Alzheimer Disease: New England

Staropoli JF. · Department of Pathology, Massachusetts General Hospital, Gray-Jackson 249, MGH, 55 Fruit St Boston, MA 02114-2696, USA. · Bioessays. · Pubmed #18623069 No free full text.

Abstract: Dysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxia-telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.

Barten DM, Albright CF. · Bristol Myers Squibb, Neuroscience Drug Discovery, 5 Research Parkway, Wallingford, CT 06492, USA. · Mol Neurobiol. · Pubmed #18581273 No free full text.

Abstract: Therapeutic approaches for Alzheimer's disease (AD) are guided by four disease characteristics: amyloid plaques, neurofibrillar tangles (NFT), neurodegeneration, and dementia. Amyloid plaques are composed largely of 4 kDa beta-amyloid (Abeta) peptides, with the more amyloidogenic, 42 amino acid form (Abeta42) as the primary species. Because multiple, rare mutations that cause early-onset, familial AD lead to increased production or aggregation of Abeta42, amyloid therapeutics aim to reduce the amount of toxic Abeta42 aggregates. Amyloid-based therapies include gamma-secretase inhibitors and modulators, BACE inhibitors, aggregation blockers, catabolism inducers, and anti-Abeta biologics. Tangles are composed of paired helical filaments of hyperphosphorylated tau protein. Tau-based therapeutics include kinase inhibitors, microtubule stabilizers, and catabolism inducers. Therapeutic strategies for neurodegeneration target multiple mechanisms, including excitotoxicity, mitochondrial dysfunction, oxidative damage, and inflammation or stimulation of neuronal viability. Although not disease modifying, cognition enhancers are important to treat the symptom of dementia. Strategies for cognition enhancement include cholinesterase inhibitors, and other approaches to enhance the signaling of cholinergic and glutamatergic neurons. In summary, plaques, tangles, neurodegeneration and dementia guide the development of multiple therapeutic approaches for AD and are the subject of this review.

Calabrese EJ. · Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts 01003, USA. · Crit Rev Toxicol. · Pubmed #18568864 No free full text.

Abstract: This article provides an evaluation of the dose-response features of drugs that are intended to improve memory, some of which have been used in the treatment of Alzheimer's disease (AD). A common feature of these drugs is that they act via an inverted U-shaped dose response, consistent with the hormetic dose response model. This article assesses historical foundations that lead to the development of AD drugs, their dose-response features and how the quantitative features of such dose responses affected drug discovery and development, and the successes and possible failures of such agents in preclinical and clinical settings. This story begins about 150 years ago with the discovery of an active agent in the Calabar bean plant called physostigmine, its unfolding medical applications, and its implications for dose-response relationships, memory enhancement, and improved drug discovery activities. The article also demonstrates the occurrence of U-shaped dose responses for memory with numerous endogenous agonists including neurosteroids, various peptides (e.g., vasopressin, CCK-8, neuropeptide Y), and other agents (e.g., epinephrine, antagonists for platelet activity factor and nicotinic receptors), supporting the generalizability of the hormetic biphasic dose response. Finally, the significance of the U-shaped dose response is critical for successful clinical application, since it defines the therapeutic window.

Zhang M. · Department of Biology, Synta Pharmaceuticals, 125 Hartwell Avenue, Lexington, MA 02421, USA. · Front Biosci. · Pubmed #18508646 No free full text.

Abstract: Extensive research has been carried out to elucidate the mechanism of neurodegenerative diseases, with special emphasis on lysosomal storage disease (LSD) and Alzheimer's disease (AD). Studies have outlined complicated profiles in both types of disorders for the role of endocytosis in disease pathogenesis and progression. Recent discoveries relating endocytosis to the pathological origin and therapeutic strategy of the diseases have yet to be addressed. In this review, I attempt to demonstrate a comprehensive analysis on the endocytic mechanism of the disease. I propose that LSD could be classified as a late endosomal trafficking disorder. I also highlight that the most critical cellular event in AD--the producing, processing, and trafficking of Abeta42 peptide--dynamically involves the entire endocytic system. I further analyze pipeline drug targets, summarize the development status of current new drugs, share thoughts on potential therapeutic strategies, and reveal that many such strategies are in close association with endocytosis. I emphasize that thoroughly understanding pathologically-relevant endocytic events is the key factor in speeding up discovery and development of novel drugs.

Solomon PR, Murphy CA. · Department of Psychology, Program in Neuroscience, Williams College, Williamstown, MA, USA. · Expert Rev Neurother. · Pubmed #18457534 No free full text.

Abstract: Recently, focus on early detection, diagnosis and treatment of Alzheimer's disease (AD) has been increasing. The rationale is that, as with any other serious illness, early intervention will lead to better outcomes for patients and families. Despite the intuitive appeal of this rationale, there is discussion and even debate regarding the issues surrounding early detection and treatment. This review begins with a futuristic case that is aimed at focusing this discussion/debate and then proceeds to consider each of the issues including: should AD screening be part of routine physical examinations? is the amyloid hypothesis correct?: implications for diagnosis and treatment? can neuroimaging studies be used to detect brain amyloid? can symptomatic medications be combined to facilitate cognition? can cognitive rehabilitation programs facilitate cognition? and can immunotherapy and other plaque-busting therapies modify the progression of AD?

Hernán MA, Alonso A, Logroscino G. · Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. · Epidemiology. · Pubmed #18414087 No free full text.

Abstract: We conducted a systematic review of published prospective studies that estimated the association between smoking and the incidence of Alzheimer disease and dementia. The relative rate for smokers versus nonsmokers ranged from 0.27 to 2.72 for Alzheimer disease (12 studies) and from 0.38 to 1.42 for dementia (6 studies). The minimum age at entry (range: 55-75 years) explained much of the between-study heterogeneity in relative rates. We conjecture that selection bias due to censoring by death may be the main explanation for the reversal of the relative rate with increasing age.

Xia W. · Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Curr Alzheimer Res. · Pubmed #18393802 No free full text.

Abstract: Mutations in two genes, presenilin 1 (PS1) and its homologue presenilin 2 (PS2), account for a majority of early onset familial Alzheimer disease cases which are characterized by intracellular neurofibrillary tangles and extracellular amyloid fibrils composed of the amyloid beta protein (Abeta). Abeta is derived from sequential cleavages of Amyloid Precursor Protein (APP) by beta-secretase and gamma-secretase, the latter is composed of four components, PS1, nicastrin (NCT), presenilin enhancer 2 (PEN-2), and anterior pharynx defective (APH-1). These components not only maintain the stability of the gamma-secretase complex but also regulate the activity of presenilinase, the protease responsible for the cleavage of full length PS1 into N-terminal and C-terminal fragments (NTF/CTF). We have previously shown that endoproteolysis of PS1 into NTF/CTF by presenilinase requires two critical aspartate residues, suggesting that PS1 may undergo autoproteolysis; full length PS1 complexes with NCT, PEN-2, APH-1 and forms the presenilinase. While these two aspartate residues are necessary for the endoproteolysis of full length PS1, they are equally critical for the gamma-secretase cleavage of multiple substrates, and it is hypothesized that the full length PS1/presenilinase is the zymogen of gamma-secretase. The inhibition profiles of presenilinase and gamma-secretase are illustrated by their biochemical similarity but are pharmacologically distinct. Since the uncleaved PS1 loop may obstruct the entry of gamma-secretase substrates to the docking site of the gamma-secretase complex, investigation of presenilinase inhibitors interfering with substrate-docking may facilitate a novel approach to identify APP specific gamma-secretase inhibitors.

Wolfe MS. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. · Curr Alzheimer Res. · Pubmed #18393800 links to  free full text

Abstract: Gamma-secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid beta-peptide (Abeta) precursor (APP), producing the Abeta peptide implicated in the pathogenesis of Alzheimer's disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. Although one gamma-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with gamma-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of gamma-secretase as therapeutic target likely depends on the ability to selectively inhibit Abeta production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of gamma-secretase modulators has revived gamma-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.

Donahue JE, Johanson CE. · Division of Neuropathology, Department of Pathology, Rhode Island Hospital, Providence, Rhode Island 02903, USA. · J Neuropathol Exp Neurol. · Pubmed #18379441 No free full text.

Abstract: There is increasing evidence for blood-brain barrier (BBB) compromise in Alzheimer disease (AD). The presence of the epsilon4 allele of the apolipoprotein E (apoE) gene is a risk factor for sporadic AD. Apolipoprotein E is essential both for maintenance of BBB integrity and for the deposition of fibrillar amyloid-beta (Abeta) that leads to the development of Abeta plaques in AD and to cerebral amyloid angiopathy. This review investigates the relationships between apoE, Abeta, and the BBB in AD. Alterations in the expression and distribution of the BBB Abeta transporters receptor for advanced glycation end-products and low-density lipoprotein receptor-related protein 1 in AD and the potential roles of apoE4 expression in adversely influencing Abeta burden and BBB permeability are also examined. Because both apoE and Abeta are ligands for low-density lipoprotein receptor-related protein 1, all 3 molecules are present in AD plaques, and most AD plaques are located close to the cerebral microvasculature. The interactions of these molecules at the BBB likely influence metabolism and clearance of Abeta and contribute to AD pathogenesis. Therapeutic alternatives targeting apoE/Abeta and sealing a compromised BBB are under development for the treatment of AD.

Kinoshita J, Clark T. · Alzheimer Research Forum, Waltham, MA, USA. · Methods Mol Biol. · Pubmed #18368375 No free full text.

Abstract: The Alzheimer Research Forum Web site ( http://www.alzforum.org ) is an independent research project to develop an online community resource to manage scientific knowledge, information, and data about Alzheimer disease (AD). Its goals are to promote rapid communication, research efficiency, and collaborative, multidisciplinary interactions. Introducing new knowledge management approaches to AD research has a potentially large societal value. AD is among the leading causes of disability and death in older people. According to the Alzheimer's Association, four million Americans currently suffer from AD. That number is expected to escalate to over 10 million in coming decades. Patients progress from memory loss to a bedridden state over many years and require near-constant care. In addition to imposing a heavy burden on family caregivers and society at large, AD and related neurodegenerative disorders are among the most complex and challenging in biomedicine. Researchers have produced an abundance of data implicating diverse biological mechanisms. Important factors include genes, environmental risks, changes in cell functions, DNA damage, accumulation of misfolded proteins, cell death, immune responses, changes related to aging, and reduced regenerative capacity. Yet there is no agreement on the fundamental causes of AD. The situations regarding Parkinson, Huntington, and amyotrophic lateral sclerosis (ALS) are similar. The challenge of integrating so much data into testable hypotheses and unified concepts is formidable. What is more, basic understanding of these diseases needs to intersect with an equally complex universe of pharmacology, medicinal chemistry, animal studies, and clinical trials. In this chapter, we will describe the approaches developed by Alzforum to achieve knowledge integration through information technology and virtual community-building. We will also propose some future directions in the application of Web-based knowledge management systems in neuromedicine.

Selkoe DJ. · Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Behav Brain Res. · Pubmed #18359102 No free full text.

Abstract: During the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid beta-protein (Abeta) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease (AD). The reasons for elevated cortical Abeta42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Abeta during some kinds of synaptic activity. Elevated levels of soluble Abeta42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts. We have identified certain APP-expressing cultured cell lines that form low-n oligomers intracellularly and release a portion of them into the medium. We find that these naturally secreted soluble oligomers--at picomolar concentrations--can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats. Abeta trimers appear to be more potent in disrupting LTP than are dimers. The cell-derived oligomers also decrease dendritic spine density in organotypic hippocampal slice cultures, and this decrease can be prevented by administration of Abeta antibodies or small-molecule modulators of Abeta aggregation. This therapeutic progress has been accompanied by advances in imaging the Abeta deposits non-invasively in humans. A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging.

Shea TB, Chan A. · Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, UMass Lowell, One University Avenue, Lowell, MA 01854, USA. · J Alzheimers Dis. · Pubmed #18334758 No free full text.

Abstract: Recent preclinical and clinical findings demonstrate that dietary supplementation with S-adenosyl methionine alleviates a variety of risk factors and hallmarks associated with Alzheimer's disease. These findings support and extend prior studies, some of which are decades old, and support the notion that nutritional supplementation may represent an important augmentation for therapy in Alzheimer's disease.

Kim Y, Wilkins KM, Tampi RR. · Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. · Drugs Aging. · Pubmed #18331071 No free full text.

Abstract: Behavioural and psychological symptoms of dementia (BPSD) have been defined as a heterogeneous range of psychological reactions, psychiatric symptoms and behaviours that may be unsafe, disruptive and impair the care of a patient in a given environment. To date, there are no US FDA-approved drugs or clear standards of pharmacological care for the treatment of BPSD. The novel antiepileptic agent gabapentin is being increasingly considered for use in the geriatric population because of its relatively favourable safety profile compared with other classes of psychiatric medications. Gabapentin has been administered to several geriatric patients with bipolar disorder and patients with dementia. It has also been reported to be successful in the treatment of a 13-year-old boy with behavioural dyscontrol, a finding that suggested a possible role for gabapentin in the treatment of other behavioural disorders. The purpose of this review was to find evidence for the use of gabapentin in the treatment of BPSD. To this end, a search was performed for case reports, case series, controlled trials and reviews of gabapentin in the treatment of this condition. The key words 'dementia', 'Alzheimer's disease' and 'gabapentin' were used. Searches were performed in PubMed, PsycINFO, Ovid MEDLINE, Cochrane Library and ClinicalTrials.gov. The search revealed that there are limited data on the efficacy of gabapentin for BPSD in the form of 11 case reports, 3 case series and 1 retrospective chart review; no controlled studies appear to have been published to date on this topic. In most of the reviewed cases, gabapentin was reported to be a well tolerated and effective treatment for BPSD. However, two case reports in which gabapentin was used in the context of agitation in dementia with Lewy bodies questioned the appropriateness of gabapentin for all types of dementia-related agitation. The dearth of available data limits support for the off-label use of gabapentin for the treatment of BPSD. Furthermore, controlled studies should be conducted before gabapentin can be clinically indicated for the successful treatment of BPSD.

Huttunen HJ, Kovacs DM. · Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass. 02129, USA. · Neurodegener Dis. · Pubmed #18322393 links to  free full text

Abstract: Accumulation of beta-amyloid peptide (Abeta) in the brain regions responsible for memory and cognitive functions is a neuropathological hallmark of Alzheimer's disease. Cholesterol may be involved in many aspects of Abeta metabolism. It affects generation, aggregation and clearance of Abeta in the brain. Not only the amount but also the distribution of cholesterol within cells appears to modulate Abeta biogenesis. ACAT is an enzyme that regulates subcellular cholesterol distribution by converting membrane cholesterol to cholesteryl esters for storage and transport. We have used various cell- and animal based models to show that inhibition of ACAT strongly reduces Abeta generation and protects from amyloid pathology. Here, we discuss data supporting ACAT inhibition as a strategy to treat Alzheimer's disease.

Neve RL. · McLean Hospital, Belmont, MA 02478, USA. · Amyloid. · Pubmed #18266116 No free full text.

Abstract: Familial Alzheimer's disease mutations in presenilin and the amyloid precursor protein (APP) are thought to cause Alzheimer's disease (AD) neurodegeneration by increasing production and aggregation of amyloid beta (Abeta). However, presenilin has functions that are distinct from its role in the gamma-secretase complex, while APP has signaling functions that transcend its role as the source of Abeta. Three recent papers highlight the potential importance of presenilin and APP signaling in the etiology of AD.

Kaneki M. · Harvard Medical School, Massachusetts General Hospital, Department of Anesthesia & Critical Care. · Clin Calcium. · Pubmed #18245893 No free full text.

Abstract: Vitamin K is a nutrient originally identified as an essential factor for blood coagulation. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone, exists widely in the otherwise healthy adult population. Both vitamin K1 and K2 have been shown to exert protective effects against osteoporosis. The new biological functions of vitamin K in bone are considered to be attributable, at least in part, to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by both vitamins K1 and K2. A recent evidence of significant correlation between polymorphism of gamma-glutamyl carboxylase gene and bone mineral density supports the role of gamma-carboxylation-dependent actions of vitamin K. In contrast, vitamin K2-specific,gamma-carboxylation-unrelated functions have recently attracted scientific attention. Recent findings of vitamin K2-specific transactivation of steroid and xenobiotic receptor (SXR/PXR) may lead to new research avenue. The impact of genotype of apoE, a major vitamin K transporter, on ostepporosis as well as Alzheimer disease and atherosclerosis, raises a question whether vitamin K is involved in the pathogenesis of these diseases. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in bone health deserve further investigations.

Selkoe DJ. · Harvard Medical School, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Nutr Rev. · Pubmed #18240556 No free full text.

Abstract: A remarkable rise in life expectancy during the past century has made Alzheimer's disease (AD) the most common form of progressive intellectual failure in humans. Patients with AD lose their most human qualities-reasoning, abstraction, language, and memory. The brain plaques that Alois Alzheimer first described 100 years ago have inspired the search for genetic alterations that underlie AD. Four genes have been unequivocally implicated to date in inherited forms of AD, where mutations or natural variations in these genes cause excessive accumulation of the amyloid beta-protein, the building block of amyloid plaques. This aggregation leads to subsequent neuronal degeneration in brain regions important for memory and cognition. The discovery of the genes involved in the mechanisms of amyloid beta-protein build-up in AD, coupled with cell culture and animal models of their involved pathways, has led to the development of specific pharmacological strategies to lower amyloid beta-protein levels as a way of treating or preventing all forms of the disease. While hard work lies ahead, the movement from basic research to the clinic in AD represents a triumph of reductionist biology applied to the most complex of all biological systems, the human cerebral cortex.

Raymond SB, Skoch J, Hills ID, Nesterov EE, Swager TM, Bacskai BJ. · Alzheimer's Disease Research Unit, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. · Eur J Nucl Med Mol Imaging. · Pubmed #18236039 No free full text.

Abstract: PURPOSE: Near-infrared fluorescent probes for amyloid-beta (Abeta) are an exciting option for molecular imaging in Alzheimer's disease research and may translate to clinical diagnostics. However, Abeta-targeted optical probes often suffer from poor specificity and slow clearance from the brain. We are designing smart optical probes that emit characteristic fluorescence signal only when bound to Abeta. METHODS: We synthesized a family of dyes and tested Abeta-binding sensitivity with fluorescence spectroscopy and tissue-staining. RESULTS: Select compounds exhibited Abeta-dependent changes in fluorescence quantum yield, lifetime, and emission spectra that may be imaged microscopically or in vivo using new lifetime and spectral fluorescence imaging techniques. CONCLUSION: Smart optical probes that turn on when bound to Abeta will improve amyloid detection and may enable quantitative molecular imaging in vivo.

Wolfe MS. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. · Curr Top Med Chem. · Pubmed #18220927 No free full text.

Abstract: Gamma-secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid beta-protein precursor, involved in Alzheimer's disease, and the Notch receptor, critical for cellular differentiation. This protease is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. Assembly of these four components leads to presenilin autoproteolysis into two subunits, each of which contributes one aspartate to the active site of an aspartyl protease. The protease contains an initial docking site for substrate, where it binds prior to passing between the two presenilin subunits to the internal water-containing active site. The extracellular region of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Modulation of APP processing without interfering with Notch signaling is an important therapeutic goal, and allosteric sites on the protease allow such selective modulation. A better structural and mechanistic understanding of gamma-secretase should ultimately allow structure-based design of more potent and selective modulators.

Park JH, Strittmatter SM. · Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA. · Curr Alzheimer Res. · Pubmed #18220524 No free full text.

Abstract: Pathophysiologic hypotheses for Alzheimer's disease (AD) are centered on the role of the amyloid plaque Abeta peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near Abeta deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traumatic injuries. Here, we consider the potential role of NgR mechanisms in AD. Both Nogo and NgR are mislocalized in AD brain samples. APP physically associates with the NgR. Overexpression of NgR decreases Abeta production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain Abeta levels, plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces Abeta levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APP and AB, implicating NgR as a blocker of secretase processing of APP. The NgR provides a novel site for modifying the course of AD and highlights the role of axonal dysfunction in the disease.

Dickerson BC, Sperling RA. · Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Neuropsychologia. · Pubmed #18206188 No free full text.

Abstract: Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.

Nelson AP, O'Connor MG. · Brigham and Women's Hospital, Division of Cognitive and Behavioral Neurology, Boston, MA 02115, USA. · CNS Spectr. · Pubmed #18204415 links to  free full text

Abstract: Mild cognitive impairment (MCI) is a clinical diagnosis in which deficits in cognitive function are evident but not of sufficient severity to warrant a diagnosis of dementia. For the majority of patients, MCI represents a transitional state between normal aging and mild dementia, usually Alzheimer's disease. Multiple subtypes of MCI are now recognized. In addition to presentations featuring memory impairment, symptoms in other cognitive domains (eg, executive function, language, visuospatial) have been identified. Neuropsychological testing can be extremely useful in making the MCI diagnosis and tracking the evolution of cognitive symptoms over time. A comprehensive test battery includes measures of baseline intellectual ability, attention, executive function, memory, language, visuospatial skills, and mood. Informant-based measures of neuropsychiatric symptoms, behaviors, and competency in instrumental activity are also included. Careful assessment can identify subtle deficits that may otherwise elude detection, particularly in individuals of superior baseline intellectual ability. As we move closer to disease-modifying therapy for Alzheimer's disease, early identification becomes critical for identifying patients who have an opportunity to benefit from treatment.

Hyde J, Perez R, Forester B. · Gerontology Institute, University of Massachusetts, 100 Morrissey Boulevard, Boston, MA 02125, USA. · Gerontologist. · Pubmed #18162569 No free full text.

Abstract: PURPOSE: This article presents an overview of what is known about dementia services in assisted living settings and suggests areas for future research. DESIGN AND METHODS: We undertook a search of Medline, the Journals of Gerontology, and The Gerontologist. We then organized publications dealing with the target subject into 10 topic areas and reviewed them. RESULTS: The article describes the demographic characteristics of cognitively impaired residents in assisted living and related residential settings in the United States, the services they receive, and process and structural elements both in specialized dementia units and in integrated assisted living settings. Finally, we review the literature on methodological issues regarding research in this area. IMPLICATIONS: It is important to generate research on processes as well as outcomes, such as dignity, individualized and pleasurable experiences, and freedom from pain and discomfort. We make recommendations for both content areas that would benefit from further research as well as methodological approaches that will yield important information in this field.

Wu J, Basha MR, Zawia NH. · Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. · J Mol Neurosci. · Pubmed #18157652 No free full text.

Abstract: Alzheimer's Disease (AD) is a progressive, irreversible neurodegenerative disease. Despite several genetic mutations (Haass et al., J. Biol. Chem. 269:17741-17748, 1994; Ancolio et al., Proc. Natl. Acad. Sci. USA 96:4119-4124, 1999; Munoz and Feldman, CMAJ 162:65-72, 2000; Gatz et al., Neurobiol. Aging 26:439-447, 2005) found in AD patients, more than 90% of AD cases are sporadic (Bertram and Tanzi, Hum. Mol. Genet. 13:R135-R141, 2004). Therefore, it is plausible that environmental exposure may be an etiologic factor in the pathogenesis of AD. The AD brain is characterized by extracellular beta-amyloid (Abeta) deposition and intracellular hyperphosphorylated tau protein. Our lab has demonstrated that developmental exposure of rodents to the heavy metal lead (Pb) increases APP (amyloid precursor protein) and Abeta production later in the aging brain (Basha et al., J. Neurosci. 25:823-829, 2005a). We also found elevations in the oxidative marker 8-oxo-dG in older animals that had been developmentally exposed to Pb (Bolin et al., FASEB J. 20:788-790, 2006) as well as promotion of amyloidogenic histopathology in primates. These findings indicate that early life experiences contribute to amyloidogenesis in old age perhaps through epigenetic pathways. Here we explore the role of epigenetics as the underlying mechanism that mediates this early exposure-latent pathogenesis with a special emphasis on alterations in the methylation profiles of CpG dinucleotides in the promoters of genes and their influence on both gene transcription and oxidative DNA damage.

Bandyopadhyay S, Goldstein LE, Lahiri DK, Rogers JT. · Laboratory for Neurochemistry, Department of Psychiatry-Neuroscience, and Genetics, Massachusetts General Hospital, Boston, MA, USA. · Curr Med Chem. · Pubmed #18045131 No free full text.

Abstract: Alzheimer's disease (AD) is the most prevalent form of dementia, and its effective disease modifying therapies are desperately needed. Promotion of non-amyloidogenic alpha-secretase cleavage of amyloid precursor protein (APP) to release soluble sAPPalpha, based on the most widely accepted "amyloid model" as a plausible mechanism for AD treatment, is the focus of this review. Modulation of alpha-secretase or "a disintegrin and metalloprotease (ADAM)"s activity via protein kinase C (PKC), calcium ion (Ca(2+)), tyrosine kinase (TK), MAP kinase (MAPK), and hormonal signaling, which regulate catabolic processing of APP, are discussed. The inhibition of amyloidogenic processing of APP by the beta- and gamma-secretase has been considered till now a promising strategy to treat AD. But beta- and gamma-secretase inhibitors, along with the available therapeutic tools for AD, have side effects. These challenges can be circumvented to certain extent; but activation of sAPPalpha release appears to be a potential alternative strategy to reduce cerebral amyloidosis. Drug screens have been performed to identify therapeutics for AD, but an effective screening strategy to isolate activators of alpha-secretase has been rarely reported. Novel reporter-based screens targeted toward APP mRNA 5' untranslated region (UTR), followed by counter-screens to detect alpha-secretase stimulators, could be important in detecting compounds to promote sAPPalpha release and reduce amyloid beta (Abeta) buildup. The primary inflammatory cytokine interleukin-1, which stimulates APP 5'UTR-directed translation of cell-associated APP, enhances processing to sAPPalpha in astrocytes and co-activates ADAM-10/ADAM-17 through MAPK signaling; thus illustrating a novel pathway that could serve as therapeutic model for AD.