bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating associations of multiple common infections with brain structure and white matter lesions: findings from prospective neuroimaging studies
Authors: Green Rebecca E , Sudre Carole H , Warren‐Gash Charlotte , Waterboer Tim , Hughes Alun D , Richards Marcus , Schott Jonathan M , Chaturvedi Nishi , Williams Dylan M
Published: December 2023

Background

Evidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common pathogens – selected based on their relevance to public health – and brain volume, hippocampal volume, and white matter lesions in two population‐based cohorts in the UK.

Method

Serology and imaging data were available for 1371 participants across two studies: the UK Biobank (N = 935, mean age(SD)[years] = 55.3(7.7) at serology; 63.8(7.7) at imaging) and the Medical Research Council National Survey of Health and Development [N = 436, mean age(SD) [years] = 63.3(1.1) years at serology; 70.7(0.7) years at imaging). Serology measures included a) serostatuses of 17 pathogens, b) total proportion of 17 pathogens exposed to, and c) total proportion of 11 neurotropic pathogens exposed to (Table 1). Associations between serology measures and outcomes (brain volume, hippocampal volume, and white matter lesion volume) were tested using linear regression. Regression models included adjustments for total intracranial volume and clinic information (basic models), and age, sex, ethnicity, education, socioeconomic position and lifestyle factors (Figure 1). Findings across cohorts were meta‐analysed using random‐effects models. The present study will be expanded to include an additional cohort (Southall and Brent Revisited,N≤1200) to add more precision for identifying associations.

Result

Seropositivity to seven pathogens associated with an outcome in basic models, and four in fully‐adjusted models: seropositivity to JC virus was associated with smaller brain volumes, Epstein‐Barr virus with larger brain volumes, Merkel cell virus with larger hippocampal volumes and fewer white matter lesions, and C.trachomatis with fewer white matter lesions (Figure 2). Neurotropic pathogen burden scores associated with smaller hippocampal volumes in basic models, but no associations were seen for either pathogen burden score in fully‐adjusted models.

Conclusion

We found some evidence of both positive and negative associations between common infections and imaging markers of subclinical cerebrovascular disease and neurodegeneration, with no evidence of relationships with pathogen burden. This work highlights key relationships for further investigation, which may reveal novel pathways associated with brain structure and cerebrovascular pathology.
Ascorbate insufficiency disrupts neuronal transmission by surface electroencephalogram in a mouse model of Alzheimer’s disease
Authors: Buchanan Rebecca A. , Wang Yuhan , Harrison Fiona E.
Published: December 2023

Background

Ascorbate, or vitamin C, is an important antioxidant obtained through diet. Alzheimer’s disease (AD) has a high oxidative stress burden due to both AD‐specific neuropathology and associated neuroinflammation. Multiple studies link lower antioxidant potential with poorer cognition and accelerated cognitive decline in both animal and human studies. Many AD patients also present with neuronal transmission abnormalities which are detectable using electroencephalogram (EEG) and correlate with earlier presentation, accelerated decline, and poorer cognition. Ascorbate may have a specific role as a neuromodulator in AD as it is released concomitantly with glutamate reuptake following excitatory neurotransmission. We hypothesize that ascorbate insufficiency alters neuronal transmission in AD including increased spike‐wave discharges and alterations in brainwave patterning consistent with glutamatergic dysfunction.

Method

Using a mouse model of AD that requires dietary ascorbate (Gulo−/−APPswe/PSEN1dE9), EEG was recorded at baseline, during 4 weeks of ascorbate depletion, and with repletion at week 5. We determined changes in global neuronal firing patterns in young (5 months) and aged (20 months) Gulo−/−APPswe/PSEN1dE9 and control male and female mice. Data were scored for changes in spike wave discharges, sleep‐wake rhythms, and brainwave power bands each week. Amyloid‐beta levels were quantified by ELISA. Protein expression levels of glutamate clearance transporters, GLT‐1 and GLAST, and ascorbate levels in cortex and liver were quantified in a separate cohort of mice.

Result

Preliminary data suggest an early increase in neuronal spike discharges with age and following ascorbate depletion. A reduction in EEG amplitude is also observed with decreasing ascorbate. Our findings are consistent with epileptiform activity and an increase in wakeful periods compared to slow‐wave and paradoxical sleep in our aged mice which are observed in AD patient subpopulations. Amyloid‐beta levels were consistent with a genotype‐ and age‐dependent increase. Expression of GLAST in cortex was decreased in Gulo−/−APPswe/PSEN1dE9 mice, and no change in Gulo−/− mice, following 1‐week of ascorbate depletion.

Conclusion

Our data suggest that maintaining optimal brain ascorbate levels may support normal epileptiform activity and a sensitivity to changes in glutamate reuptake transporters, particularly in cases in which increased neuronal spike discharges, such as in AD subpopulations, are already observed.
Syntactic processing skills in elderly people with mild cognitive impairment and mild Alzheimer’s disease
Authors: Cruz Souza Wellington , Radanovic Marcia , Carvalho Claudia Lopes , Forlenza Orestes Vicente
Published: December 2023

Background

Communication and language impairments may be found in individuals with CCL. Thus, a better understanding language processing in this group and in healthy aging is necessary. Most studies in CCL and AD have focused on naming and semantic processes, and few studies have focused on syntactic processing skills, especially in the Brazilian population.

Method

A total of 114 elderly people of both sexes, aged at least 60 years, living in the city of São Paulo, were evaluated. The subjects were divided into 32 healthy elderly, 22 with aminestic mild cognitive impairment, 43 with non‐aminestic mild cognitive impairment and 17 with mild Alzheimer’s disease. For language assessment, the Grammar Reception Test – TROG2 was used as the main instrument, as well as the tests Northwestern Anagram Test, Token Test and the Object and Verb Naming Battery. For cognitive evaluation using the tests and functionality, the following tests were used: MoCA, Rivermead Behavioral Memory Test, Tracks A and B Test, Rey‐Osterrieth Complex Figure Test, Stroop Test, Digit Extension Test, Learning Test Verbal de Rey FAS, Three Words Three Shapes Test. The functionality of the was assessed using the Lawton & Brody scale for Activities of Daily Living.

Result

Our results showed differences in performance among the control, CCL, and AD groups in the total number and the profile of correct answers according to the type of sentence tested (p<0.05). Sentences with zero anaphora structure discriminated the control group from CCLa and AD, as well as CCLna from AD; pronoun gender/number sentences discriminated controls from CCLa (p<0.05). These sentence types bring to evidence the effect of increased demand on working memory and executive functions on syntactic processing.

Conclusion

The use of the Grammar Reception Test ‐ TROG ‐ 2 instrument can be useful in the assessment of the elderly, serving as a reference to differentiate healthy aging from cognitive and language impairments. Patients with MCI already have difficulties in syntactic processing when syntactic complexity is increased, overloading working memory and executive functions. These difficulties are intensified in patients with AD.
Do we really need to normalize Hippocampal volume?
Authors: Fernandez‐Lozano Sofia , Fonov Vladimir S , Dadar Mahsa , Collins D Louis ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Hippocampal volume (HCvol) is an important biomarker in the study of neurodegeneration (1‐3). A drawback of HCvol as a clinical biomarker is its high variability across the population (4). While the common approach to account for this variability is to normalize for head‐size variability using the intracranial volume (ICV) (5), other approaches use the idea of ex‐vacuo dilation, considering the expansion of the surrounding ventricle (6,7).

Method

With a library of 80 manually segmented hippocampi and surrounding temporal horns of the lateral ventricles from healthy subjects we trained three automatic segmentation methods: multi‐atlas label fusion (MALF) (8), non‐local patch‐based segmentation (NLPB, aka SNIPE) (9) and a Convolutional Neural Network (CNN) with a U‐Net architecture (10) and compared their performance (Cohen’s Kappa). We obtained the raw and normalized Hippocampal volumes (HCvol/ICV) as well as the Hippocampal‐to‐Ventricle Ratio (HVR = HCvol/(HCvol+CSFvol)) (7) on the baseline T1w MRI scans from the ADNI dataset for each segmentation method. We used these measures to calculate the robust effect sizes (Cohen’s d) and their confidence intervals (bootstrap: 5,000 resamples) between cognitively normal (CN), mild cognitive impaired (MCI) and subjects with dementia (AD) from ADNI‐1, 2, 3 and Go.

Result

After acquisition QC (CN = 502, MCI = 815, AD = 324), Table 1 shows the number of successful HC and CSF segmentations for each method. The CNN U‐Net had the least number of failed segmentations. The CNN U‐Net also obtained the highest performance. While NLPB had similar Kappa values to MALF, it had less variability (Fig 1). On Fig 2, we show the calculated effect sizes between Diagnoses, HC measures and segmentation methods. HVR yields a greater effect size than HCvol and HCvol/ICV to separate AD from CN or MCI when using MALF. With NLPB, HVR and HCvol are better than HCvol/ICV. Finally, with the CNN U‐NET, the three metrics perform similarly.

Conclusion

The CNN U‐Net provides improved segmentations over both MALF and NLPB. Such better‐quality segmentations reduce the need for normalization. However, HVR might be better suited than ICV normalized values when working with limited quality segmentations.
Functional Interactions of Low‐density Electroencephalography During Sleep Cycles to Detect Alzheimer’s Disease
Authors: Herzog Ruben A , Haghayegh Shahab , Hu Kun , Ibanez Agustin
Published: December 2023

Background

Alzheimer’s disease (AD) causes disruption in the collective dynamics of the brain activities which can be captured by analyzing the functional interactions between electroencephalographic (EEG) signals in different regions of the brain. To better assess the AD‐related changes in the interactions, one possible approach is to increase the EEG electrode density for better spatial information. Alternatively, high order interactions within the fluctuations of low‐density EEG — a concept of the multivariate information theory — may better reveal complex EEG interactions and can be used to detect AD‐related changes in brain activities. This study is aimed to demonstrate this conceptual approach using machine learning.

Method

We analyzed overnight 4‐channel EEG recordings (left central, right central, left mastoid, and right mastoid) in the polysomnography (PSG) data collected from 28 older men in the Osteoporotic Fractures in Men Study (MrOS). 14 participants reported a history of clinical diagnosis of AD while the other 14 did not. Groups were matched in age and education. Each of 30‐second epochs of the PSG recording was scored as wake, N1, N2, N3, or rapid eye movement sleep according to the established guideline. Features based on low (2) and high order (3‐4) interactions between electrodes, i.e., total correlation (TC), dual total correlation (DTC), O‐information (O) and S‐information (S), were extracted from raw and band‐passed filtered data (δ: 0.5‐4 Hz, θ: 4‐8 Hz, α: 8‐12 Hz, β: 12‐30 Hz, γl: 30‐40 Hz, γh: 40‐100 Hz) within each wake/sleep stage. The optimal set of features was identified using a cross‐validated random forest classifier to maximize the group discrimination.

Result

AD was discriminated from control with an average area under the receiver operating characteristic curve of 0.90±0.05 using just 3 features: O (triplet) measured in the γh band within wake stage, DTC (triplet) of raw EEG within N1 stage, and TC (pairwise) in the δ band within N1 stage.

Conclusion

This proof‐of‐concept study shows the possibility of using low‐density sleep EEG to detect AD. This method might be useful for screening people with risk of AD in ambulatory setting.
Investigating the link between locus coeruleus activity during wakefulness and sleep electrophysiology using ultra‐high‐field MRI ‐ implications for AD
Authors: Gilles Vandewalle
Published: December 2023

Background

A bidirectional link between sleep regulation and Alzheimer’s disease neuropathology emerges in the literature. The locus coeruleus (LC) is the main source of norepinephrine (NE) of the brain, it is the first brain site show signs of tau pathology and is central to the regulation of arousal and sleep. It may therefore contribute to the link between sleep and AD. However, the precise role of the LC in shaping healthy sleep variability is not established in humans.

Method

Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI) and sleep questionnaires and electroencephalography (EEG) in 53 younger (N = 34; 18‐30y) and older (N = 19; 50‐70y) healthy individuals to test whether the address this first question and assess whether activity of the LC during wakefulness was associated with sleep metrics in healthy younger and older individuals.

Result

We found that higher LC activity during wakefulness probed in an auditory attentional task is associated with worse subjective sleep quality (P = 0.007) and with lower EEG theta (4‐8 Hz) power during REM sleep in late midlife (50‐70 y) (P = 0.037), but not in young (18‐30 y) individuals. Further preliminary results suggest that LC activity probed with a visual perceptual rivalry task confirm the associations. These preliminary results may indicate, however, that higher LC activity during wakefulness may be association with better sleep quality.

Conclusion

These results suggest that the inverted U‐shape between LC activity during wakefulness and brain functioning reported for cognition also pertains to some aspects of nighttime sleep. They contribute to the understanding of the role of the LC in sleep physiology and pave the to investigate its contribution to AD through sleep.
Moderate alcohol use, total brain volume, and white matter hyperintensities among racially and ethnically diverse middle‐aged adults
Authors: Guzmán Diana S. , Renteria Miguel Arce , Avila Justina F , Turney Indira C , Rossano Samantha , Johnson Aubrey S. , Smith Anna C. , Okafor Amarachukwu , Morales Clarissa , Gu Yian , Manly Jennifer J. , Brickman Adam M. , Lao Patrick J.
Published: December 2023

Background

Moderate alcohol use may provide later life cognitive benefits compared to heavy alcohol use. However, results have been mixed, with reports of both increased and decreased gray and white matter volumes with moderate drinking. Additionally, alcohol use on brain health may differ by sex and race/ethnicity. Understanding the association between brain health and moderate drinking in a representative, community‐based study will provide insight into the reported cognitive benefits. We investigated the relationship between alcohol use and total brain volume (TBV) and white matter hyperintensities (WMH) in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults.

Method

Participants (N = 350; Mage = 54±10 years; 33 Black Men, 38 Black Women, 66 Latinx Men, 166 Latinx Women, 7 White Men, 20 White Women) from the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease, a community‐based study in Northern Manhattan, underwent structural (TBV = 1051±106cm3) and vascular (WMH = 3±4cm3) MRI. Alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C). Individuals likely to be alcohol dependent (AUDIT‐C≥9) were excluded (n = 16). We assessed alcohol use and TBV or WMH, adjusting for age, in the overall group, and stratified by sex/gender groups, racial/ethnic groups, and sex/gender by race/ethnicity groups.

Result

Overall, greater TBV was associated with younger age (‐3.5cm3 [‐4.7, ‐2.3], p = 9E‐10) and greater alcohol use (5.1cm3 [‐6.8, 10.8], p = 0.085). No associations were found within men and women separately. Within race/ethnic groups, greater alcohol use was associated with greater TBV only among Latinx (7.6cm3 [0.1, 15.3], p = 0.055). Within sex/gender by race/ethnicity groups, greater alcohol use was associated with lower TBV among White men (‐36.8cm3 [‐45.0, ‐28.5], p = 1E‐3). There were no associations with WMH.

Conclusion

Moderate alcohol use was not reliably associated with brain health, but the effect was on the order of 1‐2 years of aging, in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults. However, moderate alcohol use may have effects on brain volume within specific sex/gender and race/ethnicity groups with implications for later life cognitive impairment. Future work should explore region specific associations, alcohol use factors (i.e., context of use, alcohol type, duration of use), and its relationship to change over time.
Co‐production in the PREVENT Next Generation Study: methodology and outcomes
Authors: Gregory Sarah , Amfo‐Antiri Auswell , Agyapong Nana Ama Frimpomaa , Davies Michaela , Danso Samuel O. , Farina Francesca R , Saunders Stina , Wells Katie , Willingham Katie , Booi Laura
Published: December 2023

Background

Involving patients and the public as stakeholders (hereafter described as contributors) in the design and management of research studies is increasingly recognised as central to conducting ethical, meaningful and translatable research. Consulting and co‐producing are two methods for involving public contributors in the research cycle. This abstract describes the methodology used to establish a co‐production model for the PREVENT Next Generation (NextGen) research program, alongside initial impact the contributors have had on the program. The NextGen research programs aims to explore brain health in young adults (aged 18‐39), and all contributors represent this age group.

Method

Adverts appealing for public contributors were sent to voluntary and community sector enterprises, universities, promoted on social media and spread via word of mouth. The first round of recruitment focused on contributors living in North America and Europe, with recruitment underway in Ghana. Contributors watched an introductory video, completed a form to indicate interest and were sent an invite to a virtual meeting. The aim of the initial work was to consider and feedback on the NextGen proposal, beginning the co‐production by identifying topics of interest for inclusion in planned work.

Result

Public contributors joined the initial meetings and were supportive of the need to understand more about brain health in young adults. Public contributors were interested in exploring topics such as the role of sex differences, social relationships and air pollution on brain health. Considering the focus groups (Phase 1 of NextGen), contributors advised having a choice of times that would support adults in work or education to join, as well as expressing a preference for virtual engagement for such studies.

Conclusion

Employing a public involvement and co‐production model from the initial design stage of the NextGen study has proven invaluable to identifying topics of importance to include in future studies involving this age group. Future work will continue to develop the NextGen research program work with public contributors. Expansion of the public contributors to represent different global regions is underway, and will be critical to designing an inclusive study that is meaningful to the populations from which participants are enrolled.
Manipulation of Dietary DHA does not Alter DHA Brain Uptake Kinetics in Mice Despite Changing Brain and Plasma DHA Levelsvs
Authors: Duro Marlon Vincent V. , Van Valkenburgh Juno S. , Abdullah Laila , Ingles Diana E. , Cai Zhiheng , Kerman Bilal Ersen , Wang Shaowei , Jacobs Russell E. , Sta. Maria Naomi , Zanderigo Francesca , Croteau Etienne , Cunnane Stephen , Rapoport Stanley I. , Chen Kai , Yassine Hussein N.
Published: December 2023

Background

Increased brain docosahexaenoic acid (DHA) uptake reflects a compensatory mechanism for maintaining brain DHA homeostasis and can be captured through PET‐MRI scan uptake studies using radiolabeled DHA. It has been previously shown that APOE4 status and alcohol intake alter brain DHA uptake in mice. Whether a change in DHA intake affects the brain DHA incorporation coefficient (K*) however is not known.

Method

Four‐month‐old C57BL/6J mice were fed either a diet rich in DHA (15 kcal% Fat, 1.7 g/kg ALA, and 7g/kg DHA) or deficient in DHA (15 kcal% Fat and 0.9 mg/kg ALA) for 4 months. At 8 months, anesthetized mice were subjected to dynamic PET‐MRI for 30 min following i.v. injection of 22‐[18F]fluorodocosahexaenoic acid ([18F]FDHA), prepared in‐house through radiosynthesis. Using an image‐derived cardiac input function, brain uptake was assessed by estimating [18F]FDHA K* values using both the Patlak model approach and the irreversible two‐tissue compartmental model (Irr2TCM) with and without correction of the brain radioactivity for radioactive spillover from the skull. Mice were then sacrificed, and the plasma and brains were analyzed using liquid chromatography‐mass spectrometry (LC‐MS) to evaluate differences in the unlabeled concentrations of fatty acids into phospholipids, triglycerides, and other lipids.

Result

There was no significant difference in the [18F]FDHA K* estimates (with either Patlak or Irr2TCM) between mice fed a DHA‐rich or a DHA‐deficient diet. LC‐MS based lipidomic analysis showed that the DHA‐rich diet significantly increased DHA concentration in triglycerides in plasma and in phosphatidylethanolamine in the brain.

Conclusion

These results suggest that under physiological conditions, increased dietary intake of DHA in wild‐type mice increases DHA in brain phosphatidylethanolamine and in plasma triglycerides without changing the DHA K*. The net effect likely is increased brain DHA uptake, equal to the product of unesterified DHA plasma concentration and K*. Imaging brain DHA with dynamic [18F]FDHA PET‐MRI is a potentially useful tool not only to investigate the APOE4 phenotype, which promotes DHA dysregulation, but also to assess dietary and pharmacological interventions that affect brain DHA homeostasis as well as to guide future treatments.
Using deep learning model on drawing tasks as a screening tool for mild cognitive impairment in older adults with sensory impairments
Authors: Chunharas Chaipat , Chatnuntawech Itthi , Ruengchaijatuporn Natthanan , Teerapittayanon Surat , Chotibut Thiparat , Raksasat Raksit , Sriswasdi Sira , Itthipuripat Sirawaj , Petchlorlian Aisawan , Chunamchai Sedthapong
Published: December 2023

Background

Mild cognitive impairment (MCI) and sensory impairments commonly co‐exist in an aging population (e.g., Rong et al. 2020). A previous study has shown that patients with hearing impairment tend to do worse on verbal tests (Utoomprurkporn 2020). The reason is that the patients fail to hear the task instructions and have to put in more effort which is cognitively taxing. Therefore, a non‐verbal cognitive task for MCI screening is needed.

Method

We developed a deep learning model for MCI screening which requires only drawing tasks (trail‐making task, cube‐copying task, clock drawing task) on a digital tablet as its inputs. We cross‐validated the model on 981 subjects (age 55‐89, 77% female, 29% MCI) from our healthy aging clinic. The model used VGG16 as a backbone with self‐attention layers which expect to both improve the model performance and provide visual explanations.

Result

The model can discriminate between MCI and healthy controls with an AUC of 0.84. Our model provided better visual explanations that are compatible with how experienced clinical psychologists interpret the drawings. To increase the generalizability, we further developed a second model that aims to automate the clock drawing scoring. The models were tested in patients with and without sensory impairments.

Conclusion

We investigated the feasibility of our deep learning models on drawings as a potential tool for MCI screening in an aging population with sensory impairments. The tool requires little or no human clinical experience and potentially can be used as a part of the population‐based MCI screening program.
Neuropsychological assessment as a predictor of dementia conversion in Alzheimer’s disease
Authors: Goodman Zachary T , Blennow Kaj , Zetterberg Henrik , Vontell Regina T , Rundek Tatjana , Scott William K. , Llabre Maria M , Levin Bonnie , Sun Xiaoyan
Published: December 2023

Background

Progressive cognitive decline is a characteristic of Alzheimer’s disease (AD). Identifying reliable predictors of conversion to dementia in older adults, particularly those with mild cognitive impairment (MCI), is critical for clinicians, patients, and patient families.

Method

1083 adult participants (Age: M = 73.20, SD = 6.92) were included in this study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The average follow up was over 5 years (M = 65.25, SD = 40.16). Cox proportional hazards regression models were implemented to estimate the risk of dementia. Models were built sequentially to examine changes in predictive contributions when including biomarkers and cognitive predictors.

Result

57% of participants were classified as MCI and 43% as cognitively normal (CN). By the end of study, there is an overall conversion rate of 24% from the participants with cognitive normal and MCI to dementia. Participants with MCI demonstrated significantly higher rates of conversion than those with CN (F(1,258) = 92.51, p < .001, η2 = .26). The initial model indicated greater age (HR = 1.03, p = .004), fewer years of education (HR = 0.95, p < .027), the presence of at least one APOE ε4 gene (HR = 3.23, p < .001), and higher levels of neurofilament light chain (NFL) (HR = 1.28, p < .001) predicted conversion to dementia. A second model indicated higher levels of Ab42 was predictive of lower risk (HR = 0.41, p < .001), whereas higher levels of P‐tau was predictive of greater risk (HR = 1.48, p < .001). APOE ε4 presence and NfL levels remained significant predictors. Finally, composites of memory and executive scores were added. Memory performance at baseline was highly associated with dementia risk (HR = 0.26, p < .001), with poorer performance at baseline predicting greater likelihood of conversion. Similarly, poorer performance on executive functioning tasks was predictive of dementia risk (HR = 0.57, p < .001).

Conclusion

Composite scores of memory and executive functions are strong predictors of conversion to dementia. Such composites are approximately as predictive as Ab42, and more predictive than demographics, APOE ε4 presence, baseline P‐tau and NFL.
The impact of alcohol consumption on the cognitive performance of older adults with mild cognitive impairment
Authors: Dhakal Usha , McLaughlin Sara J. , Kim Seonjin
Published: December 2023

Background

Current evidence suggests that excessive alcohol consumption increases the risk of developing dementia and cognitive decline and that mild to moderate drinking confers protection; however, findings are mixed. In those with mild cognitive impairment (MCI), evidence concerning the role of alcohol consumption is especially limited. To enhance understanding, we assessed the impact of alcohol use on cognitive trajectories in a large sample of older Americans with MCI.

Method

Using hierarchical linear mixed modeling and data from eight waves (2004‐2018) of the Health and Retirement Study (HRS), we examined the relationship between alcohol use and cognitive functioning (sum of tests of immediate and delayed word recall, a serial seven subtraction test, and counting backwards, range: 0 to 27) among 1468 adults age 60 years and older with MCI at baseline. Model covariates included APOE, demographics, functional status, and other health and lifestyle‐related factors that are associated with dementia.

Result

The average cognitive score of older adults with MCI at baseline was 9.5. While no significant association between alcohol consumption and cognitive functioning was observed at baseline, alcohol consumption was positively associated with cognitive functioning over time. Among those who did not consume alcohol, the average cognitive score declined by 0.12 points each year (β = ‐0.12, p<0.0001). Compared to those who never drank alcohol, low to moderate (male<15 and female<8 drinks; β = 0.08, p = 0.0001) and heavy (male> = 15 and female> = 8 drinks; β = 0.13, p = 0.03) drinking were associated with more favorable cognitive performance over time.

Conclusion

Findings from this study suggest that alcohol consumption confers protection against cognitive decline among older adults with MCI. Future studies are needed, however, to more fully investigate how the nature of drinking (e.g., types of drinks consumed, the number of drinking years, binge drinking) may influence the relationship between alcohol consumption and cognitive performance over time.
Attitudes of smartphone‐based hearing screening test use among patients with mild cognitive impairment: A qualitative study
Authors: Limkitisupasin Patcharaorn , Utoomprurkporn Nattawan , Tangwongchai Sookjaroen
Published: December 2023

Background

While the importance of early diagnosis of hearing loss in older adults with cognitive impairment has been increasingly highlighted, smartphone‐based self‐hearing assessments have become widely adopted due to their low cost, easy‐to‐use, and accessibility. The validity and reliability of this method have been accepted for detecting hearing loss. However, few studies were conducted on this vulnerable population. The purpose of this qualitative study was to explore older adults with mild cognitive impairment’s experiences, perceptions, and attitudes toward digital self‐hearing screening tools.

Method

Seventeen patients with mild cognitive impairment (MCI) were recruited from memory clinic in Bangkok, Thailand. Focus groups were conducted to understand self‐perception of hearing problems and their experience after using smartphone‐based hearing screening application. Thematic analysis was used to analyze the data.

Result

All focus groups discussed self‐perception of hearing loss, experience of use, as well as feedback for smartphone‐based hearing screening application. The acceptability and attitude of smartphone‐based hearing test was explored. Individual experiences varied depending on personal factors and lifestyle.

Conclusion

Digital self‐hearing screening tools emerged as potential method for screening hearing impairment. The findings of this study described opinions, feedback, and factors that contributed to the usage of smartphone‐based hearing screening applications. These findings will inform further developments of this tool based on the personalized needs of individuals with cognitive impairment, with the objective of facilitating the early detection and timely intervention for hearing loss in this population.
The synaptic biomarker contactin5 differentiates between neurodegenerative dementias
Authors: Gouda Mariam , Muqaku Besnik , Hok‐A‐Hin Yanaika S. , in ’t Veld Sjors G.J.G. , Verberk Inge M.W. , Otto Markus , Teunissen Charlotte E. , Oeckl Patrick
Published: December 2023

Background

Synapses are crucial for memory formation, and their disruption is among the earliest events in Alzheimer’s disease (AD) pathogenesis. Less is known about synaptic alterations in other types of dementia. Contactin5 (CNTN‐5) is a synaptic protein and one of the neural adhesion molecules. It contributes to synaptic formation, plasticity and is associated with dendritic morphogenesis. A GWAS identified a risk variant (rs 141684 G) in CNTN‐5 gene, which is associated with increased risk of AD development. We aimed to assess whether CNTN‐5 could be a differential diagnostic cerebrospinal fluid (CSF) biomarker for AD from other types of dementia.

Method

CNTN‐5 levels in CSF samples were measured with two methods: an in‐house developed immunoassay on the automated ELLA platform, and a multiple reaction monitoring mass spectrometry (MRM) assay. The clinical cohort included controls (n = 27), patients with AD (n = 19), patients with behavioral variant frontotemporal dementia (bvFTD) (n = 18), and patients with dementia with Lewy bodies and Parkinson’s disease dementia (PDD/DLB) (n = 18; table 1). CNTN‐5 results obtained with both methods were correlated using spearman’s correlation. Differences in CNTN‐5 levels between the diagnostic groups were assessed with Kruskal‐Wallis test and corrected with Dunn´s factor for multiple comparison.

Results

As shown in Figure 1, CNTN‐5 measurements between methods were strongly and positively correlated (rho = 0.58, p<0.001). In AD patients, CNTN‐5 levels were significantly elevated in comparison to bvFTD patients with both assays (both: p<0.05), as well as, compared to patients with DLB/PDD (MRM: p<0.05 and ELLA: p<0.01). There was no significant difference in CNTN‐5 levels between AD and controls, or between bvFTD and PDD/DLB, as shown in figure 2.

Conclusion

Our results showed that elevated CNTN‐5 is a promising synaptic biomarker, with specificity for AD. As a next step, we would look further into a larger clinical cohort, where associations between CNTN‐5 levels and cognitive stage could be thoroughly studied.
Culturally relevant protective factors and relationships with cognitive decline in First Nations Australians
Authors: Lavrencic Louise , Mack Holly , Withall Adrienne , Delbaere Kim , Broe Gerald A , Daylight Gail , Draper Brian , Lasschuit Danielle , Radford Kylie
Published: December 2023

Background

First Nations people in Australia experience dementia prevalence 3‐5 times higher than the broader Australian population. There is strong focus on risk factors (particularly biomedical) in dementia research; yet further research is required to understand protective factors, especially psychosocial and cultural determinants. Cognitive reserve (CR) refers to the brain’s adaptability when faced with age or neurodegenerative‐related changes. CR is important for understanding cognitive outcomes and dementia onset. Psychosocial factors are thought to contribute to CR, including education and work opportunities. Yet, the appropriateness of conventional CR measures for First Nations people, and the role of culturally‐specific protective factors in CR, is unclear.

Method

Data were from the Koori Growing Old Well Study, a longitudinal, population‐based study with First Nations Australians aged 60+ from 5 rural/urban communities in New South Wales (N = 336 baseline; N = 165 6‐year follow‐up, n = 68 died before follow‐up). Comprehensive and holistic interviews were carried out. Dementia and mild cognitive impairment (MCI) were based on clinical assessment and consensus review. CR factors spanned education and work opportunities, sociocultural activities/connections, creative hobbies, playing sports, and social contact. Logistic regression analyses were used to examine factors at each life stage (early/mid/late‐life) in relation to cognitive decline (incident MCI/dementia).

Result

The analyses included 155 participants (excluding N = 10 with baseline dementia). Of the early‐life factors, singing (from the Retrospective Indigenous Childhood Enrichment Scale) (OR = 0.33; 95% CI 0.13, 0.86; p = .024) was associated with a lower risk of cognitive decline in the multivariable model; and years of education (OR = 0.79; 95% CI 0.66, 0.94; p = .008) predicted cognitive decline in univariable analysis. For midlife, history of unskilled work was associated with cognitive decline (OR = 5.44; 95% CI 2.32, 12.75; p = <.001). No variables in the late‐life model were significantly associated with cognitive decline.

Conclusion

This study is the first to examine factors that may contribute to CR in First Nations communities, including culturally‐specific items. These results suggest that certain life‐course experiences may protect against cognitive decline; however, revised and sensitive measures are needed to capture nuanced differences. A culturally relevant and more comprehensive CR measure is currently being piloted with First Nations people.
Discovery of farnesyltransferase inhibitors (FTIs) with high brain exposure for treatment of Alzheimer’s disease and other tauopathies (T‐PEP Related Presentation)
Authors: Olson Steven
Published: December 2023

Background

Farnesyltransferase (FTase) is a prenyltransferase enzyme that adds farnesyldiphosphate to the cysteine of CaaX proteins. Compelling evidence suggests that FTase inhibitors (FTIs) cause lysosome activation and a dramatic increase in tau degradation (Hernandez, et al. Science Translational Medicine 11.485 (2019): eaat3005)

Method

Novel small molecule inhibitors of FTase were synthesized and tested in a luminescence‐based enzymatic assay of FTase inhibition. Active compounds were tested in ADME assays including MDCK‐MDR1 cells to evaluate permeability and transporter‐mediated efflux. Optimized compounds were evaluated in pharmacokinetics and in vivo pharmacodynamics (PD) experiments measuring enzymatic farnesylation of farnesyl alcohol azide in the mouse brain.

Result

We report the first highly brain‐penetrant FTase inhibitors. These compounds show nanomolar potency and achieve high exposure in both plasma and brain. PD experiments show that the compounds inhibit farnesylation in the CNS of our mouse model

Conclusion

Brain penetrant small molecule FTase inhibitors show promising preclinical pharmacology and are currently in the lead optimization stage of drug discovery.
LEADing advance care conversations: concordance amongst ADRD dyads
Authors: Supiano Katherine P , Clayton Jordana L , Aruscavage Nancy R , Dassel Kara B , Utz Rebecca , Iacob Eli
Published: December 2023

Background

The LEAD Guide (Life‐Planning in Early Alzheimer’s and Other Dementias)1 is a validated paper‐based dementia‐focused advance care planning (ACP) guide that addresses changes in cognition and goals of care along the ADRD continuum, preparing surrogate decision‐makers for loss of the care recipient’s decisional abilities. Achieving agreement on decision elements of ACP in care partner (CP)/care recipient (CR) dyads may reduce ambiguity, increase CP confidence, and assure that preferences and values are honored. Using multiple approaches, we developed a working definition of ACP concordance amongst ADRD dyads.

Method

Using the LEAD Guide as the foundation we developed the pilot LEAD Intervention, a community‐based NIH Stage‐1 behavioral intervention.2 This 9‐month study guided CP/CR dyads through a dementia‐focused ACP process that integrates a digital version of the LEAD Guide with ACP educational modules delivered through a web‐based platform. Dyads had the option of recording their care conversation. To understand the process of achieving dyadic consensus in elements of ACP, we conducted a scoping review of the literature and a qualitative analysis of recorded interviews.

Result

Of 61 eligible dyads, 41 completed the LEAD intervention; 7 in‐depth recordings were obtained. Our scoping review of 6,788 manuscripts identified no operational definitions of ACP concordance, 35 that revealed essential elements of successful discussion processes and only one that characterized essential qualities of CPs. Using descriptive analysis,3 seven themes illustrating agreement on ACP issues were discerned: Respect/Regard for each other; use of Clarifying Processes; Conveying Health Care Scenarios to justify wishes; Affirmation of Understanding; Recognizing Uncertainty; Humor and Expression of Positive Emotions; and Trust. Notably, all seven dyads voiced confidence that they “finished the discussion successfully,” meaning reaching a state of concordance.

Conclusion

Our synthesis of the research literature and our qualitative findings suggests that a working definition of ACP decision concordance is when the caregiver understands the patient’s values that inform the preferences and choices of the patient, understands those choices and preferences and the rationale for the choices and preferences, and expresses a willingness to accomplish the patient’s wishes to the best of their ability. This definition contributes to research clarity in ACP investigations.
Short sleep duration and hypertension: A double hit for the brain
Authors: Yiallourou Stephanie , Song Xuemei , Wiedner Crystal , Bernal Rebecca , Himali Dibya , Baril Andree‐Ann , Cavuoto Marina G. , Decarli Charles , Beiser Alexa S. , Seshadri Sudha , Himali Jayandra Jung , Pase Matthew P.
Published: December 2023

Background

The mechanisms linking short sleep duration to increased dementia risk remain unclear. Sleep duration has a powerful influence on blood pressure (BP), with short sleep durations increasing hypertension risk. Since high BP is a dementia risk factor, short sleep may increase risk of cognitive impairment via adverse effects on vascular health. We assessed whether the association of sleep duration with cognition and vascular brain injury was moderated by hypertensive status.

Method

684 dementia‐free participants (mean age 62±9 years; 53.1% female) from the community‐based Framingham Heart Study Offspring and Omni 1 cohort completed assessments of cognition, office BP, and self‐reported habitual sleep duration; 637 also completed brain MRI. Hypertensive status was defined as a combination of systolic BP ≥ 140mmHg and/or diastolic BP ≥90mmHg or use of anti‐hypertensive medication. Outcomes included the Trail Making Test B minus A, Visual Reproductions, Similarities, and white matter hyperintensity volume (WMHV) expressed as a percentage of intracranial volume. Linear regressions were performed between total sleep time and cognitive domains adjusted for demographic factors, APOE e4 positivity, use of sleeping pills, and BMI. An interaction term for hypertensive status was included in regression models.

Result

Short sleep durations of ≤5 hours/night occurred in 13% of participants and 35% were hypertensive. There were no direct associations between sleep duration and any of the outcomes. However, there was a significant interaction between sleep duration and hypertensive status when predicting the outcomes of executive function/processing speed (Trail Making) and WMHV. When data were stratified by hypertensive status, shorter sleep duration was associated with poorer executive function/processing speed scores in the hypertensive group (β±SE = 0.04±0.02 per hour increase in sleep duration, p = 0.02), but not in the normotensive group (β±SE = ‐0.01±0.01, p = 0.22). Similarly, shorter sleep duration was associated with higher WMHV burden in the hypertensive group (β±SE = ‐0.13±0.06, per hour decrease in sleep duration, p = 0.03), but not in the normotensive group (β±SE = 0.01±0.04, p = 0.760).

Conclusion

The combination of short sleep and hypertension is associated with worse cognitive performance and brain injury. Further work will examine this interaction more completely.
Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Leffa Douglas Teixeira , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Rohden Francieli , Abbas Sarah , Benedet Andrea Lessa , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Klunk William E , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick Ali
Published: December 2023

Background

Astrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐β (Aβ) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aβ and tau differs in men and women

Method

We assessed 1,016 CU individuals from three cohorts with available Aβ (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aβ‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aβ burden.An interaction between term between Aβ*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.

Result

We found that Aβ burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aβ with plasma p‐tau181 (β = 0.71,p<0.0001,Fig.1a) or p‐tau217 (β = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aβ and sex on plasma p‐tau181 (β = 0.47,p = 0.005,Fig1a) and p‐tau217 (β = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aβ and plasma p‐tau epitopes between men and women. In men but not women, Aβ‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.

Conclusion

A sex effect was observed in the association between Aβ burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aβ on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aβ therapies already showed different effects between men and women.