bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of smartphone app‐based cognitive training on cognition in community‐dwelling elderly: A randomized controlled trial
Authors: Jang Hyemin , Kim Hee Jin , Seo Sang Won , Na Duk L 
Published: December 2020

AbstractBackgroundMost of previous cognitive intervention studies provided group cognitive intervention for a short period of time, which are limited by requirement of money, time, and space in real clinical circumstances. Therefore, easily accessible way of cognitive training should be developed and tested in a large cohort of the elderly. We investigated the effectiveness of smartphone app (InBrain Trainer) based cognitive training for 12 months on cognitive improvement in the community‐dwelling healthy elderly.MethodThis App‐based Cognitive Training at Home (ACTH) study is a randomized, single‐masked, parallel group study, which was conducted between March 2018 to August 2019 at Gangnam Center for Dementia, in Seoul, South Korea. We recruited 389 healthy volunteers aged over 60 and they were randomly assigned to the intervention or control group. The intervention group experienced daily app‐based cognitive training at home (with regular feedback from administrator) and monthly group cognitive training for 12 months. All participants underwent cognitive screening test (CST) at baseline, 6 and 12 months. The primary outcome was the change in total composite score on CST, and the secondary outcomes included changes in composite scores of five cognitive domains, which were assessed using linear mixed effects models.ResultWhen the intervention‐by‐visit interaction effect was investigated, the intervention group showed a larger increase on total scores (p < 0.001 at 6 months, p = 0.001 at 12 months), on language (p <0.001 both at 6 and 12 months) and memory composite scores (p=0.006 at 6 months, p<0.001 at 12 months) compared to the control group. There was no significant difference in changes at 12 months in attention (p=0.72), visuospatial (p=0.994) and executive composite scores (p = 0.929) between the intervention and the control group. (Figure 1)ConclusionThis study demonstrated that app‐based cognitive training could enhance general cognition in the healthy elderly. Therefore, this cognitive training tool could be usefully utilized for the purpose of preventing cognitive decline on a community basis.
Threshold of white matter hyperintensity volume determines negative and positive associations between grey matter volume and hypertension
Authors: Vipin Ashwati , Wong Benjamin , Kumar Dilip , Low Audrey , Ng Kok Pin , Kandiah Nagaendran 
Published: December 2020

AbstractBackgroundHypertension and white matter hyperintensity(WMH) burden are major risk‐factors for Alzheimer’s disease[Pantoni et al.,2010;Sweeney et al.,2018]. Prior studies show variable grey matter alterations, involving both negative and positive associations, independently related to WMH and hypertension in early stages of late‐onset AD[Vipin et al.,2018;Foster‐Dingley et al.,2015;Tuladhar et al.,2015;Den Heijer et al.,2003]. However, the effect of incremental WMH load and concomitant hypertension on brain structure in young‐onset mild cognitive impairment(MCI) remains to be elucidated. Such investigations may provide better insight into relationships between WMH, hypertension and dementia risk. We thus examine the influence of increasing WMH load on grey matter volume(GMV) as well as on the association between blood pressure(BP) and GMV in young‐onset MCI. We hypothesize that WMH burden and BP will have derogatory effects on GMV, especially under high WMH conditions.MethodT1‐MRI data from 78 MCI subjects(<65years) from the Singapore‐YouNg‐Dementia‐Cohort was studied. WMH load was divided into low(0.00‐1.49ml), medium(1.50‐4.99ml) and high(>5.00ml). Voxel‐based morphometry(VBM) assessed whole‐brain voxel‐wise changes related to increasing WMH load between hypertensive(systolic‐BP>130mmHg)[Whelton et al.,2017] and non‐hypertensive subjects. Pearson’s correlation analysis tested associations between GMV from key Executive‐Control‐Network(ECN) and Default‐Mode‐Network(DMN) regions‐of‐interest(ROI)[Shirer et al.,2012] and vascular risk‐factors.ResultWhole‐brain VBM revealed less GMV reduction in hypertensive compared to non‐hypertensive subjects in frontal and temporal regions at low‐WMH load, with more pronounced effects at medium‐WMH load (Fig.1;uncorrected‐p<0.001, cluster‐size‐threshold:p<0.05). However, at high‐WMH load, hypertensive and non‐hypertensive subjects showed no differences in GMV. Additionally, at low‐WMH load, average and ROI‐specific DMN(bilateral posterior‐cingulate‐cortex, precuneus;p<0.05) and ECN(left[p<0.05] and right[p<0.10] posterior‐parietal‐cortex) GMV related positively to WMH but showed no association at medium‐WMH load. Importantly, only high‐WMH load was associated with lower ECN(p<0.05) and DMN(p<0.10) GMV(Fig.2). These associations remained regardless of hypertension status. Additionally, high systolic‐BP related to lower GMV at high‐WMH load only(Fig.3).ConclusionOur findings indicate that in young‐onset MCI, the relationship between WMH and GMV is determined by WMH load rather than hypertension status. WMH load also influences the relationship between systolic BP and GMV in young‐onset MCI. Importantly, our results suggest that WMH and hypertension influence GMV via different mechanisms and BP recommendations for dementia prevention may be different in MCI with and without WMH.
Correlation of protein tau and amyloid beta aggregates neuroinflammation and oxidative stress in 5xFAD and P301S mice
Authors: Rejc Luka , Group Kosmrlj 
Published: December 2020

AbstractBackgroundThe deposition of protein tau (Tau) and amyloid beta (Aβ) aggregates during Alzheimer disease (AD) is accompanied by other processes, mostly controlled by glial activation. Despite numerous attempts, there is little information on the role of these processes in the disease mechanism. Exact mapping and correlation of pathological changes would give information that could help reveal underlying causes for the onset of the disease. We set off to longitudinally investigate and correlate disease related processes in the brains of 5xFAD and P301S mice models.MethodNeuroinflammation and oxidative stress in P301S and 5xFAD transgenic (tg) mice were monitored longitudinally by PET‐CT imaging and compared to age‐matched healthy controls (WT). PET imaging using [18F]DPA‐714, [18F]FSPG, [18F]florbetaben, and [18F]EFAPEM1 was performed to assess levels of neuroinflammation, oxidative stress, Aβ load (5xFAD mice) and Tau aggregates (P301S) load, respectively. Uptake in the cortex (CTX) was presented as SUV or SUVr when a reference region was available. IHC staining of brain slices for Aβ, Tau deposits, neuroinflammation and oxidative stress is currently in progress.ResultPET‐CT studies showed increase of levels of Tau deposits at 8 month‐old P301S mice and Aβ levels at 6, 8 and 10 month‐old 5xFAD mice. For 5xFAD mice, [18F]DPA‐714 and [18F]FSPG uptake followed the trend of Aβ deposition, peaking at 8 months. Compared to WT mice, four‐fold increase in [18F]DPA‐714 (p<0.0001) and three‐fold increase in [18F]FSPG (p=0.0019) SUV was observed, suggesting protein deposits‐induced increase in inflammation and oxidative stress. Surprisingly, neuroinflammation and oxidative stress did not follow the trend of Tau deposition in P301S mice.ConclusionLongitudinal deposition of Aβ and Tau was in accordance with reported ex vivo data for the two animal models. Neuroinflammation and oxidative stress correspond well with the levels of Aβ, longitudinally. The two processes also occur in P301S mice brain but correspond poorly with Tau deposition. These results suggest that either Aβ and Tau aggregates affect neuroinflammation and oxidative stress differently, or that neuroinflammation and oxidative stress are independent processes. Further studies are in progress to confirm the observed data.
Masupirdine (SUVN‐502): Novel treatment option for the management of behavioral and psychological symptoms in patients with Alzheimer’s disease
Authors: Nirogi Ramakrishna , Jayarajan Pradeep , Shinde Anil K , Abraham Renny , Goyal Vinod Kumar , Benade Vijay , Ravulu Jyothsna , Jasti Venkat 
Published: December 2020

AbstractBackground5‐hydroxytryptamine‐6 (5‐HT6) receptors are G‐protein coupled receptors localized in the brain regions primarily involved in cognition and behavior i.e., cortex, dorsal hippocampus and striatum. Evidence from the studies in animal models suggests that 5‐HT6 receptor antagonist may have a potential role in controlling behavior and psychosis. Masupirdine is a pure 5‐HT6 receptor antagonist under clinical development for the management of AD and behavioral and psychological symptoms.MethodTriple therapy with masupirdine added to background dual combination treatment with donepezil and memantine was evaluated in a phase‐2 proof‐of‐concept, 26‐week, randomized, double‐blind, placebo‐controlled, multicenter, parallel groups study conducted across several sites in the United States. In this study, effects of masupirdine on the neuropsychiatric symptoms and cognition were evaluated using the Neuropsychiatric Inventory (NPI‐12) and Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS‐Cog 11), respectively in patients with moderate AD.ResultOut of 564 randomized patients, 183 patients received placebo, 184 patients received 50 mg of masupirdine and 176 patients received 100 mg of masupirdine. Masupirdine attenuated the agitation/aggression scores in the subgroup of patients who had baseline agitation/aggression. The effect observed was above the minimum clinically important difference (0.4 SD). In another subgroup of patients, masupirdine attenuated the psychotic symptoms (delusions and hallucinations) and also emergence of psychotic symptoms. Significant reduction in the cognitive decline was also noticed with masupirdine treatment in the subgroups of patients having psychotic symptoms. Masupirdine was generally safe and well tolerated in this study.ConclusionMasupirdine treatment significantly reduced the behavioral and psychological symptoms i.e., agitation/aggression and psychotic symptoms (delusions and hallucinations) with positive effect on cognition. Masupirdine could be a differentiated novel therapeutic treatment option for the management of behavioral and psychological symptoms in patients with AD.
Masupirdine (SUVN‐502): A pure 5‐HT6 receptor antagonist ameliorates aggression‐like behavior in animal models
Authors: Tadiparthi Jayaprakash , Ganuga Narender , Grandhi Venkata Ramalingayya , Medapati Rajesh Babu , Kamuju Venkatesh , Gandipudi Sudhakar , Reballi Veena , Jayarajan Pradeep , Nirogi Ramakrishna 
Published: December 2020

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) are the common behavioral changes observed in patients with Alzheimer’s disease (AD). More than 90% of people with dementia develop at least one BPSD over a 5 years time period with around 85% of patients experiences serious clinical implications. Serotonin‐6 receptor (5‐HT6R) is a G protein‐coupled receptor and is localized almost exclusively in the central nervous system including cerebral cortex and hippocampus which are important for control of mood regulation. Masupirdine is a 5‐HT6R antagonist currently in the clinical development for the management of Alzheimer’s disease.MethodMasupirdine was evaluated for its anti‐aggressive like effects in one of the most popular preclinical aggression model i.e. Resident‐Intruder task (RIT). Male CD1 mice were used to assess the anti‐aggressive like effects in RIT. Resident animals were habituated with ovariectomized female mice and intruders were habituated socially for a period of 7 days. On day 8 and 9, basal aggression level was assessed by placing an intruder animal in the home cage of resident animal for a period of 10 min. On day 11, animals were randomized based on duration of attack and aggression level was assessed post treatment. In the control group, vehicle was administered to resident animals and for remaining groups, masupirdine was administered at doses of 1, 3 and 10 mg/kg, p.o. Additionally, masupirdine was evaluated for its effects on neurotransmitters that are involved in the modulation of behavioral and psychological symptoms using rats. Suitable statistical analysis is carried by GraphPad Prism (Version 4).ResultVehicle treated group showed almost equal duration of attack with respect to basal whereas, masupirdine significantly decreased the aggressive behavior of resident animal towards intruder at all tested doses with respect to basal. Treatment with masupirdine produced significant increase in the cortical levels of dopamine and norepinephrine. These neurochemical changes by masupirdine provide the support for anti‐aggressive behavior observed in preclinical models.ConclusionResults from the current preclinical studies indicate the promising therapeutic potential for masupirdine in the treatment of agitation/aggression.
Music‐with‐movement intervention for people with mild/early cognitive impairment: An effectiveness‐implementation hybrid cluster randomized controlled trial
Authors: Cheung Daphne Sze Ki , Lai Daniel Lok Lam , Ho Lily Yuen Wah , Lai Claudia KY 
Published: December 2020

AbstractBackgroundA caregiver‐delivered, home‐based music‐with‐movement intervention (MM) for people with early dementia has been shown to reduce anxiety symptoms. Yet, caregivers reported their struggles when implementing the intervention, which reduced their motivation to sustain the intervention at home. This study is to evaluate the effectiveness of the strategies for overcoming the implementation challenges identified in the previous research and to investigate the efficacy of the intervention on psychosocial well‐being of people with mild/early cognitive impairment.MethodThis was a multi‐centre, two‐arm, cluster randomized controlled, effectiveness‐implementation hybrid trial. The program was designed to improve the psychosocial well‐being of people with mild/early dementia. Partnered centres were randomized into the intervention or wait‐list control groups, and the families recruited by them followed the group allocation correspondingly.Seven community partners recruited eighty families from different districts in Hong Kong. Intervention participants received a 12‐week MM intervention, delivered by trained family caregivers at home, and trained staff and volunteers in the centres. Participants in the control group received the identical programme after data collection.Implementation strategies included (1) partnering with different types of community service sectors for recruiting families; (2) training centre staff and volunteers for delivering the intervention and providing support; (3) using information and communication technology (ICT) for disseminating intervention materials, communication, and fidelity monitoring; and (4) introducing centre‐based activities for enhancing programme sustainability. To assess program efficacy (psychosocial well‐being) and implementation outcomes (acceptability, fidelity, practicality and sustainability), multi‐method and multi‐informant assessment strategies were used including clinical assessments, observation and interview.ResultCaregivers, volunteers and staff of the centres welcomed the use of ICT, which facilitated the delivery of the intervention. Four elderly centres have continued to use the MM programme as their routine services. The findings showed that the programme was effective in improving anxiety and depressive symptoms of elderly participants and reducing stress level of family caregivers. Booster training may need to be introduced to ensure the fidelity of intervention delivery.ConclusionThis study demonstrated that adaptive strategies were effective in overcoming the implementation challenges and the intervention helped the target population improve their emotional well‐being.
In‐vivo imaging of retinal amyloid in Alzheimer’s disease patients using curcumin as labeling fluorophore
Authors: de Ruyter Frederique Jasmine Hart 
Published: December 2020

AbstractBackgroundThe retina is increasingly recognized as a promising target to identify early changes associated with Alzheimer’s disease (AD) (London, Benhar, & Schwartz, 2013). Previous studies showed retinal amyloid in AD patients in‐vivo and in post‐mortem retinal tissue of AD patients (Koronyo et al., 2017; Koronyo‐Hamaoui et al., 2011). The objective of this proof‐of‐concept study is to non‐invasively visualize amyloid‐beta (Aß)‐plaques in the retina of AD patients with a multispectral scanning laser ophthalmoscope (mSLO), using curcumin as labeling fluorophore.MethodTwenty‐two subjects with early‐onset AD (age<70, MMSE>16) and four matched controls were recruited from the Amsterdam Dementia Cohort. Subjects underwent imaging with the mSLO at baseline and after curcumin intake. Blood samples were taken at different time points for curcumin bioavailability analysis. Three sub studies were performed with different curcumin supplements (Theracurmin™, Novasol™ and Longvida™) in different dosages and duration of intake. In all three cohorts mSLO imaging was performed with three excitation wavelengths (486nm (blue) and 518nm (green)) in order to separate retinal autofluorescence from curcumin fluorescence. Retinal fluorescence images were visually assessed.ResultBaseline fluorescence images showed no abnormalities in both AD‐patients and controls. Imaging using two excitation wavelengths showed no plaque‐like alterations in the retina after curcumin intake with any of the supplements. Blood analysis showed no detectable levels of free curcumin after Theracurmin or Novasol intake curcumin (results from the Longvida cohort are in preparation), however we did find curcumin conjugates with resembling binding characteristics as curcumin (den Haan, Morrema, Rozemuller, Bouwman, & Hoozemans, 2018).ConclusionNo difference in fluorescence before and after curcumin intake was observed in this cohort of early‐onset AD patients. This may be due to insufficient uptake of curcumin, a low curcumin signal to retinal fluorescence ratio and/or absence of retinal amyloid plaques. Given the discrepancies in literature (den Haan et al., 2018; Ho, Troncoso, Knox, Stark, & Eberhart, 2014; Schon et al., 2012; Williams et al., 2017) patient cohorts including both early and late onset AD as well as replication of post‐mortem studies are needed to unequivocally proof amyloid presence in AD retinas, as potential target for in‐vivo retinal imaging.
Investigating proteostasis in development and disease using IPSC‐neurons with MAPT mutations linked to FTD
Authors: Lines Georgie , Wray Selina , Lovejoy Christopher E.J. , Arber Charles , Casey Jackie M. , Alatza Argyro 
Published: December 2020

AbstractBackgroundMutations in the microtubule‐associated protein tau (MAPT) are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, such as high levels of tau phosphorylation, are also present in early development. iPSC‐neurons have gene expression signatures similar to fetal neurons, and iPSC‐neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC‐neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis we investigated the RNA and protein levels of proteasome subunits (B5, RPT6, PSMD11) and associated proteins (TRIM11, BAG3) in developing MAPT mutated iPSC derived neurons.MethodsHuman cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at Days 0, 10, 30 and 100, spanning the different stages of neurogenesis.ResultsGene and protein expression of the core proteasome subunit B5 remains consistent throughout development. The expression of regulatory proteasome subunits PSMD11 decreases at both the protein and RNA level. RPT6 decreases at the protein level but increases at the RNA level. BAG3 significantly decreases at the protein level. There is no significant difference in protein expression between disease and WT lines.ConclusionThis data indicates that the core 20S proteasome unit remains at consistent levels throughout development, however the expression of regulatory subunits differ. A change in regulatory subunit expression could have a direct impact on the ability of the proteasome to degrade proteins. Ongoing work is using proteasome activity assays to determine how this changes through development and is impacted by MAPT mutations.
Functional brain network correlates of theory of mind and social cognition in early Alzheimer’s disease
Authors: Valera‐Bermejo Jose Manuel , Mitolo Micaela , Cerami Chiara , Dodich Alessandra , de Marco Matteo , Venneri Annalena 
Published: December 2020

AbstractBackgroundPatients in the early stages of Alzheimer’s disease (AD) may display impairment of social cognition (SC) such as the ability to attribute intentions, beliefs or emotions to others (Theory of Mind, ToM). In healthy subjects, SC relies on multi‐network interactions that modulate brain social processing. Therefore, specific pathological changes in multiple large‐scale networks could explain the heterogeneous results of SC performance in AD found across the literature. To date, there is no resting‐state connectivity study investigating the network underpinnings of SC in AD patients.MethodsResting‐state functional MRI scans were acquired from early‐AD patients (n=46) and preprocessed using the Statistical Parametric Mapping (SPM) 12 software. Independent component analysis (ICA) was performed at a group level to isolate and reconstruct four intrinsic connectivity brain large‐scale networks, namely fronto‐parietal, salience, and anterior and posterior default mode networks (DMN). Multiple regression analyses were performed on three SC tasks of emotion recognition (ER) (Ekman 60 face task) and ToM (Reading‐the‐Mind‐in‐the‐Eyes‐Test, RMET and the Story‐based Empathy Task, SET) with the ICA extracted large‐scale network maps, controlling for age, cognitive reserve, brain reserve and disease severity.ResultsSC associations with functional connectivity maps showed positive correlations (increased intrinsic connectivity) between ER and the fronto‐parietal network in the right insular region (p <0.034) and ToM (SET) with the posterior DMN in the right precuneus (p <0.030). Conversely, negative associations (decreased intrinsic connectivity) were found between ToM‐RMET (p < 0.011), ToM‐SET (p< 0.049) and ER (p < 0.034) and the salience network in the left temporo‐parietal junction, precuneus, uncus, inferior temporal gyrus and right postcentral gyrus. Lastly, a negative association was found between ToM‐RMET and the anterior DMN (p < 0.013) in the right medial prefrontal cortex.ConclusionsThis study sheds light on how multiple network dynamics exhibit particular connectivity dissociation patterns of social processing in AD. Specific neural reorganisation via up‐regulation of the posterior DMN and fronto‐parietal network concomitant with a down‐regulation of the salience and anterior DMN could explain the characteristic pattern of decline of SC in AD. Notably, our results display consistency with regions involved in SC and ToM.