Alzheimer Disease: Massachusetts

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.

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.

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.

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.

Selkoe DJ, Wolfe MS. · Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Cell. · Pubmed #17956719 No free full text.

Abstract: The presenilin-containing gamma-secretase complex is an unusual membrane-embedded protease that processes a wide variety of integral membrane proteins, clearing protein stubs from the lipid bilayer and participating in critical signaling pathways. The protease is also central to Alzheimer's disease and certain cancers and is therefore an important therapeutic target. Here we highlight recent progress in deciphering the role of presenilin/gamma-secretase in biology and medicine and pose key questions for future study.

Seltzer B. · Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. · Drugs Aging. · Pubmed #17953456 No free full text.

Abstract: The cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine are the current mainstays in the drug treatment of Alzheimer's disease (AD). There is convincing evidence that these agents provide at least modest cognitive, behavioural and functional benefit for 6-12 months at all stages of the disease. Longer term benefits cannot be directly examined by placebo-controlled trials. Nevertheless, the results of virtually all open-label extensions of the pivotal trials, studies of patients with AD at different levels of severity and clinical trials using other designs favour treatment over no treatment for periods of up to 5 years. There are plausible biological reasons why ChEIs might be expected to work over a prolonged period of time although, to date, studies using various markers to chart the effects of medication on long-term disease progression have yielded mixed results. The most contentious issue regarding long-term treatment is economic, but the majority of available economic analyses suggest net savings over the long term if patients with AD receive persistent treatment with ChEIs.

Lemere CA, Maier M, Peng Y, Jiang L, Seabrook TJ. · Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115 USA. · Curr Alzheimer Res. · Pubmed #17908047 No free full text.

Abstract: Active and passive Abeta immunotherapy in Alzheimer's disease (AD)-like mouse models lowers cerebral amyloid-beta protein (Abeta) levels, especially if given early in the disease process, and improves cognitive deficits. In 2002, a Phase IIa clinical trial was halted due to meningoencephalitis in approximately 6% of the AD patients. It is hypothesized that the immunogen, full-length Abeta1-42, may have led to an autoimmune response. Currently, we are developing novel Abeta peptide immunogens for active immunization in amyloid precursor protein transgenic mice (APP Tg) to target Abeta B cell epitopes (within Abeta1-15) and avoid Abeta-specific T cell epitopes (Abeta16-42) so as to generate a safe and effective AD vaccine. Intranasal immunization with dendrimeric Abeta1-15 (16 copies of Abeta1-15 on a lysine core) or a tandem repeat of Abeta1-15 joined by 2 lysines and conjugated to an RGD motif with a mutated form of an E. coli-derived adjuvant generated robust Abeta titers in both wildtype and APP Tg mice. The Abeta antibodies recognized a B cell epitope within Abeta1-7, were mostly T-helper 2 associated immunoglobulin isotypes, bound human AD and APP Tg plaques, and detected Abeta oligomers. Splenic T cells reacted to the immunogens but not full-length Abeta. Six months of intranasal immunization (from 6-to-12 months of age) of J20 mice with each immunogen lowered insoluble Abeta42 by 50%, reduced plaque burden and gliosis, and increased Abeta in plasma. Interestingly, Abeta antibody generation was influenced by route of immunization. Transcutaneous immunization with dbeta1-15, but not full-length Abeta, led to high Abeta titers. In summary, our short Abeta immunogens induced robust titers of predominantly Th2 antibodies that were able to clear cerebral Abeta in the absence of Abeta-specific T cell reactivity, indicating the potential for a safer vaccine. We remain optimistic about the potential of such a vaccine for prevention and treatment of AD.

Wolfe MS, Guénette SY. · Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. · J Cell Sci. · Pubmed #17878232 links to  free full text

This publication has no abstract.

Fiala JC. · Department of Health Sciences, Boston University, Boston, MA 02215, USA. · Acta Neuropathol. · Pubmed #17805553 No free full text.

Abstract: The first ultrastructural investigations of Alzheimer's disease noted the prominence of degenerating mitochondria in the dystrophic neurites of amyloid plaques, and speculated that this degeneration might be a major contributor to plaque pathogenesis. However, the fate of these organelles has received scant consideration in the intervening decades. A number of hypotheses for the formation and progression of amyloid plaques have since been suggested, including glial secretion of amyloid, somal and synaptic secretion of amyloid-beta protein from neurons, and endosomal-lysosomal aggregation of amyloid-beta protein in the cell bodies of neurons, but none of these hypotheses fully account for the focal accumulation of amyloid in plaques. In addition to Alzheimer's disease, amyloid plaques occur in a variety of conditions, and these conditions are all accompanied by dystrophic neurites characteristic of disrupted axonal transport. The disruption of axonal transport results in the autophagocytosis of mitochondria without normal lysosomal degradation, and recent evidence from aging, traumatic injury, Alzheimer's disease and transgenic mice models of Alzheimer's disease, suggests that the degeneration of these autophagosomes may lead to amyloid production within dystrophic neurites. The theory of amyloid plaque pathogenesis has thus come full circle, back to the intuitions of the very first researchers in the field.

Findeis MA. · Satori Pharmaceuticals Incorporated, 222 Berkeley Street, Suite 1040, Boston, MA 02116, USA. · Pharmacol Ther. · Pubmed #17716740 No free full text.

Abstract: During the last 20 years, an expanding body of research has elucidated the central role of amyloid precursor protein (APP) processing and amyloid beta peptide (Abeta) production in the risk, onset, and progression of the neurodegenerative disorder Alzheimer's disease (AD), the most common form of dementia. Ongoing research is establishing a greater level of detail for our understanding of the normal functions of APP, its proteolysis products, and the mechanisms by which this processing occurs. The importance of this processing machinery in normal cellular function, such as Notch processing, has revealed specific concerns about targeting APP processing for therapeutic purposes. Aspects of AD that are now well studied include direct and indirect genetic and other risk factors for AD, APP processing, and Abeta production. Emerging from these studies is the particular importance of the long form of Abeta, Abeta42. Elevated Abeta42 levels, as well as particularly the elevation of the ratio of Abeta42 to the shorter major form Abeta40, has been identified as important in early events in the pathogenesis of AD. The specific pathological importance of Abeta42 has drawn attention to seeking drugs that will selectively lower the levels of this peptide through reduced production or increased clearance while allowing normal protein processing to remain substantially intact. An increasing variety of compounds that modulate APP processing to reduce Abeta levels are being identified, some with Abeta42 selectivity. Such compounds are now reaching clinical evaluation to determine how they may be of benefit in the treatment of AD.

Coyle JT, Geerts H, Sorra K, Amatniek J. · Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA. · J Alzheimers Dis. · Pubmed #17656829 No free full text.

Abstract: Galantamine is an approved treatment for mild to moderate Alzheimer's disease, with demonstrated benefits for cognition and functional ability in human studies. The mechanism of action that is most generally recognized as underlying the clinical benefits of galantamine is inhibition of brain acetylcholinesterase (AChE). However, an increasing body of evidence suggests that an additional mechanism, most likely allosteric modulation of nicotinic acetylcholine receptors (nAChRs), may contribute to the therapeutic effects of galantamine. This review summarizes the research on this additional mechanism, with emphasis on data derived from in vivo animal studies and open-label hypothesis-generating studies in humans. In general, these studies provide evidence of effects beyond those of AChE inhibition alone, most notably in comparisons with other AChE inhibitors, in which galantamine produced similar or greater effects at doses that provided lower levels of brain AChE inhibition. The use of nAChR agonists and antagonists in some of these studies lends support to the proposed allosteric potentiating ligand activity of galantamine at nAChRs. This dual action of galantamine may account for its therapeutic profile.

Sheridan PL, Hausdorff JM. · Behavioral Neurology Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. · Dement Geriatr Cogn Disord. · Pubmed #17622760 No free full text.

Abstract: Alzheimer's disease (AD) is generally understood as primarily affecting cognition while sparing motor function, at least until the later stages of the disease. Studies reported over the past 10 years, however, have documented a prevalence of falls in AD patients significantly higher than in age-matched normal elders; also persons with AD have been observed to have different walking patterns with characteristics that increase gait instability. Recent work in cognitive neuroscience has begun to demonstrate the necessity of intact cognition, particularly executive function, for competent motor control. We put the pieces of this puzzle together and review the current state of knowledge about gait and cognition in general along with an exploration of the association between dementia, gait impairment and falls in AD. We also briefly examine the current treatment of gait instability in AD, mainly exercise, and propose a new approach targeting cognition.

Lau FC, Shukitt-Hale B, Joseph JA. · USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · Subcell Biochem. · Pubmed #17612057 No free full text.

Abstract: It is estimated that by the year 2050 the elderly (aged 65 or older) population will double the population of children (aged 0-14) for the first time in history. The expansion of the elderly population has already taken a toll on health care systems. In order to alleviate the health care costs and increase the quality of living in the aging population, it is crucial to explore methods that may retard or reverse the deleterious effects of aging. Inflammation and oxidative stress play important roles in brain aging. Inflammatory markers, as well as cellular and molecular oxidative damage, increase during normal brain aging. This increase is accompanied by the concomitant decline in cognitive and motor performance in the elderly population, even in the absence of neurodegenerative diseases. Epidemiological studies have shown that consumption of diets rich in antioxidant and anti-inflammatory agents, such as those found in fruits and vegetables, may lower the risk of developing age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Research from our laboratory suggests that dietary supplementation with fruit or vegetable extracts can decrease the age-enhanced vulnerability to oxidative stress and inflammation. Additional research suggests that the polyphenolic compounds found in fruits such as blueberries may exert their beneficial effects through signal transduction and neuronal communication. Thus, nutritional intervention may exert therapeutic protection against age-related deficits and neurodegenerative diseases.

Dickerson BC. · Gerontology Research Unit, Alzheimer's Disease Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. · Neurotherapeutics. · Pubmed #17599702 No free full text.

Abstract: Functional MRI (fMRI) is a valuable method for use by clinical investigators to study task-related brain activation in patients with neurological or neuropsychiatric illness. Despite the relative infancy of the field, the rapid adoption of this functional neuroimaging technology has resulted from, among other factors, its ready availability, its relatively high spatial and temporal resolution, and its safety as a noninvasive imaging tool that enables multiple repeated scans over the course of a longitudinal study, and thus may lend itself well as a measure in clinical drug trials. Investigators have used fMRI to identify abnormal functional brain activity during task performance in a variety of patient populations, including those with neurodegenerative, demyelinating, cerebrovascular, and other neurological disorders that highlight the potential utility of fMRI in both basic and clinical spheres of research. In addition, fMRI studies reveal processes related to neuroplasticity, including compensatory hyperactivation, which may be a universally-occurring, adaptive neural response to insult. Functional MRI is being used to study the modulatory effects of genetic risk factors for neurological disease on brain activation; it is being applied to differential diagnosis, as a predictive biomarker of disease course, and as a means to identify neural correlates of neurotherapeutic interventions. Technological advances are rapidly occurring that should provide new applications for fMRI, including improved spatial resolution, which promises to reveal novel insights into the function of fine-scale neural circuitry of the human brain in health and disease.

Shepherd JD, Huganir RL. · The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. · Annu Rev Cell Dev Biol. · Pubmed #17506699 No free full text.

Abstract: The cellular processes that govern neuronal function are highly complex, with many basic cell biological pathways uniquely adapted to perform the elaborate information processing achieved by the brain. This is particularly evident in the trafficking and regulation of membrane proteins to and from synapses, which can be a long distance away from the cell body and number in the thousands. The regulation of neurotransmitter receptors, such as the AMPA-type glutamate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain, is a crucial mechanism for the modulation of synaptic transmission. The levels of AMPARs at synapses are very dynamic, and it is these plastic changes in synaptic function that are thought to underlie information storage in the brain. Thus, understanding the cellular machinery that controls AMPAR trafficking will be critical for understanding the cellular basis of behavior as well as many neurological diseases. Here we describe the life cycle of AMPARs, from their biogenesis, through their journey to the synapse, and ultimately through their demise, and discuss how the modulation of this process is essential for brain function.

Seltzer B. · V.A. Boston Healthcare System, Department of Neurology, Harvard Medical School, Geriatric Research Center, Boston, MA 02130, USA. · Expert Opin Pharmacother. · Pubmed #17472546 No free full text.

Abstract: Donepezil hydrochloride is the most widely prescribed drug for Alzheimer's disease (AD). The main mechanism of action through which it influences cognition and function is presumed to be the inhibition of acetylcholinesterase enzyme in the brain; however, donepezil may also impact the pathophysiology of AD at several other points. Officially approved for mild-to-moderate and severe AD, donepezil has also been shown to be effective in early-stage AD, vascular dementia, Parkinson's disease dementia/Lewy body disease and cognitive symptoms associated with multiple sclerosis. In addition, one study suggested that donepezil may delay the onset of AD in subjects with mild cognitive impairment, a prodrome to AD. The pharmacokinetics, pharmacodynamics, safety/tolerability profile and drug interaction properties of donepezil make it an easy and safe agent to use. However, in general, the efficacy of donepezil is limited, and ongoing studies are investigating other agents that may ultimately overtake its present position as the mainstay of anti-AD therapy.

Buhaescu I, Izzedine H. · Department of Internal Medicine, Saint Vincent Hospital, Worcester Medical Center, Worcester, MA, USA. · Clin Biochem. · Pubmed #17467679 No free full text.

Abstract: Mevalonate pathway is an important metabolic pathway which plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone. While extensively studied in regard with cholesterol synthesis and its implications in cardiovascular diseases, in recent years the mevalonate pathway has become a challenging and, in the meantime, fascinating topic, when a large number of experimental and clinical studies suggested that inhibition of non-sterol isoprenoids might have valuable interest in human pathology. These molecules that are essential for cell growth and differentiation appear to be potential interesting therapeutic targets for many areas of ongoing research: oncology, autoimmune disorders, atherosclerosis, and Alzheimer disease. Also, considerable progress has been made in the past decade in understanding the pathophysiology of two auto-inflammatory disorders resulting from an inherited deficiency of mevalonate kinase, the first committed enzyme of the mevalonate pathway. Here we present a brief description of the biochemistry of the mevalonate pathway, together with a review of the current knowledge of the clinical and therapeutical implications of this fascinating and complex metabolic pathway.