Survival time and differences between dementia with Lewy bodies and Alzheimer’s disease following diagnosis: A meta-analysis of longitudinal studies Christoph Mueller1,2*, Pinar Soysal1,3*, Arvid Rongve4,5, Ahmet Turan Isik6, Trevor Thompson7, Stefania Maggi8, Lee Smith9, Cristina Basso10, Robert Stewart1,2, Clive Ballard1,11, John T. O’Brien12, Dag Aarsland1,13, Brendon Stubbs1,2#, Nicola Veronese 8, 10# 1 King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK 2 South London and Maudsley NHS Foundation Trust, London, UK 3Department of Geriatric Medicine, Bezmialem Vakif University, Faculty of Medicine, Istanbul, Turkey 4 University of Bergen, Department of Clinical Medicine, Bergen, Norway 5 Department of research and innovation, Haugesund Hospital, Helse Fonna HF, Haugesund, Norway. 6 Unit for Aging Brain and Dementia, Department of Geriatric Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey. 7 Faculty of Education and Health, University of Greenwich, London, UK. 8 National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy 9 The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom. 10 Azienda Zero, Veneto Region, Venice, Italy 11 University of Exeter Medical School, Exeter, United Kingdom 12 Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK 13 Stavanger University Hospital, Stavanger, Norway * joint first author; # joint senior author Corresponding author: Christoph Mueller, MD; King’s College London, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), De Crespigny Park, London, SE5 8AF, United Kingdom; email: christoph.mueller@kcl.ac.uk; phone: +44 207 848 0626 Declarations of interest: RS has received research funding from Roche, Pfizer, Janssen, Lundbeck and In-Silico-Bioscience. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals and GE Health, and serves as paid consultant for H. Lundbeck and Axovant. CB has received honoraria and grant funding from Acadia pharmaceuticals, Lundbeck, Takeda and Axovant pharmaceutical companies. CB leads the ADP investigators group. Honoraria from Lundbeck, Lilly, Otusaka and Orion pharmaceutical companies. JO’B has acted as a consultant for GE Healthcare, TauRx, Axon, Piramal and Lilly and has received grants from Avid (Lilly). CB has received honoraria and grant funding from Acadia pharmaceuticals Lundbeck, Takeda and Axovant pharmaceutical companies. Honoraria from Lundbeck, Lilly, Otusaka and Orion pharmaceutical companies. Funding: CM, DA and RS receive salary support from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, and RS and JOB are NIHR Senior Investigators. BS is supported by Health Education England and the National Institute for Health Research HEE/NIHR ICA Programme Clinical Lectureship (ICA-CL-2017-03-001). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Abstract (197/200) Objective: To synthesize the evidence across longitudinal studies comparing survival in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Methods: We conducted a systematic review and meta-analysis of studies comparing survival in clinically diagnosed DLB to AD. Longitudinal cohort studies were identified through a systematic search of major electronic databases from inception to May 2018. A random effects meta-analysis was performed to calculate survival time and relative risk of death. Results: Overall, 11 studies were identified including 22,952 patients with dementia: 2,029 with DLB (mean diagnosis age 76.3; 47% female) compared with 20,923 with AD (mean diagnosis age 77.2; 65.1% female). Average survival time in DLB from diagnosis was 4.11 years (SD ±4.10) and in AD 5.66 (SD ±5.32) years, equating to a 1.60 (95% CI: -2.44 to -0.77) years shorter in DLB (p<0.01). Relative risk of death was increased by 1.35 (95%CI: 1.17-1.55) in DLB compared to AD (p<0.01). Differences in survival were not explained by follow-up time, age at diagnosis, gender, or cognitive score. Conclusions: There is consistent evidence for higher and earlier mortality in DLB compared to AD. This is important for all stakeholders and underlines the importance of expanding research into DLB. Key words: Dementia; Lewy bodies; Alzheimer’s disease; mortality Introduction Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia, accounting for up to a quarter of all diagnosed dementia cases (Vann Jones and O'Brien, 2014) and is estimated to be present in 1% of older adults (Ballard et al., 2013). Compared to Alzheimer’s disease (AD), DLB has been reported to have a considerably poorer prognosis and is associated with higher caregiver burden, higher costs of care, as well as increased rates of admission to general hospitals and residential care (Mueller et al., 2017a; Mueller et al., 2018). Survival in DLB has been a matter of considerable clinical and academic debate (Mueller et al., 2017a). Initial post-mortem studies suggested a rapid mortality with survival times of less than two years (McKeith et al., 1992), but a later meta-analysis of neuropathologically confirmed cases of DLB published over 20 years ago suggested a longer mean survival time after diagnosis of 6.1 years (Cercy and Bylsma, 1997). Autopsy studies, which have provided most of the initial evidence, are prone to recruit biased cohorts, as post-mortems are usually carried out in selected samples of younger patients with uncertain diagnoses and atypical features (Walker et al., 2000). The advent of operationalized clinical criteria for DLB diagnosis (McKeith et al., 1996) paved the way for larger scale cohort studies to better understand prognosis and survival. Greater awareness amongst clinicians, further revisions of the diagnostic criteria (McKeith et al., 2017), the inclusion of DLB in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (American Psychiatric Association, 2013), and the increased use of naturalistic data from electronic health records (Price et al., 2017) has led to an expanding number of publications on survival in DLB. The majority of observational studies, but not all, report shorter survival in DLB than AD (Mueller et al., 2017a). However, to the best of our knowledge, no systematic review or meta-analysis has synthesised this growing body of knowledge to describe and compare survival times from diagnosis. Given the importance of understanding the prognosis of the DLB for patients, their families and service planners, we conducted a systematic review and meta-analysis of observational studies to determine survival times from diagnosis and differences between DLB and AD and relative risk of mortality (primary aim) and assessed via meta-regression which factors might account for these differences (secondary aim). Methods This systematic review was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology [STROBE] criteria and the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] statement (Liberati et al., 2009; Wells G et al., 2012). Search strategy Two investigators (PS, NV) independently searched major databases (Pubmed, Medline, Scopus, Embase) without language restrictions, from inception until 01st May 2018. In Pubmed, the following controlled vocabulary terms and keywords were considered: (dementia lewy body or Lewy body OR Lewy bodies OR Lewy OR DLB OR LBD) and (mortality or death or survival). Similar searches were run in the other databases. Any inconsistencies were resolved by consensus with a third Author (CM). The reference lists of the articles included in the analysis were hand-searched to identify additional, potentially relevant publications. Conference abstracts were also considered. Authors were contacted at least two times in 1 month for obtaining additional information if needed. Study selection Two authors selected longitudinal cohort studies that reported survival time from dementia diagnosis (expressed in years) or in equivalents (e.g. months) in studies comparing people with DLB and AD. Inclusion/exclusion criteria We only considered studies that: (1) had a baseline and follow-up evaluation; (2) included patients with DLB, accepting all diagnostic criteria available (3) included a control group having a diagnosis of AD (accepting all diagnostic criteria available) (4) reported data on survival/mortality parameters, expressed in years (from diagnosis of these conditions to death). Studies were excluded if they: (1) did not include patients with DLB; (2) conducted in vitro and on animal models; (3) were conducted in selected samples of autopsy cases; (4) evaluated co-morbid AD pathology in patients with DLB; (5) compared AD to the Lewy body variant of AD, or (6) were reviews, book chapters and single case reports. Data extraction Two authors (PS, NV) independently extracted data from the selected studies in a standardized Microsoft Excel spreadsheet. Any disagreement was resolved with a third author (BS). The following information was extracted: 1) characteristics of the study population (e.g. sample size, demographics, setting, country in which the study was performed); 2) mean age, mean education year, percentage of females and baseline mean mini-mental state examination (MMSE) at the diagnosis; 3) diagnostic criteria of DLB and AD; 4) average age at diagnosis; 5) all data about survival. We planned to extract additional data (e.g. those regarding neuropsychiatric symptoms, disability, average age at the onset of symptoms), but since they were present in less than 4 studies (the minimum for running a meta-regression analysis), we did not include these data. Assessment of study quality Two independent reviewers (PS, NV) assessed the quality of studies, with a third available to resolve any discrepancies (BS). The Newcastle-Ottawa Scale (NOS) was used to assess study quality, which assigns a maximum of 9 points based on three quality parameters: selection, comparability, and outcome (Luchini, 2017; Wells G et al., 2012). Higher scores indicate better methodological quality. Outcomes The primary outcomes were survival data including mean survival time from diagnosis to death in DLB and AD. If expressed in other forms (e.g. median survival time, interquartile range survival time) these estimates were transformed in means and standard deviations (SDs). If the SD was not reported and was not possible to calculate from the data available in the full-text, a pooled SD was calculated, in agreement with the Cochrane guidelines (Higgins and Green, 2008). We further estimated the risk of death during the follow-up period between DLB and AD groups and performed meta-regression analyses to test whether differences in mean age and MMSE at diagnosis, follow-up time and percentage of females explained outcome differences between the studied cohorts. Statistical analysis The meta-analysis was performed using the Comprehensive Meta-Analysis 2.0 (CMA) software. The difference, in mean, of the years survived in DLB group and in the AD group was reported through a mean difference (MD) with the correspondent 95% confidence intervals (CIs). The random effects model was used to account for anticipated between-study heterogeneity (DerSimonian and Laird, 1986). This was assessed using the (DerSimonian and Laird, 1986). This was assessed using the Chi-squared and I-squared statistics, assuming that a p<0.10 for the former and a value ≥50% for the latter were indications of significant heterogeneity (Higgins and Thompson, 2002). For the primary outcome, whenever significant heterogeneit