bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of technology to monitor sleep and bed occupancy in older men and women
Authors: Ravindran Kiran Kumar Guruswamy , Monica Ciro della , Atzori Giuseppe , Enshaeifar Shirin , Mahvash‐Mohammadi Sara , Dijk Derk‐Jan , Revell Victoria 
Published: December 2021

AbstractBackgroundNocturnal disturbance is frequently observed in dementia and is a major contributor to institutionalisation. Unobtrusive technology that can quantify sleep/wake and determine bed occupancy during the major nocturnal sleep episode may be beneficial for long‐term clinical monitoring and the carer. Such technologies have, however, not been validated in older people. Here we assessed the performance of the Withings Sleep Mattress (WSM) in a heterogenous older population to ensure external validity.MethodEighteen participants (65 – 80 years, 10M:8F) completed 7‐12 days of sleep/wake monitoring at home prior to an overnight laboratory session. WSM performance was compared to gold‐standard (laboratory polysomnography [PSG] with video) and silver standard (actiwatch [AWS] and sleep diary at home). WSM data were downloaded from a third party API and the minute‐to‐minute sleep/wake timeseries extracted and time‐ordered to create a sleep profile. Discontinuities in the timeseries were labelled as ‘missing data’ events.ResultsParticipants contributed 107 nights with WSM and PSG or AWS data. In the laboratory, the overall epoch to epoch agreement (accuracy) of sleep/wake detection of WSM compared to PSG was 0.71 (sensitivity 0.8; specificity 0.45) and to AWS was 0.74 (sensitivity 0.77; specificity 0.53). Visual inspection of video recordings demonstrated that 20 of 21 ‘missing data’ events were true ‘out of bed’ events. These events were always associated with an increase in activity (AWS). At home, all 97 WSM ‘missing data’ events that occurred within the major nocturnal sleep episode defined by sleep diary data, were associated with an increase in activity levels in the AWS data and 36 of these events were also associated with an increase in light levels, indicating that the participant had left the bed. In several participants, data recorded by the WSM during daytime coincided with reported naps in the sleep diary.ConclusionAlthough WSM cannot reliably distinguish between sleep and wake, the presence/absence of data in WSM seem to be an accurate representation of whether older people are in or out of bed (bed occupancy). Thus, in dementia, this contactless, low‐burden technology may be able to provide information about nocturnal disturbances and daytime naps in bed.
Cortical microstructural changes in autosomal dominant Alzheimer’s disease
Authors: Torso Mario , Ridgway Gerard R , Hardingham Ian , Tzaferou Dimitra , Benzinger Tammie L.S. , Chance Steven A ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2021

AbstractBackgroundAutosomal dominant Alzheimer's Disease (ADAD) is an important area of study to understand the pathogenesis of AD. Previous studies suggested that mutations in the genes coding for amyloid precursor protein cause early deposition of amyloid‐β peptide (Aβ), resulting in an amyloid‐induced inflammatory response and cortical microstructural changes during the cognitively asymptomatic phase, several years before clinical onset. The aim of this work was to investigate the cortical microstructural changes in an ADAD population, using novel diffusion tensor imaging (DTI) metrics that are correlated with specific neuropathology and disruption of cortical minicolumns.MethodA total of 270 individuals from families with known mutations in the PSEN1, PSEN2, and APP genes (168 mutation carriers and 102 non‐carriers) from the Dominantly Inherited Alzheimer’s Network (DIAN) were included in the study. 3DT1 and DTI scans at baseline were used to calculate the cortical grey matter fraction, cortical thickness, mean diffusivity (MD), and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). A multivariate General Linear model (GLM) was used to investigate cross‐sectional differences. Mutation carrier status was added as a fixed factor, and “sex” and “age” as covariates. Differences across the clinical spectrum are evaluated with box‐plots of metrics grouped by clinical dementia rating (CDR) Figure 1.ResultDifferences in cortical diffusivity measures were found between mutation carriers and non‐carriers. The GLM results revealed a significant main effect of mutation carrier status (p<0.05) as well as age (p<0.001) and sex (p<0.001). Between‐subjects effects revealed that PerpPD (p<0.0001), ParlPD (p<0.0001), and MD (p<0.0001) were significantly higher in the mutation carrier group. As expected, the cortical grey matter fraction (p<0.005) and cortical thickness (p<0.01) were significantly lower in the mutation carrier group.ConclusionIn autosomal dominant (inherited) Alzheimer’s disease, differences emerge in several novel cortical diffusivity measures, years before the expected diagnosis based on parental age of onset. These findings support using cortical diffusivity measures as a surrogate of cortical microstructure quality for identification of the early stages of AD.
Constrained harmonization algorithm for pooling multi‐site datasets
Authors: Lokhande Vishnu Suresh , Mishra Akshay , Diers Kersten , Düzel Emrah , Reuter Martin , Bendlin Barbara B , Singh Vikas 
Published: December 2021

AbstractBackgroundPooling datasets from multiple studies can significantly improve statistical power: larger sample sizes can enable the identification of otherwise weak disease‐specific patterns. When modern learning methods are utilized (e.g., for predicting progression to dementia), differences in data acquisition‐methods / scanner‐protocols can enable the model to “cheat”, i.e. utilizes site‐specific artifacts rather than disease‐specific features. In this study, we develop a method to harmonize the performance of DNN classifiers across scanners/sites, via so‐called fairness constraints, thereby encouraging consistent behavior while controlling for site‐specific nuisance variables.MethodWe conducted two studies: (a) to demonstrate feasibility of pooling across sites (Site‐Pooling) and (b) to pool data across scanners (Scanner‐Pooling). For Site‐Pooling, our analysis included summaries from Freesurfer processed T1‐weighted images of the Wisconsin Alzheimer's Disease Research Center (ADRC) and German Center for Neurodegenerative Diseases (DZNE). The Freesurfer summaries were used to train a two layer neural network classifier and five‐fold cross‐validation performance was assessed. For Scanner‐Pooling experiments, Freesurfer processed MR images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to train a deep 3D convolutional network. Performance average on a held‐out test dataset was evaluated. In both cases, a constraint to equalize the performance of the trained classifier across the domains (sites/scanners) was incorporated during training.ResultTable 1 shows the results of AD/MCI classification for site‐pooling analysis. Our proposed method is compared against a naive pooling approach which does not incorporate the “harmonization constraint”. As shown, the proposed method improves the “difference of errors” measure by 8% / 7% and with only a small drop in overall error rates. Figure 1 illustrates the results from our scanner‐pooling analysis. The performance across the three scanners, GE, Siemens and Philips, is evaluated pair‐wise. A consistent improvement in harmonization is observed and only ∼2% drop in overall error rate is seen.ConclusionWe provide a harmonization constraint based algorithm to mitigate site specific differences when performing analysis of pooled brain imaging datasets in AD studies. In contrast to a method which modifies the data, we achieve harmonization by constraining the classifier to perform similarly across sites/groups/scanners, improving reproducibility.
Development and external validation of a novel dementia risk prediction score in the UK Biobank cohort
Authors: Anatürk Melis , Patel Raihaan , Georgiopoulos Georgios , Newby Danielle , Topiwala Anya G , de Lange Ann‐Marie G , Cole James H , Jansen Michelle G , Ebmeier Klaus P , Singh‐Manoux Archana , Kivimaki Mika , Suri Sana 
Published: December 2021

AbstractBackgroundGlobally, up to 40% of dementia cases may be prevented if several key risk factors, such as low education and obesity, are targeted. This has motivated interest into the development of risk scores that aim to quantify an individual’s risk of developing dementia within a given time frame. However, translation to a clinical setting has been hampered by either a lack of external validation, poor out‐of‐sample performance, or the integration of measures (e.g., MRI, cognitive testing) that are costly or time intensive to administer.This study aimed to develop a novel dementia risk score suitable for a primary care setting and compare its discrimination accuracy with other risk scores.Method208,108 UK Biobank (UKB) participants were examined, with cases of incident dementia (mean time to diagnosis ± SD = 5.91 years ± 2.02) identified through self‐report, hospital inpatient records and death certificates (n = 1,270, 0.6%). The dataset was randomly split into a training (80%) and test set (20%). Potential predictors (n = 30) included Apolipoprotein E4 (APOE4) status and cardiovascular, medical and lifestyle factors collected at baseline. Logistic LASSO regression was employed for variable selection and logistic regression was then used to derive beta coefficients for each predictor included in the UKB dementia risk score (UKB‐DRS). The area under the curve (i.e., AUC) was used to compare the discriminative ability of the UKB‐DRS to the CAIDE, ANU‐ADRI, Dementia Risk Score (i.e., DRS) and Framingham risk score, in both the test set and the Whitehall II study (WHIII, n = 2,974), which served as an external dataset.ResultThe UKB‐DRS consisted of age, sex, education, APOE4 status, a medical history of diabetes, stroke and depression and a family history of dementia. The UKB‐DRS demonstrated good discrimination accuracy in both the test set (AUC [95% ] = 0.79 [0.77, 0.82]) and external dataset (AUC [95% CI] = 0.83 [0.79,0.87]). Additionally, the UKB‐DRS outperformed all other risk scores (the DRS had the next best AUC [95% CI]: UKB = 0.77 [0.74, 0.8]; WHII = 0.77 [0.73, 0.81]).ConclusionThis study contributes a novel dementia risk score that may be used to guide primary prevention strategies.
Matrix metalloproteinase‐10 as a novel biomarker of neurodegeneration in Alzheimer’s disease
Authors: Trombetta Bianca A. , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E. 
Published: December 2021

AbstractBackgroundAlzheimer's disease (AD) is driven by cycles of protein misfolding, inflammation, and neurovascular and metabolic dysfunction. Although cerebrospinal fluid (CSF) tau and Amyloid‐β (Aβ) levels are strong indicators of AD pathology, they are inadequate for measuring disease progression or drug response. We investigated a collection of biomarkers that may represent active pathways in AD to identify novel targets for the diagnosis, staging, and pathophysiological profiling of AD.MethodImmunoassays (MesoScale Discovery, Quanterix) were used to measure a targeted selection of over 20 biomarkers in a well‐characterized cohort of 240 paired CSF and plasma samples obtained from the Penn ADCC and Center for Neurodegenerative Disease Research. The cohort was comprised of individuals with diverse diagnoses, including mild cognitive impairment (MCI), AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and cognitively unimpaired controls (CU‐N). Statistical modeling of AD severity, associations between biofluids, and differential diagnosis were performed. Regressions were adjusted for covariates, including age and sex.ResultCSF MMP‐10, FABP‐3, NfL, and YKL‐40 were significantly elevated in AD compared to CU‐N (p<0.005). MMP‐10, a regulator of blood‐brain barrier integrity, correlated significantly with CSF tau (p<0.005). The established neurodegeneration biomarkers FABP‐3 and NfL correlated significantly (p< 0.05) with CSF AD biomarkers. The neuroinflammatory marker YKL‐40 correlated significantly with CSF tau and ptau‐181 in both CSF and plasma (p<0.05). Linear regression identified a significant correlation between CSF and plasma MMP‐10 in CU‐N (p<0.005) and AD (p<0.005), but not in MCI. CSF MMP‐10 could distinguish CU‐N (AUC: 0.90), MCI (AUC: 0.71), and ALS (AUC: 0.78) from AD. Addition of FABP‐3, NfL, YKL‐40, and MMP‐10 to a logistic model increased classification accuracy between AD and CU‐N in both CSF (AUC: 0.99) and plasma (AUC: 0.788).ConclusionDevelopment of a broad biomarker panel may help clarify the interrelated pathophysiologies active in AD onset and progression. Here we highlight MMP‐10 as a novel biomarker that could provide insight on underlying vascular pathology contributing to AD pathogenesis. MMPs have also been implicated in Aβ‐induced proinflammatory response and tau aggregation. Further studies are warranted to assess the physiological significance of MMP‐10 in AD and its mechanistic role in neurodegeneration.
Hypertension, brain training and cognition in the healthy adults aged over 50 years: An online longitudinal study
Authors: Velayudhan Latha , French Thomas , Ugochukwu Aghaji , Corbett Anne , Brooker Helen , Aarsland Dag , Ballard Clive , Proitsi Petroula 
Published: December 2021

AbstractBackgroundThere have been no studies that investigate if cognitive tasks that have been proven to delay the progress of cognitive decline confound the relationship between Hypertension (HT) and cognitive function. We aimed to investigate whether brain training has a modifying effect on the relationship between HT and cognitive decline.MethodParticipants were from Platform for Research Online to Investigate Cognition and Genetics in Ageing (PROTECT), a longitudinal online study which collected information on demographic, medical and cognitive function annually, who underwent brain training intervention (BT) delivered online throughout the year; participants could choose to undertake it as many times as they wanted or not at all. Digit span, Paired associates, Self‐ordered search and verbal reasoning tests were used to test cognitive functions. Regression models was done to assess influence of hypertension and BT on cognition at follow up and whether the frequency of BT had a modifying effect on the relationship between hypertension and cognitive function from baseline to one year.Results5726 participants over the age of 50 participated in BT with mean age 61.9 (±7.05) and 77% women. 1448 (25%) participants with HT had lower scores on all the 4 cognitive measures after adjusting for BT and potential confounders, although only the association with Digit Span test was significant (beta=‐0.031 p=0.03). After testing for interactions, there was an association of HT with verbal reasoning score change for those with BT (beta=‐0.097, p=0.048). There was also an interaction between BT frequency (higher number of attempts) and HT for paired associate learning (interaction beta=‐0.118, p=0.008), whereby frequency of BT was associated with positive change (improvement) only in individuals without HT (beta=0.121, p<0.001), whereas no association was observed in individuals with HT (p>0.05).ConclusionsHT was associated with lower cognition and also seems to modify the association of BT with cognition. There was improvement of all 4 cognition with increasing number of BT attempts irrespective of HT status, and improvement in Paired Associate scores over one year for participants without HT, implying a potential beneficial role for BT. However, this needs to be validated in larger and longitudinal studies.
Myelin integrity in older adults with vascular cognitive impairment: Implications for mobility performance
Authors: Silva Narlon Cassio Boa Sorte , Dao Elizabeth , Liu‐Ambrose Teresa 
Published: December 2021

AbstractBackgroundIn individuals prone to white matter pathology, such as older adults with vascular cognitive impairment (VCI), myelin loss could contribute to mobility impairment. Using myelin water fraction (MWF), an in‐vivo technique to quantify myelin content in the brain, we investigated whether myelin content is associated with mobility performance in older adults with VCI.MethodWe analyzed cross‐sectional data from thirty‐two subjects with MRI‐evidence of subcortical ischemic VCI who underwent 3T MRI scanning protocol at the UBC MRI Research Centre (mean [SD], age = 73.8 [5.4], MoCA score = 21.3 [3.8], 65.8% female). The protocol consisted of a standard T1‐weighted contrast for acquisition of high‐resolution structural data, and a gradient and spin echo contrast (GRASE) for acquisition of MWF data. Gait speed (meters/second) collected via a 4‐meter walking test was used as a measure of mobility performance. Following a preprocessing pipeline using the FMRIB Software Library, MWF data were computed for the whole‐brain white matter, and fifteen specific white matter structures of interest. The T1‐weighted images were processed with FreeSurfer to determine estimated intracranial volume (eICV). Hierarchical regression models adjusting for eICV and MoCA were conducted to determine whether lower MWF is associated with slower gait speed.ResultIn models adjusting for eICV only, lower MWF in the superior longitudinal fasciculus was associated with slower gait speed (unstandardized B [95% CI] = 3.287 [0.052 to 6.523], R2 Change = 0.130, p = 0.047). Adjusting for MoCA scores attenuated this relationship (unstandardized B = 3.055 [‐0.155 to 6.265], R2 Change = 0.111, p = 0.061).ConclusionTo our knowledge, this is the first study to investigate whether in‐vivo lower myelin content is linked to poor mobility in this population. Our findings suggest that poor myelin integrity in specific white matter tracts of the brain may be linked to decline in mobility performance in older adults with VCI. Understanding the mechanisms by which VCI leads to mobility impairment is the first step towards developing strategies to prevent downstream unwanted health outcomes such as falls, hospitalizations, and loss of independence.
Safety, feasibility, and adherence of a daily, in‐home gamma sensory stimulation therapy with the Cognito Sensory Stimulation System in Alzheimer’s subjects
Authors: Williams Martin , Cimenser Aylin , Hempel Evan , Cotter Colleen , Shukla Mohinish , Jiang Kevin , Zhang Annie , Mrozak Holly , Konisky Alexandra , Kwan Kim , Hajos Mihaly , Malchano Zach 
Published: December 2021

AbstractBackgroundNon‐invasive, visual and auditory gamma (40 Hz) sensory stimulation demonstrates clearance of β‐amyloid plaques and tau tangles, and cognition improvement in preclinical AD models (Iaccarino, 2016, Martorell, 2019). A home‐use gamma sensory stimulation device (Cognito Therapeutics, Inc., Cambridge, MA) was developed to evoke gamma oscillations in humans. The long‐term safety and feasibility of this approach has not been previously evaluated in AD subjects.MethodOverture is a prospective 6‐month treatment study in mild‐to‐moderate AD of the Cognito device. Subjects were randomized 2:1, treatment:sham. All subjects underwent in‐clinic EEG to confirm gamma entrainment and calibrate the device. Therapy was self‐administered daily during 1‐hour sessions at home with adherence logged by device. Safety assessments included adverse event (AE) monitoring, MRIs, and physical exams. Subjects and caregivers participated in multiple in‐depth interviews to assess the feasibility of this novel therapy. Subjects had the option to enter a 12‐month extension.ResultIn total, 20,562 treatment sessions have been completed by 74 subjects in the Main and Extension period. Overall rates of AEs during the Main and Extension study periods were roughly equivalent between groups (Active: 2.5/subject, Sham: 2.9/subject). There were no unexpected serious treatment emergent adverse events. Review of MR imaging data by neuroradiology demonstrated stable findings from baseline to follow‐up and absence of ARIA in all subjects. Adherence data showed that Sham participants had a final mean adherence of 95.9%±9.0%, while treatment participants had a final mean adherence of 90.2%±13.3%, and the difference was not significant in an independent‐samples, two‐tailed t‐test (p=0.14). Participants easily adopted and adhered to daily self‐administered therapy, with 60% of enrolled participants choosing to continue into the extension.ConclusionThe interim results of the study demonstrate that long‐term, daily, self‐administered, home‐use of gamma sensory stimulation is both safe and well tolerated in mild‐to‐moderate AD subjects.
Leveraging videoconferencing supports the continuity of Alzheimer research during the COVID‐19 pandemic and beyond
Authors: Johnson Francelethia S , Lacroix Faina C , Contreras Maricarmen , Baez Penelope , Ayodele Temitope , Martinez Izri , Fonseca Sandra , Adams Larry D , Welch Jacob , Jean‐Francois Melissa N , Mena Pedro Ramon , Reitz Christiane , Vance Jeffery M , Pericak‐Vance Margaret A , Cuccaro Michael L , Beecham Gary W 
Published: December 2021

AbstractBackgroundThe COVID‐19 pandemic has placed a demand on researchers to limit in‐person contact with participants, greatly impacting Alzheimer Disease (AD) research. To address this problem, we describe here an approach to using digital technology to continue nationwide clinical recruitment and ascertainment of biological samples while adhering to COVID‐19 guidelines and travel restrictions.MethodTo accomplish this, we considered a videoconferencing approach for remote delivery of cognitive assessments. A multi‐site panel of neurologists and clinical psychologists and a detailed literature review ensured a protocol that captures the best‐practices for administering assessments through videoconferencing while ensuring consistency between remote and in‐person administration. Clinical coordinators underwent training to ensure good agreement with in‐person administration. Most aspects of the cognitive assessments easily transferred to videoconferencing, though Trail Making A and B, and Digit Symbol‐Coding were removed to protect the integrity of the evaluation. Additionally, we coordinated the collection of biological samples with a national company, Quest Diagnostics, to provide phlebotomy services at the participant’s residence. All protocols were developed under the guidance of the Human Subjects Research Office at the University of Miami and with approval of local IRB.ResultOur clinical coordinators completed over two dozen remote assessments using these protocols. Both cases and controls were enrolled, across various ethnic populations within our study. The distributions of age and 3MS were similar between in‐person and remote assessments. The uptake of videoconferencing enrollment varied among the age groups, level of impairment, at‐home support system and telemedicine readiness. For example, earlier‐onset groups had the best uptake, while older‐onset groups showed the least uptake due to a higher prevalence of telemedicine unreadiness (Lam et al., 2020; Bossen et al.,2015).ConclusionThis study demonstrates that remote enrollment and ascertainment of biological samples through videoconferencing and partnering with national mobile phlebotomy services is feasible. This approach allows researchers to continue ascertainment efforts while maintaining their participants’ autonomy through informed consent and privacy throughout the process and minimizing their exposure to COVID‐19.