bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of cognitive function and kinematic movement during self‐feeding activity
Authors: Lee Joo‐Hyun
Published: December 2023

Background

Self‐feeding is the important activity that is most closely related to daily living using motor and cognitive abilities. Especially, movement of self‐feeding includes picking up the spoon and executing the sequence of movement correctly, so it can be related to cognitive aspects. The purpose of this study is to investigate correlation with the kinematic movement during self‐feeding and cognitive function using AI software program

Method

The subjects participated in 4 normal person. In this study, the ‘simulated feeding’ task in Jebsen Taylor Hand Function test was selected. ‘Simulated Feeding’ is a task of transferring 5 beans to cup with a spoon. During task performance, a laptop and a webcam were used to record a video image, and trajectory and time value were recorded from 2D web‐cam image. Cognitive assessment tool used Trail Making Test (TMT). The spearman correlation analysis was conducted to evaluate the correlation with factors of movement and cognition during self‐feeding.

Result

It is possible to determine how far or short the hand moved depending on the length of the trajectory. The average time value shows the subject spent more time to put the beans in the spoon than to put the beans in the cup. Also, movement of self feeding were positively related to cognitive aspects..

Conclusion

We believe that quantitative assessment of movement is related to cognitive function during self‐feeding. Through this, the state of cognitive function can be indirectly confirmed. Future study will need to apply movement analysis to evaluate the cognitive decline of the elderly.
Conversational Artificial Intelligence for People Living with Dementia and their Care Partners: A Scoping Review
Authors: Gholizadeh Shadi , Freeman Amy K. , Botticelli Mark P.
Published: December 2023

Background

The inadequacy of the dementia care workforce in meeting the needs of a growing population of people living with dementia (PLwD) is a global public health challenge. There is a burgeoning interest in exploring the role of artificial intelligence‐enabled technologies, such as chatbots, neural network models, and other programs designed to intelligently simulate human conversations, in the dementia care landscape. The aim of this scoping review was to examine the themes and gaps associated with the use of these technologies in the dementia care space.

Method

Three databases (PubMed, PsychINFO, and CINAHL) were searched for English‐language, peer‐reviewed articles using keywords relating to chatbots, virtual assistants, generative pre‐trained transformer technology (GPT‐3), and dementia. The search returned 26 articles after removal of duplicates with 13 selected for inclusion into the review.

Result

Two user groups were identified, PLwD and their family care partners. Chatbots, embodied conversational agents, and intelligent virtual agents were the identified technologies. The core uses of the technology centered around 1) diagnosis and monitoring of cognitive symptoms; 2) social connection and cognitive simulation; 3) memory aids and prompts for task completion, and 4) education, training, and social support for care partners. Five key themes emerged, including 1) the need for expanded studies that go beyond superficial and simple dialogues to more complex and realistic interactions; 2) the importance of a person‐centered approach that uses knowledge about the person to guide the technology; 3) small sample sizes and weak quality across studies; 4) the need for standardized criteria to evaluate the quality of human/technology interaction; and 5) the importance of co‐creation of technology with insights from PLwD and their care partners.

Conclusion

With the growing capability to generate human‐like text for powering chatbots, conversational artificial intelligence has the potential to play an important role in the dementia care space, however the literature remains in its nascent stages. There is a need for well‐designed studies, utilizing multidisciplinary and participatory approaches, exploring the impacts of incorporating these technologies into the daily lives of PLwD and their care partners.
Intergenerational Social Mobility, Brain Structure, and Cognitive Trajectory: Findings from the Whitehall II Study
Authors: Liu Yingxu , Liu Yinghao , Cui Yuehua , Thyreau Benjamin , Zhang Ye , Taki Yasuyuki , Chen Honglei ,   Dementias Platform UK (DPUK) Data Portal
Published: December 2023

Background

Previous studies on the effects of intergenerational social mobility on cognitive outcomes were not consistent, additionally, underlining brain anatomical variation is unclear. In the present study, we aim to examine the associations of social mobility with brain structure and cognitive trajectories in older adults.

Methods

The study included 771 participants, ages 69.8 ±5.2 years, of the Whitehall II ‐ MRI substudy (2012‐2016) with data on their father’s occupation, their own occupation in mid‐life, lifestyle (smoking, drinking, physical activity, social activity, sleep disturbances, auditory difficulty, depression, obesity, hypertension), neuroimaging (T1 structural MRI) and cognitive abilities (global cognition, crystallized cognitive ability, and fluid intelligence). Social mobility was classified into stable high social class, stable low social class, upward mobility and downward mobility group based on occupational shifts from father. We used the ANCOVA tests to assess the association of social mobility with gray matter volume (GMV) and cortical thickness (CT) in various brain regions, and the growth curve modeling (GCM) to evaluate its relations to cognition over 20 years, adjusting for social lifestyle covariates and associated GMV/CT regions identified above.

Results

Social mobility was significantly related to 48 out of the 136 regions of GMV across the frontal lobe, limbic lobe, and temporal lobe; and to 4 out of the 68 regions of CT at the whole‐brain level. Stable high social class preserved the largest GMV and CT value; pair‐wise results suggest upward mobility preserved a larger GMV value than the downward mobility group (average diff. in cm3: 0.121, P<0.05); and similarly a larger CT value (average diff. in cm:0.029, P = 0.051). In GCMs, stable high social class (ref. downward mobility) had a higher entry score of fluid intelligence (b = 2.617, P<0.05), all other comparisons including the entry score and decline rate of cognitive abilities were non‐significant.

Conclusions

Our results suggest a lack of direct association between social mobility and trajectories of global cognition and crystallized cognitive ability; instead, an indirect effect through preserving the value of brain GMV and CT may occur. Additionally, an adverse causal relationship between social mobility and fluid intelligence might happen.
Interventions to Improve Bathing Experience for People Living with Dementia: A Scoping Review of Randomized Controlled Trials
Authors: Gholizadeh Shadi ,   TheKey Research Group
Published: December 2023

Background

Bathing has been identified as the most challenging activity of daily living and one that is a frequent source of conflict among persons living with dementia (PLwD) and their care partners. Research has shown a number of factors related to bathing challenges, including pain; discomfort due to a mismatch between preferences and approach; and anxiety or fear related to anosognosia,memory loss, or cognitive decline. There is a need for nonpharmacological, behavioral, evidence‐based approaches to help support an improved bathing experience for PLwD. Randomized controlled trials (RCTs) are the study design that enable researchers to most confidently determine the impact of an intervention on observed outcomes. The purpose of the present review was to determine the breadth of RCT evidence exploring interventions specifically developed to improve the bathing experience of PLwD and to report on any noted challenges with the feasibility of conducting RCTs in this area of inquiry.

Method

Two databases (PubMed and PsychINFO) were searched from inception through September 3, 2022 for English‐language articles using keywords relating to bathing/showering and dementia. The search returned 578 articles after removal of duplicates with only three meeting criteria for inclusion into the review.

Result

Themes of successful interventions included a person‐centered approach that incorporated real‐time observations and flexibility in tailoring the intervention to the needs of the specific person, increasing self‐efficacy of the care partner, consistency in coaching and practicing of skills, and the incorporation of music. Although a number of challenges were identified with the feasibility of conducting an intervention overall with this aim and population (e.g., scheduling challenges), challenges specific to the RCT design were not identified.

Conclusion

There is a dearth of high‐quality, RCT evidence exploring interventions to support in the bathing support of PwD. Because the Cochrane Handbook discourages inclusion of evidence from non‐randomized trials in reviews when it is feasible to conduct trials, it is recommended that future research in this area consider an RCT design. There is promising evidence that family and professional care partners alike can benefit from education and training specifically designed to improve the bathing experience.
CD2AP impacts Alzheimer’s disease through brain vascular function
Authors: Vandal Milene , Institoris Adam , Korin Ben , Gunn Colin , Lee Suzie , Lee Jiyeon , Bourassa Philippe , Mishra Ramesh C , Peringod Govind , Jiang Yulan , Hirai Sotaro , Belzil Camille , Reveret Louise , Tremblay Cyntia , Hashem Mada , Elias Esteban , Meilandt William , Foreman Oded , Rouse‐Girma Meron , Muruve Daniel , Nicola Wilten , Körbelin Jakob , Dunn Jeff F , Braun Andy P. , Bennett David A. A , Gordon Grant , Calon Frederic , Shaw Andrey S , Nguyen Minh Dang
Published: December 2023

Background

Cerebrovascular impairment is a key aspect of Alzheimer’s Disease (AD) pathogenesis. Brain vascular defects appear early in the disease process and are associated with cognitive dysfunction. CD2‐associated protein (CD2AP), a scaffolding protein involved cytoskeleton remodeling and membrane trafficking, is an important predisposing factor for the disease. The protein is enriched in brain endothelial cells (BECs) that forms the brain vessels, suggesting that CD2AP might contribute to AD cerebrovascular dysfunction.

Method

In this study, we used brain samples from AD volunteers, genetically modified mouse models, awake two‐photon microscopy and cell culture to investigate the function of CD2AP in the brain vasculature.

Result

We found that AD individuals with lower levels of brain vascular CD2AP displayed the poorest cognitive performance. Genetic depletion of CD2AP in BECs compromised memory function, cerebral blood flow and increased vessels vulnerability to amyloid‐beta. In BECs, CD2AP controlled the levels and signaling of Apolipoprotein E Receptor 2 (ApoER2) and activation of this pathway with Reelin glycoprotein in mice depleted of endothelial CD2AP mitigated the toxic effects of peptide.

Conclusion

In sum, deregulation of endothelial CD2AP drives cerebrovascular dysfunction, and harnessing the biology of specific brain vessel types may offer a refined therapeutic avenue for the treatment of AD.
Free‐listing and semantic knowledge: A diagnostic tool for detecting Alzheimer’s disease?
Authors: Ulep Maileen G. , Lienard Pierre
Published: December 2023

Background

A semantic memory impairment figures prominently among the manifestations of Alzheimer’s disease (AD). That impairment manifests itself relatively early in the disease trajectory with longitudinal studies showing evidence in patients with mild cognitive impairment and preclinical AD. We investigate the impact of AD on specific semantic categories integral to daily function: living kinds and artefacts.

Method

We relied on a “free‐listing task” as developed in cultural domain analysis, and assessed its relationship with other cognitive and functional tests in clinical use. We chose the written version for the elicitation of the free‐lists that we analyze here. A written format leads to the generation of longer lists than an oral elicitation. The participant pool was comprised of 19 AD patients and a control group, 15 cognitively normal age‐matched adults.

Result

The median number of items generated in each list for the patients was 12 for living things and 18 for man‐made objects, for the control group, 39 and 45, respectively. Controlling for age, education, estimate of premorbid intellectual ability, and sex, group membership (AD or control) predicts performance in the free‐listing in the two categories. Holding demographic variables constant, functional status is inversely related to the performance on free‐listing.

Conclusion

Even when provided the modality (written) to generate longer lists, individuals with AD still performed worse than controls. Our findings confirm previous observations identifying an impairment of semantic knowledge in AD. Free‐listing is effective at detecting this impairment. This easy‐to‐administer, cost‐effective tool could facilitate the fast preliminary characterization of AD in distinct cultural environments.
Therapeutic targeting of TREM2: A novel approach for treatment of AD?
Authors: Schlepckow Kai
Published: December 2023

Background

Genome‐wide association studies have revealed risk genes for developing late‐onset AD many of which are exclusively expressed by microglia in the brain. One of these microglial genes is TREM2. Studies employing mouse models of amyloid pathology have shown that TREM2 function is essential for microglia to mount a proper response to amyloid pathology. The fact that microglia exert protective effects via TREM2 at least at the early stages of amyloid deposition suggests that boosting TREM2 function pharmacologically during the early stages of AD may be a promising novel therapeutic approach.

Method

We have developed and evaluated the protective potential of agonistic anti‐TREM2 antibodies boosting TREM2 function in preclininal models of amyloid pathology and related disorders employing immunoblotting, ELISA, immunohistochemistry, scRNA‐seq, lipidomics, and TSPO‐ as well as FDG‐PET imaging.

Result

Our agonistic anti‐TREM2 antibody 4D9 binds 12 amino acids N‐terminal of the ectodomain cleavage site, inhibits proteolytic TREM2 cleavage, and potently activates downstream pSYK signaling. Boosting TREM2 signaling by 4D9 leads to improved survival of macrophages, enhanced phagocytic activity of primary microglia, lower amyloid burden in an AD mouse model as well as accelerated recovery in mouse models of demyelination. In more recent work we focused on the development of a version of 4D9 with an engineered Fc part, which allows very efficient transcytosis of the antibody across the blood brain barrier (ATV:4D9; ATV: antibody transport vehicle). We demonstrate in an AD mouse model by TSPO and FDG PET imaging that a human specific version of the antibody enhances microglial activation and brain glucose metabolism, respectively.

Conclusion

Several independent studies including our own efforts have convincingly shown amelioration of amyloid pathology in preclinical models of AD upon administration of agonistic anti‐TREM2 antibodies. Together with findings demonstrating reduced cognitive decline in patients with higher levels of CSF soluble TREM2, which serves as a surrogate marker for TREM2‐dependent microglial activity, this suggests that TREM2‐boosting therapies should be actively explored in the clinical setting. In addition, our work indicates that TSPO‐ and FDG‐PET imaging may be used to assess target engagement.
Synaptic proteasome is inhibited in Alzheimer’s disease models and is associated with memory impairment in mice
Authors: Ribeiro Felipe C. , Ferreira Danielle Cozachenco , Fortuna Juliana , de Freitas Guilherme B. , Souza Jorge M , Alves‐Leon Soniza , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Grinberg Lea T. , De Felice Fernanda G. , Lourenco Mychael V. , Ferreira Sergio T.
Published: December 2023

Background

The proteasome plays key roles in neuronal function by regulating protein turnover, quality control, and elimination of oxidized and misfolded proteins. Recent evidence indicates that proteasome activity is required for synaptic plasticity and memory, and may be altered in Alzheimer’s disease (AD).

Method

Here, we investigate proteasome function and localization at synapses in AD post‐mortem brain tissue and in experimental models of AD by using western blotting, immunocytochemistry and proteasome activity assay. We also evaluated core AD‐related features upon proteasome inhibition by using DCFDA measurement, phaloidin staining, SUnSET and mice memory tasks.

Result

We found a marked increase in ubiquitinylated proteins in post‐mortem AD hippocampi compared to controls. Using human ex vivo adult cortical tissue, primary neuronal cultures, isolated synaptosomes and in vivo experiments in mice, we show that amyloid‐b oligomers (AbOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1DE9 mice. Treatment with the proteasome inhibitor, lactacystin, induces reactive oxygen species formation and loss of dendritic spines in hippocampal neurons, inhibits hippocampal mRNA translation, and causes memory impairment in mice.

Conclusion

These findings demonstrate that synaptic proteasome activity is inhibited in post‐mortem AD brain tissue and in experimental models of AD. Results further show that proteasome inhibition is associated with spine loss and memory impairment in mice, suggesting that proteasome inhibition may contribute to synaptic and memory deficits in AD.
Longitudinal Elastic Shape Analysis of Brain Subcortical Structures
Authors: Wu Yuexuan , Zhang Zhengwu , Chan Kwun Chuen Gary , Shibata Dean , Kukull Walter A. , Srivastava Anuj , Zhu Hongtu
Published: December 2023

Background

Over the past 30 years, MRI has become a ubiquitous tool for accurately visualizing the development of the brain’s subcortical structures. However, the quantification of subcortical structures is still in its infancy due to challenges in shape extraction, representation, and modeling.

Method

A simple and efficient framework of longitudinal elastic shape analysis (LESA) is developed for subcortical structures. By employing the elastic shape analysis of static surfaces using the square root normal field (SRNF) representations, we computed shape summaries of surfaces and represented the complex subcortical structures using a small number of basis functions. Further, we statistically modeled the sparse longitudinal data to predict the spatial‐temporal shape changes of subcortical structures. We also conducted the temporal registration using the square‐root velocity function (SRVF) framework to quantify the accelerated aging of Alzheimer’s disease (AD).

Result

We applied LESA to analyze longitudinal neuroimaging data sets and showcased its wide applications in estimating continuous shape trajectories, building life‐span growth patterns, and comparing shape differences among different groups. Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, we found that from 60 to 90 years old, the AD group always had the largest left ventricle (LV) surface area and the smallest left hippocampus (LHC) surface area, followed by the MCI and NC groups. The enlargement of LV and the atrophy of LHC had different speeds among different groups. Most of the shape‐changing differences between the AD and NC groups were visible in the anterior and posterior ends of LV. The atrophy of LHC happened mainly at the posterior end with aging. The AD group had the sharpest posterior end, and the NC group deformed the least with aging. Compared with the NC group, the AD group showed an average accelerated enlargement of 2.91 years and accelerated shape change of 2.76 years in LV; an average accelerated atrophy of 2.56 years and accelerated shape change of 2.59 years in LHC. By constructing the life‐span growth trajectories, we observed increases in shape changes’ speed in both LV and LHC after 60 years old.

Conclusion

AD can significantly speed up the shape change of ventricle and hippocampus compared with normal aging.
Neutrophil extracellular traps in amyloid pathology & glymphatic impairment
Authors: Braun Molly , Sevao Mathew , Gino Elizabeth , Keil Samantha A , Pedersen Taylor J , Jang Jay , Swierz Justyna , Sanderson Keith , Jansson Deidre , Iliff Jeffrey J
Published: December 2023

Background

Activated neutrophils eject neutrophil extracellular traps (NETs) consisting of web‐like structures of DNA, histones, and granular proteins. Neutrophils traffic into the brain in Alzheimer’s disease (AD) and along with NETs are associated with amyloid beta (Aβ) plaques. However, whether NETs may impair glymphatic clearance of Aβ has never been examined. The glymphatic system is a network of perivascular pathways that provides a pathway for solutes to be cleared from the brain interstitium. Impairment of glymphatic function promotes Aβ plaque deposition. We proposed that NETs may decrease glymphatic exchange by impairing perivascular and interstitial fluid movement, resulting in impaired Aβ clearance.

Method

5XFAD mice with amyloid pathology were crossed with Pad4−/− mice lacking the ability to form NETs, generating 5XFAD mice lacking NET formation. Barnes maze, spontaneous alternation Y maze, and open field behavioral tests were performed on 5XFAD+Pad4+/+ and 5XFAD+Pad4−/− mice at 4 months old. The following week, tracer was intracisternally injected into the CSF and dynamic transcranial imaging was performed to measure tracer movement over the cortical surface. Brains were then collected after 45 minutes. Tracer influx was quantified in these brain slices and the tissue was stained for amyloid beta, GFAP, Iba1, and neutrophil markers.

Result

Pad4 gene deletion in a 5XFAD mouse model of amyloid pathology improved tracer influx, decreased amyloid burden, and improved cognitive function.

Conclusion

NETs promote glymphatic impairment, amyloid accumulation, and cognitive impairment in a mouse model of amyloid pathology. These studies highlight the important role that neutrophils and NETs play in the pathology of AD and may be a novel therapeutic target.
Etiological contributions of adolescent binge alcohol on onset of Alzheimer’s disease‐associated basal forebrain neuropathology in 5xFAD mice and post‐mortem human AUD brain
Authors: Vetreno Ryan P. , Coleman Leon G. , Crews Fulton Timm
Published: December 2023

Background

Heavy alcohol use is an etiological factor for development of dementia and may contribute to onset of Alzheimer’s disease (AD). Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including basal forebrain cholinergic neuron degeneration and proinflammatory neuroimmune activation, and evidence suggest these systems are particularly sensitive to adolescent alcohol exposure. Using the 5xFAD mouse model of AD, we tested the hypothesis that adolescent intermittent ethanol (AIE), which models human adolescent binge drinking, would accelerate onset of AD‐associated pathology in the adult basal forebrain.

Method

In Experiment 1, non‐transgenic and 5xFAD male and female mice received AIE treatment (5.0 g/kg, i.g. 2‐days on/2‐days off; postnatal day [P]30 – P55) and basal forebrain tissue collected for immunohistochemistry and gene expression analysis on P100. In Experiment 2, 5xFAD female mice received AIE treatment as described above followed by glycyrrhizic acid (GA; 150 mg/L), a high mobility group box 1 (HMGB1) inhibitor, in drinking water from P56 – P100. At study conclusion, basal forebrain tissue was collected for immunohistochemistry and gene expression analysis on P100. In Experiment 3, AD‐associated neuropathology was assessed in the post‐mortem human basal forebrain of individuals with AUD relative to age‐matched moderate drinking CONs.

Result

In Experiment 1, AIE accelerated loss of basal forebrain cholinergic neurons and heterogeneous nuclear ribonucleoprotein (hnRNP) expression in 5xFAD females, but not males, relative to age‐matched 5xFAD CONs. This was accompanied by a female‐specific accelerated accumulation of plaque markers (e.g., Aβ1‐42, Thioflavin‐S, HMGB1) as well as microglial activation and proinflammatory neuroimmune signaling genes (e.g., HMGB1, RAGE) in the adult basal forebrain. In Experiment 2, post‐AIE treatment with the HMGB1 inhibitor GA reversed AIE‐induced accelerated loss of cholinergic neurons, accumulation of plaque markers, and upregulation of microglial activation markers and proinflammatory signaling molecules. In Experiment 3, AUD individuals exhibited decreased cholinergic and hnRNP markers and increased Aβ1‐42 immunoreactivity as well as cholinergic neuron co‐expression with Aβ1‐42 that negatively correlated with an adolescent age of drinking onset.

Conclusion

These data reveal that adolescent binge ethanol exposure may be an etiological factor contributing to onset of AD‐associated neuropathology in the adult basal forebrain through HMGB1‐neuroimmune signaling.
Altered circadian rhythms effects on anxiety, locomotor activity, serotonin and nitric oxide levels in the prefrontal cortex of juvenile and adult rats
Authors: Obajuluwa Adejoke Olukayode , Lech James Chrystopher , Afolabi Olakunle Bamikole , Obajuluwa Tiwalola Madoc , Babafemi Laoye John , Edem Edem Ekpenyong
Published: December 2023

Background

Dementia and Alzheimer’s disease (AD) can be exacerbated by irregular sleep‐wake cycles, and age may be a risk factor. This study compared behavioral responses such as anxiety, motor coordination, and locomotion to altered circadian rhythms and serotonin, nitric oxide (NO), and malondialdehyde (MDA) levels in the prefrontal cortex of juvenile and adult rats.

Method

A total of thirty female Wistar rats were grouped into three (n = 5) in the following juvenile (30‐45 days old) and adult (90‐120 days old) groups: (A) Control (12L:12D cycle),(B) 24‐hour LED light exposure(12L:12L cycle) and (C) 24‐hour dark cycle (12D:12D cycle). Experimental rats were kept in the stated cycle conditions using natural lighting, LED lighting, and a dark room, respectively, for 60 days. Data were analyzed using a two‐way ANOVA (GraphPad Prism 9), and statistical significance was measured at p<0.05.

Result

Findings from the study revealed progressive weight loss in the sleep‐deprived juvenile (12L:12L) rats compared to adults (p<0.05) in the same and other groups. Also, anxiety‐like indices such as longer duration of time in the dark area of the light‐dark box, avoidance of open arm entries on the elevated plus maze, reduced line crossing activity in the open field box, etc. were markedly higher in the juvenile rats from the 12L:12L and 12D:12D groups respectively. When juvenile and adult 12L:12L and 12D:12D cycle rats data were compared to controls, severe depletion of serotonin (p<0.0001) and nitric oxide (p<0.01) levels were observed, while age‐dependent MDA levels were revealed across all groups.

Conclusion

A bi‐directional relationship was observed between age and circadian disruption effects with more severe outcomes in juveniles compared to adults and this hold interesting implications for the study of the biological clock mechanisms underlying anxiety, mood and sleep disorders in living systems.
Feasibility of Using Wearable Actigraphy for Behavioural Monitoring in Care Home Residents Living with Moderate to Severe Alzheimer’s Disease and Agitation
Authors: Guu Ta‐Wei , Aarsland Dag , Ffytche Dominic H
Published: December 2023

Background

Measuring and monitoring behaviour is difficult in people living with later stage Alzheimer’s disease and specific behavioural symptoms such as agitation and aggression (AA). Currently, subjective information given by these patients is highly susceptible to inaccurate recall, clinicians rely on answers provided by care givers, which can be biased and lack fine‐grain temporal detail. Although actigraphy watches have been useful tools for research, little is known about the feasibility of their use in agitated dementia participants and on the factors influencing watch compliance.

Method

People diagnosed with Alzheimer’s disease and significant AA symptoms living in care homes were asked to wear an actigraphy watch (GENEactiv Original) for 4 consecutive weeks. Demographic data, Functional Assessment Staging Tool (FAST) score, behavioural symptom pattern and severity were recorded using the Neuropsychiatric Inventory Nursing Home Version (NPI‐NH). Watch‐recorded wearing time and activity data were used to evaluate adherence. Care home staff were interviewed to explore factors influencing watch wearing by participants and to develop solutions to improve compliance.

Result

We recruited 28 participants (14 female) and found wearing the watch feasible overall. No statistical compliance difference was found between different groups based on age, FAST score, agitation pattern or severity; however, a significant gender difference was found with male participants being more adherent (Table). Participants were more compliant in weeks 3‐4, and first week adherence predicted overall adherence (Figure). Factors influencing compliance include the design and appearance of the watch, previous watch wearing habit, and the perceived purpose of the study. Using documents easily readable to participants and care givers to facilitate understanding of the study and to communicate challenging clinical scenarios appeared to enhance adherence.

Conclusion

Wearing an actigraphy watch for behavioural monitoring was feasible for moderate to severe Alzheimer’s disease patients with AA symptoms in care home settings. Gender‐specific design and appearance should be considered when selecting the actigraphy watch. For dementia studies planning to use an actigraphy watch, compliance can be improved by incorporating a short lead‐in phase to establish a watch wearing routine and by providing reader‐friendly documents about the watch purpose to communicate with participants and care givers.
Neuroimmune proteins can differentiate between distinct neurodegenerative diseases
Authors: Cherry Jonathan D , Baucom Zachary H. , Eppich Kaleb G , Kirsch Daniel A , Dixon Erin R , Tripodis Yorghos , Bieniek Kevin F , Farrell Kurt W. , Whitney Kristen R. , Uretsky Madeline , Crary John F. , Dickson Dennis W. , McKee Ann C.
Published: December 2023

Background

Although we have greatly increased our ability to identify the presence of neurodegenerative pathology during life, additional techniques and targets are still needed to increase diagnostic specificity. Recently, it has become evident that the neuroinflammatory response might be tailored towards distinct diseases resulting in disease specific “neuroinflammatory signatures”. Therefore, a detailed comparison of neuroinflammatory molecules present among distinct neurodegenerative diseases could provide novel information of disease specific therapeutic targets or differential biomarkers.

Method

To better examine potential neuroinflammatory signatures, a 71 immune‐related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). A partial least square regression analysis was used for unbiased clustering and identifying proteins that were distinctly correlated with each disease correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible biomarkers. Finally, histology was performed using candidate proteins to visualize cell type expression for better understanding of potential mechanistic pathways.

Result

Five clusters of neuroimmune proteins were identified and compared to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD, further validating the use as possible biomarkers.

Conclusion

Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between neuropathologies and act as novel biomarker candidate to increase specificity for in‐life diagnoses.
Using Infiltrating Adaptive Immune Cell Signatures from Single‐Nucleus Profiling to Identify Neuroimmune Interactions in Parkinson’s Disease
Authors: Chatila Zena K
Published: December 2023

Background

Affected brain areas in Parkinson’s disease (PD) show infiltration of T cells, together with increased expression of pro‐inflammatory cytokines and microglia with activated morphology, suggesting that neuroinflammation is plays a complex role in this disorder. To begin elucidating the mechanisms by which infiltrating adaptive immune cells may contribute to the demise of neurons in PD, we sought to investigate changes in T cell transcriptional signatures at the single‐cell level in post‐mortem human tissue. We also investigated the transcriptional signatures of microglia to capture interactions between the innate and adaptive immune system.

Method

We applied a single nucleus RNA‐sequencing approach to generate an unbiased transcriptomic dataset in 19 sporadic PD cases across the substantia nigra (SN), ventral tegmental area, substantia innominata, and hypothalamus, and in the SN of 14 controls.

Result

We identified three subpopulations of CD8+ T cells which are enriched in the PD SN, and a natural killer (NK) cell population is enriched in the SN of controls. These findings parallel those of other studies that show CD8+ T cells are enriched in the PD brain, and those that suggest NK cells may play a protective role against disease. In parallel, we identified a microglial subpopulation that is present in the SN of controls but depleted in SN tissue from donors with PD; this microglial population has higher expression of antigen‐presentation proteins, suggesting unique interactions with the adaptive immune system. Immune cell‐cell interactions between the identified T cell, NK cell, and microglial subpopulations were investigated through assessing co‐regulation of ligand‐receptor pairs. Unique interactions were found in the PD SN which are suggestive of recruitment of activated microglial populations to the SN by T cells, as well as T cell and microglial inhibition of NK cell signaling.

Conclusion

These findings suggest an imbalance between CD8+ T cell and NK cell activity in the PD SN, and a role for T cells in microglial activation in PD. We aim to integrate our immune genomic data with neuronal data to generate a signature of neuroimmune interactions in PD, which may ultimately be used to develop biomarkers and candidate molecules/pathways to therapeutically target specific immune interactions.
Microglial TREM2 senses TDP‐43 and protects against TDP‐43‐related neurodegeneration
Authors: Wu Long‐Jun
Published: December 2023

Background

Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 in TAR‐DNA binding protein 43 kDa (TDP‐43)‐related neurodegeneration remain largely unknown.

Method

We investigated TDP‐43 neurodegeneration via viral‐mediated expression of hTDP‐43 protein in mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. Mass cytometry analysis, mass spectrometry, surface plasmon resonance, and computational simulation were used to study the interaction between TREM2 and TDP‐43.

Result

We found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP‐43, and enhanced neuronal damage and motor function impairments. hTDP‐43 induced a TREM2‐dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. We further demonstrated an interaction between TDP‐43 and TREM2, in vitro and in vivo, in hTDP‐43‐expressing transgenic mouse brains. We computationally identified the region within hTDP‐43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues.

Conclusion

Our data reveal the novel interaction between TREM2 and TDP‐43, highlighting that TDP‐43 is a potential ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP‐43‐related neurodegeneration.
Accordance to a MIND–Style Diet is Associated with Decreased Risk of Dementia Mortality in the REasons for Geographic and Racial Disparities in Stroke (REGARDS) Cohort
Authors: Judd Suzanne E , Howard George , Tangney Christy C , Pearson Keith , Shikany James M , Cushman Mary , Wilson Nicole , Howard Virginia J , Sawyer Russell , Oladele Carol , Manly Jennifer J.
Published: December 2023

Background

The Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet (high in nuts, seeds, vegetables, berries and low in meat, dairy, and butter) has been associated with reduced risk of dementia. However, no studies have examined the role of the MIND diet in a racially diverse population nor have there been studies that have examined the association of the MIND diet with dementia mortality.

Method

We examined data from Black and White adults (age 45‐98) in the US‐based REGARDS cohort. Dietary and covariate data were collected at baseline (2002‐2007). MIND diet score was created as described by other cohort studies (Table footnote). The primary outcome was dementia‐related mortality through December 31, 2020 from the National Death Index using ICD‐10 codes F00‐F03, G30, G31.0‐G31.1, and R54. Cox proportional hazards regression was used to model MIND diet score (in tertiles and as a continuous variable) and time to dementia death. To ensure robust association across sub‐groups, we tested for interactions of MIND diet with sex, race, age, obesity, history of stroke, and baseline cognitive impairment and adjusted for competing risks.

Result

A total of 18,277 participants (mean age 64.9) had dietary data available to calculate the MIND diet score. MIND diet score was higher among females compared with males, White compared with Black participants, and college graduates. There were no differences in accordance by age. After a median of 12 years, participants with the highest MIND diet scores had the lowest risk of dementia death HR = 0.78 {95% CI; (0.66, 0.94)} comparing the 3rd tertile with the 1st tertile and after adjustment for age, race, sex, income, education, total energy, and other medical conditions (Table). This association was attenuated slightly when a competing risk analysis was considered HR = 0.84 {95%CI; (0.70, 1.00)}. There were no significant interactions observed.

Conclusion

The MIND diet score is associated with dementia death in a large bi‐racial cohort in the US. This association is robust across race, age, and sex groups. Dietary interventions using the MIND diet may further clarify whether this association is causal and whether MIND diet may be an important tool in reducing rates of dementia.
Longitudinal effects of sex on pathology accumulation, neurodegeneration and cognitive decline in Presenilin‐1 E280A mutation carriers: preliminary findings from the Colombia‐Boston (COLBOS) biomarker study
Authors: Vila‐Castelar Clara , Baena Ana Y. , Langella Stephanie , Munera Diana , Aguillon David , Alvarez Sergio , Sanchez Justin S , Kaplan Elizabeth , Aduen Paula , Guzman‐Velez Edmarie , McDowell Celina F. Pluim , Martinez Jairo E. , Noriega Daisy , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Fabrega‐Ching Sofia , Ramirez‐Gomez Liliana A. , Giudicessi Averi , Lee Hang , Johnson Keith A. , Sperling Reisa A. , Lopera Francisco , Quiroz Yakeel T.
Published: December 2023

Background

Previous work showed that females at risk for autosomal dominant Alzheimer’s disease (AD) due to a single mutation (E280A) in the Presenilin‐1 gene (PSEN1) may have greater cognitive resilience to AD‐pathology and neurodegeneration than males. However, more research is needed to clarify the effect of sex on AD risk and progression. We investigated the effects of sex on rates of amyloid and tau accumulation, neurodegeneration, and memory decline in PSEN1 mutation carriers with and without cognitive impairment, who are genetically determined to develop early‐onset dementia.

Method

A total of 66 cognitively unimpaired mutation carriers (mean age of 34.41 +/‐ 4.86 years; 38 females), and 23 cognitively impaired mutation carriers (mean age of 44.91 +/‐ 2.83 years; 17 females) from the Colombia‐Boston Biomarker (COLBOS) study completed baseline cognitive assessments. A subset of 52 participants also completed florbetapir‐ and flortaucipir‐PET, and structural MRI. Cognitive and neuroimaging follow‐up visits were completed at 2‐ (n = 29) and 4‐year (n = 13) intervals. We used linear mixed‐effects models, with random intercepts, to predict rate of change in MMSE scores, CERAD word list delayed recall, cortical amyloid burden, tau in the entorhinal, inferior temporal, and precuneus cortices, and hippocampal volume by sex, controlling for education.

Result

Over time, carriers exhibited greater cortical amyloid burden (p<.001), inferior temporal tau (p = .019), precuneus tau (p = .003), lower hippocampal volume (p = .005), and showed a trend towards lower MMSE scores (p = .059) and word list delayed recall (p<.080); entorhinal tau did not significantly increase (p = .137). Female carriers showed a steeper decline in word list delayed recall than male carriers (p = .021). There were no sex differences in the rate of accumulation of mean cortical amyloid or regional tau, hippocampal atrophy, or change in MMSE scores (all ps>.05).

Conclusion

Preliminary findings of this ongoing study suggest that despite similar rates of pathology accumulation or atrophy between female and male PSEN1 E280A carriers, female mutation carriers may have faster memory decline. Future analyses with additional participants and follow‐up intervals are needed to characterize sex differences in ADAD risk and resilience, as well as inform development of treatments and interventions.
A Dyadic Behavioral Sleep Intervention Program for Persons Living With Dementia and Their Family Caregivers: A Pilot Randomized Controlled Trial
Authors: Song Yeonsu , Papazyan Anna , Lee Diane , McCurry Susan M , Mitchell Michael N. , Irwin Michael R , Teng Edmond , Alessi Cathy A , Martin Jennifer L
Published: December 2023

Background

Untreated sleep problems in persons living with dementia (PLWD) and their caregivers impact health outcomes of both individuals and impair quality of care for caregivers. This study pilot tested preliminary effects of a dyadic sleep intervention program among this group.

Method

Thirty PLWD/caregiver dyads were randomized to a 5‐session treatment (n = 15 dyads) or a similarly structured information‐only control group (n = 15 dyads) via in‐person or video‐telehealth. Treatment was a manual‐based program incorporating key components of cognitive behavioral therapy for insomnia (CBTI), daily light exposure and walking, and a problem‐solving approach for dementia‐related behaviors and caregiving challenges. Sleep outcomes included actigraphy‐measured sleep efficiency (SE) and total awake time (TWT) at night for dyads, and Pittsburgh Sleep Quality Index (PSQI) for caregivers. Outcomes were measured at baseline, post‐treatment, and 3‐months follow‐up (main outcome time point). Recommendation adherence in the treatment group was computed and a 2 (group) by 3 (time) mixed model analysis of variance was used to test the treatment effects (p<0.20 as the threshold).

Result

Two dyads in treatment and one control dyad did not complete all five sessions. Of 13 dyads who completed all sessions of the treatment program, average % days that the dyads met their sleep schedules were 76% bedtime and 83% get‐up time for PLWD and 81% bedtime and 68% get‐up time for caregivers. From baseline to 3‐month follow‐up, SE increased by 3.2% more for PLWD in the treatment group (n = 9) compared to control (n = 9, p = 0.48) and by 3.7% more for caregivers in the treatment group (n = 12) compared to control (n = 9, p = 0.17). TWT also reduced by 19 minutes more for PLWD and 14 minutes more for caregivers in the treatment group compared to control at the 3‐month follow‐up although this was not statistically significant. Caregivers in treatment also showed non‐significant improvement on the PSQI (p>0.20).

Conclusion

A dyadic approach to sleep improvement showed evidence of benefit among PLWD and caregivers. A larger study is needed to fully evaluate these effects and compare in‐person to telehealth modalities.
Combining virtual mentalizing imagery therapy with caregiving skills for Spanish language Latino family dementia caregivers: a feasibility and acceptability study
Authors: Gomez Liliana Ramirez , Gutierrez‐Ramirez Paulina , Melero‐Dominguez Maria , Madarasmi Saira , Quiroz Yakeel T. , Jain Felipe A
Published: December 2023

Background

Spanish‐speaking family caregivers of people living with dementia have limited supportive resources in Spanish. There are few validated, culturally acceptable virtual interventions to reduce these caregivers’ psychological distress and address caregiving skill needs. We investigated the feasibility of virtual delivery of a Spanish language adaptation of mentalizing imagery therapy (MIT), which provides guided imagery and mindfulness training to improve self‐ and other‐ understanding and reduce negative psychological symptoms, in combination with caregiver skills (CS).

Methods

16 Spanish‐speaking Latino family dementia caregivers enrolled in a combined 8‐week virtual MIT‐CS program. Feasibility, acceptability, and satisfaction with MIT‐CS were assessed. The primary psychological outcome was depressive symptoms; secondary outcomes included caregiver burden and dispositional mindfulness. Feasibility thresholds for participation were set at 75% for retention, at 75% for group attendance, and at two times per week for MIT home practice. Acceptability was evaluated as overall satisfaction with MIT‐CS of at least four points on a five‐point Likert scale. Effect sizes were estimated with Cohen’s d, and statistical significance was computed with mixed linear models.

Results

Caregivers were 58±8 (mean±SD) years of age, 81.2% female, and had an average of 14±3 years of education. 69% did not have a 4‐year college degree. 94% of participants completed the group (one participant dropped out due to time constraints). Participation in weekly group meetings was 86%. Home MIT practice was performed on average 2.2±0.3 times per week. Satisfaction with MIT‐CS reached 4.5±0.9 of a possible 5 points (most responses rated excellent). Reduction in depression was observed after completion of MIT‐CS (d = ‐.42, p = .03). There was a significant improvement in mindfulness (d = .91, p = .004) and a trend toward improvement in caregiver burden (d = ‐.44, p = .1).

Conclusions

Virtual group‐delivered MIT‐CS was feasible and acceptable in a group of Latino Spanish language family dementia caregivers living in the greater Boston area. MIT‐CS demonstrated promising effect sizes for reducing depressive symptoms and caregiver burden and increasing mindfulness. Larger, randomized controlled trials of MIT‐CS should validate the efficacy of specific MIT‐CS components in this population.