bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reducing the sample size in high‐frequency biomarkers RCTs
Authors: Taylor‐Rodriguez Daniel M , Lovitz David M , Mattek Nora , Wu Chao‐Yi , Kaye Jeffrey , Dodge Hiroko H , Jedynak Bruno Michel ,   ORCATECH
Published: December 2020

AbstractBackgroundHigh‐frequency biomarkers (HFB) are measurements collected weekly, on a daily basis or even more frequently. They are designed to detect early progression from one cognitive state to a later stage. Examples include home‐based measurements, e.g., computer usage and sleep patterns. In randomized controlled trials (RCT), we aim to detect the difference in trajectories of HFB between placebo and experimental group. Current statistical analysis e.g. linear mixed effect with random intercept models detect changes in the mean trajectory but fail to detect changes in the covariance structure, thus requiring longer trials. We examined whether more careful modeling, using historical data, would reduce the sample size needed for a RCT? Objective: (1) to present a novel statistical methodology for analyzing RCTs whose outcomes are HFB based on historical data of cognitively normal subjects, and (2) to evaluate this methodology using simulated data first, then using data from the Oregon Center for Aging and Technology (ORCATECH).MethodsThe statistical methodology proposed proceeds in three phases (Figure 1). Highlights include the use of historical data for cognitively normal subjects and the use of a Gaussian process with parameterized mean function and covariance structure. Examples of results from simulated data are shown in Figure 2, demonstrating the superior power of the methodology compared to the linear mixed‐effects model. ORCATECH’s weekly computer usage data was used (Figure 3). We computed an RCT effect size with 86 cognitively normal subjects and 11 subjects who were cognitively normal at baseline, but would eventually develop MCI within 139 weeks on average (sd=72).ResultsUsing this new approach, we found an effect size of W=0.616 (Area Under the curve), outperforming a baseline method which yielded an effect size of W=0.515. Respective total sample sizes for an RCT with alpha=0.05 and power=0.8 are 74 and 1028, for the new versus the conventional approach, respectively.ConclusionsWe have shown that a careful statistical procedure allows for maximally benefiting from HFB by reducing the sample size needed for a 100 week RCT. More experiments will be necessary to validate these findings.
Angiotensin receptor blockers versus angiotensin‐converting enzyme inhibitors: Longitudinal associations with PET amyloid in the Alzheimer's Disease Neuroimaging Initiative
Authors: Ouk Michael , Wu Che‐Yuan , Rabin Jennifer S. , Edwards Jodi D. , Ramirez Joel , Masellis Mario , Swartz Richard H. , Herrmann Nathan , Lanctot Krista L. , Black Sandra E. , Swardfager Walter 
Published: December 2020

AbstractBackgroundEvidence suggests that Angiotensin II type‐1 Receptor Blockers (ARBs) and Angiotensin‐Converting Enzyme Inhibitors (ACE‐Is) may be differentially beneficial for cognition, but there is little clinical evidence supporting possible mechanisms. This study examines longitudinal associations between the use of ARBs and ACE‐Is with summary cortical and subregional brain amyloid‐β (Aβ).MethodThis study included participants with hypertension who were using an ACE‐I or ARB with available PET data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1, GO, and 2 databases (years 2010‐2018). Analyses were conducted in subgroups with normal cognition (NC) and with cognitive impairment (amnestic mild cognitive impairment or Alzheimer’s disease [AD/MCI]). The outcome was PET Aβ SUVR in a cortical summary region and subregions involved in early/late stages of Aβ accumulation. Linear mixed‐effects models with inverse probability of treatment weighting were used to compare rates of Aβ accumulation over 48 months between ARB and ACE‐I users. Models were adjusted for demographics, ApoE ε4 status, baseline MMSE, relevant comorbidities, and other concurrent antihypertensive use.ResultIn the NC group (n=124, age=74.8±5.6, 46.3% women), ARB vs. ACE‐I use was associated with a slower rate of Aβ accumulation in the cortex (β=‐0.138 [‐0.062, ‐0.223]), the inferior temporal lobe (β=‐0.165 [‐0.076, ‐0.255]), and precuneus (β=‐0.164 [‐0.075, ‐0.252]). In people with AD/MCI (n=246, age=74.5±7.3, 39.1% women), users of an ARB vs. an ACE‐I did not differ in the rate of Aβ accumulation in the cortex (β=0.019 [‐0.038, 0.075]), in the above regions (inferior temporal lobe β=‐0.027 [‐0.102, 0.048]; precuneus β=0.008 [‐0.051, 0.067]), or in areas associated with later Aβ accumulation (parietal lobes β=0.035 [‐0.027, 0.097]; frontal lobes β=0.014 [‐0.053, 0.081]).ConclusionIn cognitively‐normal adults, ARB use was associated with a significantly slower rate of Aβ accumulation. This difference may be partially explained by preservation of Aβ‐clearing effects of the angiotensin‐converting enzyme by ARBs. In contrast, there were no significant differences in AD/MCI which could reflect both plateau effects, less impact on more advanced stages, or a relatively small sample size. Prospective analyses and clinical trial evidence are warranted to confirm the potential benefit of ARB use to slow Aβ accumulation and prevent cognitive impairment.
Detecting seizure patterns in patients with Alzheimer’s disease using long‐term EEG monitoring: A feasibility study
Authors: Musaeus Christian Sandøe , Waldemar Gunhild , Larsson Henrik Bo Wiberg , Andersen Birgitte Bo , Høgh Peter , Kidmose Preben , Hasselbalch Steen Gregers , Fabricius Martin , Tøpholm Richard , Rank Mike Lind , Kjær Troels Wesenberg , Frederiksen Kristian Steen 
Published: December 2020

AbstractBackgroundSeizure patterns as detected with electroencephalography (EEG) has been suggested to be frequent in patients with Alzheimer’s disease. However, long‐term EEG monitoring to detect seizure patterns requires hospitalization for longer periods of time, which is both expensive and difficult for patients with Alzheimer’s disease.In the current feasibility study, we investigated whether it was possible for patients with Alzheimer’s disease to wear ear‐EEG for long‐term EEG monitoring of seizure patterns at home.MethodWe recruited patients who met the criteria for Alzheimer’s disease and had no previous history of epilepsy. Seizure patterns was assessed using long‐term EEG monitoring with ear‐EEG for 48 hours every three months for half a year. Furthermore, patients and relatives were instructed in the use of a seizure diary, which was used during the ear‐EEG recordings.ResultSo far, we have recruited 9 patients with Alzheimer’s disease, and all patients who underwent ear‐EEG monitoring have been able to wear the ear‐EEG for at least 24 hours including sleep. We are currently in the process of investigating whether the patients with Alzheimer’s disease show seizure patterns as measured with ear‐EEG.ConclusionLong‐term EEG monitoring using ear‐EEG seems to be feasible for measuring seizure patterns in patients with Alzheimer’s disease. If any of the patients show seizure patterns using ear‐EEG, we will be able to treat with anti‐epileptic medication, which may improve their symptoms.
Properties of TCR gamma clonotypes in AD brain and peripheral blood
Authors: Aliseychik Maria P. , Patrikeev Anton , Gusev Fedor , Grigorenko Anastasia , Andreeva Tatiana , Biragyn Arya , Rogaev Evgeny I. 
Published: December 2020

AbstractBackgroundThe immune system contributes to various neurodegenerative pathologies, including Alzheimer’s disease (AD). γδ T cells can mediate different pathological processes in the human brain, such as oncogenesis, autoimmunity, and stroke. However, the role of γδ T cells in AD have not yet been elucidated.MethodWe designed an approach based on multiplex PCR system with following library preparation and deep sequencing of the CDR3 region of TRGs. In total clonotype repertoires from 147 peripheral blood and postmortem brain samples of AD patients and control individuals without dementia were analyzed. Moreover 17 blood repertoires of patients with Parkinson’s disease (PD) were also tested.ResultOur results showed special features of peripheral blood (PB) and brain TRG repertoires: compared with the PB, the brain showed reduced TRGV9 clonotypes but was enriched in TRGV2/4/8 clonotypes. Age‐related changes were found. The reduced diversity and CDR3 length of human blood TRG repertoires and in the composition of the brain TRG repertoire, in particular, a decrease in the frequency of the TRGV9 segments and an increase in TRGV2/4/8 were identified. We developed a bioinformatic approach based on the physicochemical properties analysis of rare clones that are found in patients with AD but not in healthy individuals. Our findings revealed the enrichment of TRG clonotypes with specific properties in the brain or blood of patients with AD compared to those in controls. (Aliseychik et al. 2020) These AD‐associated clonotypes are not typical for patients with PD, for which accumulation of the AD specific clonotypes was not pronounced.ConclusionThe pilot study of TCR repertoires in AD revealed disease associated TRGs profile properties in brain and blood and implied putative AD‐associated immunogenic markers. This work was supported by the National Institute on Aging (NIA; R01 AG054712); the Russian Foundation for Basic Research (RFBR, grant no. 18‐29‐13051) and the Russian Science Foundation (RSF, grant no. 19‐75‐30039).
STRONGER 60+ Adaption of the multimodal FINGER model to prevent cognitive decline in a Swedish primary care rehabilitation unit: An effectiveness‐implementation hybrid design
Authors: Thunborg Charlotta , Åkesson Elisabet , Leavy Breiffni , Håkansson Krister , Sindi Shireen , Solomon Alina , Levak Nicholas , Kivipelto Miia 
Published: December 2020

AbstractBackgroundPreventing cognitive and physical decline in people >60 is a major public health priority. Evidence‐based programs for promoting healthy lifestyle in people 60+ are sparse. WHO has launched risk reduction guidelines for cognitive decline and dementia focusing on several lifestyle and cardiovascular risk factors. The FINGER trial is the first large RCT indicating that targeting several risk factors simultaneously can reduce cognitive and functional decline among at risk elderly persons. To develop and implement personalized, effective and feasible lifestyle interventions for real life settings, the multimodal FINGER model needs to be adopted and new evidence from recent studies implemented (e.g. importance of psychosocial factors). The aim of STRONGER 60+ is to adapt the FINGER‐model and investigate intervention effectiveness on lifestyle factors in association with cognitive‐ and physical function. By adopting a hybrid‐design, the implementation process will be followed in a real‐world setting.MethodSTRONGER 60+ will include an adapted version of the FINGER‐model, with the components of a brain‐healthy diet, exercise, cognitive training, and stimulating social activity, in addition with careful monitoring of cardiovascular risks. A co‐production design including clinicians and participants will be used. It is a 6‐monh (with 12 month follow‐up) randomized controlled, single blind parallel‐group clinical effectiveness study. Up to 160 persons will be recruited. Participants will receive either the adapted multimodal healthy lifestyle intervention or regular health advice. A measure of psychosocial states will be included to highlight the importance of tailormade interventions in the study. The intervention is designed for community‐dwelling persons ≥ 60 years, with elevated risk for dementia according to the Dementia Risk Tool risk score, MMSE ≥ 24.ResultWe are currently finalizing the resource planning, recruitment start in September 2020. With the hybrid‐design outcome evaluation we will be able to explore the process by examining; facilitators and barriers for the adaption process, the recruitment process of participants, the extent to which the target audience encounter the program, retention rate, fidelity to the FINGER‐model, dose received/delivered.ConclusionFor people at‐risk of cognitive‐ and physical decline to benefit from multimodal lifestyle intervention research, interventions tested in research settings require adaption and assessment in real‐world clinical practice.
Treatment implementation leads to improved outcomes in patients with dementia in Sweden from 2008‐2017: Experience from the Swedish Dementia Registry
Authors: Xu Hong , Garcia‐Ptacek Sara , Secnik Juraj , Hoang Minh Tuan , Tan Edwin CK , Religa Dorota , Eriksdotter Maria 
Published: December 2020

AbstractBackgroundThe efficacy of available treatments for dementia remains limited and few randomized clinical trials have been able to demonstrate the benefits of treating comorbidities in improving outcomes of patients with dementia. In this study, we evaluated temporal changes in the management of comorbidities and survival rates in incident dementia over a ten‐year period in Sweden.MethodWe included 40,219 patients with newly diagnosed dementia in memory clinics from the Swedish Dementia Registry (SveDem) during 2008‐2017 and stratified all data by one‐year blocks. We evaluated trends in the use of dementia drug treatments and selected key medications within 1‐year blocks. We then evaluated the incidence of death, major cardiovascular events (MACE), and fracture within one‐year from the diagnosis date using standardized incidence rates to account for differences in patient characteristics over time. Via Cox regression models, we explored whether adjustment for implementation of new treatments modified survival, MACE and fracture risk. Finally, survival trends were also compared against an age‐sex‐calendar year‐matched general Swedish population using standardized incidence ratios (SIR).ResultAcross 1‐year blocks, there was no difference in Mini‐Mental State Examination, and proportion of Alzheimer’s and vascular dementia over time. However, age and proportion of females and unspecified dementia decreased. The use of renin‐angiotensin‐system‐inhibitors, calcium‐channel‐blockers, statins and dementia medication memantine increased while antipsychotics, antidepressants and cholinesterase‐inhibitors decreased. After standardization for demography and comorbidities, the 1‐year risk of mortality, MACE or fracture decreased by 13%, 7% and 19%, respectively, in the year 2016 compared to the year 2008. In multivariable Cox models, per 1‐year increase, the risk of death within 1‐year decreased by 4% (HR 0.96[95% CI 0.95‐0.97]), MACE by 3% (0.97[0.96‐0.98]) and fracture by 3% (0.97[0.95‐0.98]). Compared with general population, the risk of death corresponding to a SIR reduced by 11% in the year 2016 compared to 2008.ConclusionOver the last 10 years, a reduction in the short‐term risk of death, MACE and fracture risk in patients with dementia was found in association with changes in drug prescribing practices. This suggests that implementation of established treatments for comorbidities may be beneficial for patients with dementia.
Abstract dementia risk prediction model development in low‐ and middle‐income countries: The 10/66 study
Authors: Worrall Alice Louise , Prina Matthew , Pakpahan Eduwin , Siervo Mario , Terrera Graciela Muniz , Mohan Devi , Acosta Daisy , Pichardo Guillermina Rodriguez , Sosa‐Ortiz Ana Luisa , Acosta‐Castillo Gilberto Isaac , Llibre Juan , Prince Martin J , Robinson Louise , Stephan Blossom CM ,   10/66
Published: December 2020

AbstractBackgroundMost people with dementia live in Low and Middle Income Countries (LMICs), where little research on dementia risk prediction modelling has occurred. This study aimed to develop new models to simply predict all‐cause dementia, suitable for use in LMICs. Country‐specific models were expected, due to different risk profiles.MethodData was from the 10/66 cohort study. Individuals aged ≥65 years without dementia at baseline (N=11,143) were recruited from Cuba, the Dominican Republic, Peru, Venezuela, Mexico, Puerto Rico and China. Dementia incidence was assessed over a mean follow‐up of 3.8 years (SD=1.3 years). Variables were selected to be tested that have been associated with dementia previously. Two Cox risk models were produced for each site, with and without objective cognitive variables. Predictive accuracy (c‐statistic) and calibration were tested.Result1,069 individuals progressed to dementia during follow‐up. The models had mostly moderate to good predictive accuracy. The models in the total sample performed moderately (cognitive model c‐statistic = 0.74; 95%CI: 0.72‐0.75; non‐cognitive model c‐statistic = 0.71; 95%CI: 0.70‐0.73). In each country, the cognitive models’ c‐statistics ranged from 0.70 (95%CI: 0.67‐0.74) in China to 0.84 (95%CI: 0.80‐0.88) in Peru, and the non‐cognitive models’ c‐statistics ranged from 0.67 (95%CI: 0.63‐0.71) in the Dominican Republic to 0.80 (95%CI: 0.74‐0.85) in Peru. There were no major noticeable patterns of variables included in each country‐specific model. Model calibration was however poor.ConclusionDifferent prediction models were necessary for each country, most of which had moderate to good predictive accuracy. Further research is needed to improve calibration, and to determine whether risk prediction is cost‐effective, ethical and acceptable in LMICs. Dementia risk prediction is important so that individuals at high risk can be identified, and their risk factors addressed, to help decrease the burden of dementia.
Alzheimer’s disease‐associated (hydroxy)methylomic changes in the brain and blood
Authors: Riemens Renzo Jan Maria ,   EPI‐AD Consortium
Published: December 2020

AbstractBackgroundConsiderable evidence suggests that epigenetic processes including DNA methylation and hydroxymethylation represent critical factors in the development and course of Alzheimer’s disease (AD).MethodWithin the EPI‐AD project (http://www.epi‐ad.eu/), we performed an epigenome‐wide association study (EWAS), assessing both DNA methylation and hydroxymethylation, using bulk tissues from the dorsal raphe nuclei (DRN), locus coeruleus (LC) and middle temporal gyrus (MTG) derived from AD patients and matched non‐demented controls. We followed up these analyses by exploring methylomic signatures in microdissected serotonergic DRN cells using limiting dilution bisulfite pyrosequencing. In an independent (longitudinal) cohort, we compared the blood methylome of converters to AD dementia and non‐converters at a preclinical stage.ResultWithin the DRN and LC, we revealed overlapping Braak stage‐associated epigenetic abnormalities in TNXB, ANKRD2 and MBP. Interestingly, when comparing methylation levels of TNXB in individually isolated serotonergic neurons with those of non‐serotonergic cells in the DRN, we found a significant interaction between cell‐type and condition. The AD‐associated methylation profiles were opposite in the serotonergic neurons and non‐serotonergic cells, the latter of which resembled the EWAS data. Within the MTG, we revealed epigenetic differences close to or overlapping with genes such as OXT, CHRNB1, RHBDF2 and C3 that were associated with Braak staging. By comparing the blood methylome of converters to AD dementia and non‐converters at a preclinical stage, we found that DNA methylation in the exact same region of the OXT promoter as seen in the MTG was associated with subsequent conversion to AD.ConclusionOverall, data on the MTG confirmed previous findings, identifying loci such as RHBDF2 and C3 that have been associated with AD in various EWAS studies on cortical brain regions. Notably, our brainstem work highlighted several novel epigenetic signatures that we hypothesize to play a pivotal role in early AD development. Furthermore, we show that dysregulation in TNXB methylation in the DRN is both dependent on the disease phenotype and the cell type analyzed, which warrants the need for cell‐type specific neuroepigenetic studies in AD. Finally, we demonstrate that the detection of OXT methylation at pre‐dementia stages holds potential relevance as a novel biomarker and therapeutic target.
Beyond aphasia: Natural history of the aphasia onset dementia syndromes
Authors: Erkoyun Hulya Ulugut , Stek Simone , Wagemans Lianne , Jutten Roos J. , Scheltens Philip , Pijnenburg Yolande A.L. 
Published: December 2020

AbstractBackgroundAphasic syndromes caused by neurodegenerative disease are known as Primary Progressive Aphasias (PPA). The most recent consensus criteria have classified PPA into the non‐fluent variant (nfPPA), semantic variant (svPPA) and the logopenic variant (lvPPA). Few longitudinal studies have explored the prognosis of patients with PPA. This study aims to give an overview of the clinical profile divided into different domains, the progression into other diagnoses and mortality of the different subtypes of PPA.MethodTwenty‐two patients diagnosed with nfPPA, 24 with svPPA and 18 with lvPPA between 2011 and 2019 were retrospectively collected and followed‐up for a maximum of over 6 years. Biomarkers and neuroimaging were acquired at baseline. Reported additional symptoms, neurological signs and outcomes on different neuropsychological tests during follow‐up period were collected and compared for baseline and longitudinal results. Kaplan‐ Meier survival analysis was performed for mortality rate.ResultAs expected, a language disorder was the main problem of all PPA patients at the first assessment. However, over the disease course, the subtypes exhibited a different progression pattern. Behavioural problems were prominent in svPPA whereas patients with lvPPA exhibited a greater executive and visuospatial dysfunction and episodic memory impairment (p<0.05). Unlike svPPA and lvPPA, nfPPA subjects presented a relatively pure aphasia profile initially. However, 50% of the subjects developed extrapyramidal and pyramidal signs within 4 years and progressed into other diagnoses such as corticobasal degeneration, progressive supranuclear palsy, motor neuron disease, behavioural variant frontotemporal dementia and Alzheimer’s disease. Furthermore, in this group the mortality rate was significantly higher in comparison to the other subtypes (median years 3.04 [1.06 – 5.62], p=0.001). By contrast, none of the svPPA patients progressed into another diagnosis whereas 78% of the lvPPA patients progressed to Alzheimer’s disease within 3 years (Figure 1).ConclusionTo our knowledge, this is the first study to determine the progression profiles and the entire course of the disease from the diagnosis to the death. Our results show that prognosis differs widely per PPA subgroup. Disclosing the risk of developing motor symptoms should be considered in the case of nfPPA.