Alzheimer Disease: Illinois

Carrillo MC, Sanders CA, Katz RG. · Alzheimer's Association, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #19362888 No free full text.

Abstract: The Alzheimer's Disease Neuroimaging Initiative is the largest public-private partnership on brain research underway at the National Institutes of Health. This 6-year study tracks cognitive and brain changes in normal subjects, those with mild cognitive impairment, and individuals with Alzheimer's disease. It was designed to provide better tools for performing effective clinical trials, and is slated to run until 2010. While data are being generated and analyzed, researchers involved in the study are developing an extension, i.e., the Alzheimer's Disease Neuroimaging Initiative II. The Foundation for the National Institutes of Health and the Alzheimer's Association convened a meeting to review the progress, evaluate future directions, and obtain the United States Food and Drug Administration's perspective on how the Alzheimer's Disease Neuroimaging Initiative could affect the drug-approval process.

Weintraub S, Salmon D, Mercaldo N, Ferris S, Graff-Radford NR, Chui H, Cummings J, DeCarli C, Foster NL, Galasko D, Peskind E, Dietrich W, Beekly DL, Kukull WA, Morris JC. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 320 E. Superior, Searle 11-467, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #19474567 No free full text.

Abstract: The neuropsychologic test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the National Institute on Aging consists of brief measures of attention, processing speed, executive function, episodic memory, and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered "clinically cognitively normal" based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease in a relatively well-educated sample. Regression models investigating the impact of age, education, and sex on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: (1) determining the psychometric properties of the battery; (2) establishing normative data, including norms for different ethnic minority groups; and (3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with Alzheimer disease and other forms of dementia.

Maki PM, Dumas J. · Departments of Psychiatry and Psychology, Center for Cognitive Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA. · Semin Reprod Med. · Pubmed #19401956 No free full text.

Abstract: Use of estrogen therapy in the perimenopausal and postmenopausal periods has been shown in several clinical trials to help women maintain a premenopausal level of cognitive function. What is not yet fully understood is how the neurobiological effects of estrogen contribute to these cognitive effects. This review explores data from two related bodies of human literature that provide compelling evidence in support of the biological plausibility that estrogen treatment can benefit cognition. The first half of the literature review focuses on studies from the estrogen neuroimaging literature, and the second half focuses on pharmacologic challenge studies assessing estrogen-neurotransmitter interactions. We integrate these two bodies of literature by focusing on the neurophysiologic underpinnings of estrogen effects on cognition and linking these clinical studies to preclinical studies. The focus on verbal memory is important because it is a cognitive function that has been shown to change with estrogen treatment and predict Alzheimer's disease risk but is not addressed by preclinical studies. Overall, we conclude that estrogen interacts with cholinergic and serotonergic systems to affect hippocampal and frontal cortical brain areas and thereby enhance memory, particularly at the retrieval stage.

Carrillo MC, Blackwell A, Hampel H, Lindborg J, Sperling R, Schenk D, Sevigny JJ, Ferris S, Bennett DA, Craft S, Hsu T, Klunk W. · Alzheimer's Association, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #19328456 No free full text.

Abstract: The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

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.

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).

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.

Zec RF, Burkett NR. · Center for Alzheimer Disease and Related Disorders, Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA. · NeuroRehabilitation. · Pubmed #18957729 No free full text.

Abstract: This paper discusses the various pharmacological and behavioral treatments for the cognitive, emotional, and behavioral symptoms of Alzheimer disease (AD). The medications that are currently FDA-approved for the treatment of the cognitive/functional deficits of AD will first be discussed. Next, neuropsychiatric behavioral disturbances, including hallucinations and delusions, agitation and aggression, activity disturbances, depression, and anxiety will be described along with treatment interventions. Sleep disturbance and its treatment in AD and the issue of fitness to drive a motor vehicle are also reviewed. Principles of behavioral management, tips for communication, and recommendations for caregivers are discussed. Lastly, risk and protective factors and their relevance to delaying the expression of dementia are also examined.

Cole SL, Vassar R. · Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. · J Biol Chem. · Pubmed #18650431 No free full text.

Abstract: Amyloid plaques, composed of the amyloid beta-protein (Abeta), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. Abeta fulfills a central role in AD pathogenesis, and reduction of Abeta levels should prove beneficial for AD treatment. Abeta generation is initiated by proteolysis of amyloid precursor protein (APP) by the beta-secretase enzyme BACE1. Bace1 knockout (Bace1(-/-)) mice have validated BACE1 as the authentic beta-secretase in vivo. BACE1 is essential for Abeta generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1(-/-) mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking.

Thinakaran G, Koo EH. · Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA. · J Biol Chem. · Pubmed #18650430 No free full text.

Abstract: Intracellular trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations over the past two decades. APP is the precursor to the amyloid beta-protein (Abeta), the 38-43-amino acid residue peptide that is at the heart of the amyloid cascade hypothesis of Alzheimer disease (AD). Tremendous progress has been made since the initial identification of Abeta as the principal component of brain senile plaques of individuals with AD. Specifically, molecular characterization of the secretases involved in Abeta production has facilitated cell biological investigations on APP processing and advanced efforts to model AD pathogenesis in animal models. This minireview summarizes salient features of APP trafficking and amyloidogenic processing and discusses the putative biological functions of APP.

Bigio EH. · Department of Pathology, Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, 710 N. Fairbanks Court, Chicago, IL 60611, USA. · J Neuropathol Exp Neurol. · Pubmed #18596549 No free full text.

Abstract: Great strides have been made in the last 2 years in the field of frontotemporal lobar degeneration (FTLD), particularly with respect to the genetics and molecular biology of FTLD with ubiquitinated inclusions. It is now clear that most cases of familial FTLD with ubiquitinated inclusions have mutations in the progranulin gene, located on chromosome 17. It is also clear that most ubiquitinated inclusions in FTLD with ubiquitinated inclusions are composed primarily of TAR DNA-binding protein-43. Thus, FTLDs can be separated into 2 major groups (i.e. tauopathies and ubiquitinopathies), and most of the ubiquitinopathies can now be defined as TAR DNA-binding protein-43 proteinopathies. Many of the familial FTLDs are linked to chromosome 17, including both the familial tauopathies and the familial TAR DNA-binding protein-43 proteinopathies with progranulin mutations. This review highlights the neuropathologic features and the most important discoveries of the last 2 years and places these findings into the historical context of FTLD.

Wu CK. · ADC Cognitive Neurology and Alzheimer's Disease Center, Department of Neurology, Northwestern University Feinberg School of Medicine, USA. · Med Health R I. · Pubmed #18549037 No free full text.

This publication has no abstract.

Counts SE, Perez SE, Mufson EJ. · Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street Suite 300, Chicago, Ilinois 60612, USA. · Cell Mol Life Sci. · Pubmed #18500641 No free full text.

Abstract: Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.

Malito E, Hulse RE, Tang WJ. · Ben-May Department for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, United States. · Cell Mol Life Sci. · Pubmed #18470479 No free full text.

Abstract: The accumulation of aggregates of amyloidogenic peptides is associated with numerous human diseases. One well studied example is the association between deposition of amyloid beta (Abeta) and Alzheimer's disease. Insulin degrading enzyme and neprilysin are involved in the clearance of Abeta, and presequence peptidase is suggested to play a role in the degradation of mitochondrial Abeta. Recent structural analyses reveal that these three peptidases contain a catalytic chamber (crypt) that selectively encapsulates and cleaves amyloidogenic peptides, hence the name cryptidase. The substrate selectivity of these cryptidases is determined by the size and charge distribution of their crypt as well as the conformational flexibility of substrates. The interaction of Abeta with the catalytic core of these cryptidases is controlled by conformational changes that make the catalytic chambers accessible for Abeta binding. These new structural and biochemical insights into cryptidases provide potential therapeutic strategies for the control of Abeta clearance.

Cole SL, Vassar R. · Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, Chicago Avenue, Chicago, IL, USA. · Curr Alzheimer Res. · Pubmed #18393796 No free full text.

Abstract: Amyloid plaques, hallmark neuropathological lesions in Alzheimer's disease (AD) brain, are composed of the beta-amyloid peptide (Abeta). Much evidence suggests that Abeta is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. Given the strong correlation between Abeta and AD, therapeutic strategies to lower cerebral Abeta levels should prove beneficial for AD treatment. Abeta is derived from amyloid precursor protein (APP) via cleavage by two proteases, beta- and gamma-secretase. The beta-secretase has been identified as a novel aspartic protease named BACE1 (beta-site APP Cleaving Enzyme 1) that initiates Abeta formation. Importantly, BACE1 appears to be dysregulated in AD. As the rate-limiting enzyme in Abeta generation, BACE1, in principle, is an excellent therapeutic target for strategies to reduce the production of Abeta in AD. While BACE1 knockout (BACE1-/-) mice have been instrumental in validating BACE1 as the authentic beta-secretase in vivo, data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-/- mice. Here we review the basic biology of BACE1, focusing on the regulation, structure and function of this enzyme. We pay special attention to the putative function of BACE1 during normal conditions and discuss in detail the relationship that exists between key risk factors for AD and the pathogenic alterations in BACE1 that are observed in the diseased state.

Sparks MB. · College of Nursing and Health Professions, University of Southern Indiana, Evansville, IL 47712, USA. · Crit Care Nurs Q. · Pubmed #18316939 No free full text.

Abstract: In the United States, 4.9 million people aged 65 years and older have Alzheimer's disease (AD). Medicare costs for patients with heart disease, diabetes, congestive heart failure, or chronic obstructive pulmonary disease and dementia are higher than for those without dementia. Although one principle of care for persons with AD is "do not hospitalize," comorbidities may require inpatient care. This article presents a definition, the diagnostic criteria for AD, and information about differential diagnosis, risk factors, pathology, progression, evidence base for practice, assessment, pharmacologic management, guidelines for general inpatient care, discharge planning, and interventions related to communications, environment, spirituality, special tasks (eating, protecting tubes and dressings, bathing), stages of AD, and special problems (wandering, pain, incontinence, hallucinations, aggression).

Viola KL, Velasco PT, Klein WL. · Department of Neurobiology and Physiology, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Evanston, IL 60208, USA. · J Nutr Health Aging. · Pubmed #18165846 No free full text.

Abstract: Individuals with early-stage Alzheimer's disease (AD) suffer from 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 neurologically active A beta oligomers (1). We have named these oligomers "ADDLs" (for pathogenic A beta-Derived Diffusible Ligands). ADDLs constitute metastable alternatives to the disease-defining A beta fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as A beta 12mers (2) (approximately 54 kDa) and can be found in dot-like clusters distinct from senile plaques (3). Oligomers of equal mass have been reported to occur in tgmouse AD models where they emerge concomitantly with memory failure (4), consistent with ADDL inhibition of LTP (1). In cell biology studies, ADDLs act as pathogenic gain-of-function ligands that target particular synapses, binding to synaptic spines at or near NMDA receptors (5,6). Binding produces ectopic expression of the memory-linked immediate early gene Arc. Subsequent ADDL-induced abnormalities in spine morphology and synaptic receptor composition (7) are predicted consequences of Arc overexpression, a pathology associated with memory dysfunction in tg-Arc mice. Significantly, the attack on synapses provides a plausible mechanism unifying memory dysfunction with major features of AD neuropathology; recent findings show that ADDL binding instigates synapse loss, oxidative damage, and AD-type tau hyperphosphorylation. Acting as novel neurotoxins that putatively account for memory loss and neuropathology, ADDLs present significant targets for disease-modifying therapeutics in AD.

Aggarwal NT. · Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Panminerva Med. · Pubmed #18091670 No free full text.

Abstract: A wide spectrum of cognitive ability is seen in older persons, ranging from intact cognitive function to clinically manifested dementia. The term mild cognitive impairment (MCI) is increasingly used to refer to individuals who have some cognitive impairment but do not meet the criteria for dementia. Despite a lack of consensus about precisely how to define MCI, researchers agree that the condition is relatively common in older people, and data suggest that MCI may be associated with an increased risk of Alzheimer's disease, parkinsonian signs and disability. Presently, the clinical assessment of MCI should include a detailed evaluation of cognitive functioning and the use of structural MRI can provide important diagnostic and prognostic information. Although therapeutic trials in MCI using the Choline acetylcholinesterase's have been disappointing with short term affects noted, pharmacologic prevention studies for MCI, are underway and may provide valuable data to prevent the development of this condition.

Fleischman DA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA. · Cortex. · Pubmed #17941347 No free full text.

Abstract: Two decades of research examining repetition priming in aging and Alzheimer's disease (AD) has yielded a large body of contradictory findings due to differences between studies in participant and task characteristics. Recent research that has employed methodological advances indicates that this form of implicit memory is preserved in healthy aging. When a priming deficit does occur in studies of aging, it is likely a very early signal of neurological disease. Future directions for research in this area include linking priming ability to known risk factors for development of AD, integrating priming measures into clinical neuropsychological assessment batteries, and implementing programs of cognitive retraining that enhance memory using stimulus repetition techniques.

Stutzmann GE. · Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, IL 60064, USA. · Neuroscientist. · Pubmed #17901262 No free full text.

Abstract: Alzheimer's disease (AD) is a fatal neurodegenerative disorder that has no known cure, nor is there a clear mechanistic understanding of the disease process itself. Although amyloid plaques, neurofibrillary tangles, and cognitive decline are late-stage markers of the disease, it is unclear how they are initially generated, and if they represent a cause, effect, or end phase in the pathology process. Recent studies in AD models have identified marked dysregulations in calcium signaling and related downstream pathways, which occur long before the diagnostic histopathological or cognitive changes. Under normal conditions, intracellular calcium signals are coupled to effectors that maintain a healthy physiological state. Consequently, sustained up-regulation of calcium may have pathophysiological consequences. Indeed, upon reviewing the current body of literature, increased calcium levels are functionally linked to the major features and risk factors of AD: ApoE4 expression, presenilin and APP mutations, beta amyloid plaques, hyperphosphorylation of tau, apoptosis, and synaptic dysfunction. In turn, the histopathological features of AD, once formed, are capable of further increasing calcium levels, leading to a rapid feed-forward acceleration once the disease process has taken hold. The views proposed here consider that AD pathogenesis reflects long-term calcium dysregulations that ultimately serve an enabling role in the disease process. Therefore, "Calcinists" do not necessarily reject betaAptist or Tauist doctrine, but rather believe that their genesis is associated with earlier calcium signaling dysregulations.

deToledo-Morrell L, Stoub TR, Wang C. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Prog Brain Res. · Pubmed #17765748 No free full text.

Abstract: Quantitative imaging techniques allow the in vivo investigation of age and disease related changes in the brain and their relation to cognitive function. In this chapter we review imaging evidence indicating that the entorhinal cortex and hippocampus show atrophy very early in Alzheimer's disease (AD) and in individuals who are at risk of developing AD compared to age appropriate controls. Furthermore, the extent and rate of atrophy of the entorhinal cortex, a brain region pathologically involved very early in the disease process, can predict who among the elderly will develop AD. Techniques that assess the integrity of white matter further demonstrate that alterations in the parahippocampal white matter in the region that includes the perforant path could partially disconnect the dentate gyrus and other hippocampal subfields from incoming sensory information. Such partial disconnection and degradation in transmission of sensory information in people at risk of AD and in patients with very mild AD could contribute to the memory dysfunction associated with the early stages of the disease.

Kaplan M, Mutlu EA, Benson M, Fields JZ, Banan A, Keshavarzian A. · Rush University Medical Center, Department of Internal Medicine, Section of Gastroenterology and Nutrition, 1725 West Harrison Street, Suite 206, Chicago, IL 60612-3824, United States. · Complement Ther Med. · Pubmed #17709066 No free full text.

Abstract: Complementary and alternative medicine (CAM) use has increased in popularity in recent years and herbal therapy alone is now a billion dollar market. For centuries herbs have been used as food and for medicinal purposes. Various herbs have been identified as possessing anti-inflammatory and antioxidative properties, and they are currently being used to treat inflammatory disorders as well as those caused by reactive oxygen species (ROS). Asthma, Alzheimer's disease, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and atherogenesis are all disorders where inflammation and ROS are involved in their pathogenesis. This review examines the pathogenesis of the above mentioned ROS-mediated inflammatory disorders, as well as discusses the antioxidant and anti-inflammatory mechanisms of various herbs and the clinical trials where herbs have been used to treat these disorders.

Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin Watterson D. · Center for Drug Discovery and Chemical Biology, Northwestern University Chicago, Illinois 60611, USA. · Int Rev Neurobiol. · Pubmed #17678967 No free full text.

Abstract: Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation-provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of proinflammatory cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function-driven and target-based, that show promise for development of neuroinflammation-targeted, disease-modifying therapeutics for multiple neurodegenerative disorders.

Kramer AF, Erickson KI. · Beckman Institute and Department of Psychology, University of Illinois, Urbana, IL 61801, USA. · Trends Cogn Sci. · Pubmed #17629545 No free full text.

Abstract: Given the aging populations in many countries throughout the world, there is an increasing interest in lifestyle factors and interventions that will enhance the cognitive vitality of older adults and reduce the risk for age-related neurological disorders, such as Alzheimer's disease. In this review, we evaluate the hypothesis that physical activity and exercise might serve to protect, and also enhance, cognitive and brain function across the adult lifespan. To this end, we critically review three separate literatures that have examined the influence of physical activity and exercise on cognition, brain function and brain structure of adults, including epidemiological or prospective observational studies, randomized human clinical interventions and non-human animal studies. We suggest that this literature supports the claim that physical activity enhances cognitive and brain function, and protects against the development of neurodegenerative diseases. We discuss future directions to address currently unresolved questions, such as interactions between multiple lifestyle factors on offsetting or protecting against cognitive and neural decline, and conclude that physical activity is an inexpensive treatment that could have substantial preventative and restorative properties for cognitive and brain function.

Cheng H, Vetrivel KS, Gong P, Meckler X, Parent A, Thinakaran G. · University of Chicago, IL, USA. · Nat Clin Pract Neurol. · Pubmed #17611486 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of age-related dementia. Pathologically, AD is characterized by the deposition in the brain of amyloid-beta peptides derived from proteolysis of amyloid precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase. A growing body of evidence implicates cholesterol and cholesterol-rich membrane microdomains in amyloidogenic processing of APP. Here, we review recent findings regarding the association of BACE1, gamma-secretase and APP in lipid rafts, and discuss potential therapeutic strategies for AD that are based on knowledge gleaned from the membrane environment that fosters APP processing.