bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Baseline Diffusion Tensor Imaging Biomarkers in phase 2 multi‐center PROSPECT‐ALZ study
Authors: Svaldi Diana O , Rathore Saima , Cheng Yun‐Ju , Munsie Leanne M , Fleisher Adam S , Brys Mirek , Shcherbinin Sergey
Published: January 2025

Background

Diffusion Tensor Imaging (DTI) biomarkers are increasingly utilized in clinical trials of Alzheimer’s disease (AD). They have shown promise in detecting AD related changes in white‐matter (WM) integrity (Raghavan et al., 2020) and gray‐matter (GM) microstructure (Ofori et al., 2019). Moreover, DTI‐derived connectome has been shown to be related to tau progression (Vogel et al., 2020). Our study evaluated baseline GM microstructure and WM integrity measures in the PROSPECT‐ALZ trial (NCT05063539) of LY3372689, an O‐GlcNAcase (OGA) inhibitor.

Methods

PROSPECT‐ALZ is a phase 2, randomized, double‐blind, multicenter, placebo‐controlled trial in participants with early symptomatic AD and presence of tau pathology measured using flortaucipir PET. Participants who received DTI scans (n = 223, age=73.40 (6.0), MMSE=25.6 (2.3), N female=124) were divided into groups based on visual assessment of flortaucipir images (Fleisher et al., 2021) (negative, n=56 vs positive, n = 144) and cognition (MMSE≤24, n = 81 vs MMSE>24 & MMSE≤29, n=133). Group differences in DTI scalars fractional‐anisotropy (FA), mean‐diffusivity (MD), and freewater‐fraction (FW) were evaluated in 16 GM regions and 9 WM tracts using ANCOVA (α = 0.05, LSmean±SE), adjusting for age and gender. FA and MD values were FW corrected (Conklin et al., CTAD 2023).

Results

Visually positive participants exhibited reduced FA in the hippocampus relative to negative participants (0.289±0.006 vs. 0.322±0.010). Positive participants exhibited increased MD in the hippocampus (1.224E‐03±2.328E‐05 vs. 1.055E‐03±3.692E‐05), isthmus cingulate (9.324E‐04±1.971E‐05 vs 8.440E‐04±3.126E‐05), medial temporal cortex (9.751E‐04±1.801E‐05 vs 8.772E‐04±2.855E‐05), and whole temporal cortex (1.050E‐03±1.707E‐05 vs 9.628E‐04±2.706E‐05). Finally, positive subjects exhibited increased FW in the hippocampus (0.554±0.006 vs 0.511±0.010), isthmus cingulate (0.457±0.006 vs 0.430±0.009), medial temporal cortex (0.475±0.005 vs 0.453±0.008), and whole temporal cortex (0.497±0.005 vs 0.472±0.008). No significant regional differences were found in WM. For MMSE, MD (1.243E‐03±3.141E‐05 vs 1.140E‐03±2.419E‐05) and FW (0.561±0.009 vs 0.529±0.007) in the hippocampus were significantly elevated in the more impaired group.

Conclusion

DTI was successfully implemented in phase 2 multi‐center PROSPECT‐ALZ study. Cross‐sectional analysis suggests that DTI measures can differentiate individuals based on global tau burden and cognition, presumably capturing differences in cortical microstructure. Future work will focus on multimodal evaluation of longitudinal changes in DTI, tau, and cognition.
Association of Traumatic Brain Injury with All‐cause and Dementia‐related Mortality: the Framingham Heart Study
Authors: Durape Shruti , Burton Rebecca , Joshi Prajakta S. , Chien‐Young Kurtis , Price Eden , Yhang Eukyung , Liu Yulin , Ang Ting Fang Alvin , Devine Sherral A. , Gurnani Ashita S. , Katz Douglas I , Tripodis Yorghos , Alosco Michael L. , Au Rhoda , Dams‐O'Connor Kristen , Mez Jesse
Published: January 2025

Background

Although traumatic brain injury (TBI) is known to be associated with short term mortality, its effects on long‐term mortality remain less clear. TBI is also a well‐known risk factor for dementia. We hypothesized that TBI would be associated with long‐term mortality, particularly dementia‐related mortality.

Methods

The Framingham Heart Study (FHS) is a population‐based cohort study which recruited its original cohort between 1948‐1950, and its offspring cohort between 1971‐1975. Information on TBIs was collected across the lifespan by comprehensive review of medical records, FHS health history updates and exams and self‐report. TBI occurrence and severity were operationalized using modified American Congress of Rehabilitation Medicine and Veterans Affairs/Department of Defense criteria, respectively. Dementia diagnosis was operationalized using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, and National Institute of Neurological and Communicative Diseases and Stroke/AD and Related Disorders Association criteria. Participants with history of TBI were matched to those without TBI for age and sex, with a 1:3 ratio. Participants who died within a year of TBI were excluded. Cox proportional hazards models assessed TBI risk for all‐cause mortality and cause‐specific competing risk models assessed risk for dementia‐related mortality.

Results

Over the course of study, 72.82% died, with 12.32% of deaths from dementia‐related mortality. 1,688 participants with TBI (Mean age at TBI = 69 (SD = 15.5) years, 59.89% women) and 5,064 age‐ and sex‐matched participants without TBI were followed for an average of 15±12 years after TBI. Hazard ratios (HRs) for all‐cause mortality were 1.09 (95%CI 1.00‐1.20) and 1.66 (95%CI 1.31‐2.09 for mild and moderate‐to‐severe TBI respectively. Hazard ratios (HRs) for dementia‐related mortality were 1.63 (95%CI 1.32–2.02) and 2.67 (95%CI 1.57–4.56) for mild and moderate‐to‐severe TBI respectively. Hazard ratios (HRs) for non‐dementia related mortality were 0.96 (95%CI 0.89–1.04) and 1.15 (95%CI 0.95–1.38) for mild and moderate‐to‐severe TBI respectively.

Conclusion

In a multi‐generational community‐based sample followed since the 1940s, mild and moderate‐to‐severe TBIs were associated with all‐cause mortality with the effect driven by dementia‐related mortality.
Factors associated with dementia caregiver burden across multiple Brazilian regions
Authors: Barbosa Matheus Ghossain , de Macedo Marcos Antonio Costa Ferreira , da Mata Fabiana A. F. , Ramos Ari Alex , de Oliveira Júnior Haliton Alves , Bertola Laiss , Ferri Cleusa P.
Published: January 2025

Background

The number of people with dementia (PWD) is increasing worldwide, and especially in low‐ and middle‐income countries (LMIC). Dementia’s burden extends beyond mortality and healthcare costs. In LMIC, dementia indirect costs are proportionally higher. In Brazil two thirds of the total dementia costs come from informal caregiving, mainly provided by women who quit their jobs to act as a carer for a relative.

Method

The ReNaDe project assessed dementia’s cost, unmet needs, and investment. We recruited 140 PWD‐caregiver dyads in 17 cities across the 5 Brazilian regions. PWD were selected through their public healthcare system medical charts, we included PWD 60 years and older at any dementia severity. For this analysis we evaluated the total score of the Zarit Burden Interview (ZBI) as our main outcome and used linear regression to test potential associated factors (sociodemographic, behavioral and clinical).

Result

We included 124 participants with complete data. More neuropsychiatric symptoms in the Neuropsychiatric Inventory (β = 2.07, p = 0.000), having an insufficient income to cover all household costs (β = 10.42, p = 0.001) and quitting, but not reducing, a job (β = 6.78, p = 0.045) were associated with higher burden, while having a replacement caregiver (β = ‐9.87, p = 0.001) was associated with lower burden. The caregiver or patient’s sex, age, marital status, skin color, level of education and place of residence (urban or rural) were not associated with burden level. Furthermore, the length of the caregiving role, previous training courses, the length of the dementia diagnosis, whether the caregiver is paid, lives with the patient or reports the dyad as being a target of prejudice were not associated with level of burden. Finally, the patient’s dependence level as assessed by the Katz and the Pfeffer scales were also not associated with burden.

Conclusion

Most challenges to caregiving don’t appear to directly affect level of burden. More behavioral symptoms are associated with more burden, as is losing a job/income and being the only available caregiver. Caregiver support policies should focus on providing financial support and/or care alternatives to allow for free time, as well as training on how to deal with behavioral issues.
The role of risk factors in development of dementia in the Czech Republic
Authors: Kučera Matěj
Published: January 2025

Background

In 2020, the Lancet Commission introduced a meta‐analysis featuring a life course model encompassing 12 potentially modifiable risk factors for dementia: low education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, alcohol consumption, traumatic brain injury, and air pollution. The aim of this study is to investigate the association of the aforementioned risk factors with the incidence of dementia with the incidence of dementia in the Czech Republic, capitalizing on a nation‐wide population‐based study.

Method

The analysis was based on data from Survey on Health, Ageing and Retirement in Europe (SHARE). Participants were included in the analytical sample if they fulfilled the following criteria: age of entry to the study of 65 years and higher, participation in at least two waves of SHARE, at least two measurements of cognitive function, and dementia‐free state at baseline. To study the association of risk factors with the incident dementia, we utilized Cox hazards models estimating hazard ratio (HR) with 95% confidence interval (CI).

Result

Out of the ten risk factors, five presented an association with dementia, when adjusted for age, sex and birth cohort. The strongest hazard was found for physical inactivity, followed by low education, diabetes mellitus, depression and living alone. There was a tendency of sex being an effect modifier in the association of alcohol use, living alone and low education with incident dementia.

Conclusion

In the present study, capitalizing on more than 3,500 community‐dwelling older adults, we found an association for only half of the proposed risk factors. More systematic attention should be paid to mitigating the negative effect of dementia risk factors as this could contribute to the reduction of incident dementia cases in the Czech Republic, Future studies should replicate the findings of this study in other CEE countries and ideally should have a longer follow‐up period to prevent reverse causation.
Association of markers of endothelial function with blood‐based biomarkers of Alzheimer’s Disease in individuals of admixed ancestry
Authors: Ray Nicholas R. , Kurup Jiji T. , Hamilton‐Nelson Kara L. , Griswold Anthony J. , Kunkle Brian W. , Bush William S. , Tosto Giuseppe , Ogunniyi Adesola , Akinyemi Rufus , Haines Jonathan L. , Byrd Goldie S. , Vance Jeffery M. , Pericak‐Vance Margaret A. , Beecham Gary , Reitz Christiane
Published: January 2025

Background

While Alzheimer disease (AD) is the most common cause of dementia, it has long been recognized that cardiovascular and cerebrovascular health plays a major role in cognitive function. As such, the development of accessible biomarkers to assess vascular cognitive impairment and dementia (VCID) is a key step towards identifying effective prevention and treatment strategies. While a set of blood‐based VCID biomarkers has been under investigation, there is a critical paucity of data from genetically admixed individuals. As such, the role and impact of genetic ancestry and the validity these biomarkers in diverse populations is unknown. To address this, we assessed the associations between biomarkers of endothelial function, AD, and genetic ancestry.

Method

Biomarkers include amyloid beta (Aβ)42/40 and phosphorylated tau (p‐tau)/Aβ42 ratios for AD, and vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), basic fibroblast growth factor (bFGF), vascular cell adhesion protein 1 (VCAM‐1), and intercellular adhesion molecule‐1 (ICAM‐1) for VCID. Biomarkers were collected from 256 admixed individuals sampled from Puerto Rico and Peru, and African Americans from the US. Including age and sex as covariates, mixed effects regressions were modeled separately predicting AD biomarker ratios by all VCID biomarkers, degree of African ancestry, and APOE genotype.

Result

Aβ42/40 ratio was associated with VEGF (β = ‐1.97×10‐5, P = .002), bFGF (β = ‐2.10×10‐4, P = .02), VCAM‐1 (β = 1.53×10‐5, P = 9.02×10‐4), ICAM‐1 (β = ‐3.72×10‐5, P = .01) and degree of African ancestry (β = 0.01, P = .04). Similarly, p‐tau/Aβ42 ratio was associated with VEGF (β = 0.01, P = .001), bFGF (β = 0.18, P = 5.21 × 10‐5), VCAM (β = ‐0.005, P = .02), and ICAM (β = 0.02, P = .02). No significant associations were observed for PlGF.

Conclusion

Blood‐based measures of endothelial function markers VEGF, bFGF, ICAM‐1, and VCAM‐1 are associated with both the p‐tau/Aβ42 and Aβ42/40 ratios, the latter of which is also modulated by degree of African ancestry. These observations support the notions that these CVD biomarkers may be valuable biomarkers for cognitive health in admixed individuals and inform the design of clinical trials for biomarker development across populations.
Can Routine Anti‐Inflammatory Medications Reduce Population Dementia Risk?
Authors: Richardson Connor Duncan
Published: January 2025

Background

Evidence from epidemiological and clinical studies of the effect of anti‐inflammatory medication on dementia risk has been mixed. Over the past two decades there has been recurring epidemiological evidence that the use of NSAID’s for chronic inflammatory conditions is associated with a lower incidence of dementia.

Method

Cognitive Function and Ageing Study (CFAS) undertook baseline interviews in populations aged 65+ years in England and Wales (1989‐1994). Three areas (CFAS I) were selected for new sampling two decades later (2008‐2011) with same geographical boundaries, sampling and approach methods (CFAS II). At 2 years CFAS I interviewed 5,156 (76% response) with 5,288 interviewed in CFAS II (74% response). Data on medication use and dementia status was assessed at each wave.

Result

Low dose aspirin (< 150 mg) use was associated by a reduction in dementia incidence rate (IR) in women from 60.99 (95% CI: 47.6, 78.2) per 1000 person‐years to 44.1 (95% CI: 2.0, 45.4) in 1993 and from 44.5 (33.7, 58.7) to 38.6 (27.2, 54.9) in 2013. No reduction in men was found.

Conclusion

This study shows evidence that routine use of low‐dose aspirin reduces population risk of dementia in women. Mixed results in men show further analysis is needed to asses the effect over a longer follow‐up with a broader range of anti‐inflammatory medication.
Association of late‐life cognition and brain pathology with anti‐hypertensive medications
Authors: Sood Ajay , Capuano Ana W. , Mehta Rupal I. , Barnes Lisa L. , Bennett David A. , Arvanitakis Zoe
Published: January 2025

Background

Hypertension is a risk factor for cognitive impairment and dementia. Anti‐hypertensives (AHT) are commonly used in old age, but their association with cognition and brain pathology is not well understood.

Method

To investigate the relation of AHT with change in cognitive function and postmortem brain pathology, we evaluated 4,207 older persons without known dementia at enrollment and a subset of 1880 participants who died and came to autopsy. Participants underwent yearly clinical evaluations that included an assessment of medications and neuropsychological testing across five cognitive domains. The participants who died underwent neuropathologic evaluation of neurodegenerative (amyloid, Lewy bodies, Tar DNA binding protein ‐43, hippocampal sclerosis) and cerebrovascular pathology (infarcts, amyloid angiopathy, atherosclerosis, or arteriosclerosis).

Result

Over 3,600 participants were using AHT, of which 64% were using diuretics, 55% beta‐blockers, 50% calcium channel blockers, 44% angiotensin‐converting enzyme inhibitors, and 29% angiotensin receptor blockers any time during the study. Using a linear mixed effect model adjusted for age, sex, race and education, AHT users at study entry had a higher level (estimate = 0.106, SE = 0.025, p <0.001) and a slower decline of global cognition compared to non‐users (estimate = 0.013, SE = 0.013, p = 0.013). Analyses of cognitive domains showed a similar pattern with a higher level at study entry and a slower decline of semantic memory (estimate = 0.025, SE = 0.007, p<0.001). The use of AHT was not associated with change in other domains. In a separate analysis including only participants with neuropathology, AHT use was associated with lower tau tangle density (estimate = ‐0.20, SE = 0.07, p = 0.005) after adjusting for age at death, sex, and race. The use of AHT was not associated with other neurodegenerative pathologies or cerebrovascular pathology.

Conclusion: Conclusions

AHT use in old age is associated with slower cognitive decline and fewer tau tangles in the brain. Future research will need to replicate these findings and explore underlying mechanisms by which AHTs appear to have beneficial effects on cognition.

This work is supported by the following NIH grants: P30AG10161, P30AG072975, R01AG15819, R01AG17917, 5R01NS084965, 1RF1AG059621, 1RF1AG074549, R01 AG22018.
Cognitive and physical activity are related to increased cognitive reserve in a large memory clinic cohort
Authors: Bocancea Diana I. , van Loenhoud Anna C. , Calandri Ismael Luis , Venkatraghavan Vikram , Groot Colin , de Boer Casper , Pijnenburg Yolande A.L. , Barkhof Frederik , van der Flier Wiesje M. , Ossenkoppele Rik
Published: January 2025

Background

Cognitive resilience, the ability to maintain cognitive function despite atrophy, is an important area of research in Alzheimer Disease (AD) and other neurodegenerative disorders. Life‐style factors such as participation in cognitively stimulating activity and physical activity are hypothesized to foster neural connections and enhance reserve, consequently sustaining resilience against cognitive loss. Here, we characterize cognitive and physical activity levels in a large memory clinic cohort with multiple etiologies. Further, we investigate the role of these two factors in resilience to brain atrophy across the AD continuum.

Methods

We included 4033 individuals from the memory clinic‐based Amsterdam Dementia Cohort with multiple diagnoses (Table 1). Levels of (lifetime, past and current) cognitive activity, and (current) physical activity were assessed through self‐reported questionnaires (Cognitive activity Questionnaire, CAQ and Physical Activity Scale for the Elderly, PASE). First, we tested differences in CAQ/PASE scores across the different diagnostic groups in the overall sample using linear models adjusted for age and sex. Second, zooming in on the AD continuum (i.e. amyloid‐β‐positive CU, MCI, or AD), we used linear mixed effects models adjusted for age and sex to assess whether CAQ/PASE had an interactive or additive effect on concurrent cognition and rate of decline (MMSE, memory and executive functioning domains) next to temporoparietal brain atrophy.

Results

Overall, there were differences in lifetime CAQ, current CAQ and current PASE between groups, but not in past CAQ (Figure 1). Within the AD continuum, we found that higher CAQ and higher PASE scores were associated with better cognition at baseline (Table 2). We did not find an interactive effect with brain atrophy on decline, nor an additive effect on the slope in cognition (i.e. higher activity was not associated with reduced speed of decline at similar atrophy levels).

Conclusion

Cross‐sectional effects in the AD continuum are suggestive of a reserve effect in maintaining cognition in disease. While associations with current CAQ and PASE might be (partially) explained by reverse causality, the observed effects with past CAQ suggest that early and mid‐life participation in cognitively stimulating activities provide a cognitive benefit in AD.
Precision Recommendations to Optimize Neurocognition [PREVENTION] Trial – Intervention Adherence Impacts Cerebral Blood Flow
Authors: Bramen Jennifer E. , Siddarth Prabha , Popa Emily S. , Hodes John F. , Rapozo Molly K. , Glatt Ryan M. , Ganapathi Aarthi S. , Wong Claudia L. , Porter Verna R. , Kim Mihae , Kress Gavin T , Sparks William , Tongson Ynez M. , Panos Stella E. , Hood Lee , Roach Jared C. , Merrill David A.
Published: January 2025

Background

Medical management and lifestyle are potentially crucial interventions for Alzheimer’s disease (AD). In this study, we present the relationship between adherence of a personalized multi‐modal intervention for AD on change in cerebral blood flow (CBF) after 12‐months.

Methods

The PREVENTION study is an ongoing randomized clinical trial (McEwen, 2001). Thirty‐three participants with biomarker evidence of amyloidosis had completed the study at the time of the analysis (Table 1). While both arms received personalized multi‐modal lifestyle recommendations and four medical visits, the active arm also received dietary counseling, group physical and cognitive exercise, health coaching, and nutritional supplements free of charge. We examined the effects of the 1) the intervention and 2) adherence on CBF. We hypothesized that 1) the active arm and 2) higher intervention adherence would have improved CBF in regions related to level of physical activity (Kleinloog, 2019; Chapman, 2013) and those pertinent to AD. CBF was assessed using arterial spin labeling (ASL). Adherence was measured using the clinician rating scale (CRS), which uses a scale of 1‐7 (Kemp, 1998). Participants were divided into two groups based on a cutoff of 5 (passive acceptance). One participant was excluded from this analysis due to missing CRS data. Effects were assessed using a two‐tailed t‐test.

Results

Treatment arms did not differ in any demographic measures at baseline or CRS. Preliminary findings indicate that regional blood flow declined over one year across the whole sample (Table 2). However, individuals with higher adherence experienced increased blood flow in the fusiform gyrus and less blood flow reduction, compared to those with lower adherence, in the anterior cingulate and hippocampus. Findings were borderline significant in the fusiform and anterior cingulate, but not the hippocampus.

Conclusions

In this small sample, we found evidence that higher adherence increased or attenuated decline in CBF in regions impacted by physical activity, one modality of the PREVENTION intervention. We did not see an effect in the hippocampus, possibly due to small sample size. We did not find an effect of treatment arm, potentially because both receive recommendations and medical management, and did not differ in adherence.
The real‐world implementation strategies for plasma p‐tau217 in tertiary care memory clinics in Thailand
Authors: Thanapornsangsuth Poosanu , Booncharoen Kittithatch , Khieukhajee Jedsada , Luechaipanit Watayuth , Haethaisong Thanaporn , Chongsuksantikul Adipa , Supharatpariyakorn Thirawat , Chunharas Chaipat , Likitjaroen Yuttachai , Hemachudha Thiravat
Published: January 2025

Background

Plasma tau phosphorylated at Thr217 (p‐tau217) has demonstrated excellent performance in identifying individuals with Alzheimer’s disease (AD) in both research and memory clinic settings. Nonetheless, implementing plasma p‐tau217 into clinical practice remains a challenge requiring careful clinical judgement and conservative interpretation near the cutpoint. The present study proposes a strategy that utilizes Bayes theorem in considering the clinical context, individualized (ie. non‐binary) likelihood ratios and validate it in a multicenter tertiary care memory clinic population in Bangkok, Thailand.

Method

Patients from two memory clinics: King Chulalongkorn Memorial Hospital and the Prasat Neurological Institute who underwent CSF analysis for core AD biomarkers or amyloid PET (Florbetaben) were enrolled. Evaluation by neurologists specializing in neurocognitive disorders preceded biomarker testing, resulting in prespecified clinical diagnoses. Pretest odds of amyloid positivity in these subgroups were extrapolated from Jansen, 2022 and Ossenkoppele, 2015. Plasma p‐tau217 (MSD) and p‐tau181 (Simoa) were measured. Participants were randomly divided into training and testing sets. Two Gaussian distributions (Aβ+ and Aβ‐) were generated from plasma p‐tau values in the test set, enabling the calculation of individualized likelihood ratios which posttest odds for each participant were determined. This strategy was compared to multivariable logistic regression using p‐tau, age, and APOE4 as predictor variables. Cross‐validation (ratio= 50:50) was repeated for 5,000 iterations, and performance was assessed using ROC analysis.

Result

Among 132 participants enrolled, 67.4% were female, and 43.2% had dementia. The median age was 68 years (interquartile range: 61, 75). AD was present in 54.5%, as determined by PET (54.5%) or CSF (46%). The strategy incorporating plasma p‐tau217 and pretest odds demonstrated an AUC of 0.979 (95% CI 0.958‐0.998), significantly outperforming logistic regression (AUC 0.948, p=0.0192) and p‐tau217 alone (AUC = 0.939, p=0.003). For plasma p‐tau181, the strategy showed an AUC of 0.926 (95% CI 0.876‐0.968), which is superior to p‐tau181 alone (AUC = 0.864, p=0.006) but not logistic regression (AUC 0.885, p=0.068).

Conclusion

The proposed strategy in this study offers a flexible approach to address the limitations of plasma p‐tau in clinical practice, significantly outperforming multivariable logistic regression. An online calculation tool demonstrating its use is available at https://trceid.org/diagALZ/.
Effects of Nigella Sativa oil on Tau Fluorescence in Cys‐variant dGAE and SH‐SY5Y‐derived neuronal cells
Authors: Folarin Royhaan , Imam Moyosoreoluwa
Published: January 2025

Background

Alzheimer’s disease is a neurodegenerative disease associated with the accumulation of amyloid beta proteins to form plaques and the aggregation of hyperphosphorylated tau to form neurofibrillary tangles. Human fibroblast (SH‐SY5Y) cells endogenously express Tau, and the expression is further amplified upon differentiation into neuronal cells, making it a cell model of Alzheimer’s disease. Nigella sativa oil (NSO) contains 50% thymoquinone and has been used in the treatment of various nervous system disorders. This study therefore aimed at investigating possible inhibitory effects of Nigella sativa oil on the endogenously expressed tau in the neuronal SH‐SY5Y cell model of Alzheimer’s disease and on the aggregation of Tau in the Cys variant dGAE protein.

Method

Amyloid fibrilization shall also be induced in vitro in NSO‐treated dGAE by 3 days of thermoshaking at 720 rpm at 37°C. Pre‐ and post‐aggregation samples were then analyzed for amyloid fibril assembly using the Thioflavin S dye and compared for fluorescence using a microplate reader. Neuronal cells were differentiated from human SH‐SY5Y cells using retinoic acid and thereafter incubated with varying concentrations of NSO. Changes in tau phosphorylation was assessed by immunofluorescence using a T‐tau antibody viewed under a Zeiss LSM780 confocal microscope.

Result

While the untreated post‐aggregation dGAE samples showed higher fibrillar fluorescence than the NSO‐treated post‐aggregation samples, Tau immunofluorescence was also significantly reduced in the NSO‐treated neuronal cells.

Conclusion

The Tau‐limiting effect of NSO was observed in dGAE fibrilization and in Tau immunofluorescence in SH‐SY5Y‐derived neuronal cells
Night‐to‐Night Variation of Sleep and Heart Rate in People with Mild Alzheimer’s and Their Caregivers: Preliminary Findings from a Sleep Diary and Contactless Physiological Monitoring at Home
Authors: Ravindran Kiran K.G. , Monica Ciro della , Atzori Giuseppe , Hassanin Hana , Nilforooshan Ramin , Revell Victoria Louise , Dijk Derk‐Jan
Published: January 2025

Background

Changes in sleep patterns are common in Alzheimer’s disease and impact the quality of life of both people living with Alzheimer’s (PLWA) and their caregivers. Longitudinal recordings and assessment of night‐to‐night variations in sleep and physiology can improve our understanding of how sleep influences clinical outcomes and caregiver wellbeing.

Method

We collected sleep diary and contactless sleep technology data (Withings sleep analyser, WSA) in community dwelling PLWA (N = 16, Age = 72.8 ± 5.7 years, SMMSE = 27.1 ± 1.4), caregivers (N = 8, Age = 74.4 ± 3.8 years, SMMSE = 28.6 ± 0.7) and healthy older adults (N = 23, Age = 70.7 ± 5.5 years, SMMSE = 29.0 ± 0.9) for a period of upto 14 days at home. Group differences were analysed using a mixed model with participants as random effect while coefficients of variation were used to quantify the intra‐individual variability.

Result

Sleep diary and contactless sleep and heart rate variables were successfully collected for 624 (sleep diary) and 647 (WSA) nights. Analyses of group means of the sleep diary measures revealed that the self‐reported sleep period was significantly longer (p<0.001) in PLWA compared to healthy older adults. The number of reported night awakenings was larger (p = 0.019) in caregivers compared to PLWA. The group mean of nightly minimum heart rate estimated by WSA was significantly lower (p = 0.015) in PLWA compared to healthy older adults (Figure 1).

In addition to these differences in group averages, we also observed differences in the night‐to‐night variability of sleep and heart rate measures. The variability of wake after sleep onset and sleep efficiency as reported in the sleep diary were larger in caregivers compared to PLWA and healthy older adults (p<0.05) (Figure 2). The night‐to‐night variability of maximum heart rate was larger in caregivers while the variability of minimum heart rate was larger in PLWA, and caregivers compared to healthy older adults (p<0.05).

Conclusion

These data indicated that longitudinal nocturnal recordings of sleep and physiology and analyses of night‐to‐night variability provide insights into the extent of disturbances of sleep and physiology in PLWA and their caregivers.
Assessment of fluid biomarker profiles across disease continuum in a non‐human primate model of sporadic CAA
Authors: Karimi Sohail , Patel Akash G , Nehete Pramod N , Nehete Bharti P , Debure Ludovic , Wang Fengzhu , Botello Raul Rocha , Chahine George , Zhang Qiao , Shao Yongzhao , Mulholland Michele Marie , Gray Stanton B , Hopkins William D , Wisniewski Thomas , Scholtzova Henrieta
Published: January 2025

Background

Vascular Contributions to Cognitive Impairment and Dementia (VCID) is the second most common cause of dementia. Cerebral amyloid angiopathy (CAA), as one of the vascular pathologies underlying VCID, often coexists with Alzheimer’s disease (AD). The New World non‐human primate species, squirrel monkey (SQM), is a preclinical model of AD pathology that naturally develops extensive age‐associated CAA, and therefore holds immense translational value to study biomarkers and novel therapeutic approaches for AD and CAA. We aimed to assess the validity of fluid biomarkers and an Automated Cognitive Testing System (ACTS) to monitor disease progression in SQMs.

Method

Plasma and CSF biomarkers of AD pathogenesis and neurodegeneration, cerebrovascular dysfunction/BBB integrity, and inflammation were characterized cross‐sectionally using SIMOA, ELISA, and Luminex immunoassays. A touchscreen‐based ACTS was implemented within young and geriatric SQM cohorts to assess behavioral performance.

Result

Simple linear regression models revealed increases in plasma GFAP, sTrem2, YKL‐40 (CHI3L1), and both CSF and plasma NfL concentrations across the SQM lifespan. Plasma concentrations of MMP1 and MMP2 decreased with age, while no simple linear trends in MMP3 or MMP9 were observed. By applying segmented regression analyses, we estimated changepoints in plasma NfL, GFAP, neurogranin, MMP1, MMP2, MMP3, kallikrein‐6 (neurosin), as well as CSF NfL concentrations, ranging from 13.7 to 19.4 years of SQM age. Furthermore, a preliminary analysis among select cohorts of geriatric and young animals demonstrated an age‐associated decrease in the calculated Aβ42/Aβ40 ratio and albumin index, among time‐matched CSF and plasma samples. Training on an ACTS match‐to‐sample (MTS) task revealed differences in cognitive performance, as young SQMs required significantly fewer trials than geriatric animals to achieve a passing criterion. Cognitive assessments continue on a series of more advanced behavioral tasks. Integration of all measures with neuroimaging correlates are underway.

Conclusion

The present characterizations of biomarker trajectories may help identify pathology onset and disease progression in the SQM model. Further portrayal of this species will advance our understanding of CAA pathogenesis, promoting further discoveries of diagnostic biomarkers and novel drug targets.
The association between grey matter microstructural MRI biomarkers, mid‐life blood pressure, and late‐life Alzheimer’s disease pathology
Authors: Weston Philip SJ , Coath William , Brown Thomas M. , Scott Catherine J , Malone Ian B. , Arstad Erik , Awais Ramla , Sander Kerstin , Thomas David L , Dickson John C , Schöll Michael , Richards Marcus , Fox Nick C , Zhang Hui , Cash David M , Schott Jonathan M
Published: January 2025

Background

With an aging population, it is essential to identify subtle features of brain pathology – both neurodegenerative and vascular – at an early stage, which may predict risk of future decline. We used diffusion MRI (dMRI) to assess grey matter cortical microstructure and investigate associations with 1) Alzheimer’s disease (AD) pathology and 2) mid/late‐life vascular risk (as measured by blood pressure (BP)).

Method

151 asymptomatic individuals from the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ‐PET at ∼73yrs, and [18F]MK‐6240 tau‐PET at ∼76yrs. Multi‐shell diffusion MRI was acquired; neurite orientation dispersion and density imaging (NODDI) quantified orientation dispersion index (ODI), a proxy measure of dendritic morphology/complexity, with DTI measuring mean diffusivity (MD), a less specific measure of degenerative change. Cortical volume was estimated using GIF. PET SUVRs were calculated. Amyloid load was assessed in a cortical composite region, with tau PET and MRI measures assessed in 1) a temporal meta‐ROI (analogous to early Braak stages), and 2) a larger neocortical meta‐ROI, analogous to later Braak stages. BP measurements were taken throughout mid and late life, at ages 43, 53, 63, and 73.

Result

Seventy participants were amyloid positive (A+), of whom 27 were tau positive (T+). Global cortical ODI was significantly lower in A+/T+ than A+T‐ (p=0.005) and in A+/T+ than A‐/T‐ (p=0.001), but with no significant difference between A+/T‐ and A‐/T‐. The same pattern was found for ODI in the temporal ROI. No consistent differences were found across A/T groupings for MD or volume. MD (both global and temporal) at aged 76 showed significant associations (p<0.05) with BP at ages 43, 53 and 63, but not at 73. These association remained after adjusting for A/T pathology and cortical volume. For ODI, associations with mid‐life BP were less consistent.

Conclusion

Mid‐life BP is associated with late life cortical microstructural breakdown, as measured by MD, in the absence of detectable volume changes and independent of Alzheimer’s disease (AD) pathology. ODI appears to be more sensitive and specific to dendritic tau‐related changes. Cortical dMRI offers promise in the presymptomatic identification, staging and risk stratification of both AD and vascular dementia.
The impact of mid‐life cardiovascular health on cognitive change in a bi‐ethnic cohort
Authors: Vazquez Janette , Bernal Rebecca , Trevino Hector A , Velarde Angel G , Goss Monica , van Lent Debora Melo , Hazuda Helen , Wang Chen‐Pin , Satizabal Claudia L
Published: January 2025

Background

Vascular risk factors are known contributors to cognitive decline and dementia; however, their impact on cognitive change in diverse samples is understudied. In this study, we investigated the effect of the AHA Life’s Simple 7 (LS7) on cognitive decline in the bi‐ethnic San Antonio Longitudinal Study of Aging (SALSA) cohort.

Method

We included 403 participants (mean age 57.9±3.8, 58.5% female, 52% Mexican Americans (MA), Table 1) from SALSA who were part of the San Antonio Heart Study (SAHS) launched in 1979. LS7 scores (score range 1‐13) integrated mid‐life data on diet, physical activity, body mass index (BMI), smoking, total cholesterol, blood pressure, and fasting blood glucose. We combined intermediate and ideal LS7 categories, using poor LS7 as the reference. The Mini Mental State Examination (MMSE) assessed global cognition at SALSA baseline (1992‐1996) and three follow‐up examinations. The study included individuals with complete data for computing LS7 scores, a baseline MMSE score, and at least one follow‐up MMSE exam. We used generalized estimating equations to explore the relationship between total LS7 score and single LS7 components with cognitive decline, both in the total sample and by ethnicity. The statistical model was adjusted for age, sex, education, income, and ethnicity (total sample only).

Result

No relationships were observed between LS7 total score and cognitive decline. In the overall sample and among MA, meeting intermediate or ideal physical activity goals demonstrated a mitigating effect on cognitive decline (β±SE, 0.065±0.032, p = 0.041; 0.147±0.048, p = 0.002, respectively, see Table 2 and Figure 1). Additionally, maintaining blood glucose below 125 mg/dL was associated with slower cognitive decline (0.182±0.074, p = 0.014, Table 2) among non‐Hispanic White (NHW) but not among MA (0.035±0.098, p = 0.725, Table 2). In contrast, BMI under 30 was associated with accelerated cognitive decline (‐0.012±0.050, p = 0.025, Table 2) among MA but not among NHW (‐0.012±0.056, p = 0.836, Table 2).

Conclusion

While the LS7 total score showed no significant association with cognitive decline in our bi‐ethnic cohort, notable associations were found for physical activity and blood glucose, highlighting their potential as effective preventative measures. Nonetheless, future multi‐ethnic studies are encouraged to replicate our findings, especially in larger sample sizes.
Impact of type 2 diabetes mellitus on Alzheimer’s disease ‐related pathology preceding cognitive impairment
Authors: Yu Yang Yang , Nowell Joseph , Edison Paul
Published: January 2025

Background

Alzheimer’s disease and type 2 diabetes mellitus rank among the top ten leading global causes of death. The association between diabetes and Alzheimer’s is linked to chronic low‐grade inflammation, hyperinsulinemia, and the interplay between peripheral and central insulin resistance, influencing insulin signalling. We evaluated the association between diabetes and Alzheimer’s‐related neuropathology in cognitively unimpaired older adults with diabetes.

Methods

We compared tau, cerebral glucose metabolism and amyloid in 147 cognitively normal participants, comprising 32 clinically diagnosed with diabetes and 115 without diabetes, from the Alzheimer’s Disease Neuroimaging Initiative dataset. We processed 329 available PET scans for 18F‐AV‐45, 18F‐flortaucipir and 18F‐fludeoxyglucose (FDG). Independent t‐tests and multivariate analysis were conducted for regions of interest (ROI) values, encompassing the global cortex and subsequent brain cortices, the medial temporal lobes, striatum, thalamus, and the anterior and posterior cingulate. Voxel‐wise analysis using SPM was also performed for these groups. Amyloid positive and negative subjects were evaluated separately.

Results

Cognitively unimpaired diabetic subjects exhibited higher tau uptake compared to the non‐diabetic group in the whole brain (global brain value) and individual brain cortices, including the frontal, temporal, parietal, and occipital lobes. In diabetic subjects with negative amyloid status, significance was observed in the whole brain, as well as the parietal, temporal, medial temporal lobes, and the striatum. Reduced FDG uptake was only evident in diabetic subjects with positive amyloid status in the striatum. Increased amyloid deposition was noted in the medial temporal lobe and hippocampus in subjects with diabetes compared to those without.

Conclusions

Neuropathological changes in the diabetic brain precede the manifestation of cognitive decline. Specifically, there is an increase in the presence of tau in the diabetic brain even in the absence of amyloid, indicating that tau may be the predominant driver of cognitive decline in diabetes.
Using community health workers to assess the prevalence of dementia in a community based sample of older Zambians
Authors: Mataa Mataa M , Kalungwana Lisa , Bwalya Chiti , Simushi Faith , Hachaambwa Lottie , Mwango Linah , Namangala Coolwe , Yankae Leroy , Daniel David , Tanner Jeremy A. , Elafros Melissa A
Published: January 2025

Background

In Zambia, dementia prevalence is unknown due to limited community awareness and a lack of providers skilled in recognizing and diagnosing this disease. Community healthcare workers (CHWs) are widely utilized across sub‐Saharan Africa to improve health care access, particularly HIV services. CHWs may be an untapped resource to raise awareness, screen for dementia, and support dementia care in the community. This study is piloting a community‐based model using CHWs to screen for dementia and associated risk factors in a population‐based sample of older Zambians.

Methods

Ten Zambian CHWs underwent a five‐day training led by a neuropsychologist and neurologist on symptoms of dementia, myths, and administration of the 10/66 dementia screening protocol. CHWs were then deployed in two high‐density Lusaka communities to enroll adults age >55 and a caregiver from randomly selected households. Demographics, medical history, diet, anthropomorphic measurements, HIV, and glucose testing were collected. Dementia was defined using the CSI‐D with a neuropsychologist regularly assessing community administration to assure standardization

Results

To date, 185 Zambians (mean age 67; 66% female, mean education 5.7yrs) have been enrolled. Mean household income was ZMW 1339 ($52/month). Fifty percent endorsed food insecurity in the past 30 days, whereas 25% drank alcohol. Twenty‐four (13%) participants were HIV‐positive. One hundred and two (55%) participants regularly attended community social activities. Caregivers reported that 13 (7%) participants regularly forgot family member’s names, 7 (4%) got lost in the community, and 5 (3%) got lost at home. On dementia screening, 63 (34%) screened negative for dementia (dfscore <0.12), 23 (12%) screened in the intermediate range (dfscore 0.12 to <0.184) and 99 (54%) participants screened positive for possible dementia (dfscore ≥0.184).

Conclusions

CHWs can be trained to reliably administer dementia screening measures and may serve as a resource for dementia care. High rates of positive dementia screening raise concern that these measures may be overly sensitive in this population. We are conducting additional neurological evaluation and neurocognitive testing with participants to assess CSI‐D sensitivity and specificity and to determine the prevalence of dementia and dementia risk factors in Zambia.
Development and validation of an electronic health record 3‐year risk model for diagnosis of dementia with and without Mini‐Cog scores
Authors: Hanson Leah R , Crain A Lauren , Gustafson Sally K , Werner Ann M , Svitak Aleta L , O'Keefe Lauren R , O'Connor Patrick J , Rossom Rebecca C
Published: January 2025

Background

The number people living with Alzheimer’s disease and related dementias is expected to triple by 2050, contributing to decreased quality of life, increased medical care utilization, and additional burden on an already stressed primary care system. Many clinicians lack confidence to assess, diagnose and manage cognitive impairment (CI), and more than 50% of patients with CI are undiagnosed. A tool to better identify patients at risk of CI could lead to earlier detection and diagnosis in primary care.

Method

A prediction model was developed and validated to estimate the risk of dementia diagnosis within three years using two machine learning approaches, R SuperLearner and LASSO. Patients were 65 years or older without a CI diagnosis and seen at a 2017 primary care index visit. A subgroup of patients had Mini‐Cog (MC) screening data available. Variable selection was carried out in the full population, and again in the MC subgroup. Both machine learning approaches selected variables from >1,000 features calculated from broad categories of electronic health record (EHR) and MC data documented between 2012 and the index date. Features considered came from categories including Annual Wellness Questionnaire, cognitive screens, diagnoses, encounter history, vitals, labs, medications, procedures, patient reported outcomes, social history, and vaccinations. Dementia diagnosis between index and 12/31/2020 was the outcome. Diagnostic measures were calculated from logistic regression models fit using the selected variables.

Result

The full population prediction model included data from N = 100,998 patients (training n = 70,699; validation n = 30,299), 6.0% of whom developed dementia. In the MC subgroup (training n = 47,478; validation n = 20,807) 3.6% developed dementia. Maximum predictive accuracy (AUC) was obtained using the LASSO approach. The full population model retained 33 predictors with AUC = 0.80 (95% CI 0.79 – 0.81) in the training and validation datasets. The MC prediction model retained 32 predictors and AUC = 0.83 (95% CI 0.82‐0.84) in both datasets.

Conclusion

Using MC and readily available EHR data, we were able to predict future dementia diagnoses with high accuracy. Next, we are implementing this model into an algorithm‐driven clinical decision support system and testing the system’s ability to improve diagnosis rates via a cluster‐randomized trial.