bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longterm Protective Effects of Complement C3 Lowering in Adult APP‐KI Mice
Authors: Singh Brijendra , Spooner Emma , Batista Andre F. , Saido Takaomi C. , Carroll Michael , Lemere Cynthia A. 
Published: January 2025

AbstractBackgroundPreviously, we found that germline C3 deletion protected cognition and hippocampal synapses in aged APP/PS1dE9 mice, despite increasing Aß plaques. Here, we crossed our C3 inducible conditional mouse model to APPNL‐G‐F/NL‐G‐F knockin mice to determine whether global C3 lowering in an adult amyloid mouse model would be protective.MethodsC3fl/fl;Rosa26‐Cre‐ERT2 (C3iKO) mice were crossed to C3fl/fl;APPNL‐G‐F/NL‐G‐F mice to generate APP;C3iKO mice, which received 75 mg/kg tamoxifen (TAM; n = 16) or corn oil (CO; n = 15) for 5 days at 3.6 months of age. Serum was collected after 30 days and at the termination of the study to measure C3 protein levels by ELISA. Behavioral testing was conducted at 15 months after which the mice were euthanized, and brain tissue harvested. ELISAs, immunofluorescent staining, qPCR and unbiased RNAseq of prefrontal cortical tissue were performed.ResultsSerum C3 levels were significantly reduced ∼85% 30 days post‐TAM and ∼70% at the end of the study. The TAM‐treated APP;C3iKO mice performed significantly better on the Spatial Novelty Y Maze, Novel Object Recognition and Novel Object Location tests compared to CO‐treated mice. C3 mRNA expression and protein levels in brain were significantly reduced; C1q protein levels were also reduced in brain. No difference in overall amyloid load was seen by IHC or ELISA in APP‐KI;C3iKO mice. We found no changes in overall Iba‐1 and GFAP immunoreactivity between the two groups. However, plaques were associated with fewer Iba‐1+/CD68+ microglia and AQP4+/GFAP+ astrocytes in the TAM‐treated animals. PSD‐95 post‐synaptic staining was increased in hippocampal CA3 but no difference was seen in SYP pre‐synaptic staining. C3 lowering in the APP‐KI mice resulted in significantly reduced mRNA expression of C3, TNFa, IL‐10, CX3CR1 and AQP4 but only a trend for reduced C1q mRNA by qPCR. Unbiased bulk RNAseq of prefrontal cortex identified 1071 differently expressed genes (DEGs) including 569 upregulated genes and 502 downregulated genes in the APP;C3iKO mice. Further analysis of these DEGs is underway but thus far, many of the top hits are related to synaptic signaling.ConclusionOur data indicates that global C3 lowering in adult APP‐KI mice reduced inflammation and protected synapses and cognition.Funding: NIH/NIA RF1 AG060057 (CAL)
The neutrophil to lymphocyte ratio associates with markers of Alzheimer’s disease pathology in cognitively unimpaired elderly people
Authors: Jacobs Tovia , Jacobson Sean R , Fortea Juan , Berger Jeffrey S , Vedvyas Alok , Marsh Karyn , Gonzalez Moses , Figueredo Luisa F , Plaska Chelsea Reichert , Blessing Esther M , Betensky Rebecca A , Rusinek Henry , Glodzik Lidia , Wisniewski Thomas , Osorio Ricardo S. , de Leon Mony J. , Cejudo Jaime Ramos ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

AbstractBackgroundAn elevated neutrophil‐lymphocyte ratio (NLR) has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities.MethodWe explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and NYU Center for Brain Health (CBH). Specifically, we examined associations between the NLR and cross‐sectional measures of amyloid‐β42 (Aβ42), total tau (t‐tau), and phosphorylated tau181 (p‐tau181), as well as the trajectories of these CSF measures obtained longitudinally.ResultA total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p<0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p<0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p<0.001), and a greater percentage of Aβ‐positivity (34.2% vs. 20.0%, p = 0.009) (Table 1). In the ADNI cohort, we found cross‐sectional associations between the NLR and CSF Aβ42 (β = ‐12.193, p = 0.021), but not t‐tau or p‐tau181. In the NYU cohort, we found cross‐sectional associations between the NLR and CSF t‐tau (β = 26.812, p = 0.019) and p‐tau181 (β = 3.441, p<0.001), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t‐tau (β = 100.476, p = 0.037) compared to Aβ‐ subjects or the non‐stratified cohort (Figure 1). In both cohorts, the same associations observed in the cross‐sectional analyses were observed after incoporating longitudinal CSF data (Figure 2).ConclusionWe report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t‐tau and p‐tau181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD‐biomarkers may occur as part of immunosenescence.
Utility of mobility testing in early ADRD detection
Authors: Tolea Magdalena I , Rosenfeld Amie , Besser Lilah M , Galvin James E 
Published: January 2025

AbstractBackgroundGait and balance deficiencies may be important indicators of cognitive impairment, distinguishing dementia from normal cognition (NC). It is unclear whether this extends to pre‐dementia stages of disease. Study goals were to: assess patterns of mobility across early stages of disease and identify specific measures that distinguish individuals with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI).MethodWe assessed whether mobility differentiates SCI (n = 35) from NC (n = 78) and MCI (n = 41). Using ANCOVA, we compared diagnostic groups on global (mini‐PPT; TUG) and individual (gait speed (GS), flexibility, balance, step length, single‐leg support) measures of mobility, controlling for age and baseline physical activity levels. Group separation was evaluated with logistic regression. Group differences in mobility while distinguishing between MCI etiology (AD vs non‐AD) and relationships between mobility and MRI cortical atrophy score (CAS) were analyzed and results validated against biomarker‐confirmed diagnoses (true controls/preclinical/MCI).ResultParticipants were 69±9yr old, highly educated (16±3y), mostly non‐Hispanic White (77%), and performed within normal parameters for mobility. Mobility performance decreased with disease stage (MCI>SCI>NC). All mobility measures distinguished MCI from NC (p<0.01). Dual task mobility distinguished MCI from SCI (e.g., ORTUG = 1.24, 95%CI:1.055‐1.457). AD vs non‐AD etiology accounted for most group differences in mobility. Higher mini‐PPT score was linked to lower odds of SCI vs NC (OR = 0.705 (0.543‐0.916)) stemming from significantly poorer balance in SCI (β = ‐0.3±0.1, p = 0.041). Lower GS explained MCI differences from NC (β = ‐0.1±0.03, p = 0.003) and SCI (β = ‐0.1±0.04, p = 0.027). Results were not explained by differences in age and physical activity. Small‐to‐moderate correlations between CAS and mobility (e.g., rTUG dual = 0.34, p<0.001) were found. In analyses using biomarker‐confirmed diagnoses, mobility was lower in MCI vs true controls (all p<0.01) and vs preclinical disease (p<0.05), with a trend for preclinical vs true controls (p = 0.054) validating findings on clinical diagnoses.ConclusionMobility parameters can distinguish NC from SCI and MCI highlighting: 1) dual task testing and subtle changes in balance help detect early cognitive impairments; 2) changes in GS mark more significant cognitive impairment. Mobility testing may be an important tool in early detection of ADRD in the clinical setting and can help identify targets for early intervention.
Objective memory impairment in individuals with memory complaints: baselinedata from the Brazilian Longitudinal Study of Aging (ELSI‐Brazil)
Authors: Pinho Pedro JDMR , Bertola Laiss , Teixeir Lucas Martins , Barbosa Matheus Ghossain , Lima‐Costa Maria Fernanda , Ferri Cleusa P 
Published: January 2025

AbstractBackgroundSubjective Memory Complaints (SMC) are common with aging and might be associated with objective memory impairment (MI) and with higher risk to develop dementia. This association is understudied in socially and ethnically diverse populations, such as Brazilians.MethodThis study uses the baseline data from the ELSI‐Brazil, a representative sample of 9402 Brazilians over 50 years. We used the question “Currently, how do you rate your memory?” to classify the participants as without SMC (excellent/very good/good) and with SMC (fair/bad). Memory impairment (MI) was defined through a z‐score extracted from a regression based‐norms approach (based on their age, education, and gender/sex) derived from a healthy subset of individuals from the ELSI‐Brazil study. The memory score is based on a combination of immediate and delayed response from the episodic memory test (10‐word list). Other data about sociodemographic factors (sex, age, education, income), depressive symptoms, self‐rated health, number of chronic illnesses, and activities of daily living: basic (BADL), instrumental (IADL) and advanced (AADL) were measured. We used logistic regression with robust variance to estimate the association between the above variables and MI.ResultFrom the original sample, 7831 participants had no missing data for all variables, with 3402 (41.9%) individuals with SMC and included in this study. People with SMC had a mean age of 62.6 years (SD = 9.3), a mean education of 4.7 years (SD = 3.9), and 24.8% had MI (table 1). Logistic regression shows that, in individuals with SMC, higher education, greater impairment in IADLs and AADLs, and a higher number of depressive symptoms were associated with MI. However, higher household income per capita were associated with less MI (table 2).ConclusionWhile SMC affects 42% of the original sample, objective MI affects only a quarter of these individuals, showing that most of them have complaints but not objective memory deficits. Memory impairment in individuals with memory complain is associated with higher education, lower income, depressive symptoms, and disability in instrumental and advanced activities of daily living.
Relationships between Circulating Monocyte and Brain Transcriptional Profiles in Nonhuman Primates Consuming Mediterranean versus Western Like Diets
Authors: Register Thomas C. , Frye Brett M. , Negrey Jacob D. , Johnson Corbin S.C. , Snyder‐Mackler Noah , Craft Suzanne , Montine Thomas J. , Shively Carol A. 
Published: January 2025

AbstractBackgroundMediterranean diets may reduce Alzheimer’s disease (AD) risk and preserve cognitive function relative to Western diets by protecting against inflammation. In a long term controlled randomized trial of Mediterranean vs. Western diet consumption in cynomolgus macaques (Macaca fascicularis), difficult to conduct in humans, we found significant anti‐inflammatory effects of Mediterranean diet on circulating monocyte and brain temporal cortex transcriptional profiles. Here we examine relationships between monocyte and temporal cortex gene expression profiles.Methods38 middle‐aged (mean = 12 years of age) female macaques were fed Western or Mediterranean diets for 2.5 years in a randomized nonhuman primate trial. RNAseq was used to assess transcriptional profiles in CD14+ monocytes after 15 months of diet consumption while temporal cortex was obtained after 2.5 years.ResultsCortex expression of cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. Six other cortex transcripts [i.e., “lunatic fringe” (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] higher in the Mediterranean group were associated with anti‐inflammatory/neuroprotective pathways. Monocyte patterns of gene expression predicted expression of these targets in the brain, with consistent anti‐inflammatory effects of the Mediterranean Diet relative to the Western Diet (Figure 1). Monocyte transcripts associated with inflammation, including proinflammatory components of the constitutive transcriptional response to adversity (CTRA, Cole et al. 2015), NFKB1, NFKB2, and IL6, were positively associated with temporal cortex transcript level of the pro‐inflammatory gene CDK14 (all p’s≤0.0?). In general, these proinflammatory monocyte transcript levels were negatively correlated with temporal cortex anti‐inflammatory transcripts LFNG, SLC3A2, and MRC2 (8 of 12 correlations p<0.05; 11 of 12 correlations p<0.10), consistent with an overall anti‐inflammatory effect of the Mediterranean diet.ConclusionCirculating monocyte gene expression profiles correlated with temporal cortex transcript levels consistent with anti‐inflammatory effects of the Mediterranean Diet relative to the Western Diet, suggesting that peripheral inflammation may promote neuroinflammation. Interventions including diet to target inflammation may have a role in prevention or treatment of systemic as well as neuro‐inflammation and neuropathology.
Remote App‐Based Cognitive Assessment in Aging and Pre‐Clinical Alzheimer’s Disease in a Diverse Sample of Older Adults
Authors: Mechanic‐Hamilton Dawn , Humphreys Valerie , Prusky Alex , Halberstadter Kimberly , Wolk David A. 
Published: January 2025

AbstractBackgroundMobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and generalizability of an at‐home, app‐based cognitive assessment, the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD.MethodmCAPP includes three gamified tasks (Figure 1): (1) a “concentration” memory task that includes learning and matching hidden card pairs with increasing memory load, pattern separation features (lure vs. non‐lure), and spatial memory (2) a stroop‐like task (“brick drop”) with speeded word and color identification and response inhibition components and (3) a digit‐symbol coding‐like task (“space imposters”) with increasing pairs. Participants used mCAPP at home for two weeks and completed the NACC UDS3 and additional paper and pencil tests. Participants included ninety‐three adults (72% female; age = 72.5±5.5, education = 16.4±2.6; 49.5% White, 49.5% Black/African American, 1% Multiracial) without cognitive impairment enrolled in the Penn ADRC cohort. A subgroup also completed longitudinal mCAPP testing and amyloid PET imaging.ResultParticipants played 11±4 sessions over two weeks, with 61% playing more than the assigned sessions. Most participants (97%) used a smartphone. Usability rating was 6.3±0.8 (1‐7 scale). Most participants rated the difficulty of the tasks as “just right” for Concentration (93%), Brick Drop (84%), and Space Imposters (87%) after playing the games for the first time. 70% reported preferring mobile device cognitive assessment to standard in‐person cognitive batteries. All tasks showed lower performance with increasing cognitive load (p’s<.05). mCAPP measures correlated with paper and pencil tests from analogous domains on paper and pencil measures (p’s<.01). Participants with a positive amyloid PET scan showed a trend toward slower and less accurate performance on some mCAPP measures.ConclusionThis pilot study shows mCAPP usability for at‐home use in a diverse cohort of older adults. Performance across measures indicate initial reliability and validity of mCAPP. Future work will include the evaluation of mCAPP performance relationships with biomarkers and longitudinal data analysis. Remote, accessible, and reliable cognitive assessment has the potential to reduce barriers to research participation and clinical care.
Remote Cognitive Assessment for Preoperative Evaluation in Older Adults: Feasibility and Associations with Subjective Cognitive Concerns
Authors: Wise Amy B. , Dhanam Sreya , Zhou Sara , Sinha Anika , Hernandez Kaylee , Pawar Niti , Boxer Adam L. , Chang Odmara L Barreto , Staffaroni Adam M. 
Published: January 2025

AbstractBackgroundPostoperative complications of major surgical interventions include delirium. Delirium is a risk factor for dementia, and in some cases, may signal underlying neuropathological processes. Cognitive tests that accurately predict post‐operative outcomes could identify patients with cognitive vulnerabilities who may benefit from preoperative counseling and postoperative interventions. Unfortunately, in‐person presurgical cognitive evaluations are often not available, but digital technologies may improve access. In this pilot study, we evaluate the feasibility of utilizing a smartphone app to conduct preoperative remote cognitive assessment in patients undergoing spine surgery. We also evaluate the relationship of app‐based assessments with subjective cognitive concerns.MethodWe enrolled 30 older adults (≥ 65 years old) who were scheduled for elective spinal surgery anticipated to last at least three hours. On the ALLFTD Mobile App, participants completed a battery of cognitive tests, a measure of subjective cognitive concerns (12‐item self‐reported everyday cognition scale, Ecog‐12), and a user experience survey. A subset (N = 12) had a study partner complete the 41‐item Ecog, reporting on observed changes in cognitive function over a 10‐year period prior to the surgery. Linear regressions adjusted for age evaluated the associations between subjective cognitive concerns and the objective app‐based outcomes (Flanker task and a composite of several measures).ResultAverage age of participants was 71.2 years (SD = 4.4); 46.1% were women and 75% identified as White. Most (96%) participants indicated that the time required to complete the app assessments was acceptable, 77% indicated that the app instructions were clear, and all participants indicated that the text on the app was large enough to read comfortably. Participants’ subjective cognitive concerns (ECog‐12) were significantly associated with a composite of app tasks (β = ‐0.48, p = 0.01). The executive functioning domain of the study partner Ecog was significantly associated with patient performance on an app‐based executive functioning task (β = 0.75, p = 0.007).ConclusionThese findings support the feasibility of remote preoperative assessments in older adults using smartphones. The study also provides preliminary support that these measures can objectively quantify self‐ and partner‐reported cognitive concerns. Future work will explore associations with postoperative outcomes.
Generating a novel and reliable human iPSC‐derived midbrain organoid model of sporadic progressive supranuclear palsy
Authors: Selecky Grace A. , Whitney Kristen R. , Krassner Margaret M. , Cervera Alessandra , De Sanctis Claudia , Almazan Victoria Flores , Delica Sean Thomas , Kim SoongHo , Farrell Kurt W. , Christie Thomas D. , Iida Megan A , Sarrafha Lily , Parfitt Gustavo , Walker Ruth H. , Nirenberg Melissa J , Riboldi Giulietta M. , Frucht Steven J. , Ahfeldt Tim , Temple Sally , Crary John F. 
Published: January 2025

AbstractBackgroundThe accumulation of abnormal tau protein in neurons and glia in the human brain is the defining feature of neurodegenerative diseases known as tauopathies. Progressive supranuclear palsy (PSP), the most common primary tauopathy, is typified by selective vulnerability of dopaminergic neurons and glia in the midbrain leading to an atypical parkinsonian movement disorder. To investigate candidate disease mechanisms underlying PSP, there is a critical need for model systems that more accurately recapitulate the cellular and molecular environment in the human brain. Human induced pluripotent stem cell (hiPSC)‐derived organoid models have emerged as a powerful tool to address this gap.MethodSkin biopsies were collected from living clinically diagnosed PSP patients or during autopsy. Fibroblasts were cultured and reprogrammed into hiPSCs using Sendai virus. HiPSCs were maintained with StemCultures FGF2 Discs to improve pluripotency and FACS was performed to confirm pluripotency marker expression. To generate midbrain organoids, hiPSCs were seeded into suspension spinner flasks, patterned using pharmacological directed differentiation, and grown for four months. Reliable patterning was confirmed with qRT‐PCR, immunohistochemistry and immunoblot using a panel of cell‐type specific markers. Astrocytes were extracted from mature organoids, cultured, and screened for astrocyte‐specific markers.ResultFibroblasts have been banked from twenty‐two PSP patients and seven reprogrammed into hiPSCs. Sporadic case status was determined by Sanger sequencing confirming the absence of a MAPT mutation. We found that hiPSCs grown with controlled‐release FGF2 discs were 90‐100% positive for pluripotency markers and negative for off‐target genes. During patterning, organoids displayed morphological and cytoarchitectural patterns consistent with developing neuroectoderm and midbrain. Midbrain neural progenitor and dopaminergic markers such as FOXA2, LMX1A, and TH were positive in a time‐dependent manner, with mature dopaminergic neurons expressing NURR1 and GIRK2 detected by day 30. GFAP‐positive astrocytes appeared around day 100. Astrocytes extracted from mature organoids were positive for multiple astrocyte markers.ConclusionSporadic PSP patient hiPSCs reliably differentiate into midbrain dopaminergic organoids and astrocytes, resulting in a sporadic tauopathy model containing key cell types affected in PSP. This cell collection is a valuable resource to investigate candidate mechanisms underlying tauopathy and could provide insight into cell‐type specific disease drivers.