bluuebunny/crossref_metadata_2025 huggingface dataset:
The impacts of Chinese cultural adherence to filial piety on the dementia care decision processes in East Asian communities
Authors: Kuo Ching‐Yi
Published: December 2020

Objectives

Developing knowledge of Chinese cultural adherence to filial piety helps understand Dementia in the Asian Pacific Regions regarding its dementia care practices and medical system cluster around filial piety.

Background

Chinese filial piety has been deeply rooted in East Asian culture for over five thousand years, affecting life choices, including medical treatments decisions and end‐of‐life care decisions for family members. Regardless of their level of westernization, Chinese filial piety continues to play a key role in determining timely diagnosis, and institutionalization of a person with dementia. As characterized by collectivism, filial piety also explicitly directs informal caregivers' careers paths, mental health, and physical health, especially for females. Consequently, dementia care practices and medical system in East Asian communities cluster around the level of practice of filial piety, which directly affects dementia care decision making processes as well as the welfare of a person with dementia and costs to society.

Methods

A systematic literature review for the previous decade on filial piety will be employed. Implications: Through developing knowledge of underlying cultural adherence to dementia care practices in East Asian communities, government, social policies, and professionals across the fields as a whole can develop a better supportive environment for persons with dementia and their caregivers.
Fear of memory decline predicts lower quality of life and increased memory failures in older adults: Preliminary findings from a novel fear‐avoidance of memory decline scale
Authors: Farina Francesca R , Bennett Marc P , Griffith James W , Lenaert Bert
Published: December 2020

Background

Evidence concerning the impact of dementia‐related fear on health‐related outcomes is limited. Our aim was to determine the relationship between fear of dementia, quality of life and subjective memory in older adults using a novel scale to measure fear of memory decline (FAM scale).

Method

Sixty‐seven older adults (59‐81 years) completed a 23‐item self‐report scale designed to capture experiential, cognitive and behavioral components of fear of memory decline. Memory performance was assessed using the Wechsler Memory Scale (WMS‐IV) and the Memory Failures Scale (MFS). General anxiety was assessed using the Depression, Anxiety and Stress Scales (DASS) and the Geriatric Anxiety Inventory (GAI). Quality of life was assessed using the Older Person’s Quality of Life scale (OPQOL‐35).

Result

The FAM scale demonstrated strong internal consistency (α=.82) and concurrent validity (r=.47 with GAI scores). Three latent factors were observed, which were: (1) fear‐avoidance, (2) problematic beliefs and (3) resilience. After adjusting for age, education, objective memory performance and general anxiety, higher fear‐avoidance predicted lower quality of life (p=.021) and increased memory failures (p=.022).

Conclusion

Increased fear of memory decline predicts lower quality of life and subjective memory failures in healthy older adults. Based on these findings, we propose a preliminary fear‐avoidance model that explains the development and maintenance of dementia‐related functional disability in terms of psychological processes.
Variability in tau‐atrophy relationships reveals underlying phenotypes in individuals on the Alzheimer’s disease continuum
Authors: Das Sandhitsu R , Xie Long , McCollum Lauren , de Flores Robin , Irwin David J , Nasrallah Ilya M , Dickerson Brad C , Yushkevich Paul , Wolk David A ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Tau neurofibrillary tangles (T) are thought to be the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in AD. However, there is substantial variability in the T‐N relationship – manifested in higher or lower atrophy than expected for the level of tau in a given brain region. We quantitatively describe and categorize source(s) of variability using region‐based measures of T and N to gain insight into underlying modulatory factors, including polypathology.

Method

Regional cortical thickness and 18F‐Flortaucipir SUVR were computed in 108 gray matter ROIs from cognitively‐impaired, amyloid‐positive individuals (n=137) in ADNI. ROI‐specific residuals from a robust linear fit between SUVR and cortical thickness were computed. Using a threshold of +/‐ 1.5 standard deviation (S.D.), ROIs were categorized into “positive”, “negative”, or “neutral” residual (Fig 1). The residual signs for all ROIs were used in a hierarchical clustering framework to partition the dataset.

Result

Six groups appear to represent different phenotypes summarized in Table 1. Overall, the groups differed in age, burden of white matter hyperintensity (WMH), clinical status, and MMSE. However, they did not differ in tau burden in key brain ROIs (e.g. inferotemporal cortex, precuneus, angular gyrus). Group 1 is largest, consisting of individuals with low residuals described as having a canonical “T‐N” relationship. Group 2 has significantly higher temporolimbic atrophy relative to tau with many cases having a pattern of atrophy suggestive of TDP‐43 copathology. Group 3 appears to be a resilient phenotype with less atrophy relative to tau in lateral cortical regions. Group 4 is similar to Group 2 with high temporal atrophy, but also more diffuse atrophy. Group 5 also displays resilience, particularly in the temporal lobe. Group 6 shows widespread higher atrophy relative to tau, has the lowest MMSE and highest WMH.

Conclusion

We demonstrate that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may be helpful for identifying possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials.
Is the engagement in social and cognitive type of leisure activities protective against dementia risk? Evidence from the English Longitudinal Study of Ageing
Authors: Almeida‐Meza Pamela , Steptoe Andrew , Cadar Dorina
Published: December 2020

Background

Studies have suggested that mentally stimulating activities and a socially engaged lifestyle have protective effects for dementia prevention; however, it is unclear which activities are more beneficial. This study aimed to investigate the role of cognitive and social type of leisure activities in relation to dementia incidence over a 15‐year follow up.

Methods

The analytical sample was comprised of 8,205 participants aged 50 years and older from the English Longitudinal Study of Ageing, who joined the study at wave 1 (2002‐2003), or at waves 3 (2006‐2007), or 4 (2008‐2009). Dementia was ascertained at every wave up to wave 8 (2016‐2017). Leisure activities were grouped into 6 cognitive activities (e.g. attending art classes) and 7 social activities (e.g. meeting with friends). Cox proportional hazard regression models were used to estimate the hazard ratios (HR) of dementia in relation to engagement in cognitive and social type of leisure activities. The models were adjusted for sex, marital status, education, wealth, physical health and health behaviours. A sensitivity analysis was carried out for a sub‐sample of 5,056 participants with APOEe4 data.

Results

During the follow‐up period, 413 (mean age 74) participants developed dementia. We found that with every additional cognitive activity, the hazard of dementia decreased by 11% (HR 0.89, 95% CI 0.82‐0.97, p=0.013), while for every additional social activity the hazard of dementia decreased by 8% (HR 0.92, 95% CI 0.85‐0.99, p=0.035). The association between social activities and dementia was maintained even after additional adjustment for APOEe4 (HR 0.90, 95% CI 0.81‐0.99, p=0.047), but not the association with cognitive activities. Individual analyses for each leisure item showed a significant independent association for reading the newspaper (HR 0.79, 95% CI 0.64‐0.97, p=0.029), having hobbies (HR 0.74, 95% CI 0.58‐0.93, p=0.012), and being a member of sports clubs (HR 0.71, 95% CI 0.52‐0.97, p=0.033).

Conclusions

Engagement in various cognitive and social type of leisure activities was found to be protective against dementia risk. Noticeable effects were observed for reading the newspaper, having hobbies and being a member of sports club. Interventions to engage adults in opportunities for cognitive and social leisure participation are warranted.
Citrulline supplementation modifies cognitive decline by changes in arginine and nitric oxide levels in a murine model for AD
Authors: Martinez Katia L , Garcia de la Torre Paola , Serrano Leonor , Gutiérrez Eduardo
Published: December 2020

Background

Alzheimer’s disease (AD) is a neurological disorder defined by progressive and irreversible neurodegeneration of the central nervous system and is the most common cause of dementia in older adults. This disease leads to a gradual decline of cognitive function manifested by memory impairment. The synaptic deregulation starts in the hippocampus and eventually leads to neuronal loss and cognitive impairment, this is mainly due to structural changes involving the accumulation of neuritic β‐amyloid plaques and neurofibrillary tangles (NFT) of the hyperphosphorylated tau protein. In addition to the neuronal injury, new evidence suggests the involvement of the arginine metabolism in AD pathogenesis with a decreased level found in AD patients’ brains. L‐arginine is a semi‐essential amino acid that can be metabolized to form a number of bioactive molecules such as nitric oxide, a gaseous signaling molecule that plays an important role in synaptic plasticity, learning, and memory, and can be a key factor for the stabilization and regulation of the vascular microenvironment

Method

Hence citrulline supplementation, an arginine precursor, allowed us to study of changes in arginine (by UPLC) and NO (ny the Griess method) levels, as well as changes in cognitive decline (measured by Morris Water Maze task) in a 3xTgAD mouse model.

Result

Citrulline supplementation at 5 months of age for 3 months, improved long‐term spatial memory in male mice. We found an elevation of arginine levels in CSF from both male and female mice. Finally, we found elevated arginine and nitric oxide levels in brain tissue (hippocampus),

Conclusion

Citrulline supplementation is a viable early treatment to ameliorate cognitive decline in males from this murine model of AD.
Novel MRI‐based geometric models for the quantification and prediction of morphometric changes in mild cognitive impairment converters
Authors: Lu Hanna , Chan Sandra Sau Man , Zhang Li , Lam Linda CW
Published: December 2020

Background

The longitudinal global brain atrophy has been well documented. However, the ageing effect on region‐specific cortical features in the context of brain atrophy and to what extent the measures could discriminate the individuals with different cognitive status are less investigated. We sought to quantify the ageing effect on the morphometry of left primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) in normal ageing adults and mild cognitive impairment (MCI) converters.

Method

Baseline, 1‐year and 3‐year follow‐up structural Magnetic Resonance Imaging scans from normal aging adults (n=32) and MCI converters (n=22) enrolled in the Open Access Series of Imaging Studies (OASIS). The longitudinal changes of cortical features, including cortical volume, thickness, folding and scalp‐to‐cortex distance (SCD) were examined in both groups.

Result

Among the nonlinear trajectory of region‐specific morphometry, pronounced ageing effect was only found on the SCD of left DLPFC (t = ‐2.54, p = 0.02) in MCI converters. the change of cortical folding of left M1 and the change of SCD of left DLPFC from baseline to 3‐year follow up could discriminate MCI converters from normal ageing adults. The SCD changes of left DLPFC were significantly correlated with the global cognitive decline.

Conclusion

Ageing has a prominent, but differential effect on trajectory of region‐specific cortical changes in MCI converters. Our findings suggest that surface‐based geometric measures, cortical thickness, gyrification index and SCD in particular, could be considered as valuable imaging markers and surrogate outcomes for the studies of neurodegenerative diseases.
Loneliness, affectivity and health in mild dementia: A cross‐sectional study
Authors: Laranjeira Carlos
Published: December 2020

Background

Loneliness is the perception that our social and emotional relationships are not as strong as our desired social and emotional relationships. In addition to the detrimental effect loneliness may have on general well‐being, loneliness in elderly individuals may also be associated with an increased risk of mild cognitive impairment, a precursor to dementia. Given the complexity of the feeling of loneliness and this being a psychosocial problem, it is necessary to better understand its causes and consequences with a view to its prevention, which we seek with this study to evaluate the effects of loneliness on affectivity and health in people with mild dementia.

Method

Quantitative, cross‐sectional and correlational study. Inclusion criteria were mild dementia, which was indicated by a score of 0.5 or 1.0 in the Clinical Dementia Rating Scale (CDR). The following instruments were used: (University of California, Los Angeles) Loneliness Scale (UCLA‐LS); Positive Affect and Negative Affect Scales (PANAS); and the 36‐Item Short Form Survey version 2 (SF36v2).

Result

The study included 58 subjects, of whom 34 were female, aged between 65 and 92 years (M = 73.1; SD = 5.9). There were negative correlations between loneliness and positive affectivity and health, and positive correlations between loneliness and negative affectivity. It was also found through the results obtained that the group of individuals with the lowest index of loneliness reported more Positive affectivity, less Negative affectivity and described a better general health status. It is noteworthy that the value of the correlation between loneliness and the report of mental health is quite significant, noting that these variables are inversely related, that is, when loneliness increases, mental health decreases.

Conclusion

In a perspective of intervention centered on the individual, the elderly should work with the acceptance of losses, inherent to aging and life events, which often lead to feelings of loneliness. Reducing loneliness not only promotes brain health, it is important for overall well‐being, especially as we age.
A new stochastic graph embedding method for Alzheimer’s disease early‐stage prediction and intervention evaluation
Authors: Xu Mengjia , Wang Zhijiang , Zhang Haifeng , Sanz David Lopez , Garces Pilar , Maestú Fernando , Wang Huali , Li Quanzheng , Pantazis Dimitrios
Published: December 2020

Background

Subtle alterations of functional brain networks associated with Alzheimer’s disease (AD) are important for a quantitative characterization of neurodegeneration, however prior studies primarily focused on handcrafted, domain‐specific (ad‐hoc) graph features (). Here we developed a novel deep learning model that learns unsupervised brain network embeddings and automatically extracts AD‐related neural signatures. We assessed the robustness of the model in two downstream tasks, the prediction of conversion of mild cognitively impaired (MCI) patients to AD, and the evaluation of a multi‐domain cognitive intervention to amnestic MCI patients.

Method

We developed a graph Gaussian embedding method (MG2G) that uses a 3D encoder to learn intermediate representations through a sequence of hidden layers and outputs node‐wise low‐dimensional multivariate Gaussian distributions. Advantages of our model are that i) it discovers the intrinsic dimensionality of brain networks, ii) remaps brain data into a latent space amenable for supervised tasks such as AD classification, and iii) allows the use of the Wasserstein distance (W2) to define a metric space, and pinpoint subtle brain network alterations to specific brain regions.

Result

We used the MG2G model to embed MEG alpha band resting‐state network data from 48 stable MCI (S) patients, 28 progressive MCI (P) patients, and 53 age‐matched healthy elderly (N) subjects from the Madrid cohort. The obtained latent MEG brain network embeddings predicted AD progression as in Fig. 1. MG2G achieved higher performance than a completing model (node2vec) with 82% 3‐class classification, 93% 2‐class N/S classification, and 87% 2‐class S/P classification. We also computed functional brain networks from resting state fMRI data recorded from 12 aMCI patients before and after 12‐month of multi‐domain behavioral interventions. Using the W2 distance to quantify the probabilistic node‐wise embeddings in the latent space, we identified brain regions with intervention‐related functional alterations (Figs. 2 and 3).

Conclusion

MG2G provided a novel quantitative approach to assess complex functional connectivity patterns and learn highly‐informative network representations for different stages of AD while quantifying the uncertainty in the predicted outcomes. Acknowledgements: J‐Clinic for Machine Learning in Health at MIT; PSI2009‐14415C03‐01; PSI2012‐38375‐C03‐01; B2017/BMD‐3760; FJC2018‐037401‐I; Z161100000516001; D171100008217007.
Validation of a videoconference‐based neuropsychological assessment: The e‐COG study
Authors: Gnassounou Richard , Défontaines Bénédicte , Denolle Séverine , Brun Stéphanie , Schück Stéphane , Germain Raphaël , Schwartz Déborah , Cacciamani Federica , Michon Agnès , Belin Catherine , Mailler Didier
Published: December 2020

Background

The videoconference‐based neuropsychological assessment, also called teleneuropsychology, is a promising tool for the diagnosis and follow‐up of individuals living in underserved areas, care facilities or other institutions, and even emigrants. This kind of consultation has proved particularly useful during the COVID‐19 pandemic, suggesting how it could be used more systematically. This study is the first to explore the reliability of neuropsychological teleassessment in France.

Method

In the e‐COG study, we included 150 older memory‐complainers, with an MMSE>20, seeking medical advice at a memory clinic (Pitié‐Salpêtrière Hospital) or at the Aloïs Memory Network, both based in Paris, France. At baseline, all participants underwent a comprehensive face‐to‐face neuropsychological assessment. After 4 months, the participants were randomized, so that half of them performed another face‐to‐face assessment, and the other half a teleassessment. For the teleassessment, the examiner used a MacBook Pro system with internet connection, microphone and speaker. The patient was with an assistant with no training in neuropsychology, who intervened during certain tests requiring material handling or physical contact. Two cameras were installed, one to film the entire room, and the other to film what the participant wrote or drew. We compared (i) face‐to‐face versus teleassessment scores using t‐tests and Chi2 tests (or Fisher Exact test when relevant); (ii) scores at assessment 1 versus 2, according to the administration method, using Paired t‐tests and MacNemar tests (or Bowker test when relevant).

Result

Demographic characteristics of the sample are shown in Table 1. The two assessments 4 months apart yielded overall stable scores, regardless of the method of administration (Face‐to‐Face or Video). Very few tests showed significant differences between the two assessments, but the effect size was very weak (all Cohen's d ≤ 0.35). The STAI‐Y‐A score, measuring the level of anxiety felt at the moment, was slightly but non‐significantly higher in the Face‐to‐Face (versus Video) condition (p=0.07), and therefore it seems that the remote assessment does not induce greater anxiety in the patient.

Conclusion

Neuropsychological teleassessment is a valid and promising tool that could be incorporated into the diagnostic and follow‐up processes of patients with suspected or full‐blown cognitive impairment.
Extracellular cardiolipin modulates glial phagocytosis and cytokine secretion in a toll‐like receptor 4‐dependent manner
Authors: Wenzel Tyler J , Ranger Athena L , Murray Taryn , McRae Seamus , Klegeris Andis
Published: December 2020

Background

Cardiolipin (CL) is a mitochondrial membrane phospholipid that acts as a signaling molecule when released into the extracellular space from degenerating and dying brain cells. Previous research has shown that extracellular CL inhibits secretion of pro‐inflammatory mediators by immune‐activated microglia. CL alone also increases the phagocytic activity of microglia and upregulates their expression of brain‐derived neurotrophic factor (BDNF) and glial cell‐derived neurotrophic factor (GDNF). The mechanisms by which CL modulates microglia functions, in a manner that is potentially beneficial in Alzheimer’s disease, are unknown. Furthermore, the effects of CL on astrocytes have not been explored. Since microglia and astrocytes express toll‐like receptor (TLR) 4, we hypothesized that extracellular CL interacts with this receptor, modulating immune functions of glia.

Method

We studied the effects of CL applied to the culture media on select functions of primary murine microglia and astrocytes, BV‐2 murine microglia, U118 MG human astrocytoma cells, and THP‐1 human microglia‐like cells. Secretion of inflammatory cytokines was monitored by enzyme‐linked immunosorbent assay (ELISA) or immunoblotting. The phagocytic activity of primary microglia and astrocytes was measured with fluorescent latex microspheres. The internalization of the microspheres was verified using confocal microscopy.

Result

Extracellular CL (0.4‐14 μM) alone upregulates the phagocytic activity and release of monocyte chemoattractant protein (MCP)‐1 by murine microglia and human astrocytic cells. TLR 4‐specific antagonist TAK‐242 and blocking antibodies inhibit the upregulated phagocytic activity and MCP‐1 secretion by CL‐treated microglia and human THP‐1 microglia‐like cells. CL increases the secretion of interferon (IFN) γ‐induced protein (IP)‐10 and IFN‐β by THP‐1 microglia‐like cells and human U118 MG astrocytoma cells, respectively. CL inhibits the secretion of cytotoxins by several types of activated microglia and astrocytes. Amyloid β (Aβ42) peptide‐ and lipopolysaccharide‐induced secretion of cytokines by primary murine microglia and U118 MG astrocytoma cells, respectively, is reduced by extracellular CL.

Conclusion

Extracellular CL can interact with TLR 4 to modulate select functions of microglia and astrocytes. Importantly, we demonstrate that CL inhibits amyloid‐β peptide‐induced secretion of inflammatory cytokines by microglia and reduces glia‐mediated neuron death. Therefore, CL or liposomes containing CL could be developed as potential therapeutic agents for Alzheimer’s disease.
Cognitive performance of a Brazilian sample of patients with multiple domain mild cognitive impairment and healthy elderly
Authors: Almeida Silva Geise Aline , Avolio Isabella B. , de Lima Lucio Dias Camila , de Oliveira Maira Okada , Nitrini Ricardo , Dozzi Brucki Sonia Maria , Miotto Eliane C.
Published: December 2020

Background

Mild cognitive impairment (MCI) is associated with cognitive alterations, usually related to memory, but may affect other domains. It is an intermediate condition between healthy aging and dementia and does not significantly affect an individual's activities of daily living (ADL) (Petersen,2016). This study aimed to investigate the cognitive performance of a Brazilian sample of elderly people with multiple domain MCI (mdMCI) compared to healthy controls (HC) using a comprehensive neuropsychological assessment.

Method

We included 54 subjects, 36 MCImd and 18 HC. The neuropsychological comprehensive protocol included total estimated IQ [Vocabulary (VC) and Matrix Reasoning (MR)], Digit Span (DS) from the WAIS‐III, Trail Making Test (TMT), Stroop Test (ST), Logical Memory (LM) and Visual Reproduction (VR) , Phonemic Verbal Fluency (FAS), Semantic Verbal Fluency (SVF), Boston Naming Test (BNT), Rey Auditory Verbal Learning Test (RAVLT) and Rey–Osterrieth Complex Figure Test.

Result

We observed significant differences between the groups (p<0,05) in the following cognitive domains: episodic memory [Logical Memory delayed recall (t(52)= ‐2,081; p 0,048); Visual Memory immediate recall (t(50,8)= ‐3,345; p 0,002); Visual Memory delayed recall (t(51)= ‐2,858; p 0,006); RAVLT immediate recall (t(50)= ‐2,414; p 0,19); RAVLT delayed recall (t(50)= ‐2,844; p 0,006); RAVLT recognition (t(49,3)= ‐3,408; p 0,001)]; and executive functions [Semantic Verbal Fluency (t(25,7)= ‐2,582; p 0,016)].

Conclusion

mdMCI patients obtained a lower cognitive profile in neuropsychological tests involving episodic memory (verbal and visual) and executive functions, usually affected in this population. These findings corroborate the international literature indicating similar impairments in those cognitive domains in mdMCI patients and the possibility to identify differential cognitive alterations with a comprehensive protocol of cognitive tests.
Playful multimodal activation with assessment of neuropsychological profiles in Alzheimer’s disease
Authors: Paletta Lucas , Russegger Silvia , Pszeida Martin , Murg Sandra , Orgel Thomas , Dini Amir , Jos Anna , Schuster Eva , Koster Ernst HW , Steiner Josef , Fellner Maria
Published: December 2020

Background

A key problem in developing interventions in dementia care is the lack of knowledge about the mental processes and individual dependencies between functional impairments evolving over time. Neuropsychological profiles reflect the impact of the disease on distinctive neuroanatomic networks associated with complex cognitive domains. Recently serious games have been successfully validated with high potential as dementia biomarkers but increased estimation accuracy and personalised neuropsychological profiling is still required.

Method

Tablet‐PC‐based intervention was applied within 10 weeks in Austria, engaging persons with dementia (PwD) with Alzheimer’s disease (AD) living at home in terms of playful multimodal training and activation (n=15, age M=81.7 years, MoCA score M=17.9). PwDs interacted with an integrated version of two serious games: (a) 15 PwD played ‘MIRA’, a playful version of the anti‐saccade task, and (b) 8 PwD played ‘MMA’, a suite of cognitive exercises (puzzle, memory, text gap filling). The games were introduced and assisted by trainers, some PwD learned to play alone.

Result

The score of gaze‐based MIRA showed significant correlation with MoCA score (Rho= .713**) and enabled individual MoCA score estimates with errors of less than M=2.6 MoCA points. MMA showed correlation with MoCA (Rho=p=.755*) and further MoCA subscores so that the neuropsychological profile could be established including impairments in visuospatial operations, attention, abstraction, language and recall.

Conclusion

The work outlined within the EU project PLAYTIME indicates successful steps towards daily use of gaze‐based games. MIRA together with the MMA training enables continuous estimates of Alzheimer’s mental state in general but also to estimate individual neuropsychological profiles to identify personal impairments and their course over time. The playful training app was very well accepted by PwD users and offers with its pervasive mental assessment tool a large potential for future long‐term monitoring in numerous AD care services.
Cognitive trajectory changes in African American veterans with combat PTSD
Authors: Li Ge , Jankowski Adrienne , Shofer Jane , Roggenkamp Hannah , Tsuang Debby W. , Peskind Elaine R. , Raskind Murray A.
Published: December 2020

Background

Epidemiological study shows that posttraumatic stress disorder (PTSD) has been linked to increased risk of Alzheimer’s disease (AD). However, longitudinal study of Holocaust survivors does not show accelerated cognitive decline in those with PTSD. We compared cross‐sectional and longitudinal cognitive function in a cohort of African American (AA) veterans with combat PTSD to that in a cohort of elderly AA males without PTSD to determine if PTSD was associated with a more rapid cognitive decline.

Method

Eighteen male AA Veterans with the combat PTSD who received treatment at the VA Puget Sound Health Care System in Seattle, participated in a longitudinal study of aging at UW ADRC between 2007‐16. Fifty‐four male AA subjects without PTSD were selected from the National Alzheimer’s Coordinating Center (NACC) dataset and matched by age (± 4 years), education (± 1 year), and MMSE score (± 2 points) as a comparison group (Table 1). Longitudinal data were available for 16 PTSD+ and 40 PTSD‐ participants. All participants were free of dementia or Mild Cognitive Impairment (MCI) and were assessed using the NACC Uniform Data Set version 2 (UDS 2.0) neuropsychological test battery. Linear mixed effects regression was used to estimate mean cognitive outcome at baseline and mean slope of change over follow‐up.

Result

As shown in the Figure 1, mean MMSE score at baseline and slope of change did not significantly differ between those with and without PTSD (p ≥ .35). The mean immediate and delayed recall scores from the Wechsler Memory Scale‐Revised Logical Memory were similar at baseline (p >.98) and showed no difference in change from baseline (p > .69). Similarly, there were no statistical differences in means at baseline or slope of change by group for Digit Span Forward and Backward, Category Fluency (animals and vegetables), WAIS‐R Digit Symbol test, and Trail Making Test (A and B) (all p‐values >.27).

Conclusion

Cognitive function in AA veterans with combat PTSD was comparable to AA men without PTSD over an average of 4 years. These findings need to be replicated in a larger cohort with a longer duration of follow‐up.
Lower‐resolution retrieval of scenes in older adults with subjective cognitive decline
Authors: Ruiz‐Rizzo Adriana L , Pruitt Patrick J , Finke Kathrin , Müller Hermann J , Damoiseaux Jessica S
Published: December 2020

Background

Subjective cognitive decline (SCD) can predict the progression to mild cognitive impairment. Visual memory deficits in mildly impaired patients relate to decreased activity in brain regions beyond the medial temporal lobe, such as the parahippocampal place area (PPA). PPA's response to visual scenes is weaker in healthy older than younger adults but equally associated with memory recognition. PPA's response to scenes' perceptual details during encoding might support that association. Whether perceptual detail processing is reduced in SCD can help elucidate the disparity between perceived decline and normal performance. Here we test whether older adults with SCD ('SCD') use perceptual details to a lesser extent than older adults without SCD ('CON') and whether this is observed during the encoding or retrieval of a scene memory task.

Methods

We measured BOLD‐fMRI activity in 37 healthy older adults (SCD: 16) during encoding, and calculated hit rate, false alarm rate, and total recognition accuracy during retrieval. We analyzed BOLD‐fMRI activity during scene encoding in PPA. PPA was defined based on a functional Neurosynth meta‐analysis of studies including the term "place" and further constrained to the lingual and posterior parahippocampal gyri, and posterior‐temporal and temporal‐occipital fusiform cortices. Scenes' perceptual details were quantified as the number of unique objects in it (high‐load: > 4; low‐load: < 4).

Results

During encoding, PPA activity was higher for high‐load than low‐load scenes (P = 2.08e‐06) but did not differ between SCD and CON (P = .763), indicating comparable encoding of perceptual details across groups. Nevertheless, during retrieval, SCD appeared to benefit significantly less from perceptual details than CON (P = .018), as their false alarm rates were similar for high‐ and low‐load scenes (P = .879), whereas CON's were significantly lower for high‐load than low‐load scenes (P = .002).

Conclusions

Although tentative, our results suggest that SCD encode perceptual details similar to CON but use details to a lesser extent than CON when new information must be differentiated from old information during retrieval. Accordingly, memory complaints in SCD may reflect the perception of a 'lower‐resolution' retrieval, especially in the face of new information.
Longitudinal assessment of neuroinflammation and axonal loss in white matter tracts in Alzheimer’s disease
Authors: Roy Maggie , Dumont Matthieu , Houde Jean‐Christophe , Morency Félix , Descoteaux Maxime
Published: December 2020

Background

Free‐water fraction (FW), proxy to neuroinflammation, and apparent fiber density (AFD) are two recently developed diffusion MRI (DMRI) white matter (WM) measures.

Methods

We aimed to longitudinally assess FW (24 months) and AFD (12 months) in specific WM tracts in normal controls (NC) (n = 27), MCI (n = 50) and Alzheimer’s disease (AD) (n = 16) selected from the ADNI2 database. The FW and AFD maps were computed and tractography was used to automatically extract 6 WM tracts: cingulum (CG), uncinate, inferior fronto‐occipital and inferior longitudinal fasciculi (UF, IFOF, ILF), and genu/splenium of the corpus callosum (CC2/CC7). Correlations were also performed to assess association between the changes of the FW and cortical b‐amyloid (18F‐AV45‐PET), as well as between the AFD and plasma neurofilament light chain (NfL).

Results

The FW significantly increased after 2 years in the CC2, CC7, UF and CG in AD (4‐11%), with no change in MCI and NC. For the AD group, the change of cortical b‐amyloid over 2 years was positively correlated with the change of FW in the ILF, CC2, CC7, UF and CG (r = 0.31 ‐ 0.57; P = 0.02 ‐ 0.05; Fig. 1). The AFD significantly decreased after 1 year in the CG, ILF, and IFOF in AD (7‐8%), and MCI (3‐5%), with no change in NC. Only for the AD group, the change of AFD over 1 year was negatively correlated with the change of plasma NfL in the 6 tracts of interest (r = ‐0.56 ‐ ‐0.67; P = 0.01 ‐ 0.03; Fig. 2) and in the whole white matter (r = ‐0.61; P = 0.009).

Conclusions

The longitudinal assessment of FW shows increase only in AD, while the decrease of AFD is similar in MCI and AD, hence the loss of axonal density seems to appear in earlier stages. These results may also reinforce the link between: i) cortical b‐amyloid accumulation and neuroinflammation, and ii) plasma Nfl and loss of axonal density, both shown for the first time with in‐vivo imaging biomarkers: FreeWater and Apparent Fiber Density.
Activity‐dependent reconnection of adult‐born dentate granule cells in a mouse model of frontotemporal dementia
Authors: Moreno‐Jiménez Elena P , Terreros‐Roncal Julia , Flor‐García Miguel , Llorens‐Martin María
Published: December 2020

Background

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by a loss of neurons in the frontal and temporal lobes of the brain. Tau protein is encoded by MAPT gene and its mutations cause FTD‐Tau, FTD variant. TauVLW mice carries three mutations, G272V (V), P301L (L), and R406W (W) on MAPT, increasing the susceptibility of Tau to be phosphorylated. TauVLW mice show anatomical alterations in the hippocampus as well as behavioural impairments. Importantly, the hippocampus gives rise to new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), converges in the functional integration of mature dentate granule cells (DGCs) into the trisynaptic hippocampal circuit. AHN is altered in patients with Alzheimer´s disease and in animal models of distinct neurodegenerative diseases, including FTD.

Methods

To perform an in‐depth characterization of newborn DGCs of TauVLW mice we used a combination of trail‐blazing retroviral approaches. We used Red‐Green‐Blue (RGB) retroviruses to address the morphological maturation of these neurons. We also used retroviruses that encode either PSD95:GFP or Synaptophysin (Syn):GFP, together with monosynaptic retrograde rabies virus tracing to study the connectivity of these cells. Finally, we tested the effects of the selective chemoactivation of newborn DGCs using a retrovirus that encodes the excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) H3Dmq, as modulator to counteract the alterations.

Results

These innovative approaches revealed that the newborn DGCs of TauVLW mice exhibit marked morphological and functional alterations. Importantly, similar morphological alterations are observed in DGCs of FTD patients. Newborn DGCs of TauVLW mice show impaired afferent and efferent connectivity. Moreover, they are disconnected from distal brain regions and exhibited a predominance of local inhibitory innervation. Therefore, a reduced number of activated egr‐1+ DGCs were observed. On the other hand, chemoactivation led to a complete reversal of the morphological alterations and partial reversal of the alterations in the connectivity of these cells.

Conclusions

DGCs are disconnected from distal brain regions and local sources of excitatory innervation in a mouse model of FTD. These cells exhibit remarkable similarities with those of FTD patients. Significantly, the functional defects observed in TauVLW newborn DGCs are reversed by chemoactivation.
Attitudes towards genetic susceptibility testing for Alzheimer’s disease dementia in cognitively normal adults: A survey study
Authors: Masselink Larissa A , Visser Leonie NC , Cleutjens Solange , van der Lee Sven J , van der Schaar Jetske , Scheltens Philip , van Der Flier Wiesje , Zwan Marissa D
Published: December 2020

Background

Interest in Apolipoprotein E (ApoE) genetic testing for Alzheimer’s disease dementia (AD) is increasing. Even though ApoE‐status is more often being disclosed to cognitively normal adults in clinical trials and services like 23andMe are growing, disclosure in the context of individualized risk profiling is not yet common practice. Our objective was to examine attitudes towards genetic susceptibility testing for AD in a sample of Dutch cognitively normal adults.

Method

An online survey was completed by 428 cognitively normal respondents (response rate 29%) between the age of 50 and 75 years from the Dutch Brain Research Registry (Hersenonderzoek.nl). The survey assessed interest in participating in research studies about genetic testing and disclosure, perceptions of its reasons and possible impact and degree of control respondents want in deciding to test their genetic risk (Control Preferences Scale). Furthermore, we randomly presented three fictional scenarios to assess interest in genetic risk disclosure for different risks of AD (10, 30 and 50%).

Result

The majority of respondents was interested in genetic risk disclosure (80%) and preferred to decide themselves whether to receive their genetic risk (73%) rather than leaving this decision to a health care professional. The most commonly endorsed reason for testing was contributing to scientific research (94%). When presented with specific scenarios, most respondents were still interested in their genetic risk, regardless of the presented risk (73‐79%). The three most important consequences indicated were: 1) sharing their genetic risk with their close environment (77‐89%), 2) participating in a medication trial (79‐87%) and 3) making long‐term arrangements, e.g. for retirement and health care (69‐82%). More than half of the respondents (50‐67%) would probably adjust their lifestyle, e.g. exercise more or eat healthier.

Conclusion

Our findings indicate that the majority of respondents wants to be informed about their genetic risk for AD and wants to make this decision themselves. The main reason for interest in testing is contributing to scientific research. Future studies should examine the best way to disclose genetic risk for AD by informing participants carefully and closely looking at the possible impact, especially in the context of future individualized risk profiling.
Recruitment and retention strategies to improve inclusion of family caregivers of African American older adults with dementia in advance care planning research
Authors: Grieff Abigail M , Moss Karen , Hurst Laurel Myers , Wills Celia
Published: December 2020

Background

Recruitment and retention approaches for including family caregivers of lower socioeconomic status African American older adults living with dementia for advance care planning research are currently inadequate. Such underrepresented populations often face multiple and suboptimally‐addressed obstacles to research participation. Subsequently, they are less likely than Caucasians to participate in research. Adequate recruitment and retention is essential for the conduct of high quality research to improve communication about advance directives and to achieve improved interventions to better meet the needs of underserved populations. The purpose of this study is to use a participatory design process to assess and develop enhanced approaches to optimize research recruitment and retention strategies for caregivers of lower socioeconomic status African American older adults living with dementia for advance care planning research.

Method

This qualitative descriptive study uses audio‐recorded telephone interviews conducted with up to 20 current and 20 former caregivers of lower socioeconomic status African American older adults living with dementia who previously participated in at least one research study. Interviews will be conducted with participants that will broadly explore barriers and facilitators to research participation. Audio recordings will be transcribed verbatim. Content analysis will be conducted using qualitative descriptive methods to describe themes that emerge from these data. Transcribed qualitative data will be coded using Dedoose software for qualitative analysis. SPSS software will be used for demographic data analysis.

Result

We anticipate that study findings will fill essential gaps in existing knowledge about recruitment and retention for advance care planning research participation for caregivers of lower socioeconomic status African American older adults living with dementia. This knowledge will inform changes to improve advance care planning research participation towards receipt of preference‐consistent healthcare and increasing advance directive completion rates. Study results will be provided to participants at study completion.

Conclusion

Study results will yield insights to increase advance care planning research participation in this population and will be scalable to support recruitment and retention of other underrepresented vulnerable populations for other research studies. This will lead to the use of more culturally‐tailored approaches to research recruitment and retention to increase research participation by people from diverse backgrounds.
Developing therapeutic protein disaggregases for neurodegenerative disease
Authors: Lin Jiabei , Shorter James
Published: December 2020

Background

The accumulation of abnormal protein aggregates in human brain is connected with neurodegenerative diseases. The mammalian protein‐disaggregase system comprised of Hsp110, Hsp70, and Hsp40 can protect cells from proteinopathies. However, this disaggregase system has limitations and its activity declines with age. As a therapeutic strategy for neurodegenerative disease we propose to introduce an exogenous, synthetic disaggregase machinery, based on Hsp104 that converts amyloid to soluble, functional protein. Hsp104 is a hexameric AAA+ ATPase that is critical for stress tolerance in yeast by facilitating the resolubilization of stress‐damaged, aggregated proteins. The homologues of Hsp104 are highly conserved in bacteria, fungi, and plants, but absent from metazoa. The disaggregase activity of Hsp104 can be enhanced by the presence Hsp70 and Hsp40. Hsp104 can dissolve α‐synuclein, β‐amyloid, and TDP‐43 aggregates, but impractically high Hsp104 concentrations are needed.

Method

Nimble yeast models are used to perform an initial evaluation to enhance experimental efficiency. Promising variants will be purified for further characterization and will be advanced to neuronal and glial cell models.

Result

We have engineered and evolved potentiated Hsp104 variants with minimized “off‐target” effect that eradicate α‐synuclein, β‐amyloid, or TDP‐43 misfolding and toxicity. We have discovered Hsp104 variant that reverse TDP‐43 toxicity specifically with no "off‐target" effect. We have exploited new cryo‐EM structures of Hsp104 to engineer key interfaces to yield several novel Hsp104 variants with tunable activity, which can reverse protein aggregation in the presence or absence of human Hsp70 and Hsp40.

Conclusion

These novel Hsp104 variants effectively rescue the aggregation and toxicity of diverse human neurodegenerative disease proteins and could have therapeutic utility.
Gene‐neuroimaging brain model decodes neuropathological mechanisms in Alzheimer’s disease
Authors: Adewale Quadri , Medina Yasser Iturria
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by aberrations of several biological processes/factors (e.g., genes, misfolded proteins, atrophy). Investigating the interplay between these factors at multiple scales can advance our understanding of AD and facilitate the development of cost‐effective treatments while unifying biomarkers for early AD diagnosis and prevention. We propose a mathematical framework that models how gene expression (GE) modulates the interaction between six macroscopic imaging modalities in AD progression. The identified genes and pathways provide novel insight into AD pathology.

Method

1) We pre‐processed 6 longitudinal neuroimaging data (beta‐amyloid and tau proteins, cerebral blood flow, glucose metabolism, R‐fMRI, and grey matter volume) of 157 healthy and 317 diseased subjects from ADNI. 2) Using GE data of 6 neurotypical brains from Allen Human Brain Atlas, we derived brain‐wide GE of 990 genes with leading roles in central biological functions. 3) We built a mathematical model that incorporates: (i) disease‐related longitudinal changes in neuroimaging data, (ii) GE‐modulated interactions between the different neuroimaging modalities, (iii) propagation of alterations resulting from (ii) across brain networks. 4) By evaluating the latent relationship between GE modulating effects and cognitive measures (MMSE, ADAS, executive function, memory score) of 127 subjects (converters) who advanced to subsequent stages in the AD continuum, causal genes and altered pathways in AD progression were identified.

Result

The model explains 64% of the common variance between GE‐dependent brain alterations and cognitive scores of the converters. We identified 89 disease‐driving genes, including some notable previously identified AD genetic determinants: APPB2, TOP2A, CLU, BACE1 and CD44. The biological factors causally modulated by each gene, and factor alterations resulting from the modulation were also reported; e.g., our model reveals that APPB2 gene modulates beta‐amyloid to cause longitudinal alteration of beta‐amyloid, while CLU could interact with vascular flow to alter tau protein (Fig. 1). We also identified 54 likely altered pathways in AD evolution.

Conclusion

We developed a mathematical model to investigate the influence of gene expression on multifactorial alterations of biological processes in AD progression. Our results are strongly consistent with previously reported studies and provided further insight into the molecular mechanism underlying AD progression.