bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel MRI techniques identifying vascular leak and paravascular flow reduction in early Alzheimer disease
Authors: Joseph Charles R
Published: December 2020

Background

With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. It’s dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments.

Method

We will review the known physiology and anatomy of the BBB system, its relationship to the glymphatic system and the microglial surveillance system. Ideally, human medication trials require a non or minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes.

Result

Dysfunction of this tripart system occurring in Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments.

Conclusion

High resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non‐invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.
Novel MRI techniques identifying vascular leak and paravascular flow reduction in early Alzheimer disease
Authors: Joseph Charles R
Published: December 2020

Background

With beta amyloid and tau antibody treatment trial failures, avenues directed to other aspects of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments.

Method

We will review the known physiology and anatomy of the BBB system, its relationship to the glymphatic system and the microglial surveillance system. Ideally, human medication trials require a non or minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes.

Result

Dysfunction of this tripart system occurring in Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments.

Conclusion

High resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non‐invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.
The Changing Talk: Online training (CHATO) — Developing and testing an implementation strategy for a national randomized control trial
Authors: Coleman Carissa K , Williams Kristine N , Hein Maria , Perkhounkova Yelena , Beachy Tim , Berkley Amy , Shaw Clarissa
Published: December 2020

Background

The Changing Talk (CHAT) training effectively reduces elderspeak and subsequent behavioral challenges in residents with dementia in nursing homes. The Changing Talk: Online (CHATO) training was developed to increase staff access to education using a new online format. In order to test the online training using a national nursing home (NH) sample, an implementation strategy and process evaluation were necessary to capture organizational factors, ensure consistent application across NHs, and test the most effective and efficient implementation strategies.

Methods

A planning grant was used to design an implementation strategy using an advisory board. The board consisted of NH Administrators, Directors of Nursing, Nurse Training Specialists, and a marketing consultant. Multiple products were designed including a website, implementation toolkit, training manual, posters, implementation checklist, surveys, and leadership interviews. A pilot test was then conducted to confirm the strategy in 8 nursing homes with a 90‐day implementation timeline. At the initial meeting, an implementation lead was identified. During planning phase, strategies were tailored to the organizational culture and current practices. During the training phase, weekly participation and completion rates were shared. After the training closed, surveys and interviews were conducted.

Results

An initial feasibility NH (NH0) and seven NHs (NH1‐7) were tested. The mean total implementation time was 70.3 days (SD = 9.3) with a mean planning phase of 20.1 days (SD = 6.7) and a mean training phase of 50 days (SD = 7.6). The implementation strategies varied across NHs (Table 1). The best outcomes were associated with champions, four mediums for weekly reminders, and a group reward. Leadership evaluation was positive (Tables 2 and 3). Differences between leadership perspectives will be used to make improvements prior to the national trial.

Conclusions

NH homes utilized the website and implementation toolkit to create a method of implementation tailored for their NH. Process evaluation methods were able to capture strategies used, compatibility, and NH goals for using CHATO. Evaluation of CHATO from both administration and direct care leadership provided multiple perspectives. The implementation strategy will be used to scale up the intervention and test the impact of implementation on CHATO’s primary outcomes.
Correspondence between blood‐based amyloid‐β by immuno‐precipitation mass spectrometry and PIB‐PET imaging in a population cohort
Authors: Snitz Beth E , Chang Chung‐Chou H , Zeng Xumei , Yates Nathan , Kamboh M Ilyas , Klunk William E , Lopresti Brian J , Becker Carl , Ganguli Mary
Published: December 2020

Background

Recently developed immuno‐precipitation mass spectrometry (IP‐MS) assays to measure blood‐based amyloid‐β with high accuracy holds exciting potential. Adoption of amyloid‐β measurement will be especially valuable in large population studies where not previously feasible. We evaluated the correspondence between a new IP‐MS assay developed on a commercially available platform with brain amyloid PET imaging as the gold standard.

Method

N=99 older participants without dementia, active in the population‐based Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) study, underwent blood draws at the time of brain amyloid imaging with PiB‐PET (50‐70 minutes post‐injection, SUVR with cerebellar reference). Adapting methods of Nakamura et al. (2018), immunoprecipitation from plasma was followed by time‐of‐flight MS, using a benchtop mass spectrometer, to measure relative amounts of endogenous peptides Aβ1‐40, Aβ1‐42, APP669‐711, and a stable‐isotope‐labeled internal standard. A composite plasma biomarker was calculated as the mean of the normalized ratios APP669711/Aβ142 and Aβ140/Aβ142.

Result

n= 24 (24%) of participants were PiB‐positive by a global cutoff, 7 (7%) were CDR 0.5, and 13 (13%) were APOE*4 carriers. Higher global PiB SUVR was associated with older age, higher CDR (0.5 vs. 0) and APOE*4 genotype (p’s < .05), while higher plasma composite biomarker was similarly associated with CDR and APOE*4 but not age. ROC analysis yielded an AUC of 0.78 (SE 0.05) for the composite plasma biomarker predicting PiB‐PET status, with an optimized cut‐point corresponding to sensitivity of 0.75 and specificity of 0.69. Including age and APOE*4 into the model yielded an overall AUC of 0.89, and plasma biomarker sensitivity of 0.91 and specificity of 0.77.

Conclusion

This IP‐MS assay was successfully implemented using a commercially‐available, benchtop MALDI‐TOF instrument that is easy to operate and already used in clinic settings. Concurrent prediction of amyloid status from plasma amyloid alone was significant, with moderately high accuracy. Combining plasma amyloid with age and APOE genotype improved prediction to high accuracy. Planned follow‐up of the sample with repeat PiB scans will yield yet further information about prospective prediction of brain amyloid status. This non‐invasive approach using a peripheral biomarker could be highly useful and feasible to apply in large population studies of AD risk.
Medial temporal contributions to learning, retrieval, and accuracy monitoring in verbal memory
Authors: Memel Molly B. , Casaletto Kaitlin B , Kramer Joel H.
Published: December 2020

Background

Verbal memory profiles are commonly characterized as reflective of frontal or medial temporal dysfunction in clinical practice. Frontal‐subcortical patterns are marked by intrusion errors and impoverished recall that improves with cueing and recognition. However, retrieval deficits, intrusion errors, and impoverished learning are also seen in disorders affecting the medial temporal lobes (MTL), such as Alzheimer’s disease. The aim of the current study was to determine the relative contribution of prefrontal and MTL structural integrity to verbal memory patterns typically attributed to frontal or MTL dysfunction in a mixed neurodegenerative sample.

Method

1148 participants at the UCSF Memory and Aging Center completed the CVLT‐III‐Short Form, and an MRI (T1‐weighted) scan. Participants varied in neurodegenerative syndrome. 55 functionally intact older adults were included for comparison. MRI analyses focused on a priori regions of interest including dorsolateral prefrontal cortex (DLPFC) and MTL regions (Hippocampus, Parahippocampal Gyrus, and Entorhinal Cortex). Linear regression models assessed the relative contribution of DLPFC and MTL volumes to six CVLT metrics of interest: 1. Benefit from multiple learning trials 2. Learning Slope 3. Cued Recall Gains 4. Total Intrusions 5. Recognition Gains 6. Response Bias.

Results

Although participants with smaller DLPFC volumes exhibited a greater benefit from recognition, as would be expected based on commonly characterized frontally‐mediated retrieval deficits, DLPFC volume was not associated with benefit from cueing, intrusions, or response bias. In contrast, patients with smaller MTL volumes benefited less from cued recall and recognition, and the relative contribution of MTL volume was 1.5‐2 times larger than DLPFC. Furthermore, only MTL volume was associated with intrusion errors and benefit from multiple learning trials. Performance was not associated with either region of interest in the control group.

Conclusion

While the current findings support the association between retrieval deficits and prefrontal integrity, they highlight the prominent contribution of MTL to commonly characterized frontal memory deficits, including improvements with repetition, cueing, and recognition. When interpreting verbal memory patterns in neurodegenerative samples, consideration of both PFC and MTL integrity is warranted.
Real‐time prediction of working memory performance: A machine learning‐based approach towards dementia prevention
Authors: Mirjalili Mina , Zomorrodi Reza , Hill Sean , Daskalakis Zafiris J , Rajji Tarek K
Published: December 2020

Background

MCI is a clinical state that typically precedes Alzheimer’s dementia (AD). Working memory deficits are common in MCI and affect routine activities. Thus, developing an intervention that enhances working memory could enhance day‐to‐day function in these patients and, in turn, prevention progression to dementia. Towards this goal, a model that predicts individual‐specific working memory performance in this population could be instrumental for personalized interventions. Electroencephalography (EEG) captures the time dimension of cognitive events that happen during working memory performance and could predict individual‐specific performance. EEG predictive markers can then be targeted by interventions to enhance performance.

Method

We propose a single‐trial classification process that predicts individuals’ responses i.e. target correct (TC) vs. target noncorrect (TNC) responses during a working memory task, N‐back. We applied this process to EEG data of 15 healthy participants (mean age (SD) = 29.8 (7.6)) while performing the 3‐back task. We used event related (de‐)synchronization (ERD/ERS) from EEG signals 600 milliseconds prior to stimulus presentation as input features to a support vector machine classifier. To avoid overfitting of the model, we applied recursive feature elimination and cross validation to the first two‐thirds of the task. A trained classifier was then tested on the last third of the session. Non‐parametric permutation testing was used to ensure that the extracted pattern is associated with the original data rather than a random pattern.

Result

Our model identified the brain regions where ERD/ERS predicted each individual’s working memory performance. Mean (SD) prediction accuracy across 15 participants was 70.1% (5.9). Accuracy was significantly above chance in 12 out of the 15 participants. The total number of the predictive EEG features across all participants ranged between 4 and 9. The mode was 6. As an example, in one participant, we achieved 69.2% accuracy based on 6 features: decreased parietal theta ERS; increased prefrontal theta ERS; decreased right temporal and occipital gamma ERS; and increased frontal and right temporal alpha ERD.

Conclusion

This pilot study could lead to a machine‐learning based approach to increase the efficacy of personalized AD preventative interventions by individualizing the targets for these interventions.
Association of G protein‐coupled receptor kinases with tau pathology in Alzheimer's disease
Authors: Guimaraes Thais Rafael , Swanson Eric , Kofler Julia , Thathiah Amantha
Published: December 2020

Background

Alzheimer's Disease (AD) is characterized by pathological aggregation and accumulation of hyperphosphorylated microtubule‐associated protein tau1 in intracellular neurofibrillary tangles (NFTs)2,3. Phosphorylation is a vital cellular process associated with protein homeostasis and disease4. Tau, for instance, has more than 80 putative phosphorylation sites, which regulate both physiological and pathological tau functions1. Although several tau kinases have been identified to play causative roles in AD tau pathogenesis1,5, kinase‐targeted therapies for AD have been unsuccessful thus far6. Interestingly, the kinases responsible for several putative tau phosphorylation sites remain unknown7. G protein‐coupled receptor kinases (GRKs) are a family of seven kinases (GRKs 1‐7) that are implicated in numerous peripheral and brain pathologies8,9, including a cursory association of GRKs 2 and 5 with AD10. Nevertheless, a comprehensive characterization of the expression and distribution of GRKs in the non‐demented and AD human brain has not been previously performed. We hypothesize that establishment of the GRK profile and pattern in the human brain may provide insight into the putative involvement of GRKs in tau pathobiology in AD.

Method

We performed immunohistochemical and biochemical analysis of the four ubiquitously expressed GRKs (i.e., GRKs 2, 3, 5, and 6) in relation to the expression and accumulation of tau in postmortem human hippocampal tissue from control subjects and AD patients.

Result

Western blot analysis indicates that GRK levels are similar in control and AD brains. However, a region‐specific immunohistochemical analysis reveals that all four GRKs are decreased in the CA1 of the AD hippocampus, one of the most vulnerable regions to AD pathology11,12. Interestingly, the GRKs differentially co‐localize within total and phosphorylated tau NFT pathology. Additionally, all GRKs tend to positively correlate with soluble tau levels in the AD brain. Finally, GRKs 3 and 5 display a remarkable co‐localization with late‐stage NFTs in the AD brain.

Conclusion

Collectively, our findings show that the GRKs associate with tau pathology in AD brains, suggesting that GRKs may regulate tau phosphorylation, solubility, and aggregation in AD. These results provide a foundation for future mechanistic studies addressing the putative role of GRKs in tau physiology and pathology.
Endoplasmic reticulum aggregation act as a nucleation site for autophagosome formation in an amyloid‐β model of Alzheimer’s disease
Authors: Chang Raymond Chuen‐Chung , Ho Janice Yuen Shan , Yeung Sherry Sin Hang
Published: December 2020

Background

Autophagy via formation of the autophagosome is a major cellular degradation pathway for long‐lived proteins and organelles. Dysfunction in autophagic processes are prominently linked to neurodegenerative disorders associated with an aggregation of misfolded protein. However, the underlying cellular mechanisms of how amyloid‐β (Aβ) promotes autophagy in Alzheimer’s Disease remains elusive.

Method

To investigate this, primary culture rat hippocampal neurons were transfected with GFP‐KDEL construct at DIV5 and treated with 15 µM ABO at DIV7. Either an AMPKα activator (1 mM AICAR) or inhibitor (10 µM Dorsomorphin) was applied at timed 2, 8, 24 h intervals. Cells were fixed and analysed using confocal imaging and biochemical data.

Result

Aβ‐induced autophagy was shown to begin from recruitment of ULK‐1 via an AMPK‐dependent pathway to the endoplasmic reticulum (ER). Pharmacological inhibition of AMPKα by Dorsomorphin in Aβ‐treated primary hippocampal neurons demonstrated reduced recruitment of ULK‐1 to the ER, while AMPKα activation by AICAR resulted in increased ULK‐1 recruitment to the ER. Live cell confocal imaging demonstrated intracellular interactions between ULK‐1 and the Atg14L‐Beclin1‐Vps34 complex. There were visible aggregation and ubiquitination on the ER promoting the formation of omegasomes and ultimately kick‐starting the autophagic pathway. In parallel, p62 was also found to translocate to ER aggregation sites after Aβ treatment aside from its known roles in protein shuttling towards mature autophagosomes.

Conclusion

This study demonstrates that Aβ‐induced autophagy is an AMPK‐dependent process and begins with recruitment and aggregation of important proteins such as ULK‐1 and PI3K‐III complex to the ER thereby pushing off the formation of mature autophagosomes.
The role of automatic habit in physical activity behaviours in older people: A new target for lifestyle interventions for dementia risk reduction?
Authors: Andrews Sophie C , Parekh Dinaz , Brady Brooke , Delbaere Kim , Killcross Simon , Anstey Kaarin J
Published: December 2020

Background

Physical inactivity is a key risk factor for dementia, yet physical inactivity is common in older adults. Increasing physical activity levels in this population is an urgent health priority. Automatic, context‐dependent habits may play an important role in physical activity behaviour. This study aimed to investigate the relationship between physical activity behaviours and their automaticity in older people.

Method

123 community dwelling Australians aged over 65 years (M=72.2; 81 women), recruited from participant registries, local hospital noticeboards and community groups, completed an online questionnaire. Current physical activity levels were measured using the Incidental and Planned Exercise Questionnaire, and automaticity of those physical activity behaviours were measured using the Self‐Report Habit Automaticity Index. Participants also reported demographic information, falls and medical history, and current mood symptoms.

Result

Participants reported an average of 2.28 hours planned walking (SD=2.33), 5.81 hours planned moderate/vigorous exercise (SD=4.02), and 20.5 hours incidental activity (SD=15.52) per week. Multiple regression analyses revealed that after controlling for age, gender, BMI and depression symptoms, higher automaticity scores were associated with more hours per week of planned walking (p=.012), moderate/vigorous exercise (p=.038), and incidental activity (p=.017).

Conclusion

In a sample of active older Australians, participants who engaged in higher levels of physical activity reported their activity to be more automatic than those reporting lower levels of activity, regardless of the type of physical activity engaged in. Supporting older people to make their physical activity more habitual could therefore be an effective approach to increase levels of physical activity in this population.
Global response to the provision of dementia information and support during the COVID‐19 crisis
Authors: Lynch Chris , Weidner Wendy S
Published: December 2020

Background

Dementia and COVID‐19 share the same key risk factor ‐ age. As the world reacted to the pandemic it became evident that people living with dementia were an exceptionally high‐risk group; disruption to the diagnosis pathway, provision of post diagnostic support, interruptions to research and trials. Alzheimer's Disease International responded quickly to support our global network of 102 associations, many challenged with having to re‐invent their services, including withdrawal of face‐to‐face support & confronting income crises; plus providing timely information, support and advocacy interventions to partners.

Method

Early 2020 ADI engaged our global associations to gauge the concern around COVID‐19, with insight from our member association in China. Regular contact with the WHO and our international partners gave us impetus to adapt our programme of work.

Result

ADI produced an online COVID‐19 resource; a go‐to for information, advice, experience and learning. A key resource, an advisory video from Prof. Huali Wang, China, offering health and care advice ‐ subsequently translated into a number of co‐authored articles in The Lancet; followed by a paper on 'Difficult decisions about hospital admission and triage' Through series of global webinars ADI provided up to the minute experience & information focussing on key areas ‐ care homes; the scarcity of resources; life/ deaths decision making and the rights of people with dementia to treatment. Future gazing sessions followed to ascertain the impact of COVID‐19 on the diagnosis pathway, national plans, trials and on prevalence rates. Thorough our engagement with the WHO, ADI contributed to the creation of an inter‐agency mental health and psychosocial support resource and participated in the Civil Society Working Group on NCDs. Media engagement brought vital attention and coverage to dementia, through titles including BBC World & Futures, The Economist, The Telegraph.

Conclusion

Timely responses, interventions and the provision of COVID‐19 resources has enabled our global associations to adapt their operations to better respond to the crisis and to review operational and policy strategies. Through partnership working, timely sharing of information and advice, we have facilitated a strong reaction and positive response throughout the dementia sector to this extraordinary period.
Analytical characteristics of the updated elecsys Abeta42 Gen 2 assay, including comparisons with the Gen 1 assay
Authors: Blennow Kaj , Zetterberg Henrik , Rutz Sandra , Wittig Martina , Manuilova Ekaterina , Logan Chad , Bauer Ekaterina , Stomrud Erik
Published: December 2020

Background

Cerebrospinal fluid (CSF) biomarker amyloid‐β1–42 (Abeta42), quantified using the Elecsys® Abeta42 (Gen 1) immunoassay, supports diagnosis of Alzheimer’s disease. Compared with Gen1, the updated assay Elecsys Abeta42 CSF II (Gen2) has a higher threshold for biotin interference, extended measuring range, and is re‐standardised according to certified reference Abeta42 peptide ERM‐DA480/‐481/‐482. The new Routine‐Use (RU) pre‐analytical protocol will be introduced with the Gen2 assay (reported separately). Here, we present the analytical performance of the Gen2 assay, including comparisons with Gen1.

Method

Analytical performance experiments were conducted on cobas e 601 analysers. Precision was investigated according to Clinical and Laboratory Standards Institute EP05‐A3 (21‐day experiment) using seven native and two control samples. For lot and instrument comparisons (cobas e 801 vs e 601), 125 native CSF sample pools were measured in one run. Gen1 and Gen2 were compared in two method comparison (MC) studies: in‐house study: 103 frozen CSF samples were measured in one run; external study (Pre‐analytical study 2): CSF samples from 24 patients with suspected normal pressure hydrocephalus were prospectively collected according to the RU, Roche Trial and BioFINDER protocols. MC was based on mean concentrations obtained from 3–4 aliquots per patient. Aliquot‐aliquot variability was compared for each protocol. MC analyses included calculation of Pearson’s correlation (r) and Passing‐Bablok regression fit.

Result

Precision analysis provided within‐run variability of <6% and intermediate precision of <8% for all samples. Measurements of three lots were highly correlated (r=1.00) with bias <5.2%, within the clinically relevant range. Measurements on cobas e 601 and e 801 analysers were highly correlated (r=0.995) and regression analysis yielded a slope of 0.941. Gen1 and Gen2 were strongly correlated in both MC studies (in‐house: r=0.999; external: r=0.990). Slope estimates were 0.75 and 0.79 in the in‐house and external studies, respectively (Figure). Aliquot‐aliquot variability was similar for Gen1 and Gen2 assays within each protocol and lower in the RU versus the Roche Trial protocols (Table).

Conclusion

The Abeta42 Gen2 assay strongly correlated with the Gen1 assay. High precision and low variability between lots and analysers showed the Gen2 assay provided additional benefits over Gen1 without compromising technical performance.
Association of sera levels of anti‐pemphigoid autoantibody (BP 180) with AD: A pilot case‐control study
Authors: Salama Mohamed , Shalash Ali
Published: December 2020

Background

Bullous pemphigoid (BP) is a common dermatological disease affecting the aging population. Previous research showed potential cross‐talks between BP patients and those with neurodegenerative diseases e.g. dementia. The present study assessed serum levels of autoantibodies (AIAs) against pemphigoid in a sample of Alzheimer's disease (AD) as well as Parkinson's disease (PD) patients compared to matched healthy controls.

Method

Twenty‐five PD patients were compared to fifteen AD patients and matched ten controls. All patients were evaluated clinically and their sera were collected to estimate levels of AIAs against pemphigoid. PD stages were considered clinically using UPDRS subscales, Hoehn and Yahr scale, and Schwab and England scales, while AD patients were evaluated using MoCA scale.

Result

The results showed a significant elevation in BP 180 AIAs in AD patients (37.5%) compared to PD patients (14%) and controls (10%).

Conclusion

The present findings highlight the possible role of cross‐reactivity between the skin and brain antigens in developing AD.
Reminiscence therapy using virtual reality technology affects cognitive function and morale of elderly with dementia
Authors: Tominari Maho , Uozumi Ryuji , Becker Carl , Kinoshita Ayae
Published: December 2020

Background

Japan already confronts a super‐aged society in which the number of dementia patients is increasing drastically. We need to improve care methods to meet the needs of elderly dementia patients. Thus, we developed a novel reminiscence therapy care program using a virtual reality (VR) tool for elderly people with mild dementia; then we evaluated the effect in comparison to the conventional reminiscence therapy.

Method

We measured 52 people with mild cognitive impairment using the Mini‐Mental State Examination, Revised PGC Morale Scale, Multidimensional Observation Scale for Elderly Subjects, Trail Making Tests A and B, and Word Fluency Test before and after 8 weeks of reminiscence therapy. We randomly assigned them to reminisce with either conventional still photos or VR panoramas. We compared their results using t‐tests.

Result

The scores of MMSE totals showed improvement for both groups, but it did not achieve the primary objective. The considerable improvement was seen only in the VR panoramas group. The PGC morale scale scores rose considerably higher in the VR panoramas group than in the still photo group. No definite differences were observed in other scales, neither between the two groups nor before and after the intervention.

Conclusion

Reminiscence therapy produced cognitive improvement regardless of whether still photos or VR panoramas were used as stimuli. However, reminiscence therapy with VR panoramas produced greater improvement in participants’ morale, which may enhance patients’ well‐being.
Combined low plasma Aβ42/Aβ40 ratio and high neurofilament light chain levels are associated with both cognitive and physical function declines over time in non‐dementia older adults with memory complaints
Authors: He Lingxiao , Barreto Philipe de Souto , Nguyen Andrew D , Morley John E , Li Yan , Bateman Randall J , Vellas Bruno ,   the MAPT/DSA Group
Published: December 2020

Background

Although brain amyloid deposition (Aβ) and plasma neurofilament light chain (NfL) are associated with cognitive decline, associations of combined plasma Aβ and NfL profiles with cognitive and physical functions in older adults remain unknown. The current study aimed to investigate prospective associations of combined plasma Aβ+ and NfL+ profiles with cognitive and physical functions in older adults.

Method

Plasma Aβ and NfL levels, cognitive and physical function data (n=452 participants) collected from the Multidomain Alzheimer’s Preventive Trial (MAPT, www.clinicaltrials.gov [NCT00672685]) were used in this study. The MAPT recruited 1680 non‐dementia older adults with memory complaints for a 3‐year intervention, followed by a 2‐year observational follow‐up. Cognitive function was evaluated as mini mental state examination and composite cognitive score (CCS, a mean Z‐score combining four cognitive tests). Physical function was evaluated as gait speed (4‐m usual‐pace walk test) and chair‐stand time (5‐time maximal chair‐stand test). Cognitive and physical function data measured at the moment and after blood Aβ and NfL tests were used for analysis. Participants with plasma Aβ42/Aβ40 ratios lower than 0.107 and NfL levels greater than 93.04 pg/ml were classified as Aβ+ and NfL+. Multivariable regressions and mixed effects linear models were used.

Result

At the cross‐sectional level, no significant association was found between Aβ+NfL+ and cognitive or physical function. Evaluating longitudinal changes, participants with Aβ+NfL+ had more decline in the CCS and gait speed over time, compared to the other participants. After adjusting for APOE ɛ4 genotype, Aβ+NfL+ was associated with greater decline only in CCS.

Conclusion

Combined low plasma Aβ42/Aβ40 ratio and high plasma NfL level was associated with greater declines in cognition and gait speed over time, providing further evidence of the links between cognitive and physical function.
LBE regulates the transformation of Aβ‐activated microglia from M1 state to M2
Authors: Zhongqing Sun , Chiu Kin
Published: December 2020

Background

Lycium barbarum is a traditional Chinese medicine herb that exhibits a wide variety of biological functions, such as antioxidation, neuroprotection and regulating inflammation. Amyloid‐β‐induced neuroinflammation is one of the key events in the pathogenesis of Alzheimer’s disease with microglia as the main participating cells. Amyloid‐β (Aβ) can activate microglia, change it from the resting state to M1 state, and promote the occurrence of inflammation. This study aims to inversigate the Lycium barbarum extract (LBE) could reverse the active status of microglia activated under Aβ challenge.

Method

IMG mouse microglial cells were cultured and an LDH assay was performed to determine the toxicity of Aβ and safe dose range of LBE. The ELISA, PCR and Western Blot were used to check the inflammatory factors exposed to Aβ. Immunostaining was used to detect the changes of inflammatory factors, the M1 marker is iNOS, IL‐1β, TNF‐α, and M2 marker is Arg1, Ym1.

Result

LBE had a dose‐dependent protective effect on IMG cells exposed to o‐Aβ. The ELISA results shew that LBE could decrease the expression of TNF‐α, IL‐6 and IL‐1β inflammatory factors compared with the o‐Aβ alone group in the IMG cell line. The PCR results found that LBE also could inhibit M1‐like inflammatory factors and promote M2 factors in o‐Aβ induced microglia, which is consistent with western blots (WB) results. WB result suggested that LBE suppressed the expression of iNOS, TNF‐α, IL‐6, and IL‐1β and increase the expression of Arg1 compared with the model group. LBE attenuated o‐Aβ‐induced activate microglia by modifying microglia from M1 to M2.

Conclusion

LBE could modulate the status of activated microglial cells induced by o‐Aβ, and reverse it from M1 to M2 under Aβ treatment.
Determining capacity for individuals with dementia to give sexual consent: A scoping review to guide best practice
Authors: Hand Michelle Danäe , Gibson Allison
Published: December 2020

Background

Sexual relationships in long‐term residential care facilities are common, but addressing the issue of dementia and ability to consent to sex remains unclear. Do individuals with dementia have the mental capacity to consent to sex? And how should residential facilities address the ethical dilemma of consent among individuals with dementia in consideration of their residents’ safety and right to self‐determination? The aim of this study was to review extant research on best practices for determining capacity among individuals with dementia to give consent for sexual relationships.

Methods

A systematic scoping review of scholarly literature was conducted using the search words “dementia,” “Alzheimer’s,” “consent,” “sexual,” and “sex” to locate articles in Academic Search Complete, ScienceDirect, Wiley Online and PubMed databases. Scholarly articles in peer‐reviewed journals were deemed eligible if they (a) explored how the issue of consent among individuals with dementia is perceived and determined, and (b) provided recommendations for future practice and research with individuals with dementia.

Findings

Seventeen articles met this criteria and were included in the systematic scoping review. Findings demonstrate that while much of the literature has highlighted the need for widely acknowledged explicit guidelines to determine capacity for persons with dementia to consent to sex as well as recommendations to inform organizational policy and best practices for confirming an individual’s ability to consent to sex in later life among persons with dementia.

Implications

The issue of determining capacity to consent remains a dilemma. One possible recommendation is to explore the process for determining capacity of persons with dementia to consent to other activities, such as research participation, to inform development of a protocol for professionals to evaluate capacity for consent to sexual relationships. Such an approach will be explored, along with several recommendations for future practice.
Costs of the Care for Older Persons with Dementia in their Environment (COPE) intervention when delivered through the Connecticut state Medicaid waiver program
Authors: Pizzi Laura T , Prioli Katherine M , Babcock Zachary , McAbee‐Sevick Heather , Wakefield Dorothy , Jutkowitz Eric , Fortinsky Richard H
Published: December 2020

Background

The Care of Persons with Dementia in their Environments translational study (COPE‐CT) is a Connecticut‐based randomized clinical trial conducted to evaluate the efficacy of behavioral intervention (COPE) vs. usual care (UC) for persons with dementia (PwD) and their caregivers.

Methods

PwD in both groups were enrolled in the Connecticut Home Care Program for Elders (CHCPE) and received a monthly home care plan. COPE, an in‐home behavioral intervention delivered by occupational therapists and an advance practice nurse, was designed to maximize PwD physical functioning and improve caregivers’ dementia management skills. Program costs included staff training and supervision (COPE), screening for program eligibility (COPE & UC), intervention delivery (COPE), travel time and mileage (COPE), supplies (COPE & UC), lab testing (COPE), and home care plan for one year pre‐enrollment to one year post‐enrollment (COPE & UC). Mean per‐dyad cost differences at 12 months vs. baseline were calculated for each group and compared using a difference‐in‐difference approach.

Result

291 PwD/caregiver dyads were randomized (145 COPE, 146 UC). Mean per‐dyad cost of COPE was $1,868 vs. $6.41 for UC, yielding an incremental difference‐in‐difference cost of $1,862/dyad for COPE. COPE delivery was the largest cost driver ($623/dyad) followed by travel time ($370/dyad) and lab testing ($316/dyad). UC costs were minimal and driven by supplies ($18.45/dyad). Both groups experienced a cost savings in the care plan at $82.06/dyad for COPE vs. $15.63/dyad for UC, but this difference was not statistically significant (p=0.5253).

Conclusion

Given the lack of medical treatments for dementia, in‐home programs for PwD and their caregivers are critical. COPE represents a novel approach to dementia behavioral management and caregiver support, and the intervention costs we report inform its sustainability. Future work will examine potential cost offsets in health and social service expenditures.
G Protein‐coupled receptor kinases modulate amyloid‐β generation in Alzheimer’s disease
Authors: Todd Nicholas , Huang Yunhong , Thathiah Amantha
Published: December 2020

Background

Our lab previously identified the G protein‐coupled receptor (GPCR) GPR3 as a modulator of γ‐secretase activity in Alzheimer’s disease (AD)1. The GPR3‐mediated effect on γ‐secretase activity and Aβ generation requires recruitment of the GPCR adaptor protein β‐arrestin 2 (βarr2) and subsequent βarr2 interaction with the Aph1a subunit of the γ‐secretase complex2. GPCR kinases (GRKs) phosphorylate GPCRs and generate specific phosphorylation patterns that initiate βarr2 recruitment and distinct downstream signaling3–6. Despite evidence of GRK expression changes in the human AD brain7,8, the putative involvement of GRKs in modulating pathogenic GPCR signaling or directly modulating AD pathology has not been investigated.

Method

We utilize CRISPR/Cas9 genome‐editing to generate HEK293 GRK knock‐out cell lines of each GRK that is ubiquitously expressed in the brain, namely GRK2, GRK3, GRK5, and GRK6. We perform a combination of bioluminescence resonance energy transfer (BRET), co‐immunoprecipitation, and enzyme‐linked immunosorbent assays (ELISAs) to identify the specific GRK involvement in βarr2 recruitment to GPR3 and GPR3‐mediated Aβ generation. Additionally, we investigate potential mechanisms by which βarr2 regulates γ‐secretase activity by utilizing a βarr2 recruitment assay to measure βarr2 interaction with the Aph1a subunit of the γ‐secretase complex.

Result

Interestingly, genetic deletion of GRKs 2, 3, 5, and 6 individually reduce βarr2 recruitment to GPR3; however, only GRK2‐induced βarr2 recruitment to GPR3 is involved in the regulation of GPR3‐mediated γ‐secretase activity and Aβ generation in a kinase‐dependent manner. Furthermore, alanine mutagenesis of two serine residues in the cytoplasmic tail of Aph1a these residues reduces the βarr2 interaction with Aph1a.

Conclusion

Our findings indicate that GRK2 regulates the GPR3‐mediated increase in Aβ generation and suggest that a specific GRK2 phosphorylation barcode on GPR3 modulates γ‐secretase activity. Additionally, evidence that phosphorylation of Aph1a is required for βarr2 interaction with the γ‐secretase complex suggests that GRK2, or another GRK, either directly or through activation of GPR3 may be involved in the regulation of γ‐secretase activity. Accordingly, the putative GRK2 phosphorylation barcode of GPR3 and GRK involvement in Aph1a phosphorylation are currently under investigation. These studies provide insight into the broader mechanism by which GPR3 modulates AD pathology and illuminates a novel role of GRKs AD pathogenesis.
Investigation of the effect of PGC1A gene therapy at advanced stages of Alzheimer’s disease in an animal model of amyloid pathology
Authors: Mota Bibiana Castagna , Almpani Elisavet Velentza , Nikolaou Maria Nefeli , Garcia‐Segura Monica Emili , Huang Yu‐Hsuan , Keniyopoullos Renos , Mazarakis Nicholas D , Sastre Magdalena
Published: December 2020

Background

Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. AD has no cure but symptomatic treatment, thus, an effective therapy is urgently needed. Previously in our laboratory we have explored the potential neuroprotective effects of the coactivator for the peroxisome proliferator‐activated receptor‐γ (PPARγ), ‐PGC‐1α mainly involved in the regulation of metabolic processes and mitochondrial biogenesis. PGC‐1α has been shown to be involved in different neurodegenerative diseases and its expression is reduced in the brain of AD patients. We have previously showed that the delivery of PGC‐1α through lentiviral vectors in APP23 mice, at the preclinical stage of the disease, resulted in reduction of amyloid‐β deposition, protection against neuronal loss and improvement of cognition functions. Therefore, the aim of this study was to generate a monocistronic lentiviral vector expressing PGC‐1α to investigate whether this therapy could ameliorate the cognitive deficit ofAPP23 mouse model of AD at an advanced stage of pathology.

Method

A recombinant lentiviral vector carrying human codon optimized PGC‐1αdriven by CMV promoter was constructed and produced. To determine the therapeutic effects of overexpression of PGC‐1α, we delivered the lentiviral vector carrying PGC‐1α in the frontal cortex and hippocampus of wildtype and APP23 mice at 12 months old and animals were sacrificed 3 months later. We investigated locomotor activity and anxiety (Open Field, OF), non‐spatial (Novel Object Recognition, NOR) and spatial memories (Object Location test, OLT).

Result

So far, no differences were observed in the anxiety and locomotor activity between the groups in the OF test. APP23 mice at 15 months of age showed cognitive impairment compared with controls. Interestingly, improvement in the performance in the NOR test was observed in the APP23 mice injected with PGC‐1α vector (p>0.05, two‐way ANOVA, Bonferroni post‐hoc, n=5‐10 per group). However, in the OLT test no difference was observed between the groups 3 months after the PGC‐1α delivery.

Conclusion

These preliminary results support the potential therapeutic effect of PGC1alpha on cognition at late stages of the disease.
A look at possible effects of mandated COVID‐19 social isolation on orientation scores for research participants reporting mild memory concerns
Authors: Voccia Pamela , Kruczek Katherine , Kettren Joy
Published: December 2020

Background

Due to mandated quarantine and social distancing in 2020, Florida residents temporarily ceased social activities outside the home, and modified activities of daily life that required leaving the home. Subjects continued to present for clinical trials in Alzheimer’s disease. The purpose of this data review is to determine the effect of social isolation on orientation to time, due to site‐level concerns that the mandated social isolation may have a negative impact on orientation scores for subjects reporting mild memory concerns.

Method

Data was collected for 68 subjects reporting mild memory concerns (not meeting diagnostic criteria for dementia). Orientation responses for 52 subjects evaluated prior to the social distancing mandate (January 1 – March 26, 2020), and 16 subjects evaluated post‐implementation of social distancing (April 1‐May22), were recorded for the following items: Year, Month, Date, Day of the Week. All subjects in the post‐implementation group reported that they were mostly staying home, and not participating in their typical social activities outside of the home. The means of the two groups were compared across all orientation domains.

Result

A t‐test analysis reveals that following the social distancing mandate, subject performance on measures of orientation did significantly decline, overall. The mean of the pre‐social distancing group for the 4 orientation items was 3.7. The mean of the post‐social distancing group for the 4 orientation items was 3.1. (t crit = 1.67 , t stat = 2.17 , p= 0.01). Responses significantly affected by post‐social distancing were specific to Day and Date. (Correct responses for Day: 87% pre‐quarantine, 63% post‐quarantine; correct responses for Date: 90% pre‐quarantine, 69% post quarantine). Accurate Year and Month responses appeared to be consistent across both groups.

Conclusion

Consistent with site‐level concerns that social isolation subsequent to Covid‐19 distancing guidelines could negatively impact orientation scores for subjects reporting mild memory concerns, the data collected and analyzed from January through May 2020 indicates a slight but significant decline in orientation scores post‐quarantine. Specifically, orientation to weekday and date appears to be most affected by the change in lifestyle and activities of daily living engaged in outside of the home.
Vitamin D deficiency is associated with decreased cognition independent from the disease status and AD morphology
Authors: Dogan Melike Karacam , Özkan Esra , Karakaşlı Ahmet Alp , Zengin Hatice Yağmur , Çap Duygu , Şenol Bedirhan , Karahan Sevilay , Karaosmanoğlu Ayça , Saka Esen , Ayhan Yavuz
Published: December 2020

Background

25(OH)D deficiency was associated with cognitive impairment and altered brain volumes, namely reduction in white matter and medial temporal lobe and enlargement of lateral ventricles. 25(OH)D deficiency was also associated with the development of Alzheimer's disease (AD). In this study, we aimed to investigate whether 25(OH)D levels are independently associated with cognitive performance and AD‐associated morphology in a mixed sample.

Method

The study was conducted at Hacettepe University Faculty of Medicine, Ankara, Turkey. The participants were chosen from our dementia research database.Demographic variables, 25(OH)D levels, standardized Modified Mini Mental Test (3MS) z‐scores, 1.5 T brain MRI, the data for comorbid medical conditions and current prescription drugs were used as pertinent variables. FreeSurfer v.6.0 was used for automated structural neuroimaging analysis. Based on the previous literature, AD cortical signature, predictive cortical thickness, medial temporal lobe gray matter and mean hippocampal volumes were calculated and used independently to assess AD‐related morphological changes. Cut‐off for 25(OH)D deficiency was accepted as 20 ng/ml. Statistical analyses were conducted using IBM SPSS Statistics 23 for Windows. To assess the predictive power of 25(OH)D, regression models were used with standardized 3MS scores and AD‐related areas as dependent variables. Statistical assumptions were met for all models presented. Funded by TUBITAK 214S048 and Hacettepe University THD 2018‐17363.

Result

A total of 210 patients over 55 years of age (47 AD, 15 nonAD dementia, 74 Mild and Subjective Cognitive Impairment, 74 cognitively intact) were included. Mean 25(OH) level was 22.48 ±15.8 ng/ml. 108 participants (51.4%) had 25(OH)D deficiency (AD 57%, nonAD Dementia 60%, SCI/MCI 51%, Control 46%, p>0.5). 25(OH)D deficiency was significantly associated with 3MS scores (χ2 =5.608,df=1,p=0.018). The association was also marginally significant when adjusted for age, diagnosis and medial temporal lobe gray matter volume (Exp(β): 2.472, p=0.05). 25(OH)D levels were not associated with AD‐related morphological changes on multivariate analyses.

Conclusion

Plasma 25(OH)D levels are associated with cognitive performance regardless of the diagnosis. The effect seems to be independent of AD‐related brain morphological changes. Our results suggest an independent effect of 25(OH)D levels on cognition.