bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aβ in the Lens of the Eye: A Noninvasively Detectable Early Biomarker of Alzheimer’s Disease β‐Amyloidopathy in Humans and Transgenic Mouse Model
Authors: Goldstein Lee E , Moncaster Juliet A , Moir Robert D , Minaeva Olga , Alvarez Victor E. , Clark John I , McKee Ann C. , Tanzi Rudolph E. 
Published: December 2023

AbstractBackgroundAmyloid‐β (Aβ) accumulation in brain is an early hallmark of Alzheimer’s disease (AD). We discovered Aβ deposition, β‐amyloidopathy, and colocalizing supranuclear cataracts (SNC) in lenses from people with AD (Goldstein LE et al., Lancet, 2003) and Down syndrome (DS; Moncaster JA et al., PLoS One, 2010), but not other neurodegenerative diseases or normal aging. These findings spurred development of an investigational drug‐device lens Aβ eye scanner (Sapphire II, Cognoptix) that combines an Aβ‐binding fluorescent ligand (Aftobetin) and specialized laser scanning ophthalmoscope for noninvasive measurement of lens Aβ (FDA Breakthrough Device, 2021). Early clinical results indicate that lens Aβ is an ideal biomarker for early AD detection. Here, we investigated Aβ accumulation and amyloidopathy in lens and brain.MethodTg2576 transgenic (Tg+) mice express Swedish mutant human amyloid precursor protein (hAPP‐Swe), human Aβ (hAβ), β‐amyloidopathy, and cognitive deficits (Hsiao et al., Science, 1996). Non‐transgenic (Tg–) littermates were used as controls. Lenses were examined by ex vivo lens stereomicroscopy. Brains and lenses were analyzed by Aβ immunohistochemistry, amyloid histopathology, anti‐Aβ immunogold electron microscopy, tryptic digest mass spectrometry, anti‐hAβ ELISA/immunoblotting. Quasi‐elastic light scattering hAβ‐lens protein aggregation analysis.ResultTg2576 Tg+ mice, but not Tg– controls, age‐dependently express hAPP, accumulate hAβ, and develop hAβ molecular pathology in the lens and exhibit age‐dependent Aβ supranuclear opacification that recapitulates lens pathology and SNC phenotype expression in human AD and DS. We detected hAβ in conditioned medium from Tg+ but not Tg– lens explant cultures. hAβ potently promotes mouse lens protein aggregation in vitro.ConclusionThese results support mechanistic (genotype‐phenotype) linkage between age‐dependent Aβ pathology and AD‐related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of age‐dependent supranuclear cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD‐related Aβ pathology outside the brain and support lens Aβ as an optically‐accessible biomarker for early detection and longitudinal monitoring of AD.
The Role of Socioeconomic Status in Basic Education for Illiterate Adults
Authors: Ruppert Emma Patrice , Faria Rocha João Victor , Lourandes Aida , dos Santos Tomaz Kelle Luisa , Friedlaender Clarisse Vasconcelos , de Castro Magalhães Assenção Joanna , Grinberg Lea T. , Rosen Howard J. , Rincon Luciana Paula , Ribeiro Norton Gray Ferreira , Constantina Dulce , Zacarias Ana Paula , Caramelli Paulo , Maciel Francisca Izabel Pereira , Paula França Resende Elisa 
Published: December 2023

AbstractBackgroundThe role of education is a well established protective factor regarding dementia but not much is known as to the effect of literacy acquisition in adults. Therefore, our study aims to determine whether adults enrolled in late‐life literacy programs will improve memory and cognitive reserve and the role of socioeconomic status in learning.Method108 illiterate adults were enrolled and 77 completed the assessments. For SES, only participants living in Belo Horizonte with a verifiable address were included (68). The intervention group had 34 participants that received intensive literacy training, while the 34 controls attended regular classes for six months. SES was based on the Quality of Urban Living Index (QULI) of 2016 created by the municipal council and the Municipal Human Development Index (MHDI) of 2010 made by Atlas Brasil. The instruments used were Rodrigues et al, 2015 list of words and pseudowords to assess reading and Beta III matrix reasoning for non‐verbal reasoning.ResultParticipants lived in 14 different regions of Belo Horizonte, 32 in areas with a low QULI and 36 within a high QULI. When using the HDI classification, 29 had medium MHDI, 25 had high MHDI and 14 very‐high MHDI. In regards to reading, people from low QULI areas went from reading on average 20.86 to 22.26 words and 4.21 to 5.13 pseudowords. Participants from high QULI regions went from an average of 22.14 to 25.08 words and 5.56 pseudowords to 6.86. One‐way ANOVA showed a significant effect of MHDI on post‐test Beta III scores, F (2, 37.5) = 3.64, p = 0.03. Post Hoc comparisons using Games‐Howell test indicated that the average score in high MHDI (M = 6.24, SD = 2.26) were significantly better than those with medium MHDI (M = 4.63, SD = 2.14), but no significant difference was found between high and very high or very high to medium MHDI.ConclusionParticipants from all groups improved during the assessments. However, it was also possible to see that SES has a role to play in the extent of this improvement.
Expression of inflammasome components in experimental models of Alzheimer’s disease
Authors: Stelzer Gustavo Trevizani , Tiburcio Bruna Vieira , Lima‐Filho Ricardo A S , Ferreira Sergio T. 
Published: December 2023

AbstractBackgroundThe inflammasome is a multimeric protein complex of the innate immune system commonly related to the development of inflammatory and neurodegenerative diseases. After priming and activation, inflammasome proteins are recruited and activated, leading to cellular death with cytokine release, in a process known as pyroptosis. The NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome has been associated with development and progression of Aβ‐plaque formation and tau hyperphosphorilation in post‐mortem Alzheimer’s disease (AD) brains and in mouse models. In the current study, we evaluated mRNA expression of inflammasome components in cellular and animal models of AD.MethodRT‐PCR was performed in (1) microglia cultures exposed to 500 nM amyloid‐β oligomers (AβOs) or vehicle for 24 h (N = 4), (2) hippocampi (N = 8) and prefrontal cortices (N = 7) from C57BL/6 mice that received an intracerebroventricular (icv) infusion of AβOs (10 pmol), or (3) hippocampi from APP/PS1 AD mice (N = 4). Target genes evaluated were Nlrp3, Caspase‐1, IL‐1β and IL‐18.ResultMicroglia cell cultures exposed to AβOs showed trends of increased expression of inflammasome genes, except for IL‐18. Cortices of mice that received icv infusions of AβOs showed increased inflammasome genes for IL1β, while hippocampi showed increased expression of Nlrp3 and IL‐18. APP/PS1 hippocampi showed increased Nlrp3 expression, a decrease in Cas‐1 expression, and no alterations in expression of IL‐1b and IL‐18. Among in vivo models, AbO‐infused mice presented the most robust response to AβO treatment.ConclusionMouse models are extremely susceptible to individual variance. Current results showed that the expression of inflammasome components is altered in microglial cultures exposed to AbOs, AbO‐infused mice, and in APP/PS1 mice. AbO‐infused mice appeared more sensitive to AβO‐induced increase in expression of inflammasome components. Further experiments are necessary to evaluate the optimal model to study the relationship between AD pathogenesis and NLRP3 inflammasome.
Associations between structural/social determinants of health and vulnerability for and resilience against Alzheimer’s disease and related dementias: The Healthy Brain Initiative
Authors: Besser Lilah M , Tolea Magdalena I , Chrisphonte Stephanie , Bromfield Jessica , Gibbs Gregory , Riccio Mary Lou , Getz Sarah , Kleiman Michael J , Galvin James E 
Published: December 2023

AbstractBackgroundStructural and social determinants of health (S/SDOH) encompass systems such as laws and policies and social constructs imposed by society such as race and class, as well as environmental conditions where people live, learn, work, and play. S/SDOH can significantly impact health throughout the life course by determining access to health promoting resources and opportunities, which in turn impacts modifiable risk factors (e.g., diet, physical activity, social contact) known to influence Alzheimer’s disease and related dementia (ADRD) risk. In this study, we investigate associations between multiple S/SDOH and measures of ADRD vulnerability and resilience among older adults.MethodWe used cross‐sectional data from the Comprehensive Center for Brain Health’s Healthy Brain Initiative (HBI), which is assembling a cohort of 45‐ to 85‐year‐olds with no or mild cognitive impairment (MCI); conducts comprehensive and harmonized clinical, cognitive, behavioral, and functional evaluations; and collects data on residential history and neighborhood perceptions. S/SDOH included the perceived discrimination index (range: 0‐22), area deprivation index (ADI) (range: 1‐99), perceived neighborhood greenspace (inadequate/adequate), and trust in neighbors (low/high). Linear regression (accounting for clustering by Census tract as appropriate) tested associations between the four S/SDOH measures and continuous Vulnerability Index (VI; range: 2‐13) and Resilience Index measures (RI; range: 105‐260). Models controlled for demographics and MCI (versus normal cognition).ResultParticipants (n = 111) were 69±10.5 years old, 62% women, 7% Black, 4% Asian, and 16% Hispanic. Twenty‐eight percent reported inadequate neighborhood greenspace and 16% reported low trust in neighbors. Mean discrimination scores were 5.5±6.7 and mean ADI scores were 30.2±25.9. Participants with higher ADI (estimate = 0.05, 95% CI: 0.02‐0.07), reporting higher discrimination (estimate = 0.15, 95% CI: 0.10‐0.21), and reporting neighborhoods lacking greenspace (estimate = 1.19, 95% CI = 0.38‐1.99) had higher VI scores. No other associations were observed.ConclusionThese preliminary results suggest that area deprivation, self‐reported lower amounts of neighborhood greenspace, and greater discrimination are associated with greater ADRD risk as measured by VI scores. Observed associations must be replicated with larger and more diverse samples and will be re‐evaluated as the HBI cohort accumulates (with ≥20 enrolling/month, expect ≥100 additional participants by mid‐2023) and compared with imaging and plasma ADRD biomarkers.
Lower autoimmune disease prevalence in patients with early onset Alzheimer’s disease compared to cognitively normal controls
Authors: Lachner Christian , Roemer Shanu F , Frontera Natasha L. , Li Zhuo , White Launia J , Olson Janet E. , Pottier Cyril P , Dickson Dennis W. , Graff‐Radford Neill R 
Published: December 2023

AbstractBackgroundPerturbations in immune pathways are strongly associated with Alzheimer’s disease. A positive association between autoimmune diseases and frontotemporal dementia has been reported. We explored whether early onset Alzheimer’s disease (EOAD) would associate with autoimmune diseases.MethodWe compared 313 patients with EOAD from the Mayo Clinic Florida, Alzheimer’s Disease Research Center (ADRC) Registry with matched cognitively normal controls (NC) based on age (+/‐ 2 years) and gender at 1:2 ratio. NC were derived from Mayo Clinic Biobank Project, Rochester (N = 313) and the Mayo Clinic Study of Aging (N = 313). Data abstraction was performed by trained statisticians using ICD 9&10 codes corresponding to 40 specified autoimmune diseases and/or documentation of specified immunomodulatory treatment. Data was also abstracted via retrospective record review. We further reviewed clinical records from EOAD patients with neuropathologically confirmed Alzheimer’s disease patients enrolled in the ADRC (n = 10). Each autoimmune disease type was compared between cases and controls using Fisher’s exact test. All tests were two‐sided with alpha level set at 0.05 for statistical significance. Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The prevalence of autoimmune disease in the general population was based off Hayter & Cook, 2012 and Roberts & Erdei, 2020. All data abstraction was done blinded to the clinical diagnosis and baseline demographics.ResultAutoimmune disease history was abstracted from 949 patient records (313 EOAD, 10 pathologically‐confirmed EOAD, 626 NCI). The median age was 57 years‐old. (EOAD range 28,65 yrs.; NC 30,66 yrs.). Autoimmune thyroiditis (p = 0.0008), ulcerative colitis (p = 0.011, psoriasis (<0.0001), rheumatoid arthritis (p = 0.0005), and Raynaud’s syndrome (p = 0.0021) were less prevalent in patients with EOAD compared to NC. Furthermore, patients with EOAD had a lower prevalence of immune mediated hematologic disorders.ConclusionPatients with EOAD have a lower prevalence of autoimmune diseases than NC. Immune activation identified in early onset AD patients may be unrelated to autoimmunity. Findings should be explored in late onset AD patients.
Secretome analysis of APOE3 and APOE4 iPSC‐derived mural cells indicates TGFβ as potential key player in blood‐brain barrier alterations
Authors: Broekaart Diede , Mesentier‐Louro Louise A. , Seo Joon Ho , Blanchard Joel , Pereira Ana C. 
Published: December 2023

AbstractBackgroundLoss of blood‐brain barrier (BBB) integrity is present at the earliest stages of Alzheimer’s disease and is important in its pathogenesis. Pericytes, specialized mural cells surrounding brain capillaries, play a crucial role in the regulation of BBB integrity. Interestingly, patients carrying the APOE4 variant of apolipoprotein E gene display accelerated BBB breakdown and pericyte dysfunction. However, the mechanisms through which APOE4 alters pericyte function and contribute to BBB disruption are not fully understood.MethodAPOE4‐induced alterations were investigated using human iPSC‐derived mural cells with pericyte‐like properties (iMCs) with APOE3:3 and APOE4:4 genotype. We investigated the secretome by reanalyzing previously generated RNA‐sequencing of APOE3:3 and APOE4:4 iMCs. Pericyte function was examined using the Wound Maker scratch assay and stimulation with etoposide followed by γH2A.X immunocytochemistry.ResultWe observed senescent‐like phenotypes in APOE4:4 iMC cultures including delayed regrowth after a scratch wound and increased DNA damage compared to APOE3:3 iMCs. Of the 1500 genes identified as encoding for secreted proteins, 70% were differentially expressed between APOE3:3 and APOE4:4 iMCs. Post‐analyses using Qiagen’s Ingenuity Pathway Analysis and DAVID’s Gene Ontology pointed towards senescence inducer transforming growth factor β (TGFβ), increased in APOE4:4 iMCs, as a potential key player in APOE4‐induced BBB alterations. Preliminary studies show that inhibition of TGFβ signaling ameliorates the APOE4‐induced senescent‐like phenotype in pericytes.ConclusionThese results suggest that APOE4‐induced alterations of the pericyte secretome could play an important role in dysregulating the local homeostasis of the BBB, potentially through induction of a senescence‐like cell state. Our future studies are focused on investigating APOE4‐induced changes in intercellular communication and modulation of TGFβ and senescence using a BBB in vitro model of iPSC‐derived endothelial cells, astrocytes and pericytes.
Protective variants in Alzheimer’s Disease from healthy elderly APOE‐ε4 participants
Authors: Qiao Min N , Reyes‐Dumeyer Dolly , Medrano Martin , Lantigua Rafael A. , Mayeux Richard , Vardarajan Badri N 
Published: December 2023

AbstractBackgroundPresence of the APOE‐ε4 allele is the most consistently confirmed genetic risk factor for late‐onset Alzheimer’s disease (AD) in white, non‐Hispanic populations, but the associated risks observed in African Americans and Hispanics are somewhat lower. The objective of this study was to identify protective variants that could modify or reduce the effect of APOE‐ε4 on AD risk.MethodsWe analyzed WGS data in over 3500 individuals from 600 multiplex AD families of non‐Hispanic White (NHW) and Caribbean Hispanic (CH) ancestry to identify protective variants in AD. APOE ε4 homozygosity was found in 48 healthy individuals over the age of 70, and APOE ε4 heterozygosity was found in 155 healthy individuals over the age of 80 were present in families with two of more affected samples. Protective variants were found segregating in the APOE ε4 homozygote and heterozygote individuals. We required that these variants be rare (MAF<0.1%) in GnomAD and prioritized exon coding variants that were putatively damaging to the resulting protein product. Novel or rare coding mutations segregating in ε4 unaffected subjects were tested for the effects on the age of onset of symptoms.ResultsWe identified 632 putatively protective variants that were present in at least 1% of APOE ε4 carriers and were absent in those with other APOE genotypes. 67 protective variants were present in both NHW and CH families. Pathway analysis of these segregating variants in APOE ε4 carriers are enriched in pathways involved in biological pathways and molecular functions such “actin binding”, “microtubule binding”, “extracellular matrix structural constituent”. These results suggest that protective variants promote activity of the extracellular matrix and cytoskeletal proteins leading to enhanced clearing of Aβ peptides. Variants in NBEAL1 delayed the age of onset in AD by 8.33 years respectively.ConclusionsWGS in CH and NHW families multiply affected by AD identified some healthy elderly, non‐demented APOE ε4 carriers with rare coding variants associated with delayed age of onset. Characterizing the functional role of these protective variants in AD will facilitate the creation of tractable models for investigation of disease mechanisms and potential therapies.
Development of a collaborative music therapy and social work telehealth framework to address the well‐being of community‐dwelling older adults
Authors: Reschke‐Hernandez Alaine E. , Gibson Allison , Buckner Laura Elliott , Sullivan Alisia C. , Posey Caleb , Uecker Stephanie 
Published: December 2023

AbstractBackgroundOlder adults often experience changes in health, finances, and social support, which impede community involvement and can be compounded by the onset of cognitive decline. Interprofessional collaboration can help counter such challenges. Here, researchers present a feasibility study, which demonstrated support for a novel social work and music therapy telehealth framework to promote well‐being of older adults with and without dementia. We describe the subsequent pilot study design.MethodDuring the feasibility phase, researchers field‐tested logistics and provided proof‐of‐concept of our novel framework in a randomized cross‐over design. All participants received 6 music therapy sessions via telehealth across 3 weeks (2x/week for 25 minutes) and one 30‐minute social work wellness session with service referral. Quantitative outcomes included self‐reported feelings, anxiety, depression, and loneliness to inform the utility of this framework to improve well‐being of older adults with and without dementia. We conducted semi‐structured interviews with participants and care partners, who offered input about all aspects of the study.ResultsLessons gleaned from the feasibility study, and which informed the pilot, were: 1) participants conveyed that the delivery model was acceptable, interesting, convenient, and helpful; 2) given resources and support using digital technology, older adults found telehealth to be an attractive and feasible delivery mode; 2) older adults and care partners liked music therapy and greatly disliked the recorded music option; 3) music therapists could utilize the “Clinical Practice Model” (Reschke‐Hernández, 2021) to inform provision of appropriate levels of support and challenge to older adults with and without dementia via Zoom; and 4) social workers could leverage the rapport music therapists built with participants and the information they gathered during sessions to link older adults to community resources ‐ a service older adults found more helpful and meaningful than in past social work experiences. Pilot results will be available in December 2023.ConclusionThis project advances a collaborative research partnership to improve research quality and facilitate access to services for older adults with and without dementia. The careful steps of this feasibility and pilot work will inform best practice in an innovative area of music therapy and social work professions.
Characterizing Cerebrovascular Pathologies in Brain Donors Exposed to Repetitive Head Impacts
Authors: Emrani Sheina , Koutures Anne , Tripodis Yorghos , Uretsky Madeline , Abdolmohammadi Bobak , Nowinski Christopher , Daneshvar Daniel H , Katz Douglas I , Goldstein Lee E , Martin Brett M , Palmisano Joseph N , Dams‐O'Connor Kristen , Crary John F. , Mez Jesse B. , Alvarez Victor E. , Huber Bertrand R. , McKee Ann C. , Stein Thor D. , Alosco Michael L 
Published: December 2023

AbstractBackgroundRepetitive head impacts (RHI) from American style football (ASF) and other contact sports are a known risk factor for the neurodegenerative disease chronic traumatic encephalopathy (CTE). RHI can also lead to mixed neuropathologies that uniquely contribute to clinical symptoms. Here, we compared various types of vascular and white matter pathologies between brain donors with and without exposure to RHI from different types of contact and collision sports (CCS).MethodsThe sample included 79 deceased male ASF players (RHI‐ASF) and 49 deceased male non‐ASF CCS athletes (RHI‐CCS) from the UNITE brain bank. Each RHI group had a comparison group that included similar aged (+/‐ 5 years) male brain donors without RHI from the Boston University Alzheimer’s Disease Research Center and Framingham Heart Study brain banks. The modified Ischemic Injury Scale (mIIS) served as a global indicator of vascular and white matter pathologies and is a sum of hippocampal sclerosis, infarct/lacune, microinfarct, microbleeds, laminar necrosis, arteriolosclerosis, atherosclerosis of Circle of Willis, cerebral amyloid angiopathy, and white matter rarefaction. Dementia diagnoses were made during consensus conferences. Linear or logistic regression compared the RHI vs non‐RHI groups on the mIIS and its subcomponents. Logistic regression models examined the association between mIIS and dementia. Models were adjusted for age.Results
Table 1 shows sample characteristics. The RHI‐CCS group was comprised of boxers, amateur wrestlers, and ice hockey, soccer, rugby, and lacrosse players. 94 decedents had CTE, all of whom were in an RHI exposed group. Of the mIIS components, arteriolosclerosis was the most common across all groups. White matter rarefaction was also the most frequent mIIS component for both RHI groups, but not for non‐RHI groups. Compared to their respective controls, RHI‐ASF and RHI‐CCS were associated with higher mIIS scores (Table 2). Higher mIIS scores corresponded to increased odds for having dementia in both the RHI‐ASF and RHI‐CCS groups (Table 2). White matter rarefaction best discriminated both RHI groups from non‐RHI; atherosclerosis also discriminated RHI‐CCS group (Table 3).ConclusionThese results support vascular and white matter pathologies, specifically white matter rarefaction, as prominent and clinically relevant sequelae of RHI from CCS.