bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression and increased risk of Alzheimer’s dementia: Longitudinal analyses of modifiable risk and sex‐related factors
Authors: Kim Doyoung , Wang Ruoding , Kiss Alex , Bronskill Susan E , Lanctot Krista L , Herrmann Nathan , Gallagher Damien
Published: December 2020

Background

Older adults with depression are at increased risk of Alzheimer’s dementia (AD). Most adults with AD are women. Women have two‐fold lifetime risk of depression. It is not known how sex influences the risk of depression upon AD.

Method

We used the longitudinal case series dataset from National Alzheimer’s Coordinating Center for analysis. Older adults (age 50+) with normal cognition, who visited memory clinics across the United States from September/2005 to December/2019, were followed from initial visit until first diagnosis of AD or loss to follow up. Multivariable survival analyses were conducted to determine if 1) recent and remote depression were independently predictive of AD, 2) this risk differed between the sexes, and 3) sex modifies this risk.

Result

652 of 10,739 enrolled subjects developed AD over a median follow‐up of 55.3 months. Only recently active depression (within the last 2 years) was associated with increased risk of AD (HR=2.0; 95%CI, 1.5‐2.6) independently of other significant risk factors. After stratification by sex, recent depression was an independent predictor of AD in females (HR=2.3; 95%CI, 1.7‐3.1) but not in males (HR= 1.2; 95%CI, 0.7‐2.1). No interaction between recent depression and sex in predicting the risk of AD was observed (HR=1.5; 95%CI, 0.8‐2.8).

Conclusion

Only recent history of depression was associated with higher risk of AD. This risk was significant only in women. Future analyses should determine if current findings extend to other populations and may be explained by variable distribution of neurobiological or other modifiable risk factors between the sexes.
Optimizing protocols for white matter tractography in animal models of genetic AD risk
Authors: Stout Jacques Andrew , Anderson Robert BJ , Cofer Gary , Colton Carol A , Badea Alexandra
Published: December 2020

Background

Alzheimer's disease (AD) has a tremendous effect on the brain structural and functional integrity. As previous research has shown, AD impacts gray matter areas, but also neuronal tracts connecting them [1]. One of the ways this neuronal impact can be evaluated is through the combined use of diffusion imaging and tractography modeling. However, due to the complex nature of 3D modeling, it is important to evaluate not only the tractography models, but also the imaging protocols. We have evaluated several diffusion acquisition schemes in a mouse model expressing the APOE4 genotype, associated with genetic risk for AD. We have focused on fimbria, in order to recommend optimized diffusion imaging protocols in a larger cohort of mice.

Methods

We acquired diffusion images at 50 µm3 isotropic with 46 different directions and an 8‐fold compressed sensing acceleration factor for fixed brain specimens using high‐field MRI. We used six different b‐value variations on this acquisition scheme, including single, two, and three‐shells acquisitions. The diffusion signal was reconstructed using a Q ball Constant Solid Angle reconstruction[2], and tracts were built using a deterministic maximum direction getter. The smaller tracts were pruned, and models were evaluated using Linear fascicle evaluation (LiFE) [3] in regions including the fimbria (Fig.1).

Result

We ranked the quality of the tractography models according to the number of tracts and their average size in the fimbria, as well as the correspondence between the diffusion model and predicted tract results using Life error evaluation (Fig.2). Our results favored Acq 1 (single shell b = 4000s/mm2) which had the most consistent and longest tracks, and lowest errors, followed by Acq 3 (three shells, b = 2000, 3000, 4000), and 5 (double‐shell, b = 2000, 4000).

Conclusion

Whether it was for single, dual or triple shell, the acquisitions with the greatest model error were those with at least one lower b‐value. This would indicate that for tractography models, and despite the lower signal noise levels, the use of low b‐values lead to tract distortions. Other considerations, such as reducing bias should also be introduced so as to better estimate diffusion scalar parameters.
The effect of hippocampal cis‐p tau injection in learning and memory and synaptic plasticity
Authors: Bakhtiarzadeh Fatemeh , Shahpasand Koroosh , Najafi_Zadeh Javad Mir
Published: December 2020

Background

Experimental models of Alzheimer’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The aim of this study is to introduce a new model for AD.

Method

Male C57BL/6 (3‐6 months) were divided into three groups: control, sham and cis‐p tau groups. We injected 2 µg/µl cis‐p tau or its vehicle bilaterally into the hippocampal CA1 region. Short term memory assessed (by Y‐maze test) and spatial learning and memory (by Barnes maze test were evaluated. In vitro field potential recordings were done in all three groups. Primed‐burst stimulation (PBS) protocol was applied to induce long‐term potentiation.

Result

Hippocampal injection of cis‐p tau significantly decreased spontaneous alternation 14 days and one month (p<0.001) and 4 months (p<0.05) after injection. One month after cis‐p tau injection, primary and scape latency and also primary and total error increased in Barnes maze test (p<0.05) but not at 14 days and 4 months after injection. Field potential recording showed that hippocampal injection of cis‐p tau significantly (p<0.01) disrupted maintenance of LTP in dorsal hippocampal region but had no effect on ventral region both one month and four months after the injection.

Conclusion

Cis‐p tau injection as a new model of Alzheimer’s‐like disease decreased short term memory, learning and spatial memory. Bilaterally injection of cis‐p tau impaired long term potentiation and synaptic plasticity in dorsal region of CA1 hippocampal area.
Salvaging COVID‐19 interrupted Alzheimer clinical trials using virtual patient simulations
Authors: Geerts Hugo , Van der Graaf Piet
Published: December 2020

Background

The COVID‐19 pandemic has halted many Alzheimer’s Disease clinical trials, with some forced to re‐start at different points along the trial time‐line with substantial protocol amendments and patients dropping out with substantial partial assessments. To align the functional outcomes of these protocol amendments with the original trial design at the individual patient level, we propose to use Physiology‐Based Pharmacokinetic (PBPK) and Quantitative Systems Pharmacology (QSP) Modeling to ‘correct’ the cognitive trajectory of mirror virtual patient population back to the original trail design.

Method

The Virtual Twin approach creates a PBPK computer‐simulated model of each patient with a virtual twin QSP model of trial subjects, with the same co‐medications, common genotype variants affecting metabolism and cognitive outcome; β‐amyloid and tau biomarkers. The QSP platform is a previously ADAS‐Cog calibrated model of key neuronal circuits involved in cognition, allowing to model the effects of CNS active co‐medications based on their pharmacology and genotypes based on imaging studies. In this Virtual Twin approach, the platform will be extensively validated against the actual clinical data from the completer set and the fragmented outcomes of the restarters with their individual protocol amendments, before simulating the cognitive trajectory with the original trial design for those whose trial was interrupted.

Result

Different interruption scenarios in a 24‐month AD study of a bi‐weekly amyloid antibody infusion are simulated with increased anxiolytics and anti‐depressants use after restart. The impact of changes is dependent upon the genotype combination with the 5‐HTTLPR rs 23351 > APOE > COMTVal158Met and different for placebo and active treatment. Anti‐depressants and benzo also differentially substantially affect the cognitive trajectory. We illustrate how to reconstruct the cognitive trajectory of 600 subjects (out of 1200) affected by the interruption.

Conclusion

Combining QSP modeling of the biology with PBPK modeling and extensive validation with the fragmented clinical data available, in principle allows to reconstruct the original cognitive trajectory in patients affected by the COVID‐19 interruption. In this way, the original trial design and statistical analysis plan can be applied to achieve a fair evaluation of the clinical effect of the investigative new drug.
Implementing an arts‐based recreation program for older adults in care settings
Authors: Swaminathan Swathi , Altschuler Aviva , Howard Elizabeth P , Hasher Lynn , Murphy Kelly J
Published: December 2020

Background

Research shows that older adults with memory‐support and complex‐care needs can meaningfully benefit from arts‐based activities because it can make them feel good, promote their sense of connection with personal and community identity, and stimulate thinking and memory. As a result, there is growing interest in integrating participatory arts techniques in clinical care settings. In this qualitative study, we explore therapeutic recreationists’ (TRs) experiences of implementing a visual‐arts program designed to promote learning and creative engagement.

Method

Participants were eight TRs or TR interns working in long‐term care (n = 4), short‐term residential (complex and palliative) care (n = 3), or memory day‐clinic (n = 1) settings. All implemented an arts‐based recreation program, ArtontheBrain, for at least 12 sessions over 6 weeks to older adults in their care in one‐on‐one or group sessions. ArtontheBrain is a virtual platform that delivers visual‐art content with modules designed to facilitate learning, play and storytelling (both reminiscence and imagined stories). TRs were encouraged to flexibly implement ArtontheBrain according to their judgement of how to best engage clients. TRs completed semi‐structured interviews which were then thematically analysed using NVivo 12 software.

Result

Emergent themes revealed that TRs were able to effectively use the arts‐based activity to (1) provide stimulating and appropriately paced cognitive challenges, (2) facilitate reminiscence and imagination, (3) promote conversation and social interaction, (4) learn new information about their clients’ preserved skills and interests, and (5) learn new facts about the world from their clients.

Conclusion

TRs found the arts‐based program to be a useful addition to their existing suite of care techniques. This finding complements results of studies documenting that older adults in care find arts‐based programs to be valuable in promoting their sense of wellbeing. Future research could investigate questions of who is likely to benefit from arts‐based programs and what methods are most effective for implementing arts‐based programs for older adults in care settings.
Tyramine and amyloid beta 42: A toxic synergy
Authors: Dhakal Sudip , Macreadie Ian George
Published: December 2020

Background

In synaptic cleft, trace amines play a crucial role as neurotransmitter signaling through the trace amine associated receptors. Tyramine, an important trace amine formed by decarboxylation of tyrosine, has been reported to be implicated in various diseases including schizophrenia, Parkinson's disease, migraine and Huntington's disease. However, there are no investigations to find its connection with Alzheimer's disease (AD).

Method

Genetically modified Saccharomyces cerevisiae BY4743 producing different forms of amyloid beta 42 (Aβ42) peptide including native Aβ42 and green fluorescent protein (GFP) fused to Aβ42 were treated with various concentrations of tyramine. Reactive oxygen species (ROS) produced in these strains were measured using 2′,7′‐dichlorodihydrofluorescein diacetate (H2DCF‐DA) staining in a flow cytometric analysis. Growth inhibition of the yeast strains producing GFP and GFP‐Aβ42 were analysed in presence of tyramine. Petites generated due to tyramine were estimated in both these strains and petite frequency calculated.

Result

Tyramine was found to induce ROS formation in S. cerevisiae BY4743 as well as its genetically modified variants. ROS formation in yeast strains producing native Aβ42 treated with tyramine was significantly synergistically higher as compared to experimental controls. Similarly, yeast strains producing GFP‐Aβ42 was found to be inhibited more in media containing ethanol as sole carbon source compared to GFP producing controls in presence of 3 mM tyramine. Additionally, petite frequency in yeast strains producing GFP‐Aβ42 were found to increase significantly from around 20% to nearly 80% when grown in presence of tyramine.

Conclusion

These findings suggest that tyramine in presence of Aβ42 is synergistically toxic to yeast cells by inducing ROS formation and causing petite mutation, implying possible cause of mitochondrial damage evident in AD patients. The study also demonstrates yeast as model to study compounds that have potential to exacerbate AD.
Chronic renal function impairment‐induced cognitive changes and related pathology in mice after unilateral ureteral obstruction (UUO) surgery
Authors: Ho Janice Yuen Shan , Lau Chi‐Fai , Tang Wing‐Yan , Tian Jia‐Yan , Lee Joyce , Yung Susan Sou‐Ying , Chang Raymond Chuen‐Chung
Published: December 2020

Background

Chronic kidney disease is associated with cognitive impairment. While the pathophysiology remains unclear, it has been suggested that it shares some similarity to those in Alzheimer’s disease. Currently, most studies in this area used the 5/6 nephrectomy and high adenine diet to induce renal impairment in rat or mice. Our group had successfully used the unilateral ureteral obstruction (UUO) mice as an animal model to study the cognitive changes and related pathology.

Method

Eight‐week‐old male C57BL/6N mice received the UUO operation with double ligation of their left ureter under general anesthesia. Sham operated mice received the same experimental procedure without ureteral obstruction. Cognitive and behavioral tests were performed to examine potential changes in cognition and other behavior 2, 4 or 12 weeks after the surgery. The serum, kidneys and brains were harvested for the detection of systematic inflammation markers and neurodegenerative changes.

Result

Progressive renal impairment were observed after the UUO surgery. Systematic inflammation was evident by detecting an increase in C‐reactive protein and TNF‐a levels in the UUO mice. These mice also showed a significantly worse performance in the novel object recognition test, Y‐maze test, and puzzle box test when compared to the sham control, indicated cognitive impairment. Reduction in synaptic proteins such as synapsin‐1, synaptophysin, synaptotagmin, PSD95, NMDAR2B and AMPAR, elevation of Nrf2 and 8‐Hydroxyguanosine and hyperphosphorylation of tau were found in their hippocampus.

Conclusion

We have characterized the cognitive and neuropathological changes in the UUO mice. This mouse model can be used for studying chronic kidney disease‐induced cognitive impairment and may have an implication for understanding the pathogenesis of Alzheimer’s disease.
Glial control of the local translatome in AD
Authors: Gamarra María , Blanco‐Urrejola Maite , Baleriola Jimena
Published: December 2020

Background

Under pathological conditions axons respond to Aβ oligomers by increasing localized translation which in turn contributes to neurodegeneration. Additionally, a link between intra‐dendritic translation, and Tau mislocalization and hyperphosphorilation has been found. Thus, dysregulation of local protein synthesis in neurons seems to play a relevant role in AD. Although local translation has been recently become accepted, there are several aspects of this phenomenon that are still under debate. It is unclear whether local protein synthesis is fully cell‐autonomously regulated or if it relies upon non‐neuronal cells surrounding the neurons. Our laboratory aims at deciphering the contribution of glia to local neuronal translation in physiological and Aβ‐induced pathological conditions.

Method

We performed neuron and neuron‐astroglia cultures on coverslips or on Boyden chambers to address the effect of glia on local translation. Cultures were treated with vehicle or Aβ. Boyden chambers were used for proteomic analyses of soma and neuritic extracts when cells were cultured with or without astrocytes and treated with vehicle or Aβ. Extracted samples were subjected to LC‐MS/MS and gene ontology analysis was performed with DAVID. Finally, we have addressed whether extracellular vesicles (EVs) play a role in local translation. EVs secreted by cells treated with vehicle or Aβ were isolated by ultracentrifugation. EVs or EV‐depleted media were used to treat naïve neurons and local translation was measured.

Result

Cultures on coverslips and in Boyden chambers revealed that secreted factors in the presence of astrocytes increase protein synthesis in control and Aβ‐treated neurites. We have identified 72 significantly‐regulated proteins in Aβ‐treated neurons compared to controls in the absence of astrocytes, whereas 55 proteins were significantly changed in Aβ‐treated vs controls in neuron‐astrocyte co‐cultures. Only 4 proteins were common to both cultures, suggesting that the presence of astrocytes dramatically changes the local proteome upon Aβ treatment. Finally, our experiments suggest that glial EVs distinctly regulate local protein synthesis in neurons in physiological and pathological conditions.

Conclusion

Astrocytes play a key role in the regulation of protein synthesis in neurites in both physiological and pathological conditions. Moreover, our results suggest that glia mediates its effect on neurites through EV release.
Glial cells derived from pluripotent stem cells as a suitable tool for modeling Alzheimer’s disease
Authors: Leon Juan Antonio Garcia , Palomo Laura Caceres , Davila Jose Carlos , Vitorica Javier , Gutierrez Antonia
Published: December 2020

Background

Alzheimer's disease (AD) is characterized by presenting a complex pathology, not fully resolved yet. This fact, together with the lack of reliable models, has impeded the development of effective therapies. Recently, several studies have shown that functional glial cell defects have a key role in the pathology of AD. However, this glial dysfunction, currently, cannot be correctly modeled using the available animal models, so we hypothesized that cells derived from Alzheimer's patients can serve as a better platform for studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different types of neural cells, which can be used for disease modeling, identification of new targets and drugs development.

Method

We have a collection of hiPSCs derived from patients with sporadic forms of AD. We have differentiated these cells towards neural lineage to obtain neurons and astrocytes. For the generation of oligodendrocytes (OLs), we have developed a fast and robust protocol to generate mature OLs in just 22 days.

Result

We have generated neural precursors from all the lines tested. In the case of OLs, the cells generated resemble primary OLs and can myelinate neurons in vivo and in vitro using a screening compatible platform. This platform is being transferred for the generation of the other glial cells.

Conclusion

This methodology can be used to elucidate the pathogenic pathways associated with neurodegeneration and to identify new therapeutic targets susceptible to modulation, contributing to the development of new effective drugs against AD. Acknowledgments: J.A.G.L has been supported by a contract of doctor reincorporation plan from the I Plan Propio of the University of Malaga (Spain) and by CIBERNED. The work was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co‐financed by FEDER funds from European Union (grant PI18/01557 to A.G., grant P18/1556 to JV), by Junta de Andalucia co‐financed by FEDER funds grant UMA18‐FEDERJA‐211 (to AG), by Consejeria de Salud of Junta de Andalucia (grant PI‐0276‐2018 to J.A.G.L.) and by CIBERNED.
Plasma p‐tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post‐mortem and improves the clinical characterisation of cognitive decline
Authors: Rodriguez Juan Lantero , Karikari Thomas K , Suárez‐Calvet Marc , Troakes Claire , King Andrew , Emeršič Andreja , Aarsland Dag , Hye Abdul , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J
Published: December 2020

Background

Nowadays, Alzheimer’s disease (AD) can be diagnosed in vivo using both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation has been impeded due to limitations including high cost, perceived invasiveness and limited availability. Thus, much effort has been placed in the discovery of blood biomarkers. In this context, our high performance blood immunoassay for p‐tau181 has already showed an excellent ability to specifically identify AD. Therefore, the aim of this study was to investigate if plasma p‐tau181 reflects AD pathology in post‐mortem confirmed cases and if this biomarker can successfully discriminate AD from non‐AD dementia pathologies.

Method

Using our plasma p‐tau181 assay, we studied a unique cohort of 115 individuals selected from the Maudsley and King's Healthcare Partners Dementia Case Register, which incorporates the Alzheimer's Research UK cohort. The cohort included longitudinal plasma collections and clinical evaluation at 8, 4 and 2 years followed by neuropathological examination after death.

Result

Our results demonstrate that plasma p‐tau181 accurately predicts AD pathology and Braak staging at least 8 years before death. Moreover, plasma p‐tau181 proved to accurately discriminate AD from non‐AD pathologies (AUC=97.5%, 95% CI=94.1‐100%). This strongly suggests that a clinical diagnosis of AD dementia combined with low plasma p‐tau181 levels would be useful to identify non‐AD pathology. Additionally, we described the longitudinal trajectory of plasma p‐tau181 in AD patients. We found that the main increase in plasma p‐tau181 levels occurred between 8 and 4 years before death, and later plateaus.

Conclusion

Altogether, our results demonstrate that plasma p‐tau181 is highly specific and predictive of AD pathology several years before neuropathological examination. Moreover, these results strongly support the implementation of plasma p‐tau181 in clinical diagnosis, longitudinal monitoring and therapeutic trial recruitment.
Mitochondrial DNA copy number is associated with cognitive impairment
Authors: Andrews Shea J , Goate Alison M
Published: December 2020

Background

Increasing evidence has implicated mitochondrial dysfunction in the pathogenesis of Alzheimer’s Disease. Mitochondria contain their own DNA outside of the nuclear genome, with every cell having between 100‐10,000 copies of mtDNA. Mitochondrial DNA copy number (mtDNAcn) has been used as a surrogate measure of mitochondrial function, with reduced mtDNAcn associated with age‐related diseases. The aim of this study was to evaluate the association of mtDNAcn with cognitive impairment.

Methods

We evaluated the association of mtDNAcn with the extended Clinical Dementia Rating (CDR) scale in the Mount Sinai Brain Bank (MSBB) and with mini mental state exam (MMSE) in the Religious Orders Studies and the Memory Aging Project (ROSMAP). Relative mtDNAcn was estimated as the ratio of mitochondrial genomes to nuclear genomes in 1025 non‐Hispanic white subjects (MSBB = 277; ROSMAP = 748) using whole‐genome sequencing data generated from DNA isolated from post‐mortem brain tissue (MSBB: prefrontal cortex; ROSMAP: dorsolateral prefrontal cortex [DLPFC], posterior cingulate cortex [PCC], or cerebellum). Linear regression adjusting for age of death, sex, APOE, study, mitochondrial haplogroup and source tissue were used to evaluate the association of mtDNAcn with cognitive impairment.

Results

In the MSBB, a one standard deviation decrease (1 s.d. 343) in mtDNAcn was associated with a higher CDR score (b(se) = 0.71 (0.10), p = 3.41e‐12, Fig. 1). Similarly, in ROSMAP a one standard deviation decrease (1 s.d. 1063) in mtDNAcn was associated with a lower MMSE score (b(se) = ‐4.02 (0.75), p = 1.07e‐7, Fig. 2).

Conclusion

Mitochondrial dysfunction as measured by mtDNAcn is associated with worse cognitive performance, suggesting that mitochondrial function plays a role in the pathogenesis of Alzheimer’s Disease. However, further research is needed to determine if mitochondrial dysfunction causes, mediates, or is a by‐product of AD pathogenesis, in particular whether neuronal loss is an unobserved confounder that could be driving the observed associations.
Delivery of CANTAB assessments across diverse health systems
Authors: Baker Elizabeth , Dente Pasquale , Backx Rosa , Lowther Millie , Cotter Jack , Cormack Francesca K , Barnett Jenny
Published: December 2020

Background

Assessment of cognitive function is an important component of differential diagnosis in Alzheimer’s disease and dementia and is critical to characterising the impact of the disease. Objective assessment of function provides real world evidence for assessing effectiveness of current standards of care, and evaluating interventions designed to improve outcomes. However, sensitive, reliable tools for administering standardised tests at scale have been lacking to date.

Method

Digital tools, providing near‐patient assessments in the community or at home are one way to meet the demands of patient characterisation across a range of resource settings. Cambridge Neuropsychological Automated Test Battery (CANTAB) is a set of 25 computerised assessments designed to assess cognition across a broad range of domains relevant to neurological and psychiatric conditions. A number of tests from this battery have been integrated into medical device software to assess the impact of neurological and neurodegenerative disease. These tools have been deployed in community, primary and secondary health care settings in relatively resource‐rich healthcare systems (primarily UK and US). We are exploring whether such an approach can be generalised to a lower‐middle income countries/South Asia.

Result

We will present performance of 4000 healthy participants recruited across nine regions of India on CANTAB assessments including performance on episodic memory (Paired Associates Learning (PAL)), working memory (Spatial Working Memory (SWM)) and attention (Matching to Sample (MTS)). Evidence from this study supports the suitability of our platform for delivering cognitive assessments in health care systems outside the UK. We will contrast performance of healthy participants on PAL and SWM with recent normative data collections across the UK and US; demonstrating similarity of performance and the effectiveness of assessment platforms. The demographic diversity of these normative collections supports the need to partner these tools with appropriate recruitment and operational initiatives to ensure accessibility.

Conclusion

We will reflect on how this evidence guides our current and future plans for making scientifically robust cognitive assessment tools globally available, both for increasing access to treatment, but also in the context of basic research and drug development.
Accuracy of automated scoring of verbal paired associates in a remote data collection context
Authors: Cormack Francesca K , Barnett Jennifer H , Dawson Monty , Taptiklis Nick
Published: December 2020

Background

The validation of remote testing methodologies has increased in relevance, given the impact of COVID‐19 on clinical trials. Verbal cognitive testing, which requires skilled raters, has not previously been feasible for remote testing. In previous research we had demonstrated that remote verbal cognitive testing using automatic speech recognition (ASR) was possible and showed the expected pattern of results. Here, we manually score responses to a verbal paired associates (VPA) test and explore the impact participant‐level demographic and technology related factors on scoring accuracy.

Methods

From a pool of 5,742 recordings of participants aged 17–86 years, 150 were randomly selected for manual review (age 30–70, M = 52.5). Participants were all fluent English speakers, and completed the VPA test via a device‐agnostic web‐app on their own devices. We recorded participant demographics and information regarding the operating system, browser and device on which the tasks were completed. Manual scoring was completed off‐line by trained raters through the Neurovocalix system.

Results

There was excellent agreement between the human scoring and ASR, with a Spearman correlation of 0.93 (p<0.0001) and an ICC(A,1) agreement of 1 (F(148,148) = 6951, p = <0.0001). The distribution of ASR errors was skewed, with a median of 0 and a mean of 0.97. The maximum number of scoring errors was 10, observed in two cases, where the ASR system did not detect correct responses due to very high levels of background noise or poor audio quality. We found no significant effect of age, gender, education or device on scoring errors. Key themes reported by raters as affecting the scoring accuracy were 1) slowness in responding, meaning that not the whole word was recorded, 2) the presence of significant background noise or poor audio quality 3) certain accents leading to miss‐recognition of specific words.

Conclusion

These results represent a comprehensive evaluation of the accuracy of automated scoring of verbal responses from data collected in a remote context. Overall, there is excellent accuracy. These results both demonstrate the potential utility of this approach to remote data collection as well as suggesting avenues for increasing accuracy of automated scoring.
Caregivers’ limited rights to legally act on behalf of Alzheimer patients: Learning from the Brazilian experience
Authors: Gozzo Débora
Published: December 2020

Background

The Brazilian law 13.146/2015 implemented the UNO’s Convention on the Rights of Persons with Disabilities in 2016. It modified the private law rules concerning a person’s ability to legally act, and it does not acknowledge the concept of “total disability” anymore, but only “partial disability” or “restricted legal capacity” (with the exception of minors who continue to be legally incompetent). Other persons with limited intellectual or physical capacities are now legally “partially disabled”. The reason for this change of paradigm was the legislators’ aim to follow the Convention and to strengthen the principle of human dignity, one major foundation of the constitutional system. The law was certainly meant well, but it does, however, not allow any difference among the many kinds of disabilities. Whether being physical, intellectual, mental (as Alzheimer) or else, they are indiscriminately considered as one unique disability. The legislators created a problem for patients with Alzheimer: they cannot be considered totally disabled now, even if in fact they are. The (family) caregivers are now only in charge of the economic sphere of the disabled person. Thus, every aspect of personal life is legally left for the disabled (and often helpless) person to decide, whether it factually can, or not. Caring family members could not change the circumstances. However; the Supreme Court of the State of São Paulo has recently applied a wide interpretation of the law, extending caregivers’ rights to decide about the personal sphere of the patients.

Methods

The presentation will offer a brief comparative overview over the range of the problem, thus aiming to produce the following

Results

An indiscriminate application of well‐meant rules can be counterproductive in the case of Alzheimer patients.

Conclusions

The UN Convention and national legislation should be taken from the Procrustean bed of absoluteness and instead softened and rethought in a way that caregivers can be enabled to act in the best interest of the patients.
Plasma amyloid‐β 42/40 as a predictor of cognitive decline among community‐dwelling older adults: MAPT study
Authors: Giudici Kelly V , Barreto Philipe de Souto , Li Yan , Bateman Randall J , Vellas Bruno ,   the MAPT/DSA group
Published: December 2020

Background

Plasma measures of amyloid‐β (Aβ) peptides recently emerged as a potential equivalent to brain positron‐emission tomography (PET) imaging and cerebrospinal fluid (CSF) measurements in determining Aβ status. Low plasma Aβ42/40 has been associated with Alzheimer’s disease. However, further studies are needed to validate its use for predicting cognitive impairment. This study aimed to investigate the associations between plasma Aβ42/40 and cognitive decline over time among community‐dwelling older adults.

Method

Observational study using data of 483 subjects ≥70 years (mean age 76.9 years, SD = 4.5; 59.2% women), volunteers from the Multidomain Alzheimer Preventive Trial (MAPT), who were followed for 5 years. Plasma Aβ42 and Aβ40 were measured at 12 months for 92.8% of participants and at 24 months for the rest. Participants were classified as low Aβ42/40 (≤0.107) or normal Aβ42/40. Cognitive function was assessed at 12, 24, 36, 48 and 60 months of follow‐up, by a composite cognitive score (based on four tests); Mini Mental State Examination (MMSE); Clinical Dementia Rating (CDR) sum of boxes; Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL). Linear mixed models were performed. Potential confounders included age, sex, education, body mass index, ApoE ε4 genotype and MAPT groups.

Result

From the total, 33.3% (n = 161) were classified as low plasma Aβ42/40. After adjusting for potential confounders, low plasma Aβ42/40 was associated with higher decline in composite cognitive score, decline in MMSE score and with higher increase in CDR sum of boxes after 4 years, compared to the normal Aβ42/40 group. Those with low Aβ42/40 had approximately 2‐fold acceleration in outcomes evolution. Sensitivity analysis considering the 25th percentile of Aβ42/40 (≤0.103) as an alternative cutoff provided similar findings.

Conclusion

Low plasma Aβ42/40 was associated with higher impairment in cognitive function (measured by multiple outcomes) over time among community‐dwelling older adults. Findings points towards the use of this inexpensive measure to quickly identify people at risk of Alzheimer’s disease and other neurodegenerative diseases, over more complex and expensive measures such as PET or CSF. Further studies with long follow‐ups are needed to confirm its utility in clinical practice and public health.
Absolute quantification of tau isoforms in human brain by mass spectrometry
Authors: Zola Nathalie Kyalu Ngoie , Herinckx Gaëtan , dit Ruys Sébastien Pyr , Vertommen Didier , Rider Mark H , Hanseeuw Bernard J
Published: December 2020

Background

Tauopathies are neurodegenerative disorders characterized by the brain deposition of tau protein. Characterizing the biochemical alterations of tau in vivo is challenging given its low concentration in human fluids. Immunoassays can detect tau in the cerebrospinal fluid (CSF), but cannot provide a thorough characterization (isoforms, post‐translational modifications (Fig1). Mass Spectrometry (MS) allows in vivo detection with high sensitivity and absolute quantification of any biochemical characteristics of interest. We aim to characterize tau in the CSF using MS in patients using both CSF and brain samples available. We present here preliminary results on the first brain sample analysed.

Method

Frozen brain samples of an AD patient (Braak stage VI) were obtained from the UCLouvain donation centre. We prepared a neocortical homogenate (200 mg of wet weight/ml) that we ultra‐centrifugated to separate sarkosyl‐soluble tau from insoluble tau aggregates (Diner et al., 2017). Sarkosyl‐soluble tau was isolated by immunoprecipitation with 0.5 to 4 µg of mouse monoclonal HJ8.7 antibody. Immunoprecipitated tau was eluted with 0.1 % formic acid, dried and digested with 250ng trypsin. Liquid Chromatography (LC)‐MS/MS analysis was performed using parallel reaction monitoring (PRM) to identify tau isoforms. Specific peptides for each isoform were targeted to ensure selective and sensitive detection. In parallel, we diluted this extract 5000 times (2µl in 10 ml) and harvested 1 ml of sample into which we spiked 300pg of recombinant isotopically labelled full‐length (2N‐4R) tau protein (15N labelling). This allowed us to detect 15N isotopologues of 2N and 4R isoforms and quantify endogenous tau via intensity ratios.

Result

We detected all tau isoforms (0N, 1N, 2N, 3R, 4R) by post‐acquisition analysis of the data with Skyline (Fig.2). We absolutely quantified isoforms 2N and 4R separately from other isoforms in our sarkosyl‐soluble protein extract using 15N‐tau and obtained 150 pg/µl of tau 2N and 390 pg/µl of tau 4R (Fig.3).

Conclusion

This targeted MS analysis proved to be effective for detecting and quantifying tau isoforms in the brain of one AD patient. We will soon compare this result with CSF coming from the same patient, and test CSF and brain samples coming from patients presenting non‐AD tauopathies.
Mild disease course in cognitively impaired oldest old individuals with COVID‐19: A description of two cases
Authors: Tsuang Debby W. , Payne Sarah , Jankowski Adrienne , Shutes‐David Andrew , Ritchey Katherine
Published: December 2020

Background

The COVID‐19 pandemic has swept across the world, causing a staggering number of deaths, particularly among older individuals. The most common symptoms of COVID‐19 are fever, dry cough, and shortness of breath, but delirium has been reported in older adults, including those with preexisting neurodegenerative disorders. Some research has suggested that the role of neuropsychiatric sequelae in COVID‐19, especially delirium, has been underreported and that the lack of fever and respiratory distress in this population may exacerbate underdiagnosis and subsequent mortality. Here, we discuss the variable course of COVID‐19 by detailing the course of illness in two individuals who are age 90+ with mild COVID‐19.

Method

We conducted chart reviews and telephone interviews in two patients who were age 90+. Case 1 had an outpatient follow‐up visit via teleconferencing. Due to COVID‐19 protocols, in‐person research assessments were not completed. Both were on hospice due to underlying terminal medical conditions.

Result

Both cases are age 90+ patients with dementia who receive hospice care for multiple underlying medical comorbidities. Case 1 presented at home with a low‐grade temperature that was below the CDC COVID‐19 guidelines for fever at that time; he experienced cough, confusion, and functional decline and was admitted to a COVID‐19 unit after testing positive for the disease. His workup also included a COVID‐19 laboratory panel, which was mostly abnormal (including extremely elevated brain natriuretic peptide) but had normal WBC. He did not experience further deterioration, and 22 days later, after testing COVID‐19 negative, he was discharged to a skilled nursing facility (SNF), followed by discharge to home 15 days later. Case 2 had metastatic carcinoma and a preexisting diagnosis of probable dementia with Lewy bodies. COVID‐19 was diagnosed through all‐resident screening at his SNF. He did not exhibit respiratory symptoms or fever at that time. While nursing staff reported confusion, agitation, and restlessness, these symptoms could not be differentiated from complications related to his underlying dementia. This patient was isolated within the SNF and was not hospitalized.

Conclusion

These two cases demonstrate the variability of symptom manifestation in COVID‐19 in this high‐risk population.
Multidisciplinary evaluation in cognitive behavioral sleep medicine: Leveraging behavioral neurology and sleep medicine expertise
Authors: Karageorgiou Elissaios , Sykara Konstantina , Ramirez Jeronimo Martin , Andronas Nikolaos , Mavragani Evdoxia , Mougias Michalis , Tsekou Hara , Karageorgiou Klimentini E
Published: December 2020

Background

Cognitive Behavioral Sleep Medicine is a rapidly growing discipline that aims at the comprehensive evaluation and treatment of people with cognitive or sleep symptoms, established on the bidirectional relationship between sleep disorders and neurodegeneration. On this basis, we established a comprehensive evaluation protocol for deep phenotyping of cognitive‐sleep syndromes, and present first results on its feasibility and novel cognitive to sleep associations.

Method

We enrolled 29 patients (age: 71.5 ± 11.7; education: 9.6 ± 2.8 years) with minor or major neurocognitive disorder due to predicted Alzheimer’s disease with various degrees of vascular comorbidity (MMSE = 26.0 ± 4.3) through the Sleep & Memory Center of the Neurological Institute of Athens. All patients underwent comprehensive clinical evaluations, including cognitive (Cognitive Behavioral Symptoms [CBS] score) and sleep questionnaires (Insomnia Severity Index [ISI]; Epworth Sleepiness Scale [ESS]), biochemical, imaging, and within‐day neuropsychological testing, whereas six patients have further completed novel sleep‐mediated neuropsychological tests, actigraphy and polysomnography. Exploratory analyses using Pearson ρ or Kendall τ, accordingly, were performed to examine associations of subjective complaints and daily functioning to objective cognitive and sleep metrics.

Result

Non‐memory cognitive CBS scores were highly correlated to sleep CBS scores (ρ,τ ∼ 0.51 ‐ 0.71), as well as ISI (0.56) and ESS (0.54). Memory CBS complaints in contrast correlated more with subjective insomnia symptoms (0.72 to ISI) but not hypersomnia (‐0.15 to ESS). Additionally, the CBS total score was associated to sleep‐mediated 9‐item recall (0.81) and to sleep‐mediated phonemic fluency (‐0.55), an association also noted between ESS to sleep‐mediated 9‐item recall (0.71). Of note, subjective cognitive and sleep complaints were not well correlated to within‐day neuropsychological testing (e.g., 0.13 ‐ 0.36 to MMSE). Patients who underwent actigraphy and polysomnography tolerated all procedures, and those diagnosed with sleep apnea or insomnia are effectively pursuing CPAP treatment and Cognitive Behavioral Therapy for Insomnia respectively.

Conclusion

Comprehensive evaluation of sleep and cognitive symptoms is feasible in patients with neurocognitive disorders and allows for deep phenotyping of neurodegenerative diseases. Finally, sleep‐mediated cognitive tests seem to be more sensitive than within‐day tests in reflecting real‐life symptoms, highlighting their potential utility.
A deep CNN‐based approach for predicting MCI to AD conversion
Authors: Casti Paola , Giovannetti Antonio , Susi Gianluca , Mencattini Arianna , Pusil Sandra Angelica , García María Eugenia López , Natale Corrado Di , Martinelli Eugenio
Published: December 2020

Background

Deep convolutional neural networks (CNNs) have demonstrated a considerable ability to decode various biomedical signals, including 2D and 3D neuroimaging data. Magnetoencephalography‐based functional connectivity (MEG‐FC) is proven to be a useful tool in predicting the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD), since early signs of AD may be hidden in the way neuronal activity is spatially distributed and coordinated among different brain regions. In the present work, we propose a deep learning approach for the early diagnosis of AD, able to capture the electrophysiological anomalies occurring before the conversion by exploit an image‐based coding of MEG‐FC data. The proposed approach has been tested on a set of resting‐state MEG recordings, from a longitudinal study (24 months between 2 MEG scans for each subject) involving 54 participants: 27 'progressive' patients (i.e., MCI at the time of the 1st scan converted to AD at the time of the 2nd scan), and 27 'static' patients (i.e., MCI at the time of the 1st scan remained MCI at the time of the 2nd scan).

Method

MEG and MRI data have been gathered from the 54 patients using an Elekta Vectorview system and a General Electric 1.5T MRI scanner, respectively. Source reconstruction was performed with LCMV beamformer. The obtained neural MEG sources were anatomically parcellated into 90 ROIs according to the AAL atlas. Considering the signals stemming from the 90 ROIs we extracted the MEG‐FC measures (PLV and COR), for different frequency bands [Hz]: θ(4‐8), α(8‐12), β(12‐30), and γ(30‐55). MEG‐FC has been then coded into image‐based representations and hierarchically decomposed by means of the CNN layers of 'AlexNet'. Finally, different classification techniques have been tested as predictive modules.

Result

With the proposed approach we obtained an accuracy of 0.9 in discriminating ‘static’ from ‘progressive’ patients using MEG‐FC data from the first scan. The best classification results have been obtained using the Linear Discriminant Analysis and Support Vector Machine techniques.

Conclusion

The classification of FC profiles mediated by hierarchical CNNs decomposition is a promising method for detecting the early neurophysiological anomalies characterizing the progression to AD.
Care for you at home
Authors: Patel Neela K , Davila Angelica , de Erausquin Gabriel A , Seshadri Sudha
Published: December 2020

Background

Clinical outcomes for older adults are often suboptimal because of frequent transitions among clinical settings, numerous specialists and lack of coordination of care, resulting in higher utilization and costs of care. The CARIÑO (Spanish for fondness, affection, tenderness, and love) Approach represents a highly complex set of related activities that can occur alone or be integrated to meet the patients’ needs. This approach, developed in the process of transformation into a patient centered medical home (PCMH), avoids “silos” of care and facilitates shifting to patient‐ and family‐centered care that results in patient‐driven, value‐based care and improved outcomes. Relationship building is intentional and continuous. The elements of this approach are as follows: Comprehensive, coordinated, compassionate care across various clinical settings that meets the older adults’ needs beyond the office walls; Advocating for patients and families by collaborating and maintaining relationships with other clinicians and health care partners; Respecting what matters most to your older patients (e.g., meals, mobility, money, and medicines5); Intentional activities and processes in your practice that are specific to meet the needs of older adults; Nurtured relationships with families, social service agencies, and community partners; Older adults are wise and know what they want: Listen to what they say (CARINO). Under CARINO, all coordination and relationship building with patients, caregivers, and all health care providers occurs at the clinic. CARIÑO en Su Casa takes the approach one step further, taking it into patient homes. The CARIÑO en Su Casa approach recognizes the unique needs of elderly patients that are often overlooked, particularly of underserved Hispanic elderly who lack resources such as transportation or insurance, and for whom barriers such as language and communication, and understanding how to navigate a complex health system are very significant. Such health disparities and issues with trust building and relationship building are prominent in underserved Hispanic groups in south Texas. Therefore, establishing relationships with underserved communities, as achieved by the CARIÑO approach, is crucial to improving clinical outcomes and advancing research in dementia care.