Alzheimer Disease: England

O'Brien JT. · Newcastle University, Institute for Ageing and Health, Wolfson Research Centre, Newcastle upon Tyne, UK. j.t.o' · Br J Radiol. · Pubmed #18445747 No free full text.

Abstract: Dementia is a common and growing problem, affecting 5% of the over 65 s and 20% of the over 80s. The recent availability of new treatments for dementia, as well as the importance of subtype-specific management, has renewed interest in the use of brain imaging techniques that can assist in the accurate recognition of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia (VaD) and frontotemporal dementia (FTD). Structural imaging, historically used to exclude an intracerebral lesion as a cause for dementia, is increasingly playing a role in "ruling in" diagnoses, with atrophy of the hippocampus and entorhinal cortex an early and sensitive marker for AD, and cortical and subcortical infarcts and white matter lesions characteristic of VaD. Regionally distinct patterns of hypoperfusion on single-photon emission computed tomography (SPECT) or hypometabolism on positron emission tomography (PET) can help differentiate FTD, AD and VaD, and dopaminergic loss in the basal ganglia can differentiate DLB from AD. Newer techniques show great promise to detect specific neuroreceptor changes as well as pathological underpinnings of dementia, such as amyloid and tau pathology.

Herholz K, Carter SF, Jones M. · Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK. · Br J Radiol. · Pubmed #18445746 No free full text.

Abstract: Positron emission tomography (PET) is a well-established imaging modality. Measurement of regional cerebral glucose metabolism (rCMR(glc)) using PET and [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) has become a standard technique in both oncology and dementia research. When measuring rCMR(glc) in Alzheimer's disease (AD), characteristic reductions in rCMR(glc) are found in neocortical association areas including the posterior cingulate, precuneus, temporoparietal and frontal multimodal association regions; the primary visual cortex, sensorimotor cortex, basal ganglia and cerebellum are relatively unaffected. FDG-PET has been used in the study of mild cognitive impairment (MCI) to accurately predict the subsequent decline to AD. Impairment in rCMR(glc) may be seen in individuals at high genetic risk of AD, even before clinical symptoms are apparent. Characteristic patterns of regional hypometabolism are also seen in other degenerative dementias such as frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). The use of different radioisotopes and tracers increases the versatility of PET. Tracers adopted in dementia research include (11)C-PK-11195 and (11)C-PIB, which have been used to investigate neuroinflammation and amyloid deposition, respectively, in both AD and MCI populations. It is also possible to investigate neurotransmitter systems in dementia; targets have included the cholinergic, dopaminergic and serotonergic systems. Imaging the brains of dementia patients using PET provides important information about the brain function of these individuals that would otherwise be unavailable with other imaging modalities. PET will continue to be important in future dementia research as new tracers become available to help in the early and specific diagnosis of increasingly well-defined clinical syndromes, and assist in the assessment of new therapeutic interventions.

Mills S, Cain J, Purandare N, Jackson A. · Division of Imaging Science, University of Manchester, Wolfson Molecular Imaging Centre, 27 Palatine Rd, Withington, Manchester, UK. · Br J Radiol. · Pubmed #18445743 No free full text.

Abstract: There is increasing recognition that cerebrovascular disease contributes significantly to the development and progression of patients with dementia. The concepts of pure vascular and pure degenerative dementia have been replaced with a recognition that, in many patients, there is a spectrum of neurodegenerative and vascular processes. This is supported by preliminary studies showing response to vascular therapeutics and ventriculo-peritoneal shunting in patients with Alzheimer's disease. This article examines the imaging biomarkers that are available for the characterization of microvascular abnormality in the ageing brain, with particular reference to microvascular angiopathy, cerebral embolic disease, orthostatic hypotension and abnormalities of Monro-Kellie homeostasis.

Abdulrab K, Heun R. · Medical School, University of Birmingham, Birmingham, UK. · Eur Psychiatry. · Pubmed #18434102 No free full text.

Abstract: BACKGROUND: Subjective Memory Impairment (SMI) may hold value in the elderly as a predictor of dementia. There is yet to exist any standard definition of SMI for use in research or for clinical practice. OBJECTIVE: This study aims to identify previous and current definitions of SMI used in published research and to propose a set of criteria that may help increase SMI's predictive power of future cognitive decline. METHODS: Literature searches were conducted across a number of electronic databases including Medline. RESULTS: 515 citations were identified, 336 papers were obtained, of which 44 were selected for containing definitions for SMI. These definitions varied widely in terms of the types of questions used to determine SMI and additional features pertaining to memory complaints included in the definition. CONCLUSION: There is no consistency in how SMI is defined. We propose a set of criteria aimed to increase specificity of memory complainers for those at increased risk of dementia. Further research is required to refine and validate the different criteria suggested. An international consent on the necessary criteria by experts in the field might be useful.

Stig B, Hajdú N. · University College, London Medical School Institute of Hepatology, London, United Kingdom. · Orv Hetil. · Pubmed #18426758 No free full text.

Abstract: BACKGROUND: Chronic diseases as well as complications to acute and chronic disease are repeatedly associated with accumulation in the body of glycated and lipoxidated proteins and peptides. These molecules are strongly associated with activation of a specific receptor called RAGE and a long-lasting exaggerated level of inflammation in the body. METHODS: PubMed reports in excess of 5000 papers plus about 14000 articles about the related HbA 1c , most of them published in the last five years. Most of available abstracts have been read and circa 800 full papers studied in detail. RESULTS: RAGE, a member of the immunoglobulin superfamily of cell surface molecules and receptor for advanced glycation endproducts, functions as a master switch, induces sustained activation of NF-kappaB, suppresses a series of endogenous autoregulatory functions and converts long-lasting pro-inflammatory signals into sustained cellular dysfunction and disease. Its activation is associated with high levels of dysfunctioning proteins in body fluids and tissues, and strongly associated with a series of diseases from allergy and Alzheimer to rheumatoid arthritis and urogenital disorders. Heat-treatment, irradiation and ionisation of foods increase the content in foods of AGE/ALE. CONCLUSIONS: Some processed foods are much like tobacco smoking great contributors to accumulation of glycated and lipoxidated molecules in the tissues. Change of life style: avoidance of foods rich in deranged proteins and peptides and increased consumption of antioxidants, especially polyphenols counteracts such a development.

Fitzjohn SM, Doherty AJ, Collingridge GL. · MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK. · Eur J Pharmacol. · Pubmed #18423442 No free full text.

Abstract: In the present article we show how studying synaptic mechanisms in hippocampal slice preparations provides information that may be useful in, firstly, the understanding of the aetiology of Alzheimer's disease and, secondly, in the development of novel therapies for dementia. We use several examples, drawn from our own work: (i) The identification of the function of AMPA receptors and NMDA receptors in synaptic transmission and synaptic plasticity. (ii) The discovery of mechanisms that can regulate the activation of NMDA receptors. (iii) The use of transgenic models of Alzheimer's disease. (iv) The identification of a mechanism that can account for the cognitive enhancing effects of the NMDA receptor antagonist memantine. (v) The discovery of a role of glycogen synthase kinase-3beta (tau kinase) in synaptic plasticity.

Ouldred E, Bryant C. · King's College Hospital NHS Foundation Trust, London, UK. · Br J Nurs. · Pubmed #18414252 No free full text.

Abstract: This article outlines recent guidance on dementia care and provides information on dementia, its different subtypes, the assessment process and the utility of cognitive screening tools. As dementia progresses a person may gradually lose their ability to make decisions for themselves. The Mental Capacity Act 2005 (MCA) is one of the most significant Acts to be passed in the United Kingdom, which protects people with dementia and stresses the need to advocate on behalf of this vulnerable group. The MCA is described in detail as practitioners working in the field of dementia care need to be aware of its clauses, as they are likely to require knowledge of it on a frequent basis. Dementia, delirium and depression are often mistaken for one another and useful ways to differentiate between the different conditions are given in addition to comprehensive advice about the management of people with dementia admitted to hospital with delirium.

Nalivaeva NN, Fisk LR, Belyaev ND, Turner AJ. · Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK. · Curr Alzheimer Res. · Pubmed #18393806 No free full text.

Abstract: The steady state concentration of the Alzheimer's amyloid-beta peptide in the brain represents a balance between its biosynthesis from the transmembrane amyloid precursor protein (APP), its oligomerisation into neurotoxic and stable species and its degradation by a variety of amyloid-degrading enzymes, principally metallopeptidases. These include, among others, neprilysin (NEP) and its homologue endothelin-converting enzyme (ECE), insulysin (IDE), angiotensin-converting enzyme (ACE) and matrix metalloproteinase-9 (MMP-9). In addition, the serine proteinase, plasmin, may participate in extracellular metabolism of the amyloid peptide under regulation of the plasminogen-activator inhibitor. These various amyloid-degrading enzymes have distinct subcellular localizations, and differential responses to aging, oxidative stress and pharmacological agents and their upregulation may provide a novel and viable therapeutic strategy for prevention and treatment of Alzheimer's disease. Potential approaches to manipulate expression levels of the key amyloid-degrading enzymes are highlighted.

Boche D, Nicoll JA. · Division of Clinical Neurosciences, University of Southampton, Southampton, UK. · Brain Pathol. · Pubmed #18363937 No free full text.

Abstract: In Alzheimer's disease (AD), there is abnormal accumulation of Abeta and tau proteins in the brain. There is an associated immunological response, but it is still unclear whether this is beneficial or harmful. Inflammation in AD, specifically in the form of microglial activation, has, for many years, been considered to contribute to disease progression. However, two types of evidence suggest that it may be appropriate to revise this view: first, the disappointing results of prospective clinical trials of anti-inflammatory agents and, second, the observation that microglia can clear plaques in AD following Abeta immunization. Although Abeta immunization alters AD pathology, there is limited evidence so far of benefit to cognitive function. Immunization against microorganisms is almost always used as a method of disease prevention rather than to treat a disease process that has already started. In animal models, immunotherapy at an early age can protect against Abeta accumulation and it will be interesting to see if this can usefully be applied to humans to prevent AD.

Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. · Clinical Neurosciences, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK. · Brain Pathol. · Pubmed #18363936 No free full text.

Abstract: Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-beta (Abeta) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Abeta deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain--effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Abeta is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Abeta. Failure of perivascular drainage of Abeta and deposition of Abeta in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Abeta-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Abeta and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Abeta and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.

Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S. · Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK. · Brain Pathol. · Pubmed #18363935 No free full text.

Abstract: In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.

Francis PT. · Wolfson Centre for Age-Related Diseases, King's College London, London, UK. · Neurodegener Dis. · Pubmed #18322401 No free full text.

Abstract: The glutamatergic system has long been recognised for its role in learning and memory and recent studies indicate an early loss of glutamatergic synapses in Alzheimer's disease (AD). Efforts to produce drugs which address changes in the glutamatergic system in AD are well advanced (e.g. memantine and drugs in development such as ampakines). Much less is known about the possible role of glutamate in non-cognitive behavioural changes; however, recent data from clinical trials suggest that memantine reduces agitation and aggressive behaviour in AD patients. In this context, it is important to help identify new treatment approaches to replace the use of antipsychotics in this vulnerable population.

Sampson E, Jenagaratnam L, McShane R. · Royal Free and University College Medical School, Department of Mental Health Sciences, Rowland Hill Street, London, UK, NW3 2PF. · Cochrane Database Syst Rev. · Pubmed #18254079 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Ass). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Ass. OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 15 February 2007 using the terms clioquinol, PBT*, MPAC*. The Register contains records from major health care databases, many ongoing trial databases and grey literature and is updated regularly. The Internet was searched using the term: clioquinol, PBT*, MPAC* SELECTION CRITERIA: Randomised double-blind trials in which treatment with clioquinol was administered to participants with Alzheimer's disease in parallel group comparison with placebo are included. DATA COLLECTION AND ANALYSIS: Three reviewers (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Collaboration Handbook.The primary outcome measures of interest were cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, safety and adverse effects, and death. MAIN RESULTS: There was one included trial of clioquinol (PBT1) compared with placebo in 36 patients. There was no statistically significant difference in cognition (as measured on the ADAS-Cog scale) between active treatment and placebo groups at 36 weeks. One subject in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and was thought to be possibly attributable to the drug. AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology, particularly the randomisation (subjects in the active treatment group had higher mean pre-morbid IQ as measured by the NART and this may have biased the results), the secondary analyses of results stratified by baseline disease severity and whether the study was adequately powered for the analysis of the other data collected on Ass, zinc and copper levels.

de Grey AD. · Methuselah Foundation, Cambridge, United Kingdom. · Nutr Rev. · Pubmed #18240553 No free full text.

Abstract: Several of the most prevalent and severe age-related diseases, notably Alzheimer's disease and atherosclerosis, feature the accumulation of non-degradable aggregates within the lysosomes of disease-affected cells. At an early point in disease progression, the breakdown of lysosomal contents by the resident catabolic enzymes stops working properly. A return of lysosomal enzymatic activity to pre-disease levels may restore aggregate elimination. In this review, a method of bioremediation-derived lysosomal enzyme enhancement is proposed, featuring the cellular introduction of microbial-isolated enzymes, or xenoenzymes. The benefits and challenges of using xenoenzymes to break down aggregates are discussed. As the size of our elderly population grows, the incidence of age-related diseases will increase, necessitating the exploration of radical, but potentially powerful, therapeutic strategies.

Greenfield SA, Zimmermann M, Bond CE. · The Institute for the Future of the Mind, Oxford University, UK. · FEBS J. · Pubmed #18205834 No free full text.

Abstract: This review explores the possibility that acetylcholinesterase may play a pivotal, non-hydrolytic role in neurodegeneration. More specifically, C-terminal sequences of acetylcholinesterase may act as signalling molecules in key brain regions characteristically vulnerable to Alzheimer's, Parkinson's and motor neuron disease.

Herholz K, Weisenbach S, Kalbe E. · University of Manchester, United Kingdom. · Neuropsychologia. · Pubmed #18201734 No free full text.

Abstract: Impairment of cholinergic neurotransmission is a well-established fact in Alzheimer's disease (AD) but there is controversy about its relevance at the early stages of the disease. In the recent years new techniques for in vivo imaging of key components of the cholinergic system in humans have developed. They are beginning to be applied to the very early stages of AD. Preliminary results suggest that there is early impairment of presynaptic receptors and acetylcholine esterase, the main degrading enzyme for acetylcholine, in cerebral cortex. The relation of these findings to neuronal function and post-mortem findings is being discussed.

Herholz K. · Wolfson Molecular Imaging Centre, Clinical Neuroscience, University of Manchester, 27 Palatine Road, Manchester, UK. · Eur J Nucl Med Mol Imaging. · Pubmed #18196237 No free full text.

Abstract: PURPOSE: Impairment of cholinergic neurotransmission is a well-established fact in Alzheimer's disease (AD), but there is controversy about its relevance at the early stages of the disease and in mild cognitive impairment (MCI). METHODS: In vivo positron emission tomography imaging of cortical acetylcholine esterase (AChE) activity as a marker of cholinergic innervation that is expressed by cholinergic axons and cholinoceptive neurons has demonstrated a reduction of this enzyme activity in manifest AD. The technique is also useful to measure the inhibition of cerebral AChE induced by cholinesterase inhibitors for treatment of dementia symptoms. RESULTS: A reduction of cortical AchE activity was found consistently in all studies of AD and in few cases of MCI who later concerted to AD. CONCLUSION: The in vivo findings in MCI and very mild AD are still preliminary, and studies seem to suggest that cholinergic innervation and AChE as the main degrading enzyme are both reduced, which might result in partial compensation of their effect.

Hooper C, Killick R, Lovestone S. · King's College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, UK. · J Neurochem. · Pubmed #18088381 No free full text.

Abstract: Glycogen synthase kinase 3 (GSK3) is a constitutively active, proline-directed serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. GSK3 also plays a pivotal and central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD), an observation that has led us to coin the 'GSK3 hypothesis of AD'. According to this hypothesis, over-activity of GSK3 accounts for memory impairment, tau hyper-phosphorylation, increased beta-amyloid production and local plaque-associated microglial-mediated inflammatory responses; all of which are hallmark characteristics of AD. If our 'GSK3 hypothesis of AD' is substantiated and GSK3 is indeed a causal mediator of AD then inhibitors of GSK3 would provide a novel avenue for therapeutic intervention in this devastating disorder.

Razay G, Wilcock GK. · University of Oxford, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, UK. · Expert Rev Neurother. · Pubmed #18088197 No free full text.

Abstract: Galantamine is a cholinesterase inhibitor with a dual mechanism of action. It is a reversible inhibitor of acetylcholine esterase and enhances the intrinsic action of acetylcholine on nicotinic receptors, leading to increased cholinergic neurotransmission in the CNS. Galantamine has a large volume clearance, low plasma protein binding and a high bioavailability. Short-term, double-blind, placebo-controlled studies have shown that treatment with galantamine produces small improvements on cognitive tests and global measures of change in selected patients with mild to moderately severe Alzheimer's disease. A dose of 16-24 mg/day appears to be the most efficacious, and is the licensed maintenance dose range in most territories. The magnitude of the treatment effect is similar to that of other cholinesterase inhibitors. Adverse events experienced by patients treated with galantamine are usually mild, gastrointestinal and may improve with dose reduction.

Al-Shawi R, Hafner A, Chun S, Raza S, Crutcher K, Thrasivoulou C, Simons P, Cowen T. · Centre for Biomedical Sciences, University College London, Hampstead Campus, London, UK. · Ann N Y Acad Sci. · Pubmed #18056969 No free full text.

Abstract: Several studies have sought to demonstrate that neurodegeneration during disease and in old age is associated with reduced neurotrophic support. Little positive evidence has been forthcoming, either in relation to the availability of neurotrophins or to expression and function of the relevant receptors. Recently, a novel way in which neurotrophins could contribute to neurodegeneration has been suggested. In contrast to the well-known neurotrophic functions of the mature beta-form of nerve growth factor (mNGF), its precursor proNGF has recently been shown to be abundant in the adult brain and in the brains of patients with Alzheimer's disease. proNGF is synthesized as 25 and 32 kDa isoforms, which are glycosylated to form a principal 40 kDa species. Studies of the cortical targets of NGF-responsive basal forebrain neurons show that the 40 kDa form of proNGF is secreted in response to nerve stimulation, along with the proteases needed to generate the 13 kDa mNGF, or to degrade it. We have recently found that levels of 40 kDa proNGF are elevated in the aging brain and also in targets of peripheral NGF-responsive neurons. proNGF has been shown to be neurotoxic when bound in a heterotrimer with the p75 receptor and the receptor sortilin (identical to the neurotensin receptor NTS3). Interestingly, we find that sortilin levels increase in aged central and peripheral neurons, perhaps making these neurons more vulnerable to age-related increases in proNGF. Whether elevated levels of proNGF in targets or of sortilin in neurons contribute to known patterns of age- and disease-related neurodegeneration has not been previously investigated. Using in vitro models, our preliminary data now indicate that proNGF is indeed neurotoxic for aged, but not young, NGF-responsive basal forebrain and sympathetic neurons and that blockade of sortilin rescues proNGF-induced cell death. We therefore propose that increased proNGF in targets combined with increased sortilin expression in projecting neurons contributes to age-related neuronal atrophy and degeneration.

Newton JL. · Institute for Ageing and Health, University of Newcastle upon Tyne, Care of the Elderly Offices, Royal Victoria Infirmary, Newcastle upon Tyne, UK. · Clin Interv Aging. · Pubmed #18047255 links to  free full text

Abstract: Interventions to reduce mortality and disability in older people are vital. Aspirin is cheap and effective and known to prevent cardiovascular and cerebrovascular disease, many cancers, and Alzheimer dementia. The widespread use of aspirin in older people is limited by its gastrointestinal side effects. Understanding age-related changes in gastrointestinal physiology that could put older people at risk of the side effects of aspirin may direct strategies to improve tolerance and hence lead to greater numbers of older people being able to take this effective intervention.

McKeith I. · Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, UK. · Pract Neurol. · Pubmed #18024777 No free full text.

Abstract: Parkinson's disease and dementia with Lewy bodies are two common presentations of a single, underlying disease process (Lewy body disease) which is thought to be related to dysregulation of the synaptic protein, alpha-synuclein. This article discusses the nature of the relations between Parkinson's disease and dementia with Lewy bodies, and what can be learned from them about the causes of dementia in patients with established Parkinson's disease. This is an area of clinical practice which is of increasing importance as greater numbers of ageing patients survive longer with good treatment of their motor symptoms. Precise use of terminology and a clear understanding of the biological substrates underlying symptom formation are particularly helpful to both clinicians and patients.

Parsons RB, Austen BM. · Department of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, U.K. · Biochem Soc Trans. · Pubmed #17956258 No free full text.

Abstract: The correct assembly of the BACE (beta-site amyloid precursor protein-cleaving enzyme or beta-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Abeta (amyloid beta-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE-protein interactions. This review will discuss what is currently known about these BACE-protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

Souchay C. · Leeds Memory Group, Institute of Psychological Sciences, University of Leeds, Leeds, UK. · Cortex. · Pubmed #17941355 No free full text.

Abstract: Alois Alzheimer's first publication describes his patient's inability to be aware of her condition. One hundred years later, whether or not Alzheimer's disease (AD) patients show impaired awareness of their memory deficits is still of debate. This review makes a novel contribution, arguing that the ideal empirical tool to assess this question is the metamemory framework. The fact that the metamemory framework offers models of healthy memory and metamemory function and ready-developed measures mapped onto theoretical constructs, means that it is a useful paradigm to explore the question of memory awareness. The review focuses on two as yet separate approaches: the neuropsychological models of anosognosia as well as the metamemory framework. Metamemory constructs and measures are used to evaluate Alzheimer's patients' awareness of their memory difficulties by relating the main findings to the existing neuropsychological model of anosognosia. With this approach, only very specific deficits in awareness are found: a failure to update self-beliefs, and a deficit in monitoring episodic memory, possibly related to a deficit in effortful, conscious control processes. This review also considers how the exploration of the neural correlates of metamemory can help to draw novel hypotheses on the brain regions implicated in anosognosia in AD.

Benjamin B, Burns A. · Department of Old Age Psychiatry, Second Floor, Education and Resource Centre, Wythenshawe Hopsital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK. · Expert Rev Neurother. · Pubmed #17939763 No free full text.

Abstract: Donepezil is the most widely prescribed of the cholinesterase inhibitors that has been licensed for the treatment of mild-to-moderate Alzheimer's disease. Evidence from a number of clinical trials suggests that it improves cognitive performance and stabilizes the functional abilities in people with mild-to-moderate Alzheimer's disease. Donepezil increases the amount of the neurotransmitter acetylcholine in the brain, the deficit of which is thought to play a major role in the clinical presentation of Alzheimer's disease. Studies show good safety and long-term tolerability. In addition, donepezil's pharmacokinetic properties make it convenient to prescribe. There are a number of newer drug therapies in various stages of pharmacological development, but donepezil should continue to play a major role in the treatment of Alzheimer's disease for the next few years.