bluuebunny/crossref_metadata_2025 huggingface dataset:
Neighborhood disadvantage is associated with altered cortical organization
Authors: Safai Apoorva , Johnson Sterling C. , Jonaitis Erin M. , Langhough Rebecca E. , Powell W. Ryan , Buckingham William R. , Bendlin Barbara B. , Kind Amy J.H. , Tiwari Pallavi
Published: January 2025

Background

Neighborhood disadvantage is associated with worse health and cognitive outcomes. Morphological similarity networks (MSN) is a promising approach to elucidate cortical network patterns underlying complex cognitive functions. We hypothesized that MSNs can capture intricate changes in cortical patterns related to neighborhood disadvantage and cognitive function, potentially explaining risk for later life cognitive decline among individuals who live in disadvantaged contexts.

Method

This study included cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. and their neighborhood disadvantage was indexed by the area deprivation index (ADI), a metric representing income, education, employment, and housing quality at the census block group geographic level(n=526, age=62.96±8.377, gender(M:F)=181:345, ADI(L:H)=452,74). We compared MSNs by ADI state rank scores in the two highest (9,10) and lowest (1,2) ADI deciles based on previous studies reporting strongest health effects among individuals living at the highest levels of disadvantage. Cognitive performance was indexed by six tests evaluating memory, executive functioning, and the pre‐clinical Alzheimer’s cognitive composite(PACC). T1‐weighted MRI scans of all participants underwent standard preprocessing steps in CAT12 toolbox MSN was constructed for each participant (Figure 1). We used linear regression to examine ADI associations with cognitive scores and four local and four global MSN features. Mediating effect of MSN features on the relationship between ADI and cognitive performance was statistically assessed using a non‐parametric bootstrapping (10,000) approach. Model covariates included age, gender, education (years), and total intracranial volume.

Result

ADI rank showed negative association with category fluency(CF)(β=‐0.176, p=0.039), WAIS‐DigitSymbol(β=‐0.442, p=0.011), Wechler’s Memory scale(WMS‐LM)(β=‐0.218, p=0.001) and PACC scores (β=‐0.056, p=0.001), indicating worse cognitive function among those living in more disadvantaged neighborhoods. Local network features of frontal and temporal brain regions (Figure 2a,b) differed by ADI group. Centrality of left fusiform and bankssts showed a mediating effect between association of neighborhood disadvantage and performance on the WMS and PACC scores respectively (Figure 2c).

Conclusion

Our findings suggest differences in local cortical organization by neighborhood disadvantage, which also mediated the relationship between ADI and cognitive performance, providing a possible network‐based mechanism, explaining risk for cognitive decline and dementia associated with disadvantaged neighborhoods. Future work will examine the dosage and timing of neighborhood disadvantage on structural organization of the brain.
Amyloid burden in non‐Hispanic Black vs White adults: A F18‐florbetaben PET study
Authors: Rusinek Henry , Bokacheva Louisa , Vedvyas Alok , Masurkar Arjun V. , Osorio Ricardo S. , Betensky Rebecca A , Shao Yongzhao , Chodosh Joshua , Marsh Karyn , Wisniewski Thomas
Published: January 2025

Background

Assessment of anti‐amyloid therapies for Alzheimer’s disease (AD) requires understanding racial differences in brain amyloid. We compared amyloid burden in non‐Hispanic Black/African American and White (NHB, NHW) adults in a cohort with over 40% NHB participants and explored factors associated with the inter‐group differences.

Method

We included consecutive non‐Hispanic participants who underwent brain amyloid PET‐MRI exams in 2021‐2023 at NYU Alzheimer's Disease Research Center. PET images were acquired on Siemens 3T PET‐MR system after an injection of 300 MBq of 18F‐florbetaben, reconstructed and normalized by the mean activity of the whole cerebellum. Composite SUVR was calculated by averaging frontal, parietal, temporal and cingulate cortical regions (Bullich 2021 PMID:33773598) segmented using FreeSurfer 7.1. White matter lesion (WML) volume was measured on FLAIR images. We used linear regression to test amyloid SUVR for association with demographic, cognitive, and MRI features.

Result

A total of 178 participants were enrolled (age, 72.5 ± 6.6 years old; 66% female), including 77 (43%) NHB and 101 (57%) NHW (Table 1). NHB were significantly younger than NHW, showed significantly lower memory and cognitive performance, yet also had significantly lower mean value and third quartile of amyloid SUVR distribution (Figure 1). Most measures of brain atrophy and white matter lesion load were not significantly different between groups.

Regression analysis showed that race was the strongest predictor of SUVR. This finding remained true in the regression model adjusted for age, sex, education and clinical diagnosis (Table 2).

Conclusion

Consistent with two prior studies (Xiong 2022 PMID:35218143, Deters 2021 PMID: 33568538), we found differences in amyloid SUVR distribution and an unexpected relationship to memory performance in NHB compared to NHW. The finding may stem from several factors, including social/environmental differences, cohort selection biases, cognitive reserve and educational attainment, genetics, and different resilience to amyloid burden. In our cohort, NHB and NHW had comparable volume of WML, therefore cerebrovascular disease was unlikely the primary driver. Since lower amyloid burden in NHB may create bias in inclusion in anti‐amyloid treatment trials, it merits further investigations to be better understood.
Effects of 17‐beta estradiol on inflammation and mitochondrial function in Alzheimer’s disease
Authors: Mishra Pranav , Esfahani Ehsan , Fernyhough Paul , Albensi Benedict C.
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder primarily associated with aging, but manifests as a complex interplay of multiple factors. Decline in sex‐hormones, particularly 17‐beta estradiol, is linked to the aging process. The risk for onset of AD significantly increases with aging and loss of estradiol. This is concurrent with inflammation and metabolic defects, leading to cell death. Amyloid beta (Aβ), a hallmark of AD exacerbates these processes by activating pro‐inflammatory NF‐κB, leading to sustained chronic inflammation and mitochondrial dysfunction, contributing to neurotoxicity. Estradiol imparts neuroprotection by mechanisms including the regulation of mitochondrial proteins, reduction in oxidative stress, and by decreasing inflammation. So far, our preliminary studies have demonstrated the potential of estradiol in ameliorating AD, where primary cortical neuros treated with estradiol exhibited improved mitochondrial function. For our future work, we will induce AD‐like pathology in our cell cultures by exposing them to Aβ. The objective of this study is to investigate the neuroprotective effects of estradiol against Aβ‐mediated neuroinflammation and mitochondrial dysfunction.

Method

Primary cortical neurons from C57BL/6 mouse embryos were isolated and cultured under defined conditions. Glial inhibitor AraC (2uM) was used obtain pure neuronal cultures followed by estradiol treatment (10nM). Expression levels of phosphorylated AMPK (pAMPK), PGC‐1α and NF‐κB inhibitor IKbα was measured via western blotting. Culture purity was determined using immunostaining. Oxygen Consumption Rate (OCR), an established measure of mitochondrial function was evaluated in live cells using SeahorseXF24 bioanalyzer.

Result

Immunocytochemical analysis confirmed that our primary neuronal cultures were >90% pure. Estradiol treatment increased both; the levels of cellular energy sensor pAMPK and master regulator of mitochondrial biogenesis PGC‐1α. Additionally, estradiol elevated ATP production and spare respiratory capacity in these cells. We also observed a decrease in pro‐inflammatory NF‐κB activation as estradiol decreased the phosphorylation and degradation of NF‐κB inhibitory protein IKbα.

Conclusion

Estradiol, by elevating the levels of pAMPK, PGC‐1α, ATP production and spare respiratory capacity, and by decreasing pro‐inflammatory NF‐κB activation, significantly underlines its importance in modulating mitochondrial function and inflammation in neurons. The anticipated outcomes hold promise for advancing our understanding of therapeutic strategies in alleviating neurodegenerative diseases including AD.
A supervised machine learning approach to predicting subjective cognitive decline (SCD) among diverse Hispanics/Latinos: The SOL‐INCA Study
Authors: Kuwayama Sayaka , Tarraf Wassim , Gonzalez Kevin A , Márquez Freddie , Penedo Frank J , Wassertheil‐Smoller Sylvia , Daviglus Martha L , Lamar Melissa , Gallo Linda C , González Hector M
Published: January 2025

Background

Increasingly, research evidence is identifying subjective cognitive decline (SCD) as a precursor for cognitive impairment and dementia. Identifying predictors of SCD is essential for understanding its utility as a preclinical indicator for impairment and especially pertinent for Hispanics/Latinos who have limited access to healthcare resources and clinical diagnostics and are disproportionally affected by Alzheimer’s disease and related dementias. We extend work on predictors of Mild Cognitive Impairment (MCI) in diverse Hispanics/Latinos in the US by modeling multidomain predictors of SCD.

Method

We use data (n = 4347, average baseline age = 56.4‐years) from the Hispanic Community Health Study/ Study of Latinos (HCHS/SOL; 2008‐2011; Visit 1), a multisite prospective cohort study of diverse Hispanics/Latinos, and its ancillary study, the SOL‐Investigation of Neurocognitive Aging (SOL‐INCA; average 7‐years after Visit 1). Our outcome is a composite SCD measured at SOL‐INCA by averaging the component items of the Everyday Cognition (ECog‐12) scale and is modeled using 37 cross‐domain Visit 1 indicators, previously linked to MCI, reflecting (1) sociodemographic characteristics, (2) childhood factors, (3) acculturation factors, (4) biological and (5) behavioral markers, and (6) mental and (7) functional health factors. We use supervised machine learning (ML: Random Forest = RF; regression = ML‐Reg) and standard statistical techniques (regression = Reg) for identifying leading predictors of SCD. In secondary analysis, we assess enhancement in predictive performance by accounting for Visit 1 global cognitive (GC) function.

Result

Our best performing (i.e., R‐squared) ML model (ML‐Reg) explained only 17% of the variance in SCD. Leading identified predictors of SCD included physical health scores, airflow obstruction, anxiety, mental health scores, Hispanic/Latino heritage, education, depression, income, and language and social acculturation. GC was predictive of SCD and explained an additional 5% of the variance.

Conclusion

Our findings indicate that multidomain factors contribute to SCD prediction, but the explained variance was relatively low. Biological markers, previously linked to MCI in our cohort, played a less significant role. Notably, the fit of the ML models for SCD was low relative to MCI specific models in the same population. Follow‐up work investigates how incorporating contemporaneous measures of the factors (vs. baseline alone) may improve the predictive capacity of the ML models.
Varicella zoster and the risk of dementia: understanding the interplay between age, the genome and proteome
Authors: Amin Najaf , Argentieri M Austin , Xiao Sihao , Van Duijn Cornelia M
Published: January 2025

Background

The mechanism through which common viruses such as varicella zoster virus (VZV) may trigger the onset of AD in the elderly is far from understood. The poliovirus receptor (PVR) is a protein of interest as it was associated to AD in a brain proteomics study and interacts with multiple viruses (Wingo, et al. Nat Neurosci). In this study (UKB), we examine whether plasma PVR levels are associated to AD, two of its early blood‐based biomarkers (NeFL and GFAP), ageing and VZV seropositivity.

Methods

Plasma proteins including PVR have been measured in 53,000 UKB participants using the OLINK platform. In this cohort, 592 individuals developed AD during the 13 years follow‐up. For 967 participants, seropositivity for VZV is measured. We used Cox regression to associate PVR and other proteins to AD, adjusting for age, sex, physical activity, smoking, body mass index, alcohol use, 25 medications for chronic diseases, and technical covariates. We used Mendelian Randomization (MR) to test whether PVR is likely in the causal pathway based on genetic variants in the encoding genes. Further, we associated PVR to NeFL, GFAP, a protein‐based biomarker for accelerated aging (Argentieri et al, medRxiv) and seropositivity for VZV.

Results

PVR was found to be one of the 37 plasma proteins that were significantly associated incident AD (false discovery rate < 0.05) (see Table). The MR experiment conducted suggests a causal association between PVR and AD. We further find that PVR is significantly associated with the two biomarkers of AD pathology studied, NeFL (p<2.00*10−16) as well as with GFAP (p<2.00*10−16). Since the gene encoding for PVR maps to the 19q31 region close to APOE, we adjusted for APOE genotypes. The association of PVR with AD, NeFL and GFAP remained significant. We further find that PVR is strongly associated to accelerated proteomic aging (p = 2.54*10−15) as well to VZV serum positivity (p = 0.05).

Conclusion

Our findings suggests that PVR may play a role in the interplay between VZV seropositivity, age and AD. PVR may be relevant for the association between other viruses and AD.
Impact of a High‐Performing Blood Test on Wait Times for Determination of Eligibility for a Disease‐Modifying Alzheimer’s Treatment in the U.S.
Authors: Mattke Soeren , Chen Jiahe , Hanson Mark
Published: January 2025

Background

As disease‐modifying treatments for Alzheimer’s disease (AD) are becoming available, concerns have been raised about wait times in the patient diagnostic journey due to a limited number of AD specialists and PET scanners. A high‐performance blood test used in the in primary care settings has the potential to address this concern. We estimate the impact of such a test on wait times in the U.S.

Method

We use a Markov model to predict wait times for individuals identified as eligible for AD treatment, taking into account constrained capacity for AD specialist visits and confirmatory biomarker testing. We assume that individuals would undergo a brief cognitive assessment in primary care and, if indicative of early‐stage cognitive impairment, be referred to a AD specialist under three scenarios: (1) no blood test, (2) blood test to rule out AD pathology, and (3) blood test to confirm AD pathology.

We model the U.S. population aged 55+ from 2023 to 2032, assuming that 25% of all individuals, who have never been evaluated for cognitive decline, and 5%, who were previously found to be cognitively normal, would undergo a brief cognitive test. If found to have early‐stage cognitive impairment and a blood test indicative of AD (if available), 80% would be referred to an AD specialist. The AD specialist would assess the patient and order biomarker testing for 90% of patients with confirmed early‐stage cognitive impairment. Such biomarker testing would include CSF testing (10% and not capacity constrained) and PET imaging (90%). Patients would then return to the specialist to discuss test results and a treatment indication. If the blood test were used to confirm the AD pathology, patients would skip the first specialist visit.

Result

The figure shows the expected wait times for the three scenarios.

Conclusion

The introduction of a blood test into the AD diagnostic pathway could reduce wait times substantially and prevent eligible patients from falling outside the treatment window. Ongoing work will assess additional scenarios and patient pathways as well as their cost implications.
Pharmacokinetics and Pharmacodynamics of an Antibody Targeting Pathological Tau for the Treatment of Alzheimer’s Disease: Nonclinical Studies in P301S Mice and Cynomolgus Macaques
Authors: Sadhu Chanchal , Liu Wencheng , Kundu Joydip , Thompson Jeffery , Emery Maurice , Epling Daniel , Smith Brandon , Shah Ishan , Paranjpe Maneesha , Lee Shiron , Fang Ching‐Lien , Walsh Alison , Placidi Matteo , Mathur Krishanu , Mondick John , Chapel Sunny , Ghetti Bernardino , Carter Todd , Paul Steven M. , Yao Johnny , Sah Dinah. W.Y
Published: January 2025

Background

VY‐TAU01 is a recombinant humanized IgG4 monoclonal antibody (mAb) directed against pathological tau for the treatment of patients with mild dementia or mild cognitive impairment due to Alzheimer’s disease (AD). Both VY‐TAU01 and its parental mouse IgG1 mAb Ab‐01 target an epitope in the C‐terminus of tau, bind pathological tau with high affinity and selectivity over wild‐type tau, block paired helical filament seed‐induced tau aggregates in vitro, and selectively stain tau tangles in AD and P301S mouse (C57/B6J‐Tg[Thy1‐MAPT*P301S]2541Godt) brain. Ab‐01 robustly inhibits seeding and propagation of pathological tau in a P301S mouse seeding model.

To support toxicology studies and the initiation of the first‐in‐human study, nonclinical studies have been conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of Ab‐01 in P301S mice and the PK of VY‐TAU01 in cynomolgus macaques.

Method

The PK of Ab‐01 in the P301S mouse after 5 weekly intravenous or intraperitoneal doses at 10 to 120 mg/kg and VY‐TAU01 in cynomolgus macaques after a single intravenous high or mid dose was evaluated with validated ELISAs using their target epitope peptide. The PD of Ab‐01 in the P301S mouse was also evaluated using an ELISA to quantify unbound p‐tau levels.

Result

Ab‐01 and VY‐TAU01 PK profiles in serum and cerebrospinal fluid (CSF) were characterized by a distribution phase followed by a typical elimination phase without evidence of substantial target‐mediated disposition in the respective compartments. Serum and CSF concentrations increased with increasing dose levels in an approximately dose proportional manner, and their half‐lives were approximately 9 to 13 days. CSF concentrations were 0.1 ‐ 0.2% of serum concentrations.

PD effects of Ab‐01 in the P301S mouse were robust, with up to ∼90% lowering of unbound p‐tau. Additional PD as well as PK/PD modeling results will also be presented.

Conclusion

The PK of Ab‐01 in the P301S mouse and VY‐TAU01 in the cynomolgus macaque, and CSF to serum ratios were typical of murine IgG1 and human IgG4 administered to these respective species. The PD of Ab‐01 in the P301S mouse demonstrated robust lowering of unbound p‐tau. These results support VY‐TAU01’s continued development and advancement into the clinic.
Disparity in Resilience: The role of educational attainment and APOE ε4 in Alzheimer Disease in a Puerto Rican cohort
Authors: Hamilton‐Nelson Kara L. , Rajabli Farid , Cai Dingtian , Adams Larry D. , Mena Pedro R. , Celis Katrina , Sanchez Jose Javier , Valladares Glenies S , Whitehead Patrice L. , Acosta Heriberto , McInerney Katalina F , Moise Rhoda , Griswold Anthony J. , Beecham Gary W , Feliciano‐Astacio Briseida E. , Vance Jeffery M. , Seixas Azizi A , Cuccaro Michael L. , Pericak‐Vance Margaret A
Published: January 2025

Background

Cognitive resilience research in African Americans (AA) shows that higher educational attainment (EA) can mitigate the impact of Alzheimer disease pathology (ADP). However, this mitigating effect is less pronounced in APOEε4 carriers. This finding suggests a disparity in resilience influenced by an interplay of educational and genetic factors. Expanding on this, our study examines Puerto Ricans (PR), a population with distinct social and ancestral background, to assess whether similar patterns of disparity are present. Our aim is to explore the role of education as a modifiable risk factor in Alzheimer disease (AD) and to determine whether the APOEε4 allele leads to differences in resilience among carriers and non‐carriers.

Methods

We studied 455 PR individuals, focusing on their completed education years, plasma pTau181 levels, and APOE genotypes. Using the non‐memory components of the Cognitive Dementia Rating scale, we formulated a composite score CDR‐FUNC to capture functional difficulties. EA was classified into low EA(≤9years) and high EA(>9years). We used plasma pTau181 as proxy for ADP. Those with log10(pTau181) >mean+1SD were considered as advanced pTau181 levels. Participants were also categorized based on their APOEε4 carrier status. The Mann‐WhitneyU test was used to evaluate the association between EA and CDR‐FUNC in individuals with advanced pTau181 levels and ε4 allele.

Results

The study found a correlation between EA and CDR‐FUNC in PRs with high pTau181 levels. Individuals with high EA showed better functional ability than those with low EA(p = 0.014). Additionally, we found that the effect of high EA on functional resilience was stronger in ε4 non‐carriers (p = 0.038) compared to ε4 carriers (p = 0.277).

Conclusions

Our study demonstrates that education is a modifiable risk factor for AD in PRs, contributing to resilience against ADP. Notably, we identified a disparity in the protective effect of EA between carriers and non‐carriers of the APOEε4 allele. Revealing patterns like those observed in AA, our research confirms the combined influence of education, genetics, and functional resilience in AD. The results highlight the importance of education and genetic factors across diverse ethnic and ancestral backgrounds. Our findings are essential for creating targeted interventions to improve health outcomes in PRs and diverse populations affected by AD.
Physio‐markers based on predictive models of cerebral hemodynamics yield accurate diagnosis of cognitive impairment and differentiate MCI from AD
Authors: Marmarelis Vasilis , Chui Helena C , Billinger Sandra A , Joe Elizabeth B , Shin Dae , Hashem Suhaib , Rizko Jasmin , Hazen Emily , Cardim Danilo , Zhang Rong
Published: January 2025

Background

A multi‐center study in Los Angeles (USC), Kansas City (KUMC) and Dallas (UT‐SWMC) quantified via predictive modeling the dynamics of cerebral perfusion regulation (CO2 vasoreactivity and cerebral autoregulation) in MCI/AD patients and cognitively normal controls under resting conditions. The goal was to develop model‐based physio‐markers for accurate diagnosis of MCI and pre‐clinical AD, motivated by our previous findings of significant impairment of cerebral perfusion regulation in MCI and mild AD patients.

Method

Continuous spontaneous changes in arterial blood pressure, end‐tidal CO2, cerebral blood flow velocity in middle cerebral arteries and cortical tissue oxygenation at lateral prefrontal cortex were recorded over two 6‐8 min sessions, separated by session of slow‐paced breathing (6 breaths/minute), in 53 MCI (28 APOE4 non‐carriers and 25 APOE4 carriers), 33 mild AD patients (13 APOE4 non‐carriers and 20 APOE4 carriers) and 74 age/sex‐matched cognitively normal controls (50 APOE4 non‐carriers and 24 APOE4 carriers). Using our novel modeling methodology, we obtained predictive dynamic models of cerebral perfusion regulation (dynamic CO2 vasoreactivity and cerebral autoregulation) that were used to compute a composite diagnostic index as physio‐marker of cerebral perfusion regulation dynamics under resting conditions for each participant. ROC curves were computed for differentiating MCI/AD patients from cognitively normal controls, and MCI from mild AD patients (separately for APOE4 carriers and non‐carriers).

Result

The ROC curves for differentiating MCI/AD patients from controls are shown in Figure 1, for APOE4 carriers and non‐carriers separately, and had Area Under the Curve (AUC) of 0.95 and 0.92, respectively. The ROC curves for differentiating MCI from mild AD patients are shown in Figure 2, for APOE4 carriers and non‐carriers separately, and had AUC of 0.96 and 0.92, respectively. The p‐values of mean‐difference t‐tests for all four cases were less than 10‐8
(highly significant).

Conclusion

Quantitative analysis of cerebral perfusion regulation (dynamic CO2 vasoreactivity and cerebral autoregulation), using predictive dynamic modeling of cerebral hemodynamics under resting spontaneous conditions, yielded a Composite Diagnostic Index that differentiated MCI or AD patients from controls, and MCI from AD patients (p < 10‐8 for mean‐difference t‐test). The respective ROC curves had AUC in the range of 0.92‐0.96 (see Figures 1 & 2).
There is no quick, easy, or cheap way to recruit older African Americansto aging and brain health research: Ten evidence‐based strategies for investing in community engagement
Authors: Gluck Mark A. , Fausto Bernadette A. , Thornton‐Hammonds Delores , Wright Glenda , Wilson Glenn B.
Published: January 2025

Background

With African Americans having two to three times the prevalence of Alzheimer’s disease (AD) as compared to white Americans, a critical challenge for reducing health disparities is overcoming long‐standing barriers to recruiting African Americans into aging and brain health research. Here, we describe strategies that we have found successful for recruiting over 500 older African Americans from Greater Newark, New Jersey, into brain health and AD research studies.

Method

(1). Build trust through long‐term investment in community health.

(2). Hire a large and varied engagement team with deep connections to community.

(3). Formalize community relationships through a Community Stakeholders Board.

(4). Offer frequent event programming and print materials to promote brain health.

(5). Be a resource: Respond to other community needs, even if unrelated to brain health.

(6). Empower, facilitate and recognize community members who embody brain healthy lifestyles.

(7). Recruit older men with programming that addresses men’s interests and affiliations.

(8). Support longitudinal retention through a Very Important Participants (VIP) program.

(9). Recognize current research participants as ambassadors for future recruitment.

(10). Communicate scientific results to participants and community members.

Result

These strategies require a sustained and substantial long‐term investment of time, effort, and money, towards building trust and partnerships with local community organizations and community members, with a primary emphasis on creating value for the community and local community‐based and faith‐based organizations, and a secondary consequence of encouraging research participation.

Conclusion

These strategies are readily implementable by other universities doing brain health and Alzheimer’s disease research in underrepresented communities, although they require considerable staffing and financial resources.
Differential Association of Frailty Types with Cognitive Functional Impairment
Authors: Arora Sakshi , Prasad Raghav , Sundarakumar Jonas S. , Rai Pooja
Published: January 2025

Background

The phenotype model of frailty, initially proposed by Fried, is primarily confined to the physical dimension. This study seeks to expand this model by integrating the psychological dimension. We hypothesize that this psychological frailty model is strongly associated with cognitive functional impairment (CFI) in an aging Indian population.

Method

We used baseline cross‐sectional data (n = 3943) from the ongoing Srinivaspura Aging, Neuro Senescence, and COGnition (SANSCOG) study. Physical frailty was evaluated using a modified version of Fried’s criteria, encompassing hand grip strength (HGS), gait speed (timed up and go, TUG), physical activity levels, self‐reported exhaustion, and weight loss (self‐reported or a BMI < 18.5). Depression/ anxiety symptoms were assessed using the Generalized Depression Scale (GDS‐30) and Generalized Anxiety Disorder (GAD‐7) scale, respectively. Participants were classified into four groups – non‐frail, only physically frail, individuals with depression/anxiety symptoms (GDS>10/ GAD>10), and psychologically frail (physical frailty components + depression/anxiety). CFI was assessed using the Instrumental Activities of Daily Living (IADL‐E) for elderly (cognitive disability index, CDI >16). We performed logistic regression to test the association of frailty groups with cognitive functional impairment.

Result

In this study, 8.6% exhibited CFI, 4.5% were physically frail and 3.7% were identified as psychologically frail. Adjusted logistic regression analysis indicated that risk of cognitive functional impairment was 5.9 times (95% CI: 4.0 ‐ 8.8, p<0.001) higher for psychologically frail, 3.1 times (95% CI: 2.1 ‐ 4.6, p<0.001) higher for physically frail, and 2.46 times (95% CI: 1.82 ‐ 3.3, p<0.001) higher for those with depression or anxiety symptoms, respectively. On performing logistic regression for individual components of psychological frailty, we found significant association of lower HGS (OR = 1.80, 1.39‐2.31, p<0.001), delayed TUG (OR = 1.74, 1.35‐2.24, p<0.001), exhaustion (OR = 2.40, 1.58‐2.90, p<0.001), underweight i.e., BMI <18.5 (OR = 1.51, 1.09‐2.05, p<0.05) and GAD (OR = 1.65, 1.08‐2.50, p<0.05) with CFI.

Conclusion

Psychological frailty showed increased risk of cognitive functional impairment. This highlights the importance of a comprehensive frailty assessment in clinical practice. Therefore, while designing interventions, both physical as well as psychological health should be addressed to improve functional ability in aging population.
Cross‐Culturally Translating and Validating a Dementia Attitudes Scale in Arabic, Vietnamese, Cantonese, Mandarin, and Greek
Authors: Karamacoska Diana , Jasim Nibras , Tran Mai , Caballero Gabriela E , Tsouros Emy , Chan Sonia , Shatnawi Eman , Steiner‐Lim Genevieve Z , Siette Joyce , Chan Eliza , Nguyen Kim‐Huong , Tran Hanh Dao
Published: January 2025

Background

Dementia is highly stigmatised, misperceived as a mental illness, and considered a normal part of ageing by people from culturally and linguistically diverse backgrounds in Australia. There is a lack of valid and reliable scale to measure their dementia attitudes. This study aimed to cross‐culturally translate and validate a dementia attitudes scale in Arabic, Vietnamese, Chinese, and Greek communities as they represent the main languages spoken throughout Western Sydney, Australia.

Method

A 12‐item Australian dementia attitudes scale, initially adapted from the PRISM‐PC–Dementia Screening Subscale, underwent forward and backward translation in the Arabic, Vietnamese, Cantonese, Mandarin, and Greek languages with certified translators and bilingual project team members. The translated surveys were also piloted with native speaking older community members to resolve comprehension issues. The final version of each scale was distributed online and at community events. Scale data (Arabic N = 197; Vietnamese N = 121; Cantonese N = 107; Mandarin N = 219; Greek N = 1,050) underwent reliability testing (Cronbach’s α) and exploratory factor analysis (EFA) with principal axis factoring and Promax rotation.

Result

The translated scales demonstrated high reliability across all five language groups (Cronbach α ≥ .77). The EFAs revealed distinct factor solutions for the Arabic, Vietnamese, Cantonese, and Mandarin scales, with ‘fear of labelling’ emerging as a common stigma‐related factor. Ten of the twelve items in the Greek scale did not meet retention criteria, limiting the scale’s validity.

Conclusion

The cross‐cultural translation procedures yielded reliable scale outcomes across the five languages. The distinct factor solutions for each scale highlight the impact of culture on the stigma toward dementia. These scales can help researchers and community organisations efficiently explore dementia attitudes in under‐served populations and tailor education programs to combat misperceptions. However, a more robust scale for the Greek speaking community needs to be developed.
Impact of TBI on AD‐Associated Proteins in Neuron‐Derived Small Extracellular Vesicles from the Vietnam Era Twin Study of Aging
Authors: Cullum‐Doyle Michaela , Panizzon Matthew S. , Risbrough Victoria , Sukreet Sonal , Yang Haoyi , Elman Jeremy A. , Franz Carol E. , Kremen William S. , Rissman Robert A.
Published: January 2025

Background

Alzheimer's Disease (AD) and traumatic brain injuries (TBI) are frequently associated in medical literature, with a significant prevalence of TBI history observed among individuals diagnosed with AD. Our investigation focuses on this intersection, explicitly examining the risk of AD in individuals with a history of TBI. While current targets in cerebrospinal fluid and plasma can effectively detect acute TBI, the challenge lies in identifying biosignatures associated with TBI long after injury. Neuron‐derived small extracellular vesicles (NEVs) from plasma offer potential biomarkers linked to neuronal dysfunction. Prior research has demonstrated that the AD‐associated protein amyloid‐beta (Aβ) is sequestered in NEVs, making them more sensitive biomarkers than free proteins in native plasma. To evaluate the effectiveness of NEV cargo proteins in predicting TBI exposure, we used plasma samples from the third wave of the Vietnam Era Twin Study of Aging (VETSA3). We hypothesized that previous exposure to TBI is associated with abnormalities in AD‐related proteins in circulating NEVs.

Method

Participants in the VETSA3 study, comprising a community‐based sample of male twins aged 61‐73 (average 68), self‐reported a 40% history of mild to moderate TBI. We precipitated NEVs from biobanked VETSA3 plasma samples and enriched them for the neuronal‐specific protein L1CAM using magnetic immunocapture and fluorescence‐activated cell sorting. Following the International Society of Extracellular Vesicles’ guidelines, we characterized NEVs for size, integrity, and homogeneity using NanoSight and ELISA. We quantified AD neuropathogenic proteins Aβ40–42, tau, p‐tau, and Nf‐L in NEVs using SIMOA assays. Our analyses explored the influence of TBI characteristics (number, age at occurrence, severity) on NEV cargo compared to non‐TBI individuals, assessing their utility as potential biomarkers.

Result

NEVs derived from VETSA3 plasma demonstrated similar size distributions and shape characteristics required for cargo analysis. The outcomes of the ELISA validated the presence of the NEV marker protein Flotillin‐1. A significant variation was observed in several neuropathogenic proteins, demonstrating the relationship between TBI exposure and AD.

Conclusion

Our findings give insight into TBI as a risk factor for AD and the role of NEV cargo proteins as potential clinical biomarkers of neurodegeneration.
Neflamapimod treatment reduces plasma glial fibriallary acidic protein levels in patients with pure dementia with Lewy bodies (DLB)
Authors: Alam John J , Koel‐Simmerlink Marleen JA , Conway Jennifer , Verberk Inge M.W. , Teunissen Charlotte
Published: January 2025

Background

In a 16‐week, 91‐patient placebo‐controlled clinical study in DLB (“AscenD‐LB”;NCT04001517), neflamapimod improved outcomes on the CDR Sum‐of‐Boxes (p = 0.023 vs. placebo) and Timed Up and Go test (p = 0.044 vs. placebo). Further, at the higher of two dose levels in the study neflamapimod also improved (p = 0.049 vs. placebo) outcomes in a cognitive test battery, particularly with respect to attention (p = 0.023 vs. placebo). The results were most prominent in patients with pure DLB (i.e., without Alzheimer’s disease‐related co‐pathology, assessed by plasma ptau181). While no validated biomarkers for treatment effects in DLB were available when the study was conducted, with a recent report that plasma GFAP and neurofilament‐light‐chain (NfL) discriminated MCI‐DLB from healthy controls, with GFAP being more discriminant, we evaluated the effects of neflamapimod in AscenD‐LB on plasma GFAP and NfL, both overall and in pure DLB patients.

Method

GFAP and NfL levels (pg/mL) in stored plasma samples from AscenD‐LB were determined using Simoa® platform. Design and overall results (Jiang et.al. Nature Communications, 2022), and analysis after stratification for baseline plasma ptau181 (Alam et.al. Neurology, 2023) are published.

Result

At baseline, GFAP was higher (p = 0.02) in DLB with AD co‐pathology [282(SD = 120, n = 29] versus in pure DLB [215(SD = 91), n = 28]; NfL was not. In the overall population, a reduction in GFAP levels were seen in neflamapimod‐treated participants (n = 30, ‐12.3±6.8, baseline‐to‐week16) and not in placebo‐recipients (n = 27, +3.7±7.8; p = 0.13); p = 0.13 for the difference. In pure DLB participants, the change from baseline to week 16 in GFAP was significantly different (p = 0.04) in neflamapimod‐treated participants (n = 15, ‐10.6±6.4) compared to placebo‐recipients (n = 13, +14.1±10.2). For NfL, no neflamapimod‐placebo differences were evident in either population. In the pure DLB population, the change in GFAP levels from baseline was significantly correlated to change in CDR‐SB (r = 0.54, p = 0.036; increased GFAP associated with worsening CDR‐SB, reduction in GFAP associated with improvement on CDR‐SB) among neflamapimod recipients, but not in placebo‐recipients.

Conclusion

The beneficial effects on GFAP further support that neflamapimod is clinically efficacious in patients with DLB. The results also demonstrate the potential of GFAP as biomarker to assess treatment effects in DLB, though treatment effects may be masked in patients with AD co‐pathology.
The Evaluation of Telehealth Provider Payment Parity on Health Service Utilization among Adults with High Risk Factors for Dementia in the US
Authors: Zhang Zhang
Published: January 2025

Background

Cardiometabolic diseases and mental health disorders, which are high‐risk factors for dementia and cognitive decline, are associated with higher mortality and morbidity with age. Interventions before age 60 may lessen the burden of cognitive and physical function in later life. Telehealth offers early intervention and solutions for their complex demands in continuous behavior monitoring and medication refilling. Telehealth has been catalyzed by the COVID‐19 pandemic and become a new norm in healthcare. One of the important factors driving this transformation is governments’ temporary modifications and policies. Our study aims to evaluate the impact of telehealth payment parity mandates, which require an equal payment rate for telehealth vs. in‐person outpatient visits, on overall health service utilization among populations with high‐risk factors for dementia.

Method

Using the IBM MarketScan dataset from 2019 to 2021, we leverage a policy shock using a quasi‐experiment by a two‐way fixed effect difference‐in‐differences (DiD) estimation. Our sample includes adults with cardiometabolic risks (diabetes, hypertension, or dyslipidemia) or mental health disorders. We compare the differences between the control and treated states in changes in the outcomes of interest after the onset of the pandemic.

Result

On average, the treated group had 0.18 more telehealth visits by patient by month than the control (p<0.05). Compared to the control group, the treated group had 7 percentage points higher probability of having at least one telehealth encounter by patient by month (p<0.1) and 5 percentage points increase in the proportion of outpatient visits via telehealth by patient by month (p<0.1). In addition, the payment parity did not lead to a significant increase in in‐person outpatient visits.

Conclusion

Our results suggested that the telehealth payment parity, driven by supply‐side incentives, has effectively increased telehealth adoption during and post‐pandemic. The findings addressed the public concerns that telehealth expansion policies could induce and trigger excess demand for in‐person office visits. Our study provides evidence for policymakers to establish sustainable telehealth reimbursement policies and payment models and improve equitable telehealth access for populations with high‐risk factors for dementia in the US.
Brain cell transcriptomics in vulnerable and resilient regions in Alzheimer’s Disease brains
Authors: Baldasso Gabriela Mantovani , Carello‐Collar Giovanna , Limberger Christian , Paes Rodrigo Sebben , Bastiani Marco De , Zimmer Eduardo R.
Published: January 2025

Background

Neurodegeneration is a major pathological feature of Alzheimer’s disease (AD). During this process, it is known that not only neurons are affected but also glial cells. However, the biological mechanisms driving brain cellular vulnerability and resilience to neurodegeneration in AD remain elusive. Thus, we aimed to investigate the transcriptomic profile of brain cell types in vulnerable and resilient AD regions.

Method

We searched microarray AD datasets in the Gene Expression Omnibus repository for available transcriptomics of vulnerable (hippocampus and entorhinal cortex) and resilient (cerebellum) postmortem regions. The data was downloaded using the GEOquery package. We performed gene expression deconvolution with the Population‐Specific Expression Analysis (PSEA) to obtain the differentially expressed genes (DEGs) specific for neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells (FDR‐adjusted p‐value < 0.05). We then executed functional enrichment analysis to obtain Gene Ontology (GO) of Biological Processes (GOBP) terms (clusterProfiler package). All analyses were done in R.

Result

We included eight GSEs to vulnerable regions, comprising 165 cognitively unimpaired (CU) and 182 AD individuals, and two for resilient (123 CU, 179 AD). The PSEA analysis revealed an increased percentage of DEGs in neurons and oligodendrocytes in resilient regions when compared with astrocytes, microglia, and endothelial cells (Figure 1A). By contrast, the percentage of DEGs among the cell types in vulnerable regions remained similar (Figure 1B). Interestingly, resilient regions presented more DEGs related to neurons than the vulnerable ones (Figure 1C). Microglia were the cell type with the most GOBPs number in resilient regions, while astrocytes had one (Table 1). Table 2 shows that only microglia, oligodendrocytes, and astrocytes presented GOBPs in the vulnerable regions.

Conclusion

We demonstrate that neurons are the only cell type presenting a higher number of DEGs in resilient regions compared to vulnerable regions. Other cells exhibit a similar percentage of DEGs in both resilient and vulnerable regions. Regarding GOBPs, all cell types show enriched terms in resilient regions; however, in vulnerable regions, neurons and endothelial cells do not exhibit any enriched terms. These findings suggest that neurons possess an exceptional ability to adapt in resilient regions, a trait not observed in vulnerable regions.
In vivo data‐driven patterns of Amyloid‐ and Tau accumulation associated with AD progression using 18F‐MK6240 and 18F‐NAV4694 PET
Authors: Fonov Vladimir S , Rosa‐Neto Pedro , Collins D Louis
Published: January 2025

Background

Alzheimer’s disease is a neurodegenerative disease associated with the accumulation of Amyloid‐β and Tau neurofibrillary tangles following a pattern known as Thal and Braak stages, respectively (Thal 2002; Braak 1995,2011). Recent research (Pascoal 2020) showed the possibility of recapitulating Braak's histopathological stages in vivo using PET tracer [18F]‐MK‐6240 with manually defined regions of interest. This study analyzes the joint patterns of Amyloid‐β and Tau accumulation associated with AD in a completely data‐driven fashion.

Method

We used T1w MRI, [18F]‐NAV4694, and [18F]MK6240 PET scans from 36 young individuals (47 scans), 192 healthy elderly individuals (280 scans) in the community or outpatients at the McGill University Research Centre for Studies in Aging (97 individuals with mild cognitive impairment (140 scans) and 75 patients with AD (98 scans).

T1w MRIs were pre‐processed (non‐uniformity correction, intensity normalization, stereotaxic registration, brain masking, tissue classification) and non‐linearly registered to the ADNI template using ANTs ( Avants et al 2011 ).

PET scans were linearly registered to the T1w MRI, and voxel‐wise standardized uptake value ratios (SUVR) were calculated using whole cerebellum grey matter as the reference, and then non‐linearly warped into the space of the ADNI template and downsampled to 2mm3 resolution.

All PET scans were concatenated to create a matrix 518x345846. This matrix was factorized into two low‐rank components (Krichene 2018) with the constraint that all matrix elements should be positive, spatial loadings constrained to be between 0 and 1, latent vectors ordered monotonously to capture the additive nature of disease progression, and the loadings aligned with MOCA scores, by minimizing cosine distance. We used spatial components to create pseudo‐probabilistic ROIs associated with the different stages of disease progression.

Result

Our method revealed regional patterns of joint tau and amyloid accumulation associated with AD progression, shown in Figure 1. Associated weighted SUVR average values are shown on Figure 2. The first two components, as visible on Figure 2, have almost no relationship with MOCA score and are most likely associated with off‐target bindings for both tracers.

Conclusion

This work is a stepping stone towards creation of the Tau & Amyloid AD disease staging system.
Brain glucose metabolism changes acutely following exercise and tracks with the systemic lactate response
Authors: Green Zachary D. , John Casey S. , Blankenship Anneka , Kueck Paul J , Kemna Riley E , Johnson Chelsea N , Mahnken Jonathan D , Yoksh Lauren , Burns Jeffrey M , Donald Joseph S. , Vidoni Eric D , Morris Jill K
Published: January 2025

Background

Aerobic exercise may positively affect brain health, although relationships with cognitive change are mixed. This likely is due to individual differences in the systemic physiological response to exercise. However, the acute effects of exercise on brain metabolism and biomarker responses are not well characterized in older adults or cognitively impaired individuals.

Method

The Acute Exercise Response on Brain Imaging and Cognition (AEROBIC) study is a randomized, controlled trial (NCT04299308). We enrolled older adults (60+years) who were cognitively healthy (n = 30) or cognitively impaired (n = 30) based on a clinical exam (telephone CDR). Study visits included a cardiorespiratory fitness test, Fluorodeoxyglucose [18F] PET (FDG‐PET) scans with timecourse blood draws during both rest and exercise, and resting MRI. Participants were randomized to both intensity (moderate; 45‐55% heart rate reserve (HRR) or higher (65‐75% HRR)) and PET visit order. Lactate and various exercise‐related biomarkers were measured. Each session concluded with cognitive testing (NIH Toolbox). Change in whole‐grey matter cerebral glucose metabolism from rest to exercise was registered as the primary outcome. We used general linear modeling to test for a primary effect of Condition (exercise vs. rest), as well as the effects of intensity and cognitive diagnosis, on the change in FDG‐PET SUVR and lactate AUC.

Result

FDG‐PET SUVR differed significantly between exercise (1.045 ± .082) and rest (.985 ± .077) across the entire cohort (Diff = ‐.060, t(58) = 13.8, p < .001). The effect of exercise (F(1,54) = 193.086, p < .001) was not dependent on diagnosis or intensity. Exercise increased Lactate AUC (F(1,56) = 161.988, p < .001), an effect stronger in the Higher intensity (MD = 97.0±50.8) than in the Moderate intensity (MD = 40.3±27.5; t = ‐5.252, p<0.001) group. Change between exercise conditions for lactate AUC and FDG‐PET SUVR correlated (R2 = 0.179, p<.001).

Conclusion

Acute exercise decreases brain glucose metabolism in both cognitively healthy and impaired older adults. This effect tracks with the systemic lactate response. This supports the hypothesis that increased lactate may spare glucose and be a key brain fuel during exercise. Additional work to directly measure brain lactate metabolism following exercise and understand the role of central and peripheral lactate metabolism is warranted.