bluuebunny/crossref_metadata_2025 huggingface dataset:
Demonstration of the iADRS as an integrated measure of global disease severity in early symptomatic Alzheimer’s disease using Rasch measurement theory (RMT)
Authors: Atkins Alexandra S , Marquis Sarah , Cano Stefan , Delbecque Laure , Ye Wenyu , Wessels Alette M
Published: December 2023

Background

As an outcome measure in Alzheimer’s disease (AD) clinical trials, the integrated Alzheimer’s Disease Rating Scale (iADRS) assesses the impact of cognitive loss on the ability to perform daily activities. The iADRS integrates items from the ADAS‐Cog13 and the ADCS‐iADL, providing a measure of global AD severity. The present work evaluated integration of cognitive and functional items within the iADRS using RMT, a psychometric approach that models individual items and responses on to a single measurement continuum representing a latent construct (i.e., disease severity).

Method

RMT was performed using RUMM2030 using data from the Phase 2, placebo‐controlled TRAILBLAZER‐ALZ study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD. Data from 245 participants were pooled across treatment arms and timepoints (7 timepoints over 18 months).

Result

The iADRS person separation index (PSI) was 0.89, indicating good reliability and ability to differentiate between levels of impairment. Results also indicated good item‐person targeting, with items covering the range of disease severity (mean = ‐1.27, SE = 0.67). The hierarchy of items along the iADRS measurement continuum (Figure 1) reflected observed patterns of clinical decline. Delayed episodic memory impairments preceded broader impairments in immediate memory and memory‐dependent iADLs, including talking about recent experiences (reading, television); more widespread deficits in iADL functioning (telephone use, meal preparation) emerged next, followed by multi‐domain cognitive impairments in orientation and language. While cognition (specifically memory) was impaired earlier than function, cognitive and functional items demonstrated similar rates of decline along the disease severity continuum.

Conclusion

Model fit and item placement provide support for integration of cognitive and functional items within the iADRS. Placement of items along a single continuum revealed a mixture of cognitive and functional items sensitive to impairment across the spectrum of mild symptomatic disease, and demonstrated how items work together to provide improved coverage of disease‐related impairments. The findings provide further support for the use of the iADRS in clinical trials as an integrated assessment of global disease progression in early symptomatic AD.
Examination of Genetic Risk Factors for Alzheimer’s Disease in a Cohort of Familial Longevity: the Long Life Family Study
Authors: Xicota Laura , Cheng Rong , Barral Sandra , Honig Lawrence S. , Schupf Nicole , Gu Yian , Cosentino Stephanie , Zmuda Joseph M , Perls Thomas T. , Christensen Kaare , Province Michael A , Lee Joseph H.
Published: December 2023

Background

Genetic risk factors have been explored extensively for late onset Alzheimer’s Disease (LOAD). The largest meta‐analysis GWAS studies to date (Bellenguez et al., 2022) identified 83 single nucleotide polymorphisms (SNPs) associated with LOAD in the general population. The Long Life Family Study (LLFS) is aimed to identify factors associated with familial longevity and healthy aging by examining US and Danish families. Our earlier studies have shown that LLFS families are at lower risk of several age‐related diseases, including LOAD. Here, we will: (1) compare allele frequencies and effect sizes of the identified meta‐GWAS variants against those in LLFS; and (2) assess whether a polygenic risk score (PRS) based on meta‐GWAS variants differs between LOAD vs. cognitively healthy in LLFS.

Method

We examined LLFS participants who were Non‐Hispanic Whites, had available cognitive and whole genome sequencing (WGS) (n = 4,220). Allele frequencies were estimated based on founders only. Association analyses were performed via logistic regression using Wald test and adjusting for sex, age, site, education, first principal components, and the genetic relationship matrix. PRS was calculated using a weighted formula, and to account for family structure, means for each status per family were obtained.

Result

Independent of LOAD status, 13 SNPs had significantly different allele frequencies between the two studies. Minor allele frequencies of 10 of the SNPs were lower in LLFS when compared with Bellenguez et al. When examining the relations between LOAD and the 77 available SNPs, only five variants appeared to be associated in LLFS. The direction of association differed for two of the SNPs. Lastly, estimated PRS scores did not differ by LOAD status (affected vs unaffected: ‐0.059 vs. ‐0.054, respectively).

Conclusion

Here we show that variants associated with LOAD in the general population were not necessarily associated with LOAD in in the LLFS cohort, a cohort ascertained for familial healthy aging. When estimating disease risk using genetic markers, as expected, ascertainment needs to be taken into consideration.
Predicting Brain Amyloid Status Using the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIHTB)
Authors: Cheng You , Ho Emily , Weintraub Sandra , Rentz Dorene M. , Gershon Richard C. , Das Sudeshna , Dodge Hiroko H
Published: December 2023

Background

Amyloid‐beta (Ab) plaque is a pathophysiological hallmark of Alzheimer’s disease (AD). As anti‐amyloid monoclonal antibodies enter the market, predicting brain amyloid status is critical to determine treatment eligibility. Here, we predicted brain amyloid status in the Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study using machine learning.

Methods

ARMADA, a multisite study, aimed to validate the National Institute of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in older adults with different cognitive abilities (normal, MCI, early AD dementia). We used cognition, emotion, motor, sensation scores from NIHTB, and demographics to predict amyloid status measured by PET or CSF. Each site used its own criteria to define the amyloid PET positivity (Positive for AD biomarkers, Negative, Visual reading unavailable) or CSF result (Consistent with AD, Not consistent with AD, Borderline, Indeterminate). Amyloid positivity was defined as PET being “Positive for AD biomarkers” or CSF being “Consistent with AD.” We applied LASSO and random forest models and used the area under the receiver operating curve (AUROC) to evaluate the ability to identify amyloid positivity.

Results

Of 462 ARMADA participants, 199 had either PET or CSF information (mean age 76.3 ± 7.7, 51.3% women, 42.3% some or complete college education, 50.3% graduate education, 88.9% White, 33.2% with positive AD biomarkers). The random forest model reached AUROC of 0.74 with higher specificity than sensitivity (AUROC 95% CI:0.73 – 0.76, Sensitivity 0.50, Specificity 0.88) on the held‐out test set; higher than the LASSO model (0.68 (95% CI:0.68 – 0.69)). The 10 features with the highest importance from the random forest model are: picture sequence memory, cognition total composite, cognition fluid composite, list sorting working memory, words‐in‐noise test (hearing), pattern comparison processing speed, odor identification, 2‐minutes‐walk endurance, 4‐meter walk gait speed, and picture vocabulary. Overall, our model revealed the validity of measurements in cognition, motor, and sensation domains, in associating with AD biomarkers.

Conclusion

Our results support the utilization of the NIH toolbox as an efficient and standardizable AD biomarker measurement that is better at identifying amyloid negative (i.e., high specificity) than positive (i.e., low sensitivity) cases.
Significance of a positive tau pet scan with a negative amyloid pet scan
Authors: Robinson Carling G. , Lee Jeyeon , Min Paul H , Przybelski Scott A. , Josephs Keith A , Jones David T. , Radford Jonathan Graff , Boeve Brad , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Machulda Mary M. , Fields Julie A. , Lowe Val J.
Published: December 2023

Background

The implications of a positive tau (T) Positron Emission Tomography (PET) with a negative beta amyloid (A) PET are not well understood. We investigated cognitive performance in participants who were positive on tau PET but negative on beta amyloid PET.

Method

We evaluated 98 participants from the Mayo Clinic Study of Aging (MCSA) and the Mayo Clinic Alzheimer’s Disease Research Center (ADRC) who were positive for Flortaucipir (FTP) and negative for PiB PET. Participants were classified as A‐ and T+ based on Standardized Uptake Value Ratios (SUVr) of FTP and PiB PET scans, and were matched 2:1 to amyloid negative and tau negative cognitively unimpaired controls from the MCSA. Cognitive test scores were compared between the combined ADRC/MCSA group and MCSA only group. We also examined clinical diagnoses in our cohort. The most common were Alzheimer’s Disease, mild cognitive impairment (MCI), Dementia with Lewy Bodies (DLB) and Frontotemporal dementia (FTD) amongst others.

Result

There were no significant differences in demographic features or PiB SUVr between groups. There were significant differences in APOE genotype between groups. In the combined ADRC/MCSA group, 25% of A‐T‐ and 13% of A‐T+ were APOE e4 carriers (p = 0.016), and in the MCSA only group, 27% of A‐T‐and 10% of A‐T+ were APOE e4 carriers (p = 0.010). In the combined ADRC/MCSA group, the A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini Mental Status Exam (MMSE) (p<0.001), Wechsler Memory Scale‐Revised Logical Memory I (p<0.001) and Logical Memory II (p<0.001), Auditory verbal Learning Test Delayed Recall (AVLT) (p = 0.004), Category fluency animals (p = 0.005), Category fluency vegetables (p = 0.021), Trailmaking test A (p<0.001), Trail making test B (p<0.001), Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) (p = 0.002), and Unified Parkinson’s Disease Rating Scale part III (UPDRS III) (p = 0.003). In the MCSA only group, the A‐T+ group had lower scores on Logical Memory II (p = 0.022), AVLT delated recall (p = 0.04), and WAIS‐R block design (p = 0.035) compared to the A‐T‐group.

Conclusion

Positive tau PET in the absence of beta‐amyloid positivity is associated with lower cognitive performance.
Memory retrieval activation moderates the effect of Alzheimer’s disease pathology on memory performance
Authors: Vockert Niklas , Molloy Eóin N. , Pilar Andrea Pacha , Binette Alexa Pichet , Remz Jordana , Rajah Natasha , Villeneuve Sylvia , Maass Anne
Published: December 2023

Background

Cognitive reserve (CR) is a concept explaining better than expected cognitive performance given the degree of brain disease. More specifically, as a compensation mechanism, individual differences in patterns of brain activity during fMRI tasks may explain differential susceptibility to pathological burden. CR might already manifest in early preclinical Alzheimer’s disease (AD) stages.

Method

Participants of the longitudinal PREVENT‐AD study have well‐characterized AD biomarkers via [18F]AV1451 and [18F]NAV469 PET for Aβ and tau as well as repeated MRI measurements including a memory retrieval task. Participants also completed cognitive testing with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We selected a subsample of 82 cognitively unimpaired older adults (age: 67.9 ± 4.8 years; 24 male) with (f)MRI data within 2 years of PET. PET‐ and MRI‐based ATN biomarkers were reduced to a single composite measure for AD pathological load (PL; Fig.1). We extracted mean retrieval‐related fMRI activation (hits versus correct rejections) from specific regions, comprising all task‐positive regions (pFWE < 0.05), all task‐negative regions, entorhinal cortex, precuneus, and inferior parietal cortex. Subsequently, we tested fMRI activation as a moderator variable between PL and delayed memory performance in line with the CR framework.

Result

Activation in task‐positive regions showed an interaction (moderation) effect with PL on memory performance (p = 0.033). In individuals with low retrieval activation in the task‐positive network, AD pathological load was related to poorer memory performance, whereas this association was diminished in individuals with high retrieval activation. This moderation was not significant for task‐negative regions (p = 0.104). We observed a similar interaction for tau and activity in the entorhinal cortex (p = 0.0003) as well as for Aβ and activity in the precuneus (p = 0.056) and inferior parietal cortex (p = 0.010).

Conclusion

Our results indicate that the association between early AD pathology and memory performance differs dependent on the level of fMRI activation during memory retrieval, with an attenuated effect of pathology on memory at high levels of activation. It remains open if higher activity in the retrieval network serves as a functional reserve, or whether it reflects adaptive functional changes due to early pathology.
EEG‐based Analysis Reveals Different Effective Connectivity Patterns between Healthy Controls and MCI Patients in Motion Detection Tasks
Authors: Renli Alina Brighty , Sun Boxin , Gu Ming , Li Tongtong , Kavcic Voyko , Giordani Bruno
Published: December 2023

Background

Brain connectivity has been proposed to identify people at risk for mild cognitive impairment (MCI). Existing work has mainly focused on functional connectivity which reflects the mutual dependence between brain regions. Effective connectivity, which represents the directed connectivity from one brain region to the other, is expected to provide more details on directed information flow in the brain network. The present study investigates how cognitive engagement changes the effective connectivity in the brain.

Method

Our research focuses on task‐based EEG (64‐channel), where participants were asked to perform a motion direction discrimination task. The current dataset includes 56 consensus‐diagnosed, community‐dwelling African Americans (ages 60‐90 years, 28 healthy controls (HC) and 28 MCI patients) recruited through the Wayne State Institute of Gerontology and Michigan Alzheimer’s Disease Research Center with subjective cognitive complaints.

We evaluated the effective connectivity at different time periods of the motion‐detection task across all the possible EEG region pairs using causalized convergent cross‐mapping (cCCM) of the current source density. For each task trial, the successive time periods being examined included: (I) stimulus onset to Go indication, (II) Go indication to motion‐stop, and (III) the button‐press period. For each subject, we calculated the mean, maximum and minimum of the cCCM vector for each EEG region pair and each time‐period, then selected the region pairs where the cCCM‐based effective connectivity of HC and MCI show a significant difference (p‐value<0.05).

Result

Our analysis indicated that typically, MCI participants show more active effective connectivity or need more effort from stimulus onset to Go indication and then to motion stop, but HC participants show higher maximum and minimum effective connectivity values during the button‐press period, where coherent coordination is required among many region pairs.

Conclusion

HC and MCI do show significant differences in effective connectivity during each of the three periods of a motion detection task (marked by stimulus onset, Go indication, and button‐press) over many region pairs. Our analysis provides a massive pool of possible features for future biomarker development for effective discrimination of HC and MCI.

Funding: NSF‐2032709/Li; NIH‐1R21AG046637‐01A1/Kavcic and NIH‐1R01AG054484‐01A1/Kavcic; NIH‐P30AG053760/Paulson and NIH‐P30AG072931/Paulson.
Anabolic Androgenic Steroid predisposes to the neuropathology of Alzheimer’s disease: insights from Animal model
Authors: Memudu Adejoke Elizabeth , Moses Abel O
Published: December 2023

Background

Anabolic androgenic steroids (AASs) are synthetic derivatives of testosterone use for body enhancement by athletes and its use has been abused over the years. Various studies have reported the harmful potential of AAS use, however, there is need to document its possibility as a risk factor in neuropathology of dementia. This study is to demonstrate potential of AAS as a risk factor in Alzheimer’s disease (AD) pathology by demonstrating changes in the neuro‐morphology, astrocytic proliferation and neurofibrillary tangle formation in animal model.

Method

Twenty (20) adult male Wistar rats used were divided into four groups (A‐D), treated as follows, Control (A), Olive oil as vehicle (B), oral 120mg/kg of AAS for 21days (C), and 7 days withdrawal group following 120mg/kg/ 21days of AAS intake (D). Serum was assayed for lipid peroxidation marker Malondialdehyde (MDA) and antioxidant enzyme ‐superoxide Dismutase (SOD). The prefrontal cortices were processed and stained for Nissl (chromatophilic) bodies, astrocytes immunohistochemistry and Bielschowsky stain for neurofibrillary tangles.

Result

AAS treated group has characteristic pathology of AD demonstrated by the presence of necrosis, chromatolysis, marked astrocytic proliferation and presence of neurofibrillary tangles using Bielschowsky stain along with an increase in MDA and decline in endogenous SOD activities as compared with the control and olive oil treated groups. The withdrawal group (D) had a notable or mild restoration of the neurons demonstrated by presence of few necrotic neurons, reduced reactive astrocytes (astrogliosis) proliferation, decline in MDA with an increase in SOD when compared to the AAS treated group.

Conclusion

AAS has the potential to predispose individual to the neuropathology of AD characterized by neurodegeneration, astrogliosis, neurofibrillary tangles even in the presence of endogenous antioxidant enzyme, however, upon discontinuation endogenous antioxidant enzyme level increases enabling neuro repair via mobbing off free radicals generated by AAS.
Cognitive reserve in figural and verbal memory in healthy older adults – preliminary results
Authors: Fischer Larissa , Molloy Eóin N. , Schwarck Svenja , Vockert Niklas , Hochkeppler Anne , Schumann‐Werner Beate , Büchel Anna‐Therese , Sick Florian , Kreißl Michael C. , Düzel Emrah , Maass Anne
Published: December 2023

Background

Cognitive reserve plays an important role in individual trajectories of age‐related memory decline, with education and semantic fluency representing cognitive reserve proxies (CRPs). Higher CR may attenuate well‐known effects of ageing on the brain, such as decreases in grey matter volume (GMV). We hypothesised that the known associations between age‐related GMV and cognition would be (differentially) attenuated by CRPs.

Method

We analysed 3‐Tesla T1‐weighted Multi‐Echo MPRAGE and cognitive data (Verbal Learning and Memory Test (VLMT), Rey Complex Figure Test (RCFT), and Regensburg Verbal Fluency Test (RWT)) from 51 cognitively normal adults (73.2±7.62 years, 31 male) in our new cohort established within the CRC1436 (https://sfb1436.de/). MRI data were pre‐processed and analysed using CAT12. We performed a whole‐brain linear regression to first assess age‐related reductions in GMV (covariates: sex, total intracranial volume (TIV), education), extracting mean betas for significant regions of interest (ROIs). We investigated the relationship between GMV in age‐vulnerable regions and memory using linear regressions in R (covariates: age, sex, TIV), and assessed CRPs as moderators on this relationship. Finally, we tested whether CRPs explained variance in memory performance over and above that of GMV and age. We accounted for multiple testing via Benjamini‐Hochberg‐correction.

Result

Whole brain analyses identified bilateral hippocampal GMV as negatively associated with age (Fig.1). Linear regression analyses yielded a significant positive association between bilateral hippocampal GMV and figural memory (Fig.2). However, we observed no significant moderation by CRPs on this relationship. Finally, we observed weak evidence for cognitive reserve when adjusting for GMV and age, with higher variance explained by CRPs (Table 1). Semantic fluency positively predicted a figural memory composite when adjusting for right (p = 0.006) as well as left hippocampal GMV (p = 0.014). Education positively predicted verbal memory when adjusting for right (p<0.001) as well as left hippocampal GMV (p<0.001).

Conclusion

Consistent with operational definitions, our results provide weak evidence for semantic fluency and for education as CRPs in figural and verbal memory, respectively. However, our findings are preliminary, given the future addition of more participants. Nevertheless, these results provide important first insights into cognitive reserve in this developing cohort.
Investigating the Role of the Accumulation of Depressive Symptoms for the Risk of Dementia
Authors: Klee Matthias , Bodelet Julien , Muniz‐Terrera Graciela
Published: December 2023

Background

Depressive symptoms vary over the life course and may result from a multitude of causes. With consolidating evidence about depressive symptoms as risk factor of dementia, and previous findings suggesting shared biological pathways of depression and dementia, involving e.g., inflammation, it remains unclear if depressive symptoms reflect a causal risk factor, or an early sign of dementia. We sought to explore the role of depressive symptoms accumulation over time regarding dementia incidence in old age.

Method

We applied the functional relevant life course exposure model (fRLM) to the Survey of Health Aging and Retirement in Europe (SHARE). More precisely, we modelled the accumulation of depressive symptoms, measured with the EURO‐D scale, over time utilizing functional regressions. Data from waves 2 (2006) to 8 (2020) of SHARE was used to examine the association of depressive symptoms with incident self‐report physician‐diagnosis of dementia.

Result

In total, 3,717 participants aged 65 to 70 without dementia at baseline (M [SD] age at baseline = 67.42 [1.70] years) with complete data, participation in at least 2 waves prior to dementia diagnosis or 3 waves prior to loss to follow‐up (M [SD] participation = 3.67 [0.88] waves, MD [SD] follow‐up = 8.0 [2.9] years) were included (58.7% female). Higher exposure to depressive symptoms over time was associated to higher dementia incidence (OR [95% CI] = 3.66 [1.84‐5.87]). Moreover, relevance of depressive symptoms for dementia incidence varied across time windows, suggesting differential associations of depressive symptoms to dementia risk as a function of age. Highest relevance of exposure to depressive symptoms was observed for age 72‐75, i.e., close to diagnosis (Median [SD] age at diagnosis = 76 [3.26] years).

Conclusion

While we observed an association of depressive symptoms with dementia risk, our novel approach extends on previous findings suggesting highest relevance, i.e., predictive ability of depressive symptoms close to diagnosis. Given a build‐up of pathological changes relating to dementia starting as early as two decades prior to cognitive impairment and diagnosis, this suggests depressive symptoms not to be a causal risk factor but rather an early sign or accompanying symptom of dementia.
Impact of Infection Control Measures on Effectiveness of Cognitive Stimulation Therapy
Authors: Choy Jacky Chak Pui , Wong Gloria HY
Published: December 2023

Background

People living with dementia are at higher risk of contracting and dying from SARS‐CoV‐2. Protection measures such as wearing a mask remained necessary in dementia service facilities, despite their limiting effects on communication and interactions. Their impacts on existing evidence‐based psychosocial interventions offered in these facilities, such as Cognitive Stimulation Therapy (CST), are yet unknown.

Method

Mixed‐methods study using data from a larger randomised controlled trial partially disrupted by the COVID‐19 pandemic. People with mild or moderate dementia randomised into receiving CST (n = 72) were compared with those receiving usual care (n = 72) for cognitive (ADAS‐Cog) and quality of life (QoL‐AD) changes. To investigate the impact of infection control measures on CST effectiveness, interaction effect between timing of enrolment (before vs after COVID‐19 outbreak) and intervention group was tested. Focus groups were conducted with persons with dementia who have received CST and their families (n = 22).

Result

Participants who received CST reported better quality of life (B = 4.195, F = 28.159, p <0.001) compared with those who received usual care, controlling for demographics and antidementia medications. For cognition, an interaction effect was observed (F = 4.557, p = 0.036) between timing of enrolment and group. CST maintained cognition only in groups before COVID‐19 outbreak (marginal means of ADAS‐Cog improvement: +0.453 in CST vs ‐1.465 in usual care) but not in groups after the outbreak (‐2.104 vs +0.716). Persons living with dementia and their families reported difficulties hearing, being heard, recognising and interacting with other CST group members, and reduced efforts in participation due to discomfort wearing a mask,

Conclusion

Infection control measures may reduce the cognitive benefits of CST, which may be due to their effects on speech intelligibility and other interactions in a psychosocial intervention group. In the post‐COVID era, alternative measures such as virtual CST delivered via an online meeting platform should be investigated.
Influence of Epigallocatechin gallate stabilized Gold nanoparticles in amyloid beta fibril inhibition
Authors: Subramaniyam Rajalakshmi , Balashanmugham Umamahesh
Published: December 2023

Background

A pathological Hallmark of Alzheimer’s Disease (AD) is the significant deposition of amyloid beta (Aβ) plaques in the brain. Several studies were reported to inhibit the Aβ fibrillation using nanoparticles, nanoclusters and bioconjugate nanomaterials for Alzheimer’s treatment. In recent years, natural compound (phytochemicals) have been largely used to study and identified as promising agents for the prevention and treatment of neurodegenerative diseases including AD.

Method

Gold nanoparticle with appropriate surface conjugates with higher affinity has been studied and acknowledge the interaction between Bio‐Nano interfaces. The surface covering or anchoring conjugates will play a major role in vitro and in vivo. Herein, we reported Epigallocatechin gallate (EGCG) stabilized gold nanoparticle (AuNps) were synthesised as a Aβ inhibitor.

Result

The synthesised EGCG‐AuNps Characterized using UV‐Vis Spectroscopy, DLS, XRD, SEM (EDAX) and TEM (SAED) and the biocompatibility were studied by using MTT and scratch assay. The synthesised EGCG‐AuNPs inhibiting Aβ aggregation, dissociation Aβ fibrils which lead to prevent plaque formation, which confirmed using Thioflavin T‐assay and TEM studies.

Conclusion

This work provides new insights into the synthesised AuNps as functional therapeutic agent for AD.
The impact of COVID‐19 on the quality of stroke care in people with dementia and stroke: a comparison with stroke‐only controls
Authors: Abzhandadze Tamar , Hoang Minh Tuan , Mostafaei Shayan , von Euler Mia , Xu Hong , Eriksdotter Maria , Garcia‐Ptacek Sara , Jurado Pol Grau
Published: December 2023

Background

The COVID‐19 pandemic has had a significant impact on healthcare systems worldwide, with many hospitals struggling to maintain the same level of care as before the pandemic. As a result, there is concern that the quality of stroke care for patients with dementia diagnoses may have worsened during the pandemic. Therefore, our aim was to study how the COVID‐19 pandemic has affected the quality of stroke care for patients with dementia versus without dementia after suffering a stroke.

Methods

We conducted a register‐based study, retrieving data from the Swedish Stroke Register and The Swedish registry for cognitive/dementia disorders. We included adult patients diagnosed with/without? dementia who had also suffered a stroke between 2017 and 2022. The pre‐pandemic period was defined as January 1, 2017, to February 28, 2020, while the pandemic period was defined as March 1, 2020, to September 19, 2022. The quality indicators of care were defined as care provided at specialized stroke units and assessment for rehabilitation.

Results

The study included 3205 patients with dementia and 32666 dementia‐free controls, all of whom suffered a stroke. The mean age at onset of stroke was 83 (±6.8) years for those with dementia and 74 (±15.1) years for those without. In addition, the dementia‐stroke group and stroke‐only group had 55% and 48% females, respectively. Compared to the pre‐pandemic period, a lower proportion of patients with dementia were admitted to specialized stroke units and received rehabilitation assessments during the pandemic period, with 64% versus 36% and 65% versus 36%, respectively. Additionally, a lower proportion of patients with dementia compared to stroke‐only controls were admitted to specialized stroke units (36% versus 45%) and received rehabilitation assessments (35% versus 44%) during the pandemic period.

Conclusions

Our study indicate that the COVID‐19 pandemic had a negative impact on the quality of stroke care for patients with dementia as compared to stroke‐only controls. This was evidenced by the lower proportion of patients with dementia who were admitted for care to specialized stroke units and assessed for rehabilitation during the pandemic period, compared to the pre‐pandemic period.
Brain Structure and Cognitive Dysfunction in Myotonic Dystrophy Type 2 (BraCE‐DM2)
Authors: Puwanant Araya , Flashman Laura A , Burgos‐Aguilar Carolina , Nopoulos Peggy , Craft Suzanne
Published: December 2023

Background

Myotonic dystrophy type 2 (DM2) is a pleiotropic multisystemic disease. Although progressive muscle weakness is the main symptom in DM2, almost two‐third of the patients report cognitive deficits as one of the most disabling symptoms. Emerging evidence has identified tau mis‐splicing and tangle pathology in DM2, which has prompted interest in elucidating the role of tau in DM2‐related cognitive impairment. Previous studies suggest that cerebral white matter (WM) is primarily affected in DM2. However, quantitative brain imaging studies incorporate with cognitive measures are extremely limited.

Method

3T brain MRIs were acquired in 10 adults with DM2 and 10 gender and age‐matched controls. Brain morphometry and WM integrity were assessed using T1‐MPRAGE and diffusion tensor imaging (DTI) sequences. DTI scalars, including fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and median diffusivity (MD) were compared between groups. A comprehensive battery of cognitive and behavioral measures was performed and correlated with MRI measures (Spearman’s Correlation).

Result

Of 20 participants (60% female), mean age (62.2 vs. 62.6 years) and education (16.4 vs. 17.5 years) were similar between the two groups. Compared to controls, the DM2 group showed a significant reduction in global measures of cerebral gray matter (GM) volume in both cortex and deep gray structures (mean difference, ‐0.03; p<0.01), but not the WM volume. Widespread abnormalities in DTI measures (lower FA, higher RD) were among the most robust findings in DM2 (mean differences of FA, 0.04; p<0.01 and RD, 0.00004; p<0.01), indicating that the pathology is within WM microstructures. Overall, the DM2 group scored lower than controls in all cognitive domains, particularly executive function (mean difference, ‐12.5; p = 0.04). We found a strong correlation between cerebral FA and a test of executive function (rho = 0.71, p = 0.02). Cerebral FA also showed a moderate correlation with processing speed (rho = 0.50) and apathy evaluation scale (rho = ‐0.43).

Conclusion

Our pilot data demonstrate robust differences of brain structure, explicitly measures of WM integrity and cerebral GM volume between the DM2 group vs. controls. The strong correlation between cerebral FA and executive function also supports the notion that WM integrity plays an important role in cognitive dysfunction in DM2.
Targeting ceramides in 5XFAD mice reduces amyloid plaque deposition and gliosis
Authors: Wilkerson Joseph L , Chaix Amandine , Summers Scott A , Holland William L
Published: December 2023

Background

Alzheimer’s Disease and other neurodegenerative disorders have been linked to metabolic disorders associated with aberrant lipid deposition. Sphingolipids, such as ceramides, are among the most deleterious lipids that accumulate in the AD brain. Increased ceramides have been measured in post‐mortem AD brain samples and are abundant in Aβ‐plaques. As biomarkers, ceramides in the plasma and cerebrospinal fluid correlate with AD risk. The potential of ceramide‐lowering strategies to treat or prevent AD has been underexplored. We hypothesize that ceramides are causal contributors to AD pathologies and amenable to therapeutic targeting to improve AD outcomes.

Method

To address ceramides in AD, we have targeted serine palmitoyl‐transferase (SPT), the first enzyme and rate‐limiting step in ceramide de novo synthesis, with the drug myriocin in 5XFAD mice on a regular chow diet and an obesogenic high‐fat diet. We have also generated inducible genetic models to study loss‐of‐ceramides (overexpression of the ceramide‐degrading enzyme Asah1) or gain‐of‐ceramides (overexpression of the SPT complex), specifically in neurons in the 5XFAD model. We used immunocytochemistry to assess Aβ plaque numbers and size and both astrocyte and microglial activation and numbers. Cognitive behavior was measured using a Barnes maze.

Result

5XFAD mice treated with myriocin for 17 weeks had a reduction of hippocampal ceramides. As expected, control vehicle‐treated 5XFAD mice showed a significant memory deficit during behavioral testing. Myriocin‐treated mice had significantly improved memory of the Barnes maze. Treated mice had fewer and smaller Aβ plaques and had a reduction in both astrocyte numbers and arborization in the cortex and hippocampus. Microglia were reduced in the hippocampus of treated mice. In 5XFAD mice with neuron‐specific Asah1 overexpression, Aβ plaque size and number remained unchanged compared to a 5XFAD control. However, Gfap+ astrocytes and Iba1+ microglia/monocyte activation and migration were eliminated, resulting in plaques with no associated glia and glial morphology like non‐5XFAD mice.

Conclusion

Decreasing ceramide production by myriocin treatment in 5XFAD mice reduced Aβ plaque number and size and reduced gliosis in the cortex and hippocampus. Reducing ceramides in neurons results in the abrogation of gliosis throughout the brain of a 5XFAD mouse.
Investigating ApoE4‐mediated metabolic alteration of H4 neuroglioma cells of Alzheimer’s disease
Authors: Lu Li , Kotowska Anna , Kern Stefanie , Fang Min , Rudd Timothy R. , Alexander Morgan , Scurr David , Zhu Zheying
Published: December 2023

Background

Metabolites and proteins in ApoE4‐carried H4 neuroglioma cells were analyzed to investigate the potential mechanism of the risk gene ApoE4 involved in Alzheimer’s disease (AD).

Method

Metabolomics of ApoE4‐carried and wild‐type H4 cells was performed by applying a novel workflow composed of Orbital trapping secondary ion mass spectrometry (OrbiSIMS) as a screening tool, followed by LC‐MS/MS targeted metabolomics for further confirming polar molecules. Proteins affected by ApoE4 were identified by performing LC‐MS‐based proteomics, followed by investigating the protein network and functional enrichment analysis using the STRING database.

Result

The initial OrbiSIMS approach has shown the advantages of detecting large numbers of metabolites with minimal sample preparation, small sample size and a relatively rapid analysis time, allowing 192 putatively annotated metabolites detected in our study. We found glycerophospholipid metabolism, aspartate, glutamate and alanine are the most affected pathways by ApoE4. Polar‐targeted metabolomics of LC‐MS/MS further revealed that the metabolism of taurine and hypotaurine is also affected by ApoE4. Besides, proteomics results suggest an overall metabolic process, RNA splicing process, and translation associated with ApoE4‐related AD development.

Conclusion

Our results have elucidated the metabolic alteration of H4 neuroglioma cells in the presence of ApoE4, supporting the hypothesis of the low ability of ApoE4 in transporting lipids and discovering two new potential pathways that may be involved in AD. In addition, proteomics analysis by LC‐MS further proved the ApoE4‐mediated dysfunction of nitrogen compound metabolism and RNA splicing process.
Social network typologies of Korean older adults and digital literacy differences: A latent class analysis
Authors: Park Kang‐Hyun , Park Hae Yean , Lee Hamin , Kim Mi Kyeong
Published: December 2023

Background

This study aimed to categorize older Korean adults’ social networks and analyze the characteristics and digital literacy differences among older adults according to each type.

Method

The data of 9,377 older Korean adults were analyzed using the 2020 national survey of older Koreans. Latent class analysis (LCA) was performed using the data, χ2 and variance analyses were performed to understand the characteristics of each social network type, and Scheffe post‐hoc test was performed to determine the significant differences between groups.

Result

Three social network types were derived using LCA and classified as ‘child‐centered type,’ ‘child‐friend type,’ and 'friend‐centered type.’ Results showed a statistically significant difference in digital literacy levels according to the social network types.

Conclusion

This study findings can be used to propose intervention programs and services associated with older adults’ social networks by examining the social network types of older adults and corresponding differences in digital literacy.
A Preliminary Feasibility Study on Screening Cognitive Impairment based on Multi‐Modal Biomarkers and Stacking Ensemble AI Approach
Authors: Kim Whani , Kim Jin Sung , Ko Hyun Jeong , Yun Byung Hun , Kim Yo Young , Kim Dong Han , Kwon Ui Jun , Lim Sang Kwon , Kim Bo Ri , Lee Jee Hang , Kim Geon Ha , Kim Jin Woo
Published: December 2023

Background

Early screening of cognitive impairment is crucial for patients demanding timely treatment. The need for cost‐effective, easily accessible, and accurate tools to detect cognitive decline rapidly progressed with the breakout of the COVID‐19 pandemic. In this work, we proposed a mobile‐app based cognitive assessment tool, “Alzguard‐D”, equipped with two digital biomarkers along with a cognitive task. Next, we investigated the efficacy of “Alzguard‐D” in early screening of cognitive impairment using a machine learning approach.

Method

Nine “Alzguard‐D” tasks were designed based on three biomarkers: Keystroke, speech and eye movement (Table 1; Figure 1). Total of 289 participants were recruited from the national institute of dementia, welfare center, and nursing homes. The participants first completed the Korean Mini‐Mental State Examination (K‐MMSE; 2nd Edition), then performed all tasks in “Alzguard‐D”. “Alzguard‐D” took approximately 20 to 30 minutes. The participants were then categorized to healthy control (HC; n = 241) and cognitively impaired (CI; n = 48), defined as when the scores of K‐MMSE were one standard deviation below the age, education and gender‐matched norm. Given the data, we investigated the extent in which the combination of digital biomarkers and cognitive tasks improves the screening accuracy. We used a stacking ensemble model where the first stack analyzed speech and eye movement, and the second performed the classification.

Result

The screening result confirmed that the addition of digital biomarkers collected by “Alzguard‐D” significantly improved the classification performance (p < 0.0001; sample paired t‐test). CatBoost algorithm statistically outperformed all other candidate algorithms (Bagging, Logistic Regression, LGBM, Naïve Bayes, XGBoost, Random Forest, SVM, Gradient Boosting). We then conducted an ablation study with three classifiers trained with (i) Cog+Bio, (ii) Bio and (iii) Cog. Cog+Bio achieved the highest AUC score, 0.876 (max: 0.942), followed by Bio with 0.783 (max: 0.845), then Cog with 0.677 (max: 0.726) (Figure 2).

Conclusion

A combination of cognitive and digital biomarkers significantly increased the screening performance of cognitive impairment, and employing an intermediate feature‐level ensemble approach to effectively analyze the collected multi‐modal data increased the AUC levels.
Brain pathological mechanism of weight loss preceding incident mild cognitive impairment
Authors: Chen Yaojing , Dang Mingxi , Zhang Zhanjun
Published: December 2023

Background

Weight loss in late life is associated with a higher risk of dementia and higher mortality. However, the temporal and etiological associations between weight loss and mild cognitive impairment (MCI) remain unclear.

Method

We examined 709 Alzheimer’s Disease Neuroimaging Initiative participants to investigate body mass index (BMI) trajectories preceding the progression from normal cognition to MCI (N‐t‐M progression), and to explore the association between brain pathology and BMI trajectories preceding incident MCI.

Result

During N‐t‐M progression, participants developed multiple brain pathologies, and amyloid β (Aβ) accumulation in the frontotemporal region at baseline was associated with decreased BMI (Figure 1, false discovery rate‐corrected p<0.05). For pathological changes, participants had increased accumulation of Aβ and tau, accelerated hypometabolism, and decreased gray matter volume in the brain during N‐t‐M progression. More importantly, accelerated hypometabolism (p<0.001) and gray matter atrophy (p = 0.011) were associated with a rapid decline in BMI during N‐t‐M progression.

Conclusion

These findings highlight the importance of regular monitoring of weight changes in older adults as faster BMI decline and lower BMI may be the result of brain pathology and associated with rapid progression of pathology, and provide a theoretical basis for strategies to minimize weight loss to prevent or delay MCI onset.
Detection and management of suspected infections in people with dementia: A scoping review of current practices
Authors: Ivosevic Mihaela , Waldemar Gunhild , Janbek Janet
Published: December 2023

Background

People with dementia are at increased risk for hospitalization, readmission and mortality due to infections. Timely infection detection and management is essential and is often challenged by the presence of atypical infection signs in people with dementia, difficulties in communicating their symptoms, and inadequate external support. Thus, understanding what takes place in the decision‐making processes and interventions of suspected infections is crucial to provide clarity over the best way to deliver the needed interventions.

Objective

To explore the decision‐making processes and interventions for detecting and managing suspected infections in people with dementia and involved actors and determinants. The goal was to identify existing practices and knowledge gaps to inform targeted interventions.

Methods

A scoping review was conducted through comprehensive searches of Embase and PubMed 2010‐2023, guided by research questions and predetermined inclusion (original qualitative and quantitative articles focusing on people with dementia) and exclusion criteria (palliative and end‐of‐life care). Two authors independently screened and extracted data and synthesized findings through mapping and narrative analysis.

Results

The search identified 13 933 records and 11 full‐text studies were included in the analysis. We additionally included snippets from 10 studies where parts of the findings were related to dementia. Research was mostly based on populations in the United States, followed by Sweden and the United Kingdom. Majority of research was on practices within nursing homes, and mainly concentrating on urinary and respiratory infections.

Decision‐making processes were presented in almost two thirds of the studies, with the rest being Interventions targeting healthcare staff and one targeting proxies. Interventions included decision‐support tools (computer algorithms, posters), early warning/detection systems or pathways (based on observing behavioral and physical changes in patients), a communication technique, and training/education interventions (seminars, courses, booklets).

Actors involved were dementia patients, nurses, proxies, physicians, physician assistants, and nursing and care assistants.

Conclusions

Overall, we found little attention in research towards infection detection in people with dementia, particularly outside of the nursing homes. Our findings and the highlighted knowledge gaps both inform and encourage further research which will ultimately translate into targeted interventions improving infection detection practices.
Age‐Related Enhanced BMP Signaling Elicits APOE‐Isoform Dependent Effects in IPSC Model of Alzheimer’s Disease
Authors: Linden Anne K , Affaneh Amira , Kessler John A , Peng Chian‐Yu
Published: December 2023

Background

Aging is the strongest risk factor for developing Alzheimer’s Disease (AD), and APOE is the largest genetic risk factor for developing AD. Bone morphogenic protein 4 (BMP4) expression and subsequent signaling increases 10‐fold with age and is increased in AD patients compared to age‐matched controls. Enhanced BMP signaling in aged and AD brains suggest a potential molecular cascade involved in AD pathogenesis. A potential interaction exists between increased BMP signaling across lifespan APOE expression that contribute to risk of AD.

Method

AD patient derived iPSC’s (APOE3/E4 genotype) and isogenic controls (APOE3/E3 genotype) were differentiated into astrocytes and neurons. Cells were grown for 35 days before treatment with BMP4 or vehicle for 3 days prior to fixation, protein/media collection, or preparation for single cell RNA sequencing (scRNAseq). For coculture studies, neurons and astrocytes of the same patient background were differentiated separately prior to combined plating and BMP treatment. Cocultures were in matched (APOE3/E4 neurons with APOE3/E4 astrocytes) or mismatched (APOE3/E3 neurons with APOE3/E4 astrocytes) conditions to understand the non‐cell autonomous effects of APOE genotype.

Result

Upon BMP treatment, APOE3/E4 compared to APOE3/E3 astrocytes exhibit accumulation of lipid droplets with changes in lipid composition. Increased free cholesterol levels as well as triglyceride accumulation is observed in APOE3/E4 astrocytes and is further exacerbated with BMP treatment. RNA‐sequencing analysis reveals marked decreased expression in genes related to oxidative phosphorylation and increased cholesterol synthesis and metabolism in APOE3/E4 astrocytes that is modulated by BMP treatment. In a non‐cell autonomous fashion, APOE3/E3 neurons, when paired with APOE3/E4 astrocytes, express exacerbated pTau levels and aberrant metabolic processes in a BMP‐dependent manner.

Conclusion

Our results indicate an interaction between genetic and aging factors in cellular processes relevant to AD. Enhanced BMP signaling confers aberrant lipid composition and metabolic processing in APOE3/E4 astrocytes when compared to APOE3/E3. Subsequent BMP‐dependent non‐cell autonomous effects in APOE3/E3 neurons are observed when cocultured with APOE3/E4 astrocytes. This data suggests age‐associated increase in BMP signaling may modulate APOE isoform‐dependent metabolic processes and increase risk for APOE‐mediated pathological cascades.