bluuebunny/crossref_metadata_2025 huggingface dataset:
Single nucleotide polimorphisms of the main glutamate transporter in the brain are associated with lower regional brain glucose metabolism in cognitively impaired individuals
Authors: de Oliveira Roberta dos Santos , Limberger Christian , Machado Luiza Santos , de Bastiani Marco Antônio , Schlickmann Thomas Hugentobler , Carello‐Collar Giovanna , Povala Guilherme , Pascoal Tharick A. , Zimmer Eduardo R.
Published: January 2025

Background

Astrocytes play a main role in brain energy metabolism, primarily through the metabolic cooperation with neurons. The use of [18F]fluorodeoxyglucose(FDG)‐PET has become a valuable indicator of neurodegeneration in Alzheimer's disease (AD), revealing a brain hypometabolic signature, but it is sensitive to changes in astrocyte metabolism. It is postulated that the activation of the excitatory amino acid transporter 2 (EAAT2) is the main trigger of FDG‐PET uptake in astrocytes. However, the potential relationship between single nucleotide polymorphisms (SNPs) in the gene that encodes for EAAT2 (SLC1A2) and the AD hypometabolic signature remains unknown. Here, we investigated whether SNPs in SLC1A2 affect brain glucose metabolism in cognitively impaired (CI) individuals.

Method

We assessed 331 CI individuals from the ADNI cohort with available [18F]FDG‐PET imaging data, CSF Aβ1‐42 and p‐tau181 measures, and genotyping data of SLC1A2 (Table 1). After the genetic data processing, 100 SNPs from the SLC1A2 gene were identified. In this study, we focused on the 10 SNPs more associated with [18F]FDG SUVR in an exploratory ROI‐wise analysis. Then, we performed voxel‐wise correlation analysis with RMINC, testing the association between the SLC1A2 SNP carriership and [18F]FDG‐PET, adjusting for age, sex, APOE4 status, and CSF Aβ42 and p‐tau181 levels (corrected p‐value < 0.05).

Result

Our findings revealed a negative association between four SLC1A2 SNPs and [18F]FDG‐PET in specific brain regions. This indicates that SLC1A2 SNP carriership is associated with lower regional glucose metabolism. Notably, rs57339940 carriers presented a significant cluster in the cingulate region (tmax = 3.04, p < 0.01, Figure 1A). Carriers of rs11033098 and rs11033099 exhibited bilateral clusters in areas of the lingual gyrus (tmax = 2.4806 and tmax = 2.8736, respectively, p < 0.01, Figure 1B‐C). Additionally, individuals with rs10768132 showed a substantial bilateral impact on the posterior areas of the cuneus (tmax = 2.9821, p < 0.01, Figure 1D).

Conclusion

These preliminary results show that SLC1A2 SNP carriership had a significant influence on regional glucose hypometabolism, specifically in areas comprising the occipital lobe and the cingulate region. Metabolic alterations may influence the susceptibility of those regions to accumulate amyloid in later stages of AD.
Sex‐specific relationships among risk factors in those with Mild Cognitive Impairment or Alzheimer’s disease and healthy controls
Authors: Intzandt Brittany , Ramirez Joel , Lam Benjamin , Masellis Mario , Scott Christopher J. M. , Einstein Gillian , Bherer Louis , Black Sandra E ,   ONDRI Researchers; CCNA Researchers
Published: January 2025

Background

Dementia incidence is projected to significantly increase, posing unique challenges to healthcare systems. Identifying non‐modifiable and modifiable risk factors (RF) is crucial, including sex‐specific factors, given the higher prevalence among females (60%). Here, we employed a network analysis to examine prominent RF in healthy controls compared to those with cognitive decline (CD), as well as the interrelationships and interactions of RF on CD. Additionally, sex‐specific networks were compared to identify unique RF and interactions present among sex.

Method

Healthy controls and CD individuals (mild cognitive impairment and Alzheimer’s dementia) were included from the Ontario Neurodegenerative Initiative and Canadian Consortium for Neurodegeneration in Aging (n = 339 total; 52% female; 72% CD). Non modifiable RF (e.g., age), modifiable RF (e.g., Framingham RF) and cognitive outcomes (e.g., executive functioning) were included in network modeling. Sex‐specific networks were created within the CD group and compared, as was between CD and healthy controls. Relationships among RF present in CD were identified and the strength. Nodes represented RF and edges are the pairwise dependency between RF, node centrality was investigated for the relative importance of each RF in the network.

Result

Healthy controls and CD had statistically different networks (M = 0.536; p = 0.02), and the CD network had greater connectivity (S = 2.69; p = 0.005)[Figure 1]. Male and female networks were statistically different within CD (M = 0.432; p = 0.027), and the male’s network had statistically greater connectivity than the females with CD (S = 1.24; p = 0.049)[Figure 2]. Within females, the CD had significantly greater connectivity (S = 0.90; p = 0.03)[Figure 3] than healthy controls and no difference in males (p > 0.05).

Conclusion

Our findings reveal unique sex‐specific network patterns of RF for CD, which further underscores the need for sex‐disaggregated analyses. The observed differences in heightened connectivity of typically studied RF in males, highlights a potential gap in the understanding of sex‐specific RF for Alzheimer’s. Future work should incorporate biomarkers, such as neuroimaging, to further comprehend sex‐specific RF for CD and to create the framework for precision medicine in targeting sex‐specific RF for CD.
The World‐Wide FINGERS Global Strategy for Precision Prevention of Dementia and Alzheimer’s Disease
Authors: Mangialasche Francesca , Matton Anna , Ngandu Tiia , Lehtisalo Jenni , Udeh‐Momoh Chi , Alanko Vilma , Barbera Mariagnese , de Jager Celeste A , Peltonen Markku , Perera Dinithi , Stephen Ruth , Solomon Alina , Kivipelto Miia ,   World‐Wide FINGERS network
Published: January 2025

Background

Precision Prevention –the right intervention for the right person at the right time– is a recent endeavour in the Alzheimer’s disease (AD) field, requiring the integration of multidimensional data from large, representative populations, to identify phenotypes for early and accurate detection of prevention potential.

Aims

The World‐Wide FINGERS (WW‐FINGERS) network of multidomain trials for risk reduction and prevention of dementia includes 60+ countries. The network aims to adapt and test the original model from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) which showed that a multidomain intervention can benefit cognition in older adults at‐risk of dementia. WW‐FINGERS works towards trials data harmonization, to enable joint data analysis.

Methods

International Working Groups (IWGs) focused on trials´ prominent features were established to leverage the WW‐FINGERS expertise, facilitate data harmonization and joint analysis. Mapping and harmonization of data across the trials is ongoing, via periodic meetings and RedCap‐supported digital surveys done within the network.

Results

The WW‐FINGERS network completed 14 trials, while 21 are ongoing, accounting for 18000+ participants. Trial Harmonization Guidelines were compiled, to support prospective data harmonization. Two IWGs –Cognitive Outcomes and Biorepository/Biomarkers– conducted surveys to map the current data and sample collection within the network. The Cognitive Outcome survey included data from 25 studies, showing target population ‐from asymptomatic at‐risk of dementia to early symptomatic stages‐, ethnicities within the trials (including 20% Caucasian, 10% Asian, 8% Black African, 7.5% mixed ethnicity, 4% Hispanic/Latino, 5% Caribbean), use of cognitive tests in 19 languages, with composite neuropsychological test batteries being most frequently used, capturing memory, executive function, and processing speed. The Biorepository/Biomarker survey was completed for 29 trials, including information on sample types, processing, storage, APOE availability and other biomarkers. Survey results are informing data harmonization and protocols for new trials. Additional IWGs are planned, including Neuroimaging, Non‐Cognitive outcomes and Health‐economics. Collaborations with international stakeholders are ongoing to maximize outreach and enable data sharing.

Conclusion

The WW‐FINGERS global collaboration is enabling scalability and evolution of the FINGER model, and prospective harmonization of multidomain trials, establishing the base for a Precision Prevention approach in AD and dementia.
Impacts of Informant Replacement in Industry‐Sponsored Alzheimer’s Disease Clinical Trials
Authors: Nishida Mikaela K , Nuño Michelle M , Grill Joshua D , Gillen Daniel L
Published: January 2025

Background

In Alzheimer’s disease (AD) clinical trials, participants must enroll with a study partner informant who accompanies them to visits and completes validated instruments. Mid‐trial informant replacement (IR) has been found to impact academic trial results. We hypothesized that a similar impact would be observed in industry‐sponsored trials.

Method

We conducted a retrospective analysis of two industry‐sponsored AD clinical trials testing semagacestat in mild‐to‐moderate AD. We assessed the relationship between IR and Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL) score between visits using generalized estimating equations (GEE). The outcomes of interest were mean change in ADCS‐ADL between successive visits and the mean absolute change in ADCS‐ADL between successive visits, which was used to assess variability. Both models were adjusted for a priori‐specified potential confounding variables including participant sex, age, informant type, trial, time, and previous ADCS‐ADL measurement. To analyze impacts on a primary outcome measure, we used an ANCOVA model to estimate the association between IR and 76‐week change from baseline in ADCS‐ADL, where we adjusted for participant sex, age, informant type, trial, and baseline ADCS‐ADL measurement. We conducted an F‐test to compare the variances of this change.

Result

Among N = 2642 randomized participants, 72 (∼3%) of participants experienced IR at least once with a total of 81 occurrences. For visits standardized to be three months apart, we estimated that the difference in the mean between‐visit change in ADCS‐ADL was approximately ‐1.41 points (95% CI: ‐3.52, 0.72; P = 0.194) and the difference in the mean between‐visit absolute change was approximately 1.85 points (95% CI: 0.22, 3.49; P = 0.026), comparing participants who experienced IR to similar participants who had stable informants. We did not estimate a statistically significant difference in week‐76 change from baseline ADCS‐ADL (Est. = ‐0.98, 95% CI: ‐6.02, 4.06; P = 0.702) or a significant ratio of variances (Est. = 1.09, 95% CI: 0.65, 2.17; P = 0.700) comparing this measure for participants with IR to those with stable informants.

Conclusion

IR is associated with increased variability in ADCS‐ADL measurements between successive visits and should be considered when planning AD clinical trials.
Perceived threat of Alzheimer’s disease and dementia predicting health behavior
Authors: Dhaliwal Ravneet K. , Jacova Claudia , Marx Hannah , Robertson Frank , Gehling Jacklyn
Published: January 2025

Background

Factors influencing health behaviors among older adults experiencing cognitive changes are important to understand in order to successfully promote preventative public health programs for Alzheimer’s disease and related dementias (ADRD). The Health Belief Model (HBM) has been utilized to investigate and predict health behaviors based on an individuals’ perceptions and beliefs. The aim of our study was to investigate the contribution of perceived threat (risk and worry) to individuals seeking care for cognitive changes.

Method

Participants of this study were 279 adults (M age = 73.8, range 60‐96; 54% female, 89% white, M education (years) = 14.9) recruited from the community, without neurocognitive diagnoses, and residing in the United States. They completed an online survey through Qualtrics. Participants rated their risk for developing ADRD and their worry about developing ADRD on 5‐point scales (risk: 1 = much lower than average to 5 = much higher than average; worry: 1 = not at all worried to 5 = very worried). They also answered questions about whether they noticed difficulties with their memory and cognition (yes/no), and whether they had seen a doctor for these changes (yes/no).

Result

Following the HBM, perceived threat is separated into two variables: perceived susceptibility (risk) averaged M = 2.48 (58.4% rating in the 3‐5 range) and perceived severity (worry) averaged M = 2.05 (25.8% rating in the 3‐5 range). There were 101 participants (36%) who endorsed perceiving difficulties with their memory or cognition. Of these, only 3 participants (M age = 70.3, range 70‐71; 2 females, M education (years) = 14.7) said ‘yes’ to seeing their doctor about memory or cognitive difficulties (3%), preempting further predictive analyses.

Conclusion

We found that despite endorsing memory/cognitive difficulties, and reporting above average risk and worry about ADRD, an exceedingly small number of adults aged ≥60 had consulted their doctor. Our findings align with previous research reporting that medical help‐seeking does not keep apace with perceived susceptibility to ADRD and worry in older adults. As a result, our understanding of factors that influence health behaviors, such as seeking care early on, remains limited.
The Effects of Reducing Sedentary Behavior Duration by Increasing Physical Activity, on Cognitive Function, Brain Function and Structure Across the Lifespan: A Systematic Review
Authors: Feter Natan , Pindus Dominika
Published: January 2025

Background

No study has synthesized evidence from randomized controlled trials (RCTs) testing the acute and chronic effects of reallocating sedentary time (ST) to physical activity (PA) on cognitive and brain health across the lifespan.

Method

Seven academic databases were systematically searched on October 26, 2022, with an updated search on June 23, 2023. Inclusion criteria encompassed RCTs published in English involving healthy participants aged ≥ 4 years. Acute (lasting 3 hours to 13 days) and chronic (lasting ≥ 2 weeks) interventions aiming to reduce ST and/or prolonged ST by reallocating ST to PA to improve cognition, brain function, and structure were included. Two independent assessors evaluated the study quality using the Risk of Bias 2.0 tool.

Result

We included 22 trials (n = 1,166) investigating acute (18 studies) and chronic (4 studies) effects on cognition (21 studies) and brain function (5 studies). No study investigated brain structure. Most studies included adults aged 18‐64 years (63.9%), followed by children and adolescents (4‐17 years) (27.3%) and older adults (≥65) (9.0%). Inconclusive evidence exists regarding the impact of reallocating ST to PA on brain function and cognition, attributed to the high risk of bias, limited number of studies, and diverse exercise protocols. However, emerging neurofunctional findings from a single chronic study suggest that relative to prolonged ST, introducing one bout of high‐intensity PA on most days enhanced neural efficiency of the hippocampus and parahippocampal gyrus during an episodic memory task in young adults. Interrupting ST with light PA bouts also acutely improved cerebrovascular function in young adults (1 out of 3 studies). The positive cognitive effects of acutely interrupting prolonged ST with PA were selective to inhibitory control (3 out of 6 studies) and mental flexibility (2 out of 5 studies), with largely null findings on other cognitive outcomes and chronic interventions.

Conclusion

The evidence on the acute and chronic effects of reallocating ST to PA on brain function and cognition remains inconclusive with no studies measuring brain structure. However, specific studies suggest that reallocating ST to PA may chronically enhance hippocampal function and acutely improve inhibitory control, mental flexibility, and cerebrovascular function.
Baseline Predictors of Study Discontinuation in a Preclinical Alzheimer’s Disease Clinical Trial
Authors: Raman Rema , Hussen Kedir , Donohue Michael C. , Langford Oliver , Molina‐Henry Doris P. , Aisen Paul S. S. , Sperling Reisa A , Grill Joshua D ,   the A4 Study Team
Published: January 2025

Background

Participant dropout from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. This analysis aims to identify the baseline characteristics of participants who discontinued during the blinded phase of one of the first and largest preclinical AD trial completed to date, the Anti‐Amyloid treatment in Asymptomatic AD (A4) Study.

Method

The sample consisted of all A4 trial randomized participants followed for 4.5 years through the COVID‐19 pandemic. Baseline demographic (with age centered at 73 years), clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with study discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.

Result

Of 1169 randomized participants, 339 (29%) discontinued from the trial (median follow‐up time: 759 days). Main reasons included participant unwilling to continue (55.8%) and adverse events (18.9%). From the multivariable analysis, the two main predictors of study discontinuation were baseline State‐Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p = 0.0024) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.0001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p = 0.0627) and APOEe4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p = 0.0941) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnic underrepresented group (combined due to small sample sizes), cognitive scores and amyloid/tau PET scores were not associated with study dropout.

Conclusion

Older participants and those with higher levels of anxiety at baseline were more likely to discontinue while those who had a family history of dementia or were APOEe4 carriers were less likely to dropout. Continued analyses aim to identify post‐baseline and longitudinal predictors of attrition in this preclinical AD trial.
Combination therapies targeting AD risk factors delay cognitive decline over 10 years in Alzheimer’s patient
Authors: Torrandell‐Haro Georgina , Shang Yuan , Vitali Francesca , Brinton Roberta Diaz
Published: January 2025

Background

Alzheimer’s Disease (AD) is a complex neurodegenerative disease characterized by multiple etiologies that remains without a cure. Diabetes, dyslipidemia, hypertension, and inflammation are well‐known risk factors for AD, and FDA‐approved therapeutics for these conditions have been associated with a reduced risk of developing AD. This study aims to evaluate the impact of diabetes medications (DBMD), lipid‐lowering (LIPL), antihypertensive (AHTN), and non‐steroidal anti‐inflammatory (NSD) therapeutics, alone or combined, on cognitive performance in an AD population.

Method

This study used the National Alzheimer’s Coordinating Center (NACC) database that includes longitudinal records of diagnoses, prescriptions, and cognitive performances of AD patients across the United States. A subset of 7,653 AD patients (mean age 74.1 years old) with mean baseline cognitive scores representative of a state of mild dementia was selected from 48,605 NACC participants. Change from baseline scores for Clinical Dementia Rating Sum of Boxes (CDR‐SB) and Mini‐Mental State Examination (MMSE) were compared between non‐treated and treated patients over 10 years. Differences in cognitive performance were also evaluated based on sex and APOE genotype.

Result

The quadruplet combination of DBMD+LIPL+AHTN+NSD resulted in a 44% and 35% (MMSE/CDR‐SB) delay in cognitive decline at 5 years and 47% and 35% (MMSE/CDR‐SB) delay at 10 years. The cognitive performance of AD patients treated with monotherapy of LIPL, AHTN, or NSD as assessed by MMSE and CDR‐SB was significantly delayed (10% to 24%) compared to untreated patients at 10 years. Moreover, the data indicated additive and synergistic efficacy in slowing the rate of cognitive decline with combination therapy where slower cognitive decline was observed in patients treated with an incremental number of medications. Moreover, our findings revealed sex‐ and APOE genotype‐specific impact on cognitive performance for each treatment combination, where females and APOE4 exhibited the greatest cognitive benefit of combination therapy.

Conclusion

Combination therapies targeting AD risk factors significantly slowed cognitive decline in AD patients at a magnitude comparable to or greater than beta‐amyloid immunomodulator interventions. Our findings strongly support combination precision medicine, tailored to address multiple AD risk factors within specific subpopulations based on sex and APOE genotype.
Education correlate with hippocampus volumes in African American males but not in females
Authors: Esiaka Darlingtina , Abner Erin L. , Powell David K , Jicha Gregory A , Jiang Yang
Published: January 2025

Background

Prior research shows that education is a protective factor against cognitive decline. Education can contribute to cognitive reserve and influence the formation and efficiency of neural networks in the brain. Brain volume, particularly changes in specific brain regions, such as the hippocampus, amygdala, and precuneus, plays a significant role in cognitive decline. Reduced brain volumes are associated with impairments in episodic memory and decline in higher‐order cognitive processes, a hallmark and predictive marker seen in conditions like Alzheimer’s disease. Research also suggests that brain volume measures serve as predictive markers for cognitive decline and may aid in the early detection of neurodegenerative diseases. The current study explored sex differences in the association between education and brain volumes in older Black Americans.

Method

Data from 38 African American participants (Mage = 72.81, SD = 8.43; 26 females) were derived from the University of Kentucky Alzheimer’s Disease Research Center (UK‐ADRC) cohort, and their years of education ranged from 10‐21 years (M = 15.14, SD = 2.99). The participants completed a series of tests, including a review of health history, physical and neurological exams, neuropsychological testing, and MRI scans in accordance with procedures at UK‐ADRC.

Result

We found that, in African American males, higher years of education were significantly associated with increased volume in the left hippocampus (r = .801, p <.01) and right hippocampus (r = .834, p <.01). Results also showed a trending negative association between higher levels of education and right amygdala (r = ‐.612, p = .06) in African American males. We observed no association between education and brain volumes in African American females.

Conclusion

Our findings suggest that contextual differences may interact with educational attainment to impact brain development in males versus females. Also, educational experiences may have varying effects on neuroplasticity, and brain volume changes over the lifespan, influencing cognitive aging differently in males and females. Studying how education interacts with brain volumes in males versus females can contribute to a more nuanced understanding of the relationship between education and cognitive decline. This knowledge can inform preventive measures and interventions sensitive to the unique needs and vulnerabilities of both males and females.
The FCI‐SF predicts Alzheimer’s disease related cognitive changes
Authors: Zak Ella , Schlickmann Thomas Hugentobler , Zimmer Eduardo R. , Bastiani Marco De , Bieger Andrei , Borelli Wyllians Vendramini
Published: January 2025

Background

Recognizing Alzheimer’s disease (AD) early is essential for enhancing patient outcomes. Therefore this research focused on exploring indicators of AD by investigating the role of declining financial capacity (FC) in predicting objetive cognitive impairment (OCI).

Method

We analyzed participants without OCI in Mini‐mental state examination (MMSE, Table 1) or Clinical Dementia Rating‐Sum of Boxes (CDR‐SB, Table 2) scores from the ADNI database. They had a prior completed Financial Capacity Instrument‐Short Form (FCI‐SF). Cox proportional hazard models were used to evaluate how different FCI‐SF scores influence the risk of transitioning to MMSE and CDR‐SB scores that indicate OCI and the timeframe involved. The analyses used the survminer and survival packages in R and corrected for age, gender, diagnose, race, education as covariates (p<0.05).

Result

Participant mean age (SD) for MMSE analysis was 71.3 (±6.6) years (50.8% female). The low FCI‐SF score group (HR = 25.67, 95% CI = 6.232‐105.737) was more likely to convert under the cutoff score for MMSE in the future compared to the high group. Compared to the low group, the high (HR = 0.0389, 95% CI = 0.00945‐0.1605) and mid group (HR = 0.0797, 95% CI = 0.0438‐0.1449) exhibited a lower conversion likelihood.

Mean age for CDR‐SB analysis was 71.1 (±6.4) years (51.8% female). The low group had an increased conversion risk (HR = 9.8128, 95% CI = 3.5171‐27.378) compared to the high group. The high (HR = 0.1019, 95% CI = 0.0365‐0.2843) along with the mid group (HR = 0.1993, 95% CI = 0.1207‐0.3289) had a decreased likelihood to convert compared to the low group.

Converters from the MMSE analysis had a mean (SD) examination time of 2.1 (±1.2) years prior to the conversion. CDR‐SB converters had mean (SD) of 2.2 (±1.3) years. Individuals with higher education had lower conversion likelihood.

Conclusion

A low FCI‐SF score can help predict future MMSE and CDR‐SB outcomes. According to Cox models, individuals with lower FCI‐SF scores have an increased risk of transitioning to MMSE and CDR‐SB scores that indicate OCI.
The impact of music experience on hippocampal subfields and cognitive function in older adults at risk for dementia
Authors: Espinosa Nicole , Almgren Hannes , McKinnon Andrew C , Naismith Sharon L
Published: January 2025

Background

It has been argued that engaging in musical activities throughout one's lifespan can promote neuroplasticity and protect against age‐related cognitive decline. Most of the research on this topic has been performed on professional musicians; however, general music experience across the lifespan may also have a protective effect on cognitive performance and brain health in non‐professional musicians. This study investigates the effects of lifetime music experience on hippocampal subfield grey matter (GM) volumes and memory and executive functioning in older adults at risk of dementia.

Method

168 individuals aged ≥50 years (mean age = 68.83, females = 67.9%, MMSE = 28.99 ) with (n = 87) and without (n = 81) a history of music experience and with a MMSE ≥24 were recruited from a memory clinic. Participants underwent tests of memory (Logical Memory subtest of the Wechsler Memory Scale‐III and the Rey Auditory Verbal Learning Test; RAVLT) and executive functioning (the DKEFS Colour Word Interference Test condition 3; CWIT, and the Trail Making Test part B; TMT), as well as MRI data acquisition of the hippocampus (T1 and high‐res hippocampus T2) from which the CA1, dentate gyrus (DG) and subiculum were computed (and corrected for intracranial volume) using the automated segmentation of hippocampal subfields (ASHS) software. Multiple Pearson’s partial correlational analyses adjusting for age were carried out to examine the association between music experience, hippocampal subfields, and cognition. All statistical tests were two‐tailed (alpha = 0.05).

Result

Pearson's partial correlation coefficient indicated that music experience was associated with higher scores in both tests of executive functioning, the TMT (r = 0.172; p = 0.028) and CWIT (r = 0.196; p = 0.012). However, memory was not significantly correlated with music experience. There were no differences in hippocampal subfield volumes between those who did and did not have musical experience.

Conclusion

Older adults with music experience showed significantly better executive functioning compared to those without. However, this improvement was not associated with any differences in hippocampal subfield volumes. Further research is needed to fully understand the effect of music experience on other MRI markers.
Cognitive reserve: Investigate the efficacy of resistance training on cognitive reserve in older adults with subcortical ischemic vascular cognitive impairment
Authors: Gu Yi , Hsu Chun Liang , Silva Narlon Cassio Boa Sorte , Tam Roger , Alkeridy Walid Ahmed , Lam Kevin , Liu‐Ambrose Teresa
Published: January 2025

Background

Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. White matter hyperintensities (WMH) secondary to SIVCI often result in impaired executive function. Cognitive reserve is a property of the brain that allows for preserved cognitive performance given brain injury or disease. In an unpublished cross‐sectional study, we found the strength of intra‐network connectivity in fronto‐executive network (FEN), fronto‐parietal network (FPN) and default mode network (DMN) moderated the relationship between WMH and executive function in older adults with SIVCI. Thus, these networks may be involved in cognitive reserve. Exercise is hypothesized to contribute to cognitive reserve. We explored the effect of resistance training (RT) on functional connectivity (FC) in FEN, FPN, and DMN, as well as executive function, in older adults with SIVCI.

Method

In a 12‐month randomized controlled trial that randomized adults with SIVCI to either 2x/week of RT or 2x/week of balance and tone training (BAT; control). Resting‐state functional MRI was collected from a subset of 29 participants (RT = 14; BAT = 15) at baseline and trial completion. FC of FEN, FPN, and DMN was quantified using priori‐selected region‐of‐interest masks. Executive function was measured by Trail Making Test (TMT), Digit Symbol Substitution Test (DSST) and Stroop Test (ST). Analysis of covariance was conducted to compare differences in group means of intra‐network FC of FEN, FPN and DMN and executive function tests performance at trial completion, with baseline outcome scores as covariate. Pearson correlations were computed to determine whether changes in executive performance between baseline and trial completion were related to changes in FC in the RT group.

Result

At trial completion, there were no significant between‐group differences in intra‐network FC of FEN, FPN and DMN. RT significantly improved ST performance (estimated mean change[95%CI]: ‐11.322[‐22.366, ‐0.277], p = 0.045) compared with BAT; there were no significant between‐group differences in TMT and DSST. Within RT group, improved ST performance was significantly correlated with increased intra‐network FC of FEN (r = ‐0.697, p = 0.006).

Conclusion

RT‐induced improvement in ST performance was associated with increased intra‐network FC of FEN. More research is needed to determine whether exercise training has an effect on the neural correlates of cognitive reserve.
A scalable solution for precisely measuring low abundant neurobiomarkers from micro‐sampling
Authors: Fan Tsz Wing , Kim WonHee , Thomas Corinne , Jiang Wenjing , Tan Jeremy , Xuan Feng
Published: January 2025

Background

Cutting‐edge ultrasensitive immunoassay platforms have unveiled the potential of blood‐based biomarkers, offering detection at low fg/mL levels for early neurodegenerative disorder prognosis, screening, and therapeutic monitoring. Current immunoassays, such as single molecule array (SIMOA) and mesoscale multi‐array (MSD), face limited adoption due to their reliance on specialized equipment. Additionally, they require immobilization of probe reagents and a washing process, demanding tens of thousands of proteins to achieve the Limit of Detection (LOD), leading to the requirement of high sample volume and high affinity antibodies for fg/mL sensitivity. Addressing the escalating need for non‐invasive, small‐volume sample collection, along with an accessible platform for frequent longitudinal monitoring and population‐scale screening, a solution with these features is imperative.

Method

Introducing Successive Proximity Extension Amplification Reactions (SPEAR), which employs a unique two‐factor authentication mechanism that eliminates the background in conventional homogeneous assay, detects down to single‐digit copies of proteins. SPEAR utilizes a simple three‐step wash‐free workflow adaptable to any liquid handler and readable on ubiquitous PCR machines. To showcase its utility in detecting neurobiomarkers at low concentrations in blood, we demonstrate NFL assay using just 1‐mircorliter diluted plasma sample to reach low fg/mL sensitivity with excellent precision. Comprehensive testing included spike‐in recovery, dilution linearity and specificity against neurofilaments (Nf‐M, Nf‐H, peripherin, and α‐internexin), precision and accuracy.

Result

SPEAR NFL assay exhibited remarkable LOD and Lower Limit of Quantification (LLOQ) from two commercial readily available NFL antibody pairs. The LOD was measured at 51 and 90 fg/mL using 1 µL of 1:4 diluted plasma. Robust precision was indicated by low intraplate and lot‐to‐lot %CV (6% and 7%, respectively), and high concordance against Simoa® NF‐light™ V2 Advantage Kit and MSD Splex kit using 36 K2EDTA plasma samples.

Conclusion

SPEAR has demonstrated validated sensitivity against existing NFL detection platforms. Its standout features, including minimal sample volume requirement and compatibility with standard PCR machines, coupled with advances in portable PCR machines and remote collection devices, position SPEAR as a robust and accessible tool for neurodisease diagnostic and research.
Clinical Profile of Dementia in Bed‐Bound or Home‐Bound Elderly Individuals from Low‐Income Communities in Southeast Brazil
Authors: Real Ana Paula Bernardes , de Moraes Flavia Lanna , de Moraes Edgar Nunes , Machado Carla Jorge
Published: January 2025

Background

Aging is linked to an increased risk of dementia, a significant cause of functional decline in the elderly, necessitating long‐term care.

Methods

Dementia prevalence rates by age categories were obtained for bed‐bound or home‐bound elderly individuals from a public health system’s home care service in communities of Belo Horizonte/MG, to assess the independent effect of age. Analyses were conducted using Stata/SE for Macintosh 12.0 and included descriptive measures and adjusted prevalence ratios using Poisson Regression analysis with robust standard deviations. Results were considered significant at p<0.05.

Results

A total of 1,092 dementia patients were evaluated, aged 70‐79 (28.6%), 80‐84 (19.9%), and 85‐90 (18.9%). Over half had less than 4 years of education (53.5%). The primary etiologies of dementia were Alzheimer’s disease alone (28%), isolated vascular dementia (13.8%), and mixed dementia (10.9%). The prevalence of other etiologies like frontotemporal dementia, Lewy body dementia, and dementia associated with Parkinson’s disease were low. Dementia prevalence by age group was 39.4% (60‐69 years); 55.6% (70‐79); 58.3% (80‐84); 69.6% (85‐89); 72.2% (90‐94) and 79.1% (95 years or older). Compared to the age group 60‐69 years, the PR was 1.4 for 70‐79; 1.5 for 80‐84; 1.8 for 85‐89; 1.9 for 90‐94; and 2.1 for 95 years or older (p<0.005 for all PRs). The average Charlson Comorbidity Index (CCI) was 5.1 (standard deviation 1.8), and the proportion of frail elderly was 95%. Poisson regression revealed that dementia prevalence was not affected by CCI or education level, but there was an independent effect of age group and frailty. Male gender was negatively and independently associated with dementia (PR = 0.80; p<0.001), while frailty was positively and independently associated with dementia (PR = 14.9; p<0.001).

Conclusion

The primary cause of dementia was Alzheimer’s disease, following the pattern reported in the literature. Age was independently associated with dementia. Dementia was strongly linked to the severity of the clinical‐functional frailty presented by the elderly.
Biological aging is associated with atypical neurodegenerative patterns in Alzheimer’s disease
Authors: Sreepada Lasya P , Brown Christopher , Das Sandhitsu R. , Yushkevich Paul A. , Wolk David A , McMillan Corey T
Published: January 2025

Background

Atypical presentations of Alzheimer’s disease (AD), which demonstrate more cortical involvement relative to medial temporal lobe (MTL), are generally associated with younger age of onset. Age, defined chronologically, is a primary driver of AD pathology and neurodegeneration. However, some young onset cases are typical, amnestic presentations and some older onset cases present more cortical atrophy. We hypothesize that a biological definition of age, defined using epigenetic clock measures, may be even more tightly linked to atypicality than chronological age.

Method

Subjects from ADNI with blood DNA methylation (DNAm) samples and T1 MRI (N=646, 55.7% female, 75.5 +/‐ 7.4 years, Table 1) were selected. Participants were defined as “young” (< 65 years) or “old” (> 80 years) amyloid‐negative controls or amyloid‐positive MCI/AD. DNAm was assayed on Illumina EPIC arrays.

Epigenetic age was computed by applying the Shireby cortical epigenetic clock. We then defined epigenetic age acceleration (EAA) by regressing epigenetic age against chronological age and extracting the residual. Subjects were classified as appearing “biologically younger” (EAA < 1 SD below the mean), “neutral” (EAA within 1 SD), or “biologically older” (EAA > 1 SD above the mean).

Regional cortical thickness measures were derived from MRI using FreeSurfer 5.1 and harmonized for scanner differences using longitudinal ComBat. We computed composite bilateral thickness z‐scores, adjusted for age and sex relative to controls, in the cortical AD signature anatomical ROIs (Figure 1) and the MTL (entorhinal and parahippocampal cortices). Finally, we defined an AD “mismatch” score as the signed difference of the composite cortical and MTL thickness z‐scores.

Result

Cortical thickness z‐scores were lower in MCI/AD relative to controls. Lower mismatch scores, reflecting greater cortical neurodegeneration relative to MTL, were observed in young‐onset relative to older‐onset MCI/AD. Similarly, mismatch scores were significantly lower in biologically younger cases relative to biologically older cases (t=2.5589; p = 0.01; Figure 2).

Conclusion

Our results support the notion that biological age, as measured by epigenetic modifiers, modulates the degree of atypicality in AD patients, akin to chronological age. These findings suggest that biological aspects of aging may influence the topography of AD‐related pathology and spread.
Brain morphometrics and aging with paired 3T and 7T structural MRI: 7T reduces reqiured sample size and improves statistical significance
Authors: Chu Cong , Santini Tales , Marsland Anna , Gianaros Peter , Ibrahim Tamer S
Published: January 2025

Background

During normal aging, it has been observed that brain regional volume and thickness can be altered due to atrophy. While both 3 Tesla (3T) and 7 Tesla (7T) MRI are used to study such changes, it is unknown how individual brain morphology is characterized differently when 7T MRI allows for higher‐resolution and higher tissue contrast images. In this study, we employ a large cohort of healthy subjects that have undergone both 3T and 7T MRI scans to investigate how 7T MRI improves correlation strength between brain morphometrics and aging.

Method

Paired 3T (Prisma and Trio Siemens) and 7T (TTT coil [Santini et al Sci. Rep. 2021] with Magnetom Siemens) images (T1‐weighted, 0.5x0.5x1mm3, 1x1x1mm3, 0.75x0.75x0.75mm3 respectively) are acquired with similar acquisition time (∼5 minutes) on 351 healthy participants (age=46.7 +‐ 9.12 years, 192 females). Images are preprocessed with gradient distortion correction, bias correction, and skull stripping. 279 pairs of images passed manual quality assurance without abnormalities. We used Pearson correlation coefficient to assess associations between brain morphometrics and age. Regional volumes are normalized to individual intracranial volume. Multiple tests were corrected using the Bonferroni method.

Result

Compared to 3T, the 7T dataset showed more significantly correlated regions, with 28 volume regions in common to 3T (average R3T=‐0.24 and R7T=‐0.38) and 14 more. 7T dataset also consistently exhibits stronger negative and positive (ventricles) correlation with age than 3T for both volume and thickness. The 62% subsampled 7T dataset, averaged from 20 random samples, resembled the significant volume regions of the 3T dataset while still showing stronger correlation (Figure 1). We also show that for all brain regions, volume and thickness, 35% of the 7T sample is sufficient to reach the statistical power of the complete 3T sample (Figure 2).

Conclusion

Our analysis demonstrated the advantages of 7T MRI at characterizing brain morphometrics, specifically its capacity to measure relatively small changes without needing a large sample size. The higher spatial resolution and signal to noise ratio allow for feasible longitudinal, more importantly with relatively short follow up times, and cross‐sectional analysis with reasonable sample sizes.
Acculturation scales in Dementia in US Latinos/Hispanics: A Systematic Review
Authors: Goytizolo Alicia , Rosselli Monica
Published: January 2025

Background

Acculturation is a relevant variable in the assessment of dementia. Little is known about the type of acculturation scales and the frequency in which they are used in dementia research among Latinos/Hispanics in the US. The purpose of this paper was to conduct a systematic review of published studies that investigated the use of acculturation measures toward Latinos and Hispanics who are diagnosed with dementia.

Methods

Databases were searched using four key search terms: dementia, acculturation scale, Latinos, and Hispanics. We followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) criteria, which included: a sample population of Latinos/Hispanics who were diagnosed with dementia; and the use of an acculturation scale as part of their methods. Review articles, book chapters, and dissertations were excluded. The methodology and findings of all retrieved articles were thoroughly evaluated to determine eligibility. Data were extracted from all eligible articles regarding the study population, study methods, outcomes measured, acculturation measures used, and results.

Results

The literature search using PubMed and PsychNET databases disclosed sixty‐five articles that were originally reviewed. Twenty‐eight articles were excluded as a result of not meeting the criteria. A total of eight articles were included in the current analysis with a total combined sample of 1323 individuals (Mean age = 67.5, SD; 8.39* female percentage = 0.68). Participants were recruited from California (4 studies), Texas (2 studies), New York (2 studies), Puerto Rico (1 study), Florida (1 study), Illinois (1 study), and Pennsylvania (1 study). The use of five different acculturation scales were identified (Marin Acculturation Scale, Short Acculturation Scale for Hispanics, Bidimensional Acculturation Scale for Hispanics, Abbreviated Multidimensional Acculturation Scale, and the Acculturation Rating Scale for Mexican Americans‐II). 50% of the reviewed articles found a significant association between acculturation and cognition.

Conclusions

The scales and measurements being used to determine the influence of acculturation on dementia in the Latino and Hispanic population continue to be under researched. The limited number of published studies on the topic results in an inability to generalize the conclusions on a larger scale.

*Excludes one data set due to unavailable data
Enhancing Neuropsychological MCI Classification through Olfactory Testing
Authors: Karunanayaka Prasanna , Ahmed Biyar , Elyan Rommy , Peiris Senal , Pang Ran , Kanekar Sangam , Eslinger Paul , Yang Qing
Published: January 2025

Background

As new therapeutic options emerge, earlier diagnosis is crucial for improving prevention and early intervention. The current standard for screening for MCI and AD involves comprehensive neuropsychological tests prior to performing invasive testing such as lumbar punctures or PET scans. Neuropsychological tests, however, can be variable and confounded by compensatory effects in MCI. Therefore, a more objective means of assessing cognitive deficits would be beneficial. Prominent olfactory deficits have been shown to be prevalent in early MCI and AD and can precede symptoms of memory and cognitive decline. In this study, the relationship between cognition and olfaction was investigated using comprehensive neuropsychological and olfactory testing in cognitively normal (CN) and MCI subjects.

Method

26 CN (18 females, age 65.15 ± 5.44) and 19 MCI (10 females, age 70.10 ± 7.48) participated in this study. Subjects underwent computerized multiple‐choice olfactory identification testing and forced choice olfactory threshold testing. Normalization tables were used to minimize age as a potential confounding variable. To establish a potential composite score, Principal component analysis (PCA) was performed on neuropsychological test scores which was followed by a logistic regression analysis correlating participant status (CN or MCI) versus the PCs with and without olfactory measures. An ANOVA was performed to assess the significance between these two models.

Result

Our findings show significant differences in a wide array of neuropsychological and olfactory measures (Table 1). Measures with a p‐value greater than 0.1 were excluded from the two PCs generated for the PCA. A logistic regression was performed with results and ANOVA findings shown in Table 2.

Conclusion

Olfactory testing improves the ability to differentiate between CN and MCI (Table 2), suggesting that observed olfactory deficits go above and beyond the cognitive impairments measured by neuropsychological tests in the MCI cohort. Our analysis suggests that olfactory testing can improve the sensitivity of the overall assessment of screening for early MCI diagnosis and can be potentially incorporated in a composite score. Since this is an ongoing longitudinal study, testing will be repeated, enabling further insight into the relationship between olfaction, neurodegeneration, and cognition.