract: While controversy over the role of carbohydrates in amyloidosis has existed since the initial recognition of amyloid, current understanding of the role of polysaccharides in the pathogenesis of amyloid deposition of Alzheimer disease and other amyloidoses is limited to studies of glyco-conjugates such as heparin sulfate proteoglycan. We hypothesized that polysaccharides may play a broader role in light of 1) the impaired glucose utilization in Alzheimer disease; 2) the demonstration of amylose in the Alzheimer disease brain; 3) the role of amyloid in Alzheimer disease pathogenesis. Specifically, as with glucose polymers (amyloid), we wanted to explore whether glucosamine polymers such as chitin were being synthesized and deposited as a result of impaired glucose utilization and aberrant hexosamine pathway activation. To this end, using calcofluor histochemistry, we recently demonstrated that amyloid plaques and blood vessels affected by amyloid angiopathy in subjects with sporadic and familial Alzheimer disease elicit chitin-type characteristics. Since chitin is a highly insoluble molecule and a substrate for glycan-protein interactions, chitin-like polysaccharides within the Alzheimer disease brain could provide a scaffolding for amyloid-beta deposition. As such, glucosamine may facilitate the process of amyloidosis, and /or provide neuroprotection in the Alzheimer disease brain.

Szekely CA, Breitner JC, Zandi PP. · Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. · Int Rev Psychiatry. · Pubmed #18092245 No free full text.

Abstract: The already considerable public health burden of Alzheimer's disease will likely worsen as populations around the world age. As a result, there is considerable motivation to develop effective strategies for preventing the disease. A wide variety of such strategies are under investigation and include pharmaceuticals, nutriceuticals, diet, physical activity and cognitive activity. We review here the most promising candidates and the epidemiologic evidence for their efficacy. Although none of these have yet to be definitively shown to prevent Alzheimer's disease, further research should help to clarify what role they may play in reducing the burden of this disease.

Shie FS, Woltjer RL. · Division of Mental Health and Substance Abuse, National Health Research Institutes, No.35 Keyan Road, Zhunan Town, Miaoli County 350, ROC, Taiwan. · Curr Med Chem. · Pubmed #18045132 No free full text.

Abstract: Alzheimer's disease (AD) is the leading cause of dementia. Although the etiology of AD remains controversial, the amyloid hypothesis suggests that beta-amyloid (Abeta) peptides may contribute to brain dysfunction, and microglial activation has become increasingly regarded as a potential contributor to disease pathogenesis. Microglial activation is characterized by morphological changes and by production of various effectors, and activated neuroinflammation concurrent with increased oxidative stress may contribute to damage to neurons. However, recently there has been a recognition that microglia may also play a neuroprotective role through their release of neurotrophic factors and through phagocytosis of Abeta. Thus, there is growing consensus that a favorable combination of diminished microglia-mediated neuroinflammation and enhanced Abeta clearance may be critical in AD therapy. In this review, we will discuss the role of microglial activation in AD and how pharmacologic manipulation of microglia might bear upon the treatment of AD.

Carson VB, Smarr RR. · Mental Health Services for the Assisted Living, Erickson Retirement Communities, Fallston, MD 21047-2205, USA. · Home Healthc Nurse. · Pubmed #17984641 No free full text.

This publication has no abstract.

Dias WB, Hart GW. · Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185. · Mol Biosyst. · Pubmed #17940659 No free full text.

Abstract: Similar to phosphorylation, O-GlcNAcylation (or simply GlcNAcylation) is an abundant, dynamic, and inducible post-translational modification. In some cases, GlcNAcylation and phosphorylation occur at the same or adjacent sites, modulating each other. GlcNAcylated proteins are crucial in regulating virtually all cellular processes, including signaling, cell cycle, and transcription, among others. GlcNAcylation affects protein-protein interactions, activity, stability, and expression. Several GlcNAcylated proteins are involved in diabetes and Alzheimer's disease. Hyperglycemia increases GlcNAcylation of proteins within the insulin signaling pathway and contributes to insulin resistance. In addition, hyperinsulinemia and hyperlipidemia are also associated with increased GlcNAcylation, which affect and regulate several insulin signaling proteins, as well as proteins involved on the pathology of diabetes. With respect to Alzheimer's disease, several proteins involved in the etiology of the disease, including tau, neurofilaments, beta-amyloid precursor protein, and synaptosomal proteins are GlcNAcylated in normal brain. The impairment of brain glucose uptake/metabolism is a known metabolic defect in Alzheimer's neurons. Data support the hypothesis that hypoglycemia within the brain may reduce the normal GlcNAcylation of tau, exposing kinase acceptor sites, thus leading to hyperphosphorylation, which induces tangle formation and neuronal death. Alzheimer's disease and type II diabetes represent two metabolic disorders where dysfunctional protein GlcNAcylation/phosphorylation may be important for disease pathology.

Appleby BS, Roy P, Valenti A, Lee HB. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. · Panminerva Med. · Pubmed #17912149 No free full text.

Abstract: Depression, a common neuropsychiatric syndrome associated with lower quality of life (QOL), higher mortality, and higher caregiver burden, is estimated to occur in 20-50% of Alzheimer's disease (AD) patients. Recent research suggests that depression in AD (dAD) may differ from major depression phenomenologically and etiologically. Treatment options for dAD include behavioral modifications, pharmacotherapy, and electroconvulsive therapy. Successful treatment of dAD has been reported to improve patients' mood and QOL, as well as lower caregiver burden. Further research is needed in therapeutics of dAD to enhance treatment options and effectiveness.

Hammoud DA, Hoffman JM, Pomper MG. · Department of Radiology, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB-2, Room 492, Baltimore, MD 21231, USA. · Radiology. · Pubmed #17885179 links to  free full text

Abstract: The use of molecular imaging techniques in the central nervous system (CNS) has a rich history. Most of the important developments in imaging-such as computed tomography, magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography-began with neuropsychiatric applications. These techniques and modalities were then found to be useful for imaging other organs involved with various disease processes. Molecular imaging of the CNS has enabled scientists and researchers to understand better the basic biology of brain function and the way in which various disease processes affect the brain. Unlike other organs, the brain is not easily accessible, and it has a highly selective barrier at the endothelial cell level known as the blood-brain barrier. Furthermore, the brain is the most complex cellular network known to exist. Various neurotransmitters act in either an excitatory or an inhibitory fashion on adjacent neurons through a multitude of mechanisms. The various neuronal systems and the myriad of neurotransmitter systems become altered in many diseases. Some of the most devastating diseases, including Alzheimer disease, Parkinson disease, brain tumors, psychiatric disease, and numerous degenerative neurologic diseases, affect only the brain. Molecular neuroimaging will be critical to the future understanding and treatment of these diseases. Molecular neuroimaging of the brain shows tremendous promise for clinical application. In this article, the current state and clinical applications of molecular neuroimaging will be reviewed.

Albert MS, Blacker D. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21212, USA. · Annu Rev Clin Psychol. · Pubmed #17716075 No free full text.

Abstract: Mild cognitive impairment (MCI) is a clinical syndrome thought to represent the transition between normal function and dementia. This review describes data that support the existence of such a transitional phase, outlines the heterogeneity of MCI and how that has influenced the evolving concept of MCI, and discusses the impact of heterogeneity on recent MCI clinical trials.

Bareford LM, Swaan PW. · Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Center for Nanomedicine and Cellular Drug Delivery, 20 Penn Street, Baltimore, MD 21201, USA. · Adv Drug Deliv Rev. · Pubmed #17659804 links to  free full text

Abstract: Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway has serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer's disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules.

Szekely CA, Town T, Zandi PP. · Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. · Subcell Biochem. · Pubmed #17612054 No free full text.

Abstract: Epidemiologic and laboratory studies suggest that non-steroidal anti-inflammatory drug (NSAID) use reduces the risk of Alzheimer's disease (AD). Initial reports in the early 1990's indicated that a history of arthritis, a presumed surrogate of NSAID use, was associated with a lower risk of AD. [1] These reports were followed by epidemiologic studies in which NSAID use was assessed directly and the majority of these reports confirmed the inverse association with risk for AD. [2, 3] Postmortem studies in humans [4], studies in animal models of AD [5, 6], and in vitro studies [7, 8] generally support the notion that NSAIDs can reduce the deleterious inflammation which surrounds amyloid beta (Abeta) plaques in the AD brain. In addition, some studies conducted in vitro and in rodents point to a subgroup of NSAIDs that may work by inhibiting amyloidogenic APP metabolism rather than through traditional anti-inflammatory mechanisms. [9-11] This novel property of NSAIDs is currently being explored in epidemiologic studies. Results from randomized clinical trials of NSAIDs and established AD and one trial on secondary prevention have not been promising and there have been no prevention trials completed. The feasibility of using NSAIDs as a chemopreventive agent in AD is discussed.

Chuang DM, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA. · Biol Psychiatry. · Pubmed #17572175 links to  free full text

This publication has no abstract.

Daly JW. · Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892-0820, USA. · Cell Mol Life Sci. · Pubmed #17514358 No free full text.

Abstract: Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer's disease, asthma, cancer, diabetes, and Parkinson's disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.

Castellani RJ, Moreira PI, Liu G, Dobson J, Perry G, Smith MA, Zhu X. · Department of Pathology, University of Maryland, Baltimore, MD, USA. · Neurochem Res. · Pubmed #17508283 No free full text.

Abstract: Although iron is essential in maintaining the function of the central nervous system, it is a potent source of reactive oxygen species. Excessive iron accumulation occurs in many neurodegenerative diseases including Alzheimer disease (AD), Parkinson's disease, and Creutzfeldt-Jakob disease, raising the possibility that oxidative stress is intimately involved in the neurodegenerative process. AD in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

Castellani RJ, Zhu X, Lee HG, Moreira PI, Perry G, Smith MA. · University of Maryland, Department of Pathology, Baltimore, MD 21201, USA. · Expert Rev Neurother. · Pubmed #17492899 No free full text.

Abstract: Although amyloid-beta-containing senile plaques and phospho-tau containing neurofibrillary tangles are hallmark lesions of Alzheimer disease (AD), neither is specific for AD, nor even a marker of AD. Rather, they are empirical lesions that require close correlation with age and clinical signs for optimal interpretation. In essence, these lesions represent the effect rather than the cause of disease. In this review, we discuss diagnostic criteria for AD, the relationship between pathology, pathogenesis and multiple treatment approaches that have so far been disappointing, including those that presume to address pathological lesions. An acceptance that lesion-based therapies do not address etiology or rate-limiting pathogenic factors is probably necessary for the best chance of significant advances that have thus far been elusive.

Arispe N, Diaz JC, Simakova O. · Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, USUHS, 4301 Jones Bridge Rd. Bethesda, MD 20814, USA. · Biochim Biophys Acta. · Pubmed #17490607 No free full text.

Abstract: The main pathological features in the Alzheimer's brain are progressive depositions of amyloid protein plaques among nerve cells, and neurofibrillary tangles within the nerve cells. The major components of plaques are Abeta peptides. Numerous reports have provided evidence that Abeta peptides are cytotoxic and may play a role in the pathogenesis of AD. An increasing number of research reports support the concept that the Abeta-membrane interaction event may be followed by the insertion of Abeta into the membrane in a structural configuration which forms an ion channel. This review summarizes experimental procedures which have been designed to test the hypothesis that the interaction of Abeta with a variety of membranes, both artificial and natural, results in the subsequent formation of Abeta ion channels We describe experiments, by ourselves and others, that support the view that Abeta is cytotoxic largely due to the action of Abeta channels in the cell membrane. The interaction of Abeta with the surface of the cell membrane may results in the activation of a chain of processes that, when large enough, become cytotoxic and induce cell death by apoptosis. Remarkably, the blockage of Abeta ion channels at the surface of the cell absolutely prevents the activation of these processes at different intracellular levels, thereby preserving the life of the cells. As a prospect for therapy for Alzheimer's disease, our findings at cellular level may be testable on AD animal models to elucidate the potential role and the magnitude of the contribution of the Abeta channels for induction of the disease.

Hart GW, Housley MP, Slawson C. · Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205-2185, USA. · Nature. · Pubmed #17460662 No free full text.

Abstract: All animals and plants dynamically attach and remove O-linked beta-N-acetylglucosamine (O-GlcNAc) at serine and threonine residues on myriad nuclear and cytoplasmic proteins. O-GlcNAc cycling, which is tightly regulated by the concerted actions of two highly conserved enzymes, serves as a nutrient and stress sensor. On some proteins, O-GlcNAc competes directly with phosphate for serine/threonine residues. Glycosylation with O-GlcNAc modulates signalling, and influences protein expression, degradation and trafficking. Emerging data indicate that O-GlcNAc glycosylation has a role in the aetiology of diabetes and neurodegeneration.

Farah MH. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. · Curr Drug Deliv. · Pubmed #17456035 No free full text.

Abstract: RNA interference (RNAi) has emerged as a potential therapeutic approach for neurodegenerative diseases, particularly those associated with autosomal dominant patterns of inheritance. In proof of concept experiments, several groups have demonstrated efficacy of using viral vectors expressing short hairpin RNA (shRNA) directed against therapeutically relevant genes in mouse models of neurodegenerative diseases, including spinocerebellar ataxia, Amyotrophic Lateral Sclerosis, Huntington's Disease and amyloidosis (a pathological aspect of Alzheimer's Disease). Although viral-based RNAi has limitations that most likely will preclude its usage in humans, a few recent developments underscore the potential of non-viral-based delivery of relevant RNAi as therapeutics for neurodegenerative diseases. Here, I will review the recent literature on effectiveness of RNAi as a therapeutic strategy in mouse models of neurodegenerative diseases.

Abraham KM. · Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892-5460, USA. · Curr Alzheimer Res. · Pubmed #17430238 No free full text.

Abstract: Emerging evidence suggests that components of the metabolic syndrome either in isolation or in aggregate may impact the onset or severity of neurodegenerative processes, including those physiologic changes that lead to Alzheimer's Disease (AD). Several animal models that were originally designed to interrogate the metabolic syndrome are readily available. These models can now be used to support studies that may provide new mechanistic links between the metabolic syndrome and neurodegeneration. In addition, animal strains currently being generated and phenotyped through the efforts of an array of NIDDK-supported projects are likely to provide novel and better tools to advance Alzheimer's disease research in the near future.

Driscoll I, Resnick SM. · Laboratory of Personality and Cognition, National Institute on Aging, Baltimore, MD 21224, USA. · Curr Alzheimer Res. · Pubmed #17316164 No free full text.

Abstract: There is evidence to suggest that testosterone loss constitutes a risk for cognitive decline and possibly dementia, and that elderly men might benefit from exogenous supplementation of testosterone. Studies in non-human animals repeatedly report neuroexcitatory and neuroprotective properties of testosterone and enhanced memory performance after acute or chronic treatment. Positive effects of testosterone supplementation in older men have been reported in several, but not all, studies and require replication in larger randomized clinical trials before recommendations for clinical practice can be made. The current review summarizes recent studies on the neurobiological connection between testosterone and cognitive function in humans and non-human animals. When appropriate, we use the hippocampus as a model structure given it's involvement in sexually dymorphic spatial ability and sensitivity to both androgens and aging. In addition, a number of potential explanations of the discrepancy between data obtained in humans and non-human animals are discussed.

Gupta A, Dawson TM. · Department of Neurology, John Hopkins Hospital, Pathology 509, 600 North Wolfe Street, Baltimore, MD 21287, USA. · Neurosurg Clin N Am. · Pubmed #17244560 No free full text.

Abstract: Parkinson's disease (PD) affects more than 1 million people in the United States, which makes it one of the most common age-related neurodegenerative disorders, second only to Alzheimer disease. In light of this significant health problem, this review places emphasis on the exciting prospect of using stem cells as an emerging therapeutic option in this neurologic field. To that goal, the authors first describe the clinical, genetic, and pathologic features of PD and proceed with discussing notions about disease mechanism as well as current medical and surgical treatments before focusing on the advantages, limitations, and feasibility of stem cell therapy.

Alkon DL, Sun MK, Nelson TJ. · Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Rockville, MD 20850, USA. · Trends Pharmacol Sci. · Pubmed #17218018 No free full text.

Abstract: There is strong evidence that protein kinase C (PKC) isozyme signaling pathways are causally involved in associative memory storage. Other observations have indicated that PKC signaling pathways regulate important molecular events in the neurodegenerative pathophysiology of Alzheimer's disease (AD), which is a progressive dementia that is characterized by loss of recent memory. This parallel involvement of PKC signaling in both memory and neurodegeneration indicates a common basis for the origins of both the symptoms and the pathology of AD. Here, we discuss this conceptual framework as a basis for an autopsy-validated peripheral biomarker--and for AD drug design targeting drugs (bryostatin and bryologs) that activate PKC isozymes--that has already demonstrated significant promise for treating both AD neurodegeneration and its symptomatic memory loss.

Hardy J. · Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Building, NIH Main Campus, Bethesda, MD 20892, USA. · Neurochem Res. · Pubmed #17186373 No free full text.

Abstract: In this review, I discuss the possibility that Abeta42 has a physiologic function in blood vessel homeostasis and the consequences that this might have for theories concerning the pathogenesis of Alzheimer's disease and for treatment.

Rouault TA, Cooperman S. · Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. · Semin Pediatr Neurol. · Pubmed #17101452 No free full text.

Abstract: Brain iron uptake is regulated by the expression of transferrin receptor 1 in endothelial cells of the blood-brain barrier. Transferrin-bound iron in the systemic circulation is endocytosed by brain endothelial cells, and elemental iron is released to brain interstitial fluid, likely by the iron exporter, ferroportin. Transferrin synthesized by oligodendrocytes in the brain binds much of the iron that traverses the blood-brain barrier after oxidation of the iron, most likely by a glycophosphosinositide-linked ceruloplasmin found in astrocytic foot processes that ensheathe brain endothelial cells. Neurons acquire iron from diferric transferrin, but it is less clear how glial cells acquire iron. In aging mammals, iron accumulates in the basal ganglia, and iron accumulation is believed to contribute to neurodegenerative diseases, including Parkinson and Alzheimer disease. Here we consider the possibility that iron accumulations, which are often thought to facilitate free radical generation and oxidative damage, may contain insoluble iron that is unavailable for cellular use, and the pathology associated with iron accumulations may result from functional iron deficiency in some diseases.

Onyike CU. · Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Int Rev Psychiatry. · Pubmed #17085361 No free full text.

Abstract: Cerebrovascular disease (CVD) is an important cause of psychiatric disability in the elderly. Much of this disability can be attributed to dementia and lesser degrees of cognitive impairment, which result from strokes and other forms of cerebrovascular pathology. While vascular dementia is common, estimates of its frequency vary due to its clinical and pathologic heterogeneity, the challenges involved in its measurement and its frequent co-occurrence with Alzheimer's disease. Nevertheless the clinical features and natural histories of vascular dementia can be described, and risk factors have been identified and include hypertension, diabetes mellitus, hyperlipidaemia, other conditions that promote atherosclerosis, and rare genetic mutations. While vascular dementia is not curable, treatments are available. For example, a few recent clinical trials suggest that cholinesterase inhibitors have some efficacy. Our knowledge of the risk factors has also provided opportunities for the primary and secondary prevention of vascular dementia, and indicates promising avenues for research.