bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF sTREM2 predicts markers of blood brain barrier integrity and amyloid beta metabolism independent of APOE‐ε4 status
Authors: Weiner Rebecca L. , Dumitrescu Logan , Blennow Kaj , Zetterberg Henrik , Gifford Katherine A. , Pechman Kimberly R. , Jefferson Angela L. , Hohman Timothy J. 
Published: December 2021

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor commonly studied for its roles in microglial regulation and amyloid beta deposition in Alzheimer’s disease (AD). Its soluble form, sTREM2, measurable in cerebrospinal fluid (CSF) is a novel biomarker of microglial activity. CSF sTREM2 has been associated with AD progression and biomarkers of neurodegeneration (for which tau is one), while associations with amyloid‐β biomarkers have been inconclusive. Furthermore, cerebrovascular injury commonly co‐occurs with AD, contributes to clinical progression, and drives microglial activation through independent signaling cascades. However, sTREM2 associations with cerebrovascular pathology have been largely unexplored.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6.33 , male=67%, mild cognitive impairment=47%), associations between baseline CSF sTREM2 concentrations (measured using an in‐house immunoassay) and CSF AD biomarkers (Aβx‐42, Aβ1‐42, Aβx‐40, total tau, and phosphorylated tau) and cerebrovascular injury (CSF/plasma albumin ratio) were assessed using linear regression. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status.ResultHigher baseline CSF sTREM2 concentrations predicted an increased CSF/plasma albumin ratio, indicative of compartmental blood brain barrier (BBB) permeability (p=1.36e‐07). Additionally, higher levels of sTREM2 predicted increased CSF protein levels of Aβx‐40 (p=1.53e‐09), and Aβx‐42 (p=7.73e‐03), but not Aβ1‐42 (p=0.26) levels, indicating a possible role for the TREM2 axis in regulating or responding to amyloid beta species composition. We also replicated previous associations between higher CSF sTREM2 and higher CSF tau (p=6.14e‐07) and p‐tau (p=1.82e‐08).ConclusionWe report a novel association between sTREM2 and a marker of BBB integrity, highlighting opportunities for further investigation of the TREM2 axis with cerebrovascular injury. We also report a novel association between sTREM2 and amyloid‐β abundance that does not seem to reflect amyloid burden in the brain, and we replicate an sTREM2 association with markers of neurodegeneration. Future work will seek to better characterize the timing of sTREM2 changes relative to markers of BBB dysfunction and AD pathogenesis.
Instrumental variable meta‐analysis of the effect of systolic blood pressure reduction on cognitive change: Evidence from randomized trials of antihypertensive therapies
Authors: Ackley Sarah F , Zimmerman Scott C , Pamula Meenakshi , Peterson Rachel L , George Kristen M , Whitmer Rachel A , Corrada Maria M , Hughes Tim M , Glymour Maria M 
Published: December 2021

AbstractBackgroundPrevious meta‐analyses of trials of antihypertensive drugs have only evaluated the effect of randomization to treatment on cognition, without accounting for duration of treatment or degree to which treatment decreased blood pressure. We assumed that any cognitive benefit of antihypertensive treatment would be proportional to the magnitude of change in systolic blood pressure (SBP) achieved and the duration of follow‐up during which a lower SBP was sustained.MethodWe aggregated data from randomized trials of antihypertensive drugs which reported data on change in both SBP and the Mini Mental Status Exam (MMSE). We estimated the effect of decreasing SBP on annual cognitive change for each trial using an instrumental‐variable approach. This was determined for each trial separately using maximum‐likelihood estimation, assuming differences in cognitive change between treatment arms was proportional to the difference in SBP between the groups and the duration of follow‐up. For interpretability, we expressed effects as difference in MMSE per 10mmHg change in SBP per year. Results were combined using a fixed‐effects meta‐analysis.ResultOut of 8 trials (N=70,734; follow‐up: 2.3 to 6 years), 7 suggested benefit of SBP reduction on cognitive change, with 2 of these 8 trials reaching statistical significance. No trials showed statistically significant cognitive harm. The pooled estimate suggested that a 10mmHg decrease in blood pressure slowed MMSE decline by 0.033 (95% CI: 0.023 to 0.044) points per year.ConclusionRandomized‐controlled trials of antihypertensives indicate that decreases in SBP slow cognitive decline. Even with a clinically substantial decrease in blood pressure, the average long‐term effect appears likely to be modest. Instrumental‐variable meta‐analysis can be used to provide an estimated annual benefit per change in SBP, allowing results from trials of heterogeneous treatments to be put on the same scale. Such estimates have more clinical relevance than standard intent‐to‐treat estimates.
Towards a better characterization of dementia in northeast Brazil: Numbers from a reference center in Recife
Authors: Mota Andreia Braga , Lins Maria Eduarda Pires , Lima Silva , de Oliveira Xavier Ramos Julia , Souza Ana Rita , Zacarias Bruno Felipe Vieira , Ramos Bruno , da Silva Rodrigo Cavalcanti Machado , Brandao Simone Cristina Soares , Barbosa Breno José Alencar Pires 
Published: December 2021

AbstractBackgrounddementia numbers are increasing rapidly with a substantial contribution from low and middle‐income countries. There’s a limited number of reports in Brazil, mostly modest initiatives from south‐eastern, more developed areas, such as the Tremembe study which reported a 17,5% prevalence of dementia in 630 elderly subjects. With a population of approx. million individuals, the metropolitan region of Recife is among the largest cities of Northeast Brazil, a region of profound social disparities and high prevalence of low‐literacy.Methodthis is a single‐center, descriptive and health records‐based analysis of patients evaluated in the Dementia outpatient clinic of the Neurology and Neurosurgery Unit at the Federal University of Pernambuco in the timeframe between 2018 ‐ 2019.Result60 patients had their data available and were included for descriptive analysis. Mean age was 69 years old (+ 7.6 SD) with 62% of women and 6 years of formal education. 46% of all cases were referred for evaluation from neighboring cities and states. The mean Mini‐mental state examination in the first consultation was 15/30 and patients had a significant burden of functional impairment with a mean Pfeffer score of 21/30 (+ 9.8 SD). Hypertension (40%), Diabetes (71%) and Anxiety (85%) were frequent comorbidities. Regarding access to neuroimaging methods, 75% subjects had access to either CT (16/60) or MRI (39/60) and 12 individuals were further evaluated with molecular neuroimaging (SPECT and/or FDG‐PET). Formal neuropsychological evaluation, CSF biomarkers and advanced amyloid/tau imaging were not available. Alzheimer’s dementia was diagnosed in 45% individuals and another 45% had criteria for mixed vascular and degenerative conditions. 18% presented with other neurodegenerative syndromes such as FTD and Lewy bodies dementia. The mean follow up time in our service was of 19.8 months.Conclusionpatients referred for evaluation were mostly in moderate to advanced stages of dementia, with a significant prevalence of mixed‐type and non‐Alzheimer’s pathologies. This data could suggest a referral bias and poor access to specialized clinics. Despite a modest sample size and heterogeneous data, the present study may contribute towards a better characterization of dementia numbers in Northeast Brazil.
Development and pilot data for an app‐based cognitive assessment for detecting memory and executive functioning changes in aging and pre‐clinical AD
Authors: Mechanic‐Hamilton Dawn , Lydon Sean , Miller Alex , Halberstadter Kimberly , DiCalogero Michael , Wolk David A. 
Published: December 2021

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 psychometric properties of app‐based memory and executive functioning tasks included in the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical Alzheimer’s Disease (AD).MethodThe mCAPP includes three gamified tasks: (1) a memory task that includes learning and matching hidden card pairs and incorporates 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 and incidental learning components. The cohort is also assessed with the NACC UDS3 or T‐Cog neuropsychological battery within six months of the mCAPP testing. Participants included nine older adults (44% female; age=73.9±5.4, years of education=16.6±2.3; 77% Caucasian) with normal cognition who are enrolled in the Penn ADRC cohort. In addition to in‐lab testing, a cohort of participants will also use the mCAPP at home for two weeks and remotely collected data will be presented.ResultOn the brick drop task, performance was significantly slower and less accurate on the inhibition task compared to the word and color identification tasks (p<.05). On the space imposters task, increased reaction time and decreased accuracy was observed as the number of digit‐symbol pairs increased, but the difference was not significant. Correlations with UDS 3.0 measures showed significant relationships between the brick drop word/color identification and trail making test A (TMTA) and category fluency (p<.05) as well as between the response inhibition task and category fluency and olfactory function (p<.05). The space imposters task correlated with the TMTA (p<.05). Data will also be presented on home‐based collection of all three mCAPP tasks.ConclusionThis pilot study shows feasibility and validity of app‐based tests of executive functioning and will also examine detection of subtle cognitive differences associated with preclinical AD through burst testing, home‐based data collection and on all three mCAPP measures.
Associations of smoking and biohazard exposure with Alzheimer’s disease brain and plasma biomarkers in early old age
Authors: Franz Carol E , Whitsell Nathan , Qin Yongmei Amy , Tu Xin M , Kremen William S 
Published: December 2021

AbstractBackgroundCigarette smoking and environmental exposure to other biohazardous chemicals and substances are associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Their associations with Alzheimer’s Disease (AD)‐related brain indicators of structural integrity and plasma biomarkers are less often examined.MethodAt average age 68 (range 61‐73), 1118 male participants in the Vietnam Era Twin Study of Aging (VETSA) self‐reported on cigarette smoking habits which we used to calculate pack years. Participants also self‐reported on prolonged or severe exposure to herbicides/pesticides, metal dust, Agent Orange, or other biochemical hazards. Using MRI data collected at average age 68 from approximately 470 participants, we examined a published an AD‐Brain signature based on thickness in 7 AD‐related cortical regions and hippocampal volume. We created a novel an AD‐Mean Diffusivity (AD‐MD) signature based on those same regions (higher AD‐MD scores being worse). We also examined a predicted brain age difference score (PBAD), an indicator of global accelerated brain aging. Plasma abeta42, abeta42/40 ratio, and total tau (t‐tau) were assayed using the Quanterix Simoa system. Multivariable analyses controlled for age, ethnicity, education, and the random effect of family (i.e., twin pairs).ResultsSmoking pack years at age 68 were negatively associated with AD‐Brain Signature (p<0.0001) and PBAD (p=0.0013). Pack years (p=0.0001) and Agent Orange (p=0.047) were positively associated with AD‐MD Signature. T‐tau was positively significantly associated with smoking (p=0.0039) and Agent Orange (p=0.004).ConclusionsHeavier lifetime smokers had brains more similar to brains of adults with AD, showed accelerated brain aging, and had higher levels of t‐tau in early old age. All of these are indicators of higher risk for AD. Exposure to Agent Orange, a toxic herbicide, was also related to poorer structural brain integrity and t‐tau. Smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority. The results suggest that more attention should be paid to potentially toxic environmental exposures that may increase risk for AD and other health conditions.
Cognitive reserve: Evaluating the relationship between WASI‐II Matrix Reasoning and tau accumulation using [18F]MK6240 in monolingual and bilingual individuals
Authors: Stevenson Alyssa , Rahmouni Nesrine , Stevenson Jenna , Tissot Cécile , Therriault Joseph , Lussier Firoza Z , Bezgin Gleb , Chamoun Mira , Kang Min Su , Benedet Andréa Lessa , Pascoal Tharick A. , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundCognitive reserve (CR), a protective mechanism, allows for sustained cognitive functioning in older adults with greater experiential resources. Bilingualism, an indicator of greater cognitive reserve, has been found to preserve cognitive performance in older adults despite significant disease pathology. While the association with amyloid has been well acknowledged, the effect of tau is still under investigation. In the present study, we aim to evaluate the effect of bilingualism on individuals’ cognition and tau load.MethodThis study was conducted in 331 individuals (213 cognitively unimpaired (CU)) and 116 cognitively impaired (CI; 81 MCI and 35 AD) from the TRIAD cohort. 40% of the study participants were monolingual. Wechsler Abbreviated Scale of Intelligence ‐ Second Edition (WASI‐II) was used to measure cognitive ability and reasoning in individuals. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post‐injection, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the WASI‐II score and the PET markers [18F]MK6240, correcting for age, sex, education, APOE, diagnosis and RFT was used to account for multiple comparisons.ResultOur data showed that bilingual individuals demonstrated significantly higher scores on the Wechsler Abbreviated Scale of Intelligence ‐ Second Edition (WASI‐II) in comparison to monolingual individuals. A negative association between the cognitive score and tau accumulation was found in both monolingual and bilingual groupings. In the bilingual individuals, the associated regions were precuneus area, medial and lateral lobes. In the monolingual group, the associated regions were right frontal lobe, parietal lobe and cuneus areas.ConclusionOur results demonstrate that bilingual individuals are more resilient to the accumulation of tau; shown in higher scores in cognitive ability and reasoning despite having more regions affected than their monolingual counterparts.
Ultrasound‐assisted lumbar puncture in Alzheimer's disease and related disorders research: A pilot study
Authors: Goldfarb Danielle , Viramontes Daniel , Callan Michael , Liebsack Carolyn , Goddard Molly , Reade Marina , Malek‐Ahmadi Michael H. , Weidman David , Tsai Po‐Heng , Wu Teresa , Grimsman Jason , Atri Alireza 
Published: December 2021

AbstractBackgroundLumbar puncture (LP) and collection of cerebrospinal fluid (CSF) are increasingly essential in Alzheimer’s disease and related disorders (ADRD) research. Ultrasound‐assisted lumbar puncture (Us‐LP) has not been studied in ADRD research and could improve LP success rates through more accurate anatomical site selection, precise planning, and individualized intra‐procedure adjustments. This pilot study assessed the feasibility, utility, and tolerability of Us‐LP in ADRD research.MethodLP clinician‐researchers from ADRD centers completed simulation‐based Us‐LP training using the Philips Lumify system, a portable hand‐held transducer connecting to a tablet. Thereafter, clinician‐researchers had the option to use Us‐LP during research LPs. Participant demographics and attitudes about LP were obtained prior to LP. The clinician‐researchers completed a post‐LP questionnaire assessing procedural details, choices, and LP performance.ResultFollowing training, four clinician‐researchers implemented Us‐LP into their practices. Between August 2019‐March 2020, 58 research participants (Table 1) underwent LP. Clinician‐researchers used Us‐LP on 37/58 (64%) participants. Compared to conventional‐LP, Us‐LP choice was associated with higher/highest BMI and older/oldest age categories (Tables 2,3). A U‐shaped relationship between BMI and Age in Us‐LP choice was noted (Figure 1). Us‐LP was also the choice in all who were most obese; in most who were moderately overweight‐to‐obese; and in all who were oldest and moderately overweight‐to‐obese. There were no differences between those receiving conventional‐LP compared to US‐LP with respect to participant history of chronic pain or headache, prior attitudes about LP, success rate, or post‐LP complications.ConclusionTraining clinician‐researchers in Us‐LP and implementing portable hand‐held Us‐LP for ADRD research studies demonstrated feasibility, utility and tolerability. Pilot data indicated that clinician‐researchers were more likely to use Us‐LP in perceived challenging cases including the most obese, and those oldest and moderately overweight‐to‐obese. More studies are needed to determine if using Us‐LP in ADRD research will improve LP success rates, tolerability, and participant willingness to undergo LP. Improving these factors will accelerate CSF biomarker, aging and ADRD research. Furthermore, with potential availability of AD disease‐modifying treatments in the coming years, LP and CSF collection are likely to play a crucial role in patient selection for treatment.
World Trade Center neurotoxic exposures are associated with elevated plasma amyloid, total‐tau and neurofilament light in responders
Authors: Diminich Erica D. , Clouston Sean A.P. , Vega Irving , Gandy Samuel , Bromet Evelyn , Luft Benjamin J. 
Published: December 2021

AbstractBackgroundThe collapse of the World Trade Center towers on September 11th 2001 resulted in a 16‐acre environmental toxic disaster. More than 1.2 million tons of construction material and carcinogens including polycyclic aromatic hydrocarbons, gypsum and metals coalesced, resulting in a highly alkaline dust cloud. Police and Law enforcement were among the most highly exposed group.MethodIn this retrospective cohort study, we included a subset of high exposure Responders (n=424) with cross sectional plasma samples of amyloid β40, amyloid β42, total‐tau, neurofilament light and a baseline evaluation of cognitive functioning assessed with the Montreal Cognitive Assessment (MoCA) to examine long‐term associations between WTC neurotoxic exposures (e.g. diesel exhaust, chemicals) with levels of proteins associated with neuropathological characteristics of Alzheimer’s disease and neurodegeneration. Spearman rho p values adjusted for multiple comparisons using the false discovery rate (FDR=0.05) examined associations with participant characteristics and plasma concentrations. Multivariate regressions ascertained independent effects of WTC neurotoxic exposures in predicting plasma biomarker concentrations.ResultResponders were on average 54.3 years at blood draw. Worse performance on the baseline MoCA was associated with higher levels of Aβ40. Plasma Aβ40 and NfL were inversely correlated with dust exposure, Aβ42 and ratio Aβ42‐40 were inversely correlated with total hours on site during 9/11‐9/14 and working in enclosed work areas was associated with higher concentrations of Aβ40 and lower concentrations of ratio Aβ42‐40. Diesel exhaust exposure predicted levels of Aβ40, total tau and NfL whereas early exposure predicted Aβ42 concentrations and dust exposure predicted ratio Aβ42‐40.ConclusionDifferences across inhaled neurotoxins and time of arrival may have differential long‐term effects on blood‐based protein biomarkers of neuropathology and brain health.
Age‐related ventricular expansion is not spatially concordant with MR‐visible periventricular white matter disease
Authors: Schwartz Daniel L , Hung Caela , Lahna David , Roese Natalie E , Woltjer Randy L , Silbert Lisa C 
Published: December 2021

AbstractBackgroundVentricular expansion (VE) is recognized as one of the earliest predictors of Alzheimer’s disease (AD); however, VE is also ubiquitous in normal aging. VE is reportedly caused by an ex vacuo mechanism, whereby tissue that appears as periventricular white matter hyperintensity visible on FLAIR MRI (PVH) experiences white matter (WM) atrophy and is subsumed by the lateral ventricles. This longitudinal study sought to test the degree to which the locations into which the ventricles expand were previously PVH as opposed to other tissues.MethodSixty‐five cognitively intact aged subjects each received 2‐6 T1‐weighted and FLAIR MRIs (Table 1). Each volume was rigidly coregistered to the baseline volume and gray matter (GM), lateral ventricular and PVH masks were generated for each timepoint. Ventricular growth masks (VG) were generated for each subsequent timepoint, each VG voxel was classified into either GM, PVH, or normal appearing white matter (NAWM) per overlap with previous timepoint tissue masks (Figure 1A).ResultOverall, average VE between visits was 5.1cm3. Over all subjects and visits, 4.2% of VE occurred where tissue had been previously marked as PVH, 16.1% of VE occurred where tissue had previously been marked as GM, including subcortical GM and the hippocampus, and 75.4% of VE occurred in tissue that had been previously marked as NAWM (Figure 1B).ConclusionThe results support an alternative explanation for VE; that is, that ex vacuo expansion of the lateral ventricles may not be the primary mechanism by which ventriculomegaly occurs in aging. One possible explanation is that unaltered CSF production in the face of dysfunctional CSF egress dynamics causes fluid stasis and reflux which increases pressure in the lateral ventricles.