Publications by authors named "Emma R L C Vardy"

16 Publications

  • Page 1 of 1

Quality improvement and delirium.

Eur Geriatr Med 2020 02 3;11(1):33-43. Epub 2019 Dec 3.

Department of Information and Business Intelligence, Salford Royal NHS Foundation Trust, Salford Care Organisation, Part of Northern Care Alliance NHS Group, Stott Lane, Salford, M6 8HD, UK.

Purpose: Quality improvement (QI) is a useful methodology that can be used to make timely improvements in clinical practice. This review gives a broad picture of what QI is and the methodology this entails. An overview of how QI has been applied in the field of delirium to date is provided as well as a discussion of how this area may be developed in the future.

Methods: As part of the review, a literature search was completed to assess the literature published to date on QI and delirium. Literature relating to delirium in the context of a variety of clinical specialties is also presented as well as a summary of short films that can be used for purposes of awareness raising.

Results: We found that QI has so far been an under-utilized methodology in the context of delirium and that studies that adhere to general guidance on reporting are few.

Conclusion: We suggest that well-designed QI studies would be beneficial to improve the assessment, management and care of delirium. The methodology may also be used to embed educational resources. In this review, we describe the theory behind QI and also suggest some resources that may be useful in any QI delirium project.
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http://dx.doi.org/10.1007/s41999-019-00268-zDOI Listing
February 2020

Phenylketonuria, co-morbidity, and ageing: A review.

J Inherit Metab Dis 2020 03 1;43(2):167-178. Epub 2020 Jan 1.

National Society for Phenylketonuria, Preston, UK.

Phenylketonuria (PKU) is a metabolic condition which, left untreated, results in severe and irreversible brain damage. Newborn screening and the development of the low phenylalanine (Phe) diet have transformed the outcomes for people with PKU. Those who have benefited from early treatment are now approaching their fifth and sixth decade. It is therefore timely to consider multi-morbidity in PKU and the effects of ageing, in parallel with the wider benefits of emerging treatment options in addition to dietary relaxation. We have conducted the first literature review of co-morbidity and ageing in the context of PKU. Avenues explored have emerged from limited study of multi-morbidity to date and the knowledge and critical enquiry of the authors. Findings suggest PKU to have a wider impact than brain development, and result in several intriguing questions that require investigation to attain the best outcomes for people with PKU in adulthood moving through to older age. We recognise the difficulty in studying longitudinal outcomes in rare diseases and emphasise the necessity to develop PKU registries and cohorts that facilitate well-designed studies to answer some of the questions raised in this review. Whilst awaiting new information in these areas we propose that clinicians engage with patients to make personalised and well-informed decisions around Phe control and assessment for co-morbidity.
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http://dx.doi.org/10.1002/jimd.12186DOI Listing
March 2020

Plasma metals as potential biomarkers in dementia: a case-control study in patients with sporadic Alzheimer's disease.

Biometals 2018 04 7;31(2):267-276. Epub 2018 Mar 7.

Centre for Advanced Discovery and Experimental Therapeutics (CADET), Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Sporadic Alzheimer's disease (AD) is a neurodegenerative disorder that causes the most prevalent form of age-related dementia but its pathogenesis remains obscure. Altered regulation of metals, particularly pan-cerebral copper deficiency, and more regionally-localized perturbation of other metals, are prominent in AD brain although data on how these CNS perturbations are reflected in the peripheral bloodstream are inconsistent to date. To assess the potential use of metal dysregulation to generate biomarkers in AD, we performed a case-control study of seven essential metals and selenium, measured by inductively coupled plasma mass-spectrometry, in samples from AD and matched control cases. Metals were sodium, potassium, calcium, magnesium, iron, zinc, and copper. In the whole study-group and in female participants, plasma metal levels did not differ between cases and controls. In males by contrast, there was moderate evidence that zinc levels trended towards increase in AD [10.8 (10.2-11.5)] µmol/L, mean (± 95% CI; P = 0.021) compared with controls [10.2 (9.6-10.4)]. Thus alterations in plasma zinc levels differed between genders in AD. In correlational analysis, there was evidence for an increased number of 'strong' metal co-regulations in AD cases and differential co-modulations of metal pairs: copper-sodium (R = - 0.03, R = 0.65; P = 0.009), and copper-calcium (R = - 0.01, R = 0.65; P = 0.01) were significant in AD males, potentially consistent with reported evidence for dysregulation of copper in severely damaged brain regions in AD. In conclusion, our data suggest that the measurement of metals co-regulation in plasma may provide a useful representation of those metal perturbations taking place in the AD brain and therefore might be useful as plasma-based biomarkers.
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http://dx.doi.org/10.1007/s10534-018-0089-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978903PMC
April 2018

Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer's disease: metabolic basis for dementia.

Sci Rep 2016 06 9;6:27524. Epub 2016 Jun 9.

School of Biological Sciences, and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, New Zealand.

Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer's disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem case-control study. Glucose, sorbitol and fructose were markedly elevated in all AD brain regions, whereas copper was correspondingly deficient throughout (all P < 0.0001). In the ante-mortem case-control study, by contrast, plasma-glucose and plasma-copper levels did not differ between patients and controls. There were pervasive defects in regulation of glucose and copper in AD brain but no evidence for corresponding systemic abnormalities in plasma. Elevation of brain glucose and deficient brain copper potentially contribute to the pathogenesis of neurodegeneration in AD.
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http://dx.doi.org/10.1038/srep27524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899713PMC
June 2016

Review of delirium in patients with Parkinson's disease.

J Neurol 2015 Nov 10;262(11):2401-10. Epub 2015 May 10.

Department of Older Peoples Medicine, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Rd, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, UK.

Parkinson's disease (PD) is common and has a number of associated neuropsychiatric disturbances. Of these, delirium has historically been under-recognised. Delirium is an acute disturbance of attention and awareness that fluctuates, and is accompanied by an additional disturbance of cognition. As delirium is known to carry a particularly poor prognosis in terms of morbidity and mortality, and the relationship between delirium and dementia is becoming better defined, we completed a literature review of delirium in the context of PD. A literature search was completed using the databases PubMed, Embase and Ovid Medline. PubMed (1945-2014) was searched in September 2014; Embase (1974-2014); and Ovid Medline (1946-2014) in October 2014. The search terms 'delirium' and 'Parkinsons' in combination were used. Large studies using a robust definition of delirium were lacking in PD. There is the suggestion that PD is a risk factor for delirium and that delirium negatively impacts upon the motor symptom trajectory. Deficits in the neurotransmitters dopamine and acetylcholine are implicated in the pathophysiology of delirium in PD. Systemic inflammation also appears to have a role. Treatment of delirium in PD should include medication review and cautious use of atypical antipsychotics where pharmacological treatment is indicated. Of the atypical antipsychotics studied, quetiapine has the least extrapyramidal side effects. Evidence suggests a specific link between delirium and PD but well-designed clinical studies to evaluate the prevalence, impact and treatment of delirium in PD are required. Given the potential to improve outcomes through delirium prevention we conclude that delirium in PD is an area worthy of further study.
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http://dx.doi.org/10.1007/s00415-015-7760-1DOI Listing
November 2015

18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease.

J Nucl Med 2015 Mar 5;56(3):386-91. Epub 2015 Feb 5.

Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, United Kingdom

Unlabelled: Pathologic deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer disease (AD) but not a feature of frontotemporal dementia (FTD). PET ligands for Aβ protein are increasingly used in diagnosis and research of dementia syndromes. Here, we report a PET study using (18)F-florbetapir in healthy controls and patients with AD and FTD.

Methods: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis.

Results: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control.

Conclusion: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.
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http://dx.doi.org/10.2967/jnumed.114.147454DOI Listing
March 2015

Delirium and dementia with Lewy bodies: distinct diagnoses or part of the same spectrum?

J Neurol Neurosurg Psychiatry 2015 Jan 23;86(1):50-9. Epub 2014 May 23.

Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK Department of Psychiatry, University of Cambridge, Cambridgeshire and Peterborough NHS Foundation Trust, Level E4 Cambridge Biomedical Campus, Cambridge, UK.

Dementia with Lewy bodies (DLB) is recognised as the second most common form of dementia in older people. Delirium is a condition of acute brain dysfunction for which a pre-existing diagnosis of dementia is a risk factor. Conversely delirium is associated with an increased risk of developing dementia. The reasons for this bidirectional relationship are not well understood. Our aim was to review possible similarities in the clinical presentation and pathophysiology between delirium and DLB, and explore possible links between these diagnoses. A systematic search using Medline, Embase and Psychinfo was performed. References were scanned for relevant articles, supplemented by articles identified from reference lists and those known to the authors. 94 articles were selected for inclusion in the review. Delirium and DLB share a number of clinical similarities, including global impairment of cognition, fluctuations in attention and perceptual abnormalities. Delirium is a frequent presenting feature of DLB. In terms of pathophysiological mechanisms, cholinergic dysfunction and genetics may provide a common link. Neuroimaging studies suggest a brain vulnerability in delirium which may also occur in dementia. The basal ganglia, which play a key role in DLB, have also been implicated in delirium. The role of Cerebrospinal fluid (CSF) and serum biomarkers for both diagnoses is an interesting area although some results are conflicting and further work in this area is needed. Delirium and DLB share a number of features and we hypothesise that delirium may, in some cases, represent early or 'prodromal' DLB. Further research is needed to test the novel hypothesis that delirium may be an early marker for future DLB, which would aid early diagnosis of DLB and identify those at high risk.
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http://dx.doi.org/10.1136/jnnp-2013-306389DOI Listing
January 2015

Distinct cognitive phenotypes in Alzheimer's disease in older people.

Int Psychogeriatr 2013 Oct 5;25(10):1659-66. Epub 2013 Jul 5.

Department of Older Peoples Medicine, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, High Heaton, Newcastle upon Tyne, UK.

Background: Alzheimer's disease (AD) is considered to be a disorder predominantly affecting memory. It is increasingly recognized that the cognitive profile may be heterogeneous. We hypothesized that it would be possible to define distinct “cognitive phenotypes” in older people with AD.

Methods: Participants from three individual studies were included, consisting of 109 patients with a diagnosis of probable AD, and 91 age- and gender-matched control participants. All had demographic and cognitive assessment data available, including the Cambridge Cognitive Examination of the Elderly (CAMCOG). The CAMCOG scores and sub-scores were further analyzed using hierarchical cluster analysis and factor analysis.

Results: Three clusters were identified. The scores loaded onto three factors representing the domains of attention, praxis, calculation, and perception; memory; and language comprehension and executive function. The main difference between the clusters related to degree of memory impairment. The composite score for memory between the clusters remained significantly different despite adjustment for illness duration and age of onset (p < 0.001).

Conclusions: These data suggest clinical heterogeneity within an older group of people with AD. This may have implications for diagnosis, prognosis, response to currently available treatments, and the development of novel therapies.
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http://dx.doi.org/10.1017/S1041610213000914DOI Listing
October 2013

Alkaline phosphatase is increased in both brain and plasma in Alzheimer's disease.

Neurodegener Dis 2012 20;9(1):31-7. Epub 2011 Oct 20.

Neurodegeneration and Mental Health Research Group, School of Community-Based Medicine, University of Manchester, UK.

Background: Tissue non-specific alkaline phosphatase (TNAP) has been shown to promote the neurotoxicity of extracellular tau which contributes to the spread of pathology in Alzheimer's disease (AD).

Objective: To investigate changes in TNAP activity in the hippocampus in both sporadic and familial AD, and to examine whether changes in neuronal TNAP are reflected systemically by looking at changes in plasma TNAP activity in AD.

Methods: We measured the activity of TNAP in the hippocampus in sporadic AD, familial AD and appropriate age-matched controls, and in an ageing series (age: 25-88 years) of brains. In addition, we measured TNAP activity in plasma from 110 AD and 110 non-demented control participants.

Results: TNAP activity was significantly increased in the hippocampus in sporadic (by 56%; p = 0.038) and familial AD (by 121%; p = 0.042) compared with the age-matched controls. However, there was no correlation of TNAP activity with age. Furthermore, plasma TNAP activity was increased in AD (by 13%; p = 0.018) and inversely correlated with cognitive function (r(s) = -0.211; p = 0.027).

Conclusion: Together, these data indicate that TNAP is increased in both sporadic and familial AD but not in the aged brain, indicating that the increase is likely a consequence of AD-associated changes in the brain. The neuronal change in TNAP is reflected in an increase in plasma TNAP in AD and is inversely correlated with cognitive function.
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http://dx.doi.org/10.1159/000329722DOI Listing
March 2012

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Nat Genet 2011 May 3;43(5):429-35. Epub 2011 Apr 3.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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http://dx.doi.org/10.1038/ng.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084173PMC
May 2011

Cognitive phenotypes in Alzheimer's disease and genetic variants in ACE and IDE.

Neurobiol Aging 2012 Jul 12;33(7):1486.e1-2. Epub 2011 Jan 12.

Cerebral Function Unit, Salford Royal NHS Foundation Trust, Salford, UK.

Alzheimer's disease (AD) is generally considered to be a disorder primarily affecting memory. It is increasingly recognized that the clinical presentation or "cognitive phenotype" is variable. The apolipoprotein E ε4 (APOE ε4) allele has been associated with an amnestic presentation, but does not appear to fully explain the high prevalence of family history within this group. We examined polymorphisms in the genes ACE and IDE in relation to cognitive phenotype. In this study 276 participants with AD were categorized into 1 of 4 cognitive phenotype classifications: typical, amnestic, language, and posterior. Family history and possession of the APOE ε4 allele were most prevalent in the amnestic group. Of the 10 genetic variants of IDE, and the 3 genetic variants of ACE studied, only ACErs4291 and ACErs1800764 were nominally associated with the amnestic presentation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.11.003DOI Listing
July 2012

Plasma angiotensin-converting enzyme in Alzheimer's disease.

J Alzheimers Dis 2009 ;16(3):609-18

Divison of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.

The insertion allele in the gene encoding angiotensin-converting enzyme (ACE) is a risk factor for Alzheimer's disease (AD) and ACE is one of several peptidases that have the ability to degrade the neurotoxic amyloid-beta peptide. ACE is a membrane-bound peptidase that is also present in a soluble form in plasma as a result of a zinc metalloprotease-mediated shedding event. Here we aimed to determine whether there is a difference in ACE in the plasma of late-onset clinically diagnosed AD patients (n = 94) as compared to age-matched non-demented control subjects (n = 188). Plasma ACE was lower in the AD subjects as compared to the controls both at baseline (p = 0.072) and after two years (p = 0.05). There was a greater reduction in plasma ACE in the AD subjects as compared to the control subjects over the two years. Plasma ACE did not correlate with cognitive function. The observed reduction in plasma ACE in AD may reflect a general decrease in the zinc metalloprotease-mediated shedding of a subset of membrane-bound proteins.
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http://dx.doi.org/10.3233/JAD-2009-1002DOI Listing
May 2009

Increased circulating insulin-like growth factor-1 in late-onset Alzheimer's disease.

J Alzheimers Dis 2007 Dec;12(4):285-90

Academic Unit of Molecular Vascular Medicine, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, LS2 9JT, UK.

Background: Insulin-like growth factor (IGF)-1 has been implicated in the pathogenesis of Alzheimer's disease (AD).

Methods: We compared the level of circulating total and bioavailable IGF-1, by simultaneous measurements of IGF-1 and IGF binding protein (IGFBP)-3, between 87 patients diagnosed with AD and 126 age and sex matched control subjects without cognitive impairment. Blood samples were collected and IGF-1 and IGFBP-3 measured by ELISA. Subjects were also genotyped for apolipoprotein E.

Results: Total circulating IGF-1 levels were significantly raised in the AD group as compared to the control group (p=0.022). There was no significant difference in the circulating level of IGFBP-3 between the two groups. When the IGF-1 levels were ratioed against IGFBP-3 levels as an indicator of unbound, bioavailable circulating IGF-1, there was a significant increase in the molar IGF-1:IGFBP-3 ratio in the AD subjects (0.181 +/- 0.006) as compared to the controls (0.156 +/- 0.004) (p< 0.001). Logistic regression analysis revealed that an increase in the IGF-1:IGFBP-3 molar ratio increased the risk of AD significantly.

Conclusion: The results of increased total and free circulating IGF-1 support the hypothesis that in its early stages late-onset AD reflects a state of resistance to IGF-1.
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http://dx.doi.org/10.3233/jad-2007-12401DOI Listing
December 2007

Emerging therapeutics for Alzheimer's disease.

Expert Rev Neurother 2006 May;6(5):695-704

University of Leeds, Academic Unit of Molecular Vascular Medicine, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, Leeds LS2 9JT, UK.

Alzheimer's disease (AD) is the most common form of dementia, with prevalence and the accompanying socioeconomic impact set to increase over the coming decades. Currently available medications result, at best, in modest cognitive improvement. With increasing understanding of the underlying pathology, new therapeutic targets are being identified at an ever-increasing rate. The key pathological events in the AD brain are deposition of insoluble amyloid-beta peptide (Abeta), formation of neurofibrillary tangles and neuroinflammation leading, ultimately, to neuronal cell death. Each of these will be considered, in detail, in terms of the variety of therapeutic approaches currently being investigated and mechanisms that may prove amenable to intervention in the future.
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http://dx.doi.org/10.1586/14737175.6.5.695DOI Listing
May 2006

Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease.

Trends Mol Med 2005 Oct 8;11(10):464-72. Epub 2005 Sep 8.

Academic Unit of Molecular Vascular Medicine, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK.

The accumulation of the amyloid-beta peptide, the main constituent of the "amyloid plaque", is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amyloid precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme alpha-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's disease. A more complex knowledge of these proteases takes us one step closer to developing "disease-modifying" therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimer's disease become a reality.
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http://dx.doi.org/10.1016/j.molmed.2005.08.004DOI Listing
October 2005