bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression in Alzheimer’s disease hospitalized patients: A descriptive analysis of a nationwide database
Authors: Brás Bernardo , Ferreira Ana Rita , Gonçalves‐Pinho Manuel , Freitas Alberto , Fernandes Lia
Published: June 2023

Background

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. About 40‐50% of AD patients are also affected by depression, with mounting evidence suggesting its association with worse disease prognosis and negative outcomes, such as lower quality of life, higher mortality, and more hospitalizations, with a prolonged length of stay (LoS) and greater socioeconomic burden. This study aimed to describe the main sociodemographic characteristics and hospitalization outcomes of AD patients with a register of depression.

Method

A retrospective observational study was conducted using a Portuguese nationwide hospitalization database from all mainland public hospitals. All episodes of inpatients ≥65 years old with a primary or secondary diagnosis of AD (ICD‐9‐CM code 331.0), with a concomitant register of depression at any diagnostic position (codes 296.2X, 296.3X and 311), discharged between 2008‐2015, were selected. Descriptive statistics were performed using SPSS IBM v26®.

Result

A total of 1.637 hospitalizations were analysed. An upward trend has been registered from 65 (2008) to 407 episodes (2015), with most episodes occurring in female patients (73,7%), with a mean age of 80±6 (SD) years. Pneumonia (15,0%), urinary tract infections (8,5%), fracture of neck of femur/hip (6,5%), acute cerebrovascular disease (5,3%), and delirium, dementia, amnestic and other cognitive disorders (4,4%) were the most frequent primary diagnoses. A median LoS of 8 days (Q1‐Q3: 5‐14) was observed and a total of 162 (9,9%) patients died during hospitalization. Each episode had a mean estimated hospitalization charge of 3.219,15€, which represents a sum of 5.269.750,98€ for the total episodes analysed.

Conclusion

The increased register of depression can be explained by the improvement in the quality of hospital‐coded data, particularly secondary coding. Moreover, the data raises awareness of depression impact in the number, duration, and cost of hospitalized patients with AD, which could conduce to more diligent healthcare interventions.
Theta‐Gamma Phase‐Amplitude Coupling Deficit in Streptozotocin AD Rat Model
Authors: Sedghizadeh Mohammad Javad , Taei Afsaneh Asgari , Karimani Farnaz , Dargahi Leila , Aghajan Hamid , Dehaqani Mohammad‐Reza Abolghasemi
Published: June 2023

Background

Theta rhythms are known to encode sensory information and reflect their effect into gamma oscillations through a modulation process known as theta‐gamma phase‐amplitude coupling (PAC) (Amemiya et al., Cell Reports 2018). The role of the PAC as a network‐level indicator of cognitive impairment in disorders such as dementia and Alzheimer’s disease has received much attention recently (Zheng et al. Nature communication 2020).

Injection of Streptozotocin (STZ) in animals is reported to cause resistance to insulin uptake in the brain, leading to memory and cognitive impairment (Kamat, Neural Regeneration Research 2015). The current study examines the induced deficit in the PAC as an early indicator of neurodegenerative effects of STZ.

Method

3 adult male Wistar rats were included in this study (270 – 300 g). Intraventricular injection of STZ was performed at a dose of 3 mg / Kg with a volume of 10 μl. Two stainless steel electrodes were implanted in the hippocampus (CA1) and medial prefrontal cortex (mPFC). The rats were free to move during recording. LFP data were recorded and segmented into windows of 20 s. Preprocessing and noisy trial rejection were employed for artifact removal, and the theta‐gamma PAC was measured using the mean vector length (tf‐MVL) method (Munia et al., Scientific Reports 2019).

Result

One week after STZ injection, the theta‐gamma PAC values did not show a significant change but after two weeks variation was observed. During this period, the power of different frequency bands was also measured and no significant change was observed even after two weeks. Theta‐gamma PAC deficiency was observed in both regions (CA1 and mPFC).

Conclusion

STZ’s intracerebro‐ventricular injection is known to produce cognitive deficits along with an increase in Aβ deposition. This study reports that cross‐frequency coupling deficiency is also observed in this AD mouse model. Moreover, the PAC deficit was detected earlier than any change was observed in the spectral analysis of the data, suggesting that it can serve as a diagnosis tool for memory impairment due to neurodegeneration in the STZ mouse model of AD.
Using remote evaluations to cognitively test African American communities reduces racial disparities and enhances Alzheimer’s disease awareness
Authors: Johnson David K , Adesida Praise , Montenegro Esteban , Merrick Shanette
Published: June 2023

Background

African Americans are at greater risk for cognitive decline and development of Alzheimer’s Disease than any other ethnic population. Systemic and financial barriers block access to healthcare in many African American communities, preventing possibility for evaluation and treatment. During the COVID pandemic, Neurobehavioral Systems, Inc (NBS) augmented the California Cognitive Assessment Battery to become a take‐home and remote administered platform that ensured a convenient and safe cognitive evaluation. Preliminary analysis assessed the usability of the tablets among healthy African American adults.

Method

Twelve out of the 20 participants recruited from East Oakland, California, took part in this study. The average participant age was 52.58 (SD = 15.22), ranging from 22 to 69 years old, 58.3% were female. About 33.3% of the participants obtained a higher education after high school, the level of education ranging from high school diploma to graduate degree. Symptoms of dementia were not reported.

Participants were repeat tested two times between March and April 2021. Testing kits contained a Microsoft Pro tablet, charger, headset, mouse, modem, and USB port, provided by NBS. Units were set up and taken down in participants’ homes by an NBS staff before and after each cognitive evaluation, respectively. The tablet’s software, California Cognitive Assessment Battery, or CCAB, was created by NBS to maintain communication between a remote evaluator and the test‐taker throughout testing.

Result

Twelve African Americans adults, 58.3% women and 33.3% holding a degree higher than a high school diploma, were evaluated consecutively for two days from March through April 2021. In general, the 30‐test battery could be completed within 2 hours. Of those participating, 100% completed all 30 tests within the allotted time.

Conclusion

During a verbal exit interview with their examiner, participants preferred the remote evaluation for its comfortability and convenience, and the test helped show their cognitive ability and areas that needed work. These results demonstrated that remotely monitored cognitive evaluations administered at home have great promise in reducing healthcare disparities between African Americans and other ethnicities.
Use of modified Telephone Interview for Cognitive Status (TICS‐M) for cognitive impairment analysis one year after COVID‐19 hospitalization in Brazil
Authors: Sacramento Luiz Gustavo Guimarães , Sousa Danielle Calil , Leite Arnaldo Santos , Fernandes Bruna Achtschin , Caramelli Paulo , Marinho Carolina Coimbra
Published: June 2023

Background

COVID‐19 infection primarily affects the respiratory system despite of short and medium‐term cognitive impairment has been increasingly reported. The Modified Telephone Interview for Cognitive Status (TICS‐M), validated for cognitive screening after stroke, assesses domains such as orientation, attention/calculation, language, and immediate and delayed episodic memory. Thus, the TICS‐M might be useful to remotely screen for cognitive impairment in individuals affected by COVID‐19.

Method

Cross‐sectional multicenter study in Belo Horizonte, Brazil, with participants hospitalized with COVID‐19 confirmed by RT‐PCR or serology. All patients were aged 18+ years. Clinical and sociodemographic data were obtained through electronic medical records and/or interviews. Cognitive impairment screening was performed one year after hospital admission using the TICS‐M, with a cutoff point of 14 out of 39.

Result

Ninety‐six patients were submitted to the test, of which 50 (52.1%) were women, 72 (75%) were self‐declared non‐white, 59 (64.15%) did not complete elementary school and the median age was 62 years (interquartile range 49‐69). There was no significant association between lower TICS‐M scores and sociodemographic data or previous medical history, except for higher educational level that appears to be a protective factor to lower scores on TICS‐M (OR 0.089, 95% CI:0,01‐0,7, p 0.008), which is demonstrated in Table 1. There was also no association between the scores and the clinical course during hospitalization as displayed in Table 2. Furthermore, length of hospital stay (p = 0.232) and length of stay in Intensive Care Unit (p = 0.565) did not impact the scores.

Conclusion

In this study, 15% of the sample had cognitive impairment one year after hospitalization for COVID‐19 according to TICS‐M. The absence of an association between known risk factors for cognitive deficits and worse scores on the TICS‐M might have been influenced by the fact that only 13.5% of our sample did not have comorbidities. Lower education level was the only factor associated with worse scores, which indicates a possible need to adapt the test or the cutoff point for different educational levels.
Construction of a questionnaire to evaluate cognitive domains based on the diagnostic criteria of the Diagnostic and Statistical Manual of mental disorders ‐ DSM‐5 for neurocognitive disorders
Authors: Diniz Maissa Ferreira , de Faria Rocha João Victor , de Souza Sarah Mendonça Mendes , Lin Filipe Jin Jen , Costa Giulia , Bicalho Maria Aparecida Camargo , Malloy‐Diniz Leandro F , de Paula Jonas Jardim , de Mattos Viana Bernardo
Published: June 2023

Background

The functional status decline is an important marker for the diagnosis of Neurocognitive Disorders and it is essential in the differentiation between mild and major cognitive impairment. Thus, instruments that assess cognitive‐functional status decline in Portuguese are important for the care of Brazilian older adults.

Method

Development of a cognitive‐functional status assessment questionnaire through six steps: (1) Psychological system definition; (2) Properties and subsystems; (3) Dimensionality; (4) Constructive and Operational Definitions; (5) Operationalization of items; (6) Analysis of the items. The analysis of the items included the performance of a semantic analysis by judges and a pilot group composed of older adults and their informants.

Result

The Questionnaire for Assessment of Cognitive Domains and Functionality (QACDF) was developed with 30 items, 5 items per each one of the six DSM5’s cognitive domains, in Likert format, and with an informant and patient versions. Each item of the questionnaire was developed to assess a change in a functional status/behavior or cognitive complaint that was most related to a cognitive domain and its subsystem. The general agreement index among the judges ranged from 0.68 to 0.91 (68% to 91%), with an agreement greater than 70% for most domains. The pilot study included 15 older adults with an average age of 79 years (SD = 6.9), average education of 4 years (SD = 4.4), and their respective informants, with an average age of 50.9 years (SD = 11.3), and average schooling of 13.8 years (SD = 4.5). In the pilot study, adjustments were made in some of the items, such as simplifying and reducing instructions, as well as replacing terms that were difficult to understand among participants. Adequate agreement results were obtained for most items in the first analysis performed. The QACDF was reviewed and submitted to a second analysis by judges composed of Brazilian’s top references in dementia assessment.

Conclusion

The QADCF has semantic characteristics suitable for Brazilian older adults and the adequate agreement among judges suggests a substantial theoretical correlation of the items to cognitive domains and functional status/behavior/cognitive complaint. Studies of its application in clinical scenarios are suggested.
The effect of virtual reality and physical exercise training on cognitive function in older adults with mild cognitive impairment
Authors: Thapa Ngeemasara , Park Hye‐Jin , Yang Ja‐Gyeong , Park Kyung Won , Park Hyuntae
Published: June 2023

Background

Numerous studies have shown that aerobic and resistance exercises, including leisure time physical activity help to reduce the risk of cognitive decline. Recently potential of cognitive training using immersive virtual reality (VR) has been growing in the non‐pharmacological interventions for mild cognitive impairment (MCI). However, there are not enough studies comparing the impact of two different interventional approaches on cognition and brain function especially on MCI patients. Therefore, we investigated the effectiveness of two non‐pharmacological intervention using VR and aerobic‐and resistance physical exercise (PE) on cognitive and brain function of older adults with MCI.

Method

This study included 99 participants (70.8 ± 5.4) with MCI randomly assigned to PE, VR, and control group. The PE training consisted of aerobic and resistance exercise performed for 50 mins 5 times/week for 12 weeks. The immersive VR‐based cognitive training consisted of series of cognitive games. 24 sessions of VR training (three days/week) were performed, and each session was 100 mins long. Global cognitive function was measured with Mini‐Mental State Examination (MMSE) test. Resting‐state electroencephalography (EEG) of neural oscillatory activity in different frequency bands was measured. Physical function was measured with hand grip strength (HGS), gait speed and timed up and go test.

Result

After the intervention period, VR significantly enhanced global cognition (p<0.045) and HGS (p<0.001) whereas PE significantly improved HGS (p<0.001) compared to baseline. One way Analysis of variance (ANOVA) of resting state EEG showed decreased theta/beta power ratio (TBR) (p<0.018) in the central region of the brain in PE group compared to the control group. Although not significant, VR group also showed decreased TBR compared to control group.

Conclusion

Our study findings suggest that VR based cognitive training enhances both global cognition and physical function of older adults with MCI. The decrease in resting state TBR in PE and VR group also indicated improved attention. Further studies should peruse the effect of VR exergaming intervention, a combination of PE and cognitive games, to yield peak benefits on MCI patients.
Cardiorespiratory fitness is an important marker of cognitive performance in older Latin Americans
Authors: Johnson David K , Montenegro Esteban , Kramer Abigail , Salazar‐Villanea Monica , Cahn‐Weiner Deborah
Published: June 2023

Background

Our previous research with older non‐Hispanic whites demonstrated that with increasing cardiorespiratory fitness (CRF) there was a concomitant linear increase in processing speed (PS) performance. PS has also been found in a number of reports as a potential precursor to memory decline associated with Alzheimer’s disease and cognitive aging. The purpose of this study was to examine whether the same cognitive benefits imbued by CRF generalize within a healthy Latino aging community living in Costa Rica (CR).

Method

415 community dwelling older adults (315 CR and 100 non‐Hispanic whites living in the United States) with a mean age of 71 (SD = 5.29) years old were recruited from the Epidemiology and Development of Alzheimer’s Disease (EDAD), a large international study of Latino cognitive aging. Participants completed neuropsychological testing and a graded treadmill exercise stress test. We compared the relationship between Oxygen Uptake Efficiency Slope (OUES) and a composite measure of PS (Digit Symbol, Block Design, and Stroop Color Naming). Confirmatory factor analysis was conducted.

Result

CRF (OUES) significantly predicted PS within the CR (B = 0.50; p < .001) group and non‐Hispanic white (B = 0.25; p < .05) group after controlling for age and sex. The relationship between CRF and the PS factor showed a non‐significant misfit when the relationship was constrained to be equal on both groups (χ² (1) = 0.39, p = 0.53), hence the relationship is equivalent between groups.

Conclusion

In a healthy sample of older individuals living in CR we found the same score profile and interrelationships that were identified among non‐Hispanic whites living in the United States. CRF and PS are clinically meaningful therapeutic targets for dementia prevention among older Latin Americans.
Association between 18F – FDG uptake and global cognitive performance in individuals at risk of dementia
Authors: Jaramillo‐Jimenez Alberto , Khalifa Khadija Nasralla , Tovar Diego , Borda Miguel Germán , Sonnesyn Hogne , Ferreira Daniel , Buter Tirza C.E. , Maple‐Grødem Jodi , Oppedal Ketil , Aarsland Dag
Published: June 2023

Background

Cardiometabolic disorders (CMD) and Mild Cognitive Impairment (MCI) have been associated with an increased risk of developing dementia. However, brain glucose metabolism has not been compared between patients with CMD and MCI, and little is known about its associations with global cognitive performance. Here we examined regional brain 18F – FDG uptake in patients with CMD and MCI, and analyzed its potential associations with global cognitive performance.

Methods

55 patients with increased risk for developing dementia were recruited (MCI = 22; CMD = 33) in this cross‐sectional study. As a measure of brain glucose metabolism, PET/CT was performed and the mean uptake value in brain regions of interest (ROI) was obtained and standardized by whole brain uptake. Global cognitive performance was examined using the Mini‐Mental State Examination (MMSE). Group differences in brain metabolism and cognitive performance were examined. We conducted separate linear regression models considering standardized MMSE as the dependent variable, and mean 18F – FDG uptake in each of the ROI (and its CMD/MCI group‐interactions) as independent variables. Our models were adjusted by age, gender, years of education, and presence of at least one APOE e4 allele, and corrected for multiple testing with the False Discovery Ratio (FDR < 0.01).

Results

The CMD and MCI groups were comparable in age, gender, education, and mean 18F‐FDG uptake across all the ROIs, but significantly different in MMSE (Table 1). Adjusted models for global cognitive performance showed significant group interactions with the mean 18F – FDG uptake in bilateral caudate and hippocampus, as well as in left‐hemisphere amygdala, cuneus, fusiform gyrus, and opercular part of the inferior frontal gyrus. Thus, significant negative associations of 18F – FDG uptake in the above ROIs and cognitive performance was observed in the MCI group (Figure 1 & Table 2).

Conclusions

In MCI patients, reduced global cognitive performance was significantly associated with high brain glucose metabolism in bilateral caudate and hippocampus, and with the left fusiform gyrus, cuneus, and inferior frontal gyrus (opercular part). These asymmetric associations between high metabolism and low cognitive performance could suggest compensatory effects in MCI patients but further research is needed to confirm this hypothesis.
Associations between placental growth factor, white matter lesions, and vascular risk factors in non‐demented elderly individuals
Authors: Gertje Eske Christiane , Janelidze Shorena , van Westen Danielle , Stomrud Erik , Palmqvist Sebastian , Hansson Oskar , Mattsson‐Carlgren Niklas
Published: June 2023

Background

Placental growth factor (PlGF) is a pro‐inflammatory marker of angiogenesis, which may play a role in cardiovascular disease and is upregulated by hyperglycemia. In non‐demented elderly, cerebrospinal fluid (CSF) PlGF is strongly associated with white matter lesions (WML), a commonly used measure of cerebrovascular disease. However, it is unclear to what degree CSF PlGF and WML provide overlapping or complementary information about pathological processes in the brain. To investigate this, we tested associations for different vascular risk factors with CSF PlGF and WML.

Methods

495 cognitively unimpaired (CU) elderly and 247 patients with mild cognitive impairment (MCI) from the Swedish BIOFINDER study were included. CSF samples were analyzed for PlGF, Aβ40 and Aβ42. Information about the vascular risk factors stroke (present in 8%), hypertension (35%), diabetes (9%), and ischemic heart disease (IHD) (10%) was collected. Associations between WML and PlGF as well as their associations with these risk factors were tested with linear regression models. Analyses were adjusted for age, gender, Aβ status, and intracranial volume.

Results

PlGF was associated with WML in the whole group (β = 0.18; CI 0.14‐0.22), and in diagnostic subgroups CU (β = 0.16; CI 0.10‐0.21) and MCI (β = 0.17; CI 0.11‐0.24). Stroke (β = 0.44; CI 0.29‐0.59) and hypertension (β = 0.12; CI 0.03‐0.20) were associated with WML, whereas diabetes (β = 0.37; CI 0.15‐0.60) was associated with PlGF. There was also a nominally significant association between WML and IHD (β = 0.15; CI 0.017‐0.29). In diagnostic subgroups, associations between stroke and WML were significant in CU (β = 0.35; CI 0.12‐0.59), and MCI (β = 0.38; CI 0.20‐0.57) after correction for multiple comparison.

Conclusion

We confirmed that PlGF is strongly associated with WML. However, PlGF and WML were differentially associated with vascular risk factors. PlGF was strongly associated with diabetes, which could indicate alterations in endothelial function, frequently seen in diabetes complications. In contrast, WML was associated with stroke and hypertension, both associated with cerebrovascular disease. This suggests that WML and PlGF contribute complementary information about vascular disease processes in the brain.
High ß‐synuclein plasma levels are coupled with amyloid PET positivity in memory clinic patients
Authors: Bluma Marina , Oeckl Patrick , Bucci Marco , Halbgebauer Steffen , Chiotis Konstantinos , Sandebring‐Matton Anna , Kivipelto Miia , Savitcheva Irina , Otto Markus , Nordberg Agneta K
Published: June 2023

Background

Synaptic dysfunction plays a key role in cognitive decline during progression of Alzheimer’s disease (AD). Higher levels of several synaptic proteins including the presynaptic protein ß‐synuclein have been measured in cerebrospinal fluid (CSF) of individuals with AD. Recently a quantitative assay using mass spectrometry allowed detection of ß‐synuclein in plasma. The aim of this study was to investigate the relationship between plasma ß‐synuclein levels and brain amyloid‐β (Aβ) plaque load in a cohort of memory clinic patients who underwent [18F]flutemetamol PET.

Method

A clinical cohort of 118 patients (age = 65.6±8.3, 65F/53M), who despite extensive clinical assessment (including neuropsychological testing, CT/MRI, CSF biomarker analysis) at the Karolinska University Hospital, Sweden had an uncertain diagnosis and were referred to [18F]flutemetamol PET, was included in this work. The diagnostic groups were as follows: mild cognitive impairment (MCI, n = 16 Aβ+, and n = 24 Aβ‐), AD (n = 53), non‐AD dementia (n = 20),no dementia (n = 5). Plasma and CSF ß‐synuclein were measured using targeted mass spectrometry and ELISA.

Result

We found a significant correlation between β‐synuclein values in plasma and CSF (p<0.001), with higher plasma β‐synuclein levels in AD (11.53±3.25pg/mL,p<0.001) compared to MCI Aβ‐ (7.74±2.63pg/mL) and non‐AD (8.18±3.00 pg/mL), and also between MCI Aβ+ (10.85±2.75pg/mL,p<0.01) in comparison to MCI Aβ‐. No significant difference was observed in plasma/CSF β‐synuclein levels between AD and MCI Aβ+. 18F‐Flutemetamol uptake positively correlated with plasma ß‐synuclein levels in the whole sample (R2 = 0.29,p<0.001) and in the MCI group (R2 = 0.26,p<0.01) (after controlling for sex and age). Individuals with comparable [18F]flutemetamol uptake values showed great variability in plasma ß‐synuclein levels. No correlation was observed between plasma ß‐synuclein and MMSE, brain atrophy, or white matter changes.

Conclusion

In a clinical cohort of patients with [18F]flutemetamol‐PET, significantly elevated ß‐synuclein in plasma mirrored the higher levels of ß‐synuclein in CSF of Aß+ individuals. In the AD continuum, plasma ß‐synuclein seemed to capture pathological processes which were more closely associated with amyloid‐pathology rather than neuronal loss or clinical stage of the disease. The variability in plasma ß‐synuclein levels of Aß+ subjects warrants further exploration of factors that might contribute to increased plasma ß‐synuclein.
Myricetin prevents high molecular weight Aβ1‐42 oligomer‐induced neurotoxicity through antioxidant effects in cell membranes and mitochondria
Authors: Kimura Atsushi Michael , Tsuji Mayumi , Teplow David B , Murakami Hidetomo , Ono Kenjiro
Published: June 2023

Background

Excessive accumulation of amyloid β‐protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer’s disease (AD). Protofibrils, one of the high‐molecular‐weight Aβ oligomers (HMW‐Aβo), are implicated to be important targets of disease modifying therapy of AD.

We previously reported that phenolic compounds such as myricetin inhibit Aβ1‐40, Aβ1‐42, and α‐synuclein aggregations, including their oligomerizations, which may exert protective effects against AD and Parkinson’s disease. The purpose of this study was to clarify the detailed mechanism of the protective effect of myricetin against the neurotoxicity of HMW‐Aβo in SH‐SY5Y cells.

Method

To assess the effect of myricetin on HMW‐Aβo‐induced oxidative stress, we systematically examined the level of membrane oxidative damage by measuring cell membrane lipid peroxidation, membrane fluidity, and cell membrane potential, and the mitochondrial oxidative damage was evaluated by mitochondrial permeability transition (MPT), mitochondrial reactive oxygen species (ROS), and manganese‐superoxide dismutase (Mn‐SOD), and adenosine triphosphate (ATP) assay in SH‐SY5Y cells.

Result

Myricetin has been found to increased cell viability by suppression of HMW‐Aβo‐induced membrane disruption in SH‐SY5Y cells, as shown in reducing membrane phospholipid peroxidation and increasing membrane fluidity and membrane resistance. Myricetin has also been found to suppress HMW‐Aβo‐induced mitochondria dysfunction, as demonstrated in decreasing MPT, Mn‐SOD, and ATP generation, raising mitochondrial membrane potential, and increasing mitochondrial‐ROS generation.

Conclusion

These results suggest that myricetin preventing HMW‐Aβo‐induced neurotoxicity through multiple antioxidant functions may be developed as a disease‐modifying agent against AD.
Skill building blocks: Asynchronous online learning through interactive thematic instruction
Authors: Brown Nancy L , Rubin Vicki de Klerk
Published: June 2023

Background

Among non‐pharmacological strategies, research shows that the Validation method (VM) developed by Naomi Feil provides a theoretical framework enabling professionals and caregivers to better understand the reasons behind the behavior of the older person with dementia. Built upon the stage‐specific communication techniques of empathy, observation, listening, and verbal and non‐verbal skills, the relationship, emotions, lived experience, values, significant relationships, social roles, sensorial, physical, social and psychological losses of the older person are taken into account. With the increased need for online learning due to COVID‐19, Validation Training Institute (VTI) designed and implemented the Skill Building Blocks, an interactive thematic video‐based instruction, to provide an interactive online learning environment to facilitate user‐friendly self‐study and real‐time access to knowledge. Thematic instruction strategy relates to the learners’ life experience which more easily increases interest and engagement in the content, strengthens knowledge retention, and enables behavioral modelling for application to the real world.

Method

To boost learning and transfer of knowledge, cognitive load theory was applied wherein tasks are divided into smaller building blocks that are individual but included among a collection of related themes. The 6 ‘on‐demand’ videos deliver asynchronous learning followed by ‘exercises’ to reinforce learning and process information. This study, based on the cognitive theory of multimedia learning, investigated the participants’ reflection and learning performance through pre and post‐questionnaires using the Likert scale of 1 through 5, and the IMMS (Instructional Material Motivation Survey) which measures attention, relevance, confidence, and satisfaction. An online focus group of participants concluded the data collection process.

Result

Learners express confidence and satisfaction with the user‐friendly, thematic design of each block that utilizes a variety of multimedia learning experiences including video, exercises, and quizzes that reinforces transfer of knowledge as well as cognitive learning. Techniques learned and practiced in each block were applicable to real life situations and could be applied immediately after each block.

Conclusion

Techniques taught through Skill Building Blocks proved to be relevant to the learners’ life experience, effective in retention and transfer of skills, and proved to be motivating for continued application in the real world.
Real‐time Neurofeedback Rewards Memory‐related Potentials in Older Brains
Authors: Liu Ziming , Jiang Yang , Zhao Xiaopeng
Published: June 2023

Background

Electroencephalogram (EEG)‐based neurofeedback (NF) allows reward of desired brain activity in milliseconds. Compared to frequency power‐based approach during resting state EEG, event‐related potentials (ERPs) based NF during a task is technically challenging because of the cost of computation over a time window. We have previously established that left‐frontal memory‐related potentials discriminate normal cognitive aging from age‐ and education‐ matched older adults with risk of mild cognitive impairment (MCI). To modulate brainwaves during working memory retrieval towards healthier patterns, we develop an ERP‐based neurofeedback protocol to reward better memory‐related potentials.

Method

The training protocol is developed based on a modified delayed match‐to‐sample task also known as Bluegrass working memory paradigm. During each memory trial, a participant holds the sample target image in his/her working memory and responds whether each subsequent image is a Match or Nonmatch to the memory target by pressing the button. Real‐time classification of extracted ERP features is analyzed after stimulus onset, the dynamic machine‐learning program then modifies the stimulus by turning it into vivid color (reward) or leaving it with black‐and‐white (unrewarded). The processing pipeline has been developed using ERPs of older adults with and without MCI. The left frontal sites (F3 and F7) were preprocessed by re‐referencing and filtering with a 0.05 – 40 Hz band‐pass filter. For each participant, the EEG of 5 offline base trials in a 300‐600ms time window was used as a baseline. The ERP difference of the baseline versus the subsequent single trial is calculated to determine whether the image will be colored or left at black‐and‐white.

Result

Our newly developed ERP‐neurofeedback protocol has succeeded in providing visual feedback based on fluctuation of single trial ERP in real time. The program was also designed to fit in each individual due to varied sensibility to NF. Currently we are to examine the feasibility and effectiveness of the proposed protocol by measuring memory indicators before and after NF training sessions.

Conclusion

We have developed a new protocol using ERP‐based neurofeedback to improve personalized memory retrieval. The program is the first step to intervention trials for enhancing successful memory by rewarding desired memory‐related potentials in older brains.
A case study on AI and robot‐assisted psychoeducational support for Alzheimer’s caregivers
Authors: Yuan Fengpei , Proctor Lauren , Blackburn Jordis , Bray Robert , Mukherjee Namrata , Bowland Sharon , Lopez Ruth Palan , Li Shuai , Zhao Xiaopeng
Published: June 2023

Background

More than 6.2 million older Americans live with Alzheimer’s disease and related dementias (AD/ADRD). Dementia care is mostly provided by family or friends. This long‐duration, time‐intensive care can negatively impact caregivers’ physical and mental health. Dementia caregivers often feel unprepared for their roles. Resources for Enhancing Alzheimer’s Caregiver Health: Offering Useful Treatments (REACH OUT) interventions have been shown to improve caregivers’ health. However, it is challenging and resource‐intensive to implement such interventions in real‐world settings. Artificial intelligence and robotics demonstrate the potential to assist delivering intervention and support caregivers.

Method

We developed a Friendly AI‐ and Robotics‐based REACH (FAIR‐REACH) program to deliver a modified version of REACH OUT using a friendly humanoid social robot, Pepper. FAIR‐REACH included five modules: introduction to AD/ADRD and caregiving, safety information, healthy lifestyle guide, stress and relaxation, and caregiving challenges. The robot delivered the program using multimodal presentation, including a touchscreen tablet, verbal and nonverbal communication. In each module, a list of topics were displayed on Pepper’s tablet for users to choose. Approaches were employed to enable Pepper to deliver interventions engagingly, interactively, and empathetically. After supplying information on the chosen topic, the robot asked users a question relevant to the content and provided a follow‐up comment. We tested FAIR‐REACH on 2 participants and used questionnaires to assess acceptance and user experience.

Result

The participants were 1 female and 1 male, both aged 65‐75. P1 previously worked as a paid in‐home caregiver. P2 currently acts as an informal caregiver. Both participants believed that FAIR‐REACH were useful for dementia caregivers. The program was perceived as easy to use. The robot’s appearance was pleasing to participants and the tablet designs (e.g., layout) were attractive to them. Participants provided suggestions on the robot’s functions, for example, speaking more slowly, talking with caregivers more interactively, and answering caregivers’ questions.

Conclusion

In the case study, the FAIR‐REACH was perceived as easy to use and helpful. The future work includes refining FAIR‐REACH to improve user experience according to the feedback/suggestions collected from the case study and assessing the feasibility, Usability, and effectiveness with a large number of dementia caregivers.
PAS‐MCI: Design and rationale for a randomized controlled trial to enhance prefrontal cortical plasticity and working memory in individuals with amnestic mild cognitive impairment
Authors: Genadry François , Ledwos Nicole , Kumar Sanjeev , Bowie Christopher R. , Daskalakis Zafiris J. , Fischer Corinne E. , Herrmann Nathan , Mulsant Benoit H. , Pollock Bruce G. , Zomorrodi Reza , Blumberger Daniel M. , Rajji Tarek K.
Published: June 2023

Amnestic Mild Cognitive Impairment (aMCI) is a prodromal stage to Alzheimer’s disease dementia (AD). Improving prefrontal cortical function in individuals with MCI could prevent progression from aMCI to AD. A key mechanism that has been linked to memory formation is cortical plasticity. Paired Associative Stimulation (PAS) is an intervention that uses transcranial magnetic stimulation (TMS) to enhance cortical plasticity. When delivered to the prefrontal cortex in individuals with AD, it has shown promise to improve prefrontal cortical plasticity and working memory.

PAS‐MCI is a randomized controlled trial (RCT) that aims to assess: (1) dorsolateral prefrontal cortex (DLPFC) plasticity in individuals with aMCI compared to cognitively unimpaired control (CU) participants, (2) the efficacy of PAS delivered for 10 days bilaterally to the DLPFC of individuals with aMCI in enhancing their DLPFC plasticity, working memory, and executive function, and (3) whether changes in DLPFC plasticity mediate changes in working memory and executive function.

100 aMCI and 50 CU control participants will be assessed clinically and cognitively, and undergo PAS combined with electroencephalography (PAS‐EEG) to characterize left DLPFC plasticity. The aMCI participants are randomized (1:1) to receive 10 daily sessions of either active or sham PAS delivered to the bilateral DLPFC. On Day 0, 7, and 28 following the PAS course, participants undergo repeat cognitive testing and PAS‐EEG to assess changes in working memory, executive function, and left DLPFC plasticity.

As of February 1st, 2022, 14 aMCI and 9 CU participants consented, of which 5 aMCI and 4 CU participants completed the study. 7 aMCI participants were excluded because of: a contraindication for TMS (n = 1), having dementia (n = 1), and having non‐amnestic MCI (n = 5); 1 withdrew due to fatigue; and 1 is pending enrollment. 3 CU participants were excluded because of low cognitive scores; 1 withdrew due to not tolerating TMS; and 1 is pending enrollment.

If successful, this RCT will establish the short‐term efficacy of PAS, a new TMS approach to enhance prefrontal cortical function in individuals with aMCI. A follow‐up longer‐term trial will be then needed to assess whether PAS could prevent cognitive decline and progression to AD.
Novel digital biomarker identification in Alzheimer’s Disease and related dementias
Authors: Wu Chao‐Yi , Cesnakova Lucy , Goldsack Jennifer C , Stefko Danielle , Kaye Jeffrey A , Au Rhoda
Published: June 2023

Background

The gold standard method for assessing the efficacy of dementia treatments, the Alzheimer’s Disease (AD) Assessment Scale‐Cognitive Subscale (ADAS‐Cog), has limitations of use based on the level of cognitive decline of a patient, the need for an in‐person evaluation, and the sampling of a time point in the patient experience. However, measuring factors associated with patient disease progression is key to not only assessing treatment efficacy, but also to predicting patient trajectory. New measures are needed to fill the gaps associated with the ADAS‐Cog, and digital tools are poised to reveal novel biomarkers of AD and related dementias (ADRD) with the added benefit of continuous measurements in a real‐world setting that give voice to patients unable to directly communicate experiences.

Method

A systematic literature review conducted globally of over two million publications is used to identify meaningful aspects of health and physiological characteristics of ADRD. In‐person interviews of patients, caregivers, clinicians, and scientists (n = 50) supplement the findings of the review and, taken together in a mixed methods approach, allow for the creation and dissemination of a survey of the larger ADRD population (n = 2500) regarding the clinical and patient‐centric value of potential measures.

Result

Previous efforts led to the creation of a database of over 300 digital endpoints used in previous and ongoing trials, including several related to ADRD and cognition (i.e., blink count, activity, acoustic/linguistic measures). The resulting list of candidate biomarkers from the mixed methods study is assessed for feasibility of digital measurement, cultural inclusivity, clinical relevance, and accuracy of representation of patient lived experience to produce an optimized set of digital biomarkers defining a meaningful aspect of health in ADRD.

Conclusion

Digital biomarker measurement, particularly in ADRD, allows for a richer, more comprehensive understanding of the patient’s lived experience, the patient’s disease progression, and the efficacy of treatments. Capturing novel digital biomarkers continuously and in a real‐world setting provides patients, caregivers, and clinicians with useful insights absent of the limitations associated with the ADAS‐Cog. This digital approach further lays the foundation for the development of patient‐centric measures acceptable to clinicians, regulators, and payers.
MAPS: Music and psychology & social connections – a protocol for a pilot dyadic intervention for caregivers and people living with younger‐onset dementia
Authors: Loi Samantha M , Cadwallader Claire , Flynn Libby , Stretton‐Smith Phoebe , Bryant Christina , Baker Felicity
Published: June 2023

Background

Younger‐onset dementia (YOD) has its onset at <65 years old, represents 5% of all dementias and affects people and their families during significant productive years of life. People living with YOD and their caregivers face unique challenges, and can feel isolated, less supported and at higher risk of depressive and anxiety symptoms. There is a scarcity of interventions for both caregivers and people with YOD. Cognitive behaviour therapy (CBT) and music therapy (MT) have evidence‐based positive effects in older adults with dementia and their caregivers, but are yet to be trialled in younger people. MT may be perceived as less threatening and motivate engagement. Social networking may also be a useful forum for sharing content and has been previously utilised in caregiver support groups.

Method

MAPS is a 7‐week manualised online group program for people living with YOD and caregiver dyads. Weekly sessions (80‐90 minutes with a break) will be co‐facilitated by a psychologist and music therapist, and will include joint sessions with both members of the dyad (sessions 1 and 6), and separate sessions for the caregivers and the people living with YOD (sessions 2 to 5). The two major themes are: 1) Dealing with the challenges and changes associated with being a caregiver/living with YOD; and 2) Finding ways to be positive and focusing on the things they value. MAPS will utilise a combination of CBT techniques and MT methods, with the production of two songs per group and “homework”. A closed, private Facebook group will be used for sharing content and resources. The major outcome measure will be improvement in Depression Anxiety and Stress Scores, using the DASS21. Focus groups for qualitative feedback will occur in the final session, 7.

Result

Pending

Conclusion

If successful this pilot has the ability to be expanded for larger outreach.
Atrophy patterns in subjects at increased risk of Alzheimer’s Disease
Authors: Liu Hangfan , Li Karl , Grothe Michel J. , Rashid Tanweer , Seshadri Sudha , Toledo Jon B. , Habes Mohamad
Published: June 2023

Background

Cognitively impaired individuals have multiple contributing conditions leading to heterogeneous atrophy patterns. Unfortunately, neuroimaging data is usually contaminated by noise, which can lead to spurious non‐clinically relevant clusters. Identification of true disease specific clusters requires techniques robust against noise.

Method

We developed an unsupervised approach named COllaborative Clustering based on Adaptive Laplace modeling (CoCAL) to simultaneously cluster individuals and features while removing noise. We derived the distributions of the coefficients produced by non‐negative matrix tri‐factorization (Fig. 1). We applied CoCAL to the PREVENT‐AD dataset, a cohort of cognitively unimpaired participants with a family history of Alzheimer’s Disease (AD). The groups clustered by CoCAL were compared by student’s t‐test with FDR correction, and each cluster is evaluated by Alzheimer’s Progression Score (APS).

Result

Experimental results on a synthetic dataset demonstrated superior clustering performance of CoCAL over several benchmark clustering methods including k‐means and conventional matrix factorization based clustering methods. On the PREVENT‐AD dataset, two clusters (G1 and G2) were identified by CoCAL (Table 1). The corresponding t‐test statistic values of regions with p‐values < 0.05 are plotted in Fig. 2. Cluster G1 showed higher APS compared to G2 (APS scores: 0.197 ± 0.0562 [G1] vs ‐0.080 ± 0.0539 [G2], p < 0.001). There were no significant differences in sex, age and APOE ε4 status between the groups.

Conclusion

When applying CoCAL to the PREVENT‐AD cohort, two distinctive atrophy patterns emerge: a parietotemporal cluster (G1) and a fronto‐occipital cluster (G2). G1 corresponds well with classic patterns of cortical atrophy in AD, and participants in this group demonstrate higher APS than G2 participants. In contrast, the greater atrophy in the frontal and occipital lobes in the G2 cluster may reflect either gray matter atrophy from vascular contributions, or the frontal variant of AD. Further investigations into the progression of these different clusters and sub‐networks within the cluster could yield insight for more targeted management of AD.
Emotional characteristics associate with fronto‐amygdala connectivity in older‐old adults: Results from I‐CONECT
Authors: Pruitt Patrick J , Yu Kexin , Lahna David , Schwartz Daniel , Peltier Scott J , Silbert Lisa C , Dodge Hiroko H
Published: June 2023

Background

Research into the emotional health of older adults, as it relates to brain network function, lags research into cognitive health, despite the importance of emotional health to quality of life. Here, we examine associations between three summary scores of emotional health from the NIH Toolbox Emotion Battery (NIHTB‐EB) – negative affect, social satisfaction, and psychological well‐being – and their associations with intrinsic brain network functional connectivity within three systems implicated in emotional function – the default mode network (DMN), salience network (SAL), and amygdala‐based connectivity.

Method

Fifty participants completed resting‐state functional magnetic resonance imaging (rs‐fMRI; 33 women, 80.7±4.4 years). We used two analytic approaches:

Seed‐to‐voxel (amygdala): We extracted timeseries from bilateral amygdalae for a voxelwise, whole‐brain analysis. Separate analyses were conducted for each NIHTB‐EB summary score.

ROI‐to‐ROI (DMN/SAL): Pairwise correlations were averaged to provide a single measure of within‐network connectivity for each network. ROI‐to‐ROI analyses were calculated in separate regression models using each NIHTB‐EB summary score to predict connectivity within each brain network.

NIHTB‐EB outcomes were generated with subscale scores weighted by factor loading. Both sets of analyses included age, sex, site, in‐scanner motion, and cognitive status (unimpaired cognition or mild cognitive impairment).

Result

Psychological well‐being associated negatively with amygdala connectivity with ventromedial prefrontal cortex (vmPFC; Fig1; peak T = ‐4.28; MNI xyz: [‐6,24,‐24]; k = 63 voxels). Conversely, negative affect associated positively with amygdala connectivity with vmPFC (Fig2; T = 4.24; [8,22,‐22]; k = 27).

NIHTB‐EB summary scores did not associate with DMN or SAL connectivity.

Conclusion

These results highlight the relevance of fronto‐amygdala connectivity in understanding emotional aging in older‐old adults. Previous research suggests that the inhibition of amygdala activity by frontal regions plays a key role in emotion regulation. In this light, diminished amygdala‐vmPFC connectivity may reflect better emotion regulation, which here associates with higher levels of psychological well‐being and lower levels of negative affect.

While research on younger adults has established the relevance of DMN and SAL connectivity to emotional health, this work suggests that these networks may not be as relevant to emotional health in the older‐old population. These results should be interpreted with caution, as they use an uncorrected voxelwise threshold (p<0.001).