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1.
Acta Neuropathol Commun ; 7(1): 174, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703599

RESUMO

Microglial function is highly dependent on cell motility, with baseline motility required for homeostatic surveillance activity and directed motility to migrate towards a source of injury. Experimental evidence suggests impaired microglial motility in Alzheimer's disease (AD) and therefore we have investigated whether the expression of proteins associated with motility is altered in AD and affected by the Aß immunotherapy using post-mortem brain tissue of 32 controls, 44 AD cases, and 16 AD cases from our unique group of patients immunised against Aß42 (iAD).Sections of brain were immunolabelled and quantified for (i) the motility-related microglial proteins Iba1, cofilin 1 (CFL1), coronin-1a (CORO1A) and P2RY12, and (ii) pan-Aß, Aß42 and phosphorylated tau (ptau). The neuroinflammatory environment was characterised using Meso Scale Discovery multiplex assays. The expression of all four motility-related proteins was unmodified in AD compared with controls, whereas Iba1 and P2RY12, the homeostatic markers, were increased in the iAD group compared with AD. Iba1 and P2RY12 showed significant positive correlations with Aß in controls but not in the AD or iAD groups. Pro- and anti-inflammatory proteins were increased in AD, whereas immunotherapy appears to result in a slightly less pro-inflammatory environment.Our findings suggest that as Aß appears during the ageing process, the homeostatic Iba1 and P2RY12 -positive microglia respond to Aß, but this response is absent in AD. Aß-immunisation promoted increased Iba1 and P2RY12 expression, likely reflecting increased baseline microglial motility but without restoring the profile observed in controls.

2.
PLoS One ; 14(7): e0218111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31283791

RESUMO

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

3.
Brain ; 142(7): 2113-2126, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31157360

RESUMO

We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-ß immunotherapy for Alzheimer's disease. Twenty-two participants of a clinical trial of active amyloid-ß42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-ß removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer's neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer's disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer's patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (ρ = - 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer's disease actively immunized against amyloid-ß can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer's disease in Alzheimer's therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer's pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.

5.
Transl Psychiatry ; 9(1): 154, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127079

RESUMO

Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer's disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer's Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.

6.
Trials ; 20(1): 191, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944040

RESUMO

BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. DISCUSSION: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01843075 . Registration 30 April 2013.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Atividades Cotidianas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ensaios Clínicos Fase II como Assunto , Cognição/efeitos dos fármacos , Método Duplo-Cego , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Memória/efeitos dos fármacos , Estudos Multicêntricos como Assunto , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Reino Unido
7.
Acta Neuropathol Commun ; 6(1): 88, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30193587

RESUMO

Clinical studies indicate that systemic infections accelerate cognitive decline in Alzheimer's disease. Animal models suggest that this may be due to enhanced pro-inflammatory changes in the brain. We have performed a post-mortem human study to determine whether systemic infection modifies the neuropathology and in particular, neuroinflammation, in the late-stage of the disease.Sections of cerebral cortex and underlying white matter from controls and Alzheimer's patients who died with or without a terminal systemic infection were immunolabelled and quantified for: (i) Αß and phosphorylated-tau; (ii) the inflammation-related proteins Iba1, CD68, HLA-DR, FcγRs (CD64, CD32a, CD32b, CD16), CHIL3L1, IL4R and CCR2; and (iii) T-cell marker CD3. In Alzheimer's disease, the synaptic proteins synaptophysin and PSD-95 were quantified by ELISA, and the inflammatory proteins and mRNAs by MesoScale Discovery Multiplex Assays and qPCR, respectively.Systemic infection in Alzheimer's disease was associated with decreased CD16 (p = 0.027, grey matter) and CD68 (p = 0.015, white matter); increased CD64 (p = 0.017, white matter) as well as increased protein expression of IL6 (p = 0.047) and decreased IL5 (p = 0.007), IL7 (p = 0.002), IL12/IL23p40 (p = 0.001), IL15 (p = 0.008), IL16 (p < 0.001) and IL17A (p < 0.001). Increased expression of anti-inflammatory genes CHI3L1 (p = 0.012) and IL4R (p = 0.004) were detected in this group. T-cell recruitment to the brain was reduced when systemic infection was present. However, exposure to systemic infection did not modify the pathology. In Alzheimer's disease, CD68 (p = 0.026), CD64 (p = 0.002), CHI3L1 (p = 0.016), IL4R (p = 0.005) and CCR2 (p = 0.010) were increased independently of systemic infection.Our findings suggest that systemic infections modify neuroinflammatory processes in Alzheimer's disease. However, rather than promoting pro-inflammatory changes, as observed in experimental models, they seem to promote an anti-inflammatory, potentially immunosuppressive, environment in the human brain.

8.
Alzheimers Res Ther ; 10(1): 73, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30060761

RESUMO

Since the publication of this article [1], it has come to the attention of the authors that information for one of the authors was not included in the competing interests section. Craig Richie has declared potential competing interests with the following companies; Janssen, Eisai, Pfizer, Eli Lilly, Roche Diagnostics, Boeringher Ingleheim, Novartis, AC Immune, Ixico, Aridhia, Amgen, Berry Consultants, Lundbeck, Sanofi, Quintiles (IQVIA) and Takeda. The full competing interests section for this article can be found below.

9.
Autoimmun Rev ; 17(9): 919-925, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30005856

RESUMO

Dementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta-amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Demência/tratamento farmacológico , Inflamação/tratamento farmacológico , Antirreumáticos/farmacologia , Artrite Reumatoide/patologia , Humanos
10.
JAMA Neurol ; 75(9): 1114-1123, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29799984

RESUMO

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were ß-amyloid positive vs those who were ß-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive ß-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

12.
Brain Pathol ; 28(5): 603-610, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29027727

RESUMO

Aß immunization of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aß removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aß immunization, we have assessed the impact of previous Aß immunization on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunized with AN1792 (iAD) and from 27 nonimmunized AD (cAD) cases was immunolabeled for proapoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3ß on tyrosine 216 (GSK3ßtyr216 ), p53 and Cdk5/p35. Expression of these proteins was analyzed in relation to immunization status and other clinical data. The antigen load of all of these proapoptotic proteins was significantly lower in iAD than cAD (P < 0.0001). In cAD, significant correlations (P < 0.001) were observed between: Cdk5/p35 and GSK3ßtyr216 ; a-casp3 and Aß42 ; p53 and age at death. In iAD, significant correlations were found between GSK3ßtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aß42 ; and Cdk5/p35 and Aß-antibody level. Although neuronal loss was increased by immunization with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.

13.
Alzheimers Res Ther ; 9(1): 85, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-29070066

RESUMO

CONTEXT: This commentary discusses the implications of disease-modifying treatments for Alzheimer's disease which seem likely to appear in the next few years and results from a meeting of British experts in neurodegenerative diseases in Edinburgh. The availability of such treatments would help change public and professional attitudes and accelerate engagement with the prodromal and preclinical populations who might benefit from them. However, this would require an updated understanding of Alzheimer's disease, namely the important distinction between Alzheimer's disease and Alzheimer's dementia. CONSENSUS: Since treatments are likely to be most effective in the early stages, identification of clinically relevant brain changes (for example, amyloid burden using imaging or cerebrospinal fluid biomarkers) will be crucial. While current biomarkers could be useful in identifying eligibility for new therapies, trial data are not available to aid decisions about stopping or continuing treatment in clinical practice. Therefore, effective monitoring of safety and effectiveness when these treatments are introduced into clinical practice will be necessary to inform wide-scale use. Equity of access is key but there is a tension between universal access for everyone with a diagnosis of Alzheimer's disease and specifying an eligible population most likely to respond. We propose the resources necessary for an optimal care pathway as well as the necessary education and training for primary and secondary care. CONCLUSION: The majority of current services in the UK and elsewhere would not be able to accommodate the specialist investigations required to select patients and prescribe these therapies. Therefore, a stepped approach would be necessary: from innovating sentinel clinical-academic centres that already have capacity to deliver the necessary phase IV trials, through early adoption in a hub and spoke model, to nationwide adoption for true equity of access. The optimism generated by recent and anticipated developments in the understanding and treatment of Alzheimer's disease presents a great opportunity to innovate and adapt our services to incorporate the next exciting development in the field of dementia.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Pessoal de Saúde/educação , Política de Saúde , Acesso aos Serviços de Saúde , Humanos , Encaminhamento e Consulta , Reino Unido
14.
Health Technol Assess ; 21(26): 1-192, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28625273

RESUMO

BACKGROUND: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. OBJECTIVES: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). DATA SOURCES: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. REVIEW METHODS: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. RESULTS: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. LIMITATIONS: Most of the trials included participants with Alzheimer's disease, so recommendations may not apply to other types of dementia. We did not conduct economic analyses. The PPI consultation was limited to members of the Alzheimer's Society Research Network. CONCLUSIONS: Cognitive outcomes and biological markers form the core outcome set for future disease modification trials, measured by the MMSE or ADAS-Cog, and structural MRI in a subset of participants. FUTURE WORK: We envisage that the core set may be superseded in the future, particularly for other types of dementia. There is a need to develop an algorithm to compare scores on the MMSE and ADAS-Cog. STUDY REGISTRATION: The project was registered with Core Outcome Measures in Effectiveness Trials [ www.comet-initiative.org/studies/details/819?result=true (accessed 7 April 2016)]. The systematic review protocol is registered as PROSPERO CRD42015027346. FUNDING: The National Institute for Health Research Health Technology Assessment programme.


Assuntos
Demência/terapia , Testes de Estado Mental e Demência/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Atividades Cotidianas , Idoso , Doença de Alzheimer/terapia , Biomarcadores , Cuidadores , Conferências de Consenso como Assunto , Progressão da Doença , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Literatura de Revisão como Assunto , Resultado do Tratamento
15.
PLoS One ; 12(6): e0179521, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28662127

RESUMO

BACKGROUND: There are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia. METHODS AND FINDINGS: We defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer's disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer's society focus groups. Attendees at a consensus conference (experts in dementia research, disease-modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification. LIMITATIONS: Most trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties. INTERPRETATION: This is the first review to identify the 81 outcome measures the research community uses for disease-modifying trials in mild-to-moderate dementia. Our recommendations will facilitate designing, comparing and meta-analysing disease modification trials in mild-to-moderate dementia, increasing their value. TRIAL REGISTRATION: PROSPERO no. CRD42015027346.


Assuntos
Demência/patologia , Progressão da Doença , Grupos Focais , Humanos , Avaliação de Resultados (Cuidados de Saúde)
16.
Brain Behav Immun ; 62: 212-218, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28161475

RESUMO

INTRODUCTION: Previous investigations have demonstrated that major depression is associated with particular patterns of cytokine signalling. The primary aim of this study was to examine peripheral pro-inflammatory and anti-inflammatory cytokines and immune balance in Generalised Anxiety Disorder (GAD). METHODS: A case-controlled cross-sectional study design was employed: 54 patients with GAD and 64 healthy controls were recruited. Participants completed self-report measures of anxiety and depression. Two pro-inflammatory and two anti-inflammatory cytokines were measured using multiplex technology. RESULTS: Case-control logistic regression analyses revealed significant differences in serum levels of IL-10, TNF-α, and IFN-γ between GAD and control groups after adjusting for age, gender, body mass index, smoking and alcohol consumption: these group differences were independent of the presence or degree of depression. Comparison of pro-inflammatory to anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF-α/IL10, TNF-α/IL4, IFN-γ/IL10, and IFN-γ/IL4 in the GAD group compared to the control group. CONCLUSIONS: This study is the first to investigate both pro- and anti-inflammatory cytokines and their balance in patients with GAD in comparison to healthy controls. The findings indicate a relatively increased pro-inflammatory response and decreased anti-inflammatory response and provide the first demonstration of an altered cytokine balance in GAD. Serum cytokine levels in GAD were independent of the presence of depression.


Assuntos
Transtornos de Ansiedade/sangue , Citocinas/sangue , Mediadores da Inflamação/sangue , Adolescente , Adulto , Idoso , Ansiedade/sangue , Estudos de Casos e Controles , Estudos Transversais , Depressão/sangue , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Autorrelato , Adulto Jovem
17.
J Psychopharmacol ; 31(2): 147-168, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28103749

RESUMO

The British Association for Psychopharmacology coordinated a meeting of experts to review and revise its previous 2011 guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A-D, with A having the strongest evidence base (from randomised controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and both structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography and single photon emission computerised tomography) brain imaging can improve diagnostic accuracy in particular situations (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for cognition in mild to moderate Alzheimer's disease (A), memantine for moderate to severe Alzheimer's disease (A) and combination therapy (cholinesterase inhibitors and memantine) may be beneficial (B). Drugs should not be stopped just because dementia severity increases (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E, nutritional supplements and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (both Parkinson's disease dementia and dementia with Lewy bodies), and memantine may be helpful (A). No drugs are clearly effective in vascular dementia, though cholinesterase inhibitors are beneficial in mixed dementia (B). Early evidence suggests multifactorial interventions may have potential to prevent or delay the onset of dementia (B). Though the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition in those with or at high risk of Alzheimer's disease are in progress. Though results of pivotal studies in early (prodromal/mild) Alzheimer's disease are awaited, results to date in more established (mild to moderate) Alzheimer's disease have been equivocal and no disease modifying agents are either licensed or can be currently recommended for clinical use.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Demência/tratamento farmacológico , Memantina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Terapia Combinada/métodos , Demência/diagnóstico , Humanos , Psicofarmacologia/métodos
18.
Int J Geriatr Psychiatry ; 32(12): 1205-1216, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-27739182

RESUMO

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Indanos/uso terapêutico , Memantina/uso terapêutico , Piperidinas/uso terapêutico , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/economia , Inibidores da Colinesterase/economia , Cognição , Análise Custo-Benefício , Donepezila , Método Duplo-Cego , Inglaterra , Feminino , Custos de Cuidados de Saúde , Humanos , Indanos/economia , Memantina/economia , Piperidinas/economia , Qualidade de Vida , País de Gales
19.
Trials ; 17(1): 324, 2016 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-27430267

RESUMO

BACKGROUND: Vascular dementia is the second most common cause of dementia affecting over seven million people worldwide, yet there are no licensed treatments. There is an urgent need for a clinical trial in this patient group. Subcortical ischaemic vascular dementia is the most common variant of vascular dementia. This randomised trial will investigate whether use of calcium channel blockade with amlodipine, a commonly used agent, can provide the first evidence-based pharmacological treatment for subcortical ischaemic vascular dementia. METHODS/DESIGN: This is a randomised controlled trial of calcium channel blockade with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT) to test the hypothesis that treatment with amlodipine can improve outcomes for these patients in a phase IIb, multi-centre, double-blind, placebo-controlled randomised trial. The primary outcome is the change from baseline to 12 months in the Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog). Secondary outcomes include cognitive function, executive function, clinical global impression of change, change in blood pressure, quantitative evaluation of lesion accrual based on magnetic resonance imaging (MRI), health-related quality of life, activities of daily living, non-cognitive dementia symptoms, care-giver burden and care-giver health-related quality of life, cost-effectiveness and institutionalisation. A total of 588 patients will be randomised in a 1:1 ratio to either amlodipine or placebo, recruited from sites across the UK and enrolled in the trial for 104 weeks. DISCUSSION: There are no treatments licensed for vascular dementia. The most common subtype is subcortical ischaemic vascular dementia (SIVD). This study is designed to investigate whether amlodipine can produce benefits compared to placebo in established SIVD. It is estimated that the numbers of people with VaD and SIVD will increase globally in the future and the results of this study should inform important treatment decisions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31208535 . Registered on 7 March 2014.


Assuntos
Anlodipino/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Demência Vascular/tratamento farmacológico , Atividades Cotidianas , Anlodipino/efeitos adversos , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/psicologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Protocolos Clínicos , Cognição/efeitos dos fármacos , Demência Vascular/diagnóstico , Demência Vascular/fisiopatologia , Demência Vascular/psicologia , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Qualidade de Vida , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , Reino Unido
20.
J Neurochem ; 138(5): 653-93, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27248001

RESUMO

Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article.


Assuntos
Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Imunidade Inata/imunologia , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Sistema Nervoso Central/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Neurodegenerativas/imunologia
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