Alzheimer Disease: England

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Brown DR. · Department of Biology and Biochemistry, University of Bath, UK. · FEBS J. · Pubmed #17617228 No free full text.

This publication has no abstract.

Weller RO. · Department of Microbiology and Pathology, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK. · J Pathol. · Pubmed #11329133 No free full text.

Abstract: Analysis of lumbar cerebrospinal fluid (CSF) plays a major role in the investigation of central nervous system disease, but how well do the changes in the CSF reflect pathology within the brain and spinal cord parenchyma? Both Creutzfeldt-Jakob (CJD) and Alzheimer's disease (AD) are characterized by the deposition of insoluble beta-pleated sheet peptides [prion protein (PrP) and beta-amyloid (Abeta), respectively] in the extracellular spaces of grey matter in the brain, but there is discordance in both diseases between the peptide levels in the brain and in the CSF. Experimental studies using tracers have shown that interstitial fluid (ISF) drains through very narrow intercellular spaces within grey matter into bulk flow perivascular channels that surround penetrating arteries. ISF then flows to the surface of the brain and joins CSF to drain to cervical lymph nodes. Such drainage of ISF and CSF to regional lymph nodes in the rat plays a significant role in B-cell and T-cell immune reactions within the brain. In man, the pia mater separates the periarterial ISF drainage pathways from the CSF in the subarachnoid space. The almost complete lack of insoluble protease-resistant PrP entering the CSF from the brain in patients with CJD, reported by Wong et al. in this issue of the Journal of Pathology, illustrates the limitations of ISF drainage pathways for the elimination of insoluble peptides from brain tissue. Insoluble Abeta accumulates in the extracellular spaces as plaques in AD and in periarterial ISF drainage pathways as cerebral amyloid angiopathy. Soluble Abeta appears to become entrapped by the insoluble Abeta in the ISF drainage pathways; thus, as the level of soluble Abeta in the brain rises in AD, the level in the CSF falls. Thus, the changes in the CSF do not accurately reflect the accumulation of the abnormal peptides in the brain parenchyma in either CJD or AD. In both diseases, facilitation of ISF drainage and elimination of PrP and Abeta peptides from the extracellular spaces of the brain may lead to practical therapeutic strategies for these devastating disorders.

Krishnan S, Cairns R, Howard R. · Mental Health of Older Adults, Maudsley Hospital, Denmark Hill, London, UK, SE5 8AZ. · Cochrane Database Syst Rev. · Pubmed #19370677 No free full text.

Abstract: BACKGROUND: Following the discovery of an endogenous cannabinoid system and the identification of specific cannabinoid receptors in the central nervous system, much work has been done to investigate the main effects of these compounds. There is increasing evidence that the cannabinoid system may regulate neurodegenerative processes such as excessive glutamate production, oxidative stress and neuroinflammation. Neurodegeneration is a feature common to the various types of dementia and this has led to interest in whether cannabinoids may be clinically useful in the treatment of people with dementia. Recent studies have also shown that cannabinoids may have more specific effects in interrupting the pathological process in Alzheimer's disease. OBJECTIVES: To determine from available research whether cannabinoids are clinically effective in the treatment of dementia. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 11 April 2008 using the terms: cannabis or cannabinoid* or endocannabinoid* or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: All double-blind and single (rater)-blind randomized placebo controlled trials assessing the efficacy of cannabinoids at any dose in the treatment of people with dementia. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined the retrieved studies for inclusion according to the selection criteria. They then independently assessed the methodological quality of selected trials and extracted data where possible. MAIN RESULTS: Only one study met the inclusion criteria. The data in the study report were presented in such a way that they could not be extracted for further analysis and there was insufficient quantitative data to validate the results. AUTHORS' CONCLUSIONS: This review finds no evidence that cannabinoids are effective in the improvement of disturbed behaviour in dementia or in the treatment of other symptoms of dementia. More randomized double-blind placebo controlled trials are needed to determine whether cannabinoids are clinically effective in the treatment of dementia.

Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE. · Centre for Statistics in Medicine, University of Oxford, Wolfson College, Linton Road, Oxford, UK, OX2 6UD. · Cochrane Database Syst Rev. · Pubmed #19370562 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 27 March 2008 using the terms: Rivastigmine OR exelon OR ENA OR "SDZ ENA 713" . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: Nine trials, involving 4775 participants, were included in the analyses. Use of rivastigmine in high doses was associated with statistically significant benefits on several measures. High-dose rivastigmine (6 to 12 mg daily) was associated with a two-point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -1.99, 95% confidence interval -2.49 to -1.50, on an intention-to-treat basis) and a 2.2 point improvement in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks. At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function. There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo. There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine. The 2008 update includes a new study testing two types of rivastigmine transdermal patch, one delivering a higher dose than previously tested (17.4 mg/day) and a smaller patch delivering 9.6 mg/day. The efficacy of the smaller patch was not significantly different compared with the capsules of similar daily dose, but was associated with significantly fewer adverse events of nausea, vomiting, dizziness and asthenia. The efficacy of the larger patch was not significantly different compared with the smaller patch, but the smaller patch was associated with significantly fewer adverse events of nausea, vomiting, weight loss and dizziness. There appears to be advantages associated with the smaller patch compared with both the higher dose patch and the 6-12 mg/day capsules. AUTHORS' CONCLUSIONS: Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in the rate of decline of cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both. This review has not examined economic data.

Buckingham SD, Jones AK, Brown LA, Sattelle DB. · Medical Research Council Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX. · Pharmacol Rev. · Pubmed #19293145 No free full text.

Abstract: Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the beta-amyloid protein (Abeta) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a reduction in nAChR numbers. The Abeta(1-42) protein, which is toxic to neurons, is critical to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Abeta causes neuronal death. We examine the evidence for a role in Abeta(1-42) toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Abeta peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Abeta peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Abeta(1-42) may offer the prospect of new routes to therapy for AD.

Burns A, Iliffe S. · University of Manchester Psychiatry Research Group, Manchester M13 9PL. · BMJ. · Pubmed #19196745 No free full text.

This publication has no abstract.

Mohan M, Bennett C, Carpenter PK. · Department of Neuropsychiatry, Neuropsychology and Epileptology, Burden Centre, North Bristol Trust, Frenchay Hospital, Bristol, Avon, UK, BS16 1JB. · Cochrane Database Syst Rev. · Pubmed #19160344 No free full text.

Abstract: BACKGROUND: Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). Acetylcholine is a chemical found in the brain that has an important role in memory, attention, reason and language. Rivastigmine is a "pseudo-irreversible" inhibitor of acetylcholinesterase, which is thought to maintain levels of acetylcholine. Rivastigmine can improve cognitive function and slow the decline of AD in the general population over time. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population. OBJECTIVES: To determine the effectiveness and safety of rivastigmine for people with DS who develop AD. SEARCH STRATEGY: CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of rivastigmine as well as experts in the field, to ask about reports of unpublished or ongoing trials. SELECTION CRITERIA: Randomised controlled trials of participants with DS and AD in which treatment with rivastigmine was administered compared with a placebo group. DATA COLLECTION AND ANALYSIS: No study was identified which met inclusion criteria for this review. MAIN RESULTS: No study was identified which met inclusion criteria for this review. AUTHORS' CONCLUSIONS: As there are no included trials, recommendations cannot be made about rivastigmine for AD in DS. Well-designed, adequately powered studies are required.

Mohan M, Bennett C, Carpenter PK. · Department of Neuropsychiatry, Neuropsychology and Epileptology, Burden Centre, North Bristol Trust, Frenchay Hospital, Bristol, Avon, UK, BS16 1JB. · Cochrane Database Syst Rev. · Pubmed #19160343 No free full text.

Abstract: BACKGROUND: Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to the pathogenesis of cerebral ischemias and AD. Memantine acts as an antagonist of N-methyl-D-aspartate (NMDA) type receptors, which is thought to reduce abnormal activation of glutamate neurotransmission. It binds with a low affinity to the NMDA receptor and so should not prevent learning and the formation of memory. Memantine can improve cognitive function and slow the decline of AD in the general population over time, and is the subject of this review. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population. OBJECTIVES: To determine the effectiveness and safety of memantine for people with DS who develop AD. SEARCH STRATEGY: CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of memantine, as well as experts in the field, to ask about reports of unpublished or ongoing trials. SELECTION CRITERIA: Randomised controlled trials of participants with DS and AD in which treatment with memantine was administered compared with a placebo group. DATA COLLECTION AND ANALYSIS: No study was identified which met the inclusion criteria for this review. MAIN RESULTS: No study was identified which met inclusion criteria for this review, however there is an on-going randomised controlled study being conducted in the UK and data are expected in 2009. AUTHORS' CONCLUSIONS: As there are no included trials, recommendations cannot be made about memantine for AD in DS. Well-designed, adequately powered studies are required.

Mohan M, Bennett C, Carpenter PK. · Department of Neuropsychiatry, Neuropsychology and Epileptology, Burden Centre, North Bristol Trust, Frenchay Hospital, Bristol, Avon, UK, BS16 1JB. · Cochrane Database Syst Rev. · Pubmed #19160342 No free full text.

Abstract: BACKGROUND: Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). Acetylcholine is a chemical found in the brain that has an important role in memory, attention, reason and language. Galantamine both inhibits the activity of acetylcholinesterase and increases the level of acetylcholine. Galantamine can improve cognitive function and slow the decline of AD in the general population over time. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population. OBJECTIVES: To determine the effectiveness and safety of galantamine for people with DS who develop AD. SEARCH STRATEGY: CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of galantamine as well as experts in the field, to ask about reports of unpublished or ongoing trials. SELECTION CRITERIA: Randomised controlled trials of participants with DS and AD in which treatment with galantamine was administered compared with a placebo group. DATA COLLECTION AND ANALYSIS: No study was identified which met inclusion criteria for this review. MAIN RESULTS: No study was identified which met inclusion criteria for this review. AUTHORS' CONCLUSIONS: As there are no included trials, recommendations cannot be made about galantamine for AD in DS. Well-designed, adequately powered studies are required.

Mohan M, Carpenter PK, Bennett C. · Department of Neuropsychiatry, Neuropsychology and Epileptology, Burden Centre, North Bristol Trust, Frenchay Hospital, Bristol, Avon, UK, BS16 1JB. · Cochrane Database Syst Rev. · Pubmed #19160328 No free full text.

Abstract: BACKGROUND: Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome [DS]. Acetylcholine is a chemical found in the brain that has an important role in memory, attention, reason and language. Donepezil a reversible inhibitor of acetylcholinesterase, which is thought to maintain levels of acetylcholine, and is reported to have some benefits for people with AD in the general population. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population. OBJECTIVES: To determine the effectiveness and safety of donepezil for people with DS who develop AD. SEARCH STRATEGY: CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of donepezil as well as experts in the field, to ask about reports of unpublished or ongoing trials. SELECTION CRITERIA: Randomised controlled trials of participants with DS and AD in which treatment with donepezil was administered compared with a placebo group. DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports of the one relevant study identified. MAIN RESULTS: The one study included in this review is a small (n=30) randomised controlled trial lasting 24 weeks. It was followed-up by an open label study with a crossover design.No significant differences were found on any four validated outcomes including global functioning and three measures of cognitive abilities and behavioural problems. 6 out of 16 carers (37%) of participants on donepezil and 2 out of 15 (13%) on placebo reported improvement. No data were available for day to day skills, institutionalisation, reduction in carers' stress or economic outcomes. Half the intervention group and 20% of the placebo group reported adverse events; two participants left because of adverse events. AUTHORS' CONCLUSIONS: To date there is only one small randomised controlled study on the effect of donepezil. This shows, at best, a modest, non statistically significant trend in favour of people with Down syndrome and Alzheimer's dementia who are able to tolerate donepezil (this drug is currently only dispensed in relatively large doses and is contraindicated for those with cardiac and respiratory problems).This study does not provide good evidence on which to base practice. Findings in an open-label follow up to this study suggest possible benefit in some individuals. Further, larger randomised controlled studies with longer-term follow up are required.

Thompson PW, Lockhart A. · GlaxoSmithKline, R&D China, UK Hub, Cambridge, UK. · Drug Discov Today. · Pubmed #19135168 No free full text.

Abstract: As a wave of 'disease modifying' (DM) therapies for Alzheimer's disease (AD) progresses towards the later stages of clinical development, an evaluation of our ability to measure relevant pharmacodynamic effects of such therapies is warranted. Reducing accumulation of amyloid beta (Abeta)-peptide in the brain parenchyma is the primary objective of most current DM approaches. Although a number of methods are available to measure Abeta in blood, cerebrospinal fluid (CSF) and the cerebrum, putative DM-induced changes in the levels of the peptides may not be fully captured, and the reasons for any such changes are not fully understood. Additional candidate biofluid (tau and isoprostanes) and imaging (MRI, FDG-PET) measures may provide alternative supporting evidence of drug activity and subsequent clinical efficacy in patient populations.

Burns A. · Psychiatry Research Group, University of Manchester, Manchester M13 9PL, UK. · Lancet Neurol. · Pubmed #19081500 No free full text.

This publication has no abstract.

Rodríguez JJ, Olabarria M, Chvatal A, Verkhratsky A. · Faculty of Life Sciences, The University of Manchester, Manchester, UK. · Cell Death Differ. · Pubmed #19057621 No free full text.

Abstract: Astrocytes, the most numerous cells in the brain, weave the canvas of the grey matter and act as the main element of the homoeostatic system of the brain. They shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the blood-brain barrier, control microenvironment of the central nervous system and defend nervous system against multitude of insults. Here, we overview the pathological potential of astroglia in various forms of dementias, and hypothesise that both atrophy of astroglia and reactive hypertrophic astrogliosis may develop in parallel during neurodegenerative processes resulting in dementia. We also show that in the transgenic model of Alzheimer's disease, reactive hypertrophic astrocytes surround the neuritic plaques, whereas throughout the brain parenchyma astroglial cells undergo atrophy. Astroglial atrophy may account for early changes in synaptic plasticity and cognitive impairments, which develop before gross neurodegenerative alterations.

Paradise M, Cooper C, Livingston G. · Department of Mental Health Sciences, University College London, UK. · Int Psychogeriatr. · Pubmed #19026089 No free full text.

Abstract: BACKGROUND: According to the cognitive reserve model, higher levels of education compensate for the neuropathology of Alzheimer's disease (AD), delaying its clinical manifestations. This model suggests that for any level of cognitive impairment, people with more education have worse neuropathology than those with less education and will therefore have shorter survival post-diagnosis. This is the first systematic review of the relationship between more education and decreased survival in people with AD. METHODS: We reviewed the literature systematically, searching electronic databases and reference lists of included studies. We used Centre for Evidence Based Medicine criteria for inclusion and rating of the validity of cohort studies that reported the relationship of education to survival in people with AD. RESULTS: 22 studies met inclusion criteria. We found Grade A evidence (highest evidence level) that more education was not associated with decreased survival post-diagnosis in AD. Only one of 11 studies rated 1b (highest level of quality) supported our hypothesis that more education predicted reduced survival after adjusting for age, gender and dementia severity; it comprised African-Caribbean participants, who had on average more severe cognitive impairment than other studies' participants. CONCLUSIONS: Education delays the onset of the dementia syndrome in AD, but does not lead to earlier death after diagnosis.

Tarnaris A, Kitchen ND, Watkins LD. · Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom. · J Neurosurg. · Pubmed #18991499 No free full text.

Abstract: OBJECT: Normal pressure hydrocephalus (NPH) represents a treatable form of dementia. Recent estimates of the incidence of this condition are in the region of 5% of patients with dementia. The symptoms of NPH can vary among individuals and may be confused with those of patients with multi-infarct dementia, dementia of the Alzheimer type, or even Parkinson disease. Traditionally the diagnosis of NPH could only be confirmed postoperatively by a favorable outcome to surgical diversion of CSF. The object of this literature review was to examine the role of structural and functional imaging in providing biomarkers of favorable surgical outcome. METHODS: A Medline search was undertaken for the years 1980-2006, using the following terms: normal pressure hydrocephalus, adult hydrocephalus, chronic hydrocephalus, imaging, neuroimaging, imaging studies, outcomes, surgical outcomes, prognosis, prognostic value, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS: The query revealed 16 studies that correlated imaging with surgical outcomes offering accuracy results. Three studies fulfilled the statistical criteria of a biomarker. A dementia Alzheimer-type pattern on SPECT in patients with idiopathic NPH, the presence of CSF flow void on MR imaging, and the N-acetylaspartate/choline ratio in patients with the secondary form are able to predict surgical outcomes with high accuracy. CONCLUSIONS: There is at present Level A evidence for using MR spectroscopy in patients with secondary NPH, and Level B evidence for using SPECT and phase-contrast MR imaging to select patients with idiopathic NPH for shunt placement. The studies, however, need to be repeated by other groups. The current work should act as a platform to design further studies with larger sample sizes.

Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P, Anonymous00415. · Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #18667359 No free full text.

Abstract: Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions.

Hands S, Sinadinos C, Wyttenbach A. · Southampton Neuroscience Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK. · Biochim Biophys Acta. · Pubmed #18582603 No free full text.

Abstract: The coordinated regulation of gene expression and protein interactions determines how mammalian nervous systems develop and retain function and plasticity over extended periods of time such as a human life span. By studying mutations that occur in a group of genes associated with chronic neurodegeneration, the polyglutamine (polyQ) disorders, it has emerged that CAG/glutamine stretches play important roles in transcriptional regulation and protein-protein interactions. However, it is still unclear what the many structural and functional roles of CAG and other low-complexity sequences in eukaryotic genomes are, despite being the most commonly shared peptide fragments in such proteomes. In this review we examine the function of genes responsible for at least 10 polyglutamine disorders in relation to the nervous system and how expansion mutations lead to neuronal dysfunction, by particularly focusing on Huntington's disease (HD). We argue that the molecular and cellular pathways that turn out to be dysfunctional during such diseases, as a consequence of a CAG expansion, are also involved in the ageing of the central nervous system. These are pathways that control protein degradation systems (including molecular chaperones), axonal transport, redox-homeostasis and bioenergetics. CAG expansion mutations confer novel properties on proteins that lead to a slow-progressing neuronal pathology and cell death similar to that found in other age-related conditions such as Alzheimer's and Parkinson's diseases.

Hamer M, Chida Y. · Psychobiology Group, Department of Epidemiology and Public Health, University College London, UK. · Psychol Med. · Pubmed #18570697 No free full text.

Abstract: BACKGROUND: The association between physical activity and risk of neurodegenerative diseases is not well established. We therefore aimed to quantify this association using meta-analytical techniques. METHOD: We searched Medline, the Cochrane Database of Systematic Reviews and Web of Science databases from 1990 to 2007 for prospective epidemiological studies of physical activity and incident dementia, Alzheimer's and Parkinson's disease. We excluded studies of physical activity and cognitive decline without diagnosis of a neurodegenerative disease. Information on study design, participant characteristics, measurement of exposure and outcome variables, adjustment for potential confounding, and estimates of associations was abstracted independently by the two investigators. RESULTS: We included 16 prospective studies in the overall analysis, which incorporated 163797 non-demented participants at baseline with 3,219 cases at follow-up. We calculated pooled relative risk (RR) using a random effects model. The RR of dementia in the highest physical activity category compared with the lowest was 0.72 [95% confidence interval (CI) 0.60-0.86, p<0.001], for Alzheimer's, 0.55 (95% CI 0.36-0.84, p=0.006), and for Parkinson's 0.82 (95% CI 0.57-1.18, p=0.28). CONCLUSIONS: Our results suggest that physical activity is inversely associated with risk of dementia. Future studies should examine the optimal dose of physical activity to induce protection, which presently remains unclear.

Sastre M, Walter J, Gentleman SM. · Division of Neuroscience and Mental Health, Imperial College London, The Hammersmith Hospital, Du cane Road, London W12 0NN, UK. · J Neuroinflammation. · Pubmed #18564425 links to  free full text

Abstract: There is now a large body of evidence linking inflammation to Alzheimer's disease (AD). This association manifests itself neuropathologically in the presence of activated microglia and astrocytes around neuritic plaques and increased levels of inflammatory mediators in the brains of AD patients. It is considered that amyloid-beta peptide (Abeta), which is derived from the processing of the longer amyloid precursor protein (APP), could be the most important stimulator of this response, and therefore determining the role of the different secretases involved in its generation is essential for a better understanding of the regulation of inflammation in AD. The finding that certain non-steroidal anti-inflammatory drugs (NSAIDs) can affect the processing of APP by inhibiting beta- and gamma-secretases, together with recent revelations that these enzymes may be regulated by inflammation, suggest that they could be an interesting target for anti-inflammatory drugs. In this review we will discuss some of these issues and the role of the secretases in inflammation, independent of their effect on Abeta formation.

De Vos KJ, Grierson AJ, Ackerley S, Miller CC. · MRC Center for Neurodegeneration Research, Institute of Psychiatry, King's College, London SE5 8AF, United Kingdom. · Annu Rev Neurosci. · Pubmed #18558852 No free full text.

Abstract: Many major human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), display axonal pathologies including abnormal accumulations of proteins and organelles. Such pathologies highlight damage to the axon as part of the pathogenic process and, in particular, damage to transport of cargoes through axons. Indeed, we now know that disruption of axonal transport is an early and perhaps causative event in many of these diseases. Here, we review the role of axonal transport in neurodegenerative disease.

Itzhaki RF, Wozniak MA. · Faculty of Life Science, The University of Manchester, Manchester, UK. · J Alzheimers Dis. · Pubmed #18487848 No free full text.

Abstract: Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet its causes and that of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor - the type 4 allele of the apolipoprotein gene, a known susceptibility factor - is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are also discussed. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.

Griffiths HH, Morten IJ, Hooper NM. · University of Leeds, Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences and Leeds Institute of Genetics, Health and Therapeutics, Leeds LS2 9JT, UK. · Expert Opin Ther Targets. · Pubmed #18479216 No free full text.

Abstract: BACKGROUND: The amyloid beta (Abeta) peptide is critical to the development of Alzheimer's disease (AD), the major neurodegenerative disease of the elderly for which there is currently no cure. OBJECTIVE: To review the literature on emerging treatments and potential therapeutic strategies for AD. METHODS: Available published literature and information from pharmaceutical companies was utilised. RESULTS/CONCLUSION: Several of the current treatments to combat AD are aimed at inhibiting the production, blocking the oligomerisation/aggregation or enhancing the degradation of Abeta. In our opinion, albeit based on limited available data, a future potential therapeutic strategy is to mimic the mechanism by which the normal cellular form of the prion protein inhibits the beta-secretase beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and hence the production of Abeta.

Spector A, Woods B, Orrell M. · Sub-Department of Clinical Health Psychology, University College London, Gower Street, London WC1E 6BT, UK. · Expert Rev Neurother. · Pubmed #18457532 No free full text.

Abstract: In recent years, there has been an increase in the recognition and use of psychosocial interventions for dementia. This has coincided with an increase in high-quality research in the area, and restrictions in the use of drug therapies for Alzheimer's disease in the UK. Cognitive stimulation therapy (CST) is a brief group treatment for people with mild-to-moderate dementia, based on the theoretical concepts of reality orientation and cognitive stimulation. It involves 14 sessions of themed activities which typically run twice a week over a 7-week period. A multicenter, randomized controlled trial showed significant benefits in cognition and participant-rated quality of life when comparing CST versus no treatment. These benefits in cognition were comparable to those gained through medication, and CST also proved to be cost-effective. Influenced by this research, the latest guidelines released by NICE recommended cognitive stimulation only as an intervention for treating the cognitive symptoms of dementia. This perspective describes how CST was developed and evaluated, its use in clinical settings and issues for future investigation, such as individualized CST.

Scahill RI, Fox NC. · Dementia Research Centre, 8-11 Queen Square, London WC1N 3BG, UK. · Br J Radiol. · Pubmed #18445749 No free full text.

Abstract: Dementia represents one of the major public health problems facing ageing populations, with 20% of those over 80 years of age suffering from this disorder. The advent of therapeutic agents has brought about an increasing demand for a more accurate and earlier diagnosis, and the value of neuroimaging in improving the diagnostic process is becoming widely accepted. Neuroimaging assessments may add weight to a diagnosis of neurodegeneration as opposed to healthy ageing, improve the differential diagnosis, aid in the prediction of conversion to dementia in individuals at a higher risk of developing the disorder, track disease progression and provide an outcome measure for assessment of drug efficacy.