bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of neuropsychological test performance between minoritized and White individuals with frontotemporal degeneration
Authors: Matyi Melanie A , Rhodes Emma , Emrani Sheina , Jin Hannah A , Irwin David J , McMillan Corey T , Massimo Lauren
Published: January 2025

Background

Minoritized groups are an understudied population in frontotemporal degeneration (FTD) research. Recently, we demonstrated distinct neuropsychiatric symptom profiles in Black relative to White individuals with FTD but cognition across these groups has not been reported. This knowledge gap has potential implications for the care of individuals with FTD from minoritized groups. Here we evaluated neuropsychological performance across Black and White individuals with FTD using the National Alzheimer’s Coordinating Center (NACC) Uniform Dataset (UDS).

Methods

Individuals with a behavioral variant FTD or primary progressive aphasia diagnosis, neuropsychological data, and self‐identified as non‐Hispanic White (n = 1318) or Black (n = 30‐76) were included. Data from UDS versions (1‐3) were adjusted for age, sex, and education using established norms. Linear regressions examined the association between race and normative cognitive scores (see Table 1 for measures and sample sizes), covarying for CDR‐Global. Chi‐square tests then examined group differences in the proportion of participants classified as impaired (≤‐1.5 normative score).

Results

Black individuals on average had lower scores (Fig. 1) and greater likelihood of impairment (Fig. 2) on measures of global cognition (β = ‐3.07; χ2 = 9.65), digits backward (β = ‐.624; χ2 = 4.53), trails A (β = ‐2.22; χ2 = 19.54) and B (β = ‐1.20; χ2 = 7.79), and naming (β = ‐1.79; χ2 = 12.4). We did not identify any neuropsychological tests where White individuals performed worse than Black individuals.

Conclusions

Neuropsychological data in representative populations is severely lacking in the NACC cohort diagnosed with FTD, comprised of only 3% Black individuals and 7% other minoritized groups. We observed that on average Black individuals have reduced performance relative to their White counterparts on several cognitive domains. Importantly, performance differences translated to the classification of a greater proportion of Black, compared to White, individuals as impaired, in part because available norms do not account for race. Of note, our ability to i) explore differences in cognition across minoritized groups and ii) assess for differences in cognitive decline was hampered by the limited sample of participants from minoritized groups with available data. Future efforts must focus on increasing research participation in underrepresented populations with FTD to evaluate potential sources of the observed differences across racial groups and support the diverse needs of all individuals.
Sleep, Alzheimer pathology and risk of clinical progression in cognitively unimpaired older adults
Authors: Mohammediyan Bery , Baril Andree‐Ann , Fajardo Alfonso , Poirier Judes , Soucy Jean‐Paul , Villeneuve Sylvia
Published: January 2025

Background

Increasing evidence suggests a link between sleep and Alzheimer disease’s (AD) pathology and cognitive decline. We investigated whether sleep disturbances might be accompanied by faster AD pathology accumulation and/or cognitive decline before the onset of cognitive symptoms.

Method

We investigated cross‐sectional and longitudinal associations between sleep quality, AD pathology and cognition in 220 participants from the PREVENT‐AD cohort. A subsample of 99 participants had longitudinal amyloid and tau PET data (mean follow‐up:4.33±0.53y, range: 1.59 – 6.11y) and a subsample of 218 had longitudinal cognitive evaluations (mean follow‐up:0.80±0.50y, range 1‐9). We used the PSQI global score and the actigraphy day‐to‐day sleep efficiency and fragmentation index variability, amyloid and tau‐PET to measure amyloid and tau respectively and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. All participants were cognitively unimpaired at their first sleep measurement and 32 individuals developed mild cognitive impairment (MCI) during the study. In supplementary analyses individuals were classified as having high or low to moderated levels of amyloid based on a centiloid of 40. We used robust linear models (RLM) and ANOVAs to assess the association between sleep, and AD pathology and cognition.

Result

We found that higher levels of amyloid pathology were associated with greater day‐to‐day sleep efficiency and fragmentation index variability (Fig. 1). Higher levels of tau pathology were associated with greater day‐to‐day sleep efficiency and fragmentation variability (Fig. 1). We further found longitudinal associations between annual amyloid change and greater day‐to‐day sleep efficiency variability (Fig. 1). These associations were only present in individuals who had centiloid values lower than or equal to 40 (Fig. 2). While no association was found between sleep quality and cognition, individuals who developed MCI (n = 32) had higher baseline PSQI scores (Fig. 3) and greater day‐to‐day sleep efficiency (Fig. 3) years before they were classified as MCI.

Conclusion

Higher variability in sleep quality and worst self‐reported sleep relates to AD pathology. Subjective and objective sleep impairments were also present years prior the development of MCI. Sleep variability and subjective sleep assessment changes might precede sleep disruptions observed later in the disease, which could promote further pathological processes in the brain.
Lipid peroxidation in patients with vascular mild cognitive impairment from a memory and antioxidants in vascular impairment trial (MOVE‐IT)
Authors: Kang Yejin , Chen Jinghan Jenny , Mah Ethan , Survilla Kate , Vieira Danielle , Herrmann Nathan , Gallagher Damien , Andreazza Ana C. , Black Sandra E , Oh Paul I. , Swardfager Walter , Graham Simon J. , Ramirez Joel , Marzolini Susan , Lanctôt Krista L.
Published: January 2025

Background

Oxidative stress (OS) has been a target of interest for vascular dementia, given its implications in pathogenesis. OS may be important in prodromal stage, such as vascular mild cognitive impairment (vMCI), and examining OS markers in vMCI may help better understand biological processes in the onset of cognitive impairment. Our study compared OS levels in vMCI vs controls, and explored whether OS markers predicted the response to antioxidant treatments in vMCI.

Method

Cardiac rehabilitation patients with cardiovascular risk factors (CVRFs) were recruited as vMCI (1SD below norms in executive function (EF), memory, processing speed or working memory) or cognitively‐healthy controls. vMCI patients were classified as probable vMCI if they had neuroimaging evidence of vascular pathology. vMCI patients were randomized to 2400mg N‐acetylcysteine (NAC) or placebo in a 24‐week, double‐blind trial. Serum 8‐isoprostane (8ISO), 4‐hydroxynonenal (4HNE) and lipid hydroperoxides (LPH) collection and cognitive assessments were done at three time points. ANCOVA models adjusting for age, sex and CVRFs compared OS markers between groups at baseline. Linear mixed‐effects models were used for longitudinal analyses.

Result

LPH levels were significantly lower in vMCI (n = 60) compared to controls (n = 16) (0.86±0.45 vs 1.18±0.31, F(1,62) = 7.0, p = 0.011). 4HNE were significantly higher in vMCI compared to controls (1.03±0.06 vs 0.99±0.04, F(1,70) = 6.6, p = 0.012). vMCI patients had significantly higher 4HNE/LPH (0.17±0.44 vs –0.18±0.29, F(1,62) = 9.3, p = 0.003) and (8ISO+4HNE)/LPH ratio (0.41±0.45 vs 0.13±0.38, F(1,62) = 5.9, p = 0.018) compared to controls. In probable vMCI group (n = 25), there was significant decreases in 4HNE/LPH (β = ‐0.68, SE = 0.27, p = 0.02) and (8ISO+4HNE)/LPH ratio (β = ‐0.65, SE = 0.28, p = 0.028) after NAC treatment. A significant time by baseline 8ISO effect on EF in the NAC group was observed (β = 0.78, SE = 0.26, p<0.01) after adjusting for age, sex and education.

Conclusion

This study showed that the ratios of late‐ to early‐phase lipid peroxidation markers were significantly elevated in vMCI groups compared to controls. This aligns with existing literature that altered lipid peroxidation may be implicated in vMCI. Antioxidant treatments decreased OS in probable vMCI groups, and higher baseline 8ISO was associated with greater improvement in EF in the NAC group, suggesting that probable vMCI patients with high OS may be appropriately targeted for antioxidant treatments.
Association between Amyloid Burden and Health‐Related Resource Use
Authors: Zhu Carolyn W , Hedden Trey , Elder Gregory A. , Grossman Hillel , Neugroschl Judith A. , Schimming Corbett , Aloysi Amy , Sano Mary
Published: January 2025

Background

Several disease modifying treatment (DMT) in early AD have shown effectiveness in reducing rate of decline on cognition and function. Earlier analyses using participants who are likely targets for clinical trial and treatment showed treatment effects may have important effects on patients’ work capacity and need for informal care. However, amyloid pathology was not examined. This study explores the relationship between amyloid burden and health‐related resource use.

Method

Participants enrolled in the Mount Sinai Alzheimer’s Disease Research Center with CDR = 0.5 or 1 and clinical diagnosis of MCI or AD. Health‐related resource use was self‐reported by participant and/or study partner using the Resource Use Inventory (RUI). Amyloid images received a clinical read by a neuro‐radiologist who was blinded to patient characteristics used to determine amyloid status. Two‐part or hurdle models were used adjusting for age, sex, race/ethnicity, education, comorbidities, baseline CDR Sum of Boxes (CDR‐SB), and years of follow up.

Result

Sample included 56 participants (28 amyloid positive, 28 negative) who had 1 or more RUI assessments (average follow up = 2.6±1.5 years). At baseline, average age = 73±8, 17±3 years of schooling, 54% female, 66% White, 20% Black, 11% Hispanic. 91% CDR = 0.5, 13% cognitively normal, 63% MCI, 25% AD; MMSE = 26±3, CDR‐SB = 1.8±1.8, comorbidities = 5.5±2.5.

There were no statistically significant differences (at p = 0.05) in participants' characteristics except that proportion of participants who were White was higher in those who were amyloid positive (86%) than negative (46%) (p = 0.002). No Hispanic participant was amyloid positive. Follow up was longer in those who were amyloid negative (3±1.4 years) than amyloid positive (2.2±1.4 years). Baseline RUI items were not statistically significantly different by amyloid positivity.

At baseline, amyloid positivity was associated with lower likelihood of participation in employment/volunteering. Among those who used help, amyloid positivity was associated with higher home health care hours. Over time, likelihood of receiving informal help increased and participation in employment/volunteering decreased. Data did not reveal any interaction between amyloid positivity and time.

Conclusion

Results from this small sample of participants that reflects AD clinical trial populations suggest amyloid burden may be associated with higher health‐related resource use.
Reliability of the remote digital self‐administered Stricker Learning Span, Symbols Test and Mayo Test DRIVE Screening Battery Composite
Authors: Hughes Morgan A , Frank Ryan D. , Fan Winnie Z. , Christianson Teresa J. , Kremers Walter K. , Stricker John L. , Boots Elizabeth A. , Machulda Mary M. , Fields Julie A. , Hassenstab Jason J. , Aduen Paula , Lucas John A. , Graff‐Radford Jonathan , Vemuri Prashanthi , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Stricker Nikki H.
Published: January 2025

Background

Mayo Test DRIVE (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based multi‐device (smartphone, tablet, personal computer) platform optimized for remote self‐administered cognitive assessment that includes a computer‐adaptive word list memory test (Stricker Learning Span; SLS), a measure of processing speed/executive functioning (Symbols Test) and a score combining both the memory and processing speed/executive functioning measures (MTD Composite). We aimed to determine the reliability of MTD measures across follow‐up sessions.

Method

Individuals participating in this ancillary study who completed at least two and up to four complete MTD sessions were included, resulting in 1,293 participants (mean age = 70.6, SD = 11.6; mean education = 15.6, SD = 2.3; 48.6% male; 96.9% White; 99.1% non‐Hispanic; 97.1% cognitively unimpaired) from parent studies (see Table 1). MTD raw scores were winsorized at 1% and 99% to minimize the impact of outliers. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed ICCs and results are described using descriptives from Koo et al. (2016). ICCs for in‐person‐administered traditional neuropsychological measures are also reported alongside MTD for a subset of participants newly enrolled into the MCSA (to ensure participants were test naïve to both MTD and in‐person tests).

Result

Reliability was good for the MTD Composite raw [total ICC = 0.78; see Table 2 for session‐to‐session ICCs and 95% CIs], and moderate‐to‐good for the primary outcome variables for each subtest [total ICC = 0.74 for both SLS and Symbols]. Weighting by accuracy negatively impacted reliability of Symbols and the Composite; without this weighting, MTD Composite and Symbols variables showed higher reliability (MTD Composite z total ICC = 0.80; Symbols response time total ICC = 0.84; see Table 2). Alternative methods of defining response time on Symbols showed nearly identical reliability values. SLS sum of trials (primary variable) had subtly higher reliability than separate measures of learning (1‐5 correct, max span) or delay. Reliability of remote MTD and in‐person‐administered measures and select comparisons are provided in Table 3.

Conclusion

MTD showed moderate to good reliability, similar to in‐person‐administered traditional neuropsychological tests. Future work will examine the effect of demographics, device type, and session interference on reliability.
A Multi‐Pathway Blood‐Based Biomarker Panel Reveals Stereotyped Progression of Blood Biomarker Changes in Alzheimer’s Disease
Authors: Wilson Edward N.
Published: January 2025

Background

Blood‐based biomarkers have emerged as critical tools for detecting Alzheimer’s disease (AD) pathologies decades prior to the onset of clinical symptoms. However, research has been slow to realize the enormous potential of blood‐based biomarkers to capture multiple pathologies and inter‐individual complexities in the biology underlying AD.

Method

We curated a panel of blood‐based biomarkers sensitive to multiple aspects of AD pathology, including vascular, neuronal, immune, along with amyloid and tau. The integrative blood biomarker panel was evaluated in participants along the AD continuum from the Stanford Alzheimer’s Disease Research Center.

Result

Remarkably, participants across the AD continuum exhibit a stereotyped temporal evolution of blood‐based biomarker change such that the first blood‐based biomarkers to change were plasma amyloid, followed by astrocytic GFAP, neuronal p‐tau, neuronal NfL, and finally by vascular marker VCAM1. Deviations to this sequence were rare and indicated other non‐AD neurodegeneration or the presence of familial AD genetic mutations.

Conclusion

The results reveal a natural sequence in pathologic change in AD‐related blood biomarkers. This sensitive blood biomarker panel can be leveraged for precise disease staging and treatment monitoring as we enter a new era of AD therapeutics.
The effects of added sugar intake on cardiometabolic health and memory recall in midlife adults
Authors: Decker Kevin P. , Rigas Zoe , Rizzi Nicholas A. , Awad Catherine , Sanjana Faria , Cohen Matthew L. , Lennon Shannon L. , Martens Christopher R.
Published: January 2025

Background

Aging is the primary risk factor for Alzheimer’s disease (AD) which is the most common cause of dementia. The risk factors for AD emerge during midlife and are similar to cardiometabolic diseases. Midlife cardiometabolic changes are worsened by poor lifestyle habits, such as consuming a Western Diet (WD), which is partially characterized by high added sugar intake (i.e., all caloric sweeteners added to food during cooking or processing). This study aimed to investigate if short‐term consumption of excessive added sugars acutely alters cardiometabolic risk factors and hippocampal‐dependent memory function in midlife adults (50‐64 years old). We hypothesized that, compared to a low added sugar diet, the high added sugar diet would be detrimental to cardiometabolic and brain health.

Method

In a randomized order, 26 participants (10 males / 16 females) were assigned to consume a 10‐day high‐added sugar (HS: 25% total calories) and low‐ added sugar (LS: 5% total calories) diet. At the end of each diet, blood was sampled, blood pressure was measured, and memory recall was tested using the Hopkins Verbal Learning Test (HVLT) and the Brief Visuospatial Memory Test (BVMT).

Result

Compared to the LS diet, the HS diet significantly increased plasma triglycerides (LS: 91±31; HS: 102±30 mg/dL; p = 0.04) and mean arterial blood pressure (LS: 80±7; HS: 85±9 mmHg; p = 0.002). After the HS diet, total memory recall scores were significantly lower for BVMT: (LS: 26.0±5.2; HS 23.3±5.9 correct responses; p = 0.02) but not the HVLT. Compared to the LS diet, delayed memory recall scores were significantly lower after the HS diet for both tests [(HVLT: (LS: 10.5±1.5; HS 9.9±1.7 correct responses; p = 0.03) and BVMT: (LS: 10.1±1.6; HS 8.8±2.2 correct responses; p = 0.002)].

Conclusion

A short‐term (10‐day) diet with an excessive amount of added sugars increases cardiometabolic risk factors, whichmay make the brain susceptible to lower memory recall in otherwise healthy midlife adults. This study highlights the importance of diet on cardiometabolic and brain health in midlife adults. Future studies should examine the long‐term impact of added sugars on AD risk and explore the underlying mechanisms by which added sugars contribute to cognitive aging.
The Association Between Pulse Wave Velocity and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease
Authors: Kim Hyena , Kulshreshtha Ambar , Alonso Alvaro , Goldstein Felicia , Gold Matthew , Lah James J.
Published: January 2025

Background

Prior studies have demonstrated a negative correlation between arterial stiffness and cognitive function, suggesting that pulse wave velocity (PWV) could be a promising noninvasive vascular biomarker for detecting cognitive decline. However, the link between PWV and specific Alzheimer’s Disease (AD) cerebrospinal fluid (CSF) biomarkers has not been examined. This cross‐sectional study examines the association between PWV and AD CSF tau/Aβ ratios.

Method

We analyzed the cross‐sectional association between PWV and AD CSF biomarkers in the Emory Healthy Brain study (EHBS). Participants with normal cognition were enrolled in the EHBS, a preclinical AD biomarker discovery project, to identify early signs of cognitive decline. Participants are cognitively normal without functional limitations and are without neurological diagnoses suggesting prodromal or current degenerative disease. Participants had detailed cognitive and vascular tests and consented to lumbar puncture. CSF pTau/Aβ42 and tTau/Aβ42 ratios were converted into binary variables using established cutoff values of 0.022 and 0.26, respectively. We used an established cut‐off for PWV of 6.7 m/s, which indicates higher arterial stiffness. Unadjusted and adjusted analyses for age, race, sex, education, and CVD risk factors were conducted using logistic regression.

Result

Of 751 participants, 69% were female, 84% were White, and 12% were Black. The mean age was 62, and the mean educational attainment was 17. There were 12% of participants with AD CSF biomarker positivity for tTau/Aβ42 and 16% for pTau/Aβ42. In unadjusted models, higher PWV had 103% (OR = 2.03, 95% CI 1.31‐3.14, p‐value, 0.002) greater odds of AD biomarker positivity for tTau/Aβ42 and 76% (OR = 1.76, 95% CI, 1.18‐2.63, p‐value, 0.006) greater odds of AD biomarker positivity for pTau/Aβ42 compared to participants with lower PWV. In the adjusted model, participants with higher PWV had 73% (OR = 1.73, 95% CI 1.09‐2.74, p‐value, 0.02) greater odds of AD biomarker positivity for tTau/Aβ42 and 49% (OR = 1.49, 95% Cl, 0.98‐2.29, p‐value, 0.07) for pTau/Aβ42 compared to participants with lower PWV.

Conclusion

Increased arterial stiffness, as measured by PWV, is associated with AD CSF biomarker positivity. Future longitudinal studies should assess whether PWV is effective for screening and early detection of AD pathology.
Kinetic and X‐ray Structural Characterization of Phospholipase C Gamma 2 PLCG2–an Emerging Target for Alzheimer’s Disease
Authors: Kaiser Bridget L , Lendy Emma K , Morato Nicolas , Feng Yunfei , Beck Daniel E , Putt Karson S , Cooks Graham , Mesecar Andrew D.
Published: January 2025

Background

PLCG2 is signal‐transduction protein identified as a potential drug target for the treatment of Alzheimer’s disease (AD). PLCG2 is regulated by stimulation of the TREM2 pathway in microglia, which results in phagocytosis of beta‐amyloid. PLCG2 catalyzes the cleavage of PI(4,5)P2 into IP3 and diacylglycerol, resulting in increased cell motility, phagocytosis, and proliferation in microglia. Studies found that a naturally occurring PLCG2 variant, P522R, stimulates PLCG2 activity and is associated with decreased AD risk, making PLCG2 an appealing target as an AD therapeutic. Current drug discovery efforts for this enzyme are limited by no publicly available structures of full‐length PLCG2 and limited kinetic characterization studies. In this study, kinetic and structural studies of wild‐type and the P522R variant of PLCG2 are explored and presented.

Method

PLCG2 was expressed and purified from baculovirus infected Sf9 cells for in‐vitro studies. Kinetic characterization of PLCG2 was accomplished using a continuous fluorescence‐based assay and a mass spectrometry‐based end‐point assay called Desorption Ionization Mass Spectrometry (DESI‐MS). Structural studies of PLCG2 wild‐type and P522R variant were pursued using single‐particle cryo‐EM and X‐ray crystallography.

Result

Kinetic parameters were quantified with both the fluorescence and label‐free DESI assays and found to be similar between assays. X‐ray data on wild‐type PLCG2 crystals were collected to 2.8Å. The current X‐ray structural model reveals an intact active site with bound calcium atom and first‐sphere waters, but a missing nSH2 domain (no observable electron density). Cryo‐EM maps of wild‐type and P522R are consistent with the X‐ray structural model including poor density for the nSH2 domain. Comparison of human PLCG2 structural models to AlphaFold and rat PLCG1 models reveals differences in domain xSH2 domain positions.

Conclusion

Human PLCG2 is highly active in solution as determined by kinetic studies using two different biochemical assays. The X‐ray and cryo‐EM structures of PLCG2 reveal significant conformational flexibility of the nSH2 domain which may be an important function in it binding to other proteins in the plasma membrane.

This research was supported by grant 1U54 AG065181 (IUSM‐Purdue TREAT‐AD Center) from the National Institute of Aging, National Institutes of Health.
A Phase 2 Clinical Trial of AR1004 in Patients with Mild Cognitive Impairment
Authors: Kim Fred , Xi Tianyang , Choung Jai Jun , Jeon Eunjung , Choi Gesun
Published: January 2025

Background

Mild Cognitive Impairment (MCI) is a condition in which an individual shows declines in memory or mental function beyond the normal range for their age. Symptoms are not as severe as those with dementia, and people with MCI are able to carry out daily activities.

AR1004, known as banhasasim‐tang (BHS), is a natural herbal product used in traditional Korean medicine for the treatment of dyspepsia. In a lipopolysaccharide (LPS)‐induced mouse model, AR1004 was able to alleviate cognitive impairment and neuroinflammation. Moreover, in a scopolamine‐induced mouse model, AR1004 also demonstrated neuroprotective effects and improved cognitive function.

Method

AriBio Co., Ltd. is conducting a Phase 2, placebo‐controlled trial for AR1004. The trial will take place in South Korea and will enroll up to 100 55‐80 years old males and females with MCI confirmed by cognitive assessment and plasma ptau‐217 levels. Participants will be randomly assigned in a 1:1 ratio to orally administer either AR1004 or matching placebo twice daily for 24 weeks. The primary endpoint is change from baseline in ADAS‐Cog 13. Secondary endpoints include Neurological Screening Battery tests of memory, attention, language, and executive function. Biomarker evaluations include Aβ42/40 ratio, GFAP, NfL, and pTau‐217. Safety will be assessed throughout the trial.

Result

Results are expected to be reported in 2026.

Conclusions

Traditional medicines such as AR1004 have been used extensively by the general public, but have rarely been tested in clinical trials of cognitive disorders. This Phase 2 trial will determine if AR1004 has benefit in improving cognitive and functional performance in people with MCI. IND approval has been granted by the Ministry of Food and Drug Safety (MFDS), and patient enrollment is planned to begin H2 2024. If results show that AR1004 has benefit in improving cognitive function, it will offer a safe alternative to the currently available treatment options.
Physical Activity, Comorbid Health Symptoms and Falls in Diverse Older Americans at Different Cognitive Stages
Authors: Malatyali Ayse , Wiese Lisa Ann Kirk , Cidav Tom , Thiamwong Ladda , Xie Rui
Published: January 2025

Background

Engagement in regular physical activity is considered one of the most effective interventions in fall prevention, while physical inactivity is often associated with an increased risk of falls. However, research on the relationship between physical activity and falls in older adults at different cognitive stages is limited. This study describes the association of physical activity and comorbid health symptoms (depression, obesity, pain, and shortness of breath) with falls in persons with normal cognition (NC) and impaired cognition (IC).

Method

We conducted a cross‐sectional study on Health and Retirement Study participants aged 65 and above (N = 8,943) using datasets from the 2020 interviews. Our measures include the 27‐point cognition scale, physical activity questionnaire, Center for Epidemiological Studies Depression scale, and health questionnaire.

Result

Main logistic regression results (Table 2) showed that participants with IC were 26% more likely to fall than those with NC. Participants with moderate and high physical activity engagement were less likely to fall (31% and 36%, respectively) than physically inactive participants. However, there was no significant association between mild activity and physical inactivity. In our stratified models (Table 3), each physical activity level was significantly associated with a decreased risk of falls in the IC group, with high activity engagement showing the strongest effect. We observed similar significant trends in the NC group for high and moderate activity engagement but not mild activity. Black participants were 37% to 39% less likely to fall in the NC and IC groups. Although the risk of falling was 29% less in Hispanic participants in the NC group, the association of ethnicity and falls was non‐significant in the IC group. Women had a higher risk of falls than men; the effect of this relationship was marginal in the IC group and significant in the NC group. Depression, pain, and shortness of breath were significantly associated with falls in both cognition groups, whereas the relationship between obesity and falls was significant only in the NC group.

Conclusion

These findings inform fall prevention programs for older persons at different cognitive stages, considering ethnic, racial, and gender disparities and comorbid symptoms.
Association of Nutrition and Gut Microbiome Composition in Puerto Ricans with Alzheimer’s Disease Compared to Healthy Controls
Authors: Soler‐Llompart Cecilia Michelle , Godoy‐Vitorino Filipa , Santiago‐Berríos Michel , Bonilla Aidaliz Llorens‐ , Morales Hiram , Herrero‐Rivera Carlos Alberto , Colon‐Pardo Verónica , Olivieri‐Henry Gerianne , Sala‐Morales Ana Cecilia , Sepulveda Vanessa
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common cause of dementia, consisting of a highly debilitating disorder. It disproportionately affects Caribbean Hispanics, including Puerto Ricans living on the island, where it ranks as the fourth leading cause of death. Reported disparities in AD severity and mortality within this population may stem from various factors, including nutrition, lifestyle, socioeconomic risk status, and more prevalent chronic diseases. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition, leading to cognitive impairment. Diet also plays a role in modulating gut microbiome composition and diversity. Our study aims to examine how nutritional choices influence the microbiota composition and diversity of Puerto Ricans with AD compared to cognitively intact controls.

Method

Forty participants (n = 40), 22 with AD and 18 controls, were clinically and cognitively assessed using Montreal Cognitive Assessment (MoCA). Stool samples were collected for genomic DNA extractions and microbiome characterization. A nutritional questionnaire was administered to participants.

Result

While no significant differences were observed in the frequency of consumption of fruits and vegetables between AD vs. controls (p‐value 0.58), AD participants had a higher likelihood of consuming grains/ fiber more frequently (p‐value 0.05). There are no significant differences in bacterial diversity and richness between AD vs. controls regarding weekly legume, fruits, vegetables, and sweets intake. However, differences at the phylum taxa levels were observed. Cognitively intact participants with lower weekly consumption of sweets and increased consumption of fruits, vegetables, and legumes exhibited a higher abundance of Bacteroides.

Conclusion

Diet choices with more frequent consumption of vegetables, fruits, and legumes and fewer sweets were associated with a higher abundance of Bacteroides in control participants. These bacteria are known for the production of butyrate, a compound with neuroprotective and anti‐inflammatory properties known to maintain homeostasis of the GI mucosa barriers. A better understanding of how nutritional choices influence the gut microbiome will be an invaluable approach to the development of modulation‐based therapeutic interventions to serve as part of a multidisciplinary approach to aim for better gut health in the AD population.
Quality of Life of People Living with Dementia and Care Partners in 3 Countries: Canada, The Netherlands and Poland
Authors: Ilali Marwa
Published: January 2025

The global prevalence of dementia is on a concerning rise, currently affecting 55 million people. It is projected to triple in the next 30 years, leading to a profound impact on the quality of life (QoL) for both people living with dementia (PLWDs) and care partners (CPs). The compounded challenges, encompassing mental, physical, and financial aspects, significantly affect the QoL of PLWDs and CPs, creating an urgent need for comprehensive understanding and tailored interventions. Beyond medical considerations, ethical principles highlight respecting the autonomy and dignity of PLWDs, requiring a delicate balance in meeting their care needs while minimizing CPs' burden. Long‐term care planning is imperative at both individual and societal levels, necessitating sustainable healthcare policies and supportive environments. Existing healthcare and social care responses have limitations, underlining the need for rigorous scientific inquiry to enhance understanding, address unique needs, and improve QoL. The purpose of this research is to explore the multifaceted aspects of improving QoL for PLWDs and CPs in Canada, the Netherlands, and Poland. It seeks to identify predictors, understand experiences, and propose recommendations to improve QoL in the three countries. To address these objectives, the research questions are: What are the predictors of QoL among PLWDs and CPs in Canada, the Netherlands, and Poland? How do PLWDs and CPs experience dementia in these diverse regions? What recommendations can be identified to enhance the QoL of PLWDs and CPs? Employing a results‐based convergent synthesis design approach, this research involves conducting a cross‐sectional survey utilizing random forest models to determine predictors of QoL. Semi‐structured interviews and focus groups with PLWDs and CPs explore their experiences with living with dementia. Deliberative dialogues with diverse stakeholders, including PLWDs, CPs, primary care providers, and policymakers, are facilitated to generate recommendations. To contribute actionable knowledge, evidence‐based recommendations, and support frameworks to enhance the QoL of PLWDs and CPs.
Brain‐Wide Cellular‐Resolution Quantification of Amyloid Plaques and Microglia in AD Model Mice
Authors: Wheeler Damian G. , Guanzon Nathaniel , Murry Alexandria , May Emily , Gallegos Yessenia , Redd Chase , Azevedo Ricardo , Gandhi Sunil
Published: January 2025

Background

Recent advances in optical clearing and light sheet imaging have opened an exciting new avenue for brain‐wide, cellular resolution immunostaining at the forefront of a dimensional shift from 2D to 3D histology. When looking for read‐outs of genetic or pharmacological manipulations that affect the entire brain, traditional 2D immunohistochemistry approaches limit observations to brain regions of interest. Providing access to the intricate anatomy of the whole intact brain, tissue clearing offers neuroscientists unbiased and complete views of brain anatomy and function. One area where these methods have particular utility is in the development of CNS therapeutics where they can be used to examine the regional distribution of the therapeutics in the brain as well as brain‐wide target engagement and phenotypic efficacy. Toward this end, we have focused on Alzheimer’s Disease models developing clearing, imaging and quantification methods for brain‐wide regional quantification of amyloid plaques and microglia.

Methods

Using our optimized iDISCO‐based tissue clearing method and our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image micron‐scale resolution immunoreactivity across entire intact mouse brains in <20 min. Further, our AI‐powered Voxels software identifies individual immunostained cells and objects throughout the brain and aligns them to the Allen Reference Atlas to produce an unbiased, regionalized read‐out of cellular patterns across 100’s brain areas.

Results

Using antibodies targeting the microglial protein Iba1, we can label microglia across the entire brain. We have developed multiple workflows to count microglia, provide metrics of shape and measure microglial activation. We have also trained machine learning algorithms to identify 6E10 antibody‐labeled β‐Amyloid throughout the brain and differentially quantify amyloid immunoreactivity in plaques and neuronal cell bodies. In 5xFAD Tg mice, rather than displaying the ramified morphology seen in WT mice, microglia become condensed and colocalize with β‐Amyloid plaques. Our automated methods segment and quantify these plaque‐associated microglia (PAMs) throughout the brain.

Conclusion

These new methods for whole‐brain, next generation 3D immunohistochemistry are ideally suited to pre‐clinical studies for unbiased, complete and anatomically precise mapping of the efficacy of CNS therapeutics affecting amyloid deposition and neuroinflammation.

We thank NIMH for Grant R43MH122070.
The Relationship Between Weight‐Adjusted Waist Index (WWI) and Cognitive Function in Older Adults: A Cross‐Sectional Analysis of the NHANES 2011‐2014 Data
Authors: Qiu Xichenhui , Wei Changning
Published: January 2025

Background

The impact of obesity on cognitive function has engendered considerable interest. Weight‐adjusted waist index (WWI) emerged as a novel and innovative marker of obesity that has responded to weight‐independent abdominal obesity. However, the association between WWI and cognitive function remains unclear. To address this gap, the present study aims to explore the relationship between weight‐adjusted waist index (WWI) and cognitive performance in older adults.

Method

The datasets from the National Health and Nutrition Examination Survey (NHANES) 2011‐2014 were used in a cross‐sectional investigation. Multivariate regression and smoothing curve fitting were used to investigate the linear and nonlinear relationship between WWI and cognitive function, which was tested by neuropsychological tests, including CERAD‐WL, AFT, and DSST, respectively. Subgroup analysis and interaction tests were used to test whether this relationship was stable across groups. Machine learning models based on random forest facilitated the analysis of associations between WWI and cognitive metrics.

Result

A total of 3472 participants were involved in the analysis. Results showed that WWI was significantly negatively associated with low scores on the CERAD‐WL [‐0.96 (‐1.30, ‐0.62)], AFT [‐0.77 (‐1.05, ‐0.49)], and DSST [‐3.67 (‐4.55, ‐2.79)], and this relationship remained stable after converting the WWI to a categorical variable. In addition, this significant negative association was more pronounced in men than women and diminished with advancing age. Non‐linear threshold effects were noted, with the correlations intensifying between WWI and CERAD‐WL when WWI surpassed 12.25, AFT when WWI surpassed 11.54, and DSST when WWI surpassed 11.66.

Conclusion

A higher WWI, indicative of increased abdominal obesity, was correlated with deficits in learning, memory, verbal fluency, and processing speed among older adults. The results suggest that abdominal obesity may be an essential factor in cognitive decline in older adults. The results demonstrated the importance of interventions to reduce abdominal obesity in protecting cognitive performance in older adults.
Repurposing renin‐angiotensin system‐targeting medications for treatment of cerebral amyloid angiopathy and associated cognitive‐behavioral deficits in Tg‐SwDI mice
Authors: Hernandez Ariana , Noto Natalia , Vogel Chana , Uribe Iliana , Bonetti Julianna , Wind Eleanor , Pulido‐Correa Victoria , Jeneske Mikayla , Echeverria Bianca , Restrepo Yazmin , Moen Shay , Chiduruppa Vedika , Speth Robert , Robison Lisa S
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA), the accumulation of amyloid proteins in the cerebral vasculature, increases the risk of stroke and vascular cognitive impairment and dementia (VCID). Not only is there no treatment for CAA, but the condition is also highly comorbid with Alzheimer’s disease (AD), and its presence may serve as a contraindication to treating patients with anti‐amyloid therapies due to an increased risk of hemorrhage and edema. Therefore, it is crucial to identify novel treatments for individuals with CAA. Epidemiological studies suggest that certain antihypertensive medications, including those that target the renin‐angiotensin system (RAS), are associated with a decreased risk of dementia. This study assesses whether two FDA‐approved RAS‐targeting drugs: telmisartan [a moderately brain‐penetrant angiotensin receptor blocker (ARB)], and lisinopril [a brain‐penetrant angiotensin‐converting enzyme (ACE) inhibitor]; can be repurposed for the treatment of CAA.

Methods

At either ∼3 months (early intervention) or ∼8 months (later intervention) of age, male and female Tg‐SwDI mice began treatment with either telmisartan (1 mg/kg/day) or lisinopril (15 mg/kg/day) dissolved in drinking water or received plain drinking water only. Age‐ and sex‐matched C57BL/6J mice receiving plain drinking water served as wild‐type controls. Following 4 months of treatment, mice underwent blood pressure measurement followed by behavioral testing prior to euthanasia.

Results

Voluntary oral consumption delivered doses similar to the target dose for both drugs. At the doses used, telmisartan and lisinopril treatment did not significantly reduce blood pressure in Tg‐SwDI mice. Our findings thus far suggest that these drug treatments, particularly lisinopril, may mitigate cognitive‐behavioral deficits observed in Tg‐SwDI mice.

Conclusions

Ongoing experiments are being completed to increase sample sizes and investigate the potential benefits of telmisartan and lisinopril to mitigate neuropathological and cognitive impairment in Tg‐SwDI mice. If findings support our hypothesis, this will demonstrate that these drugs could be repurposed to prevent and/or treat CAA, reducing the worldwide burden of stroke and dementia.
Associations Between Alzheimer’s Disease and Obesity: Clinical Trials of NA‐831 for AD and NA‐931 for Obesity
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern
Published: January 2025

Background

NA‐831 is a new drug candidate, exhibiting neuroprotection, neurogenesis and memory enhancing properties for the treatment of Alzheimer’s Disease (AD). NA‐931 is an analog of NA‐831, regulating the homeostasis of the triple: IGF‐1, GLP‐1 and GIP functions for obesity.

Method

A randomized clinical trial of NA‐831 was performed in 112 participants with mild and moderate AD, half received the drugs and half received placebo. The patients with MCI received 10 mg of NA‐831 and patients with mild and moderate AD received 30 mg of NA‐831 or placebo orally per day. Subjects with MCI to meet the NIA‐AA core clinical criteria, CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline. MMSE score ≥22. Subjects with mild & moderate AD to meet the NIA‐AA core clinical criteria. MMSE: 17‐21.

Animal Studies of NA‐931: A 14‐day study in diet‐induced obesity DIO‐NASH mice was conducted to evaluate the treatment of NA‐931 on obesity.

Result

NA‐831 showed a significant improvement for patients with mild and moderate AD with the ADAS‐Cog‐13 score change of an average of 4.1 as compared to the placebo after 24 weeks of treatment (p = 0.001; ITT). CIBIC‐Plus showed 78% patients improved (p = 0.01; ITT). mNA‐831 was well‐tolerated at 30 mg/day. It was observed that 66% (12 of 18) patients having diabetes amongst 56 patients on the NA‐831 drug treatment reported a loss of 17‐23% of body weight over 6 months. Only 4 of 7% of 56 patients on placebo reported a loss of 3‐5% over 6 months. There were no serious adverse events observed.

The study in DIO‐NASH mice had demonstrated that treatment with NA‐931 resulted in significant reductions in body weight up to 26% (p<0.0001), as well as reductions in plasma glucose and plasma triglycerides up to 23% and 34%, respectively (p<0.003 for each). NA‐931can reduce the body mass index, without causing the muscle loss.

Conclusion

An association of Alzheimer’s disease and diabetes obesity has been suggested with clinical results of NA‐831 and NA‐931. However, whether this association is causal requires further evaluation.
Brain health in the clinical practice of Spanish neurologists: a national cross‐sectional survey
Authors: Lage‐Martinez Carmen , Zuniga Raquel Gutierrez , Giménez Sandra , Nowak Rafal , Zegarra‐Valdivia Jonathan Adrian , Falgàs Neus , Balasa Mircea , Lawlor Brian A , Leroi Iracema
Published: January 2025

Background

Brain Health (BH) perspectives and practices among health care professionals constitute a crucial piece of information for developing tailored initiatives to foster BH at the regional level. We aim to characterize knowledge and clinical practices associated with BH in Spanish neurologists by a cross‐sectional survey.

Method

An original online survey was distributed by email among all members of the Spanish Society of Neurology. The survey included four sections: BH knowledge; BH‐related clinical practices; perspectives about the importance of BH in neurology practice; and limiting factors for BH promotion in daily practice.

Result

400 neurologists participated in the survey, and 75.8% fully completed it. Participants were 61.7% females, mainly workers in tertiary (71.0%) and public hospitals (85.7%), and 74.2% had a sub‐specialization. Many participants considered to be familiar (41.7%) or somehow familiar (43.6%) with the concept and recommendations of BH, but 48.7% did not know any supporting scientific study. A substantial percentage of respondents considered that BH cannot be improved in aging (19.2%) or dementia (21.1%). Clinical interview was the main tool to evaluate BH (81.3%), but 22.1% of neurologists did not routinely explore BH. A higher percentage of females than males declared to regularly ask patients about their familiar situation (68.9% vs 53.0%, p 0.018) and social activities (62.9% vs 47.8%, p 0.019) and recommended more frequently healthy diet (75.7% vs 64.9%, p 0.0080). Also, more females considered that it is important to develop BH plans (98.9% vs 89.4% males), even adjusting by age (p <0.0001). The main limiting factor for BH evaluation and promotion during clinical visits were time constraints (in 76.8% of cases), followed by scarcity of support resources (61.3%), but a significant number of neurologists with <10 years of experience considered lack of education about official BH recommendations as a limitation (26.5% vs 14.0% in >20 years, p 0.047).

Conclusion

This survey was conducted as a situational analysis to guide next steps of the BH roadmap in Spain. While time constraints and scarcity of resources should be approached from a health policy perspective, we identify poor BH knowledge as an opportunity to improve BH related practices, especially among young neurologists.
Evaluating the Impact of Cardiometabolic Risk Factors on Neuroimaging‐Based Brain Age: A Deep Learning Approach
Authors: Tavakoli Fatemeh , Ma Da , Ge Yaorong
Published: January 2025

Background

Mid‐life and late‐life cardiometabolic abnormality are known modifiable risk factors for late‐life dementia. Neuroimaging‐based “brain age” has shown as a surrogate marker for brain health. This study aims to investigate the relationship between effect of cardiometabolic risk factors (CMRF) and accelerated brain aging,

Method

T1‐weighted 3D MRIs from a total of 965 participants (47‐81 years, 53% female) in the UKBiobank data were included in this study. (80%( = 772) training and 20%( = 193) validation). 9 CMRF was extracted, including diastolic blood pressure (dbp), pulse rate (pr), glycated haemoglobin (HbA1c), HDL, glucos, systolic blood pressure (sbp), cholesterol, triglycerides. A brain‐age model pre‐trained using the UKBiobankd data – the Simple Fully Convolutional Network (SFCN) – was fine‐tuned on the brain‐extracted data derived from FreeSurfer (v5.3.0). The brain age gap (BAG) was calculated as the difference between their chronological age and the predicted brain age. Correlation between the CMRF and BAG was derived using the generalized linear model controlling the demographic factors, including age and sex.

Result

The model exhibited high accuracy with a training MAE of 2.05 years and a validation MAE of 2.77 years. Significant associations with the BAG were observed for sbp across genders with a p‐value of 0.0415, with gender‐specific correlations found for cholesterol and sbp in females (p = 0.0242 and 0.0163) and no significant correlations between males’ BAG and any CMRF.

Conclusion

This study discerned the significance of cholesterol and systolic blood pressure as predictors of brain age, emphasizing their potential as markers for brain health in this demographic. Additionally, the observed gender disparities in the association of CMRFs with BAG highlight the necessity for gender‐specific considerations in the assessment and intervention of brain aging.