Alzheimer Disease: US Central Zone

Bossen AL, Specht JK, McKenzie SE. · The University of Iowa College of Nursing, Iowa City 52242-1121, USA. · J Gerontol Nurs. · Pubmed #19326824 No free full text.

Abstract: The focus of this literature search was on the needs of older adults with Alzheimer's disease (AD). Very little research has been published directly related to the concept of needs, so concepts were identified by implicitly pulling them from the foci of articles. Identified articles were written outside the framework of the person with AD-from the perspective of the providers and caregivers. To get the person's perspective, the search was expanded to find"self-identified" needs of the person with AD and by widening the medical subject heading terms. The collection of work found indicated retained awareness of the person with AD well into the disease process and that this awareness is not recognized by professionals or caregivers. The result is that older adults with AD are not consulted in determining their needs or having a voice in their plan of care. Also identified were the needs for early diagnosis, to be heard, for information and knowledge, for safety, health promotion, and emotional and cognitive support.

Ghosh AK. · Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. · J Med Chem. · Pubmed #19323561 No free full text.

This publication has no abstract.

Bezprozvanny I. · Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. · Sci Signal. · Pubmed #19318622 No free full text.

Abstract: The brains of patients with Alzheimer's disease (AD) contain abundant plaques composed of beta-amyloid (Abeta) peptides. It has been assumed that amyloid plaques and soluble Abeta oligomers induce neuronal pathology in AD; however, the mechanism by which amyloid mediates pathological effects is not clearly understood. In vivo calcium (Ca2+) imaging and array tomography studies with AD mouse models are providing new insights into the changes that occur in brain structure and function as a result of amyloid plaque accumulation. The unexpected lesson from these studies is that amyloid plaques result in both localized and global changes in brain function. The amyloid-induced effects include short-range changes in neuronal Ca2+ concentrations, medium-range changes in neuronal activity and synaptic density, and long-range changes in Ca2+ signaling in astrocytes and induction of intracellular Ca2+ waves spreading through a network of astrocytes. These results have potential implications for understanding synaptic and neuronal network dysfunction in AD brains.

Lovell MA. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. · J Alzheimers Dis. · Pubmed #19276540 No free full text.

Abstract: Although multiple studies have suggested a role for alterations of zinc (Zn) and zinc transport (ZnT) proteins in the pathogenesis of Alzheimer's disease, the exact role of this essential trace element in the progression of the disease remains unclear. The following review discusses the normal role of Zn and ZnT proteins in brain and the potential effects of their alteration in the pathogenesis of Alzheimer's disease, particularly in the processing of the amyloid-beta protein precursor and amyloid-beta peptide generation and aggregation.

Lambert MP, Velasco PT, Viola KL, Klein WL. · Northwestern University, Dept. of Neurobiology and Physiology, and the Cognitive Neurology and Alzheimer's Disease Center, Evanston, IL 60208, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275637 No free full text.

Abstract: Individuals with early Alzheimer's disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by toxic Abeta oligomers (also known as ADDLs). ADDLs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Abeta fibrils deposited in amyloid plaques. The AD-like cellular pathologies induced by ADDLs suggest their impact could provide a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Discovery of these new toxins has provided an appealing target for disease-modifying immunotherapy. For optimal protection against these toxins, antibodies should bind to the pathological oligomers without being depleted by their monomeric subunits, which are rapidly generated by membrane protein turnover. A solution to this problem is likely to come from the continued development of conformation-specific antibodies, as described here. Prototype conformation-specific antibodies, not yet in the clinic, have been introduced and utilized in multiple applications for their ability to bind with high specificity and affinity to ADDLs. It can be anticipated that further development of such antibodies for use in clinical trials will come in the near future.

Henry RG, Smith BJ. · Department of Dental Services (160), Veterans Affairs Medical Center, Cooper Dr. Division, Lexington, KY 40502, USA. · Dent Clin North Am. · Pubmed #19269397 No free full text.

Abstract: Neurologic diseases represent some of the most common disabling and costly conditions in older age. Alzheimer disease and cerebrovascular accidents (strokes) are two of the most common neurologic conditions, and represent the leading causes of nursing home placement. Dental professionals will be caring for older patients who have age-associated neurologic diseases, including Alzheimer disease and stroke because of the increased longevity of the United States population coupled with improved survivorship of these conditions as a result of advanced medical diagnosis and treatment. Understanding the clinical manifestations of these two common, but distinctly different, neurologic conditions will enable dental professionals to provide safe and rational dental care.

Joyner N. · Altru Health System, Grand Forks, ND, USA. · Prairie Rose. · Pubmed #19264074 No free full text.

This publication has no abstract.

Shub D, Darvishi R, Kunik ME. · Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA. · Geriatrics. · Pubmed #19256583 No free full text.

Abstract: The prevalence of insomnia increases with age and affects up to 35% of community-dwelling adults with dementia. Sleep disturbances and associated cognitive and behavioral symptoms in this patient population can be a significant contributor to morbidity, mortality, and caregiver burden. Despite the frequency with which sleep disorders are encountered in primary care, few evidence-based guidelines are available to guide physician treatment plans. Sedative-hypnotic medications are commonly prescribed but are associated with significant adverse effects and have limited efficacy data. Non-pharmacologic treatments can be safe and effective adjuncts or alternatives to medications but are often underused in clinical practice. This article reviews practical applications of modalities such as light therapy, exercise, and sleep-hygiene modification in treating insomnia in persons with dementia.

Conn PJ, Jones CK, Lindsley CW. · Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Medical Center, Nashville, TN 37232, USA. · Trends Pharmacol Sci. · Pubmed #19201489 No free full text.

Abstract: Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer's disease (AD) and other disorders involving impaired cognitive function. More recent evidence indicates that mAChR activators might also have utility in treating psychosis and other symptoms associated with schizophrenia and other central nervous system (CNS) disorders. Efforts to develop mAChR subtype-selective agonists have been hampered by difficulty in achieving high selectivity for individual mAChR subtypes important for CNS function (M(1) and M(4)) and adverse effects due to activation of peripheral mAChRs (especially M(2) and M(3)). Major advances have now been achieved in the discovery of allosteric agonists and positive allosteric modulators of M(1) and M(4) that show greater selectivity for individual mAChR subtypes than do previous mAChR agonists. Early studies indicate that these allosteric mAChR activators have properties needed for optimization as potential clinical candidates and have robust effects in animal models that predict efficacy in the treatment of AD, schizophrenia and related disorders.

Grossberg GT, Pejović V, Miller ML, Graham SM. · Department of Neurology and Psychiatry, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. · Dement Geriatr Cogn Disord. · Pubmed #19194105 links to  free full text

Abstract: Memantine is a moderate-affinity, uncompetitive antagonist of N-methyl-D-aspartate receptors, approved for the treatment of moderate to severe Alzheimer's disease (AD). Available data suggest that, in addition to its benefits on cognition, function, and global status, memantine treatment may also help alleviate behavioral symptoms. This article provides an overview of the prevalence, assessment, and treatment of behavioral disturbances in AD, and summarizes current knowledge regarding the effects of memantine on the behavior of community-dwelling patients. We searched EMBASE and PubMed (January 1992 to October 2008) for reports on memantine trials that involved outpatients with moderate to severe AD. All previously unpublished data were obtained from Forest Laboratories, Inc. Behavioral outcomes were assessed in three completed, double-blind, placebo-controlled trials.Overall, patients who received memantine performed better on behavioral measures than those treated with placebo. Post-hoc analyses suggest that memantine treatment was associated with a reduced severity or emergence of specific symptoms, particularly agitation and aggression. Prospective, well-designed trials are warranted to evaluate the efficacy of memantine in patients with significant behavioral symptoms.

Gaugler JE, Yu F, Krichbaum K, Wyman JF. · Center on Aging, School of Nursing, University of Minnesota, Minneapolis, Minnesota, USA. · Med Care. · Pubmed #19169120 No free full text.

Abstract: OBJECTIVE: The objective of this systematic review was to identify factors that consistently predict nursing home admission (NHA) in persons with dementia. METHODS: Studies published in English were retrieved by searching the MEDLINE (1966-2006), PSYCINFO (1950-2006), CINAHL (1982-2006), and Digital Dissertations (1950-2006) databases. Bibliographies of retrieved studies were also searched. Information on study characteristics and empirical results were extracted using a standardized protocol. RESULTS: Of 782 relevant studies identified 80 were selected for review based upon eligibility criteria. The most consistent predictors of NHA in persons with dementia included severity of cognitive impairment, Alzheimer disease diagnosis, basic activity of daily living dependencies, behavioral symptoms, and depression. Caregivers who indicated greater emotional stress, a desire to institutionalize the care recipient, and feelings of being "trapped" in care responsibilities were more likely to admit persons with dementia to nursing homes. Demographic variables, incontinence, and service use did not consistently predict NHA. CONCLUSIONS: Several results seemed to challenge conventional assumptions of what precipitates NHA among persons with dementia. Caregiver stressors in conjunction with care recipient characteristics are important to consider when assessing NHA risk. The findings emphasize the need to construct more complex models of institutionalization when designing risk measures to target interventions.

Kerwin DR. · Geriatric Memory Disorders Clinic and Division of Geriatrics and Gerontology, Medical College of Wisconsin, Milwaukee, WI, USA. · J Fam Pract. · Pubmed #19141265 No free full text.

This publication has no abstract.

Lukiw WJ. · LSU Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, La 70112-2272, USA. · World Rev Nutr Diet. · Pubmed #19136839 No free full text.

This publication has no abstract.

Nelson PT, Braak H, Markesbery WR. · Department of Pathology and Division of Neuropathology, University of Kentucky Medical Center, Sanders-Brown Center on Aging, Lexington, KY 40536-0230, USA. · J Neuropathol Exp Neurol. · Pubmed #19104448 links to  free full text

Abstract: Amyloid plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of Alzheimer disease (AD). There is controversy regarding the use of current diagnostic criteria for AD and whether amyloid plaques and NFTs contribute to cognitive impairment. Because AD is specific to humans, rigorous and comprehensiveclinicopathologic studies are necessary to test and refine hypotheses of AD diagnosis and pathogenesis. Neither the clinical nor the pathological aspects of AD evolve in a linear manner, but thepredictable sequence of AD pathology allows for stage-based correlations with cognitive deterioration. We discuss subsets of patients with clinical dementia who lack amyloid plaques and NFTs and, conversely, whether individuals without antemortem cognitive impairment can harbor severe AD-type pathological findings at autopsy. There are many medical, technical, and anatomical challenges to clinicopathologic studies in AD. For example, at least two thirds of persons older than 80 years have non-AD brain diseases that can effect on cognitive function. We argue that existing data strongly support the hypothesis that both amyloid plaques and NFTs contribute to cognitive impairment.

Ghribi O. · Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, ND 58202, USA. · J Alzheimers Dis. · Pubmed #19096164 No free full text.

Abstract: Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-beta (Abeta) peptide levels. Accumulation of Abeta in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Abeta levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-beta protein precursor (AbetaPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Abeta levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.

Banks WA. · GRECC, Veterans Affairs Medical Center-St. Louis, and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, 915 N. Grand Blvd, St. Louis, MO 63106, USA. · BMC Neurosci. · Pubmed #19090999 links to  free full text

Abstract: Development of therapeutics for the central nervous system is one of the most challenging areas in drug development. This is primarily because, in addition to all of the other complications one faces in developing new drugs targeting peripheral sites, one must also negotiate the blood-brain barrier (BBB). There are dozens of strategies to overcome the obstacle of the BBB, but many of these are bound to fail, barring extreme serendipity, because they are based on an inaccurate or incomplete picture of the BBB. This article therefore starts with a brief review of the BBB as it pertains to drug development. It then examines some examples of the delivery of drugs to the central nervous system that are relevant to Alzheimer's disease, placing emphasis on peptides, antibodies, and antisense oligonucleotides.

Han SD, Bangen KJ, Bondi MW. · Department of Psychology, Loyola University Chicago, Chicago, Ill., USA. · Dement Geriatr Cogn Disord. · Pubmed #19088472 links to  free full text

Abstract: There has been a recent proliferation of functional magnetic resonance imaging (fMRI) studies that interpret between-group or within-group differences in brain response patterns as evidence for compensatory neural recruitment. However, it is currently a challenge to determine whether these observed differences are truly attributable to compensatory neural recruitment or whether they are indicative of some other cognitive or physiological process. Therefore, the need for a standardized set of criteria for interpreting whether differences in brain response patterns are compensatory in nature is great. Focusing on studies of aging and potentially prodromal Alzheimer's disease conditions (genetic risk, mild cognitive impairment), we critically review the functional neuroimaging literature purporting evidence for compensatory neural recruitment. Finally, we end with a comprehensive model set of criteria for ascertaining the degree to which a 'compensatory' interpretation may be supported. This proposed model addresses significant brain region, activation pattern, and behavioral performance considerations, and is therefore termed the Region-Activation-Performance model (RAP model).

Knopman DS. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Cogn Behav Neurol. · Pubmed #19057167 No free full text.

Abstract: The field of clinical trials and therapeutics in Alzheimer disease (AD) is little more than 20 years old. Considerable progress has been made in crafting appropriate designs for clinical trials of promising therapeutic agents for AD. This article reviews basic issues in diagnostic criteria, choice of outcome measures, duration of trials and analytic strategies. Through trial and error, a general set of strategies has evolved for the assessment of putative therapies for mild to moderate AD. The experience of the past 2 decades has set the stage for discovering the next generation of anti-AD drugs and introducing those therapies at milder stages of the disease.

Guay DR. · Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA. · Consult Pharm. · Pubmed #19032006 No free full text.

Abstract: OBJECTIVE: To assess the potential role of a new transdermal (TD) formulation of rivastigmine in the management of Alzheimer's disease. DATA SOURCE: MEDLINE/PUBMED and EMBASE searches (1986-February 2008) were conducted to identify pertinent English-language studies of TD rivastigmine. STUDY SELECTION AND DATA EXTRACTION: All studies evaluating any aspect of TD rivastigmine, including in vivo animal experimentation. DATA SYNTHESIS: Rivastigmine is the first acetylcholinesterase inhibitor to be marketed in a TD formulation. This formulation was marketed to potentially improve patient/caregiver adherence and ameliorate the gastrointestinal (GI) intolerance of the oral product. The TD formulation significantly reduces GI intolerance (manifested as nausea, vomiting, abdominal pain/cramping, anorexia, and weight loss) as compared with oral doses producing the same degree of systemic exposure, as a result of the lower peak plasma concentration, lower degree of peak-trough concentration fluctuation, and prolonged time to peak concentration achieved with the TD formulation. CONCLUSION: Despite the advantages of TD rivastigmine just described, a number of questions still exist with this formulation. The effects of environmental factors on drug pharmacokinetics are unknown (e.g., febrile disease states, skin abrasions/tears). The TD formulation has not eliminated the need for titration to the target dose. The true effect of this formulation on adherence is unknown (consider the dexterity necessary to access the patch from its packaging and apply it and the complexities of rotating application sites). If the patient removes the patch inappropriately, the number of available application sites falls substantially, making site rotation difficult. For patients with swallowing difficulties, oral liquid formulations of donepezil, galantamine, and rivastigmine may be easier alternatives to TD rivastigmine. Unique advantages of TD rivastigmine have not been convincingly established.

Lukiw WJ, Bazan NG. · Department of Ophthalmology, LSU Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. · J Nutr. · Pubmed #19022980 No free full text.

Abstract: The dietary essential PUFA docosahexaenoic acid [DHA; 22:6(n-3)] is a critical contributor to cell structure and function in the nervous system, and deficits in DHA abundance are associated with cognitive decline during aging and in neurodegenerative disease. Recent studies underscore the importance of DHA-derived neuroprotectin D1 (NPD1) in the homeostatic regulation of brain cell survival and repair involving neurotrophic, antiapoptotic and antiinflammatory signaling. Emerging evidence suggests that NPD1 synthesis is activated by growth factors and neurotrophins. Evolving research indicates that NPD1 has important determinant and regulatory interactions with the molecular-genetic mechanisms affecting beta-amyloid precursor protein (betaAPP) and amyloid beta (Abeta) peptide neurobiology. Deficits in DHA or its peroxidation appear to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in Alzheimer disease (AD), a common and progressive age-related neurological disorder unique to structures and processes of the human brain. This article briefly reviews our current understanding of the interactions of DHA and NPD1 on betaAPP processing and Abeta peptide signaling and how this contributes to oxidative and pathogenic processes characteristic of aging and AD pathology.

Bazan NG. · Neuroscience Center of Excellence and Department of Ophthalmology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. · J Lipid Res. · Pubmed #19018037 No free full text.

Abstract: Docosahexaenoic acid (DHA), the main omega-3 fatty acid, is concentrated and avidly retained in membrane phospholipids of the nervous system. DHA is involved in brain and retina function, aging, and neurological and psychiatric/behavioral illnesses. Neuroprotectin D1 (NPD1), the first-identified stereoselective bioactive product of DHA, exerts neuroprotection in models of experimental stroke by down-regulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflammatory signaling, and infarct size. Moreover, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression. Photoreceptor membranes display the highest content of DHA of any cell. Retinal pigment epithelial cells participate in the phagocytosis of the tips of photoreceptor cells (photoreceptor outer segment renewal). There is a DHA retrieval-intercellular mechanism between both types of cells that conserves this fatty acid during this process. NPD1 promotes homeostatic regulation of the integrity of these two cells, particularly during oxidative stress, and this protective signaling may be relevant in retinal degenerative diseases. Moreover, neurotrophins are NPD1-synthesis agonists, and NPD1 content is decreased in the CA1 region of the hippocampus of Alzheimer's patients. Overall, NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Abeta42 production and its neurotoxicity. Thus, NPD1 elicits potent cell-protective, anti-inflammatory, prosurvival repair signaling.

Xu J, Ikezu T. · Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA. · J Neuroimmune Pharmacol. · Pubmed #19016329 No free full text.

Abstract: Although the introduction of highly active antiretroviral therapy (HAART) has led to a strong reduction of HIV-associated dementia (HAD) incidence, the prevalence of minor HIV-1-associated neurocognitive disorder (HAND) is rising among AIDS patients. HAART medication has shifted neuropathology from a subacute encephalitic condition to a subtle neurodegenerative process involving synaptic and dendritic degeneration, particularly of hippocampal neurons that are spared prior to HAART medication. Considerable neuroinflammation coupled with mononuclear phagocyte activation is present in HAART-medicated brains, particularly in the hippocampus. Accumulating evidence suggests that the resultant elevated secretion of pro-inflammatory cytokines such as interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta can increase amyloid-beta peptide (Abeta) generation and reduce Abeta clearance. Recent advancements in Alzheimer's disease (AD) research identified Abeta biogenesis and clearance venues that are potentially influenced by HIV viral infection, providing new insights into beta-amyloidosis segregation in HIV patients. Our study suggests enhanced beta-amyloidosis in ART-treated HAD and HIV-associated encephalitis brains and suppression of Abeta clearance by viral infection of human primary macrophages. A growing awareness of potential convergent mechanisms leading to neurodegeneration shared by HIV and Abeta points to a significant chance of comorbidity of AD and HAND in senile HIV patients, which calls for a need of basic studies.

Kamat CD, Gadal S, Mhatre M, Williamson KS, Pye QN, Hensley K. · Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. · J Alzheimers Dis. · Pubmed #18997301 links to  free full text

Abstract: Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (alpha-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson's disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate's mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials.

Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. · Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, USA. · Mini Rev Med Chem. · Pubmed #18991755 No free full text.

Abstract: Alzheimer disease treatment has yet to yield a successful therapy that addresses the source of the damage found in brains. Of the varied proposed theories of AD etiology, reactive oxygen species (ROS) generation is cited as a common factor. Efforts to reduce the pathology associated with ROS via antioxidants therefore offer new hope to patients suffering from this devastative disease.

Mufson EJ, Counts SE, Perez SE, Ginsberg SD. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Expert Rev Neurother. · Pubmed #18986241 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75(NTR)) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75(NTR) may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.