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1.  Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer’s disease 
Journal of neurology  2009;256(5):717-720.
Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer’s disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of Aβ and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on Aβ and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared Aβ and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). Aβ accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs.
doi:10.1007/s00415-009-5000-2
PMCID: PMC4120887  PMID: 19240967
Alzheimer’s disease; Cholinesterase inhibitors; Amyloid; Tau; Neuropathology
2.  EXPLORATORY ANALYSIS OF SEVEN ALZHEIMER’S DISEASE GENES: DISEASE PROGRESSION 
Neurobiology of aging  2012;34(4):1310.e1-1310.e7.
The relationships between GWAS-identified and replicated genetic variants associated to Alzheimer’s disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. 701 AD patients with at least three different cognitive evaluations and genotypic information for APOE and six GWAS-significant SNPs were selected for this study. Mean differences in GDS and MMSE were evaluated using non-parametric tests, GLM and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor (AChEI), memantine or both. Relationships between therapeutic protocols, genetic markers and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared to GG carriers at the end of the follow up (MMSE mean difference= −0.57 C.I.95%[−1.145−0.009], p=0.047). This observations remained unaltered after covariate adjustments although did not achieve predefined multiple testing significance threshold. PICALM SNP also displayed a significant effect protecting against rapid progression during pharmacogenetics assays although it observed effect displayed heterogeneity among AD therapeutic protocols (p=0.039). None of studied genetic markers was convincingly linked to AD progression or drug response. However, by using different statistical approaches, PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.
doi:10.1016/j.neurobiolaging.2012.08.014
PMCID: PMC4097044  PMID: 23036585
3.  Improving Well-being and Health for People with Dementia (WHELD): study protocol for a randomised controlled trial 
Trials  2014;15:284.
Background
People with dementia living in care homes often have complex mental health problems, disabilities and social needs. Providing more comprehensive training for staff working in care home environments is a high national priority. It is important that this training is evidence based and delivers improvement for people with dementia residing in these environments. Well-being and Health for People with Dementia (WHELD) combines the most effective elements of existing approaches to develop a comprehensive but practical staff training intervention. This optimised intervention is based on a factorial study and qualitative evaluation, to combine: training on person-centred care, promoting person-centred activities and interactions, and providing care home staff and general practitioners with updated knowledge regarding the optimal use of psychotropic medications for persons with dementia in care homes.
Design
The trial will be a randomised controlled two-arm cluster single blind trial that will take place for nine months across 80 care homes in the United Kingdom.
Discussion
The overarching goal of this trial is to determine whether this optimised WHELD intervention is more effective in improving the quality of life and mental health than the usual care provided to people with dementia living in nursing homes. This study will be the largest and best powered randomised controlled trial (RCT) evaluating the benefits of an augmented person-centred care training intervention in care homes worldwide.
Trial registration
Current controlled trials ISRCTN62237498
Date registered: 5 September 2013
doi:10.1186/1745-6215-15-284
PMCID: PMC4227075  PMID: 25016303
Dementia care homes; Quality of life; Antipsychotic medication; Behavioural symptoms; Cost effectiveness; Implementation; Person-centred care; Social interaction
4.  Treatment effect of memantine on survival in dementia with Lewy bodies and Parkinson's disease with dementia: a prospective study 
BMJ Open  2014;4(7):e005158.
Objective
To investigate the effect on survival of treatment with memantine in patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD).
Methods
75 patients with DLB and PDD were included in a prospective double-blinded randomised placebo-controlled trial (RCT) of memantine, of whom long-term follow-up was available for 42. Treatment response was recorded 24 weeks from baseline and measured by Clinical Global Impression of Change (CGIC). The participants were grouped as responders (CGIC 1–3) or non-responders (CGIC 4–7). The 24-week RCT was followed by open-label treatment and survival was recorded at 36 months.
Results
After 36-month follow-up, patients in the memantine group had a longer length of survival compared with patients in the placebo group (log rank x²=4.02, p=0.045). Within the active treatment group, survival analysis 36 months from baseline showed that the memantine responders, based on CGIC, had higher rates of survival compared with the non-responders (log rank x²=6.595, p=0.010). Similar results were not seen in the placebo group.
Conclusions
Early treatment with memantine and a positive clinical response to memantine predicted longer survival in patients with DLB and PDD. This suggests a possible disease-modifying effect and also has implications for health economic analysis. However, owing to the small study sample, our results should merely be considered as generating a hypothesis which needs to be evaluated in larger studies.
Trial registration number
ISRCTN89624516.
doi:10.1136/bmjopen-2014-005158
PMCID: PMC4091277  PMID: 24993765
5.  Neurogenic abnormalities in Alzheimer’s disease differ between stages of neurogenesis and are partly related to cholinergic pathology 
Neurobiology of disease  2012;47(2):155-162.
Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer’s disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology. We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and β-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density.
In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and β-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. Of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers.
Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental influence on neurogenesis. We conclude that neurogenic abnormalities in AD differ between phases and areas of neurogenesis and stages of AD; while hippocampal stem cells (Musashi-1) decrease, proliferation (nestin) increases and differentiation/migration phase as well as axonal/dendritic targeting (doublecortin and β-III-tubulin) remains virtually unchanged. This suggests an attenuation of stem cells together with compensatory increased proliferation that, however, does not result in an increased number of migratory neuroblasts and differentiated neurons in AD.
doi:10.1016/j.nbd.2012.03.033
PMCID: PMC4075422  PMID: 22504537
Alzheimer’s disease; Neurogenesis; Musashi-1; Cholinergic pathology; Nestin
6.  Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome☆ 
Neurobiology of Aging  2014;35(6):1513.e1-1513.e5.
It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.
doi:10.1016/j.neurobiolaging.2013.12.022
PMCID: PMC3969241  PMID: 24462566
Down syndrome; BACE2; Alzheimer's disease; rs2252576
7.  Dynamin1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia 
F1000Research  2014;3:108.
Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer’s disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies).
Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.
doi:10.12688/f1000research.3786.1
PMCID: PMC4309165
Alzheimer’s disease; Dementia with Lewy bodies; Parkinson’s disease with dementia; synaptic dysfunction; vesicle recycling; synaptic plasticity; beta amyloid; tau; cognitive impairment
8.  Prevention of Decline in Cognition after Stroke Trial (PODCAST): a study protocol for a factorial randomised controlled trial of intensive versus guideline lowering of blood pressure and lipids 
Trials  2013;14:401.
Background
Stroke is a common cause of cognitive impairment and dementia. However, effective strategies for reducing the risk of post-stroke dementia remain undefined. Potential strategies include intensive lowering of blood pressure and/or lipids.
Methods/Design
Design: multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial phase IV trial in secondary and primary care.
Participants: 100 participants from 30 UK Stroke Research Network sites who are post- ischemic stroke or intracerebral haemorrhage by three to seven months.
Interventions - all patients (1:1): intensive versus guideline blood pressure lowering (target systolic < 125 mmHg versus < 140 mmHg).
Interventions - ischemic stroke (1:1): intensive versus guideline lipid lowering (target low density lipoprotein-cholesterol (LDL-c) < 1.4 mmol/l versus < 3 mmol/l).
Hypotheses: does ‘intensive’ blood pressure lowering therapy and/or ‘intensive’ lipid control reduce cognitive decline and dementia in people with ischemic stroke; and does ‘intensive’ blood pressure lowering therapy reduce cognitive decline and dementia in patients with hemorrhagic stroke.
Primary outcome: Addenbrooke’s Cognitive Examination-Revised.
Secondary outcomes: feasibility of recruitment and retention of participants, tolerability and safety of the interventions, achieving and maintaining the blood pressure and lipid targets, maintaining differences in systolic blood pressure (> 10 mmHg) and low density lipoprotein-cholesterol (> 1 mmol/l) between the treatment groups, and performing clinic and telephone follow-up of cognition measures.
Randomisation: using stratification, minimization and simple randomization.
Blinding: participants receive open-label management. Cognition is assessed both unblinded (in clinic) and blinded (by telephone) to treatment. Adjudication of events (dementia, vascular, serious adverse events) is blinded to management.
Discussion
The PODCAST trial is ongoing with 78 patients recruited to date from 22 sites. Outcomes of cognitive impairment and dementia are accruing.
Trial registration
ISRCTN85562386
doi:10.1186/1745-6215-14-401
PMCID: PMC4222827  PMID: 24266960
Stroke; Post-stroke cognitive impairment; Post-stroke dementia; Blood pressure lowering; Lipid lowering
9.  Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease 
Pharmaceuticals  2013;6(10):1304-1321.
Alzheimer’s Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.
doi:10.3390/ph6101304
PMCID: PMC3817602  PMID: 24275851
Alzheimer’s; repositioning; treatment; drug
10.  Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome 
Neurobiology of Aging  2013;34(10):2441.e1-2441.e5.
It is known that individuals with Down syndrome develop Alzheimer’s disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer’s disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer’s disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer’s disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer’s disease in Down syndrome.
doi:10.1016/j.neurobiolaging.2013.03.018
PMCID: PMC3898582  PMID: 23601808
Genome-wide association study; Down syndrome; Alzheimer’s disease; PICALM; APOE
12.  Feasibility study of an optimised person-centred intervention to improve mental health and reduce antipsychotics amongst people with dementia in care homes: study protocol for a randomised controlled trial 
Trials  2013;14:13.
Background
People living in care homes often have complex mental and physical health problems, disabilities and social needs which are compounded by the use of psychiatric and other drugs. In the UK dementia care is a national priority with a vast impact on services. WHELD combines the most effective elements of existing approaches to develop a comprehensive but practical intervention. This will be achieved by training care staff to provide care that is focused on an understanding of the individual and their needs; and by using additional components such as exercise, activities and social interaction to improve mental health and quality of life (QoL) and reduce the use of sedative drugs.
Design
Work Package 3 (WP3) is the pilot randomised trial and qualitative evaluation to help develop a future definitive randomised controlled clinical trial. The study design is a cluster randomised 2x2x2 factorial design with two replications in 16 care homes. Each care home is randomized to receive one of the eight possible permutations of the four key interventions, with each possible combination delivered in two of the 16 homes. Each cluster includes a minimum of 12 participants (depending upon size of the care home, the number of people with dementia and the number consenting).
Discussion
The overarching goal of the programme is to provide an effective, simple and practical intervention which improves the mental health of, and reduces sedative drug use in, people with dementia in care homes and which can be implemented nationally in all UK care homes as an NHS intervention.
Trial Registration
Current controlled trials ISRCTN40313497
doi:10.1186/1745-6215-14-13
PMCID: PMC3617007  PMID: 23305152
Dementia; Care homes; Quality of life; Antipsychotic medication; Behavioural symptoms; Cost-effectiveness; Implementation; Person-centred care; Exercise; Social interaction
14.  Optimised Anaesthesia to Reduce Post Operative Cognitive Decline (POCD) in Older Patients Undergoing Elective Surgery, a Randomised Controlled Trial 
PLoS ONE  2012;7(6):e37410.
Background
The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery.
Methods and Trial Design
The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery.
Results
In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ2 = 17.9 p<0.0001), moderate (χ2 = 7.8 p = 0.005) and severe (χ2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, χ2 = 5.1 p = 0.02 and χ2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ2 = 4.4 p = 0·037 and χ2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z =  −2.1 p = 0.03, MWU Z = −2.7 p = 0.004, MWU Z = −3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = −2.9 p = 0.003, MWU Z = −3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = −2.4 p = .0.018, MWU Z = −2.4 p = 0.019).
Conclusion
POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment.
Trial Registration
Controlled-Trials.com ISRCTN39503939
doi:10.1371/journal.pone.0037410
PMCID: PMC3376123  PMID: 22719840
15.  Efficacy of Memantine for Agitation in Alzheimer’s Dementia: A Randomised Double-Blind Placebo Controlled Trial 
PLoS ONE  2012;7(5):e35185.
Background
Agitation in Alzheimer’s disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD.
Methods and Findings
We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower −3.0; −8.3 to 2.2, p = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (−6.9; −12.2 to −1.6; p = 0.012) and 12 (−9.6; −15.0 to −4.3 p = 0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD.
Conclusions
Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms.
Trial Registration
ClinicalTrials.gov NCT00371059
Trial Registration
International Standard Randomised Controlled Trial 24953404
doi:10.1371/journal.pone.0035185
PMCID: PMC3342281  PMID: 22567095
16.  Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates 
We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.
doi:10.4061/2011/495025
PMCID: PMC3182340  PMID: 21966597
17.  Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial 
Objective To determine whether a systematic approach to the treatment of pain can reduce agitation in people with moderate to severe dementia living in nursing homes.
Design Cluster randomised controlled trial.
Setting 60 clusters (single independent nursing home units) in 18 nursing homes within five municipalities of western Norway.
Participants 352 residents with moderate to severe dementia and clinically significant behavioural disturbances randomised to a stepwise protocol for the treatment of pain for eight weeks with additional follow-up four weeks after the end of treatment (33 clusters; n=175) or to usual treatment (control, 27 clusters; n=177).
Intervention Participants in the intervention group received individual daily treatment of pain for eight weeks according to the stepwise protocol, with paracetamol (acetaminophen), morphine, buprenorphine transdermal patch, or pregabaline. The control group received usual treatment and care.
Main outcome measures Primary outcome measure was agitation (scores on Cohen-Mansfield agitation inventory). Secondary outcome measures were aggression (scores on neuropsychiatric inventory-nursing home version), pain (scores on mobilisation-observation-behaviour-intensity-dementia-2), activities of daily living, and cognition (mini-mental state examination).
Results Agitation was significantly reduced in the intervention group compared with control group after eight weeks (repeated measures analysis of covariance adjusting for baseline score, P<0.001): the average reduction in scores for agitation was 17% (treatment effect estimate −7.0, 95% confidence interval −3.7 to −10.3). Treatment of pain was also significantly beneficial for the overall severity of neuropsychiatric symptoms (−9.0, −5.5 to −12.6) and pain (−1.3, −0.8 to −1.7), but the groups did not differ significantly for activities of daily living or cognition.
Conclusion A systematic approach to the management of pain significantly reduced agitation in residents of nursing homes with moderate to severe dementia. Effective management of pain can play an important part in the treatment of agitation and could reduce the number of unnecessary prescriptions for psychotropic drugs in this population.
Trial registration ClinicalTrials.gov NCT01021696 and Norwegian Medicines Agency EudraCTnr 2008-007490-20.
doi:10.1136/bmj.d4065
PMCID: PMC3137923  PMID: 21765198
18.  Identification of Novel α-Synuclein Isoforms in Human Brain Tissue by using an Online NanoLC-ESI-FTICR-MS Method 
Neurochemical Research  2011;36(11):2029-2042.
Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn1–140) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn1–139 and Ac-α-syn1–103) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA).
doi:10.1007/s11064-011-0527-x
PMCID: PMC3183298  PMID: 21674238
Cerebrospinal fluid; Immunoprecipitation; Neurodegenerative diseases; Mass spectrometry; Synuclein
19.  An Intron 7 Polymorphism in APP Affects the Age of Onset of Dementia in Down Syndrome 
People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt5−8, in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt5−8 and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD.
doi:10.4061/2011/929102
PMCID: PMC3010675  PMID: 21197396
20.  Putting brain training to the test 
Nature  2010;465(7299):775-778.
‘Brain training’, or the quest for improved cognitive function through the regular use of computerised tests, is a multimillion pound industry1, yet scientific evidence to support its efficacy is lacking. Modest effects have been reported in some studies of older individuals2,3 and preschool children4, and video gamers out perform non-gamers on some tests of visual attention5. However, the widely held belief that commercially available computerised brain trainers improve general cognitive function in the wider population lacks empirical support. The central question is not whether performance on cognitive tests can be improved by training, but rather, whether those benefits transfer to other untrained tasks or lead to any general improvement in the level of cognitive functioning. Here we report the results of a six-week online study in which 11,430 participants trained several times each week on cognitive tasks designed to improve reasoning, memory, planning, visuospatial skills and attention. Although improvements were observed in every one of the cognitive tasks that were trained, no evidence was found for transfer effects to untrained tasks, even when those tasks were cognitively closely related.
doi:10.1038/nature09042
PMCID: PMC2884087  PMID: 20407435
21.  Parkinson's disease with dementia: comparing patients with and without Alzheimer pathology 
Subjects with Parkinson's disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer's disease (AD). The objective is to identify clinical and neuropathological differences between PDD (PD with dementia) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD-AD (N = 23) and PDD+AD (N = 28). A small subset of subjects with PDD-AD and PDD+AD had received at least one standardized neuropsychological assessment. PDD+AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms prior to the onset of dementia. Education, responsiveness of L-Dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, mean MMSE, GDS, FAST and UPDRS scores did not differ significantly between the two groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared to PDD-AD. This study suggests that it is difficult to distinguish PDD+AD and PDD-AD on the basis of movement, clinical, and neuropsychological assessment. PDD-AD and PDD+AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathological diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology.
doi:10.1097/WAD.0b013e31819c5ef4
PMCID: PMC2760034  PMID: 19812474
Parkinson' disease with dementia; Alzheimer's Disease; Dementia with Lewy Bodies; assessment of dementia
22.  DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease – a multicentre RCT 
Trials  2009;10:57.
Background
Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.
Method
DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization.
Discussion
There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point.
Trial registration
Current controlled trials ISRCTN49545035
doi:10.1186/1745-6215-10-57
PMCID: PMC2723100  PMID: 19630974
23.  Incidence and Prediction of Falls in Dementia: A Prospective Study in Older People 
PLoS ONE  2009;4(5):e5521.
Background
Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia.
Methods and Findings
179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer's disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson's disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11–18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11–5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52–4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19–3.80), autonomic symptom score (HR per point 0–36: 1.055, 1.012–1.099), and Cornell depression score (HR per point 0–40: 1.053, 1.01–1.099). Higher levels of physical activity were protective (HR per point 0–9: 0.827, 0.716–0.956).
Conclusions
The management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority.
doi:10.1371/journal.pone.0005521
PMCID: PMC2677107  PMID: 19436724
24.  A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)  
PLoS Medicine  2008;5(4):e76.
Background
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.
Methods and Findings
Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.
Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.
Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.
Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.
Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).
Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.
Conclusions
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.
Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).
In a randomized trial of patients with dementia, Clive Ballard and colleagues show that withdrawal of neuroleptics had no overall detrimental effect, and by some measures improved, functional and cognitive status.
Editors' Summary
Background
The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer's Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.
Why Was the Study Done?
Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.
What Did the Researchers Do and Find?
The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients' cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.
At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.
What Do these Findings Mean?
The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050076.
Alzheimer's Disease International is an umbrella organisation of organisations worldwide
The Alzheimer's Research Trust in the UK is a charity funding research to cure or prevent dementias
The US National Institutes of Aging has information on Alzheimer Disease in English and Spanish
Two governmental regulatory agencies—the Medicines and Healthcare Products Regulatory Agency in the UK and the Food and Drug Administration in the US—offer information about antipsychotics in people with dementia
doi:10.1371/journal.pmed.0050076
PMCID: PMC2276521  PMID: 18384230

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