bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of neurodevelopmental gene variants implicated in age‐related brain morphological changes and cortical atrophy
Authors: Vacher Michael , Porter Tenielle , Milicic Lidija , Dore Vincent , Bourgeat Pierrick , Villemagne Victor L.L. , Doecke James D. , Laws Simon M. , Heng Julian Ik‐Tsen 
Published: December 2021

AbstractBackgroundNeurodevelopmental genes and their associated protein products are involved in a number of biological processes essential for brain assembly. Despite their relative importance, the impact of genetic variation in neurodevelopmental genes on the neurodegenerative and neurocognitive changes that occur in Alzheimer’s disease, is poorly characterised. Here, we investigated the associations between Single Nucleotide Polymorphisms (SNPs) in neurodevelopmental genes and brain volumetrics.MethodFrom a curated list of 40 genes related to neurodevelopmental processes, we identified a set of 233 independent SNPs. The genotype data was generated from 715 unrelated individuals (Amyloid Beta (Ab) ‐ N=328, Ab+ N=387), enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We focused this research on the cortical grey, subcortical white matter, ventricular, and hippocampal volumes and used linear mixed models to assess whether specific genotypes were associated to regional volume changes over time. The associations with the traits of interest were assessed cross‐sectionally at baseline and longitudinally, over a 12‐year time span.ResultAt baseline, cross‐sectional analyses revealed one significant association between the variant, rs2923137, located in DRC7 (<20KB KATNB1) and ventricular volume (p = 2.13e‐4, β = 5.8). In the longitudinal analyses, we found that rs1142749, a marker located near TUBB4B, was consistently associated with accelerated rate of change in grey matter (p = 9.2e‐4, β = 0.034), hippocampal (p = 2.9e‐3, β = 0.025) and ventricular volume (p = 2.1e‐3, β = ‐0.028). Further, we observed that the strength and effects of these associations were exacerbated in Ab+ individuals but were absent in Ab negative sub‐population. Another noticeable link was identified between rs2555172 (DCHS1) and hippocampal volume change (p = 1.4e‐3, β = ‐0.024). The identified associations were independent of variation due to the APOE e4 allele and remained significant after correction for multiple comparisons.ConclusionThe results support the hypothesis that genes associated with neurodevelopmental processes and signalling mechanisms are relevant to Alzheimer’s Disease. The identified associations suggest that mutations in key neurodevelopment genes could be linked to accelerated atrophy in specific areas of the brain.
Effect of cognitive reserve and amyloid deposition on sleep‐dependent cognition in older adults
Authors: Ourry Valentin , Rehel Stéphane , André Claire , Gonneaud Julie , Moulinet Inès , Kuhn Elizabeth , Touron Edelweiss , Landeau Brigitte , Mézenge Florence , Paly Léo , Delarue Marion , De la Sayette Vincent , Chetelat Gaël , Rauchs Géraldine ,   the Medit‐Ageing Research Group
Published: December 2021

AbstractBackgroundSleep, especially slow wave sleep (SWS), favors efficient cognitive functioning. This effect may be impaired in aging, but might be modulated by cognitive reserve. Indeed, a study reported that highly educated older adults were able to better tolerate the negative effects of subjective sleep disturbances on verbal fluency scores. Growing evidence also suggests that sleep may favor amyloid clearance. In this context, we investigated the effect of cognitive reserve and amyloid deposition on the links between SWS and cognitive performance in older adults.MethodsBaseline data of 135 cognitively unimpaired older adults (mean age ± SD: 69.3 ± 3.8 y) from the Age‐Well cohort were analysed. Participants underwent a neuropsychological assessment, a polysomnography, and a florbetapir PET scan to measure amyloid deposition. Cognitive reserve was estimated using a socio‐behavioral proxy, the Lifetime of Experiences Questionnaire. We conducted linear regressions between SWS (% of total sleep time) and 1) executive functions and 2) episodic memory composite scores. Standardized residuals were extracted so that higher values reflect a better cognition than expected (i.e., greater cognitive resilience). Then, we performed linear regressions with these residuals as dependent variables and cognitive reserve or amyloid deposition as independent variables. Analyses were repeated with age, sex and the apnea‐hypopnea index as covariates.ResultsSWS (%) was positively associated with executive functions (p=0.021) and episodic memory (p=0.017) composite scores (Figure 1). For both cognitive domains, higher residuals were associated with better cognitive reserve and lower amyloid deposition (p<0.05) (Figure 2). All links with cognitive reserve remained significant after controlling for the covariates (p<0.05), while those with amyloid deposition were close to the significance threshold (p=0.085 and p=0.054 for executive functions and episodic memory respectively).ConclusionsIndividuals with higher cognitive reserve or, to a lesser extent, lower amyloid deposition, were able to better tolerate the effects of low amounts of SWS on executive and episodic memory performance. Cognitive reserve may help maintaining cognitive performance even when sleep is disrupted (i.e., cognitive resilience to sleep changes), while amyloid deposition would increase the vulnerability to poor sleep quality. These findings are important to understand the factors promoting successful aging.
Atrophy in dopaminergic pathways is associated with emergence of delusions in patients with Alzheimer’s disease
Authors: Manca Riccardo , Valera‐Bermejo Jose Manuel , Venneri Annalena ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2021

AbstractBackgroundPeople with advanced Alzheimer’s disease (AD) may present with delusions that are associated with worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study aimed to investigate whether differences in cognitive and grey matter (GM) volume decline can be detected in the year before symptom onset between patients with AD who will and will not develop delusions.MethodTwo samples of patients with AD, 63 who will (AD‐D) and 63 who will not develop delusions (AD‐ND) over a year as recorded by means of the NPI, were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and matched for diagnosis, cognitive status, age, education, sex, handedness and APOE genotype. Sixty‐three additional matched healthy controls (HC) were selected. Group‐by‐time models were used to compare cognitive and clinical data across groups, as well as GM maps by means of VBM. Change in NPI scores was used as covariate. Post hoc analyses were performed to investigate AD‐D vs AD‐ND differences in volume decline in areas found to be more atrophic in the AD‐D group and in brainstem nuclei connected to these areas.ResultNo neurocognitive differences were observed between patient groups either prior to or at symptom onset. When the two patient groups were compared to HC, the AD‐ND showed no greater atrophy over time while greater atrophy in the left caudate was observed in the AD‐D group. Post hoc analyses revealed greater GM loss in the AD‐D group in both caudate bodies and dopaminergic nuclei (i.e. the substantia nigra and the ventral tegmental area), but not in serotoninergic nuclei.ConclusionPatients with AD who will develop delusion showed faster neurodegeneration prior to symptom onset in dopaminergic systems, especially in the nigrostriatal pathway. Therefore, alterations in dopamine neurotransmission due to AD‐related pathology may explain the emergence of delusional thoughts in this population, consistently with the dopaminergic hypothesis of positive symptoms in schizophrenia.
Graduation study design: Evaluation of once‐weekly subcutaneous administration of gantenerumab on brain amyloid load
Authors: Boess Frank , Sakaoka Shunsuke , Abi‐Saab Danielle , Scelsi Marzia Antonella , Delmar Paul , Hofmann Carsten , Klein Gregory , Baudler Monika , Doody Rachelle , Kerchner Geoffrey A 
Published: December 2021

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Aβ), is a potential disease‐modifying treatment for early Alzheimer’s disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post‐hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to a target dose of up to 1200 mg confirmed significant Aβ removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of gantenerumab in early AD, using a 1020 mg/month regimen at target dose (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). These studies maximise exposure with a single titration scheme and target dose regardless of APOE genotype over more than two years of treatment. The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (Q1W) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous Q1W administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience.MethodsIn this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg every 4 weeks (Q4W), followed by 255 mg Q4W and Q2W for 12 weeks each, and a target dose of 255 mg Q1W. This target dose is equivalent to the 1020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a Q1W dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography (PET). Secondary objectives include the assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, cognitive and functional assessments.ResultResults to come.ConclusionThe GRADUATION study will determine the effect of once‐weekly administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home.References: (1) Ostrowitzki et al., 2017; Alzheimers Res Ther. 9:95. (2) Klein et al., 2019; Alzheimers Res Ther. 11:101.
Performance on autobiographical memory tests measuring contextual details is impaired in subjective cognitive decline and mild cognitive impairment
Authors: Bruus Anna Elise , Waldemar Gunhild , Vogel Asmus 
Published: December 2021

AbstractBackgroundThe neuropathological hallmarks of Alzheimer’s disease (AD) occur many years prior to the onset of clinical symptoms. Subjective memory decline can occur during this phase, but no standardized, clinically usable neuropsychological tests are currently able to detect such changes. Autobiographical memory (AM) tests tap a brain network affected in “preclinical” AD. The aim of this study was to investigate whether AM test performance was impaired in persons with Subjective Cognitive Decline (SCD) and in persons with Mild Cognitive Impairment (MCI) and mild dementia due to AD.MethodWe included 17 SCD patients diagnosed according to international SCD criteria, 17 amnestic MCI (aMCI) patients, and 17 patients with mild dementia due to AD. A group of 30 healthy controls was also examined. All participants were ≥ 45 years old and had MMSE scores of ≥ 24. AM was assessed using the Columbia Autobiographical Memory Interview – Short Form (CAMI‐SF) and an instrument, which we named the 3 Events Test. Both measure the specificity of AM and the ability to provide details about personal experiences. We also applied cognitive and neuropsychiatric screening tests and a traditional neuropsychological battery.ResultFor the 3 Events Test, a significant effect of group was found. Post‐hoc testing showed that participants with SCD, aMCI, or mild AD produced significantly fewer contextual details than the healthy controls. An ANOVA also showed a significant effect of group for the CAMI‐SF, and post‐hoc testing showed that the aMCI and mild AD groups were able to answer fewer questions or gave less detailed answers compared to the other groups. The total scores on the CAMI‐SF were lower in the SCD group than in the control group, but the difference was not significant.ConclusionAM was compromised in SCD, aMCI, and mild AD, as reflected by lower scores on the 3 Events Test compared to the control group. Thus, AM may be impaired in very early AD – even in the phases where standard episodic memory tests show no decline. AM tests could be useful in the attempt to verify subjective memory problems, and a decline on such a test could indicate later cognitive decline.
Comparison of language and narrative features of individuals among amnestic mild cognitive impairment and healthy adults
Authors: Karali Fenise Selin , MAVIS Ilknur , Cinar Nilgun 
Published: December 2021

AbstractBackgroundMild Cognitive Impairment (MCI) is a stage between normal aging and dementia. Even though individuals have some decline in cognition due to normal aging, preserved daily life functioning skills is the main distinction between dementia and MCI. Individuals with MCI experience mild impairments in memory, language and judgement.MCI is classified in two subtypes: one is amnestic MCI which is characterized by memory impairment, the other one is non‐amnestic MCI in which other cognitive domains are impaired. Individuals with amnestic MCI (aMCI) are at increased risk of developing Alzheimer disease (AD). The purpose of this study is to determine the language and narration skills of individuals with aMCI and to compare their scores with healthy participants.MethodFor this purpose, the Test Your Memory – Turkish Version (TYM‐TR), the Turkish Picture Naming Test (T‐RAT), the Aphasia Language Assessment Test (ADD) Repetition Subtest, the Turkish Nonword Repetition Test (TAST) were administered to 60 participants between the ages of 60‐85, 30 with aMCI and 30 healthy individuals. Pyramid and Palm Trees Test (PPTT) and the Multilingual Assessment Instrument for Narratives (MAIN‐TR) Dog Story Retelling tasks were also administered.ResultAfter the distribution of the data was examined, those with normal distribution were compared between the groups with independent samples T test and the data that did not show a normal distribution were calculated using non‐parametric Mann Whitney‐U. As a result of the statistical analysis, it was determined that nonword repetition differed significantly between the groups. As for macrostructures, it was determined that there was a difference between the groups in terms of story structure and comprehension. As for the other parameters, even though the average of healthy individuals was higher, no significant difference was found between the groups.ConclusionThis study is the first on the language and narrative skills of the participants with aMCI in Turkish, and it is thought that it will shed light on the language skills of individuals with aMCI during the neurodegeneration process. Determining the changes in language skills is very important in setting goals for Language and Speech Therapy.
Psychosocial effects of the humanoid socially assistive robot Coach Pepper on informal caregivers of people with dementia: A mixed‐methods study
Authors: Zuschnegg Julia , Schüssler Sandra , Paletta Lucas , Voithofer Claudia , Lodron Gerald , Orgel Thomas , Russegger Silvia , Schneeberger Michael , Fellner Maria , Steiner Josef , Pansy‐Resch Sandra , Holter Magdalena , Prodromou Dimitrios , Brunsch Sebastian , Carnevale Lorenzo , Lammer Lara , Koini Marisa 
Published: December 2021

AbstractBackgroundDementia care is largely provided by informal caregivers, which can present significant challenges and increase caregivers’ burden. Humanoid socially assistive robots (SARs) have the potential to provide assistance, but evidence is missing. The aim was to explore the psychosocial effects of Coach Pepper (humanoid SAR system “AMIGO” combined with a tablet PC‐based dementia training) versus an exclusive tablet PC‐based dementia training on informal caregivers of people with dementia living at home (as well as their experiences).MethodA randomized controlled trial with a complementary qualitative part was performed (May 2019‐March 2020). 32 informal caregivers of people with dementia living at home participated in the study. The intervention group received Coach Pepper and the control group received only the tablet‐based dementia training. The duration of the intervention was three weeks per household. Data was collected at baseline and after the intervention by standardized questionnaires for caregiver burden (primary outcome), quality of life, depressive symptoms and affect. Additionally, interviews about caregivers’ experiences were conducted in the intervention group.ResultParticipants were on average 58.2 (±12.5) years old and predominantly female (68.8%). Quality of life, depressive symptoms and affect demonstrated no significant differences regarding between‐group mean changes, neither did caregivers’ burden, which showed decreasing tendencies of burden in the intervention and control group (Zarit Burden Interview, ‐2.7±8.7 vs. ‐4.4±6.4, p=0.2552). Qualitative findings revealed that participants had positive attitudes regarding Coach Pepper and experienced it as neutral in terms of burden. Some stated that Coach Pepper provided relief/more free time by entertaining the persons with dementia. However, some participants stated that they had to invest additional time until the person with dementia was able to engage with Coach Pepper and that its usability should be improved in certain areas (e.g., communication) to constitute more support for caregivers.ConclusionCoach Pepper had no significant psychosocial effects on informal caregivers of people with dementia. Qualitative findings demonstrated the participants' positive attitudes but highlighted a need for improvement regarding its usability. This study contributes to the development/modification of Coach Pepper based on caregivers’ needs in dementia care.
Web application for single‐case AD subtyping and staging based on SuStaIn model
Authors: Archetti Damiano , Oxtoby Neil P. , Alexander Daniel C. , Redolfi Alberto 
Published: December 2021

AbstractBackgroundIn recent years, statistical and machine learning algorithms allowed advancements in many fields of healthcare research, but such methods are still mostly used by technical experts. Their implementation in user‐friendly software/web interfaces is fundamental for their broader adoption by patient‐facing physicians.MethodA validated SuStaIn (Young et al, 2019, https://doi.org/10.1038/s41467-018-05892-0) model for atrophy patterns in Alzheimer’s Disease (AD) was used as core for a web application. The model was trained using volumes of relevant brain regions of 1031 subjects from the Alzheimer’s Disease Neuroimaging Initiative and validated using 731 subjects from the OASIS, PharmaCog and ViTA Cohorts. Biomarkers used to train and validate the model were corrected against the effects of age, sex, education, APOE genotype and total intracranial volume (TIV). The model was exploited in the web application for single‐case scenarios. The user is required to input age and sex of the subject and upload an MRI scan which is processed with Freesurfer 5.3 to extract relevant brain volumes. Volumes are corrected against the effects of sex, age and TIV and converted into z‐scores used to compute the most likely among the three subtypes defined by the model and stage the subject on the relative z‐scores progression sequence. Results are summarized in a report (Fig. 1) and sent to the user via e‐mail. The web application skips the correction against education and APOE genotype as these factors may be unavailable and their influence on volumes should be minor. The validity of the different correction procedure was tested by subtyping and staging 50 subjects from the training set using the web application. Outputs were compared with the results of the validated model.ResultThe web application was built and deployed on the neuGRID platform, and it is available at https://www.neugrid2.eu/index.php/ml-tools/sustain/. All subjects tested on the web application were assigned the same subtype as the validated model, although an average difference equal to 2.2 positions was observed for the staging.ConclusionThis web application implementing a SuStaIn model for AD atrophy subtypes represents a first example of advanced data‐driven algorithms implemented in a user‐friendly tool usable by clinicians in daily practice.
BDNF shown to partially mediate greater verbal learning performances in women as compared to men in a cohort enriched with risk for Alzheimer’s disease
Authors: Edmunds Kyle J. , Mamlouk Gabriella M. , Okonkwo Ozioma C. , Rogers Christine C. 
Published: December 2021

AbstractBackgroundIt is established that the sex‐based prevalence of Alzheimer’s disease (AD) is greater in women, though the mechanisms underlying this difference are not well understood. Furthermore, in cognitively normal adults, women consistently score higher than men in verbal learning ability, a primary domain of cognitive function sensitive to decline from AD progression. The sex‐specific mechanisms of action of brain‐derived neurotrophic factor (BDNF), a growth factor important for memory and long‐term brain health, may explain observed sex‐based differences in cognitive decline. The purpose of this study was to investigate whether sex‐based differences in verbal learning and memory (VLM) are mediated by BDNF expression in a cohort of cognitively normal adults at risk for AD.MethodWisconsin Registry for Alzheimer’s Prevention (WRAP) participants (n=201, age 63.81±6.04, 66.2% women, 65.7% family history of AD, 38% APOE‐ε4 carriers, without known cognitive decline) underwent the Rey Auditory Verbal Learning Test (RAVLT), trials 3‐5 and delayed recall, to assess VLM function. BDNF serum levels were measured using Human BDNF Quatikine Immunoassay DBD00 from R&D Systems. Mediation analysis was performed using the Hayes and Preacher macro for IBM SPSS, adjusting for age, time between variable collection, APOE‐ε4 status, parental AD history, and hippocampal volume.ResultRegression models indicated significantly higher levels of BDNF in women (F(6,191)=2.38, p=0.031, R2 =0.07, β=‐2280.89, t(191)=‐2.52). Women were found to have significantly higher VLM scores (F(6,191)=7.22, p<0.0001, R2=0.18, β=‐0.68, t(191)=‐4.58). Greater BDNF levels indicated higher VLM scores (β<0.00, t(190)=2.49, p=0.014). Controlling for BDNF as a mediator attenuated the effect of sex on VLM, indicating partial mediation from BDNF (β=‐0.61, t(190)=‐4.12, p=0001).ConclusionThis study shows that BDNF level partially mediates the higher scores of women in VLM in a cohort of cognitively normal adults at‐risk for AD, suggesting that sex‐specific differences in BDNF expression may partially explain the differing prevalence of AD between the sexes. However, this difference is likely due to many additional factors, and it is still unknown whether this relationship persists throughout clinical AD. Research is needed on the relationship between BDNF, sex, and VLM in individuals with cognitive impairment, as well as the direct interactions between these factors.