bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship of Alzheimer’s Disease, Stroke and Ancestry in the Puerto Rican Alzheimer Disease Population.
Authors: Feliciano‐Astacio Briseida E. , Beecham Gary W. , Hamilton‐Nelson Kara L. , Silva‐Vergara Concepcion , Contreras Maricarmen , Mena Pedro Ramon , Adams Larry D. , Acosta Heriberto , Feliciano Nereida I , Lopez Alexandra , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A. 
Published: December 2022

AbstractBackgroundThe Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) patient cohort was developed to investigate AD and the associated genetics factors in the Puerto Rican population. PRADI recruitment was a snowball sampling, with both island‐wide geographic distribution, and extensions of the PR communities in the continental US. A prior analysis suggested that stroke is a contributing factor to AD in the PR population. In this study we further evaluated the association between stroke and AD, while considering also age, gender, and ancestry.MethodWe assessed 1063 elderly PR individuals for dementia and obtained a medical history. Affection status or mild cognitive impairment was established using standard AD clinical criteria (NINCDS‐ADRDA). Medical history was obtained by a self‐report or informant report. The global ancestry was assessed through the ADMIXTURE program. Differences between affected and cognitively unimpaired (CU) individuals were initially evaluated using a chi‐square test (for age, gender, global ancestry, and stroke) and a t‐test for the age at the exam time. Follow‐up analyses on stroke were performed using logistic regression with age‐at‐exam, gender, and global ancestry proportions as covariates in the model. Initially we assess how stroke is associated with AD, while accounting for age, sex, and global ancestry analysis without APOE, results on the first table. The first table is the model without APOE. Then a second tab turns it around and looks at what factors are associated with Stroke, in the context of AD.ResultIn the PRADI population stroke is associated with an increased risk of AD dementia (p=0.012); this association persists even after accounting for APOE dosage (p=0.017). Additionally, age, gender and APOE dosage were all also associated with increased AD risk (p <0.05) (table 1). AD correlated with Stroke (p=0.013). Gender was also associated with stroke, with females having a decreased risk of stroke (p=0.0021). APOE dosage and ancestry proportions measured through ADMIXTURE approach were not associated with stroke (table 2).ConclusionStroke was independently associated to AD after controlling for APOE dosage. In contrast, age and gender were associated with stroke whereas global ancestry and APOE dosage were not.
Granulocyte‐Macrophage Colony‐Stimulating Factor Reduces Two Major Pathological Hallmarks of Alzheimer’s Disease and Astrogliosis in the TgF344‐AD Rat Model
Authors: Ahmed Md. Mahiuddin , Wang Athena Ching‐Jung , Boyd Timothy D. , Solano D. Adriana , Vielle Anne , Markham Neil , Coughlan Christina M , Chial Heidi J , Vergara M. Natalia , Potter Huntington 
Published: December 2022

AbstractBackgroundGranulocyte‐macrophage colony‐stimulating factor (GM‐CSF), a hematopoietic growth factor and the innate immune system modulator, has shown therapeutic and neuroprotective effects in animal models of Alzheimer’s disease (AD), Parkinson’s disease, Down syndrome, stroke, and normal aging. Recently, Potter et al. (2021) published the results of a Phase2 clinical trial in mild‐to‐moderate AD subjects showing that recombinant human GM‐CSF (sargramostim) treatment shifted both MMSE scores and plasma biomarkers of neurodegeneration toward normal. Cohen et al. (2013) developed a transgenic rat model (TgF344‐AD) that expresses the Swedish mutant human APP (APPsw) and mutant human presenilin 1 (PSEN1 deltaE9) genes that cause familial AD. In addition to cerebral amyloidosis, neuronal loss, and cognitive deficits, TgF344‐AD rats also show age‐dependent tauopathy including overexpression of phosphorylated tau and neurofibrillary tangle formation, which are not present in mouse models of AD. To evaluate the potential ability of GM‐CSF to reverse and/or prevent the full range of AD pathology, we treated ∼20‐month‐old TgF344‐AD rats with GM‐CSF or saline, and investigated AD pathology in the brain and retina. We also analyzed biomarkers in plasma using MSD and SIMOA neuroinflammation panels.MethodTgF344‐AD rats were injected subcutaneously with GM‐CSF (83.3ug/kg/day; 5days/week) or with saline (200ul/day) for 24 injections total over 32 days. On day 32, blood samples were collected, plasma samples were used for biomarkers assays, and brain and retinal tissues were processed for immunohistochemistry and immunoblotting.ResultTgF344‐AD rats treated with GM‐CSF showed a significant reduction in amyloid plaque deposition in the cortex and a strong trend towards reduced plaque deposition in the hippocampal CA region compared to saline‐treated TgF344‐AD rats. We also observed a trend of reduced phosphorylated tau expression in the cortex and hippocampal region in GM‐CSF‐treated TgF344‐AD rats. In addition, GM‐CSF treatment significantly reduced astrogliosis in the CA1 and dentate gyrus/hilus regions of TgF344‐AD rats.ConclusionAlthough experiments are ongoing, our findings indicate that GM‐CSF treatment rescues two major pathological hallmarks of AD and neuroinflammation (astrogliosis) in TgF344‐AD rats. Our results suggest that GM‐CSF/sargramostim/Leukine® may be a potential therapeutic not only for reducing amyloidosis, but also for reducing levels of hyperphosphorylated tau and other relevant pathological manifestations of AD.
The Bay Area Verbal Learning Test (BAVLT)
Authors: Williams Garrett , Hall Kathleen , Geraci Kristin , Blank Michael , Baldo Juliana , Schendel Krista , Chok Jas M. , Lwi Sandy J. , Herron Tim , Wyma‐Hughes John , Woods David L. 
Published: December 2022

AbstractBackgroundVerbal learning tests are sensitive measures of memory decline in pre‐clinical Alzheimer’s Disease with recall scores correlating with amyloid and tau burden (Bejanin et al., 2017). Here we describe a digital version of the Bay Area Verbal Learn‐ing Test (BAVLT) (Woods et al., 2017)— a brief (8.5 minute), fully automated verbal learning test administered from participants’ homes.MethodThe BAVLT was administered to 399 healthy adults (41.5% female, Age = 64.4 years, ±15.0) from their homes using a tablet‐based testing interface (Figure 1). Participants underwent two test sessions on successive days and were remotely monitored via the test interface’s remote proctoring function.Participants were instructed to remember two lists — each with 12 words in four semantic categories. List A was presented three times with immediate recall after each presentation, followed by a single presentation and recall of distractor List B, then an uncued recall of List A. Thirty minutes later, participants completed a List A delayed recall, followed by a 2‐choice List A recognition test (Figure 2).ResultThe BAVLT showed excellent test‐retest reliability (r = 0.86 total, r = 0.73 delayed). Multiple regression analysis of total recall scores revealed significant effects of age (p< 10–13) (Figure 2), gender (p< 10–11), vocabulary (p<10‐15), and education (p<0.03), with these four variables aggregately accounting for 37.4% of variance. Total recall scores improved over list presentations and increased by 0.97 standard deviations on repeat testing (p<10‐15) (Figure 3).ConclusionAt‐home administration of the BAVLT demonstrated excellent psychometric properties that are similar to those of well‐established verbal learning tests such as the CVLT (Delis et al., 1987).
Differential impact of APOE on associations between phosphorylated tau 181 and multi‐domain cognitive outcomes using cerebrospinal fluid and plasma markers
Authors: Weigand Alexandra J. , Ortiz Gema , Walker Kayla S. , Galasko Douglas R. , Bondi Mark W. , Thomas Kelsey R. 
Published: December 2022

AbstractBackgroundBiomarkers of phosphorylated tau have previously been linked to cognitive function in prodromal Alzheimer’s disease (AD). However, the differential dynamics of various biomarker methods used as indicators of tau accumulation remain under investigation, particularly with respect to their associations with cognitive function and the moderating influence of APOE.MethodData for 741 participants from the Alzheimer’s Disease Neuroimaging Initiative with concurrent plasma, cerebrospinal fluid (CSF), and neuropsychological data were included. T‐tests assessed for cognitive classification (cognitively unimpaired [CU] vs mild cognitive impairment [MCI]) and APOE ε4 [carrier vs. non‐carrier] differences in levels of tau phosphorylated at threonine 181 (p‐tau181) measured in plasma and CSF. Multiple linear regression assessed for a main effect of plasma and CSF p‐tau181 on domains of memory, language, and executive function, as well as the moderating effect of APOE ε4 status, adjusting for age, sex, education, and cognitive classification. Sensitivity analyses included CSF amyloid‐beta 1‐42 as a covariate and stratified by cognitive classification.ResultResults indicated that both the MCI group and the APOE ε4 carrier group had significantly higher levels of plasma (cognitive group t=5.84, p<.001; APOE group t=4.89, p<.001) and CSF p‐tau181 (cognitive group t=5.14, p<.001; APOE group t=10.18, p<.001). For plasma p‐tau181, a main effect was observed only for memory (t=‐2.20, p=.03), whereas APOE ε4 interactions were observed only for language (t=‐2.65, p=.01) and executive function (t=‐2.19, p=.03) with ε4 carriers exhibiting a stronger negative association. For CSF p‐tau181, both a main effect (t=‐5.04, p<.001) and APOE ε4 interaction (t=‐2.10, p=.04) were observed only for memory. Sensitivity analyses revealed that these findings were driven by the MCI group and were largely unchanged when including amyloid‐beta 1‐42 as a covariate.ConclusionPlasma and CSF p‐tau181 are both elevated in the context of increased AD risk and both are associated with poorer memory. However, different patterns for plasma p‐tau181 emerge across other cognitive domains (i.e., language, executive function) when APOE ε4 carrier status is considered. However, future research (particularly in more representative samples) is needed given prior research demonstrating increased sensitivity of CSF relative to plasma.
Association between plasma Alzheimer’s disease markers and MRI markers of cerebral small vessel disease and neurodegeneration: the SMART‐MR Study
Authors: Twait Emma L. , Gerritsen Lotte , Moonen Justine E. , Verberk Inge M.W. , Teunissen Charlotte E. , Visser Pieter Jelle , van der Flier Wiesje M. , Geerlings Mirjam I. ,   the NCDC Consortium
Published: December 2022

AbstractBackgroundBiomarkers for Alzheimer’s disease (AD), including amyloid‐beta (Abeta) and phosphorylated‐tau have recently been accurately detected in blood. Non‐specific biomarkers such as neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) have been added as complementary biomarkers to fully investigate AD etiology in vivo. This has increased the possibility to examine relationships with other pathways to AD, such as white matter hyperintensities (WMH) and brain atrophy on MRI. Our aim was to explore the relationship between plasma AD biomarkers and MRI markers of cerebral small vessel disease and neurodegeneration in mid‐ and late life.MethodData from 594 individuals (mean (SD) age: 64 (8) years; 17% female) were included from the SMART‐MR Study, a prospective cohort study of non‐demented individuals with a history of vascular disease from the UMC Utrecht in the Netherlands. MRI markers of CSVD included WMH, presence of infarcts, total brain volume (TBV), and hippocampal volume (HV) assessed on 1.5T MRI. AD plasma markers (Abeta1‐40, Abeta1‐42, pTau‐181, NFL, and GFAP) were assessed using Single Molecular Array (Simoa; Quanterix) assays. Linear regressions were performed for each plasma marker, as well as Abeta1‐42/Abeta1‐40 ratio, with age, sex, education, and intracranial volume, with WMH volume, TBV, and HV. Additionally, logistic regressions were performed for the presence of infarcts, including lacunar infarcts and cortical infarcts, corrected for age, sex, and education. Plasma AD levels were converted to z‐scores. P < 0.01 was considered statistically significant.ResultHigher NFL and pTau‐181 were associated with larger WMH volume (B NFL=0.17, 95% CI=0.06;0.29, p=0.003; B pTau‐181=0.16, 95% CI=0.06;0.26, p=0.001). Higher Abeta1‐40 (B=‐0.11, 95% CI=‐0.17;‐0.05, p<0.001) levels were associated with lower HV. Higher NFL (B=‐5.63, 95% CI=‐8.95;‐2.31, p<0.001) and Abeta1‐42 (B=‐3.61, 95% CI=‐6.26;‐0.96, p=0.008) were associated with lower TBV. Regarding infarcts, higher NFL was associated with any infarct (OR=1.42, 95% CI=1.13;1.78, p=0.003). Higher GFAP was marginally associated only with cortical infarcts (OR=1.45, 95% CI=1.09;1.92, p=0.01).ConclusionWithin non‐demented adults with a history vascular disease, plasma AD markers differentially mapped to MRI markers. NFL and pTau‐181 were associated with markers reflecting vascular damage, whereas amyloid markers were associated with atrophy in the TBV and HV.
Subjective Cognitive Decline Interacts with Sex and Education on CSF β‐Amyloid.
Authors: Bolton Corey J , Zetterberg Henrik , Blennow Kaj , Jefferson Angela L. , Hohman Timothy J. , Gifford Katherine A. 
Published: December 2022

AbstractBackgroundSubjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer’s disease (AD) biomarkers in non‐demented older adults.MethodVanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 129, 73±7 years, 33% mild cognitive impairment, 28% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test 3rd edition Reading subtest to assess reading level at baseline. Cerebrospinal fluid (CSF) biomarkers for AD (β‐amyloid42 (Aβ42), Aβ42/40 ratio, phosphorylated tau, tau, neurofilament light) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, cognitive diagnosis, and Geriatric Depression Scale scores (minus points for cognition). Follow‐up models assessed SCD x reading level, SCD x education, and SCD x sex interactions on AD biomarkers.ResultIn main effect models, higher SCD was associated with lower Aβ42 and Aβ42/40 ratio (p‐values<0.005) but not associated with tau, p‐tau, or NfL levels (p‐values>0.38). SCD score interacted with education on Aβ42 and Aβ42/40 ratio (p‐values<0.005), such that associations were stronger in individuals with higher education. In stratified models, no significant associations were observed in any individual educational tertile (p‐values>0.07). SCD score interacted with sex on Aβ42/40 ratio (p = 0.03). In stratified models, higher SCD was associated with lower Aβ42/40 ratio in men (p = 0.002) but not in women (p = 0.89). Reading level did not interact with SCD score on any biomarker (p‐values>0.19), though significant associations between SCD score and Aβ42 and Aβ42/40 ratio were observed in the higher reading level (p‐values<0.005), but not the lower reading level group (p‐values>0.11).ConclusionAmong community‐dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD may be most useful in detecting early AD pathology in individuals of higher education and men. SCD was not associated with CSF markers of tau or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.
Mechanisms of Protection in Early and Mid‐Stage Alzheimer’s Disease by Treatment with NAD+ Preserving Compound
Authors: Chaubey Kalyani , Vázquez‐Rosa Edwin , Shin Min‐Kyoo , Dhar Matasha , Franke Kathryn , Cintrón‐Pérez Coral , Koh Yeojung , Yu Youngmin , Barker Sarah , Miller Emiko , Rose Sophia , Bud Zea , Fujioka Hisashi , Sridharan Preethy , Pieper Andrew A. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) currently affects around 6 million Americans and is growing exponentially with our aging population. Impaired homeostasis of nicotinamide adenine dinucleotide (NAD+) impacts several neurodegenerative diseases, including AD. Aging and traumatic brain injury, two of the principle causes of AD, are also associated with impaired NAD+ homeostasis.MethodWe measured NAD+ levels in brain tissue from two different cohorts of patients with AD, along with matched controls, as well in 5xFAD mice and WT littermates. We also evaluated the efficacy of treating 5xFAD mice with the NAD+ stabilizing compound P7C3‐A20, at various stages throughout disease progression. Outcome measures included neurobehavioral assay and immunohistochemical and biochemical assessment of pathology, as well as brain NAD+ levels.ResultWe detected significantly decreased NAD+ levels in the brains of human patients with AD, relative to matched control brain tissue. We also detected significantly decreased NAD+ in the brains of 5xFAD mice, relative to WT littermates, throughout the disease process across young, mid, and old age. Treatment of 5xFAD mice with P7C3‐A20 restored NAD+ levels in the brain of 5xFAD mice at the same time points, and also protected from cognitive decline and depression‐like behavior. Treatment with P7C3‐A20 also decreased Aβ plaque load, neuroinflammation, axonal degeneration, and blood‐brain barrier deterioration, in both male and female 5xFAD mice.ConclusionDisruption in NAD+ homeostasis is a hallmark of AD, and we demonstrate here that treatment with the NAD+‐stabilizing molecule P7C3‐A20 prevents and reverses AD‐like behavior and pathology in 5xFAD mice. This provides proof of principle for a potential new approach to treating patients with AD.
Grip Strength as a Potential Biomarker for Insoluble Tau Accumulation
Authors: Alava Bryan , Esser Karyn , Abisambra Jose F. F 
Published: December 2022

AbstractBackgroundThe risk of Alzheimer’s Disease (AD) is associated with muscle weakness, but the molecular basis of this association is unknown. Beyond motor function, skeletal muscle is a highly metabolic endocrine organ, and it crosstalks with other systems. Therefore, disruptions in skeletal muscle health may influence whole‐body homeostasis with AD progression. Accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD. Neurodegeneration could negatively impact muscle function; likewise, dysfunctional skeletal muscle can also deleteriously impact the environment of whole‐body processes, including tau pathogenesis. Therefore, measuring temporal changes in muscle function relative to insoluble tau accumulation would offer insight into whether skeletal muscle contributes to the progression of tau pathology.MethodsMale and female inducible muscle specific Bmal1 knockout (iMSBmal1KO) mice were used to model muscle weakness. Intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (n= 15) and yellow fluorescent protein (YFP) (n=18) were done at postnatal day 0. Grip strength, rotarod, and body composition were measured at 16 weeks. At 18 weeks, intraperitoneal injections were performed with either tamoxifen (n=8 tau, 11 YFP) or corn oil (n=7 tau, 7 YFP) to delete the core clock gene Bmal1 exclusively in skeletal muscle. Brains were harvested at 24 weeks. Soluble and insoluble tau were biochemically measured after a sarkosyl extraction protocol. Immunohistochemistry was performed. An additional cohort of wildtype C57BL/6 mice were intracerebroventricularly injected with AAV‐P301L human tau (n= 11) and the empty AAV construct (n= 10). Grip strength was measured at 10 and 12 weeks.ResultsGrip strength was reduced at 16 weeks in the mutant tau treated iMSBmal1KO mice, two weeks before induced muscle weakness, and 10 weeks before NFTs are reported in this tauopathy model. Insoluble tau was detected biochemically at 24 weeks. Grip strength was reduced in tau treated wildtype mice at 10 and 12 weeks.ConclusionsChanges in grip strength preceded NFT formation in this tauopathy model in both iMSBmal1 transgenic and wildtype mice. This suggests that a) muscle weakness may serve as a biomarker and b) that disrupted skeletal muscle health may be capable of contributing to tauopathy progression.
[18F]PI‐2620 PET in four‐repeat tauopathies: a preliminary study
Authors: Soleimani‐Meigooni David N. , Thomas Wesley P. , Brendel Matthias , Vento Stephanie , Heuer Hilary W. , Ljubenkov Peter A. , Rojas Julio C. , Chen Miranda , Iaccarino Leonardo , La Joie Renaud , Mundada Nidhi S. , Boeve Bradley F. , Grossman Murray , Dickerson Bradford C. , Irwin David J. , Litvan Irene , Pantelyat Alex , Tartaglia Carmela , Rabinovici Gil D. , Baker Suzanne L. , Boxer Adam L. 
Published: December 2022

AbstractBackgroundThere is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [18F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA).Method38 participants underwent amyloid and [18F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [18F]PI‐2620 was administered. [18F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS.ResultPatients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p < 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, rs < 0.44, p > 0.05 uncorrected).Conclusion[18F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.