Changes in the locus coeruleus during the course of Alzheimer's disease and their relationship to cortical pathology.

AIMS: In Alzheimer's disease (AD), the locus coeruleus (LC) undergoes early and extensive neuronal loss, preceded by abnormal intracellular tau aggregation, decades before the onset of clinical disease. Neuromelanin-sensitive MRI has been proposed as a method to image these changes during life. Surprisingly, human post-mortem studies have not examined how changes in LC during the course of the disease relate to cerebral pathology following the loss of the LC projection to the cortex. METHODS: Immunohistochemistry was used to examine markers for 4G8 (pan-Aß) and AT8 (ptau), LC integrity (neuromelanin, dopamine ß-hydroxylase [DßH], tyrosine hydroxylase [TH]) and microglia (Iba1, CD68, HLA-DR) in the LC and related temporal lobe pathology of 59 post-mortem brains grouped by disease severity determined by Braak stage (0-II, III-IV and V-VI). The inflammatory environment was assessed using multiplex assays. RESULTS: Changes in the LC with increasing Braak stage included increased neuronal loss (p < 0.001) and microglial Iba1 (p = 0.005) together with a reduction in neuromelanin (p < 0.001), DßH (p = 0.002) and TH (p = 0.041). Interestingly in LC, increased ptau and loss of neuromelanin were detected from Braak stage III-IV (p = 0.001). At Braak stage V/VI, the inflammatory environment was different in the LC vs TL, highlighting the anatomical heterogeneity of the inflammatory response. CONCLUSIONS: Here, we report the first quantification of neuromelanin during the course of AD and its relationship to AD pathology and neuroinflammation in the TL. Our findings of neuromelanin loss early in AD and before the neuroinflammatory reaction support the use of neuromelanin-MRI as a sensitive technique to identify early changes in AD.

Inflammation in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets.

Prevalence of cognitive impairment in patients with rheumatoid arthritis: a cross sectional study.

OBJECTIVE: To explore the role of chronic inflammation in rheumatoid arthritis (RA) on cognition. METHODS AND ANALYSIS: Six hundred sixty-one men and women aged ≥55 years who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for RA were recruited from three healthcare trusts in the United Kingdom (UK) between May 2018 and March 2020. Study participants took part in interviews which captured sociodemographic information, followed by an assessment of cognition. RA specific clinical characteristics were obtained from hospital medical records. Participants were cognitively assessed using the Montreal Cognitive Assessment (MoCA) and were classified as cognitively impaired if they scored ≤27/30 points. Linear regression analyses were conducted to identify which demographic and clinical variables were potential predictors of cognitive impairment. RESULTS: The average age of participants was 67.6 years and 67% (444/661) were women. 72% (458/634; 95% CI 0.69 to 0.76) of participants were classified as cognitively impaired (MoCA≤27). Greater cognitive impairment was associated with older age (p = .006), being male (p = .041) and higher disease activity score (DAS28) (with moderate (DAS28 > 3.1) (p = 0.008) and high (DAS28 > 5.1) (p = 0.008)) compared to those in remission (DAS28 ≤ 2.6). There was no association between MoCA score and education, disease duration, RF status, anti-cyclic citrullinated peptide (anti-CCP) status, RA medication type or use of glucocorticoids or non-steroidal anti-inflammatory drugs (p > 0.05). CONCLUSION: This study suggests that cognitive impairment is highly prevalent in older adults with RA. This impairment appears to be associated with higher RA disease activity and supports the concept that chronic systemic inflammation might accelerate cognitive decline. This underlines the importance of controlling the inflammatory response.

Peripheral immunophenotype in dementia with Lewy bodies and Alzheimer's disease: an observational clinical study.

BACKGROUND: Inflammation plays a key role in the aetiology and progression of Alzheimer's disease (AD). However, the immunophenotype of the second most common neurodegenerative cause of dementia, dementia with Lewy bodies (DLB), remains unclear. To date there have been no studies examining peripheral inflammation in DLB using multiplex immunoassay and flow cytometry concomitantly. We hypothesised that, using blood biomarkers, DLB would show an increased proinflammatory profile compared with controls, and that there would be a distinct profile compared with AD. METHODS: 93 participants (31 with DLB, 31 with AD and 31 healthy older controls) completed a single study visit for neuropsychiatric testing and phlebotomy. Peripheral blood mononuclear cells were quantified for T and B cell subsets using flow cytometry, and serum cytokine concentrations were measured using multiplex immunoassay. RESULTS: We detected reduced relative numbers of helper T cells and reduced activation of B cells in DLB compared with AD. Additionally, interleukin (IL)-1ß was detected more frequently in DLB and the serum concentration of IL-6 was increased compared with controls. CONCLUSIONS: Peripheral inflammation is altered in DLB compared with AD, with T cell subset analysis supporting a possible shift towards senescence of the adaptive immune system in DLB. Furthermore, there is a proinflammatory signature of serum cytokines in DLB. Identification of this unique peripheral immunophenotype in DLB could guide development of an immune-based biomarker and direct future work exploring potential immune modulation as a novel treatment.

Persistent neuropathological effects 14 years following amyloid-ß immunization in Alzheimer's disease.

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.

Systemic infections and inflammation affect chronic neurodegeneration.

It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.

Peripheral inflammatory cytokines and immune balance in Generalised Anxiety Disorder: Case-controlled study.

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.

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

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.

Targeting innate immunity for neurodegenerative disorders of the central nervous system.

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.

Effect of active Aß immunotherapy on neurons in human Alzheimer's disease.

Amyloid ß peptide (Aß) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aß immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Aß42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aß42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Aß removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aß immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

Common polygenic variation enhances risk prediction for Alzheimer's disease.

The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.

Donepezil and memantine for moderate-to-severe Alzheimer's disease.

BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).

Effect of amyloid-ß (Aß) immunization on hyperphosphorylated tau: a potential role for glycogen synthase kinase (GSK)-3ß.

AIMS: Active amyloid-ß (Aß) immunotherapy in Alzheimer's disease (AD) induces removal of Aß and phosphorylated tau (ptau). Glycogen synthase kinase (GSK)-3ß is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA-dependent protein kinase (pPKR). Using a post-mortem cohort of immunized AD cases, we investigated the effect of Aß immunization on GSK-3ß expression and pPKR. METHODS: We immunostained 11 immunized AD cases and 28 unimmunized AD cases for active, inactive and total GSK-3ß, and for pPKR. Quantification of protein load was performed in the hippocampal region including CA1, subiculum and entorhinal cortex. RESULTS: All three areas showed a significant decrease in the three forms of GSK-3ß (P < 0.05) and a nonsignificant trend towards lower pPKR load in the immunized AD cases compared with the unimmunized AD cases. CONCLUSION: The lower GSK-3ß expression generated by Aß immunotherapy shows evidence of a modification of the signalling pathway induced by GSK-3ß leading to the overall reduction of tau, supporting the contention that in humans, GSK-3ß unifies Aß and tau-related neuropathology.

Aß immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy.

Aß immunotherapy for Alzheimer's disease (AD) results in the removal of Aß plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aß transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aß immunotherapy. 12 Aß42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aß42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aß immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aß42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aß to the cerebral vasculature induced by Aß immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aß. ARIA occurring in some current trials of Aß immunotherapy may reflect an extreme form of these vascular changes.

Inflammatory components in human Alzheimer's disease and after active amyloid-ß42 immunization.

Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-ß immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-ß42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-ß and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-ß42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-ß42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-ß immunization, the microglial functional state is altered in association with reduced amyloid-ß and tau pathology. The results suggest that, in the long term, amyloid-ß immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.

The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug.

Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer's disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = -1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = -0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention.

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial.

BACKGROUND: Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS: To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD: A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS: There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS: In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers.

Male sex hormones and systemic inflammation in Alzheimer disease.

Several studies have shown that the levels of sex hormones in men with Alzheimer disease (AD) differ from men without AD. Therefore, male sex hormones have been postulated as risk modifiers in AD, possibly through immunomodulatory effects on known inflammatory AD risk factors, such as tumor necrosis factor α (TNF-α). We conducted a cross-sectional study of sex hormones and TNF-α levels in 94 community-dwelling men with AD. Comparisons were made with normal values derived from the literature. Men with AD had lower free testosterone levels than non-AD men (1-sample t test: age <80, P=0.0002; age ≥80, P<0.0001), and higher luteinizing hormone (LH) levels (Wilcoxon signed rank test: age <80, P=0.001; age ≥80, P<0.0001). Within the cohort of men with AD, there was a positive correlation between LH and TNF-α (Spearman r=0.25, P=0.019), and this remained significant after correcting for age (partial r=0.21, P=0.05). These data support the hypothesis that sex hormones and the immune system influence each other in AD. Furthermore, modulatory effects between LH and TNF-α may provide a mechanism for an effect of male sex hormones on AD risk.