bluuebunny/crossref_metadata_2025 huggingface dataset:
Excessive mortality risk associated with new opioid use in older people with dementia
Authors: Jensen‐Dahm Christina , Janbek Janet , Gasse Christiane , Laursen Thomas Munk , Waldemar Gunhild
Published: December 2023

Background

Opioids have been associated with an increased excess mortality‐risk in the general population. Older people with dementia have been prescribed opioids more frequent and the use of strong opioids has increased considerably over the past decade among older people with dementia. Whether opioids are associated with an excess mortality risk in older people with dementia is unknown.

Method

Matched cohort study using nationwide registries. All Danish residents aged 65 years and older diagnosed with dementia between 01.01.2008‐31.12.2018 were included. Exposure was defined as first opioid prescription after dementia diagnosis (1 year washout before diagnosis). Persons exposed to opioids were matched with up to two unexposed persons on age and sex. Cox proportional hazards models were used to compare rates of death within 180 days after the initiation of opioid treatment and adjusted for potential confounders (time since diagnosis, nursing home residency, comorbidity, admission within 30 days, number of medications).

Result

Forty‐two percent (31,619/75,471) of older people with dementia redeemed a prescription for an opioid after their diagnosis of dementia. We matched 31,619 exposed persons to 63,235 unexposed. Among the exposed, 10,642 (33.7%) died within 180 days after initiating their first opioid prescription compared with 3980 (6.4%) of the unexposed, yielding a 4‐fold increased excess mortality risk (adjusted Hazard ratio (95% CI): 4.13 (3.98‐4.30)). Strong opioids were associated with a 6‐fold increased mortality risk (6.34 (6.00‐6.69)), whereas the risk was lower for weak opioids (2.52 (2.38‐2.67). Among those who had redeemed transdermal fentanyl as their first prescription, 65.3% died within the first 180 days compared with 6.7% in the unexposed with a risk of 8.03 (7.02‐9.18). The risk was greatest within the first 14 days, where the mortality (for all opioids) was increased 11‐fold (10.95 (9.87‐12.15)), but there was still a 2‐fold increased mortality risk after 90 days (2.36 (2.21‐2.52)).

Conclusion

New opioid use was frequent among elderly with dementia, and this was associated with a markedly increased excess mortality, which is worrisome. The data calls for more research to identify sub‐groups with highest excess mortality risk to make a risk–benefit assessment and guidelines to assure appropriate prescribing.
Differential expression of mitochondrial energy producing genes in AD brains compromise ATP Synthesis and neuronal viability and stimulate inflammatory pathways and ROS synthesis
Authors: Castora Frank J , Kerns Kimberly A , Pflanzer Haley K , Shelton Morgan G , Coleman Randolph A.
Published: December 2023

Background

Mitochondrial dysfunction is a critical component in the pathogenesis of Alzheimer’s disease (AD) where deficits in oxidative capacity and energy production have been observed.

Method

A focused array of 84 genes involved in energy production in mitochondria was used to determine whether changes in these genes compromise mitochondrial function and other important biological processes or pathways.

Result

We find that a majority of these genes is down‐regulated in AD brains. These AD‐related gene expression changes are seen to affect a number of biological functions and pathologic conditions, including metabolism of nucleotides, synthesis of ATP, and nerve cell viability. The most affected complexes appear to be RCI and RCV. Particularly important are NDUFA10, ATP5PD, and ATP5F1B. Others to note are UQCRC1, a component of RC III, and COX6A1, a component of RC IV. Interestingly, GAPDH, a gene seen to be down regulated in our previous study of mitochondrial biogenesis, is also found to be downregulated in the current study. Lastly, BCS1L, a ubiquinol‐cytochrome c reductase complex (RC III) chaperone involved in assembly of RC III is one of the more substantially up‐regulated genes (+8.02‐fold) in AD brains.

Conclusion

There are significant gene expression changes in a small number of nuclear encoded mitochondrial genes involved in energy production in AD brains. These impact nucleotide synthesis and pro‐ and anti‐inflammatory pathways and reflect the mitochondrial dysfunction associated with neuronal cell death and AD..
Design and development of the intelligent voice recognition‐based cognitive assessment WeChat mini‐program
Authors: Wu Jingnan , Chen Nan , Xia Huanhuan , Wang Ziming , Li Yatian
Published: December 2023

Background

Early screening of mild cognitive impairment (MCI) is crucial for the elderly to access formal diagnosis and intervention of Alzheimer’s Disease (AD) and related dementias (ADRD) at early stages. Owing to the rapid development of artificial intelligence (AI) and voice recognition technology, the detection method using speech patterns as digital biomarkers collected by digital consumer devices can accommodate a huge demand for early and large‐scale detection. We here reported the design and development of the Shanghai Cognitive Screening (SCS) mini‐program, the first intelligent voice recognition‐based cognitive assessment WeChat mini‐program in China.

Method

The SCS mini‐program was developed based on the cognitive paradigm and classic pencil‐and‐paper neuropsychological assessments (e.g. Montreal cognitive assessment basic [MoCA‐B]). Through Automatic Speech Recognition (ASR), users speak to complete tasks including Naming, Immediate Recall, Delayed Recall, Symbol Digit Modalities Test (SDMT), Delayed RecallII, and Recognition (Figure 1). The acoustic, phonetics, and linguistic speech pattern variables would also be extracted and processed as digital biomarkers. The SCS intelligent prediction model enrolls speech pattern digital biomarkers, individual task scores, and time use variables with age, gender, and education level as linking variables, which enables to grade the user’s global cognitive function and individual cognitive domains (Figure 2).

Result

After completing all tasks in the SCS, users can immediately read the comprehensive results which are divided into 4 categories corresponding to 4 grading intervals: “healthy” (cognitively normal), “low risk” (suspected SCD), “medium‐high risk” (suspected MCI), and “high risk” (suspected AD). We also use a radar chart with scores of cognitive domains (i.e., memory, attention, visual perception, language, and executive functions), a memory trend graph (i.e., immediate and delayed recalls), an attention persistence graph, and related advice in the automatically generated report (Figure 3).

Conclusion

The SCS mini‐program is more efficient and economical compared to traditional paper‐based cognitive assessments. It is suitable for clinical cognitive assessment, remote self‐rating, and community screening for MCI and dementias among Chinese older adults and other ADRD high‐risk groups. Clinical trials are yet to be conducted to validate the accuracy and diagnostic value of the SCS WeChat mini‐program.
Biomedical and Psychosocial determinants of Alzheimer’s disease among elderly living in India
Authors: Mishra VijayKumar , Rawal Tina
Published: December 2023

Background

Ageing not only affects physical health but also contributes in decline of mental health of older people. Memory or cognitive ability is an important factor in health and well‐being of older adults. In India, cognition ability among older adults adversely affects many activities of daily living including quality of life. The neurological disease such as Alzheimer (or Dementia) has risen among Indian people age 60 years or above, due to various biomedical risk factors including disease mechanisms. This research has done to understand the psychosocial and biomedical predictors of Alzheimer’s’ disease among older people (60 years or above).

Method

This study has used the data from Longitudinal Ageing Study in India (LASI). LASI is a nationally representative survey on various socioeconomic and health aspects of older adults living in India. LASI (Wave‐1) was done with a sample of 31,902 older people (age 60 years or above). Logistic regression modeling was used to understand the predictors of Alzheimer’s disease among elderly, while multivariate decomposition analysis was used in order to understand the contributing factors of Alzheimer’s illness among poor and non‐poor elderly.

Result

Around 3% of elderly (60 years or above) had any neurological illness, while around 1.2% of elderly had Alzheimer’s (or Dementia). The prevalence of Alzheimer’s (or Dementia) was relatively higher among poor elderly, as compared to non‐poor. The prevalence of Alzheimer’s (or Dementia) was found higher among female elderly as compared to males. This study has found Education (years of schooling), activity of daily living (ADL), living arrangements, depression, MPCE quintile, access to health care, pension, self‐rated health and loss of natural teeth, as the predictors of Alzheimer’s’ (or Dementia) disease among elderly living in India.

Conclusion

Alzheimer’s (or Dementia) disease is a concern among India elderly as it affects overall quality of life. However, focusing on preventable factors (such as health financing, counselling) may help in decreasing the effect of this disease at some extent. Therefore, policy makers in India should consider on all possible risk factors of Alzheimer’s (or Dementia) for well‐being of elderly (especially poor or living alone).
Factors Related to Cognitive Resilience according to Education Level in Normal and Cognitively Impaired Individuals
Authors: Kim Yeshin , Jang Hyemin , Soung YongGwon , Na Duk L. , Jang Jae Won , Seo Sang Won
Published: December 2023

Background

Cognitive resilience (CR) is a concept to explain the difference between pathologic burden and cognitive function. Understanding CR is important as increasing CR can be applied to dementia prevention strategies. CR is closely related to education and it was widely used as proxy for CR. However, using an education as proxy of CR may have limitation in reflecting the CR of low educated individuals. Related factors to CR can be different according to the educational level. However, factors related to low educated individuals has not been sufficiently investigated. Therefore, we aimed to investigate factors related to cognitive resilience in low‐ and highly educated individuals using residual approach.

Method

We collected 1,085 patients who underwent neuropsychological assessment and MRI from the Establishment of Precision Medicine Platform for Early Diagnosis of Mild Cognitive Impairment (PREMIER) Cohort (305 SCD, 639 MCI, 141 AD). To capture CR using residual approach, firstly, cognitive score was predicted on global cortical thickness, adjusted for age, sex, education, and disease stage. Then, individual differences between predicted and observed cognitive score were used as the measure of CR(CR_rsd). Next, we divided the participants into two groups based on their education level. To investigate the factors related to CR_rsd between two groups, we used multiple linear regression and logistic regression model after adjusted age, sex. Demographic, socioeconomic and psychiatric factors were evaluated.

Result

Mean age was 70.5 years and 65.3% were female. There were 286 patients in low educated group (26.4%). Depression, literacy, cognitive activity, and presence of diabetes were related to CR_rsd. Literacy was related to CR_rsd in both low‐ and high‐education group (low education group, p = 0.035; high education group, p = <0.001). Depression was associated with low CR_rsd only in high education group (p = 0.001). Cognitive activity was associated with high CR_rsd in both group (low education group, p = 0.042; high education group, p = <0.001). However, social activity was only related to high CR_rsd low education group (p = 0.044).

Conclusion

Our findings suggest that factors related to CR could be different according to the educational level.
Comparing Clinical Diagnosis of Domains of Impairment in individuals with Mild Cognitive Impairment with the NIH Toolbox‐Cognitive Battery Performance
Authors: Bross Jordan R , Maher Amanda Cook , Pal Subhamoy , Perrin Cameron K , Reader Jonathan M , Bhaumik Arijit K , Fisher Jordan , Gregoire Allyson , Persad Carol C , Hampstead Benjamin M. , Giordani Bruno
Published: December 2023

Background

Mild Cognitive Impairment (MCI) represents the phase between age‐associated cognitive decline and Alzheimer’s disease and related dementias. Examination of these individuals may be especially important through computer‐based batteries such as the NIH Toolbox‐Cognition Battery (NIHTB‐CB). To inform NIHTB‐CB validity, we compared MCI patients’ performance against categories of cognitive impairment defined by the consensus‐based clinical diagnosis form of the National Alzheimer’s Disease Coordinating Center (NACC) Unified Data Set UDS3. We expected a correspondence between MCI consensus‐based clinical deficit areas and specific NIHTB‐CB task performance.

Method

Retrospective data analysis was conducted on 65 MCI participants from the Michigan Alzheimer’s Disease Research Center, with a mean age of 74±8.3, 65% female, who completed UDS3 and NIHTB‐CB measures. The UDS3 forms consist of interviews, medical/neurological examinations, and neuropsychological testing, with a clinical consensus‐based diagnosis form listing domains of cognitive impairment representing memory, language, attention, executive, and visuospatial functioning. Four domain impairment groupings with a minimum of 10 participants each were established (Executive Functioning, n = 10; Memory, n = 27; Memory+Executive Functioning, n = 17; and Memory+Language n = 11) and compared to NIHTH‐CB performance. ANOVAs adjusted for demographics and post hoc tests were conducted to differentiate across clinical consensus categories for the MCI participants.

Result

Two NIHTB‐CB measures yielded significant differences across the clinical grouping: Picture Sequence Memory (PSM, F = 3.3, p = 0.03) and Pattern Comparison (PC, F = 4.1, p = 0.01). For PSM, post hoc tests demonstrated higher scores for the Executive compared to Memory+Executive (PSM: p<0.02) groups with a trend for Executive versus Memory groups (p<.07). For PC, the Memory group performed better than both the Memory+Executive (p<.02) and Memory+Language (p<.04).

Conclusion

The better memory performance on PSM of the MCI Executive group compared to the two groups with memory impairment is consistent with expectation. PC, as a measure of executive ability and processing speed was sensitive to clinically diagnosed executive impairment. Lower scores for the Memory+Language group on PC were unexpected. Efficient language functioning may be necessary for complex pattern comparison as dimensions shift. Findings support the validity of NIHTB‐CB. They also suggest the need for additional research on language demands for executive measures.
Cognitive symptoms associated with COVID‐19: neuropsychological and biochemical characterization
Authors: Guillén Núria , Pérez‐Millan Agnès , Martínez Neus Falgàs , Botí María Ángeles , Tort‐Merino Adrià , Lledó‐Ibáñez Gema María , Ruiz‐García Raquel , Naranjo Laura , Rami Lorena , Sala‐Llonch Roser , Balasa Mircea , Lladó Albert , Sanchez‐Valle Raquel
Published: December 2023

Background

Despite previous studies establishing cognitive impairment as a major complaint in post‐acute COVID‐19 syndrome (PACS), a deeper understanding of the neuropsychological features and underlying causes is needed. We aimed to characterize the cognitive profile of patients affected with cognitive PACS and the influence of biological and psychological factors.

Method

We performed a prospective single‐center study. We included participants with confirmed SARS‐CoV‐2 infection and long‐term symptoms ≥ 8 weeks after onset who were referred to our unit because of cognitive complaints. All participants completed a comprehensive neuropsychological battery (NPS) and questionnaires assessing depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), apathy (Starkstein Apathy Scale) and fatigue (Multidimensional Fatigue Inventory) at baseline and +1, +3 and +6 months. We collected blood samples and cerebrospinal fluid (CSF) to obtain biochemical and immunological profiles. Group comparisons, correlations and Principal component analysis (PCA) were performed. Longitudinal analyses are ongoing.

Result

Forty‐nine participants were included (79.6% female, mean age 50.1 (SD 7.9). At the time of assessment, they presented multiple symptoms other than cognitive complaints (88% fatigue, 61% headache, 63% dyspnea, and 10% fever). The NPS showed that executive functions were the most affected (up to 29% of the sample had at least one test altered), followed by memory (at least one test altered in 25%) (Figure 1). On the contrary, language and praxis were preserved. Participants presented with anxiety symptoms (minimal 8.7%, mild in 34.8%, moderate 26.1%, severe 30.4%), depressive symptoms (none 34.8%, mild 26.1%, borderline clinical depression 23.9%, moderate 8.7%, severe 6.5%), and clinically relevant apathy in 64.4%.

The sample presented a mean score of total fatigue of 58 (min 48, max 68), (scores 20‐100). Fever and or moderate/severe anxiety were associated with lower scores in some memory and executive functions subtests (Figure 2). Most of the variability in the sample was explained by executive functions subtests (PCA, Figure 3). Patients presented increased levels of interleukins (IL) IL‐1b, IL‐17a and IL‐18 in CSF compared to controls.

Conclusion

Cognitive PACS predominantly affected executive functions and memory. Fever and moderate/severe anxiety were associated with worse cognitive outcomes. Several inflammatory markers were altered in cognitive PACS.
Identifying glial cell‐surface proteins critical in normal brain aging
Authors: Harrison Erin M , Burns Madeline P , Li Hongjie
Published: December 2023

Background

Glial cells play a variety of supportive functions to facilitate effective neural communication, including maintaining an effective immune response, myelination of axons, and maintaining extracellular homeostasis. Glia also display age‐related transcriptomic and morphological alterations, and glial cell metabolism is altered in Alzheimer’s Disease (AD). Fully characterizing age‐related alterations to the cell‐surface proteosome of glial cells in both healthy and pathogenic forms of brain aging could provide further insight into how neuron‐glia interactions facilitate brain aging and identify novel biomarkers and treatment targets of AD.

Method

We performed tissue‐specific in‐situ cell surface proteomics on young (5‐day old) and aged (50‐day old) D. melanogaster utilizing the protocol developed by Li et al. (2020) with the Repo driver to target glial cells. From this, we identified 19 genes of interest with the most significant age‐related increase in protein expression and performed a broad genetic screen to identify how knockdown of genes upregulated with age in glial cells impacted fly lifespan. For this, we utilized the Repo‐GS‐UAS system to screen several transgenic D. melanogaster RNAi lines for the genes of interest, with 2‐3 RNAi lines per gene.

Result

Based on a Gene Ontology (GO) analysis of the most upregulated candidate genes, we observed that most were associated with cell localization and transport. Additionally, from our preliminary screen, we have identified five top candidate genes of interest that, when knocked down, appear to increase average fly lifespan relative to the controls. Currently, we are in the process of validating the initial lifespan results, repeating lifespan screens of the top candidate genes in a new glial GS line and a glial Gal4 line.

Conclusion

We have identified genes that appear to extend lifespan when knocked down and could serve as targets for further study. These results can provide a basis of understanding healthy brain aging and could serve as a basis of comparison to AD models.
“It’s a lonely journey”: Personal experiences and psychosocial distress among Chinese American dementia family caregivers
Authors: Hong Y. Alicia , Shen Kang , Park Van Ta , Han Hae‐Ra , Cleaveland Carol W
Published: December 2023

Background

Chinese American dementia caregivers are a growing but understudied population. Prior survey studies suggest they experience high rates of depressive symptoms and adverse health outcomes, but data are limited on their caregiving experiences, distress processes, and related contextual factors. The current study aims to address the literature gap with a qualitative investigation.

Method

In‐depth interviews were conducted with 18 Chinese American dementia caregivers. An interview guide was developed priori based on literature on family dementia caregivers and stress process theories. All interviews were transcribed verbatim, thematic content analysis was conducted.

Result

Participants’ ages ranged from 39 to 85 with a median age of 60 years. 70% were female, and 64% had limited English proficiency. A conceptual framework of caregiving distress process was developed based on the interview guide and major themes emerged from the data. Caregiving stress stems from a complex interaction of care‐recipients’ and caregivers’ characteristics; stress leads high levels psychosocial distress, including poor sleep, depression and anxiety, and chronic conditions. The distress process is attenuated by caregivers’ help‐ seeking, social support, and use of formal services; it is also negatively influenced by caregivers’ poor self‐care, social isolation, and self‐perceived poor mastery of caregiving. The distress experienced by Chinese American dementia caregivers is a dynamic process in the caregiving context at multiple levels, including their social networks, available health and social services, immigration policies, and social norms. Participants described their caregiving experience as a “lonely journey”, reflecting their isolation and limited social support.

Conclusion

Our data suggest that Chinese American dementia caregivers, especially those with limited English proficiency, experience elevated psychosocial distress. They face daunting barriers to social support and health services due to their immigrant and minority status. Culturally appropriate targeted intervention is urgently needed for this underserved and vulnerable population.
A Polygenic Risk Score for Hand Grip Strength is Associated with Cognitive Function in Mid‐to‐Late Life Adults
Authors: Bercovitch Rachel , Tio Earvin S. , Felsky Daniel
Published: December 2023

Background

Lower muscular fitness is a risk factor for Alzheimer’s disease (AD). Hand grip strength (HGS) specifically ‐ a proxy for muscular fitness ‐ is a heritable predictor of cognitive decline in aging adults. However, the genetic component of HGS has not yet been explored with respect to cognitive decline. Therefore, we examined the association between a polygenic risk score (PRS) for hand grip strength (HGS) and cognitive function in mid‐to‐late life individuals.

Method

We accessed data for 22,759 unrelated adults of European ancestry (ages 45‐86) from the Canadian Longitudinal Study on Aging (CLSA), calculating a PRS for HGS using the PRS‐CS‐Auto method and summary statistics from Willems et al., 2017. Linear models were used to test for PRS effects on baseline memory and executive function t‐scores, co‐varying for physical activity and other lifestyle and demographic factors. We also explored interactions with measured hand grip strength, physical activity level, sex, and age. Finally, we tested if our HGS‐PRS was able to significantly augment the predictive performance of a benchmark AD‐PRS, calculated using summary statistics from Bellenguez et al., 2022.

Result

A higher HGS‐PRS was associated with better global cognitive performance (p = 6.05e‐08). This effect remained significant after controlling for a full set of covariates, including cardiovascular fitness, physical activity, and lean muscle mass (p = 3.14e‐05). Interaction models revealed that age, sex, measured grip strength, and level of physical activity did not change the relationship between HGS‐PRS and cognition. Finally, when assessing whether the HGS‐PRS could augment the predictive performance of an established AD‐PRS, we found significant improvements to models of memory (p = .0035), executive function (p = 7.13e‐06), and global cognition (p = 3.07e‐06). While statistically significant, the additional variance explained in cognition was very small (improvement in R2∼0.1%).

Conclusion

Genetic predisposition for greater HGS is significantly associated with better cognitive performance in mid‐late life, regardless of sex, fitness, or levels of physical activity. It is therefore possible that direct mind‐muscle connections account for this observation, rather than indirect effects of active lifestyle. Further analyses on longitudinal cognitive outcomes and intermediate brain functional phenotypes are warranted.
The association between change and stability in subjective health ratings and dementia risk: a multi‐cohort study in Swedish and Danish twins
Authors: Pilgrim Matthew JD , Finkel Deborah , Beam Christopher R.
Published: December 2023

Background

Poorer self‐rated health (SRH) is associated with increased dementia risk (Stephan et al., 2021). However, it is unclear whether genetic and/or environmental variance accounts for this risk. Although SRH declines with age (Finkel et al. 2020), it is unknown whether rates of change in SRH are independently associated with dementia outcomes. Using a validated latent dementia index (LDI) (Beam et al., 2022), we tested whether stability and change components of SRH predicted LDI via genetic and environmental pathways in two international cohorts of twins.

Method

Our data consisted of two samples of monozygotic (MZ) and dizygotic (DZ) twins. We used data from the Swedish Adoption Twin Study of Aging (SATSA; Ntwins = 548, Npairs = 339) and the Longitudinal Study of Aging Danish Twins (LSADT; Ntwins = 3238, Npairs = 2561). Bivariate Cholesky decompositions and three‐level growth‐curve models with predictive intercepts and slopes were used for our cross‐sectional and longitudinal analyses respectively. All models were estimated in Mplus (Muthen & Muthen, 2017) using maximum likelihood with robust standard errors.

Results

Cross‐sectional model results indicate that those with poorer SRH have lower LDI scores (b = ‐0.01, p = .008), even after adjusting for shared genetic covariance, age, sex, education, and depressive symptoms. Predictive growth models indicate that rates of change in SRH are negatively associated with LDI after adjusting for age, sex, education, and depressive symptoms (b = ‐0.17, p = .032). The degree of genetic confounding in the association between rates of change and LDI was inconclusive.

Conclusion

Our study provides novel insights into the relationship between individual ratings of health and dementia risk. SRH predicted dementia likelihood after controlling for genetic confounding, opening up the possibility that subjective ratings of health account for unique variance in dementia risk. Additionally, changes in SRH also predicted dementia likelihood beyond their mean score. Taken together these results highlight the importance of subjective health measures in understanding dementia risk.
Piloting a Mediterranean Ketogenic Nutrition Program to Address Pain in Older Adults with Mild Cognitive Impairment
Authors: Sheffler Julia L , Klejc Kamelia , Cruz‐Almeida Yenisel
Published: December 2023

Background

Pain is a persistent problem in older adults associated with poorer quality of life, greater risk of falls, functional impairment, and risk for cognitive impairment. Psychosocial and lifestyle interventions may be especially important to consider in older populations who may be more susceptible to negative side effects of pain medications. Ketogenic nutrition (KN) is one promising option that may offer a nonpharmacologic pathway for treating pain; however, KN is also a relatively strict and complex diet associated with challenges in dissemination and long‐term adherence, especially in older adults with memory impairments.

Method

This pilot clinical trial (N = 58) evaluated a 6‐week Mediterranean KN program designed to evaluate adherence and preliminary effects of the program on pain in individuals with possible mild cognitive impairment (aged 60‐85). Participants completed daily at‐home urine ketone testing during the program, weekly evaluations of psychosocial and health characteristics, and three in‐person assessments of health, ketones, pain, and other relevant measures.

Results

Analyses demonstrated significant improvement in pain intensity across the assessment period. Average daily urine ketone level and average self‐reported adherence across the 6‐week program were both positively correlated with improvements in pain‐related quality of life (ps<.05).

Conclusion

Findings offer preliminary evidence that a group, Mediterranean KN program and adherence to this type of nutrition may reduce the experience of pain and pain‐related outcomes for older adults.
Classifying Memory Clinic Patients Using the Digital Clock Drawing TestTM, Mini‐Mental State Examination, and Philadelphia (repeatable) Verbal Learning Test
Authors: Libon David J , Swenson Rodney , Jannati Ali , Bates David , Tobyne Sean , Pascual‐Leone Alvaro , Gomes‐Osman Joyce Rios
Published: December 2023

Background

Digital cognitive assessments (DCA) enable quick, sensitive, and reliable assessment of neurocognitive operations that underlie dementia and mild cognitive impairment (MCI). We examined how well the DCTclockTM DCA, Mini‐Mental State Examination (MMSE), and Philadelphia (repeatable) Veral Learning Test (PrVLT) can classify memory clinic patients by cognitive impairment profile.

Method

106 serial referrals to an outpatient memory clinic were assessed with the DCTclock, MMSE, and P(r)VLT. Using statistical criteria for subtle cognitive impairment (SCI, Edmonds et al., 2015) and MCI (Jak et al., 2008), patients were classified into cognitively normal (CN, n = 21), SCI (n = 33), amnestic MCI (aMCI, n = 22), and dysexecutive/mixed MCI (d/mMCI, n = 30) groups. A series of stepwise logistic regression analyses were conducted with CN participants as the criterion group.

Result

In the first analysis (Table 1), P(r)VLT‐recognition (X2= 24.39, p<0.001) entered the model first followed by the DCTclock Score (X2= 16.68, p<0.001). P(r)VLT‐recognition classified aMCI patients (Wald = 11.21, p<0.001). DCTclock (Wald = 8.97, p<0.001) and P(r)VLT‐recognition (Wald = 4.06, p<0.001) classified d/mMCI patients. In the second analysis the four command DCTclock composites were analyzed, excluding the MMSE and P(r)VLT‐recognition scores, Spatial Reasoning classified patients into their respective groups (SCI, Wald = 3.68, p<0.055; aMCI, Wald = 8.84, p<0.003; d/mMCI, Wald = 19.12 p<0.001). Third, analyzing DCTclock command Spatial Reasoning, MMSE, and P(r)VLT‐recognition, the P(r)VLT score, again, entered first (X2= 24.39, p<0.001) followed by DCTclock Spatial Reasoning (X2= 18.95, p<0.001). DCTclock Spatial Reasoning classified SCI patients (Wald = 4.66, p<0.031), P(r)VLT‐recognition classified aMCI patients (Wald = 9.11, p<0.003), and both DCTclock command Spatial Reasoning (Wald = 10.56, p<0.001) and P(r)VLT‐recognition (Wald = 3.32, p<.068) classified d/mMCI patients.

Conclusion

Unlike the MMSE that takes 10‐15 minutes to administer and is scored subjectively, all DCTclock data are digitally obtained and automatically scored, requiring no examiner interface for administration and interpretation, thus obviating clinical judgment, ensuring inter‐rater reliability, and enabling more efficient cognitive assessments. In this series of logistic regression analyses, a combination of DCTclock and P(r)VLT clearly outperformed the MMSE in classifying non‐demented memory clinic patients into cognitively normal, subtle cognitive impairment, and MCI subtypes. These results support the efficacy of DCAs in clinical trials and to screen for emergent cognitive impairment in primary care and specialty medical practices.
Optimising remote sampling of NfL and GFAP using blood cards in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort
Authors: Goldsmith Sophie E , Swift Imogen J , Oh Lara , Laban Rhiannon , Zetterberg Henrik , Esteve Aitana Sogorb , Rohrer Jonathan D.
Published: December 2023

Background

In recent years, blood‐based biomarkers have become key measures in the study of dementia, including frontotemporal dementia (FTD), with use in diagnosis and clinical trial outcomes. Remote collection of blood samples provides a more accessible and cost‐effective alternative to regular clinic visits and allows for more frequent measures to be taken. This is particularly relevant as we progress into an era of clinical trials in FTD. The aim of this current study was to assess whether neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), markers previously shown be increased in genetic forms of FTD, can be measured using dried blood cards and to optimise the protocol for this.

Method

10 participants from the University College London GENFI study (three C9orf72 mutation carriers, four GRN mutation carriers and three mutation negative controls) were included in this pilot study. Blood samples were collected by venepuncture from each participant: one sample for plasma analysis and one sample which was used to pipette whole blood on to a blood card. NfL and GFAP concentrations were subsequently quantified using the Simoa multiplex Neurology 4‐Plex A (N4PA) assay in both plasma and the dried blood card. Total protein concentration was measured with the Bradford protein assay and used to correct for variable concentrations of blood card spots. The effect of incubation temperature and time as well as freeze thaw cycles were also assessed as part of the optimisation process.

Result

In this pilot cohort, blood card GFAP concentration (BSA corrected) very strongly correlated with matched plasma GFAP (r = 0.897, p = 0.0004), whilst blood card NfL concentration (BSA corrected) strongly correlated with matched plasma NfL (r = 0.721, p = 0.0234). Incubation temperature impacted total protein concentration in the blood cards, but freeze‐thaw and incubation time did not.

Conclusion

This pilot study shows that NfL and GFAP concentrations can be successfully quantified using dried blood cards and results strongly correlate with plasma measures. Future work will involve investigating whether these biomarkers can be measured in blood cards obtained with capillary blood through lancet‐based fingerprick collection and assessing the feasibility of home collection.
Relationships between excessive daytime sleepiness and arterial stiffness with cognitive function in a racially diverse high‐risk cohort
Authors: Butts Brittany , Hu William T. , Verble Danielle D , Likos Kelly D. S. , Bliwise Donald , Trotti Lynn Marie , Benameur Karima , McCart Alisha W , Cook Jordan A , Hammerschlag Bruno L , Nimmagadda Nivi , Russ Amber , Wharton Whitney
Published: December 2023

Background

As pathologic processes leading to Alzheimer’s disease (AD) begin many years before clinical diagnosis, assessment of pre‐clinical AD risk factors in high‐risk individuals is needed. Excessive daytime sleepiness (EDS) is associated with increased cardiovascular dysfunction, neuroinflammation, and neurodegeneration, leading to cognitive impairment. We tested the hypothesis that EDS and increased arterial stiffness are related to worse cognitive function in a cohort of Black or African American (B/AA) and non‐Hispanic White (NHW) participants.

Method

A community‐based racially diverse sample of cognitively unimpaired adults (47‐83 years), most (87%) with a family history of AD, were enrolled. Cognitive testing took one hour and included domains of executive function, working memory, and verbal and visuospatial ability and language. Daytime sleepiness was measured with Epworth Sleepiness Scale (ESS); EDS was defined as ESS≥10. Arterial stiffness was measured using pulse wave velocity (PWV).

Result

Participants (N = 85) were 64±8 years of age, 75% female, 48% B/AA, and highly educated (81% ≥college). Mean central blood pressures were 126±18 mmHg (systolic) and 80±10 mmHg (diastolic), with no differences by race or sex. Scores were lower among B/AA versus NHW participants for Judgement of Line of Orientation (17.71±6.0 versus 23.53±6.0, p<.001, Cohen’s d = .083) and Multilingual Naming Test (28.25±2.7 versus 30.57±2.0, p = .005, d = .950). EDS was present among 15% of participants and associated with lower scores on Digit Symbol (p = .004, d = .917), and Multilingual Naming Test (p = .006, d = 1.455). Total time on Trails A was higher among those with EDS (36s versus 30s, p = .040, d = .575). Higher PWV values were associated with lower scores on Digit Symbol Substitution (r = ‐.259, p = .029), Buschke Selective Reminding Test (‐.298, p = .012), CERAD Word List (‐.306, p = .009), F‐A‐S (r = ‐.253, p = .033), and Animal Fluency (r = ‐.326, p = .006).

Conclusion

In a racially diverse cohort at risk for AD, we found that excessive self‐reported daytime sleepiness and increased arterial stiffness were associated with worse scores across multiple cognitive domains. Poor sleep and vascular dysfunction are known contributors to AD pathology, providing potential modifiable targets of intervention to reduce or delay the development of AD in cognitively normal, but high‐risk individuals. Further work is needed for a better understanding of modifiable AD risk factors in diverse populations
Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice
Authors: Obenaus Andre , Singh Aditya , Pad Rojina , Iyer Anika , Ketsan Tia , Jullienne Amandine
Published: December 2023

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAβKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.

Methods

Contrast‐enhanced PWI MRI (9.4T) was undertaken from hAβKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.

Results

Compared to WT mice at 18mo of age, hAβKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p<0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAβKI only mice.

Conclusions

The 18mo hAβKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).
Functionally Informed Polygenic Risk Scores for Alzheimer’s Disease
Authors: Sale Rebecca L , Betti Michael J , Kaas Garrett , Gamazon Eric R
Published: December 2023

Background

Alzheimer’s Disease (AD) is a heritable, neurodegenerative disease. Most AD cases can be categorized as Late Onset Alzheimer’s Disease (LOAD) cases, which are polygenic. Genome Wide Association Studies (GWAS) of LOAD have identified several associated single nucleotide polymorphisms (SNPs). These variants are in 75 genetic loci, and have implicated a diverse array of genes, cell types, and biological pathways in LOAD. Additionally, many associated variants are not in protein coding regions of the genome. However, it is difficult to determine if all associated variants are functionally relevant and contribute to the etiology or progression of the disease. Here, we present CoRE‐BED, a variant annotation tool that can categorize SNPs into functional classes, such as promoters or enhancers, for a given cell type. These functional variants in each cell type are subsequently used to determine functional variant contributions to LOAD heritability and risk.

Method

We annotated a recently published GWAS of AD (Bellenguez et al 2022) using CoRE‐BED. CoRE‐BED leverages 19 functional assays across 33 distinct cell types from EpiMap to classify variants into functional categories for each supported cell type. Annotated variants were used to estimate cell type specific partitioned heritability using LD Score Regression. Finally, annotated variants were used to build cell type specific Polygenic Risk Scores (PRS). PRS was tested using multiple PRS software and utilized the annotated GWAS as a training dataset and independent cases and controls derived from Vanderbilt University’s biobank, BioVU.

Result

CoRE‐BED provided functional classifications for all variants in the GWAS for individual tissue types. Variants that pass genome wide significance (P < 5×10−8) are enriched for functional annotations. Immune related cell types contribute the greatest proportion of partitioned heritability. Standard PRS methods outperform cell type informed PRS measures.

Conclusion

CoRE‐BED is a robust annotation tool that can determine functional annotations at the SNP level. AD GWAS significant associations overlap with functionally annotated SNPs in multiple cell types. Partitioned heritability indicates that immune related cell types may play an important role in the heritability of AD. However, conventional methods for PRS still provide the most robust means to predict AD risk.
Are There Differences in Screening MMSE Interview Durations Between Subjects Who Maintain Severity and Subjects Who Drop Below Screening Inclusionary MMSE Thresholds at Baseline? An Exploratory Analysis.
Authors: Kott Alan , Wang Xingmei , Miller David S.
Published: December 2023

Background

We have previously identified a large proportion of subjects (> 10%) entering clinical trials in early Alzheimer’s disease to possibly suffer from Baseline inflation (Kott, 2023). Without useful predictive markers, the identification of these subjects happens only when these subjects are already randomized into the trial. Our prior analyses showed an almost linear relationship between MMSE interview duration and MMSE total score (Kott, 2022). To be able to identify possible subjects with MMSE score inflation at Screening, we wanted to test the hypothesis that those subjects with likely inflated MMSE scores had significantly longer scale administration times, possibly corresponding to increased symptom severity below the MMSE inclusionary threshold.

Method

Data from 6,922 subjects were pooled from 6 early AD clinical trials. We restricted the analysis to interviews between 3 and 30 minutes long, shorter interviews are technically not possible and longer interviews likely indicate user error. This decreased the sample to 6,717 subjects. Subjects were dichotomized into subjects meeting Screening MMSE criteria at Baseline and subjects who dropped below the Screening MMSE criteria at Baseline. A generalized linear model was fitted to the data with the Screening MMSE duration used as the predicted variable and type of subject (drops below criteria yes/no) as the predictor variable correcting for the MMSE score at Screening.

Result

937 subjects no longer met MMSE inclusion criteria at Baseline. For those subjects, MMSE interview duration increased significantly (∼40 seconds).

Conclusion

Our post‐hoc analysis found significantly longer Screening MMSE interview durations in subjects who no longer met MMSE inclusion cutoffs at Baseline. The increase was consistent with our hypothesis and likely reflects that these subjects had their Screening MMSE scores inflated in order to meet inclusion criteria. We suggest including prolonged MMSE durations in analytical programs as a marker of possible MMSE score inflation alongside other markers, like MMSE vs ADAS‐Cog discordance. We plan additional analyses to better understand this problem.
Do Caregivers of Alzheimer’s Disease Have Adequate Levels of Physical Activity?
Authors: Menengiç Kübra Nur , Bülbül Nazlı Gamze , Doğan İdil Arasan , Kendirli Sude , Çınar Nilgün
Published: December 2023

Background

The care of individuals with Alzheimer’s disease is mostly provided by their spouses and children. It is stated that an average of 18 billion hours is spent annually on informal care provided by family members. It is known that caregiving affects both physical and mental health. The burden of care that arises in this process increases the stress and burnout levels of caregivers, causing psychological symptoms, especially depression and anxiety. However, it has been shown in many studies that the incidence of chronic diseases in caregivers is high. The level of physical activity, which is one of the most important determinants of living a healthy life, has an impact on the physical and mental health of individuals. In this study, we aimed to examine the physical activity levels of family members who care for individuals with Alzheimer’s disease.

Method

The sociodemographic information of the caregivers and the functional levels of the patients they care for were recorded in the forms we prepared. Physical activity level was evaluated with the ‘Quick Assessment of Physical Activity Scale’.

Result

Of the caregivers participating in the study, 88.4% were female and 11.6% were male. The mean age was 53.89±11.9 years. 79.7% of them were not working actively. 40.6% of caregivers diagnosed with Alzheimer’s disease were completely dependent on their caregivers in daily life. It was found that 6.7% of the participants were physically inactive and 66.7% had insufficient physical activity.

Conclusion

It was observed that the percentage of physically inactive Alzheimer’s disease caregivers was above the average of individuals in the same age group living in Turkey. In this context, we think that it is important to investigate the economic, social and psychological factors that cause a sedentary lifestyle in caregivers. Considering the positive effects of physical activity on physical and mental health, it is important to provide conditions that support caregivers to be more active. In order to reduce the economic and social burden of Alzheimer’s disease in society, public health policies should not only be formed to cover individuals with Alzheimer’s disease, but also strategies should be included for the needs of caregivers.