bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of Alzheimer’s by a Multimodal Lifestyle Protocol – Working‐mechanisms for Memory Gains: Mouse‐PAW
Authors: Alanko Vilma , Eroli Francesca , Solomon Alina , Hartmann Tobias , Kivipelto Miia , Nilsson Per , Maioli Silvia , Matton Anna
Published: December 2023

Background

The approach of changing multiple lifestyle factors simultaneously targeting different risk factors is expected to have the greatest potential in preventing or delaying the progression of dementia. Nevertheless, it is largely unidentified what are the biological working mechanism underlying the positive findings from clinical trials of multimodal lifestyle interventions.

Method

We have set up a novel protocol to study multimodal lifestyle intervention in mice. The protocol was developed to recapitulate the FINGER (NCT01041989) and MIND‐AD (NCT03249688) clinical trials. In the lifestyle Prevention of Alzheimer’s Working‐mechanisms (PAW) group, mice were given access to running wheels (voluntary exercise), Fortasyn Connect (healthy diet), and they were subjected to cognitive training in an IntelliCage (IC) environment. To separately investigate the effects of an intervention resembling vascular monitoring, a group of mice was given Atorvastatin and Enalapril mixed in the diet. Control mice were housed in normal conditions. We included 12 wild‐type female C57BL/J6 mice six‐months‐of‐age per group. The full intervention lasted for 8 weeks.

Result

The study aimed to evaluate the feasibility of this innovative housing setup that provides a lifestyle intervention for the mice. The housing setup furthermore provides diverse data for individual mice on their learning and physical activity. Definite strengths of the protocol are the minimal need for mouse handling, the possibility of group housing, and that the intervention runs fully in a homecage environment. During the intervention, the PAW group undergoes cognitive training in the form of learning the location (corner) of a bottle from which they receive water (positive reinforcement). Regardless of individual variation in learning different cognitive training paradigms, PAW mice on a group level were able to reduce the error rates (incorrect corner visits) by approximately 25% in all paradigms.

Conclusion

We constructed a way of performing multimodal lifestyle intervention in mice in a homecage environment, which provides a platform for detailed mechanistic studies. Moreover, our protocol minimizes stress due to handling and provides quantitative data for both cognitive training and exercise. The future steps involve studying animal models of cognitive decline, Alzheimer’s disease and vascular/metabolic dysfunction to assess mechanisms impacted by lifestyle change.
Geo‐Cultural Influence on Quality of Life and Activities of Daily Living in Older Adults with Alzheimer’s disease
Authors: Appleman Erica R. , Machizawa Sayaka , Stenclik Jessica , Kamat Rujvi , Iacob Andrei
Published: December 2023

Background

In addition to measures of cognition, global Alzheimer’s disease (AD) clinical trials commonly include measures to assess functional status (activities of daily living; ADLs) and quality of life (QoL) reported by participants and study partners. Most common assessments were validated with North American, White, English‐speaking populations and research suggests that these are not free from cultural and linguistic influence. ADLs and QoL may exhibit regional differences due to socioeconomic and cultural factors. It is important to understand how geo‐cultural factors influence these measures, which are often used as trial efficacy endpoints. In this study, we examined the impact of geo‐cultural region on ADCS‐MCI‐ADL and QoL‐AD when considering baseline cognitive status.

Method

This study included electronic ADCS‐MCI‐ADL, QoL‐AD, and ADAS‐Cog data from two multi‐national AD clinical trials of participants with prodromal to mild AD. Data were collected from three geo‐cultural regions: Asia (n = 688); Western Europe (WE; n = 589); and North America (NA; n = 1925). Participants were stratified into five cohorts based on ADAS‐Cog13 scores.

Result

QoL‐AD Study Partner and AD Participant scores varied significantly across geo‐cultural regions (Kruskal‐Wallis test; p<0.0001). Both study partner‐reported and participant reported QoL‐AD scores in Asia were lower than scores in NA and WE for all ADAS‐Cog13 cohorts (Dunn’s test; p<0.0001). QoL‐AD AD Participant scores in NA and WE did not differ. For participants with lower cognitive performance (ADAS‐Cog > 40th percentile), study partner‐reported QoL‐AD scores in NA were significantly higher than those in WE (Dunn’s test; p<0.05), but there was not significant difference on the participant‐reported QoL‐AD scores between these regions. ADCS‐MCI‐ADL scores were not significantly different across groups.

Conclusion

Our study found that QoL‐AD, but not ADCS‐MCI‐ADL scores differed significantly across geo‐cultural regions when considering baseline cognitive performance. Both participant and study‐partner reported QoL was lower in Asia than in WE and NA. Cross‐regional differences in QoL may also be moderated by baseline cognitive performance. Different social norms and aging expectation, healthcare resources, and trial participation may have contributed to the regional variance observed. Future studies should examine if specific constructs are more contextually dependent on the local culture.
Equating the ADAS‐Cog and MMSE to Cogstate Brief Battery scores
Authors: Barbone Jordan Mark , Khurshid Kiran , Edgar Chris J. , Maruff Paul
Published: December 2023

Background

The Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog) and Mini‐Mental State Examination (MMSE) are used as clinical outcome assessments (COAs) to investigate Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD). The Cogstate Brief Battery (CBB) is a digital assessment of psychomotor function, attention, visual learning, and working memory. Digital assessments may overcome limitations of traditional assessments but score conversions haven’t been undertaken.

Method

Data were aggregated for baseline visits from the A4, ADNI, and AXON studies. Participants included healthy/cognitively normal (HC), MCI, pre‐clinical AD, and mild AD. An equipercentile linking routine for single‐group designs, using bootstrap‐resampled standard error (SE; variability of estimated CBB scores for each COA score) and bias (mean differences of resampled results from full model) metrics, was employed to fit score distributions. Reaction time (RT; log10 ms) and accuracy (proportion correct) for each of the CBB tests and two composite accuracy (LWM) and reaction time (ATT) scores were fit to ADAS‐Cog and MMSE totals.

Result

Data for 8,878 participants were analyzed (HC = 4,021; PC = 773; MCI = 420; AD = 414; Unclassified/Mixed = 3,250). Scores ranged from 0‐39 (ADAS‐Cog13), 0‐27 (ADAS‐Cog11), and 9‐30 (MMSE). Estimates of CBB scores by COA scores showed expected associations between assessments. CBB composites for Accuracy and RT at MMSE > = 26 were estimated at approximately 0.7‐0.9 and 2.8‐2.6 respectively. SE in ADAS‐Cog and MMSE totals from CBB scores were larger for scores which reflect worse performance and were from smaller samples (accuracy: > 0.10; RT > 1.0). MMSE RT SE estimates were significantly smaller (all < 0.2) than ADAS‐Cog estimates. Results of both ADAS‐Cog versions were virtually identical.

Conclusion

Tables for converting ADAS‐Cog and MMSE totals to CBB scores will be provided. Results can be reliably converted when performance is clinically better. Lack of samples in lower performance ranges presents an issue for reliable conversion. Demonstrating how traditional COAs compare to digital assessments can aid clinical interpretation and the understanding of limitations in each assessment. Using score equating tables may help establish a robust method for exploring associations and differences between assessments and scores.
Behavioral symptoms of Alzheimer’s disease and autism spectrum disorder: Insights to guide future non‐pharmacological interventions
Authors: Rhodus Elizabeth K. , Barber Justin M , Abner Erin L , Kryscio Richard J , Nelson Peter T. , Van Eldik Linda J. J. , Jicha Gregory
Published: December 2023

Background

Many behavioral and psychiatric symptoms of dementia (BPSD) share similarities with those described in pediatric autism spectrum disorder (ASD), including anxiety, depression, and communication deficits. However, the possibility of late‐life onset of behaviors stereotypic of ASD in Alzheimer’s disease (AD) has been poorly explored. Findings of three studies are presented here to illustrate associations in behaviors between ASD and AD.

Methods

Care partners of persons with cognitive impairment (MCI or dementia) from the University of Kentucky Alzheimer’s Disease Research Center community‐based longitudinal cohort were surveyed using the Gilliam Autism Rating Scale‐2 (GARS‐2). Analyses included t‐tests, chi‐square, analysis of variance, and linear regression models to explore frequency of ASD behaviors in this cohort, and the relationship of behaviors represented in the GARS‐2 compared to behavioral categories used in AD assessment (Neuropsychiatric Inventory‐Questionnaire; NPI‐Q). Lastly, cross‐sectional postmortem neuropathological analyses compared “Autism Possible” to “Autism Unlikely” in available cases.

Results

Analyses included 142 GARS‐2 respondents. A substantial number of participants presented with ASD‐like behaviors, and those with high Autism Index scores had significantly younger age at onset (71.1±11.0 vs. 76.7±8.3; p = 0.034) and more severe cognitive impairment than those who scored in the “Autism Unlikely” range. ASD‐like behaviors were also significantly correlated with BPSD severity ratings (r = 0.47; p < 0.001). In neuropathological analyses, the two groups differed in the frontal and temporal regions, specific to tau pathology.

Conclusion

These findings suggest that ASD‐like behaviors may emerge in AD as a result of shared neurological substrates, given that such behaviors are associated with an earlier age of onset and more severe cognitive impairment. With emerging evidence linking BPSD and ASD, additional research is needed to understand shared mechanisms, as well as development of novel treatment approaches to address behavioral symptoms of AD.
Continuous associations between remote self‐administered cognitive measures and amyloid and tau PET biomarkers of Alzheimer’s disease
Authors: Boots Elizabeth A. , Frank Ryan D. , Fan Winnie Z. , Christianson Teresa J. , Karstens Aimee J. , Kremers Walter K. , Stricker John L. , Machulda Mary M. , Fields Julie A. , Hassenstab Jason J. , Graff‐Radford Jonathan , Vemuri Prashanthi , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C. , Stricker Nikki H.
Published: December 2023

Background

Easily accessible and self‐administered cognitive assessments that can aide early identification of individuals at risk for Alzheimer’s disease (AD) dementia are critical for timely intervention. Mayo Test Drive (MTD) is a remote, self‐administered, multi‐device compatible, web‐based cognitive assessment (Stricker et al., 2022). We investigated continuous associations between MTD and amyloid and tau PET biomarkers and compared the strength of association to PET biomarkers and in‐person cognitive measures.

Method

556 adults from the Mayo Clinic Study of Aging participated (mean age = 70.6; mean education = 16.0 years; 50.7% female; 97.5% white). Participants were predominantly cognitively unimpaired (95.3%; 4.7% had a consensus diagnosis of mild cognitive impairment). Participants completed (1) brain amyloid and tau PET scans, (2) in‐person neuropsychological assessment including Mayo Preclinical Alzheimer’s disease Cognitive Composite (Mayo‐PACC) and Global‐z, and (3) remote MTD comprised of the Stricker Learning Span (SLS) and the Symbols test, which are combined into an MTD composite. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers [amyloid meta‐region of interest (ROI), tau meta‐ROI, and tau entorhinal cortex (EC)‐ROI)] and composite and subtest scores from remote and in‐person measures. Davidson‐Mackinnon J‐test compared R‐squared values of models with remote versus in‐person composites.

Result

Lower performances on MTD composite and Mayo‐PACC were associated with higher amyloid meta‐ROI (p’s<.05; Table 1). MTD composite was also negatively associated with tau meta‐ROI and EC‐ROI (p’s<.05). For memory measures, SLS sum of trials was negatively associated with tau meta‐ROI (p = .01) and EC‐ROI (p<.001) with no associations between AVLT sum of trials and PET (p’s≥.06; Table 2). Among processing speed/executive function measures, worse Trails B performance was associated with higher amyloid meta‐ROI (p<.001). Symbols and Digit Symbol Coding were not associated with PET (p’s≥.29). A multivariable model with MTD explained significantly less variance (p = .04) for amyloid meta‐ROI (adjusted R‐squared = 0.165) than a multivariable model with Mayo‐PACC (adjusted R‐squared = 0.176); remote and in‐person composite measures were comparable for other associations (p’s>.05).

Conclusion

MTD is associated with continuous measures of amyloid and tau PET biomarkers of AD, demonstrating criterion validity for MTD. Several associations were comparable to relationships between gold‐standard in‐person neuropsychological tests and imaging biomarkers.
Low circulating choline levels correlate with Alzheimer’s disease pathology severity and cognitive impairment
Authors: Judd Jessica M , Winslow Wendy , Jasbi Paniz , Klein‐Seetharaman Judith , Velazquez Ramon
Published: December 2023

Background

Modifiable environmental risk factors may help reduce Alzheimer’s disease (AD) incidence. Choline plays key roles in healthy body and brain function (Blusztajn, 1998) and supplementation above the adequate daily intake (ADI) reduces AD pathology (Velazquez et al., 2019). Choline deficiency increases AD risk and pathology (Dave et al., 2023; Yuan et al., 2022). Notably, recent reports estimate that ∼90% of Americans do not reach the ADI for dietary choline (Zeisel, 2017), making it imperative to better understand the link between choline and AD risk.

Method

We obtained serum samples from severe AD (AD‐Sev; Braak stage VI), moderate AD (AD‐Mod; Braak stage IV), and healthy control (CON; < Braak stage III) subjects (n = 12/group; balanced for sex) from the Banner Sun Health Research Institute’s Brain and Body Donation Program. Cognitive test scores (Mini‐Mental State Examination (MMSE)), plaque burden, and Braak stage was characterized by Banner Sun Health. We assessed free choline, acetylcholine (ACh), and TNFα levels. Gas‐chromatography‐mass spectrometry was used to profile aqueous metabolites and short‐chain fatty acids.

Result

There were no significant group differences for post‐mortem interval (M = 3.79). We found disease associated differences, where AD‐Sev and AD‐Mod patients had lower levels of free choline and ACh, and higher levels of pro‐inflammatory cytokine TNFα, than CON. AD‐Mod showed a significant difference in all these measurements compared to AD‐Sev. Free choline and ACh were positively correlated to MMSE scores, whereas free choline and ACh levels were negatively correlated with total plaque and Braak Stage. Free choline and ACh were negatively correlated with TNFα. Metabolomics analysis revealed significant differences (p < 0.05) in the metabolisms of beta‐alanine, linoleic acid, and of taurine and hypotaurine.

Conclusion

Collectively, as free choline and ACh levels decreased, AD pathology increased. Free choline was also associated with MMSE score. Increased TNFα was observed in cases with lower choline, illustrating increased inflammation. Together, this data expands on our recent (Dave et al., 2023) and others (Yuan et al., 2022) publications, highlighting links between low choline and AD risk.
Regional dementia diagnostic intensity and healthcare use among older U.S. adults living with Alzheimer’s disease and other related dementias
Authors: Davis Matthew A.
Published: December 2023

Background

Recent studies have demonstrated that the diagnosis of Alzheimer’s disease and other related dementias (ADRD) varies across the U.S. Residing in an area of high ADRD identification may be associated with better care; yet, healthcare use according to regional ADRD diagnosis intensity has not be examined.

Method

We conducted a cross‐sectional study using a 20% sample of 2018 Fee‐For‐Service Medicare older Americans (age≥65). Diagnosis codes were to identify those who received a new ADRD diagnosis (incident cohort) and those who died with an ADRD diagnosis (decedent cohort). An established measure of ADRD diagnostic intensity across the 306 U.S. Hospital Referral Regions was used and collapsed into terciles. We constructed measures of healthcare use (e.g., outpatient visits, inpatient use) in the first year following diagnosis and the last six months of life. Measures of preventable hospitalizations among those newly diagnosed and measures on life‐prolonging treatment among ADRD decedents were also constructed. Mixed models were used to adjust for sociodemographic characteristics and comorbidity and account for clustering within region of residence.

Result

We identified 158,908 older Americans who received a new ADRD diagnosis and 97,431 ADRD decedents in 2018. The mean age of the incident ADRD cohort was 82.8 (SD = 8.0) and 85.9 (SD = 7.8) among the decedent cohort. Across both cohorts, approximately 61% were female and 83% were While older adults. In adjusted analyses among the incident cohort, the only two differences across tercile of ADRD diagnostic intensity were mean No. of home health days (from 26.4 in T1 (lowest) to 40.3 in T3 (highest), p‐value<0.001) and mean No. of inpatient days, p‐value = 0.01 (Table 1). After adjusting for differences, outpatient, inpatient, and life‐prolonging treatment did not vary across tercile of ADRD diagnostic intensity among ADRD decedents – except for mean No. of home health days, p‐value< 0.001, hospice use in the last year of life, p‐value = 0.03, and ‘other inpatient’ as a place of death, p‐value = 0.02 (Table 2 and Figure 1).

Conclusion

Across the disease course of ADRD, regional ADRD diagnostic intensity is not associated with worse healthcare (e.g., ED use, preventable hospitalization) but is associated with home healthcare and higher hospice use.
Education protects against the detrimental effect of hippocampal atrophy on episodic memory decline
Authors: LaPlume Annalise , Mellah Samira , Rajah Natasha , Belleville Sylvie
Published: December 2023

Background

Hippocampal volume loss and episodic memory decline are early signs of Alzheimer’s disease (AD). Cognitive reserve refers to individual differences that enable people to perform cognitive tasks at a higher level than expected based on their current level of neurodegeneration (Stern et al., 2020).In the current study we test the hypothesis that education, a sociobehavioural proxy of reserve, moderates the association between hippocampal atrophy and memory function in persons at preclinical stages of AD.

Method

Data from the Quebec Consortium for the early identification of Alzheimer’s disease were used (CIMAQ; Belleville et al., 2019). Sixty two older adults (38 females, 24 males; mean age = 74 years old, SD = 5.4, range = 65‐88; mean education = 15 years, SD = 3.3, range = 7‐22) were diagnosed with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Anatomical 3D‐T1‐w MRIs were collected at baseline and used to calculate hippocampal volume with FreeSurfer 5.3 (Belleville et al., 2021). A Face‐Name associative memory test was conducted at three time points: baseline, two years later, and four years later. Memory change was measured as the average individual slope (over three time points) of associative memory accuracy (correctly recognizing face‐name pairs). Analyses were conducted with using R (R Core Team, 2020).

Result

Years of education significantly moderated the effect of hippocampal volume on memory over time, β = ‐1.97 (SE = 0.93; 95% CI = ‐3.83, ‐0.11), p = .04. Hippocampal volume had a significant negative correlation with memory over time in people with lower education levels (1 SD below the mean), but not for mean levels or higher education levels (1 SD above the mean; Figure 1). A Johnson‐Neyman plot revealed that people with over 14 years of education showed resilience to the negative association of hippocampal volume loss and memory over time, while those with 14 years or below did not (Figure 2).

Conclusion

Educational attainment contributes to cognitive reserve by buffering against the detrimental effect of hippocampal atrophy on declining associative memory in preclinical AD. The current findings offer practical relevance by showing that 14 years is a threshold amount of education that confers a protective influence against memory decline.
The relationship of neuroticism to amyloid and tau pathologies in cognitively normal older adults
Authors: Bacci Julia R. , Hennessee Joseph P. , Smith Evan T. , Monier Sarah A. , Park Denise C.
Published: December 2023

Background

Prior work has shown that individuals with higher levels of neuroticism are at an increased risk of developing Alzheimer’s Disease (AD). Increasing evidence has indicated an association of increased neuroticism to increased amyloid‐beta (Aβ) and tau burdens, suggesting that this personality trait is a risk factor for increased pathological accumulations. However, the cross‐sectional nature of these studies do not offer the ability to infer causality. Here, we replicate and extend upon previous work, assessing the relationship of neuroticism to AD pathologies in 60 older adults across three time‐points.

Method

This study included 60 cognitively normal participants from the Dallas LifeSpan Brain Study, aged 50+, that completed three time‐points of cortical Aβ scanning and a baseline personality assessment. Linear regressions were used to model the relationship of neuroticism to cortical Aβ burden (n = 60) and cortical tau burden (n = 48). Utilizing linear mixed effects models, neuroticism was used to predict cortical Aβ accumulation over 7‐10 years.

Result

We found that the effects of neuroticism on AD pathologies differs by brain regions and facets of neuroticism. Most notably, increased neuroticism predicted increased global Aβ burden (p = .042) beyond the effects of baseline age, sex, education, and depressive symptoms. When we further investigated this relationship using the facets comprising the neuroticism score, only the anger‐hostility facet of neuroticism predicted increased global Aβ burden (p = .003). Regional investigations demonstrated a significant effect of neuroticism on Aβ burden in the anterior cingulate cortex (p = .028), lateral parietal cortex (p = .035), and the posterior cingulate cortex (p = .021) and a trending effect in the dorsolateral prefrontal cortex (DLPFC) (p = .054). Contrary to our hypotheses, we did not find a significant effect of neuroticism on global or regional Aβ accumulation. Tau analyses detected an effect of neuroticism on tau burden in the DLPFC (p = .03), a predetermined region of interest. Additionally, only the anger‐hostility facet of neuroticism significantly predicted global tau burden (p = .036).

Conclusion

This work demonstrates that certain regions of the brain may be at an increased risk for AD pathologies in individuals with higher neuroticism. Specific facets of neuroticism, such as anger‐hostility, may also confer additional risk for these augmented accumulations.
Cerebral amyloid angiopathy is associated with higher gray matter regional R2 relaxation rate: An ex‐vivo MRI and pathology study
Authors: Yasar Md Tahmid , Evia Arnold M , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid‐β (Aβ) protein in the walls of cortical and meningeal small vessels. CAA is common in older adults. It has been linked to intracerebral hemorrhage and cognitive decline. In this study, the association of CAA with the transverse relaxation rate R2 values was investigated in gray matter regions from a large number of community‐based older adults.

Method

Cerebral hemispheres from 802 older adults participating in four cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, and the Clinical Core of the Rush Alzheimer’s Disease Research Center (Fig. 1a) were included in this work. All hemispheres were imaged ex‐vivo using 3T MRI scanners. R2 maps were generated from multi‐echo spin‐echo images. Gray matter was segmented into 34 cortical and 8 subcortical regions. Median R2 values were obtained from each region.

Following ex‐vivo MRI, all hemispheres underwent detailed neuropathologic assessment (Fig. 1b). Evaluated neuropathologies included: CAA, Aβ plaques, neurofibrillary tangles, gross infarcts, microinfarcts, TDP‐43 pathology, hippocampal sclerosis, Lewy bodies, atherosclerosis, and arteriolosclerosis.

Multiple linear regression was conducted in each segmented gray matter region separately to test the association of the corresponding median R2 value with the global CAA score, controlling for all other neuropathologies, age at death, sex, education, postmortem interval to fixation and to imaging, and scanners. False discovery rate (FDR) was used to correct for multiple comparisons. Statistical significance was set at p<0.05.

Result

A significant positive association of median R2 with CAA pathology was found in several cortical regions of the temporal and frontal lobes as well as in subcortical structures (Fig. 2,3). No gray matter region showed lower median R2 for higher CAA score. Furthermore, we obtained similar findings when also controlling in the linear regression models for normalized regional volume and for clinical variables such as history of hypertension, diabetes, smoking, blood pressure levels, and the presence of the APOE‐ε4 allele.

Conclusion

This investigation showed that CAA is independently associated with elongated R2 in cortical regions of the temporal and frontal lobes as well as in subcortical structures.
Sharing History through Active Reminiscence and Photo‐imagery: Effect of Walking Reminiscence Therapy on Mental Health Among Older Black Adults in Gentrifying Neighborhoods
Authors: Fennell Charles T , Fuller Patrice , Aron Sophia , Wachana Ann , Kaye Jeffrey A , Croff Raina
Published: December 2023

Background

Older Black adults facing gentrification may engage less in neighborhood walking and social opportunities because of gentrification’s effect on mental health. Reminiscence therapy promotes coping which mediates negative feelings, improves mood and emotional well‐being, and improves depressive symptoms.

Method

The Sharing History Through Active Reminiscence and Photo‐Imagery (SHARP) Study integrated reminiscence with neighborhood walking. In two pilots (n = 19 healthy; n = 21 including 8 with MCI) Black adults aged >55 engaged in image‐prompted conversations about local history while walking 1‐mile 3x/week for 6 months in Portland, Oregon’s historically Black neighborhoods. At months 1, 3, and 6, surveys assessed past‐month mental health and mood. Focus groups assessed participant satisfaction with the intervention.

Result

Seventy‐five percent of participants completed all pilot measures, including all 8 with MCI. Pre/post rankings of “all,” “most,” or “a good bit” of the time (vs. “some,” “little,” or “none of the time”) in the past 4 weeks feeling downhearted/blue was maintained in Pilot 1 at 8%, but in Pilot 2 increased 0% to 10% (healthy) and decreased 13% to 0% (MCI). Feeling calm or peaceful increased in Pilot 1 67% to 83%, and in Pilot 2 60% to 80% (healthy) and 50% to 75% (MCI). Having lots of energy decreased in Pilot 1 92% to 83%, and increased in Pilot 2 70% to 80% (healthy) and 14% to 88% (MCI). In pilots combined, 93% ranked their mood “better” right after group walks and 90% ranked their mood “better” since walks began. In discussions, participants described reminiscing while walking as “joyful,” “very important,” and “something to look forward to.” Conversational reminiscence helped them “become more engaged,” “go through all their feelings” and “respond to changes in a healthy manner."

Conclusion

Reminiscence therapy, particularly when paired with walking, may be critical for developing positive coping to mediate the trauma of gentrification and improve mood among older Black adults. Group reminiscence therapy may help healthy and impaired older Black adults cope with neighborhood changes and maintain good mental health, critical for supporting other healthy behaviors like physical and social activity that may prevent cognitive decline and onset of dementia symptoms.
The impact of female reproductive period length, parity, and hormonal replacement therapy on cognitive performance
Authors: Keinert Ana A M , Bertola Laiss , Lima‐Costa Maria Fernanda , Ferri Cleusa P , Barbosa Matheus Ghossain
Published: December 2023

Background

Some evidence suggests that Alzheimer’s disease and cognitive decline are more prevalent in women and that risk factors specific to the female sex could be involved. The aim of this study is to estimate the association between the length of female reproductive period, parity, hormonal replacement therapy (HRT) and later life cognition in a large cohort of Brazilian older adults.

Method

We analyzed cross‐sectional data from 4,558 women and 3,799 men. Cognitive function was measured through a global cognitive score composed of orientation, verbal fluency, and memory tests. Age at menarche and menopause, parity and use of HRT were self‐reported. Multiple linear regression analyses were performed to identify hormone related factors associated with current cognitive functioning in women, adjusting for relevant covariates. Afterwards, we performed an analysis among men for number of children.

Result

Higher parity was associated with worse cognitive functioning (β = ‐0.01, p < 0.001), while lengthier reproductive life (β = 0.00, p = 0.001) and HRT use (β = 0.04, p = 0.023) were associated with better cognitive performance. We performed a sensitivity analysis, after dividing women into parity groups. When compared with 0 births, the group with 1‐5 had better cognition (β = 0.08, p = 0.001), while the other groups displayed no differences. After excluding nulliparous women, compared to women with 1‐5 births, women with 6‐10 (β = ‐0.1, p < 0.001) and 11+ births (β = ‐0.16, p < 0.001) had an increasingly worse cognitive performance. We also analyzed number of children data for men, which had no impact on cognition (β = ‐0.00, p = 0.688).

Conclusion

Results indicate a protective effect on cognition of longer reproductive life, HRT use and 1‐5 childbirths, when compared to being nulliparous or having 6+ births. Among men, number of children was not associated with cognitive performance. These findings indicate a positive effect of estrogen on the brain, unrelated to current offspring. This effect might be mitigated by frequent pregnancies, but a smaller number of childbirths may not be enough to exert an impact, while bringing positive psychological effects that are protective for cognition.
Design and application of a game‐based WeChat mini‐program for screening cognitive impairments in Chinese older adults
Authors: Wu Jingnan , Chen Nan , Xia Huanhuan , Wang Ziming , Li Yatian
Published: December 2023

Background

Early screening for mild cognitive impairment (MCI) is the key method to prevent and delay dementia. Digital screening tools are more efficient than traditional paper‐and‐pencil cognitive assessments, and gamified versions would promote engagement and completion rates. We introduced here the design and development of the Game‐based Cognitive Assessment ‐ 3 Minute Version (G3) WeChat mini‐program for MCI screening in Chinese older adults.

Method

G3 is a battery of three one‐minute digital games built within the WeChat platform. Developed based on the cognitive paradigm and classic neuropsychological tests such as Trail Making Test (TMT), the Silhouettes test, the Brief Visuospatial Memory Test‐Revised (BVMT‐R) test, and California Card Sorting Tests (CCST), the G3 mini‐games, “Number Ordering”, “Species Sorting”, and “Gold finding” would measure the computational and executive function, abstractive function and visual perception, memory, and attention, respectively. In each game, the difficulty will be automatically adjusted according to performance. G3 integrates users’ game scores, age, gender, and education levels, to generate a comprehensive assessment of cognitive function with results of the six cognitive domains (Figure 2).

Result

As of August 31, 2022, more than 11 million users have completed G3 tests, 85.38% of them are aged under 40, and 2.05% of them are aged over 60 (Figure 3). Although people in all age groups have desired to know their cognitive function, the number of users decreased as people aged. Among users aged 40‐70, more females than males participated in G3 games, indicating middle‐aged and older women paid more attention to cognitive function. Among users over 45 years old, those of lower education levels (primary school or no education), middle levels (middle or high school), and university degrees accounted for 2.93%, 32.4%, and 59.65% respectively. The completion rate of users aged over 45 is 92.28%, and those over 80 years exceeded 86%.

Conclusion

The G3 was a battery of three novel 1‐minute game‐based digital cognitive tests. The process is simple, efficient, and interesting. It is a promising tool for self‐administering, advancing large‐scale community screening, and social education for MCI in Chinese older adults, warranting further clinical trials to validate its feasibility, sensitivity, and diagnostic value.
Modulating amyloid‐beta proteostasis in the brain of 5xFAD mice by selective expression of angiotensin converting enzyme in microglia
Authors: Gomez Andrew , Wu Shaogen , Byun Hyae Ran , Muro Alek , Muhammad AKM Ghulam , Li Lin , Tourtellotte Warren G
Published: December 2023

Background

Alzheimer’s Disease (AD) is a common and progressive neurodegenerative disease characterized by abnormalities in amyloid‐beta (Ab) proteostasis in the brain. Abnormal cleavage of Ab and aggregation into extracellular amyloid‐containing plaques is widely believed to contribute to neuroinflammation, synapse loss and neurotoxicity in AD. Microglia are brain‐resident myeloid‐lineage cells that mediate synapse homeostasis and the immune response to Ab deposition in the brain, and many Genome‐Wide Association Studies (GWAS) have identified late‐onset AD (LOAD) risk‐associated genes that are primarily expressed in microglia, suggesting their important role in disease pathogenesis (Kunkle et al., 2019, Wightman et al. 2021). Identifying signaling pathways in microglia that modulate Ab proteostasis may provide important targets for disease therapy.

Method

The gene encoding for Angiotensin Converting Enzyme (ACE) has been identified as an AD risk‐associated gene (Kunkle et al., 2019, Wightman et al, 2021), and ACE modulates the function of myeloid‐lineage cells, such as neutrophils and macrophages. ACE expression in macrophages appears to modulate their ability to decrease Ab plaque load in the brain and reverse cognitive abnormalities in AD model mice. Here, we developed a novel mouse model to express ACE specifically in microglia (RACE). We mated RACE mice to 5xFAD mice and examined the role of ACE expression in microglia using molecular, physiologic and behavioral techniques. Single nucleus RNA sequencing (10x Genomics) and digital spatial profiling on tissues sections (Nanostring GeoMx) was used to identify gene expression modulated by ACE in microglia.

Result

We find that ACE expression in microglia in 5xFAD mice increases amyloid phagocytosis, reduces plaque burden, rescues synapse and neuron loss, enhances microglial recruitment to plaques, rescues learning and memory deficits, and modulates gene expression associated with injury and autophagy in plaque‐associated microglia. Single‐nucleus RNA sequencing, proteomic profiling, synaptic plasticity, and pharmacological studies are in process to interrogate the molecular basis of ACE function in microglia.

Conclusion

ACE expression in microglia has the remarkable capacity to restore Ab proteostasis, rescue synapse and neuron loss, and learning and memory abnormalities in 5xFAD mice. Signaling pathways and gene expression modulated by ACE in microglia may be targets for novel disease therapy.
APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow
Authors: Kapoor Arunima , Dutt Shubir , Alitin John Paul M , Jang Jung Yun , Gaubert Aimée , Nguyen Amy , Sible Isabel J , Marshall Anisa J , Shenasa Fatemah , Engstrom Allie , Bradford David , Rodgers Kathleen E. , Shao Xingfeng , Wang Danny J.J. , Nation Daniel A.
Published: December 2023

Background

Perivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.

Method

Independently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.

Result

After accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.

Conclusion

These findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.
Interrogating CD33 exon‐2 skipping in iPSC‐derived microglia
Authors: Murchison Angela , Schmid Benjamin , Liu Jihua , Covarrubias Stephanie , Holst Bjørn , Cribbs David H. , Poon Wayne W.
Published: December 2023

Background

AD Genome‐wide association studies (AD‐GWAS) of late‐onset AD (LOAD) have identified single nucleotide polymorphisms (SNPs) within genes predominantly expressed in microglia (TREM2, TYROBP, CD33, CR1, PILRA, PLCG2, INPP5D, BIN1, MS4 gene family) or upregulated in microglia in association with disease (APOE, TREM2); these risk SNPs can either confer increased or decreased AD risk and implicate microglia function and neuroimmune mechanisms in disease etiology. One identified AD GWAS risk SNP is closely associated with the CD33 gene, confers protection, but is in linkage disequilibrium with rs12459419. The rs12459419 SNP is located at the 5′ intron‐exon junction of CD33 exon 2 and promotes exon skipping during CD33 pre‐mRNA splicing in microglia. Exon 2 skipping removes the immunoglobulin domain from full‐length CD33 (CD33M) leading to a truncated isoform (CD33‐D2).

Method

Here, we generated exon‐2 deleted iPSCs (CD33Delta2/Delta2) from three patient iPSCs (CD33C/C) in order to investigate the impact of exon‐2 skipping on microglia function. These iPSC lines were differentiated to microglia in order to determine the mechanistic impact of exon‐2 skipping on microglia function.

Result

Exon‐2 skipping results in a microglia signature identified in the ex vivo brain.

Conclusion

The interferon microglia signature may be indicative of a protective microglia phenotype that mitigates AD risk
Non‐imaging measures to predict variability in white matter changes relevant to VCID
Authors: Raghavan Sheelakumari , Przybelski Scott A. , Lesnick Timothy G. , Reid Robert I. , Fought Angela J. , Gebre Robel K , Algeciras‐Schimnich Alicia , Machulda Mary M. , Vassilaki Maria , Knopman David S. , Jack Clifford R. , Petersen Ron , Graff‐Radford Jonathan , Vemuri Prashanthi
Published: December 2023

Background

Small vessel disease (SVD) is a common vascular contributor to cognitive impairment and dementia. In this work, we evaluated and compared non‐imaging measures that can predict variability in SVD related white matter (WM) damage in a population‐based sample.

Method

We identified 752 participants in the population‐based sample of Mayo Clinic Study of Aging (≥50 years of age), who had at least 2 diffusion tensor imaging (DTI) scans and white matter hyperintensity (WMH) assessments along with baseline demographics, systemic vascular health, lifestyle, motor impairment, behavioral symptoms, and plasma markers (Summarized in Figure 1). We computed the WM markers of SVD: fractional anisotropy of genu of the corpus callosum (Genu‐FA) representative of early WM changes, WMH representative of late WM changes, and Vascular WM score (combination of Genu‐FA and WMH). Using all available data, we fit linear mixed effect models and evaluated predictors of WM markers by considering each category of features independently (with demographics) as well as by combining all categories of features

Result

Plasma, gait, systemic vascular, and life‐style measures were significant predictors of all three WM markers of SVD (Figure 2). The predictors of early and late WM slightly differed such that there were no additional significant contributions from behavioral and plasma measures to Genu‐FA. In the final composite models shown in Table 1, higher gait speed, lower number of cardiovascular and metabolic conditions (CMC) and lower Unified Parkinson’s disease rating scale scores were associated with better Genu‐FA whereas higher CMC, Beck Anxiety Inventory scores (BAI), and glial acidic protein (GFAP) levels were associated with higher burden of WMH.

Conclusion

Our observations evaluated the non‐imaging markers of greater WM damage that are relevant to vascular contributions to cognitive impairment to dementia (VCID). We found that in addition to higher vascular risk, worse plasma GFAP, gait measures, and BAI scores were predictors of greater WM damage. Some non‐imaging markers were more associated with early WM changes and others with late WM changes.
Mitochondrial DNA copy number predicts dementia risk with early mobility impairment
Authors: Tian Qu , Zweibaum David , Qian Yong , Pilling Luke , Casanova Francesco , Atkins Janice L , Melzer David , Ding Jun , Ferrucci Luigi
Published: December 2023

Background

Mobility impairment precedes Alzheimer’s disease (AD) and dementia. Potential mechanisms may involve mitochondrial dysfunction which is a hallmark of aging and links to both mobility impairment and brain health. In this study, we aimed to determine whether mitochondrial DNA copy number (mtDNA‐CN), a blood‐based marker related to mitochondrial function, would predict future dementia with and without the presence of early mobility impairment.

Method

In the UK Biobank, we estimated mtDNA‐CN using fastMitoCalc from complete Whole Genome Sequencing data at study entry. Dementia diagnoses were ascertained from medical records, including AD and non‐AD dementia. Early mobility impairment was defined as having slow walking pace by self‐report at study entry. The absence of mobility impairment was defined as having steady average or brisk walking pace. In participants who were free of dementia at study entry, we examined the association between mtDNA‐CN and future dementia with and without early mobility impairment using cox proportional hazard models, adjusted for age, sex, ethnicity, body mass index, apolipoprotein ε4 carrier status, assessment center, and technical covariates related to mtDNA‐CN.

Result

Among 188,706 participants (mean age = 56±8 years, 55% women, 94% White), 13,821 reported slow walking pace at study entry and 2,564 developed dementia (1,085 AD, 1,479 non‐AD dementia) over a mean follow‐up of 12.5 years. After covariate adjustment, each standard deviation higher mtDNA‐CN (i.e. 16) was marginally associated with a lower risk of any dementia (HR = 0.96, 95%CI: 0.91‐1.00, p = 0.063). Among those who reported slow walking pace at study entry, each standard deviation higher mtDNA‐CN was associated with a 12% lower risk of developing any dementia (HR = 0.88, 95%CI: 0.783‐0.991, p = 0.034). There was a trend toward significance for non‐AD dementia (HR = 0.87, 95%CI: 0.754‐1.01, p = 0.065), and not for AD dementia (HR = 0.89, 95% CI: 0.727‐1.09, p = 0.245). Among those without early mobility impairment, mtDNA‐CN was not significantly associated with dementia (HR = 0.97, 95%CI: 0.92‐1.02, p = 0.176).

Conclusion

In a large sample of community‐dwelling adults, higher mtDNA‐CN is associated with a lower risk of developing dementia especially accompanied by early mobility impairment. Maintaining mitochondrial function in aging may protect against dementia that is preceded by mobility impairment.
Cognitive stimulation for people with dementia in nursing homes: results of a feasibility study examining a new 24/7 approach (CogStim24)
Authors: Seven Ümran Sema , Folkerts Ann‐Kristin , Guicheteau Julie , Dichter Martin , Köpke Sascha , Kalbe Elke
Published: December 2023

Background

Cognitive stimulation is known to be effective to enhance global cognition and quality of life in PwD, so far there is a clear undersupply with this intervention which is typically provided in guided small groups.

Aim

To assess the feasibility of a new continuous 24/7 cognitive stimulation program (CogStim24) based on a process evaluation and to examine possible effects of CogStim24 on the primary outcome global cognition in people with dementia (PwD) and secondary outcomes including quality of life, behavioral and psychiatric symptoms in PwD as well as work‐related quality of life and stress experiences of nursing and care staff.

Methods

The CogStim24 program is a complex intervention which was developed to be conducted as an everyday intervention during routine care, and includes cognitively stimulating techniques, e.g., based on reminiscence therapy, multisensory stimulation, and physical activity. In four nursing homes, N = 20 nursing and care staff took part in the 11‐week CogStim24 training program. The intervention was conducted to N = 40 PwD. (Neuro)Psychological assessments was conducted pre‐ and after‐staff training, as well as after a 6‐week implementation phase. A process evaluation will be performed.

Results

The staff training and the intervention were demonstrated to be feasible in the context of a nursing home. Currently, the implementation process is evaluated and an efficacy analysis is performed.

Discussion

The study has the potential to serve as a basis for a large multicenter cluster randomized controlled trial. The interdisciplinarity and the mixed‐methods approach will help to generate detailed information on practicability and mechanisms of impact. This is important for the further development of the intervention as well as for facilitating the implementation of the intervention. PwD and nursing home staff are involved in all relevant steps of program development and evaluation. The CogStim24 24/7 approach has the potential to reach many more PwD, including those who are bedridden.