bluuebunny/crossref_metadata_2025 huggingface dataset:
Loneliness and cognitive decline in the community: Examining demographic and APOE4 status differences
Authors: Desai Pankaja , Krueger Kristin R , de Leon Carlos Mendes , Wilson Robert S. , Rajan Kumar B , Evans Denis A
Published: June 2023

Background

Limited information exists regarding patterns of loneliness and relationships among subgroups of older adults in the community. We evaluated demographic and APOE4 status differences in associations between loneliness and cognitive decline in older adults.

Method

Participants (N = 7,696) were selected from the Chicago Health and Aging Project (CHAP), a longitudinal population‐based study, who completed at least two measurement time points of neuropsychological testing, including individual tests of episodic memory, perceptual speed, and the Mini‐Mental State Examination (MMSE). The mean of individual test scores was taken to calculate composite global cognitive function. Loneliness was measured using an item from the Center for Epidemiologic Studies‐Depression Scale (modified). Mixed effects regression models evaluated associations between loneliness and decline in global cognitive function and individual tests, by race, sex, and APOE4 (one or more copies of e4 allele (any) vs. none). Modeling included adjustments such as sex, race, age, education, chronic conditions, cognitive activities, statin prescription, and interactions with time for each.

Result

A higher percentage of participants that were female (74% vs. 61%), African American compared to Non‐Hispanic White (72% vs. 63%), with older mean age (74 vs. 72 years) reported loneliness. The prevalence of loneliness was similar across APOE4 status. The interaction/ synergy of loneliness with time had statistically significant associations with global cognition (β = ‐0.010, p = 0.005), episodic memory (β = ‐0.010, p = 0.017), and MMSE (β = ‐0.015, p = 0.000) for women. This interaction was statistically significant in associations with global cognition (β = ‐0.012, p = 0.001), episodic memory (β = ‐0.011, p = 0.012), and MMSE (β = ‐0.018, p = 0.000) among African American participants. This interaction also showed the following statistically significant associations by APOE4 status: any (β = ‐0.012, p = 0.034) and none (β = ‐0.007, p = 0.049) for global cognition, none (β = ‐0.009, p = 0.039) for episodic memory, and any (β = ‐0.017, p = 0.009) and none (β = ‐0.011, p = 0.004) for MMSE.

Conclusion

Loneliness is differentially associated with global cognitive decline based on race and sex but not APOE4 status. More research is needed to understand relationships between loneliness and biological mechanisms and how to best account for demographic characteristics when intervening on loneliness.
Developing and evaluating a formal care decision‐making intervention for African American parent‐adult daughter dementia dyads: A mixed‐methods study
Authors: Johnson Kalisha Bonds , Monin Joan , Daniel Gaea , Powell Wizdom , Lyons Karen S. , Hepburn Kenneth
Published: June 2023

Background

African American older adults are suggested to be two times more likely to develop Alzheimer’s disease and related dementias (ADRD) compared to non‐Latinx White older adults. As a result, there is a need for more African American caregivers. The largest group of caregivers of African American persons living with ADRD, African American adult daughters, must navigate decision making related to formal care. Formal care—paid health care services for older adults usually associated with an institution— is important in the treatment of ADRD and maintaining quality of life.

Method

Guided by the NIA Health Disparities Research Framework, Black Family Social‐Ecological Context Model, and Superwoman Schema, this presentation will describe a clinical trial that is designing a culturally tailored prototype intervention to support the formal care decision‐making process for African American persons living with ADRD and evaluating the feasibility and efficacy of the prototype intervention. The prototype intervention focuses on both members of the dyad’s quality of life as well as formal care utilization by the African American person living with ADRD. The design process will recruit 76 African American dementia dyads (70 dyads for quantitative and qualitative data collection to aid in the development of the prototype intervention and 6 dyads to use design thinking approaches to develop the prototype intervention) and will be tested with 20 African American dementia dyads using a pretest posttest design with two follow ups at 1 month and 3 months post intervention.

Result

Data will be presented regarding factors influencing the feasibility of implementing a dyadic intervention as an early‐stage investigator. We will focus on the planning process (e.g., IRB approval, study setup, and project management), recruitment strategies (e.g., recruitment videos), recruitment challenges (e.g., consent and eligibility), and mutual engagement of both members of the dyad.

Conclusion

In the early stages of planning and recruitment of dementia dyads, there are challenges and key strategies to consider when conducting a dyadic clinical trial as an early‐stage investigator.
Predicting change in semantic fluency performance over time in patients with progressive speech and language disorders
Authors: Meade Gabriela , Martin Peter R. , Clark Heather M , Duffy Joseph R , Whitwell Jennifer L , Josephs Keith A , Utianski Rene L
Published: June 2023

Background

The semantic fluency task involves naming as many items as possible in a given category (e.g., animals) in one minute. It is often interpreted as a measure of word retrieval, but also draws on executive function abilities to organize responses and develop task‐specific strategies. Indeed, both language skills and dementia severity ratings have recently been found to correlate with semantic fluency performance in patients with primary progressive aphasia (Riello et al., 2022; Scheffel et al., 2021). Here, we focused instead on how performance on language and executive function measures predicts longitudinal change in semantic fluency performance in patients with progressive agrammatic aphasia and/or apraxia of speech (AOS).

Method

Patients with isolated agrammatic aphasia (n = 10), isolated AOS (n = 42), or a combination of the two (n = 59) with 1‐7 visits (mean = 2.19) were included. We used Bayesian hierarchical linear models to investigate whether baseline measures of executive function or language were associated with the rate at which semantic fluency performance changes over time while accounting for baseline diagnosis group, sex, education, age at baseline, and baseline disease duration.

Result

Semantic fluency performance declined over time, at a similar rate irrespective of diagnostic group (isolated or combined aphasia or AOS; Figure 1). Across all patients, higher executive function abilities at baseline, as indicated by faster Trails Making Test B completion times, predicted higher baseline semantic fluency performance and also a steeper annual rate of decline (Figure 2). Similarly, higher fluency ratings during the Western Aphasia Battery‐Revised picture description at baseline were associated with higher baseline semantic fluency performance and faster decline. Baseline performance on the Boston Naming Test and Token Test were also associated with baseline semantic fluency, but not with longitudinal change.

Conclusion

These results better delineate how language and executive function abilities support performance in the semantic fluency task. Higher abilities in those areas at baseline do not appear to be protective over time. Rather, the differences in semantic fluency that are present at baseline disappear as the disease progresses.
The influence of age on cognitive test performance as measured by the original and extended version of the Alzheimer’s disease assessment scale in the SIU longitudinal cognitive aging study
Authors: Agamah Alikem Miriam , Zec Ronald F , Kohlrus Stephanie R. , Ala Tom , Hollinshead Madison G. , Bakir Danah , Porter Nicholas , Unnam Pavani , Chaulagain Suchana , Hascup Erin R. , Trivedi Mehul Alkesh
Published: June 2023

Background

Since the 1980s, the Alzheimer’s Disease Assessment Scale (ADAS) has been used to evaluate cognitive aging in Alzheimer’s disease (AD) and is considered the gold standard for assessing the efficacy of medications for treatment of AD. One criticism of the original ADAS (oADAS) is that this measure is not sensitive to pre‐dementia syndromes such as mild cognitive impairment (MCI). Previous studies have found that increasing age is associated with poorer neuropsychological functioning. In the present study, we examined the influence of age on the oADAS. We hypothesized that increasing age would be associated with increased error scores on both the oADAS and an extended version of this measure (eADAS) after controlling for gender and education.

Method

We included data from 938 adults who were enrolled in the SIU Longitudinal Cognitive Aging Study (LCAS) as normal controls. The vast majority of the cohort was White/Not‐Hispanic (98.9%) and female (72.4%). Mean age and education were 67.3 years and 14.9 years, respectively. Participants who met the diagnostic criteria for MCI, dementia, and/or other neurological or psychiatric conditions at baseline or developed these conditions within three consecutive study visits were excluded. The oADAS was administered using standardized methods. The eADAS included short‐delay recall and recognition trials for the first word‐list, a short‐delay true‐false word recognition trial for the second word‐list, a letter‐digit timed psychomotor test, supermarket fluency, spontaneous clock drawing, three additional items to the object naming subtest, three additional figures to copy, and a similarities test.

Result

The mean oADAS and eADAS scores were 3.9 and 8.7, respectively. Linear regression analysis revealed that both gender and education were associated with higher error scores for both the oADAS and eADAS (p < 0.001). After controlling for gender and education, increasing age was also found to be associated with higher error scores for both the oADAS and eADAS (p < 0.001).

Conclusion

Our results are consistent with previous literature showing age effects on oADAS scores and also extend these findings to the eADAS. Future research determining the sensitivity of the extended ADAS to the transition from normal aging to MCI and dementia are ongoing.
Comparison of skin carotenoid content scores and dietary intake between cognitively normal older adults and older adults with Alzheimer’s Disease: A matched‐pair analysis
Authors: Keller Jessica E , Taylor Matthew K , Smith Aaron N. , Burns Jeffrey M. , Swerdlow Russell H , Sullivan Debra K
Published: June 2023

Background

Alzheimer’s Disease (AD) is a systemic metabolic disease with a variable number and type of clinical symptoms mostly impacting the brain. Skin carotenoid content (SCC) is an objective measure of carotenoid‐containing fruit and vegetable intake that has been validated in diverse populations. Our previous findings suggest SCC scores are impacted by various metabolic disease states. Therefore, our objective was to analyze SCC scores and dietary intake across matched pairs including unimpaired adults and those with AD.

Method

Baseline data from two dietary interventions (NCT03860792, NCT03841539) were analyzed. Pairs are exact matches for sex, race/ethnicity, and education and are matched within two years of age and 4 kg/m2 body mass index. Each pair (n = 12 pairs) includes one cognitively normal (MMSE > 25), community dwelling older adult (‘CN’) and one community dwelling older adult with AD (‘AD’). Baseline self‐reported dietary intake data (3‐day food records) were collected, reviewed, and entered into the Nutrition Data System for Research (NDSR 2019) database by a Registered Dietitian. SCC scores were collected through pressure‐mediated reflection spectroscopy via VeggieMeter® (Longevity Link Corporation, Holladay, UT). Two‐sample independent t‐tests assuming unequal variances were used to compare differences in SCC scores and dietary intake. Significance was set at p = 0.05.

Result

There was a significant difference in SCC scores between matched pairs (SCC scores: CN 284.25, AD 207.67, p = 0.008). There was no difference between pairs for total daily energy (kcal/day; p = 0.60), fat (g/day; p = 0.91), carbohydrate (g/day; p = 0.85), or protein (g/day; p = 0.26) intake. Both groups had similar food group intake (p‐value range 0.09‐0.79), including all fruit and vegetable groups except CN had higher intake of non‐citrus fruit (p = 0.046). Total fruit (p = 0.09) and fruit plus vegetable (p = 0.24) were not different between pairs. Dietary intake by individual carotenoid was not significantly different (total vitamin A, p = 0.48; beta‐carotene, p = 0.49; alpha‐carotene, p = 0.57; beta‐cryptoxanthin, p = 0.60; lutein plus zeaxanthin, p = 0.07; lycopene, p = 0.37).

Conclusion

Individuals with AD have lower carotenoid skin content compared to matched cognitively unimpaired individuals. These differences are not explained by differences in diet suggesting that AD may be associated with disease‐associated biochemical features that are metabolism‐related and not limited to the brain.
A multianalyte plasma protein signature associated with cognitive function in a healthy ageing population
Authors: Mehta Kanika , Gupta Veer Bala , Mohebbi Mohammadreza , Pasco Julie A , Williams Lana J , Walder Ken , Ng Boon
Published: June 2023

Background

Several studies have been conducted towards the identification of biomarkers for Alzheimer’s disease (AD); however, there are limited biomarker studies investigating the preclinical phase prior to the incidence of AD. The present study aims to identify a multianalyte panel of blood biomarkers associated with overall cognitive function in a healthy ageing male population.

Method

A multiple reaction monitoring (MRM)‐based targeted proteomic analysis was conducted using plasma samples of 448 male participants. The abundance levels of 269 plasma proteins known to participate in several physiological processes such as lipid transport, oxidative stress, inflammation, cytoskeleton signalling and complement pathway were measured. Protein concentration values outside the limit of quantitation were assigned as missing and proteins with greater than 10% missing values were removed from the analysis. Consequently, 125 proteins were included in the statistical analysis. In order to build a multimarker model, the least absolute shrinkage and selection operator (LASSO) regression analysis was conducted. This was followed by pathway mapping of the proteins selected by the model.

Result

Preliminary analysis revealed a 12‐marker model (R‐squared = 32%) comprising age and the following proteins: Apolipoprotein A‐I, Apolipoprotein C‐I, Alpha‐1‐acid glycoprotein 1, Carboxypeptidase N catalytic chain, Coagulation factor XI, Complement C1q subcomponent subunit B, Glutathione peroxidase 3, Neuropilin‐2, Insulin‐like growth factor‐binding protein complex acid labile subunit, Protein AMBP and Lysozyme C.

Conclusion

A multianalyte panel consisting of plasma proteins was built for predicting cognitive function using cross‐sectional analysis methods. Furthermore, to predict long‐term cognitive changes, follow‐up assessments will be required.
Long‐COVID causal impacts on cognitive ability of mild‐cognitive impaired population from large‐scale electronic health record using heterogeneous causal effect model
Authors: Alam Mohammad Arif Ul , Mahi Atqiya Munawara , Rahman Md Mahmudur , Alam Saima , Nunes Anthony
Published: June 2023

Background

Identification of long‐COVID impacts on human cognitive ability is important but Randomized Controlled Trial (RCT) is not possible. Virtual RCT (VRCT) can be done from electronic health record (EHR) which requires to address heterogeneity appropriately.

Method

We design new method for VRCT on COVID intervention among Mild Cognitive Impaired (MCI) population. We select patients (n = 71,900) from National COVID Cohort Collaborative (N3C) data who meet our inclusion criteria (Table‐1 and Table‐2). We compute 28 Cognitive Impairment (CI)‐related covariates (Table‐3). Final outcome is CI and COVID‐19 diagnosis is intervention. To formulate a placebo like intervention virtually, we compute covariates: (i) For COVID positive patients, consider pre‐COVID histories, (ii) For Non‐COVID having transition MCI‐to‐CI, consider 6 months before first CI diagnosis, (iii) For Non‐COVID having no transition MCI‐to‐CI, consider 6 months before last recorded data. We utilize Heterogenous Causal Effects using Random Forest (HCE‐RF) model[1] to estimate COVID‐19 effects on 7 different CI outcomes. HCE‐RF, proven method in machine learning (ML)‐based VRCT, estimates conditional average causal effect (CATE) where 0 and 1 mean no and highest risk.

Result

COVID‐19 causes (details Table‐4) 54% (CATE:0.5489 CI[0.5428, 0.5618]) higher risk of developing any kind of dementia within 6‐months LongCOVID given the patient has prior MCI which is higher for severe (0.6498 CI: [0.6066, 0.6817]) and little bit lower, for mild COVID‐19 (0.5489 CI: [0.5428, 0.5618]). Similarly, COVID‐19 with different severity (mild‐to‐severe) causes significant higher risks of developing mixed dementia of any two types, Alzheimer’s disease or Vascular dementia without behavioral disturbance among MCI patients compared with COVID‐19 uninfected population. On the other hand, COVID‐19 infection causes no significant risk of developing presenile, senile and vascular dementia without behavioral disturbance for MCI patients in 6 months LongCOVID.

Conclusion

We proposed new method of developing VRCT cohort on observational data to identify disease intervention effect on disease progression in presence of heterogeneity of causes and effects and it on EHR data to identify LongCOVID (6 months) causal risks on MCI patients in developing different CIs. Our method can be utilized to uncover many hidden effects of COVID‐19 on observational data.

[1] https://doi.org/10.3386/w24678
Benefit of plasma exchange with albumin replacement on individual items of the quality of life‐Alzheimer’s disease score
Authors: Stewart Walter F , Lipton Richard B. , Gomez‐Ulloa David , Runken M Chris , Grifols Carlota , Iaconangelo Charlie , Serrano Daniel
Published: June 2023

Background

Alzheimer Management By Albumin Replacement (AMBAR) is a multicenter, randomized, placebo‐controlled, Phase IIb/III clinical trial that evaluated the efficacy and safety of Plasma Exchange with Albumin replacement (PE‐A) in patients with mild‐to‐moderate Alzheimer’s disease (Boada et al., Alzheimers Dement. 2020). PE‐A has demonstrated an overall benefit in quality of life as measured by the Quality of Life‐Alzheimer’s disease (QoL‐AD) score (Boada et al., Alzheimers Dement. 2021). We evaluated PE‐A treatment benefit for each of 13 individual patient‐rated QoL‐AD items.

Method

A cumulative logistic mixed model was applied on the Full Analysis Set (FAS) population. The odds that a patient receiving PE‐A would have a more favorable response (i.e., higher item score) than a similar subject receiving placebo was estimated at final visit for each QoL‐AD item. Age, baseline MMSE score, and baseline individual QoL‐AD item responses were included as covariates.

Result

The FAS included 76 placebo patients and 229 PE‐A‐treated patients. A significant PE‐A treatment effect vs. placebo at final visit was observed for QoL‐AD item 4: Living situation (“How do you feel about the place you live now?“) [Odds Ratio (OR) = 3.92 (95% CI: 1.38‐11.12), p = 0.010] and for QoL‐AD item 13: Life as a whole (“When you think about your life as a whole, everything together, how do you feel about your life?”) [OR = 3.80 (95% CI: 1.32‐10.91), p = 0.013].

Conclusion

The analysis demonstrated that when compared to patients on placebo, patients receiving PE‐A were more likely to have a favorable response for the QoL‐AD items “Living situation” and “Life as a whole”, suggesting that the reported benefit of PE‐A vs. placebo on the full QoL‐AD score is also observed in these individual QoL‐AD items.
Executive function may underlie cognitive reserve: A 3‐year follow‐up study
Authors: Seo Eun Hyun , Yoon Hyung‐Jun , Lim Ho Jae , Lee Kun Ho
Published: June 2023

Background

The hypothetical concept of cognitive reserve (CR) has been proposed to explain why someone can manage to function normally even in the presence of brain pathology. However, it still remains to be determined what components constitute such resilience against Alzheimer’s disease (AD) pathology. In the current study we investigated the characteristics of cognitively normal (CN) elders with high CR.

Method

We included CN participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea. We selected a group of CN individuals who showed a significant amyloid‐beta (aß) deposition at baseline and stayed CN over the follow‐up period. They were defined as high CR group. For comparison purpose, individuals with a significant aß deposition at baseline but converted to MCI at follow‐up were also included. In the final analysis, 94 high CR group and 24 control group were included. Group comparisons in socio‐demographic, clinical and cognitive variables were performed using χ2 tests and ANOVA controlling for age, education, gender, and follow‐up month.

Result

Mean follow‐up month were 43.37. There were no group differences in education, gender, socio‐economic status, family history of dementia or stroke, medical conditions, body mass index, subjective memory complaints, and instrumental activities of daily living. However, high CR group was younger and had shorter follow‐up period, therefore such variables were controlled when cognitive tests were compared. High CR group was more religious (p < 0.001), showed higher complexity in former job (p = 0.009), and higher level of executive functoning (Digit Dpan Backward, p = 0.012; Fluency test, p = 0.008; Boston Naming Test, p = 0.014; Trail Making Test part B, p = 0.017) than control group. There were no group differences in episodic memory tests and visuospatial abilities.

Conclusion

Individuals with high CR could cope better with AD pathology. Many factors have been suggested to be associated with CR. Regarding cognitive process involved, our findings suggest that executive function plays an important role in constituting high CR. Preserved executive function may, at least in part, underlie CR.
The National Israel Brain Repository: Characterizing those who sign and do not sign intent to autopsy
Authors: Manzali Sigalit , Ravona‐Springer Ramit , Ouyang Yuxia , Lin Hung‐Mo , Heymann Anthony , Greenbaum Lior , Liraz‐Zaltsman Sigal , Beeri Michal Schnaider
Published: June 2023

Background

Collection of postmortem human brain and spinal cords for research is invaluable, especially in neurodegeneration, since human clinicopathologic data may lead to better understanding their pathophysiology and to new therapeutic targets. The National Israel Brain Repository was established in 2018 and began recruiting donors from two large‐scale community‐based studies of individuals at high dementia risk: older adults with type 2 diabetes (Israel Diabetes and Cognitive Decline study‐IDCD) and middle‐aged offspring of AD patients (The Israel Registry for Alzheimer’s Prevention‐ IRAP).We compared sociodemographic, cardiovascular (CVRFs)and cognitive characteristics of individuals who agreed and did not agree to sign intent to autopsy (ITA)

Method

In the IDCD, of the 750 active participants, we approached 636. Of them, 196 (31%) agreed to sign ITA.IRAP has 480 active participants of whom 395 were approached and of them 176 (45%) agreed to sign ITA. All participants are from the Maccabi Health Services, providing CVRF data since 1998. Using t‐test we compared the groups on sociodemographic and CVRFs. For IDCD, which averages 36‐months cognitive follow ups, mixed regression models adjusting for age, sex and education tested whether signing ITA predicted cognitive trajectories. For IRAP, whose follow‐ups have only recently begun, we used linear regressions adjusting for the same covariates, compared cognitive functioning between those the two groups

Result

In the IRAP sample, participants who signed ITA did not differ from those who did not sign on any of the characteristics except for HbA1c (Table 1). In the IDCD sample, those who signed ITA had higher education, creatinine, and BMI and better motor function (hand grip and 3‐meter walk). Finally, those who signed ITA had a slower rate of decline in episodic memory (Estimate = 0.002, SE = 0.001, p = 0.05)

Conclusion

Our results suggest that middle‐aged adults at high AD risk willing to donate their brains to science do not differ in sociodemographic or CVRFs from those who do not wish to be organ donors. In contrast, older adults at high dementia risk due to T2D who signed ITA are more educated, have better motor function and a slower rate of cognitive decline suggesting a selection bias towards better health.Development of strategies to diminish this selection bias are warranted.
Association of microbiota‐derived products with astrogliosis and neurodegeneration in patients with Alzheimer’s Disease
Authors: Marizzoni Moira , Mirabelli Peppino , Mombelli Elisa , Coppola Luigi , Lopizzo Nicola , Luongo Delia , Naviglio Daniele , Salamone Dominic , Salvatore Marco , Cattaneo Annamaria , Frisoni Giovanni B
Published: June 2023

Background

Microbiota‐derived short chain fatty acids (SCFA) and liposaccharide (LPS) could modulate astrocyte and neuronal activity. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are markers of astroglial activation and neuronal damage, can be measured in blood samples and have been associated with Alzheimer’s disease (AD) pathology. The aim of the present study was to assess the association of SCFAs and LPS with GFAP and NfL in 13 amyloid‐β‐negative cognitively unimpaired individuals (CU), 38 patients with cognitive impairment and no brain amyloidosis (CI‐NAD) and 34 patients with cognitive impairment and amyloid‐β positivity (CI‐AD).

Method

Blood levels of 4 SCFAs (acetate, propionate, valerate and butyrate) were measured by GC‐FID gaschromatography, LPS by ELISA, and GFAP and NfL by single‐molecule array technology.

Result

Plasma valerate, LPS and GFAP concentrations were increased in CI‐AD compared with CI‐NAD and CU (p<0.034), acetate was increased in CI‐AD as well as decreased in CI‐NAD as compared with CU (p<0.018) and NfL was increased in both CI groups (p<0.023). In the pooled group of CI‐AD and CU, there were significant associations between plasma LPS and valerate with higher GFAP and NfL (p<0.032). Conversely, in the pooled group of CI‐NAD and CU, there were associations between plasma acetate with lower level of GFAP and NfL (p<0.026).

Conclusion

Valerate and LPS were associated with astrogliosis and neuronal damage only in patients with AD. These results suggest that microbiota‐derived molecules might be mediators along the gut‐brain axis and contribute to AD pathology by modulating microglial and neuronal activity.
Cognitive dispersion as a function of cognitive reserve: influence on cognition and functional connectivity in a healthy middle‐aged population
Authors: Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Solé‐Padullés Cristina , Cabello‐Toscano María , Abellaneda‐Pérez Kilian , Cattaneo Gabriele , Sánchez Javier Solana , Alviarez‐Schulze Vanessa , Tormos‐Muñoz Josep M. , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: June 2023

Background

Cognitive dispersion index (CDI), a measure of intraindividual variability across neuropsychological tests, is considered a sensitive marker of prodromic stages of Alzheimer’s Disease (Halliday et al. J. Intell 2018;6(1):12). CDI has been negatively associated with cognitive reserve (CR), another factor that influences the risk of dementia (Stern et al. Alzh&Dement 2020;16(9):1305‐1311). Nevertheless, how these two elements interact with each other and are linked with cognition and brain state (e.g., functional connectivity), remains unclear. Our aim was to investigate whether CDI has a differential influence on cognitive performance (CP) and on resting‐state functional connectivity (rsFC) as a function of CR level, in a healthy middle‐aged sample.

Method

Five hundred forty‐four healthy volunteers (aged 53.11±7.10 years; 269 female) from the Barcelona Brain Health Initiative cohort (BBHI, https://bbhi.cat/en), were stratified by CR (median = 14) into High CR (HCR, N = 230) and Low CR (LCR, N = 314) using the cognitive reserve questionnaire (CRQ; Rami et al. Rev Neurol 2011;52(4):195‐201). CDI was extracted by intraindividual standard deviation method (Costa et al. Clinic Neuropsychol 2019;33(2):369‐389) and CP was calculated as a global cognition composite score including episodic memory, speed of processing and executive function tests. Functional magnetic resonance imaging (fMRI) was acquired, and measures of rsFC within networks were computed through Shirer atlas (Shirer et al. Cerebral Cortex 2012;22(1):158‐165). Statistical analyses were based on univariate ANCOVA GLMs, and partial correlations adjusted by age and gender.

Result

Though no significant group interaction was found, a negative correlation between CDI and CP was identified for the HCR group (r = ‐0.170,p = 0.010; Fig.1A). On fMRI there was a significant group difference (HCR vs. LCR) in the association between CDI and rsFC in anterior salience network (aSN: F = 5.005,p = 0.026), where only HCR participants showed a significant negative association between CDI and aSN rsFC values (r = ‐0.187,p = 0.010; Fig.1B&C).

Conclusion

Our findings suggested that CDI has a clearly measurable effect on HCR participants, both in terms of its effect on CP and on rsFC. These results highlight the value of considering CDI measurements when performing neuropsychological assessments in middle‐aged individuals, particularly in those with high CR estimates.
A novel, humanized late‐onset Alzheimer’s disease mouse model expressing APOEe4, Trem2*R47H, and amyloid‐beta
Authors: Kotredes Kevin P , Oblak Adrian L , Pandey Ravi S , Territo Paul R , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T
Published: June 2023

Background

Late‐onset Alzheimer’s disease (LOAD) is the most common form of dementia without an approved therapy. Transgenic overexpression animal models do not effectively produce the heterogeneity observed clinically in LOAD patients and thus are not ideal for therapy development. Hence, the Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant risk factors. Analysis of aging LOAD2 mice that better phenocopy human disease will inform the further development of subsequent generations of models and reveal more appropriate molecular targets useful in the treatment of LOAD.

Method

Two risk factors of LOAD, APOEe4 and Trem2*R47H, were incorporated into C57BL/6J mice along with humanized amyloid‐beta to produce the LOAD2 model. Mice were aged up to 24 months. In some mice, high‐fat diet replaced normal mouse chow. An animal phenotyping pipeline was employed to qualify and align with neurodegenerative disease states and phenotypes observed in human patients. In vivo imaging in addition to behavior and wellness assays were performed, as were analyses of blood and brain tissue for risk‐factor‐related alterations in neuropathology, transcriptomics, metabolomics, and proteomics.

Result

Aged LOAD2 mice on high‐fat diet present altered cytokine profiles in the brain, and peripherally, however no overt hippocampal pathology nor differences in long‐term potentiation were observed. Expression of human amyloid did not yield plaque formation in 18‐month mice. High‐fat diet was a strong determinant during behavioral phenotyping. Correlation of transcriptional profiling with human AMP‐AD modules determined individual and synergistic effects between genetic and environmental risk factors compared to human data. Continuing efforts to dissect the clinically‐relevant downstream effects of sex, age, genotype, and diet in these animals remain.

Conclusion

The MODEL‐AD consortium has established the LOAD2 mouse model to study the effects of genetic and environmental risk factors of LOAD. This strain serves as a platform for the incorporation of additional AD risk factors (both genetic and environmental) to more closely align phenotypes in the mouse to outcomes observed in the clinic. Here we show the evidence of emerging disease pathology in an animal model exposed to genetic and environmental risk factors.
Incidence of subjective cognitive decline in a private practice memory clinic
Authors: Pippenger Mark A
Published: June 2023

Background

Subjective Cognitive Decline (SCD) has been one focus of interest in dementia research, partly because of the concept that some people with SCD may be in the earliest stage of Alzheimer Disease (AD). The prevalence of SCD has been reported as ranging from 15‐54%, but most estimates come either from population‐based studies or from academic Memory Clinics. The author is the sole provider in a Memory Clinic established in a private‐practice healthcare company in a large US city, and evaluates all new patient referrals for cognitive complaints.

Method

All new patient evaluations for referrals to the Novant Health Memory Clinic in Charlotte, NC, for a period of one year (2021), were reviewed. The number of cases diagnosed as having AD, the number diagnosed with Mild Cognitive Impairment (MCI), and the number with SCD, were tabulated. AD and MCI were diagnosed according to the clinical criteria from the National Institute on Aging and Alzheimer’s Association. Diagnosis of SCD was made according to the criteria published by the Subjective Cognitive Decline Initiative (SCD‐I) Working Group.

Result

During 2021, there were a total of 886 new patient evaluations in the Memory Clinic. Of those, 323 (36%) patients met clinical criteria for AD, 272 (31%) met criteria for MCI, and 211 (24%) for SCD.

Conclusion

SCD is relatively common in the private practice Memory Clinic setting. This could afford a potential to identify those people without dementia, who are at risk for later developing AD. The high prevalence of SCD may also create a market for unproven treatments for memory loss.
Modality matters for health disparity groups on the Montreal Cognitive Assessment (MoCA): Findings from the Einstein Aging Study (EAS)
Authors: Wang Cuiling , Nester Caroline O. , Chang Katherine H , Rabin Laura , Ezzati Ali , Lipton Richard B. , Katz Mindy J.
Published: June 2023

Background

The Telephone‐Montreal Cognitive Assessment (T‐MoCA) is a widely‐used, remotely administered cognitive screen. The T‐MoCA demonstrates adequate psychometric properties and may be used when standard, in‐person administration of the MoCA is not feasible (Katz et al., 2020). There is a critical need to investigate the agreement of the T‐MoCA across administration modalities (in‐person versus telehealth) among ethnically and racially diverse populations.

Methods

The Einstein Aging Study (EAS) includes a community‐based of racially/ethnically diverse community‐dwelling individuals, ≥ age 70 from the Bronx, NY. Participants (N = 424) were free of dementia at enrollment and completed the T‐MoCA along with in‐person neuropsychological tests including the MoCA‐22, which excludes items unsuitable for telephone administration paralleling the T‐MoCA (Table 1). Intraclass correlation coefficients (ICCs) between T‐MoCA and MoCA‐22 were used to measure agreement. Linear mixed effects models were applied to compare mean scores and ICCs among ethnic/racial groups, with and without adjusting for age, gender, education and depressive symptoms.

Results

Participants were on average 78.2 years, 65.8% female, 47.6% non‐Hispanic White, 38.0% non‐Hispanic Black, and 14.4% Hispanic. There was no significant difference between mean T‐MoCA and MoCA‐22 scores and no differential associations with age, gender, education, and depressive symptoms. For both modalities, NH Black (difference ‐1.54, p<.0001) and Hispanic (difference ‐2.04, p<.0001) groups demonstrated significantly lower scores compared to non‐Hispanic Whites (Table 2). As shown in Table 2, ICCs among non‐Hispanic White, non‐Hispanic Black, and Hispanic groups were 0.64, 0.50 and 0.42, respectively, and comparisons of ICCs to non‐Hispanic White were significantly lower in non‐Hispanic Black (p = 0.0495) and borderline significant in Hispanic participants (p = 0.0552). Findings were similar after adjusting for covariates.

Conclusion

The agreement between telephone and in‐person modalities of the MoCA was weaker in non‐Hispanic Black and Hispanic participants (compared to non‐Hispanic White). Further investigation of factors and/or items that contribute to these lower correlations is warranted. Although the T‐MoCA and other remotely administered cognitive screens have the potential to broaden accessibility to marginalized groups, researchers must use caution when developing or selecting appropriate demographically adjusted norms and interpreting scores of diverse older adults.
Age‐related cognitive decline are manifested by decreased event‐related delta and theta oscillations
Authors: Düzenli Seren , Gündüz Duygu Hünerli , Yener Görsev
Published: June 2023

Background

Event‐related oscillations (EROs) during cognitive paradigms reflect several cognitive functions in the brain. Event‐related delta responses are related to signal detection and decision making processes whereas theta is associated with working memory and selective attention (Yener and Başar, 2013; Başar et al., 2016). During physiological aging, EROs may be altered. The aim of the current study was to investigate time‐frequency measurements of event‐related oscillations in younger and older healthy participants.

Method

Fifty‐nine healthy participants were included in this study. They were divided into two subgroups as younger and older according to the age median score. Thirty younger healthy participants (mean age 22.37 years; standard deviation: 2.85) and 25 older healthy adults (mean age 56.48 years; standard deviation: 9.71) were completed a visual oddball task during EEG recording. Event‐related band power was assessed using event‐related spectral perturbation. Inter‐trial coherence values were analyzed by phase‐locking measurements. Event‐related power and phase‐locking analysis were performed for delta (0.5‐3.5 Hz), and theta frequency band (4‐7 Hz) over frontal (F3, Fz, F4), central (C3, Cz, C4), parietal (P3, Pz, P4), occipital (O1, Oz, O2) electrode locations. Repeated measures of ANOVA were used for statistical analysis.

Result

There were main GROUP effects for both event‐related delta [F(1,53) = 6.328, p = .015, ηp
2 = .107, Figure 1] and theta power [F(1,53) = 28.069, p<.001, ηp
2 = .346, Figure 2], indicating older healthy adults had reduced power values compared to younger healthy individuals (for all; p<.016). Furthermore, an interaction effect of Anterior‐Posterior Electrode Location x Group was found for theta power [F(3,159) = 13.869, p<.001, ηp
2 = .207], showing older healthy individuals had reductions in all electrode locations (for all; p<.017). Lastly, event‐related theta phase‐locking values were found to be reduced in older healthy adults [F(1,53) = 5.512, p = .023, ηp
2 = .094, Figure 3].

Conclusion

The present study demonstrated older healthy participants had decreased event‐related delta and theta responses during visual oddball paradigm. These reductions may be explained by the alterations in cognitive capacities such as working memory/attention and decline in processing information during healthy aging.

Acknowledgement: The inclusion of younger healthy participants in this study was supported by Ankara University Scientific Research Projects Coordination Unit (Project Number: 16L02000001).
Neurologic manifestations in hospitalized patients with COVID‐19
Authors: Thakkar Kajal , Goldberg Alan , Gomez Joanne S , Suboc Tisha Marie , de Lavallaz Jeanne M Du Fay , Bouroukas Athina , Volgman Annabelle Santos , Williams Kim Allan , Aggarwal Neelum T.
Published: June 2023

Background

To investigate the effect of pre‐existing neurological symptoms and disease in coronavirus disease 2019 (COVID‐19) health outcomes in a large Illinois‐based cohort.

Method

A multicenter retrospective study analyzed differences in a cohort of COVID‐19 positive patients with and without baseline neurological symptoms or disease admitted to RUSH University Systems for Health from March to November 2020. We measured sex and health outcome differences in hospitalization rates, symptoms during initial admission, complications, readmissions, and mortality of the two groups.

Result

Of the total of 1708 hospitalized COVID‐19 positive patients (mean age: 58.04, 930 males) — 31% [527] patients had a history of neurological symptoms and/or disease, 9% [140] with dementia. Nonspecific symptoms during hospitalization including myalgia (19%), headache (11%), epilepsy (0.8%), tremors (3%), and abdominal pain (11%) were reported more frequently in patients with a neurologic history. Female patients with pre‐existing neurological conditions were hospitalized more than their male counterparts (40% versus 24%). Compared to those with no neurological conditions, patients with neurological conditions had higher rates of complications, such as acute myocardial infarction (13% vs. 8%; p = 0.002) and deep vein thrombosis/pulmonary embolism (14% vs. 10%; p = 0.02). Multivariate analysis showed that history of stroke and migraines are independently associated with readmission to a hospital floor (generalized linear model, z = 2.092, z = 3.320, p = 0.036, p < 0.001, respectively); of those readmitted, 13% had a history of dementia. Of the patients that died in hospital, 6% had a history of dementia.

Conclusion

Neurologic manifestations are common in hospitalized COVID‐19 positive patients and are associated with higher rates of complications during hospitalization. The increasing evidence for SARS CoV‐2’s impact on the central nervous system raises important questions on the long‐term consequences of this virus to patients with pre‐existing brain injury.
Learning from anti‐tau antibody clinical trials using computer simulation of spatial tau propagation
Authors: Geerts Hugo , Bergeler Silke , Walker Mike , Spiros Athan
Published: June 2023

Background

Based on the tau spreading hypothesis, anti‐tau antibodies have been developed that can bind to and eliminate the misfolded tau protein during the short extracellular period. However, trials with tau antibodies have come up short in improving clinical outcome in Progressive Supranuclear Palsy (PSP) or Alzheimer’s Disease (AD). It is unclear whether the negative outcomes were due to insufficient target engagement and to what extent the change of tau CSF biomarkers reflected the brain pharmacodynamics.

Method

A Quantitative Systems Pharmacology (QSP) computer platform of tau biology has been developed including tau species diversity and their respective concentration, neuronal activity‐dependent tau secretion, tau binding to membrane surface receptors HSPG and LRP1, tau‐antibody binding and subsequent internalization of tau at the synaptic cleft. This model is combined with a Physiology‐Based PharmacoKinetic (PBPK) model to derive brain target exposure of tau antibodies. In addition, a PBPK model is used to simulate the level of plasma and CSF biomarkers.

Result

The platform was calibrated with preclinical in‐vitro cellular assays and after injection of brain extract in Transgene mouse models and was further humanized using published data on seed‐competent tau from postmortem AD brain at different Braak stages. Combining the extracellular antibody exposure, the spatial dimensions and the dynamics of tau secretion, diffusion and binding to the membrane surface receptors, the model suggests that a very limited fraction (10‐20%) of misfolded tau protein can be captured by antibodies and cleared. Even less reduction (5‐10%) is predicted for Progressive Supranuclear Palsy due to the higher affinity of PSP‐4R tau for membrane surface receptors. The reductions in misfolded tau protein are greatest in earlier stages of the disease. With regard to epitope selection, we identify conditions where high specificity (i.e. monomeric vs misfolded tau) is superior to high sensitivity (affinity).

Conclusion

Advanced Quantitative Systems Pharmacology computer modeling combining drug exposure dynamics with mechanistic modeling allows to (1) generate testable hypotheses for the outcomes of current therapeutic interventions, (2) support improved clinical trial designs in terms of dosing, patient selection, background amyloid therapy and disease stage and (3) ultimately prioritize targets for addressing tau pathology.
Identifying prognostic factors of dementia in individuals with mild cognitive impairment (MCI): Are statistical models adequate?
Authors: Wang Meng , Sajobi Tolulope , Ganesh Aravind , Seitz Dallas , Chekouo Thierry , Forkert Nils D , Borrie Michael , Camicioli Richard , Hsiung Ging‐Yuek Robin , Masellis Mario , Moorhouse Paige , Hogan David B , Trataglia Maria Carmela , Ismail Zahinoor , Smith Eric E.
Published: June 2023

Background

Identifying prognostic factors of MCI to dementia conversion is crucial. Most risk scores are developed based on selected variables using data‐driven methods from available variables in patient data. However, there is mixed evidence about the reliability of predictors selected based on data alone. Structured expert elicitation (SEE) is one approach to elicit clinician expert knowledge about relevant predictors for dementia risk. This study aims to identify critical predictors of dementia risk in persons with MCI from both SEE and random survival forests (RSF) and compare the differences between the two approaches.

Method

Clinical expert knowledge was quantified using SEE methodology: 11 experts (6 neurologists, 3 geriatricians, and 2 geriatric psychiatrists) were recruited to complete two rounds of surveys to rank predictors of dementia risk. RSF variable importance was used to assess the rank order of the potential predictors, according to the corresponding reduction of predictive accuracy when the predictor is replaced with its random permutation value risk using data from the Prospective Registry for Persons with Memory Symptoms of the Cognitive Neurosciences Clinic at the University of Calgary (N = 273; 26 potential predictors).

Result

According to experts, the SEE revealed age and cerebrospinal fluid profile patterns consistent with Alzheimer’s disease (AD) as the two most important predictors of dementia risk in persons with MCI. In contrast, data‐driven RSF approach, using information from routine clinical practice without AD biomarkers, identified the Consortium to Establish a Registry for AD total score and the Montreal cognitive assessment (MoCA) total score as the most important predictors. Both approaches identified four common variables (among the top 10 predictors) included age, signs of parkinsonism, MoCA total score, and behaviour impairment.

Conclusion

Our findings revealed discrepancies between a data‐driven approach and SEE in identifying significant predictors of dementia in people with MCI. The SEE identified some crucial predictors, such as AD biomarker status, that are not routinely collected in registries and observational studies or available in widespread practice. Most published risk scores are not used in practice. This study offers a possible explanation: what is important to clinicians may be not included in the risk scores.