bluuebunny/crossref_metadata_2025 huggingface dataset:
RuRh Bimetallene Nanoring as High‐efficiency pH‐Universal Catalyst for Hydrogen Evolution Reaction
Authors: Mu Xueqin , Gu Jiani , Feng Feiyan , Xiao Ziyin , Chen Changyun , Liu Suli , Mu Shichun
Published: December 2020

Electrocatalysis of the hydrogen evolution reaction (HER) is a vital and demanding, yet challenging, task to produce clean energy applications. Here, the RuRh2 bimetallene nanoring with rich structural defects is designed and successfully synthesized by a mixed‐solvent strategy, displaying ascendant HER performance with high mass activity at −0.05 and −0.07 V, separately higher than that of the commercial Pt catalyst. Also, it maintains steady hydrogen bubble evolution even after 30 000 potential cycles in acid media. Furthermore, the RuRh2 bimetallene nanoring shows an outstanding activity in both alkaline and neutral media, outperforming that of Pt catalysts and other reported HER catalysts. A combination of atomic‐scale structure observation and density functional theory calculations demonstrates that both the grain boundaries and symmetry breaking of RuRh2 bimetallene cannot only weaken the adsorption strength of atomic hydrogen, but also facilitate the transfer of electrons and the adsorption of reactants, further boosting the HER electrocatalytic performance in all pH values.
Cold tolerance of diverse stevia cultigens under controlled environment conditions
Authors: Kozik Elzbieta U. , Yücesan Buhara , Saravitz Carole , Wehner Todd C.
Published: December 2020

Low temperature is a major limiting factor for the growth and development of many crops, including stevia (Stevia rebaudiana Bertoni), a natural low‐calorie sweetener. In this study, 14 stevia half‐sib families selected from several populations were evaluated for chilling stress using controlled growth chambers. The experiment was set up as a split‐plot arrangement in a randomized complete block design. Whole plots were chilling temperatures (2, 0, –2, or ‐4 °C) and subplots were the combination of 14 cultigens and 5 chilling durations (2–10 d of chilling). Genetic differences were large at chilling temperatures of +2 °C for a duration of 10 d, 0 °C for 8 d, or –2 °C for a duration of 6 d. Ten days of chilling induced severe damage in all cultigens except for the three with the highest tolerance (7947‐3, 7918‐1, and 7686‐6). In this study, 5 of 14 cultigens were highly susceptible, 8 were moderately susceptible, and 1 was tolerant after 6 d of chilling at –2 °C (7947‐3).
Low‐Power Computing with Neuromorphic Engineering
Authors: Liu Dingbang , Yu Hao , Chai Yang
Published: December 2020

The increasing power consumption in the existing computation architecture presents grand challenges for the performance and reliability of very‐large‐scale integrated circuits. Inspired by the characteristics of the human brain for processing complicated tasks with low power, neuromorphic computing is intensively investigated for decreasing power consumption and enriching computation functions. Hardware implementation of neuromorphic computing with emerging devices substantially reduces power consumption down to a few mW cm−2, compared with the central processing unit based on conventional Si complementary metal–oxide semiconductor (CMOS) technologies (50–100 W cm−2). Herein, a brief introduction on the characteristics of neuromorphic computing is provided. Then, emerging devices for low‐power neuromorphic computing are overviewed, e.g., resistive random access memory with low power consumption (< pJ) per synaptic event. A few computation models for artificial neural networks (NNs), including spiking neural network (SNN) and deep neural network (DNN), which boost power efficiency by simplifying the computing procedure and minimizing memory access are discussed. A few examples for system‐level demonstration are described, such as mixed synchronous–asynchronous and reconfigurable convolution neuron network (CNN)–recurrent NN (RNN) for low‐power computing.
Distinct neuropsychological presentation and progression between early‐ and late‐onset Alzheimer’s disease
Authors: Tort‐Merino Adrià , Balasa Mircea , Olives Jaume , Contador José , Falgàs Neus , Castellví Magdalena , Juncà Jordi , Borrejo‐Écija Sergi , Bosch Beatriz , Fernández‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Rami Lorena , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2020

Background

Early‐onset Alzheimer’s disease (EOAD, onset before 65 years), is the most common early‐onset neurodegenerative dementia. However, it still represents a diagnostic challenge especially when compared with late‐onset Alzheimer’s disease (LOAD). Our aim was to describe and compare the neuropsychological presentation at diagnosis and its progression in patients with EOAD and LOAD.

Methods

One‐hundred ninety‐five participants were included and classified accordingly to their CSF AD biomarker profile and clinical status: 46 young controls (Y‐CTR) aged below 65 years (age=57.4±4.7; MMSE=28.7±1.6), 23 old controls (O‐CTR) aged 65 or above (age=69.7±3.7; MMSE=28.0±1.4), 89 EOAD (age=59.8±4.2; MMSE=22.6±3.9) and 37 LOAD (age=74.5±4.8; MMSE=24.3±3.1). All subjects underwent clinical and neuropsychological assessment, APOE genotyping and lumbar puncture at baseline. Clinical and neuropsychological follow‐up was performed annually over 2 years.

Results

No differences were found in terms of gender or years of education among the study groups. APOE4 was more frequent in EOAD and LOAD groups than controls (p<0.01). As expected, the control groups presented higher CSF Aβ42 and lower CSF tau and p‐tau levels than AD groups (Table 1). Baseline neuropsychological assessment (Figure 1) revealed differences between EOAD and LOAD in global cognitive function (p<0.05), ideomotor (p<0.05) and constructional (p<0.01) praxis, visuoperceptive (p<0.05) and visuospatial (p<0.01) function and working memory (p<0.05). When comparing controls and AD groups, EOAD performed significantly worse than Y‐CTR in all cognitive domains while LOAD showed differences with O‐CTR in memory, language and executive function but obtained a similar performance in ideomotor and constructional praxis, visuospatial function, attention and working memory. Longitudinally (Figure 2), no differences between EOAD and LOAD were observed on memory or language domains but EOAD showed higher decline in global cognitive function (p<0.05), ideomotor (p<0.05) and constructional (p<0.01) praxis, visuoperceptive (p<0.05) and visuospatial (p<0.01) function, attention (p<0.05) and working memory (p<0.05).

Conclusions

Early‐ and late‐onset AD present distinct neuropsychological profiles at diagnosis with EOAD displaying higher difficulties in non‐memory domains and a more aggressive course. The present data may help on enhancing EOAD diagnosis and therefore on ensuring an earlier intervention in this population.
Stakeholder engagement for successful practice change in long‐term care: Evaluating the Feasible and Sustainable Culture Change Initiative (FASCCI) model
Authors: Caspar Sienna
Published: December 2020

Background and Objectives

Interventions aimed at increasing the provision of relational and person‐centred care in long‐term care (LTC) homes that do not address contextual and system issues most often fail. Promoting positive change in LTC homes requires a multilevel, systems approach. The objective of this study was to evaluate the feasibility and effectiveness of the Feasible and Sustainable Culture Change Initiative (FASCCI) model for change for improving the provision of person‐centred mealtime practices in a LTC home.

Methods

A single‐group, time series design was used to assess the impact of the FASCCI model for change on outcome measures across four time periods (pre‐intervention, 2‐month, 4‐month and 6‐month follow‐up). Mealtime observations (n=38) using the Mealtime Scan (MTS+) were completed over the course of six‐months in a single dining room. Interviews (n=21) were also conducted to examine treatment fidelity and to ascertain the study participants’ perceptions of the process for making improvements using the FASCCI model.

Results

We observed increases in care staffs’ capacity to consistently provide relational and person‐centred care during mealtimes. Mealtime environment scores started increasing immediately following the intervention, with statistically significant improvements noted in all mealtime environment scales by six‐months, including the: physical environment (z=‐3.43, p=0.004); social environment (z=‐4.17, p<0.001); relationship‐centred care (z= ‐4.121, p<0.001); and overall quality of dining environment (z= ‐4.08, p<0.001). Analysis of data from qualitative interviews demonstrated that use of the FASCCI model resulted in improved team leadership, communication, and collaborative decision‐making.

Conclusions

This study offers evidence that the FASCCI model provides a promising approach for improving the provision of relationship‐centred mealtime practices in LTC homes. Our findings reinforce the importance of cultivating and implementing workforce practices that increase staff empowerment and enable and encourage collaborative decision‐making. We found these practices to be essential to the outcomes associated with the improved relationship‐centred care practices that occurred during this study. This is consistent with the small but growing body of evidence demonstrating that staff empowerment has a significant effect on overall quality of resident care.
Measuring dose in a tailored lighting intervention to improve sleep and mood in Alzheimer's disease patients
Authors: Figueiro Mariana G , Page Erik , Rea Mark S
Published: December 2020

Background

Daytime light helps consolidate sleep in persons with Alzheimer's disease and related dementia (ADRD), but light levels required are high and available lighting fixtures cannot deliver the light level and spectrum needed for the circadian system. Moreover, ambient light levels cannot be measured to determine treatment dose. The present study tested whether a tailored lighting intervention could improve sleep in eight ADRD patients living in long‐term care facilities and used a novel device to measure light dose (RAD).

Method

In a crossover, repeated‐measures design, we exposed ADRD participants (MMSE<24) to an active (circadian stimulus, CS=0.3) and inactive (CS=0.1) tailored lighting intervention for successive 4‐week periods, spaced by a 4‐week washout period. RAD devices, calibrated to measure circadian light, were placed in spaces where the intervention was administered. The lighting intervention was energized from wake time until 6:00 pm. Measures of sleep disturbances (Pittsburgh Sleep Quality Index, PSQI and actigraph) and mood (Cornell Scale for Depression in Dementia, CSDD) were collected at baseline and during the last weeks of each intervention periods.

Result

Compared to their respective baseline conditions, the active lighting intervention significantly decreased wake percent and increased sleep percent. Compared to baseline and to the inactive intervention, PSQI scores reduced in the active intervention. Depression scores were significantly lower after the active than after the inactive intervention. The mean ± SEM PSQI scores was 10.9±1.1 and 7.3±0.7 at baseline and after active intervention and 10.0±1.0 and 10.3±1.6 at baseline and after the inactive intervention. The mean ± SEM CSDD scores was 9.0±1.7 and 8.0±1.3 at baseline and after active intervention and 12.0±1.6 and 12.0±2.1 at baseline and after the inactive intervention.

Conclusion

When carefully delivered to patients’ eyes and monitored with a calibrated instrument, daytime light can improve sleep and mood in nursing home residents with AD/ADRD. Additional data need to be collected to extend these preliminary results.
Non‐pharmacological management of Alzheimer's disease: A qualitative study in Mauritius
Authors: Dorkhy Geeta Devi , Goorah Smita
Published: December 2020

Background

The major form of dementia is Alzheimer’s disease (AD). In Mauritius it was estimated in year 2015 that around 12,000 persons had Alzheimer’s disease (Alzheimer disease International). Many of the pharmacological therapies provide only modest results in AD. Therefore, apart from pharmacological therapies, non‐pharmacological treatment (NPT) which can influence cognitive performance such as cognitive training, occupational therapy, reminiscence therapy, are being highly investigated. The only NGO in Mauritius is “Alzheimer’s Association”, from where the persons with AD were recruited.

Method

Non‐interventional methods of qualitative study was carried out with in‐depth semi‐structured, one‐to‐one interviews lasting 30‐45 minutes. This was audio recorded. An informed consent from the carer or patient‐relative prior to starting was ensured. Open‐ended questions were used, relating to NPT, to yield in‐depth responses about people’s experiences, perceptions, opinions, feelings, and knowledge. Data analysis of qualitative research data proceeded with coding and decoding.

Result

Qualitative study (n=20) emerged with 7 main themes. Among these, dependency on family was identified as an important theme. Responses of the person with AD was mainly related to their experiences, perceptions, opinions, feelings, and various levels of dependency.

Conclusion

Non‐pharmacological interventions has an important role to prolong the active age of older individuals, as well as to maintain quality of life. There is still a greater demand on the market for non‐pharmacological interventions and Mauritius should plan and devise national guidelines to deal with the unmet proportion of elderly so as to curb for future health equality and stability.
Modulation of histone deacetylase 2 (HDAC2) drives neuronal gene expression, mitochondrial dynamics and AD pathophysiology in human stem cell derived neurons
Authors: Frankowski Harald , Berry Bonnie J. , Yeboah Fred , Evitts Kira , Kinoshita Chizuru , Kinoshita Yoshito , Morrison Richard S. , Young Jessica E.
Published: December 2020

Background

Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. Aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression has been implicated in Alzheimer’s disease (AD) and brain aging. In vitro models of AD and other neurodegenerative disorders using human induced pluripotent stem cells (hiPSCs) are being increasingly utilized and have provided novel insights into disease mechanisms. However, the role of HDAC2 in living, human neurons and how its manipulation in an AD model may affect disease phenotypes has not been investigated.

Method

We used human induced pluripotent stem cells and lentiviral‐mediated manipulation of HDAC2 in hiPSC‐derived neurons to study the effects of increasing or decreasing HDAC2 expression on neuronal mitochondrial gene expression, morphology, and AD phenotypes.

Result

In this study, we show that levels of HDAC2 naturally decrease as hiPSCs are differentiated towards a neuronal lineage and that this suppression of HDAC2 inversely corresponds to an increase in neuronal‐specific isoforms of Endophilin‐B1, a multifunctional protein involved in mitochondrial dynamics. Manipulation of HDAC2 and Endophilin‐B1 using lentiviral approaches shows that knock‐down of HDAC2 or overexpression of Endophilin‐B1 promote mitochondrial elongation in hiPSC‐derived neurons, but HDAC2 knock‐down specifically influences genes regulating neuronal mitochondrial dynamics. We also observe that the endogenous decrease in HDAC2 levels upon neuronal differentiation also correlates with natural increases in neuronal activity and knock‐down of HDAC2 in differentiated neurons increases expression of genes related to neuronal synapses and further increases neuronal firing. Finally, we demonstrate that knock‐down of HDAC2 reduces amyloid beta peptides and the phospho/total Tau ratio in iPSC‐derived neurons.

Conclusion

Collectively, our study demonstrates that HDAC2 regulates key neuronal functional and bioenergetic pathways in hiPSC‐derived neurons and suggests that HDAC2 may represent a novel therapeutic target for AD.
Pathological significance of neuron‐derived EVs in Alzheimer's disease and their potential as biomarkers
Authors: Kudo Takashi , Akamine Shoshin , Yanagida Kanta , Marutani Noriko , Kanayama Daisuke , Tokuda Takahiko , Ishikawa Mitsuru , Morimoto Satoru , Maeda Sumihiro , Okano Hideyuki
Published: December 2020

Background

It has recently been reported that pathological molecules of Alzheimer’s disease (AD), such as tau, are transmitted through extracellular vesicles (EVs). We hypothesized that AD‐related proteins are detectable in neuron‐derived EVs (NDE) present in peripheral blood, since the pathological proteins will be protected by the lipid bilayer of EVs from degradation. The objective of the study is to assess the novel NDE isolation method for the quantification of AD‐related proteins using ultra‐sensitive digital ELISA method.

Method

Blood‐derived EVs were first isolated from control and AD patients, and the degradation efficiency of AD‐related proteins in the blood and EVs was assessed by protease treatment in vitro. The remaining AD‐related molecules were quantified by Simoa HD‐1 Analyzer. The amount of protease‐resistant AD‐related proteins in the blood‐derived EVs was compared between healthy control subjects and AD patients. Next, NDE was affinity‐purified from peripheral blood‐derived EVs and conditioned medium of iPS‐derived neurons/astrocyte using novel antibodies specific to neuron‐specific membrane protein X (MPX). The purification efficiency was assessed by quantification of neuronal markers present in the isolated NDE.

Result

Protease treatment of human plasma degraded more than 99% of Aβ40 and Aβ42 present in the blood. On the other hand, around 5% of tau in the blood was protease‐resistant implied that the 5% of tau in blood might be protected from proteases by the EV structure. Actually, in blood‐derived EV fraction, more than 50% of tau was protease resistant, although Aβ40 and Aβ42 were hardly detectable after protease treatment, indicated that 50% of EV‐associated tau was compartmentalized inside of the EV. Furthermore, we succeeded in efficient separation of NDE from blood‐derived EV fraction using anti‐MPX antibody.

Conclusion

The present study revealed the difference in the amount of protease‐resistant Aβ40, Aβ42 and tau in the blood, which are more enriched in blood‐derived EVs. This phenomenon may be strongly involved in the transmission of AD pathological proteins through EVs. In addition, the novel NDE isolation method may be highly beneficial for the future development of NDE biomarkers.
CSF Aβ42, P‐tau and noradrenaline metabolite MHPG levels are synergistically related to cortical thickness in a memory clinic population
Authors: van Hooren Roy W.E. , Verhey Frans R.J. , Ramakers Inez H.G.B. , Jansen Willemijn J. , Jacobs Heidi I.L.
Published: December 2020

Background

The earliest signs of tau pathology have been traced back to the locus coeruleus (LC). The LC is the primary site for the synthesis of noradrenaline in the brain and there is evidence for LC volume loss as early as preclinical Braak stage 1 of Alzheimer's disease (AD). Increased levels of a noradrenaline metabolite called 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) have been found in advanced AD, while there is also a correlation between MHPG levels and cognitive performance. Additionally, MHPG may be an upstream driver of amyloid and tau pathology in AD, while both of these hallmark pathologies are linked to cortical thickness. Therefore, this study investigates the association between the noradrenergic system and AD pathology in relation to cortical thickness as a measure of structural brain morphology.

Method

The study sample included a total of 77 patients from the memory clinic with a mean age of 63 years, of whom 49 (64%) were male. Of this sample, 36 patients had subjective memory complaints (cognitively unimpaired) and 41 patients were cognitively impaired (mild cognitive impairment or AD). All patients had complete cerebrospinal fluid (CSF) measures of MHPG, Aß42 and p‐tau. Vertex‐based cortical thickness analyses were performed using FreeSurfer V6.0 while correcting for age, sex, education and MMSE score. Critical p‐values were adjusted for multiple comparisons using cluster‐based correction.

Result

Results showed interaction effects between MHPG levels and AD pathology to predict cortical thickness. As MHPG levels increased, both lower levels of CSF Aß42 and higher levels of CSF p‐tau were incrementally associated with lower cortical thickness. Moreover, higher AD signature p‐tau/Aß42 ratio was similarly associated with lower cortical thickness as MHPG increased. Results remained significant after the addition of apolipoprotein E4 information.

Conclusion

Our results suggest that synergistic relationships exist between MHPG, levels of AD pathology and cortical thickness. These findings provide support for an influential role of the noradrenergic system in AD, in tandem with established AD pathologies. These results suggest that in addition to clinical trials focusing on amyloid and tau pathologies, noradrenergic targets for pharmaceutical interventions may also be a promising focus.
Early diagnosis for Alzheimer’s disease: Clinical criteria and use of biomarkers
Authors: De Souza da Silva Raquel Carolina , da Cunha Ludmila Souza , de Almeida Fonseca Marcilene Maria
Published: December 2020

Background

Alzheimer's disease (AD) is by definition a functional cognitive decline that causes gradual memory loss, compromising areas of the brain responsible for cognition, function and behavior. AD is responsible for 60‐70% of dementias, affecting about 25 million people worldwide. Therefore, the early diagnosis allows therapeutic intervention with reduction of treatment costs, prolongation of autonomy and delay in the onset of the dementia process.

Method

The bibliographic research was performed in digital platforms, using articles published in the last 11 years in Spanish, English and Portuguese. Its aspects of early clinical diagnosis were analyzed and compared with the results observed in clinical and imaging examinations.

Result

In DSM‐5, AD was separated into three stages: preclinical, mild cognitive impairment (MCI) and dementia. Studies indicate that subtle changes can be detected years / decades before the first clinical symptoms that characterize MCI through biomarkers. Today, there is no obligation for memory loss to precede other symptoms, sensory and motor changes may be present 5‐15 years earlier in the early stages. Clinically, the patient needs to have cognitive and behavioral symptoms that affect daily activities, showing a reduction in their performance that cannot be attributed to other neurocognitive disorders, evidenced in anamnesis taken from the patient and a family member who is aware of the condition and conducting neuropsychological tests or cognitive assessment such as the Mini‐Mental. It is important to remember that tests such as computed tomography or magnetic resonance imaging of the skull should be performed to rule out differential diagnoses, since CSF examination may help to identify infectious dementia of the central nervous system.

Conclusion

The percentage of clinically identified cases decreases as the stages of AD are earlier. However, tests with biomarkers are at the same time more sensitive and specific to the diagnosis of AD and may expose the disease even before the onset of symptoms due to the marking of the dementia triggering gene.
Associations of truncal body composition with cognitive status in patients with dementia
Authors: Kim Seonah , Kim Jin Ok , Kwon Kyoung JA , Kim Dong Wook , Han Seol‐Heui , Moon Yeonsil
Published: December 2020

Background

Cognitive impairment is one of the most common age‐related diseases, and there are many modifiable risk factors, such as obesity and sarcopenia, which are extensively researched these days. Although many studies examined the relationship between obesity and cognitive impairment, the common methods to measure obesity have a limitation that they do not accurately measure truncal fat. Moreover, as truncal muscles are an indispensable component for movement for activity, it could be expected that the many truncal muscles are related to better cognitive functions. The objective of this study is to investigate the relationship between truncal body composition (fat and muscle) and cognitive impairment in patients with dementia in Korea.

Method

Female over 60 years of age with probable Alzheimer’s Disease were recruited between November 2014 and September 2015. The Mini‐Mental state examination, Global deterioration scale and Clinical dementia rating scale were used to assess the cognitive functions. Both truncal fat and muscle mass were measured using body dual energy X‐ray absorptiometry, and used as a percentage of body weight (TMM% and TFM%). Correlations between truncal composition and cognitive status were assessed by simple correlation analysis, which was followed by partial correlation analysis with age, educational years.

Result

TFM% was not related to cognitive impairment. In contrast, TMM% had a significantly negative correlation with all three cognitive assessment scores. After further adjusting for age and educational years, there was still a relationship between TMM% and cognitive functions

Conclusion

While truncal fat mass showed no relevance with cognitive functions, the truncal muscle mass was negatively correlated with cognitive status. The truncal muscle mass is thought to affect cognitive status in dementia patients somehow.
Design, synthesis and pharmacological evaluation of some 1,4‐benzoquinone‐piperazine hybrids for the management of cognitive dysfunction in Alzheimer’s disease
Authors: Silakari Pragati , Piplani Poonam
Published: December 2020

Background

Cognitive dysfunction is one of the testimonial indications of neurological disorder like Alzheimer’s disease. Based on the causative factors four main hypotheses have facilitated to draw sketch of real situation of AD, i.e. cholinergic misbalance, neurofibrillary tangles, senile plaques, and oxidative stress. The inhibition of acetylcholinesterase (AChE) has been a promising target for the management of AD which is mainly associated with the decreased level of acetylcholine (ACh). Currently, only four AChE inhibitors (tacrine, rivastigmine, donepezil and galanthamine) have been approved by the FDA for the symptomatic treatment of AD. However, these acetylcholinesterase inhibitors are not devoid of side effects and have lesser CNS permeability. A series of 1,4‐benzoquinone‐piperazine hybrid molecules were designed and synthesized based on the best pharmacophoric features against the target AChE and evaluated for their AChE inhibitory activity for the development of novel potent molecules for the management of cognitive decline in AD.

Method

Atom based 3D QSSR study of 1,4‐benzoquinone hybrids as acetylcholinesterase inhibitors for its selective binding with AChE was performed. Molecules were designed on the basis of the best model features and were docked with 3D crystal structure of AChE with the target. These designed hybrid molecules of 1,4‐benzoquinone and piperazine moiety were synthesized and evaluated as acetylcholinesterase inhibitors.

Result

The best 3D‐QSSR model displayed acceptable values of statistical parameters. The designed molecules showed good binding interactions with the important amino acids of the target protein. These molecules were synthesized and evaluated for their cognition improvements abilities. Out of all the synthesized compounds, few were selected for passive avoidance memory elevator test based on their in vitro AChE inhibitory activity. These molecules showed comparable improvement in the memory with that of the standard drug donepezil.

Conclusion

The statistical measures of the best model clearly indicate that the generated model has satisfactory prediction power for new molecules. Out of all the synthesized molecules, some compounds showed significant in vitro AChE activity along with improved memory function during step down passive avoidance studies. Hence the present study facilitates the process of designing, synthesis and development of new potent and selective AChE inhibitors.
Epilepsy in early onset Alzheimer’s disease
Authors: Haoudy Sarah , Jonveaux Therese , Aron Olivier , Puisieux Salomé , Hopes Lucie , Tyvaert Louise
Published: December 2020

Background

Epilepsy seems to be an important comorbidity in patients with Alzheimer’s disease (AD), especially in young onset AD (<65 years old). At this time epileptic seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline and early institutionalization. Seizures may also be a marker of a more aggressive subtype of AD.

This study aims to determine the prevalence of the epileptic comorbidity in patients with early onset AD. Secondly, it will investigate the temporal relationship between AD and epilepsy and extract specific characteristics of AD patients at higher risk of epilepsy.

Method

All patients diagnosed as early‐onset Alzheimer disease between 2013 and 2019, with abnormal CSF biomarkers for Alzheimer disease, and followed at the University Hospital of Nancy (AD regional center) were selected. Patients with cortical focal lesion or old history of epilepsy were excluded. The usual clinical follow‐up was extended with a prolonged EEG and a specific consultation with an epilepsy expert. Based on this dedicated interrogation and EEG results, patients were then classified as epileptic or non‐epileptic. We collected demographic data and information on epilepsy and AD disorders.

Result

Among the 22 included patients, 10 were classified as epileptic with a prevalence of 45%. Considering seizure types, patients presented generalized seizures (n=4), typical temporal seizures (n=4), myoclonus (n=1) and extratemporal seizures (n=1). EEG recordings were not useful in our population. Epileptic patients presented a more severe cognitive decline than patients without seizures (MMSE 8.4+/‐6.9 versus MMSE non epileptic 20.9 +/‐ 5.45). 100% of patients with a MMSE <10 had epileptic comorbidity. In our population, epilepsy never occurred before AD diagnosis.

Conclusion

Epilepsy appears to be a frequent comorbidity in early onset AD patients, with a prevalence of 45% in our study. This comorbidity seems to be a marker for severe AD. The role of the epileptic disorder in the acceleration of cognitive decline as the positive impact of antiepileptic drugs still need to be determined.
Cell‐type‐specific and sex‐dependent changes in the chromatin accessibility landscape in late‐onset Alzheimer’s disease brains
Authors: Chiba‐Falek Ornit , Barrera Julio , Song Lingyun , Safi Alexias , Yu Young Jun , Garrett Melanie , Gamache Julia , Chipman Danielle , Ashley‐Koch Allison , Crawford Gregory
Published: December 2020

Background

Decoding the genetic mechanisms of late‐onset Alzheimer’s disease (LOAD) is a major challenge in the post‐GWAS era, since the majority of the LOAD associated SNPs are in noncoding regions. Noncoding disease‐associated loci have been shown to be enriched for regulatory elements in tissues and cells relevant to the disease. Thus, post‐GWAS research requires an in‐depth characterization of cell‐type‐specific DNA regulatory elements and gene expression patterns.

Methods

We conducted ATAC‐seq profiling using NeuN sorted‐nuclei from 40 frozen brain tissues to determine LOAD‐specific changes in chromatin accessibility landscape in a cell‐type specific manner. We complemented these experiments by generating single‐nuclei(sn)RNA‐seq data from a subset group of the same brain samples.

Results

The study has five major findings for the field of LOAD epigenetics. First, we generated a map of LOAD‐associated cell‐type specific chromatin accessibility sites. Second, we identified 211 LOAD‐specific differential chromatin accessibility sites in neuronal‐nuclei. Third, we provided a catalogue of 842 female‐specific disease‐associated chromatin accessibility sites in non‐neuronal cells. Forth, we showed that the LOAD‐associated cell‐type‐specific changes in chromatin accessibility overlapped with ∼25% of the LOAD‐GWAS regions. Thus, suggesting a noncoding regulatory mechanism, namely chromatin accessibility, by which several LOAD‐GWAS loci may exert their pathogenic effect. Fifth, we functionally validated the ATAC‐seq findings using snRNA‐seq datasets. Data integration identified overlaps between the LOAD‐specific ATAC‐seq signals with the transcriptome profiles of known and new LOAD loci and demonstrated that LOAD‐associated changes in chromatin accessibility can result in gene dysregulation.

Conclusion

To our knowledge, this study represents the first and most comprehensive systematic interrogation of the chromatin accessibility landscape in LOAD and the functional effect on gene dysregulation. Moreover, the outcomes unveiled how cell‐type‐specific and sex‐dependent alterations in chromatin structure and transcription programs are associated with LOAD. These findings enhance the interpretation of LOAD‐GWAS discoveries towards translating association to causation, provide potential pathomechanisms, and suggest novel LOAD‐loci. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology.
Memory palaces to improve quality of life in Alzheimer's disease
Authors: Bormans Kasper ,   Leuven School for Mass Communication Research
Published: December 2020

Background

Dementia is the problem of the future in health care. Dementia is hard for the person living with it, but even more burdensome for his/her environment. The conversational dialogue seems to decline. Dementia is more than memory‐loss, there is also communication‐loss. The primary objective is to examine whether the addition of (augmented) reality to communication strategies can reconnect subjects in the early phase of Alzheimer's Disease (AD) with their caregivers and family members. The secondary objective includes a follow‐up on quality of life (QOL‐AD), feelings of depression (GDS 15) and connectedness (QCPR) of subjects in the early phase of AD and their significant others.

Method

We have developed a mobile health‐application (MemoryHome) which allows caregivers to construct virtual scale models of the residential settings / at home situation. These models function as memory palaces in which photos of significant others are connected to the architectural, spatial environment. It is a visual‐audio‐guide through a well‐known environment and subjects in the early phase of AD can make this walk together with a caregiver or a family member.

Result

Our intervention is non‐pharmacological, rather inexpensive, patient‐friendly, unconventional and easy to combine with regular treatment of Alzheimer’s disease. Data were collected in two different environments: in homecare and residential settings. Results showed a modest but positive relation with quality of life, connectedness between caregivers and their family members and the absence of feelings of geriatric depression.

Conclusion

The mobile application MemoryHome is a convenient instrument to reinforce the dialogue that seemed to diminish between patients and their environment.

The application allows participants to independently improve the recall and recognition of familiar faces.
Cognitive reserve and resilience: Possible mechanisms of dementia prevention
Authors: Livingston Gill , Selbaek Geir , Rockwood Kenneth , Huntley Jonathan D , Sommerlad Andrew , Mukadam Naaheed
Published: December 2020

Background

Predictions about future dementia prevalence vary but usually suggest large increases in numbers of people with dementia as the population ages. However, in some countries, for example, the US, UK and Netherlands, while overall numbers of people with dementia are growing as predicted, the age‐specific incidence rates of dementia have decreased substantially. This is probably due to educational, socio‐economic, health and lifestyle changes.

Method

We reviewed known risk factors listed in the 2017 Lancet commission: education, hypertension, hearing impairment, smoking, obesity, depression, exercise, diabetes and social contact; literature about cognitive reserve and considered effective interventions for these risks.

Result

Cognitive reserve is the brain resilience which allows for cognition maintenance despite neuropathological damage. Early, mid and late life factors are all important. Early‐life factors, such as education, are important for cognitive reserve and those with more education build greater cognitive reserve. Lifelong higher educational attainment also reduces dementia risk. Cognitive reserve is not static and is affected by a number of factors. Quantifying it uses proxy measures such as education, residual approaches (the variance of cognition not explained by demographic variables and brain measures) or identifying underlying brain functional. People in more cognitively demanding jobs tend to show less cognitive deterioration before, and sometimes after retirement than those in less demanding jobs. Hypertension and obesity in mid‐life are risk factors for dementia, as is hearing impairment. More frequent social contacts at age 60 years is associated with lower dementia risk over 15 years of follow‐up. Smoking in late life increases the risk of dementia. In later life people’s physical health may moderate the susceptibility to neuropathology. Those who are frail may develop Alzheimer’s disease with a lesser burden of neuropathology. Older people otherwise in good physical health can sustain a higher burden of neuropathology without cognitive impairment. There are however relatively few evidence based interventions and we will discuss what interventions we found in systematic review and what developments are still needed.

Conclusion

There are clinically and economically effective interventions. It is important to consider the stage of the life course when thinking about possible effective interventions to prevent dementia.
Amyloid, pTau, NfL, and GFAP as biomarkers for Alzheimer’s disease
Authors: Thijssen Elisabeth H. , Verberk Inge M.W. , Stoops Erik , Boxer Adam L. , Teunissen Charlotte E.
Published: December 2020

Background

Alzheimer's disease (AD) is a multifactorial disease, with ongoing amyloid and tau accumulation, axonal damage and astrocytosis. Blood‐based biomarkers reflecting these processes are potentially valuable for patient selection for clinical trials, for monitoring disease progression and treatment effects, and for the differential diagnosis of AD. Several studies have shown that plasma amyloid beta (Abeta) 42 and 40 concentrations, phosphorylated tau (pTau) at amino acid 181 or 217, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are changed in AD. Therefore, our studies are driven by the idea that combination of several markers will provide a more complete picture of the full complexity of AD.

Method

The results presented were obtained in several retrospective clinical cohort studies in memory clinics. Plasma Abeta 42 and 40, GFAP, and NfL were measured with Simoa technology, using homebrew assays (Amyblood, ADx), and commercial kits (Quanterix). pTau181 and 217 were measured using MSD technology with Lilly antibodies. Based on positive Amyblood and GFAP results, a novel 4‐plex assay was developed (AUMC, Quanterix, ADx). Results will be presented on the use pTau217 and of the measurement of combinations of Abeta isoforms, GFAP, and NfL for differential diagnosis of AD, Lewy body dementia, and Frontotemporal lobar degeneration (FTLD).

Result

The plasma markers are analyzed in over 1100 subjects. The Abeta 42/40 ratio decreased 1.2 fold in cases in the AD spectrum with a positive amyloid‐PET status, compared to amyloid negative cases. pTau181 concentrations were increased 2.4 fold in cases with tau accumulation measured with FTP‐PET, and pTau181 was increased 2.3 fold in AD compared to FTLD. NfL was increased 1.4‐2.3 fold in AD and FTLD patients compared to controls. GFAP levels were increased 1.8 fold in amyloid‐PET cases. Combining GFAP and the Abeta 42/40 ratio together with APOE e4 carriership resulted in an AUC of 88% differentiating amyloid‐PET positive from negative cases.

Conclusion

Individual blood‐based biomarkers reflect different physiological processes in the brain. Creating a panel of t markers could provide a more complete picture of ongoing pathological processes and likely increases diagnostic accuracy to be suitable for blood‐based screening of AD and enable personalized medicine.
Optimizing meaningful engagement among persons living with dementia through sensitivity to differing situations and realities
Authors: Kemp Candace Lynn , Epps Fayron , Bender Alexis A , Hill Andrea M , Ciofi Joy , Duong Stephen , Manley Pamela R
Published: December 2020

Background

Meaningful engagement is a critical dimension of quality of life and quality of care for persons living with dementia and an area highlighted in recent Alzheimer’s Association Dementia Care Practice Recommendations. Defined broadly as participation in an activity, including the “the act of being occupied or involved in an external stimulus,” engagement has implications for well‐being, mental health, and cognitive and physical function and shows promise as a non‐pharmacological strategy for addressing anxiety, depression, and behavioral expressions. Across long‐term care settings, including assisted living, meaningful engagement among persons with dementia represents a significant challenge. This poster presents findings from our ongoing 5‐year study conducted in the United States and funded by the National Institute on Aging (R01AG062310). The overall goal of the study is to identify best care practices aimed at recognizing, creating, and maintaining optimal meaningful engagement opportunities for persons with dementia that enhance their quality of life. Guided by grounded theory methods, our research involves: participant observation; formal and informal interviewing with residents, assisted living staff, family and friends, and others involved in residents’ daily lives and routines. Here, we report on analysis of data collected over a one‐year period in 4 diverse care settings. As expected, residents’ meaningful engagement experiences were highly variable. Residents’ cognitive and physical function also varied widely and typically fluctuated over time, influencing meaningful engagement opportunities. Awareness of and sensitivity to residents differing situations and for some, differing realities, were essential to optimizing meaningful engagement experiences among this heterogeneous and dynamic population. Care partners, including care staff and families and friends, who met residents “where they’re at” had more success collaborating with them to create positive engagement experiences compared to those who did not. We offer data‐driven recommendations for research and practice including the need to emphasize and promote person‐ and relationship‐centered care.
Vitamin deficiencies in geriatric memory patients
Authors: Przybelski Anna Gabriel , Vogt Nicholas M , Bendlin Barbara B , Przybelski Robert J
Published: December 2020

Introduction

Aging is the primary risk factor for dementia, and vitamin deficiencies are common in geriatric patients. Vitamins B12 and folate are commonly checked in memory patients, but other CNS‐significant vitamins such as B6 (pyridoxine), B1 (thiamine), and vitamin D are not. The purpose of this study was to determine prevalence of deficiencies of these vitamins in geriatric memory patients.

Methods

All new patients presenting to a university geriatrics memory clinic were assessed for vitamin B1, B6, B12, and vitamin D (total 25‐OHD) levels on the day of their first visit unless these studies were done in the prior 6 months or their health system required laboratory tests be done only through their primary care provider. Laboratory tests were performed through the university laboratory routine methods. No fasting or other special arrangements were made for the tests. Only test results obtained at the first visit, with neuropsychological evaluation were evaluated. A retrospective review of the medical records from the most recent 12 months provided the data presented here. Deficiency thresholds used for the study were: B1 <70 nmol/L, B6 <30 nmol/L, B12 <300 pg/mL, and D <30 ng/nL.

Results

Records from 203 patients were reviewed; 189 had at one or more vitamin level obtained at the first visit. Of those patients, 68 (40%) had at least one vitamin deficiency; 35 (19%) had two deficiencies, 7 (3%) had three deficiencies, and 1 patient was deficient in all four. The number of patients that had a particular vitamin level done and the number with a deficiency are shown in the table.

Discussion

Almost half of the geriatric patients were deficient in at least one vitamin. Vitamins B6 and D were the most common deficiencies, yet these are not routinely tested in memory patients. The commonly tested B12 showed a deficiency rate of only 16% compared to 37% and 33% for vitamins B6 and D respectively. Treating these vitamin deficiencies that can affect cognition will enhance function and increase the likelihood of effective medical treatment and successful research studies.
Why do we need an Asian brain template in clinical trials of Alzheimer's disease? A comparative study of brain structures between Asian vs Caucasian brains
Authors: Kang Dong Woo , Lee Chang Uk , Lim Hyun Kook
Published: December 2020

Background

There is a recognized need for the creation of ethnic‐specific brain templates of cognitively normal older adults for the purpose of evaluating structural and functional brain imaging data in the normal aging process and neurodegenerative disease including Alzheimer’s disease. However, previous studies of racial difference in cortical thickness of cognitively normal older adults have been restricted to small sample size and have not adequately controlled biases. We aimed to compare cerebral cortical thickness between cognitively normal older adults of East Asians and of Caucasians adjusting for age, gender, education.

Method

We evaluated the brain cortical thickness by using FreeSurfer on standard T1‐weighted images of cognitively normal older adults in East Asians [n= 321 (60’s = 166, 70’s = 155)] and Caucasians [n= 282 (60’s = 111, 70’s = 171)], and examined the difference in cortical thickness between two races by whole brain analysis (ANCOVA adjusting age, education, MMSE scores, corrected p < 0.05, FDR correction).

Result

East Asians were shown to have a higher cortical thickness in bilateral superior frontal, lateral and medial orbitofrontal, middle temporal, left superior parietal, right inferior parietal, and inferior temporal cortex and lower cortical thickness in bilateral parahippocampus, postcentral, lateral occipital, left transverse temporal, lingual, precuneus, right superior temporal, fusiform cortex than Caucasians. Additionally, interactions between age and race had an impact on cortical thickness in right superior frontal cortex.

Conclusion

The findings indicated that there was a significant difference in cortical thickness between cognitively healthy elderly in East Asians and in Caucasians according to the brain regions. The findings could contribute to a better understanding of the race‐specific structural change in the normal aging and provide an importance of an ethnic‐specific template for evaluating the structural and functional brain imaging in the healthy aging and neurodegenerative disease including Alzheimer’s disease.