Alzheimer Disease: New York

Fillit HM, Doody RS, Binaso K, Crooks GM, Ferris SH, Farlow MR, Leifer B, Mills C, Minkoff N, Orland B, Reichman WE, Salloway S. · Alzheimer's Drug Discovery Foundation and Institute for the Study of Aging New York, New York 10019, USA. · Am J Geriatr Pharmacother. · Pubmed #17157793 No free full text.

Abstract: BACKGROUND: Alzheimer's disease and related dementias (ADRDs) are increasingly recognized as important causes of impaired cognition, function, and quality of life, as well as excess medical care utilization and costs in the elderly Medicare managed care population. Evidence-based clinical practice guidelines for ADRDs were published in 2001. More recent studies have resulted in the approval of new agents and demonstrated an expanded role for antidementia therapy in various types of dementia, settings of care, stages of disease, and the use of combination therapy. However, these clinical guidelines have not been updated in the past few years. OBJECTIVE: The goal of this article was to provide practical recommendations developed by a panel of experts that address issues of early diagnosis, treatment, and care management of ADRDs. The panel also addressed the societal and managed care implications. METHODS: A panel of leading experts was convened to develop consensus recommendations for the treatment and management of dementia based on currently available evidence and the panel's informed expert opinion. The panel comprised 12 leading experts, including clinical investigators and practitioners in geriatric medicine, neurology, psychiatry, and psychology; managed care medical and pharmacy directors; a health systems medical director; and a health policy expert. In addition, articles were collected based on PubMed searches (2000-2005) that were relevant to the key issues identified. Search terms included Alzheimer's disease, dementia, clinical practice guidelines, clinical trials, screening and assessment, and managed care. RESULTS: ADRDs represent a significant clinical and economic burden to individuals and society, including Medicare managed care organizations (MCOs). Appropriate utilization of antidementia therapy and care management is vitally important to achieving quality of life and care for dementia patients and their caregivers, and for managing the excess costs of Alzheimer's disease. The recommendations address relevant, practical, and timely concerns that are faced on a daily basis by practitioners and by Medicare MCO medical management programs in the care of dementia patients. These consensus recommendations attempt to describe a reasonable current standard for the provision of quality care for patients with dementia. The panel recommendations support the use of screening for cognitive impairment and the use of antidementia therapy for ADRDs in different stages of disease and types of dementia in all clinical settings. The panel members evaluated the use of the 3 marketed cholinesterase inhibitors-donepezil, galantamine, and rivastigmine-as well as the N-methyl-D-aspartate antagonist memantine. Recommendations for using these medications are made with an appreciation of the difficulties in translating the results from investigational clinical trials into clinical practice. CONCLUSIONS: The recommendations of the expert panel represent a clear consensus that nihilism in the diagnosis, treatment, and management of ADRDs is unwarranted, impairs quality of care, and is ultimately not costeffective.

Fillit H, Cummings J. · Mount Sinai Medical Center, New York City, USA. · Manag Care Interface. · Pubmed #10747691 No free full text.

Abstract: The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diagnostic and treatment guidelines and to integrate these guidelines for use in MCOs. This paper presents conclusions from this panel and provides an algorithm for the treatment of AD specifically for managed care settings. When combined with other necessary efforts to educate providers, these guidelines should improve the cost-effectiveness and quality of care for individuals with dementia in managed care.

Reisberg B, Shulman MB. · Aging and Dementia Research Center, New York University School of Medicine, New York, NY, USA. · Alzheimers Dement. · Pubmed #19328449 No free full text.

This publication has no abstract.

Fillit H, Nash DT, Shineman D. · Institute for the Study of Aging and Alzheimer's Drug Discovery Foundation, New York, NY, USA. · Alzheimers Dement. · Pubmed #19328448 No free full text.

This publication has no abstract.

Fillit HM, Refolo LM. · The Institute for the Study of Aging, 1414 Avenue of the Americas, Suite 1502, New York, NY, USA. · Curr Alzheimer Res. · Pubmed #15974904 No free full text.

This publication has no abstract.

Refolo LM, Fillit HM. · The Institute for the Study of Aging, New York, NY, USA. · J Mol Neurosci. · Pubmed #15314243 No free full text.

This publication has no abstract.

Pasinetti GM, Pompl PN. · Neuroinflammation Research Laboratories, Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY 10029, USA. · Lancet Neurol. · Pubmed #12849357 No free full text.

This publication has no abstract.

Iadecola C, Gorelick PB. · Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA. · Stroke. · Pubmed #12574528 links to  free full text

This publication has no abstract.

Fillit HM, Refolo LM. · The Institute for the Study of Aging, New York, NY, USA. · J Mol Neurosci. · Pubmed #12540049 No free full text.

This publication has no abstract.

Yan SD, Bierhaus A, Nawroth PP, Stern DM. · Department of Pathology, College of Physicians & Surgeons of Columbia University, New York City, NY, USA. · J Alzheimers Dis. · Pubmed #19387116 No free full text.

Abstract: Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.

Luchsinger JA, Gustafson DR. · Gertrude H. Sergievsky Center, New York, NY 10032, USA. · J Alzheimers Dis. · Pubmed #19387106 links to  free full text

Abstract: This manuscript provides a comprehensive review of the epidemiologic evidence linking the continuum of adiposity and type 2 diabetes (T2D) with Alzheimer's disease (AD). The mechanisms relating adiposity and T2D to AD may include hyperinsulinemia, advanced products of glycosylation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of AD but the data on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of AD. Hyperinsulinemia is a risk factor for T2D, and numerous studies have shown a relation of T2D with higher AD risk. The implication of these associations is that a large proportion of the world population may be at increased risk of AD given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D. However these associations may present a unique opportunity for prevention and treatment of AD. Several studies in the prevention and treatment of T2D are currently conducting, or have planned, cognition ancillary studies. In addition, clinical trials using insulin sensitizers in the treatment or prevention of AD are under way.

Wisniewski T. · New York University School of Medicine, Millhauser Laboratory, New York, NY 10016, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355935 No free full text.

This publication has no abstract.

Li H, Wolfe MS, Selkoe DJ. · Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. · Structure. · Pubmed #19278647 No free full text.

Abstract: Gamma-Secretase is an intramembrane protease complex that mediates the Notch signaling pathway and the production of amyloid beta-proteins. As such, this enzyme has emerged as an important target for development of novel therapeutics for Alzheimer disease and cancer. Great progress has been made in the identification and characterization of the membrane complex and its biological functions. One major challenge now is to illuminate the structure of this fascinating and important protease at atomic resolution. Here, we review recent progress on biochemical and biophysical probing of the structure of the four-component complex and discuss obstacles and potential pathways toward elucidating its detailed structure.

Williamson J, Goldman J, Marder KS. · Taub Institute for Research on Alzheimer Disease and the Aging Brain and the Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, Department of Neurology, New York, NY 10032, USA. · Neurologist. · Pubmed #19276785 No free full text.

Abstract: BACKGROUND: Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD. REVIEW SUMMARY: In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD. CONCLUSIONS: New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals.

Deane R, Bell RD, Sagare A, Zlokovic BV. · Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275634 No free full text.

Abstract: The main receptors for amyloid-beta peptide (Abeta) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Abeta 'sinker' that sequesters some 70 to 90 % of plasma Abeta peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Abeta are reduced which increases free Abeta fraction in plasma. This in turn may increase brain Abeta burden through decreased Abeta efflux and/or increased Abeta influx across the BBB. In Abeta immunotherapy, anti-Abeta antibody sequestration of plasma Abeta enhances the peripheral Abeta 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Abeta antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Abeta antibody/Abeta immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Abeta burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Abeta is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Abeta. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Abeta 'sink' action, hold potential to reduce brain Abeta and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.

Morimoto RI, Cuervo AM. · Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA. · J Gerontol A Biol Sci Med Sci. · Pubmed #19228787 No free full text.

Abstract: All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. Alterations in these fine-tuned mechanisms underlie the pathogenesis of severe human diseases including, among others, common neurodegenerative disorders such as Alzheimer's or Parkinson's disease. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age, even in the absence of disease, and it likely contributes to different aspects of "normal" aging. A group of experts in different aspects of the biology of aging met recently to discuss the implications of altered protein homeostasis in aging, the current gaps in our understanding of the mechanisms responsible for proteome maintenance, and future opportunities for discovery in this area. We summarize here some of the key topics and main outcomes of the discussions.

Luo W, Rodina A, Chiosis G. · Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University and Fisher Foundation for Alzheimer's Disease, New York, NY 10021, USA. · BMC Neurosci. · Pubmed #19090995 links to  free full text

Abstract: Both malignant transformation and neurodegeneration, as it occurs in Alzheimer's disease, are complex and lengthy multistep processes characterized by abnormal expression, post-translational modification, and processing of certain proteins. To maintain and allow the accumulation of these dysregulated processes, and to facilitate the step-wise evolution of the disease phenotype, cells must co-opt a compensatory regulatory mechanism. In cancer, this role has been attributed to heat shock protein 90 (Hsp90), a molecular chaperone that maintains the functional conformation of multiple proteins involved in cell-specific oncogenic processes. In this sense, at the phenotypic level, Hsp90 appears to serve as a biochemical buffer for the numerous cancer-specific lesions that are characteristic of diverse tumors. The current review proposes a similar role for Hsp90 in neurodegeneration. It will present experimentally demonstrated, but also hypothetical, roles that suggest Hsp90 can act as a regulator of pathogenic changes that lead to the neurodegenerative phenotype in Alzheimer's disease.

Vingtdeux V, Dreses-Werringloer U, Zhao H, Davies P, Marambaud P. · Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA. · BMC Neurosci. · Pubmed #19090994 links to  free full text

Abstract: Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in Alzheimer's disease.

Wisniewski T, Sadowski M. · Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. · BMC Neurosci. · Pubmed #19090993 links to  free full text

Abstract: Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble beta-amyloid (sAbeta) to oligomeric, fibrillar Abeta. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Abeta aggregation, including beta-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology.

Gibson GE, Karuppagounder SS, Shi Q. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, NY 10605, USA. · Ann N Y Acad Sci. · Pubmed #19076444 No free full text.

Abstract: Considerable data support the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions, such as cell redox states and acute versus chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of mitochondrial deficits and a reduction in oxidative stress will reduce clinical and pathological changes and benefit patients.

Mosconi L, Pupi A, De Leon MJ. · Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. · Ann N Y Acad Sci. · Pubmed #19076441 links to  free full text

Abstract: One of the main features of Alzheimer's disease (AD) is the severe reduction of the cerebral metabolic rate for glucose (CMRglc). In vivo imaging using positron emission tomography with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG-PET) demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. Increasing evidence suggests that CMRglc reductions occur at the preclinical stages of AD. CMRglc reductions were observed on FDG-PET before the onset of disease in several groups of at-risk individuals, including patients with mild cognitive impairment (MCI), often a prodrome to AD; presymptomatic individuals carrying mutations responsible for early-onset familial AD; cognitively normal elderly individuals followed for several years until they declined to MCI and eventually to AD; normal, middle-aged individuals who expressed subjective memory complaints and were carriers of the apolipoprotein E epsilon-4 allele, a strong genetic risk factor for late-onset AD. However, the causes of the early metabolic dysfunction forerunning the onset of AD are not known. An increasing body of evidence indicates a deficient or altered energy metabolism that could change the overall oxidative microenvironment for neurons during the pathogenesis and progression of AD, leading to alterations in mitochondrial enzymes and in glucose metabolism in AD brain tissue. The present paper reviews findings that implicate hypometabolism and oxidative stress as crucial players in the initiation and progression of synaptic pathology in AD.

Blass JP. · Burke Medical Research Institute, Weill Cornell Medical College, White Plains, NY 10605, USA. · Ann N Y Acad Sci. · Pubmed #19076437 No free full text.

Abstract: It is rational to try to normalize changes that correlate with the severity of the clinical disabilities in Alzheimer's disease (AD) rather than focusing on other of the many abnormalities in end-stage AD brain that relate only theoretically to the clinical manifestations. The neurobiological measure that correlates most closely to the degree of cognitive deterioration is reduction in cerebral metabolic rate. An attempt to treat this abnormality in AD patients is described; it is based, in part, on metabolic control theory. Encouraging results of a preliminary double-blind clinical trial do not allow confident conclusions but do support the need for more intensive examination of this approach to AD treatment.

Yan Y, Wang C. · Biology department, Rensselear Polytechnic Institute, Troy, NY 12180, USA. · Curr Alzheimer Res. · Pubmed #19075581 No free full text.

Abstract: It is widely accepted that Abeta42 aggregation is a central event in the pathogenesis of Alzheimer's disease. Abeta42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. There are a number of physiological molecules that can protect Abeta42 from aggregation. Promoting such protective molecules and mechanisms against Abeta42 aggregation may be a novel direction in AD drug discovery. One of the most striking protective molecules is none other than Abeta40, which inhibits Abeta42 aggregation in a specific and dosage dependent manner. Abeta40 is a critical, built-in mechanism against Abeta42 aggregation. A number of other molecules and mechanisms also inhibit Abeta42 aggregation, such as heat shock proteins, L-PGDS, heme and methionine oxidation. The relevance of these protective mechanisms to AD pathogenesis and intervention is discussed.

Iadecola C, Park L, Capone C. · Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th Street; KB410, New York, NY 10021, USA. · Stroke. · Pubmed #19064785 links to  free full text

Abstract: Aging, Alzheimer disease, and hypertension, major determinants of cognitive dysfunction, are associated with profound alterations in the structure and function of cerebral blood vessels. These vascular alterations may impair the delivery of energy substrates and nutrients to the active brain, and impede the clearance of potentially toxic metabolic byproducts. Reactive oxygen species derived form the enzyme NADPH oxidase are key pathogenic effectors of the cerebrovascular dysregulation. The resulting alterations in the homeostasis of the cerebral microenvironment may lead to cellular dysfunction and death and to cognitive impairment. The prominent role that cerebrovascular oxidative stress plays in conditions associated with cognitive impairment suggests new therapeutic opportunities to counteract and, possibly, reverse the devastating effects of cerebrovascular dysfunction on the brain.

Luchsinger JA, Gustafson DR. · Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA. · Curr Opin Clin Nutr Metab Care. · Pubmed #19057182 No free full text.

Abstract: PURPOSE OF REVIEW: Alzheimer's disease is the most common form of dementia. There are no known preventive or curative measures. There is increasing evidence for the role of total adiposity, usually measured clinically as BMI, and central adiposity, in Alzheimer's disease. This topic is of enormous public health importance given the global epidemic of high adiposity and its consequences. RECENT FINDINGS: Salient publications in 2007 and 2008 showed that (a) central adiposity in middle age predicts dementia in old age; (b) the relation between high adiposity and dementia is attenuated with older age; (c) waist circumference in old age, a measure of central adiposity, may be a better predictor of dementia than BMI; (d) lower BMI predicts dementia in elderly people; and (e) weight loss may precede dementia diagnosis by decades, which may explain seemingly paradoxical findings. SUMMARY: The possibility that high adiposity increases Alzheimer's disease risk is alarming given global trends of overweight and obesity in the general population. However, prevention and manipulation of adiposity may also provide a means to prevent Alzheimer's disease. Treatment of weight loss in Alzheimer's disease may also be important but is beyond the score of this review.