Alzheimer's Disease Reviews: 2003
(75 References)
(2003). "Alzheimer's disease: emerging noncholinergic treatments." Geriatrics 58 Suppl: 3-14, inside back cover.
With population trends skewing toward a larger percentage of elderly, Alzheimer's disease is projected to afflict many millions in the United States and around the world in the next 50 years. In terms of cost and psychological burden, the anticipated burden of this disease on caregivers and society at large is staggering. It is hoped that, with the development of new insights into the processes of this devastating illness and the development of new medications that may interrupt those processes, the projected incidence and impact of AD may be modified in the near future.
Areosa, S. A. and F. Sherriff (2003). "Memantine for dementia." Cochrane Database Syst Rev(1): CD003154.
BACKGROUND: Alzheimer's disease, vascular and mixed dementia are the commonest forms of dementia in older people. There is evidence that the excitatory activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease and in the damage from an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning. OBJECTIVES: To determine the clinical efficacy and safety of memantine for people with Alzheimer's disease, vascular, or mixed dementia. SEARCH STRATEGY: Trials were identified from a search of the Trial-based Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 9 October 2002 using the terms: memantin*, D-145, DMAA, DRG-0267. All major health care databases and trial databases within the scope of the group are searched regularly to keep this Register up to date. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomized and unconfounded trials in which memantine was administered to people with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted, pooled where possible, and weighted mean differences, standardized mean differences or odds ratios were estimated. Intention-to-treat (ITT) and observed cases (OC) analyses are reported, where data were available. MAIN RESULTS: There were a total of seven trials that met inclusion criteria, of which five had sufficient data for analysis. The analysis of change from baseline for cognition gave statistically significant results in favour of memantine (20 mg/day) (MD: -2,83 95% CI -4.37 to -1.29, P=0.0003) at 28 weeks and for memantine (30mg/day) at 6 weeks (MD: -3.04. 95% CI -5.68 to -0.40, P=0.02). Effects on Activities of Daily living (ADL) were difficult to interpret. One study provided data using a non-validated scale for measuring five simple instrumental tasks under the guidance of an investigator. When pooled with another study the analysis gave statistically significant results in favour of memantine for 30 mg/day at 6 weeks (SMD: -1.36 95% CI -1.77 to -0.96, P=0.0003). Mood and behaviour: One trial provided data on memantine 30 mg/day at 6 weeks using the NOSIE scale. The OC analysis found statistically significant differences in favour of treatment (MD: 23.30 95% CI 17.83 to 28.77, P<0.00001). Global scales: The analysis revealed a statistically significant difference in favour of memantine (20mg/day ) at 6 weeks (MD: -12.30 95% CI -16.90 to -7.70, P<0.00001). Similar results were found for larger doses (memantine 30 mg/day) at 6 weeks in a pooled meta-analysis of two other studies (WMD: -10.77 95% CI -13.46 to -8.09, P<0.00001). With regard to the Global Impression of Change three studies found statistically significant results in favour of 10, 20 and 30 mg/day of memantine compared with placebo at 6 or 12 weeks. There was a benefit in favour of memantine (20 mg/day) compared with placebo at 6 weeks, for the numbers improved ( 24/41 compared with 11/41)(OR, 3.85, 95% CI 1.52 to 9.75, P=0.004), in favour of memantine (30 mg/day) compared with placebo at 6 weeks, for the numbers improved ( 20/30 compared with 8/29)(OR, 5.25, 95% CI 1.72 to 15.98, P=0.004) and in favour of memantine (10 mg/day) compared with placebo at 12 weeks, for the numbers improved ( 60/82 compared with 38/84)(OR, 3.30, 95% CI 1.72 to 6.33, P=0.0003). In general memantine seemed to be well tolerated. There was no statistically significant difference between memantine and placebo for the three studies that reported adverse events.There were some data on specific adverse events. In one study the incidence of restlessness by the end of the treatment at 6 weeks was statistically significantly lower in the placebo group than in the group taking memantine 30 mg/day (15/30 compared with 2/29) (OR 13.50, 95% CI 2.71 to 67.19, P=0.001). The number of dropouts was similar in treatment and placebo groups at 6 or 28 weeks time for memantine 20 mg/day and at 6 weeks for memantine 30 mg/day. REVIEWER'S CONCLUSIONS: Memantine is a safe drug and may be useful for treating Alzheimer's, vascular,and mixed dementia of all severities. Most of the trials so far reported have been small and not long enough to detect clinically important benefits. However there is a possible benefit on cognition and global measures, and an early improvement in behaviour in people with dementia. More studies are needed.
Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.
The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.
Birks, J. and L. Flicker (2003). "Selegiline for Alzheimer's disease." Cochrane Database Syst Rev(1): CD000442.
BACKGROUND: Alzheimer's disease is the most common cause of dementia in older people accounting for some 60% of cases with late-onset cognitive deterioration. It is now thought that several neurotransmitter dysfunctions are involved from an early stage in the pathogenesis of Alzheimer's disease-associated cognitive decline. The efficacy of selegiline for symptoms of Alzheimer's disease remains controversial and is reflected by its low rate of prescription and the lack of approval by several regulatory authorities in Europe and elsewhere. Reasons for this uncertainty involve the modest overall effects observed in some trials, the lack of benefit observed in several trials, the use of cross-over designs which harbour methodological problems in a disease like dementia and the difficulty in interpreting results from trials when a variety of measurement scales are used to assess outcomes. OBJECTIVES: The objective of this review is to assess whether or not selegiline improves the well-being of patients with Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'selegiline', 'l-deprenyl', "eldepryl" and "monamine oxidase inhibitor-B". MEDLINE, PsycLIT and EMBASE electronic databases were searched with the above terms in addition to using the group strategy (see group details) to limit the searches to randomised controlled trials. SELECTION CRITERIA: All unconfounded, double-blind, randomised controlled trials in which treatment with selegiline was administered for more than a day and compared to placebo in patients with dementia. DATA COLLECTION AND ANALYSIS: An individual patient data meta-analysis of selegiline, Wilcock 2002 provides much of the data that are available for this review. Seven studies provided individual patient data and this was pooled with summary statistics from the published papers of the other nine studies. Where possible, intention-to-treat data were used but usually the meta analyses were restricted to completers' data (data on people who completed the study). MAIN RESULTS: There are 17 included trials. There were very few significant treatment effects and these were all in favour of selegiline; cognition at 4-6 weeks and 8-17 weeks, and activities of daily living at 4-6 weeks. There is little evidence of adverse effects caused by selegiline, and few withdrew from trials, apart from the Sano trial. The analyses were conducted on data available. There was no attempt to correct for missing patients because there were so few and withdrawal was probably unconnected with treatment. All trials examined the cognitive effects of selegiline, and in addition 12 trials examined the behavioural and mood effects. The meta-analysis revealed benefits on memory function, shown by improvement in the memory tests from several cognitive tests (the Randt Memory Index from Agnoli 1990 and Agnoli 1992, the BSRT from Sunderland 1992, prose recall from Filip 1991, ADAS-cog from Lawlor 1997, the Wechsler Memory Scale from Loeb 1990 and Mangoni 1991, the Rey -AVL from Piccinin 1990, and the MMSE from Sano 1995, Tariot 1998, Filip 1991, Freedman 1996, Burke 1993 and Riekkinen 1993). The combined memory tests, and overall the combined cognitive tests, analysed using standardised mean differences, showed an improvement due to selegiline compared with placebo at 4-6 weeks (SMD 0.39, 95%CI 0.07 to 0.72, P = 0.02, random effects model ) and 8-17 weeks, ( SMD 0.44, 95%CI 0.04 to 0.84, P = 0.03, random effects model). The meta-analyses of emotional state show no treatment effects. Several studies assessed activities of daily living using several different scales, the GBS-motor function from Agnoli 1990, the NOSIE-daily living from Filip 1991, the BDS-daily living from Loeb 1990 and Mangoni 1991, the DS from Sano 1995 and PIADL from Tariot 1998. The combined tests, analysed using the standardised mean difference, showed an improvement due to selegiline at 4-6 weeks (SMD -0.27, 95% CIs -0.41 to -0.13, P = <.001). The global rating scales, the BDS used by Burke 1993 and Tariot 1998, and the GBS used by Agnoli 1990 and Agnoli 1992, and the GDS used by Freedman 1996 and the CGI by Filip 1991, analysed using standardised mean differences showed no effect of selegiline. A variety of adverse effects were recorded, but very few patients left a trial as a direct result. Four studies reported no side effects. Mangoni 1991 reported poor tolerability for 3 patients out of 68 on treatment and 1 out of 51 on placebo, resulting in dropouts. Small numbers found equally in both groups reported anxiety, agitation, dizziness, nausea and dyspepsia. Piccinin 1990 reported that selegiline was well tolerated with few adverse reactions (dizziness and orthostatic hypotension) and no resulting drop outs. Burke 1993 and Loeb 1990 both reported that selegiline was very well tolerated with no serious side effects. Sano 1995 reported 49 categories of adverse events but found no differences between the 4 arms of the factorial trial. Freedman 1996 reported unequal numbers of dropouts in the trial with 7 subjects withdrawing from the selegiline group and only 1 subject from the placebo group. The meta-analyses of the numbers suffering adverse effects, and of the numbers of withdrawals before the end of the trial show no difference between control and selegiline. REVIEWER'S CONCLUSIONS: Despite its initial promise, ie the potential neuroprotective properties, and its role in the treatment of Parkinson's disease sufferers, selegiline for Alzheimer's disease has proved disappointing. Although there is no evidence of a significant adverse event profile, there is also no evidence of a clinically meaningful benefit for Alzheimer's disease sufferers. This is true irrespective of the outcome measure evaluated, ie cognition, emotional state, activities of daily living, and global assessment, whether in the short, or longer term (up to 69 weeks), where this has been assessed. There would seem to be no justification, therefore, to use it in the treatment of people with Alzheimer's disease, nor for any further studies of its efficacy in Alzheimer's disease.
Blumenthal, H. T. (2003). "The aging-disease dichotomy: true or false?" J Gerontol A Biol Sci Med Sci 58(2): 138-45.
Brown, S. A., S. L. Upchurch, et al. (2003). "A framework for developing a coding scheme for meta-analysis." West J Nurs Res 25(2): 205-22.
The prominence of systematic reviews as bases for evidence-based practice is increasingly recognized and has significance for practice disciplines such as nursing. Synthesizing research findings is key to informing the clinical care of individuals burdened with health problems. A major issue in conducting such reviews involves developing reliable and valid coding procedures for extracting data from the research literature. A formalized process is described for developing coding instruments that have been used in five separate studies. Initial instrument development for a diabetes self-management education meta-analysis is described, followed by a discussion of adapting the instruments for subsequent meta-analytic studies of self-management interventions in diabetes care and of interventions to reduce caregiver burden of individuals with Alzheimer's disease dementia. Although time and effort are required for development of coding processes for research synthesis, these instrument development activities are one of the critical elements of producing reliable and clinically useful information.
Buettner, L. and A. Kolanowski (2003). "Practice guidelines for recreation therapy in the care of people with dementia." Geriatr Nurs 24(1): 18-23; quiz 24-5.
Activity is a basic human need expressed in work and leisure pursuits. Unfortunately, people with dementia have a low rate of activity participation because of associated physical and cognitive constraints. Recently, the American Therapeutic Recreation Association (ATRA) held a consensus meeting to address this issue and formulate practice guidelines for recreation therapy in the care of people with dementia. The consensus document presents an evidence-based intervention theory that draws on the science of two disciplines: nursing and recreation therapy. This article reports on the ATRA guidelines and illustrates their applicability in a case study of a resident with severe aggression associated with dementia.
Butany, J. W., S. Verma, et al. (2003). "Genetic abnormalities of the endothelium." Microsc Res Tech 60(1): 30-7.
Endothelial cell dysfunction plays an important role in the development and progression of cardiovascular and other disease. The purpose of this review is to discuss some of the genetic diseases known to adversely affect endothelial function. Although the list is exhaustive, we focus our discussion on primary pulmonary hypertension, diabetes mellitus, Alzheimer's disease, Crohn's disease, Von-Hippel-Lindau disease, familial Mediterranean fever, thrombotic microangiopathy, and key vascular malformations. Endothelial dysfunction results from a complex interplay between genetic and environmental factors. This review highlights some of the growing body of evidence implicating endothelial dysfunction as an important mediator of diverse diseases.
Caviness, J. N. (2003). "Myoclonus and neurodegenerative disease--what's in a name?" Parkinsonism Relat Disord 9(4): 185-92.
Myoclonus is a clinical symptom (or sign) defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or inhibitions. It may be classified by examination findings, etiology, or physiological characteristics. The main physiological categories for myocolonus are cortical, cortical-subcortical, subcortical, segmental, and peripheral. Neurodegenerative syndromes are potential causes of symptomatic myoclonus. Such syndromes include multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism linked to chromosome 17, Huntington's disease, dentato-rubro-pallido-luysian atrophy, Alzheimer's disease, and Parkinson's disease, and other Lewy body disorders. Each neurodegenerative syndrome can have overlapping as well as distinctive clinical neurophysiological properties. However, claims of differentiating between neurodegenerative disorders by using the presence or absence of small amplitude distal action myclonus appear unwarranted. When the myoclonus is small and repetitive, it may not be possible to distinguish it from tremor by phenotypic appearance alone. In this case, clinical neurophysiological offers an opportunity to provide greater differentiation of the phenomenon. More study of the myoclonus in neurodegenerative disease will lead to a better understanding of the processes that cause phenotypic variability among these disorders.
Clark, C. M. and J. H. Karlawish (2003). "Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies." Ann Intern Med 138(5): 400-10.
Alzheimer disease is a complex neurodegenerative dementing illness. It has become a major public health problem because of its increasing prevalence, long duration, high cost of care, and lack of disease-modifying therapy. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology associated with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. The identification of disease-causing autosomal dominant mutations as well as gene polymorphisms that alter the risk for pathology indicate that Alzheimer disease is a genetically complex disorder. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in diagnosis and treatment. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease-specific pathology hold the potential for accurately diagnosing Alzheimer disease at the earliest stage of the illness--the time when disease-modifying treatment will be most effective. Currently available cholinesterase inhibition therapy targets the cognitive symptoms. However, the goal of new therapies under development is halting the pathologic cascade and potentially reversing the course of the disease. If these new therapies are successful, they will represent a remarkable medical advance for patients and the families who care for them.
Cotter, V. T., C. M. Clark, et al. (2003). "Cognitive function assessment in individuals at risk for Alzheimer's disease." J Am Acad Nurse Pract 15(2): 79-86.
PURPOSE: To describe brief assessments of functional performance and cognition to detect Alzheimer's disease (AD) and depression in older adults for the primary care provider. DATA SOURCES: Review of the literature. CONCLUSIONS: It is important for the clinician to interview both the patient and a knowledgeable informant to assess changes in the patients' functioning in daily life tasks and to administer brief screening tests to detect cognitive impairment and depression in older adults. Several suggested instruments for use in the primary care setting are included. IMPLICATIONS FOR PRACTICE: Standardized assessments of functional performance and brief cognitive tests identify individuals with clinically meaningful cognitive impairment and provide baseline measurement against which to compare future assessments.
Cuajungco, M. P. and K. Y. Faget (2003). "Zinc takes the center stage: its paradoxical role in Alzheimer's disease." Brain Res Brain Res Rev 41(1): 44-56.
There is compelling evidence that the etiology of Alzheimer's disease (AD) involves characteristic amyloid-beta (Abeta) deposition, oxidative stress, and anomalous metal-Abeta protein interaction. New studies have implicated redox active metals such as copper, iron, and zinc as key mediating factors in the pathophysiology of Alzheimer's disease. There is also evidence that drugs with metal chelating properties could produce a significant reversal of amyloid-beta plaque deposition in vitro and in vivo. This paper reviews current observations on the etiologic role of zinc in AD. We also discuss the interactions of zinc and copper with Abeta, a factor that purportedly facilitates disease processes. Finally, we review the protective role of zinc against Abeta cytotoxicity and hypothesize how the apparent effect of zinc on AD pathology may be paradoxical, The Zinc Paradox. Indeed, complex pathologic stressors inherent to the Alzheimer's diseased brain dictate whether or not zinc will be neuroprotective or neurodegenerative. Further research on the zinc paradox in AD is needed in order to elucidate the exact role zinc plays in AD pathogenesis.
Cummings, J. L. (2003). "Alzheimer's disease: from molecular biology to neuropsychiatry." Semin Clin Neuropsychiatry 8(1): 31-6.
Alzheimer's disease is a clinical syndrome reflecting the topography and rate of progression of amyloid-associated cell death and dysfunction. Abnormal processing of amyloid precursor protein or enhanced accumulation of brain amyloid incites multiple pathogenetic pathway including inflammation, oxidation, and tau protein hyperphosphorylation that lead to neuronal death. The molecular biology of Alzheimer's disease provides insight into the clinical phenotype. The steps of the amyloid cascade present multiple targets for drug development and identification of effective disease-modifying anti-Alzheimer's disease treatments.
Driscoll, M. and B. Gerstbrein (2003). "Dying for a cause: invertebrate genetics takes on human neurodegeneration." Nat Rev Genet 4(3): 181-94.
If invertebrate neurons are injured by hostile environments or aberrant proteins they die much like human neurons, indicating that the powerful advantages of invertebrate molecular genetics might be successfully used for testing specific hypotheses about human neurological diseases, for drug discovery and for non-biased screens for suppressors and enhancers of neurodegeneration. Recent molecular dissection of the genetic requirements for hypoxia, excitotoxicity and death in models of Alzheimer disease, polyglutamine-expansion disorders, Parkinson disease and more, is providing mechanistic insights into neurotoxicity and suggesting new therapeutic interventions. An emerging theme is that neuronal crises of distinct origins might converge to disrupt common cellular functions, such as protein folding and turnover.
Dugu, M., J. Neugroschl, et al. (2003). "Review of dementia." Mt Sinai J Med 70(1): 45-53.
Elderly persons are at increased risk for developing dementia, and this risk increases with age. It is important to understand the following points: (a). how to diagnose dementia; (b). the etiology of the most common dementias (including Alzheimer s disease, ischemic vascular dementia, and diffuse Lewy body dementia); (c). some medical conditions which could contribute to symptoms of dementia; (d). the pathophysiology of Alzheimer s disease; and (e). management problems faced by caregivers for dementia patients. This review aims to educate clinicians to focus on caregivers issues and the need for long-term planning.
El-Guendy, N. and V. M. Rangnekar (2003). "Apoptosis by Par-4 in cancer and neurodegenerative diseases." Exp Cell Res 283(1): 51-66.
Prostate apoptosis response-4 (par-4) is a pro-apoptotic gene identified in prostate cancer cells undergoing apoptosis. Par-4 protein, which contains a leucine zipper domain at the carboxy-terminus, functions as a transcriptional repressor in the nucleus. Par-4 selectively induces apoptosis in androgen-independent prostate cancer cells and Ras-transformed cells but not in androgen-dependent prostate cancer cells or normal cells. Cells that are resistant to apoptosis by Par-4 alone, however, are greatly sensitized by Par-4 to the action of other pro-apoptotic insults such as growth factor withdrawal, tumor necrosis factor, ionizing radiation, intracellular calcium elevation, or those involved in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and stroke. Apoptosis induction by Par-4 involves a complex mechanism that requires activation of the Fas death receptor signaling pathway and coparallel inhibition of cell survival NF-kappaB transcription activity. The unique ability of Par-4 to induce apoptosis in cancer cells but not normal cells and the ability of Par-4 antisense or dominant-negative mutant to abrogate apoptosis in neurodegenerative disease paradigms makes it an appealing candidate for molecular therapy of cancer and neuronal diseases.
Erkinjuntti, T. and K. Rockwood (2003). "Vascular dementia." Semin Clin Neuropsychiatry 8(1): 37-45.
Vascular dementia (VaD) is a term used to describe a particular constellation of cognitive and functional impairment, and is now generally seen as a subset of the larger syndrome of vascular cognitive impairment (VCI). The latter is seen as cognitive impairment in the face of cerebrovascular disease. VCI can be classified clinically by whether patients meet criteria for dementia, and whether the syndrome is distinct or overlaps with primary neurodegenerative diseases, such as Alzheimer's disease. This clinical classification can be further classified by neuroimaging, with subgroups that show cortical infarction, subcortical infarction and white matter changes, each alone or in combination. Understood in this way, VCI is likely the most common form of cognitive impairment in the population. Attempts to treat VaD had varying degrees of success, but it now appears that many forms of VCI might be preventable, especially with good control of vascular risk factors in middle age.
Forbes, D. A. (2003). "An example of the use of systematic reviews to answer an effectiveness question." West J Nurs Res 25(2): 179-92.
Systematic reviews assist nurses, other health care providers, decision makers, and consumers in managing the explosion of health care information by synthesizing valid data and reporting the effects of interventions. Nurses are increasingly using systematic reviews to guide their practice and develop policy. The purpose of the article is to outline the steps involved in conducting a systematic review with examples taken from a systematic review titled "Strategies to Manage the Behavioral Symptoms Associated With Alzheimer's Disease." The steps of a systematic review include: (a) formulating a well-defined question, (b) developing relevance and validity tools, (c) conducting a comprehensive search to retrieve published and unpublished reports, (d) assessing the reports using relevance and validity tools, (e) data extraction, (f) synthesis of the findings, and (g) report writing. Understanding the steps involved in a systematic review will assist nurses in critically appraising reviews and in conducting their own reviews.
Golde, T. E. and C. B. Eckman (2003). "Physiologic and pathologic events mediated by intramembranous and juxtamembranous proteolysis." Sci STKE 2003(172): RE4.
Intramembranous proteolysis (IP) is a recently recognized mechanism for transmembrane signal transduction that involves proteolysis of transmembrane proteins within their membrane-spanning domains. Juxtamembranous proteolysis (JP) is similar, but proteolytic cleavage of a transmembrane protein occurs at a site close to, but not within, the transmembrane domain of the target protein. In both IP and JP, a soluble domain of a transmembrane protein is released from its membrane tether. This domain can then transmit a signal either locally or at some distance from the site of cleavage. In certain signaling pathways, JP and IP are linked. JP on one side of the membrane results in secondary IP, which then releases a signaling domain from the membrane. Whereas well-characterized proteases such as caspases, the proteasome, and metalloprotease disintegrins, have been implicated in JP, three families of multipass membrane proteases (MpMPs) have now been shown to carry out IP. Recent studies of events mediated by IP and JP indicate that they regulate key cellular signaling events including pathways involved in sterol regulation, cell fate selection, and growth regulation. Moreover, IP and JP have important roles in certain diseases such as Alzheimer's disease. Because some of the proteases mediating IP and JP can be selectivity inhibited, inhibitors targeting these proteases are likely to alter both physiologic and pathologic events triggered by IP and JP.
Golde, T. E. (2003). "Alzheimer disease therapy: can the amyloid cascade be halted?" J Clin Invest 111(1): 11-8.
Grainger, D. J. and J. Reckless (2003). "Broad-spectrum chemokine inhibitors (BSCIs) and their anti-inflammatory effects in vivo." Biochem Pharmacol 65(7): 1027-34.
Inappropriate inflammation is a component of a wide range of human diseases, including autoimmune disease, atherosclerosis, osteoporosis and Alzheimer's disease. Chemokines play an important role in orchestrating leukocyte recruitment during inflammation, and therefore represent an important target for anti-inflammatory therapies. Unfortunately, the chemokine system is complex, with about 50 ligands and 20 receptors, often acting with redundancy, making selection of appropriate specific antagonists difficult. One approach to overcoming this difficulty may be the development of broad-spectrum chemokine inhibitors (BSCIs). Here we review the present state of knowledge on BSCIs, including their activity in vitro and their anti-inflammatory effects in vivo, and discuss the future development of BSCIs as anti-inflammatory therapies for use in the clinic.
Gupta, A. and K. Pansari (2003). "The association between blood coagulation markers, atherothrombosis and dementia." Int J Clin Pract 57(2): 107-11.
Abnormalities of coagulation and the fibrinolytic system leading to a hypercoagulable state could lead to accelerated atherogenesis. The abnormalities of haemostasis and resulting ischaemic cerebrovascular disease may contribute to cognitive decline in the elderly. There is increasing evidence in the literature of haemostatic abnormalities not only in vascular dementia but also in patients with Alzheimer's dementia. Among the serum markers of hypercoagulability leading to thrombosis and dementia, serum fibrinogen has been one of the factors most commonly studied. Modification and control of these serum markers of hypercoagulability offer an exciting approach to the control of dementia in the community. This article explores the association between serum markers of hypercoagulability, associated atherothrombosis and the risk of dementia.
Harrison, P. J. and M. J. Owen (2003). "Genes for schizophrenia? Recent findings and their pathophysiological implications." Lancet 361(9355): 417-9.
CONTEXT: Schizophrenia is highly heritable, but the genes have remained elusive. Identifying the genes is essential if the pathogenesis and pathophysiology of schizophrenia is finally to be understood, and to give the prospect of more effective treatment. STARTING POINT: H Stefansson and colleagues (Am J Hum Genet 2002; 71: 877-92) showed association of the neuregulin (NRG1) gene with schizophrenia. Other recent papers describe six additional susceptibility genes. Replications are already being reported for some of them. The genes are biologically plausible, and may have convergent effects on glutamatergic and other synapses. We review the evidence for each gene, the possible pathogenic mechanisms, and the implications of the findings. WHERE NEXT? Given earlier failures to replicate apparent breakthroughs, the results should be viewed with caution. Unequivocal replications remain the top priority. The respective contributions of each gene, epistatic effects, and functional interactions between the gene products, all need investigation. Confirmation that any of the genes is a true susceptibility gene for schizophrenia could trigger the same rapid therapeutic progress as has occurred recently in Alzheimer's disease.
Head, B. (2003). "Palliative care for persons with dementia." Home Healthc Nurse 21(1): 53-60; quiz 61.
Home care and hospice nurses provide invaluable care for patients with Alzheimer's Disease and related disorders. Often these patients have advanced disease and may be approaching the end of life. This article describes a palliative care approach to providing comprehensive assessment, care planning, and interventions enhancing the functioning and quality of life for both the patient and family coping with this illness.
Howes, M. J., N. S. Perry, et al. (2003). "Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders." Phytother Res 17(1): 1-18.
In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD) and other memory related disorders. An ethnopharmacological approach has provided leads to identifying potential new drugs from plant sources, including those for memory disorders. There are numerous drugs available in Western medicine that have been directly isolated from plants, or are derived from templates of compounds from plant sources. For example, some alkaloids from plant sources have been investigated for their potential in AD therapy, and are now in clinical use (e.g. galantamine from Galanthus nivalis L. is used in the United Kingdom). Various other plant species have shown favourable effects in AD, or pharmacological activities indicating the potential for use in AD therapy. This article reviews some of the plants and their active constituents that have been used in traditional medicine, including Ayurvedic, Chinese, European and Japanese medicine, for their reputed cognitive-enhancing and antidementia effects. Plants and their constituents with pharmacological activities that may be relevant to the treatment of cognitive disorders, including enhancement of cholinergic function in the central nervous system, anti-cholinesterase (anti-ChE), antiinflammatory, antioxidant and oestrogenic effects, are discussed.
Iadecola, C. and P. B. Gorelick (2003). "Converging pathogenic mechanisms in vascular and neurodegenerative dementia." Stroke 34(2): 335-7.
Karlawish, J. H. and C. M. Clark (2003). "Diagnostic evaluation of elderly patients with mild memory problems." Ann Intern Med 138(5): 411-9.
This case-based discussion focuses on the clinical presentation and diagnostic assessment of a uniquely challenging group of elderly patients: those with symptoms of mild memory problems. Such patients present a challenge to clinicians because of flux in our understandings of normal, age-related cognitive changes; of cognitive changes due to neurodegenerative illnesses; and of the relationships between depression and cognitive impairment. In addition, symptoms of memory problems may be reported by an observer rather than by the patient. These challenges warrant stepwise evaluation of elderly patients who present with symptoms of memory loss.
Kneebone, II and P. R. Martin (2003). "Coping and caregivers of people with dementia." Br J Health Psychol 8(Pt 1): 1-17.
PURPOSE: To critically review the research based on Lazarus and Folkman's (1984) stress and coping model, in respect to the coping of those caring for persons with dementia in the community, in an attempt to establish its implications for interventions aimed at improving caregiver adjustment. METHOD: Published material on the coping of caregivers of persons with dementia was identified through computerized literature searches (Med-line, Psych-Info) to December 1999, employing search terms including Alzheimer's disease, dementia, caregiving, caregiver burden, adaptation, psychological, coping, and stress. Studies were chosen to be considered in detail, based on the reviewer's opinion that they would contribute to an understanding of the current state of the research and its clinical implications. This material was then critically reviewed against the tenets of Lazarus and Folkman's (1984) model. RESULTS: Sixteen studies were selected to be included in the review, 12 cross-sectional and 4 longitudinal. Seven of the studies did not incorporate coping measures specific to caregiving and/or assess coping in respect of specific caregiver problems. Nine of the studies did do this. The research suggests that a general tendency towards problemsolving and acceptance styles of coping is likely to be advantageous to caregivers of people with dementia. CONCLUSIONS: Despite this finding, it is concluded that the ability of the research to inform the clinician is severely limited. It is proposed that while longitudinal studies considered specific caregiver problems which incorporate coping measures specific to the caregiving task may improve understanding, a substantial revision of methodology and perspective may be required to produce findings that are likely to influence practice.
Lahiri, D. K., M. R. Farlow, et al. (2003). "A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease." Curr Drug Targets 4(2): 97-112.
Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the beta-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as beta-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and gamma-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.
Lanctot, K. L., N. Herrmann, et al. (2003). "Correlates of response to acetylcholinesterase inhibitor therapy in Alzheimer's disease." J Psychiatry Neurosci 28(1): 13-26.
Cholinesterase inhibitors improve cognition and behaviour in some patients with Alzheimer's disease (AD). Studies that have focused on methods to predict response to anticholinesterase therapy and markers for response are reviewed. Among the possible predictors of improvement in cognitive outcomes are apolipoprotein genotype, pretreatment postural blood pressure drop, quantitative electroencephalography (qEEG) and disease progression rate. Of these, qEEG profile after a single dose of an acetylcholinesterase inhibitor was consistently found to be a good predictor of cognitive response. Studies have assessed baseline behavioural profiles and baseline single-photon emission computed tomographic profiles as possible predictors of improvement of behavioural symptoms of AD, but these require further study. Possible markers of response during drug treatment include red blood cell cholinesterase inhibition, cerebrospinal fluid monoamine measurement, pupillary response and platelet amyloid precursor protein analyses. Although they, too, require further study, the analysis of platelet amyloid precursor protein may have value as a correlate of the putative disease-modifying effects of long-term treatment. Studying correlates of response may help to elucidate the mechanism of action of acetylcholinesterase inhibitors.
Laws, S. M., E. Hone, et al. (2003). "Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription." J Neurochem 84(6): 1215-36.
Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (> 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The epsilon4 allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the varepsilon 4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOE epsilon4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the epsilon2/epsilon3/epsilon4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the epsilon2/epsilon3/epsilon4 locus.
Leboeuf, R. (2003). "Homocysteine and Alzheimer's disease." J Am Diet Assoc 103(3): 304-7.
Lemstra, A. W., P. Eikelenboom, et al. (2003). "The cholinergic deficiency syndrome and its therapeutic implications." Gerontology 49(1): 55-60.
Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer's disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer's disease, Lewy body dementia and Parkinson's disease and to respond well to cholinesterase inhibitor therapy.
Leung, G. M., R. Y. Yeung, et al. (2003). "The economics of Alzheimer disease." Dement Geriatr Cogn Disord 15(1): 34-43.
Economic assessments of health and healthcare have become an integral part of policy decisions in the last decade. Increasingly, this trend is extending to medical decision-making in day-to-day patient-provider interactions. Alzheimer disease (AD) offers a potent example of the clinical and economic issues at stake with its diagnostic techniques, pharmacotherapies, and public health and policy implications. This review introduces basic economic concepts in examining the impact of AD and related care. It presents a summary of the latest economics research on cost estimates of AD and on economic evaluations of diagnostic and management interventions in terms of cost-of-illness and cost-effectiveness studies respectively. Empirical and conceptual issues about the interpretation of costs and the uses of evaluative methods are also discussed. We found that the economic costs attributable to AD care is highly variable mostly due to non-standardised methodologies and geographical variations in care patterns. There is, however, little doubt that the impact is substantial and is expected to worsen with the demographic, epidemiologic, technologic and economic transitions worldwide. There are comparatively fewer studies on the cost-effectiveness of interventions in AD. Most of the published work revolves around pharmacotherapeutics while relatively little has been done on diagnostics, patient care programmes and programmes for caregivers. We conclude that there are significant opportunities to strengthen research on standardised cost-of-illness analyses and new cost-effectiveness studies on a broader range of AD interventions.
Liu, B. and J. S. Hong (2003). "Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention." J Pharmacol Exp Ther 304(1): 1-7.
Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.
Long, C. O. and J. Dougherty (2003). "What's new in Alzheimer's disease?" Home Healthc Nurse 21(1): 8-14; quiz 15.
Major changes in the care and treatment of dementia of the Alzheimer's type have been made, and more are looming on the horizon. This article presents current information regarding pathology, diagnosis, causes, and treatment options. Additionally, the newest medications and alternative approaches to this prevalent disease are discussed.
Lu, K. P., Y. C. Liou, et al. (2003). "Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease." Bioessays 25(2): 174-81.
The reversible phosphorylation of proteins on serine/threonine residues preceding proline (Ser/Thr-Pro) is a major regulatory mechanism for the control of a series of cell cycle events. Although phosphorylation is thought to regulate protein function by inducing conformational changes, little is known about most of these conformational changes and their significance. Recent studies indicate that the conformation and function of a subset of these phosphorylated proteins are controlled by the prolyl isomerase Pin1 through isomerization of specific phosphorylated Ser/Thr-Pro bonds. Furthermore, compelling evidence supports the idea that proline-directed phosphorylation and subsequent isomerization play a critical role not only in cell cycle control, but also in the development of Alzheimer's disease, where postmitotic neurons display various cell cycle markers, especially mitotic events, prior to degeneration.
Mathisen, P. M. (2003). "Gene discovery and validation for neurodegenerative diseases." Drug Discov Today 8(1): 39-46.
Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.
Mattson, M. P., W. Duan, et al. (2003). "Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms." J Neurochem 84(3): 417-31.
Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.
McGeer, P. L. and E. McGeer (2003). "Is there a future for vaccination as a treatment for Alzheimer's disease?" Neurobiol Aging 24(3): 391-5.
Vaccination of APP transgenic mice with Abeta has been shown to prevent amyloid deposits. A clinical trial of Abeta vaccination in Alzheimer's disease (AD) was halted due to serious neurological complications developing in some patients. Such complications were not observed in transgenic mice. Since human APP is not a mouse self-protein, vaccination of mice with Abeta should not produce an autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q poorly recognizes human Abeta so complement activation is much weaker in transgenic mice than in AD. Vaccination will increase complement activation through formation of antigen-antibody complexes. In mice this will enhance phagocytosis. But in AD, where complement is already overactivated, and where the senile plaques are relatively insoluble, this stimulation should increase production of the membrane attack complex, adding to the autodestruction of neurons. The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically.
McKeith, I. G., D. J. Burn, et al. (2003). "Dementia with Lewy bodies." Semin Clin Neuropsychiatry 8(1): 46-57.
The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.
Michaelis, M. L. (2003). "Drugs targeting Alzheimer's disease: some things old and some things new." J Pharmacol Exp Ther 304(3): 897-904.
Enormous effort is now being devoted to developing drugs that slow neurodegeneration in Alzheimer's disease (AD), although insights into AD genetics and molecular pathogenesis only arose in the last 15 years. Acetylcholinesterase inhibitors that temporarily slow loss of cognitive function remain the only approved AD drugs. Discovery of mutations in three genes leading to severe early onset AD was critical in focusing attention on the role of amyloid peptides (Abeta) in neuronal cell death, and enhanced understanding of the biology of these peptides has led to an array of mechanism-based drug discovery strategies. These include inhibitors for Abeta-generating proteases, agents that prevent or reverse Abeta oligomerization, immunotherapies to reduce Abeta in brain and plasma, and drugs to modulate cholesterol-mediated effects on Abeta transport. Strategies are also underway to minimize toxic effects of Abeta fibrils on neurons, and these include antioxidants, blockers of glutamate-mediated excitotoxicity, and modulators of inflammatory responses within the brain. Although several approaches involve new agents for recently discovered targets, many are based on new applications of existing drugs such as statins and nonsteroidal anti-inflammatory drugs. Discovery of abnormally phosphorylated tau protein in neurofibrillary tangles in AD brain has led to strategies for identifying selective inhibitors of tau kinases and central nervous system/brain-permeable drugs that help maintain microtubule integrity. Clearly, a large gap exists between our understanding of the cellular cascades targeted in drug discovery and widespread failure of the nervous system that AD represents. Nevertheless, the pace of recent research clearly supports optimism that slowing progression of AD will soon be possible.
Miller, A. L. (2003). "The methionine-homocysteine cycle and its effects on cognitive diseases." Altern Med Rev 8(1): 7-19.
Homocysteine, a sulfur-containing amino acid, is a metabolite of the essential amino acid methionine, and exists at a critical biochemical intersection in the methionine cycle - between S-adenosylmethionine, the indispensable ubiquitous methyl donor, and vitamins B12 and folic acid. High blood levels of homocysteine signal a breakdown in this vital process, resulting in far-reaching biochemical and life consequences. The link between homocysteine and cardiovascular disease is well established, and decreasing plasma total homocysteine by providing nutritional cofactors for its metabolism has been shown to reduce the risk of cardiovascular events. Information has been emerging regarding a connection between homocysteine metabolism and cognitive function, from mild cognitive decline (age-related memory loss) to vascular dementia and Alzheimer's disease. Significant deficiencies in the homocysteine re-methylation cofactors cobalamin (B12) and folate, as well as the trans-sulfuration cofactor vitamin B6, are commonly seen in the elderly population, with a resultant increase in homocysteine with advancing age. Hyperhomocysteinemia has been shown to be an independent risk factor for cognitive dysfunction. Indirect and direct vascular damage can be caused by homocysteine, which has been implicated in vascular dementia, with an increased risk of multiple brain infarcts and dementia as homocysteine levels rise. A significant correlation has been found between risk of Alzheimer's disease and high plasma levels of homocysteine, as well as low levels of folic acid, and vitamins B6 and B12. All of these disease associations are thought to be interrelated via increased homocysteine and S-adenosylhomocysteine and subsequent hypomethylation of numerous substances, including DNA and proteins, that render vascular structures and neurons more susceptible to damage and apoptosis. Providing the nutritional cofactors for proper functioning of the methionine cycle may improve methylation and protect the brain from damage. Further studies need to be performed to assess whether this will also reduce the risk of cognitive diseases and/or improve cognitive functioning.
Moylett, E. H. and I. C. Hanson (2003). "29. Immunization." J Allergy Clin Immunol 111(2 Suppl): S754-65.
The medical dictionary defines immunization as the "protection of susceptible individuals from communicable diseases by the administration of a living modified agent, a suspension of killed organisms, or an inactivated toxin." This elegant description can be expanded to include twenty-first century approaches to immunization that include recombinant technology, reassortment virus techniques, live vectors, DNA vaccines, and the expansion of the field to encompass noncommunicable diseases such as Alzheimer's disease, autoimmunity, and tumor immunogenetics. Integral to the success of immunization is our knowledge of the immune system's memory of antigens, yet our understanding of this fundamental feature remains limited. On a global scale, communicable diseases remain the number-one cause of morbidity and mortality; hence Jenner's pioneering work with its birth in 1796 still has a challenging and exciting future.
Murphy, J. V. and A. Patil (2003). "Stimulation of the nervous system for the management of seizures: current and future developments." CNS Drugs 17(2): 101-15.
Vagal nerve stimulation (VNS) for the treatment of refractory epilepsy appears to have started from the theory that since VNS can alter the EEG, it may influence epilepsy. It proved effective in several models of epilepsy and was then tried in short-term, open-label and double-blind trials, leading to approval in Canada, Europe and the US. Follow-up observations in these patients demonstrated continued improvement in seizure control for up to 2 years. Close to 50% of treated patients have achieved at least a 50% reduction in seizure frequency. This therapy was also useful as rescue therapy for ongoing seizures in some patients; many patients are more alert. The initial trials were completed in patients >/=12 years of age with refractory partial seizures. Subsequently, similar benefits were shown in patients with tuberous sclerosis complex, Lennox-Gastaut syndrome, hypothalamic hamartomas and primary generalised seizures. Implanting the generator and leads is technically easy, and complications are few. The method of action is largely unknown, although VNS appears to alter metabolic activity in specific brain nuclei. Considering that improvement in mood is frequently found in patients using VNS, it has undergone trials in patients with depression. Other illnesses deserving exploration with this unusual therapy are Alzheimer's disease and autism. Some aspects of VNS have proven disappointing. Although patients have fewer seizures, the number of antiepileptic drugs they take is not significantly reduced. In addition, there is no way to accurately predict the end of life of the generator. Optimal stimulation parameters, if they exist, are unknown. Deep brain stimulation is a new method for controlling medically refractory seizures. It is based on the observation that thalamic stimulation can influence the EEG over a wide area. Several thalamic nuclei have been the object of stimulation in different groups of patients. Intraoperative brain imaging is essential for electrode placement. The procedure is done under local anaesthesia. Experience with this therapy is currently limited, but growing.
Nouspikel, T. and P. C. Hanawalt (2003). "When parsimony backfires: neglecting DNA repair may doom neurons in Alzheimer's disease." Bioessays 25(2): 168-73.
Taking advantage of the fact that they need not replicate their DNA, terminally differentiated neurons only repair their expressed genes and largely dispense with the burden of removing damage from most of their genome. However, they may pay a heavy price for this laxity if unforeseen circumstances, such as a pathological condition like Alzheimer's disease, cause them to re-enter the cell cycle. The lifetime accumulation of unrepaired lesions in the silent genes of neurons is likely to be significant and may result in aborting the mitotic process and triggering cell death if the cells attempt to express these dormant genes and resume DNA replication.
Nussbaum, R. L. and C. E. Ellis (2003). "Alzheimer's disease and Parkinson's disease." N Engl J Med 348(14): 1356-64.
Papadopoulo, V. (2003). "Peripheral benzodiazepine receptor: structure and function in health and disease." Ann Pharm Fr 61(1): 30-50.
In vitro studies using biochemical, pharmacological and molecular approaches demonstrated that the peripheral-type benzodiazepine receptor (PBR) is a mitochondrial protein, involved in the regulation of cholesterol transport from the outer to the inner mitochondrial membrane, the rate-determining step in steroid biosynthesis. In vivo animal models and ontogeny studies validated the role of PBR in steroidogenesis. Targeted disruption of the PBR gene in Leydig cells resulted in the arrest of cholesterol transport into mitochondria and steroid formation. Molecular modeling of PBR suggested that it might function as a channel for cholesterol. Indeed, cholesterol uptake and transport by bacteria cells was induced upon PBR expression. Amino acid deletion and site-directed mutagenesis studies identified a cholesterol recognition/interaction amino acid consensus sequence in the cytoplasmic carboxy-terminus of the receptor. In vitro reconstitution experiments demonstrated that the 18 kDa PBR protein binds with high affinity both drug ligands and cholesterol, suggesting that this protein might serve numerous functions considering the critical role of cholesterol in membrane biogenesis and human pathology. In this context, PBR expression correlated with the quality of kidney preservation, indicating that it might serve as an index of kidney and mitochondrial viability during ischemia-reperfusion injury. PBR overexpression was also found to be a prognostic indicator of the aggressive phenotype in breast, colorectal and prostate cancers. Moreover, in Alzheimer's disease brain specimens, PBR levels were increased and paralleled the elevated neurosteroid synthesis observed in specific brain areas. The role for PBR in these pathological conditions remains to be elucidated. paralleled the elevated neurosteroid synthesis observed in specific brain areas. The role for PBR in these pathological conditions remains to be elucidated.
Petrella, J. R., R. E. Coleman, et al. (2003). "Neuroimaging and early diagnosis of Alzheimer disease: a look to the future." Radiology 226(2): 315-36.
Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. Current consensus statements have emphasized the need for early recognition and the fact that a diagnosis of AD can be made with high accuracy by using clinical, neuropsychologic, and imaging assessments. Magnetic resonance (MR) or computed tomographic (CT) imaging is recommended for the routine evaluation of AD. Coronal MR images can be useful to document or quantify atrophy of the hippocampus and entorhinal cortex, both of which occur early in the disease process. Both volumetric and subtraction MR techniques can be used to quantify and monitor dementia progression and rates of regional atrophy. MR measures are also increasingly being used to monitor treatment effects in clinical trials of cognitive enhancers and antidementia agents. Positron emission tomography (PET) and single photon emission CT offer value in the differential diagnosis of AD from other cortical and subcortical dementias and may also offer prognostic value. In addition, PET studies have demonstrated that subtle abnormalities may be apparent in the prodromal stages of AD and in subjects who carry susceptibility genes. PET ligands are in late-stage development for demonstration of amyloid plaques, and human studies have already begun. Functional MR-based memory challenge tests are in development as well.
Poveda, A. M. (2003). "An anthropological perspective of Alzheimer disease." Geriatr Nurs 24(1): 26-31.
This article deals with Alzheimer disease (AD) from an anthropological perspective. It describes the basis of my research: social representations and practices with regard to Alzheimer dementia. An analysis of the sociocultural construction of the AD process and the practices of caring for people who have it can improve nursing practice in this field. This approach helps us achieve a better understanding of this condition and provides a framework for providing care in a more appropriate and contextualized way. To achieve this aim, my research is based on three points of analysis derived from the main axes: the domestic and family context of Alzheimer dementia, the biomedical discourse and social construction of the condition, and the loss of self and social death of the person with AD.
Rigaud, A. S., L. Traykov, et al. (2003). "[Cognitive decline and hypertension]." Arch Mal Coeur Vaiss 96(1): 47-51.
The prevalence and incidence of degenerative and vascular dementia increase exponentially with age. Several studies in recent years have implicated hypertension as a risk factor not only for vascular dementia but also for degenerative dementia such as Alzheimer's disease. This is an important finding because it suggests that the treatment of hypertension could reduce the incidence of dementia. In particular, the results of the Syst-Eur study, showing that a calcium inhibitor, nitrendipine, could reduce not only the incidence of stroke but also that of dementia, should be confirmed.
Robinson, S. R., G. M. Bishop, et al. (2003). "Alzheimer vaccine: amyloid-beta on trial." Bioessays 25(3): 283-8.
A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid-beta (Abeta) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Abeta, while leaving the functionally-relevant forms of Abeta and its precursor protein untouched. Furthermore, an approach needs to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Abeta contribute to the pathogenesis of AD.
Robinson, B. (2003). "Cost of anemia in the elderly." J Am Geriatr Soc 51(3 Suppl): S14-7.
As the aging population and the incidence of age-related health conditions increase, the cost of healthcare is also expected to rise. Anemia commonly occurs in the elderly, and is associated with a number of health conditions such as falls, weakness, and immobility. It can also lead to more-serious complications such as cardiovascular and neurological impairments. Consequently, anemia can have a significant effect on healthcare requirements and healthcare expenditure. Research is needed into the opportunity to reduce costs.
Robinson, K. M. (2003). "Understanding hypersexuality: a behavioral disorder of dementia." Home Healthc Nurse 21(1): 43-7.
Although a rare manifestation of Alzheimer's Disease, hypersexuality is one of the most embarrassing behaviors for both informal and formal caregivers. This article presents an overview of the causes of the problem along with strategies home care and hospice nurses can use to teach families how to decrease the social isolation these patients experience.
Savitz, S. L., S. Malhotra, et al. (2003). "Cell transplants offer promise for stroke recovery." J Cardiovasc Nurs 18(1): 57-61.
Cell transplantation is an experimental approach to restore brain function in neurodegenerative disorders such as Parkinson's and Huntington's disease. Transplantation also represents a possible strategy to repair the brain after a stroke. Various cell types are under investigation in experimental stroke studies. This review discusses the different graft sources and presents preliminary data on the transplantation of neural progenitor cells after stroke in rats. Following transplantation, progenitor cells proliferated and differentiated into all the different brain cell types, including neurons, and they repopulated the ischemic infarct. These results suggest that cell transplantation may serve as a future restorative therapy for stroke and other neurologic disorders such as Parkinson's disease, Alzheimer's disease, trauma, and multiple sclerosis.
Saykin, A. J. and H. A. Wishart (2003). "Mild cognitive impairment: conceptual issues and structural and functional brain correlates." Semin Clin Neuropsychiatry 8(1): 12-30.
Mild cognitive impairment (MCI) is a prevalent condition among older adults that carries a high risk of progression to Alzheimer's disease or other dementias. Given the potential for delaying or preventing the onset of dementia, efforts aimed at early detection and early intervention are important. The current paper reviews the conceptualization and diagnosis of MCI, assessment of memory complaints and deficits in the elderly, as well as recent research on the neurobiological basis of the disorder, including neurochemical, structural, and functional neuroimaging findings.
Sevick, M. A., T. McConnell, et al. (2003). "Conducting research related to treatment of Alzheimer's disease. Ethical issues." J Gerontol Nurs 29(2): 6-12.
Researchers are obligated to protect the rights of study participants. Protecting the rights of patients with Alzheimer's disease (AD) is particularly complicated because of the special needs of this patient population, and the characteristics of developing treatments and technologies. Respecting autonomy and the right to self-determination are complicated by difficulties associated with assuring competence, understanding, and voluntariness in the informed consent process. Protecting patients with AD from harm may be complicated because new treatments have subtle side effects that may be difficult to detect in patients experiencing communication difficulties. Harm to patients with AD also may occur from withholding proven treatments in placebo-controlled trials, and in the use of genetic testing. Issues of justice in the allocation of research dollars and the ability of patients with AD to participate in research are also discussed. By recognizing potential pitfalls, researchers involved in testing new treatments for patients with AD can take proper steps to assure ethical treatment of study participants.
Sheffler, D. J. and B. L. Roth (2003). "Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor." Trends Pharmacol Sci 24(3): 107-9.
Salvinorin A, a neoclerodane diterpene, is the most potent naturally occurring hallucinogen known and rivals the synthetic hallucinogen lysergic acid diethylamide in potency. Recently, the molecular target of salvinorin A was identified as the kappa opioid receptor (KOR). Salvinorin A represents the only known non-nitrogenous KOR selective agonist. Based on the selectivity of salvinorin A for the KOR, this receptor represents a potential molecular target for the development of drugs to treat disorders characterized by alterations in perception, including schizophrenia, Alzheimer's disease and bipolar disorder.
Shigeta, M. and A. Homma (2003). "[Mild cognitive impairment: current update]." Nippon Ronen Igakkai Zasshi 40(1): 1-6.
Shoji, M. (2003). "[Development of animal models for therapy of Alzheimer's disease]." Nippon Ronen Igakkai Zasshi 40(1): 27-9.
Siegel-Axel, D. I. (2003). "Cerivastatin: a cellular and molecular drug for the future?" Cell Mol Life Sci 60(1): 144-64.
The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market--the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future.
Szatmari, S. Z. and P. J. Whitehouse (2003). "Vinpocetine for cognitive impairment and dementia." Cochrane Database Syst Rev(1): CD003119.
BACKGROUND: Vinpocetine is a synthetic ethyl ester of apovincamine, a vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca minor) and discovered in the late 1960s. Although used in human treatment for over twenty years, it has not been approved by any regulatory body for the treatment of cognitive impairment. Basic sciences studies have been used to claim a variety of potentially important effects in the brain. However, despite these many proposed mechanisms and targets, the relevance of this basic science to clinical studies is unclear. OBJECTIVES: To assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimer's disease, mixed (vascular and Alzheimer's disease) and other dementias. SEARCH STRATEGY: The Cochrane Dementia & Cognitive Improvement Group's Specialized Register was searched using the terms vinpocetin*, cavinton, kavinton, Rgh-4405, Tcv-3B, "ethyl apovincaminate", vinRx, periwinkle, "myrtle vincapervinc" and cezayirmeneksesi. The manufacturers of vinpocetine were asked for information on trials of vinpocetine for dementia. In addition we tried to collect articles not listed in MEDLINE or other sources on the Internet (e.g. articles in Hungarian and Romanian). SELECTION CRITERIA: All human, unconfounded, double-blind, randomized trials in which treatment with vinpocetine was administered for more than a day and compared to control in patients with vascular dementia, Alzheimer's dementia or mixed Alzheimer's and vascular dementia and other dementias. Non-randomized trials were excluded. DATA COLLECTION AND ANALYSIS: Data were independently extracted by the two reviewers (SzSz and PW) and cross-checked. Data from "washout" periods were not used for the analysis. For continuous or ordinal variables, such as cognitive test results, the main outcomes of interest were the change in score from baseline. The categorical outcome of global impression was transformed to binary data (improved or not improved) as was the occurrence of adverse effects; here the endpoint itself was of interest the Peto method of the "typical odds ratio" was used. A test for heterogeneity of treatment effects between the trials was made if appropriate. Data synthesis and analysis were performed using the Cochrane Review Manager software (RevMan version 4.1). MAIN RESULTS: All identified studies were performed before the 1990s and used various terms and criteria for cognitive decline and dementia. The three studies included in the review involved a total of 583 people with dementia treated with vinpocetine or placebo. The reports of these studies did not make possible any differentiation of effects for degenerative or vascular dementia. The results show benefit associated with treatment with vinpocetine 30mg/day and 60 mg/day compared with placebo, but the number of patients treated for 6 months or more was small. Only one study extended treatment to one year. Adverse effects were inconsistently reported and without regard for relationship to dose. The available data do not demonstrate many problems of adverse effects but intention-to-treat data were not available for any of the trials. REVIEWER'S CONCLUSIONS: Although the basic science is interesting, the evidence for beneficial effect of vinpocetine on patients with dementia is inconclusive and does not support clinical use. The drug seems to have few adverse effects at the doses used in the studies. Large studies evaluating the use of vinpocetine for people suffering from well defined types of cognitive impairment are needed to explore possible efficacy of this treatment.
Temussi, P. A., L. Masino, et al. (2003). "From Alzheimer to Huntington: why is a structural understanding so difficult?" Embo J 22(3): 355-61.
An increasing family of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, prion encephalopathies and cystic fibrosis is associated with aggregation of misfolded polypeptide chains which are toxic to the cell. Knowledge of the three-dimensional structure of the proteins implicated is essential for understanding why and how endogenous proteins may adopt a non-native fold. Yet, structural work has been hampered by the difficulty of handling proteins insoluble or prone to aggregation, and at the same time that is why it is interesting to study these molecules. In this review, we compare the structural knowledge accumulated for two paradigmatic misfolding disorders, Alzheimer's disease (AD) and the family of poly-glutamine diseases (poly-Q) and discuss some of the hypotheses suggested for explaining aggregate formation. While a common mechanism between these pathologies remains to be proven, a direct comparison may help in designing new strategies for approaching their study.
Trinh, N. H., J. Hoblyn, et al. (2003). "Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis." Jama 289(2): 210-6.
CONTEXT: Cholinesterase inhibitors are the primary treatment for the cognitive symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated with neuropsychiatric and functional deficits, but results from randomized controlled trials of cholinesterase inhibitors are conflicting. OBJECTIVE: To conduct a systematic review and meta-analysis to quantify the efficacy of cholinesterase inhibitors for neuropsychiatric and functional outcomes in patients with mild to moderate AD. DATA SOURCES: We performed a literature search of trials using MEDLINE (January 1966-December 2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the Cochrane Controlled Trials Register. We retrieved English- and non-English-language articles for review and collected references from bibliographies of reviews, original research articles, and other articles of interest. We searched for both published and unpublished trials, contacting researchers and pharmaceutical companies. STUDY SELECTION: We included 29 parallel-group or crossover randomized, double-blind, placebo-controlled trials of outpatients who were diagnosed as having mild to moderate probable AD and were treated for at least 1 month with a cholinesterase inhibitor. Sixteen trials included neuropsychiatric and 18 included functional measures. DATA EXTRACTION: Two investigators (N.H.T. and J.H.) independently extracted study methods, sources of bias, and outcomes. Neuropsychiatric outcomes were measured with the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed with the weighted mean difference method. Functional outcomes were measured with several activities of daily living (ADL) and instrumental activities of daily living (IADL) scales and analyzed with the standardized mean difference method. DATA SYNTHESIS: For neuropsychiatric outcomes, 10 trials included the ADAS-noncog and 6 included the NPI. Compared with placebo, patients randomized to cholinesterase inhibitors improved 1.72 points on the NPI (95% confidence interval [CI], 0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points). For functional outcomes, 14 trials used ADL and 13 trials used IADL scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various cholinesterase inhibitors. CONCLUSIONS: These results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.
Tsuboi, Y., K. Kakimoto, et al. (2003). "Increased hepatocyte growth factor level in cerebrospinal fluid in Alzheimer's disease." Acta Neurol Scand 107(2): 81-6.
BACKGROUND & OBJECTIVE: Hepatocyte growth factor (HGF), also known as the scatter factor, is a potent mitogen for mature hepatocytes, and also has multifunctional effects on some cells in various organs. Recently, we have found expression and localization of HGF in white matter astrocytes in human brain tissues. Furthermore, immunohistochemistry using anti-HGF antibody revealed more intense immunolabeling in Alzheimer's disease (AD) than control brains. The aim of the study is to investigate the level of HGF in cerebrospinal fluid (CSF) from patients with AD. MATERIAL AND METHODS: We examined the level of HGF in CSF from 34 AD and 15 age-matched disease control patients by highly sensitive enzyme-linked immunoabsorbent assay (ELISA) system. RESULTS: Consistent with the immunohistochemical data, a significantly higher concentration of HGF in AD CSF was found as compared with controls. A significant correlation was also seen between CSF HGF levels and white matter high-signal foci determined on brain magnetic resonance imaging (MRI) in AD patients. CONCLUSION: These results indicate that CSF HGF levels correspond with the white matter damage in AD brain.
Tully, T., R. Bourtchouladze, et al. (2003). "Targeting the CREB pathway for memory enhancers." Nat Rev Drug Discov 2(4): 267-77.
Today, the clinical notion of 'memory disorder' is largely synonymous with 'Alzheimer's disease.' Only 50% of all dementias are of the Alzheimer's type though, and dementias represent only the more severe of all learning/memory disorders that derive from heredity, disease, injury or age. Perhaps as many as 30 million Americans suffer some type of clinically recognized memory disorder. To date, therapeutic drugs of only one class have been approved for the treatment of Alzheimer's disease. Fortunately, basic research during the past 25 years has begun to define a 'chemistry of brain plasticity,' which is suggesting new gene targets for the discovery of memory enhancers.
Tuppurainen, M. and S. Saarikoski (2003). "Estrogens and aging." Adv Neurol 91: 101-6.
Vagnucci, A. H., Jr. and W. W. Li (2003). "Alzheimer's disease and angiogenesis." Lancet 361(9357): 605-8.
Despite enormous investigative efforts, the pathological basis for Alzheimer's disease remains unclear. Suggested mechanisms for the disorder include cerebral hypoperfusion, inflammation, gene polymorphisms, and molecular lesions in the brain. In this Hypothesis, we argue that the vascular endothelial cell has a central role in the progressive destruction of cortical neurons in Alzheimer's disease. In Alzheimer's disease, the brain endothelium secretes the precursor substrate for the beta-amyloid plaque and a neurotoxic peptide that selectively kills cortical neurons. Large populations of endothelial cells are activated by angiogenesis due to brain hypoxia and inflammation. Results of epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs, statins, histamine H2-receptor blockers, or calcium-channel blockers seems to prevent Alzheimer's disease. We think this benefit is largely due to these drugs' ability to inhibit angiogenesis. If Alzheimer's disease is an angiogenesis-dependent disorder, then development of antiangiogenic drugs targeting the abnormal brain endothelial cell might be able to prevent and treat this disease. We suggest several laboratory and clinical approaches for testing our hypothesis.
Waldman, A. and L. Kritharides (2003). "The pleiotropic effects of HMG-CoA reductase inhibitors: their role in osteoporosis and dementia." Drugs 63(2): 139-52.
HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and its inhibition exerts profound effects on cellular metabolism. Inhibitors of this enzyme are used in clinical practice to lower plasma cholesterol levels and are commonly collectively referred to as 'statins'. A number of in vitro, in vivo animal, and clinical studies suggest that properties of statins other than cholesterol lowering may be of biological importance. These diverse properties are often referred to as 'pleiotropic' and suggest that statins may affect a number of diseases of ageing. In this article we review the biological plausibility and clinical evidence of a role for statins in modulating two diseases of ageing: osteoporosis and dementia (including Alzheimer's disease). In both diseases, there is a sound cellular and laboratory basis for a plausible therapeutic effect of statins. In the case of osteoporosis, there are conflicting data regarding clinical benefit, with both negative and positive results reported. In particular, secondary analyses of randomised, controlled studies have shown no reduction of fracture risk by statins. In the case of dementia there are fewer clinical studies but there is clear anticipated benefit in macrovascular dementias attributable to statin-mediated reduction of the risk of stroke. Overall, there are a lack of prospective, placebo-controlled, randomised data testing statins and modulation of the risk of osteoporosis-related fracture or of clinical dementia, where these are primary outcomes. Until such data are available, the use of statins appears promising but cannot be recommended as a primary therapeutic modality for either condition.
Wardlaw, J. M., P. A. Sandercock, et al. (2003). "Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?" Stroke 34(3): 806-12.
BACKGROUND: The pathogenesis of and relationship between small deep (lacunar) infarcts, cerebral white matter disease (leukoaraiosis or white matter hyperintensities), and progressive cognitive impairment or dementia are much debated. SUMMARY OF COMMENT: We hypothesize that cerebral small-vessel endothelial (ie, blood-brain barrier) dysfunction, with leakage of plasma components into the vessel wall and surrounding brain tissue leading to neuronal damage, may contribute to the development of 3 overlapping and disabling cerebrovascular conditions: lacunar stroke, leukoaraiosis, and dementia. This hypothesis could explain the link between ischemic cerebral small-vessel disease and several apparently clinically distinct dementia syndromes. This hypothesis is supported by pathological, epidemiological, and experimental studies in lacunar stroke and leukoaraiosis and observations on the blood-brain barrier with MRI. We suspect that the potential significance of blood-brain barrier failure as a pathogenetic step linking vascular disease with common, disabling brain diseases of insidious onset has been overlooked. For example, lipohyalinosis, which has a pathological appearance of uncertain origin and is possibly responsible for some discrete lacunar infarcts, may be one end of a clinical spectrum of illness manifested by blood-brain barrier failure. CONCLUSIONS: Proof that blood-brain barrier failure is key to these conditions could provide a target for new treatments to reduce the effects of vascular disease on the brain and prevent cognitive decline and dementia.
Watson, G. S. and S. Craft (2003). "The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment." CNS Drugs 17(1): 27-45.
An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in Alzheimer's disease may contribute to the disease pathophysiology and clinical symptoms. It has long been known that insulin is essential for energy metabolism in the periphery. In the past 2 decades, convergent findings have begun to demonstrate that insulin also plays a role in energy metabolism and other aspects of CNS function. Investigators reported 20 years ago that insulin and insulin receptors were densely but selectively expressed in the brain, including the medial temporal regions that support the formation of memory. It has recently been demonstrated that insulin-sensitive glucose transporters are localised to the same regions supporting memory and that insulin plays a role in memory functions. Collectively, these findings suggest that insulin may contribute to normal cognitive functioning and that insulin abnormalities may exacerbate cognitive impairments, such as those associated with Alzheimer's disease. Insulin may also play a role in regulating the amyloid precursor protein and its derivative beta-amyloid (Abeta), which is associated with senile plaques, a neuropathological hallmark of Alzheimer's disease. It has been proposed that insulin can accelerate the intracellular trafficking of Abeta and interfere with its degradation. These findings are consistent with the notion that insulin abnormalities may potentially influence levels of Abeta in the brains of patients with Alzheimer's disease. The increased occurrence of insulin resistance in Alzheimer's disease and the numerous mechanisms through which insulin may affect clinical and pathological aspects of the disease suggest that improving insulin effectiveness may have therapeutic benefit for patients with Alzheimer's disease. The thiazolidinedione rosiglitazone has been shown to have a potent insulin-sensitising action that appears to be mediated through the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma agonists, such as rosiglitazone, also have anti-inflammatory effects that may be of therapeutic benefit in patients with Alzheimer's disease. This review presents evidence suggesting that insulin resistance plays a role in the pathophysiology and clinical symptoms of Alzheimer's disease. Based on this evidence, we propose that tr