bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computer‐administered neuropsychological assessment batteries: Validity, reliability, and user experience in an Australian sample of community‐living older adults in the CogSCAN Study
Authors: Kochan Nicole A. , Croot Karen , Crawford John D. , Allison Karen C , Rossie Matilda , Brodaty Henry , Lam Ben C. P. , Henry Julie D , Lee Teresa , Draper Brian , Close Jacqueline , Ong Min Yee , Bentvelzen Adam , Sachdev Perminder S. 
Published: December 2022

AbstractBackgroundAccess to a “gold‐standard” in‐person neuropsychological assessment to detect cognitive decline in older adults using paper‐and‐pencil (PnP) tests is limited. Computerized neuropsychological assessments (CNAs) potentially provide lower cost, scalable, accessible alternatives but critical psychometric data on the validity, reliability and user‐experience of CNAs in older adults are lacking.Method263 community‐dwelling individuals aged 60 years and older without dementia were assigned to complete two CNA batteries and one standardised neuropsychological assessment with 14 PnP tests, one week apart (Construct Validity Group) or two CNAs on two occasions, one month apart (Reliability Group). CNAs were self‐administered under supervision. Orders of CNA batteries, and of CNA and PnP sessions were counterbalanced (Figure 1). Participants completed questionnaires evaluating their experience after each CNA battery. Four CNA batteries were investigated: Cambridge Brain Sciences (CBS), CANTAB, Cogstate, and NIH Toolbox, each containing 5—8 tests; key variables recommended by the test developers were examined (Table 1).ResultParticipant characteristics are summarised in Table 2. Concurrent Validity: Modest correlations (r’s of 0.3‐0.6) between CNA and PnP measures were observed for all CNA batteries, generally aligning with corresponding domains, though notably reflecting the multidimensionality of cognitive measures (Table 3); the strongest associations (r ≥0.5) were with attention and processing speed measures across three CNA batteries, also NIH Toolbox vocabulary, memory and executive measures.Reliability: One‐month test‐retest reliabilities of individual measures were variable (Table 4); across three batteries some, typically speed measures, had reliability coefficients ≥ 0.7.
User Experience: Completion rates were high (96‐100%). Usability ratings of CNAs were high on average, although variability was large for CBS (Figure 2). Ratings of acceptability were lower than usability, though on average, participants endorsed CNAs positively.ConclusionA selection of computerized measures demonstrated adequate psychometric standards for concurrent validity with ‘gold standard’ in‐person neuropsychological assessments, alongside good usability and acceptability, though test‐retest reliability was low for many measures. CogSCAN’s comprehensive comparative data will guide researchers in selecting the most suitable CNA measures for older adults. Work in progress is investigating CNA validity, reliability and user experience in older adults with cognitive decline and culturally and linguistically diverse older adults.
Assessing synaptic integrity in Alzheimer’s brain with UCB‐J
Authors: Kumar Amit , Nordberg Agneta K 
Published: December 2022

AbstractBackgroundSynaptic loss is an eminent feature of Alzheimer’s disease (AD). Synapses critical for neuronal transmission are regulated by synaptic vesicles (SV), which expresses an integral transmembrane protein called SV protein 2A (SV2A) throughout the brain. Notably, reduced SV2A expression has been implicated in AD and other proteinopathies. UCB‐J is a recently developed PET‐tracer, which target SV2A, to study synaptic integrity in different neurological disorders. Though several UCB‐J in vivo PET studies have been published in AD, there have been some discrepancies between the findings. Many of these studies indicated potential correlations between tau deposition, atrophy, cognitive‐impairment, and loss of UCB‐J binding. Based on these in vivo observations, we found it of utmost relevance to perform extensive pre‐clinical validation of UCB‐J in AD brains with postmortem brain imaging techniques.MethodWe performed radioligand binding assays (saturation and competition) alongside large brain section autoradiography in AD and control brains.Result
3H‐UCB‐J competition studies with unlabelled‐UCB‐J showed one‐binding site (IC50: ∼ 10 nM) in the frontal cortex (FC) of AD and control brains. Saturation studies in FC region of AD and control brains showed much higher specific binding in synaptosomal membrane P2‐fraction (Bmax: 5.8 ‐ 8.7 pmol/mg, Kd ∼ 5.0 nM) as compared to brain homogenates (Bmax: 0.09 ‐ 0.18 pmol/mg, Kd ∼ 4.0 nM). P2‐fraction saturation binding study clearly highlighted the loss of UCB‐J binding in FC of AD brain as compared to control brain. In contrast, large brain hemisphere section autoradiography incubated with 3H‐UCB‐J showed unexpectedly higher regional binding in AD brain sections as compared to control, motivating further mechanistic pre‐clinical validation with other synaptic markers in AD and other proteinopathies.ConclusionOur findings explicitly demonstrated high specificity of UCB‐J for SV2A in AD and control brains. UCB‐J specific binding was much higher in P2‐fraction than brain homogenate (P2‐fraction > brain homogenate) and highlighted the expected loss of UCB‐J binding in AD brain. Competition and saturation binding studies complemented each other and showed only one‐binding site with nM‐affinity in AD and control brains. Unanticipated high UCB‐J binding in AD brain in autoradiography studies indicate potential interaction with other brain tissue component, warrant further investigation.
Do the extracellular vesicles excreted during neuronal cell death play a neuron‐glia signalling role in neurodegeneration.
Authors: Barnard Jodi Louise 
Published: December 2022

AbstractBackgroundDuring neurodegeneration, dying neuronal cells may trigger neuroinflammatory responses or inform neighbouring glial cells of their dying status by releasing extracellular vesicles. Karyoptosis is a novel cell death caused by a block in autophagy which was first discovered in a dentatorubral‐pallidoluysian atrophy (DRPLA) mouse model. During karyoptosis cells exhibit signs of nucleophagy (nuclear breakdown) and vesicle expulsion. Understanding the molecular underpinnings of neurodegeneration is important for informing possible therapeutic intervention. Our hypothesis is that dying neurons release vesicles which are phagocytosed by microglia, and this leads to an inflammatory response.MethodUsing ex vivo samples from the DRPLA mouse model, immunofluorescence, and confocal imaging, we studied the phenotype of microglia pathologically. We used disease‐relevant brain regions with high levels of karyoptosis, such as the dentate nucleus. To further understand the microglial response and visualise the likely phagocytosis of these vesicles, we are also using a human neuroblastoma cell line to induce karyoptosis and purify the released vesicles for application to cultured BV2 microglia‐like cells.ResultOur initial data shows that more microglia are present in pathological areas with high karyoptosis activity in the DRPLA mice. Analysis of these microglia revealed an increased cell soma size, decreased branch length, and decreased intersections per microglia in the DRPLA model, all of which suggest the increased activation and de‐ramification of microglia in DRPLA mice.ConclusionThese findings indicate differences in the total number, activity, and overall phenotype of microglia in areas with high karyoptosis in this DRPLA model. This suggests that the vesicles released during this cell death process may be influencing microglia. Future work will focus on replicating these findings in vitro. Extracellular vesicles collected from human neuroblastoma will be applied to cultured microglia to visualise the uptake of vesicles, decode their contents, and further characterise any microglial response. This work will help further the understanding of how neuron‐glia signalling contributes to neurodegeneration.
C‐reactive protein (CRP) blood concentrations associate with reduced global system segregation in middle‐aged individuals
Authors: Bartrés‐Faz David , Wang Yunpeng , Cabello‐Toscano María , Cattaneo Gabriele , Solé‐Padullés Cristina , Vaqué‐Alcázar Lídia , Mulet‐Pons Lídia , Sánchez Javier Solana , Tormos‐Muñoz Josep Mª , Drevon Christian A , Gundersen Thomas , Fjell Anders M , Walhovd Kristine B 
Published: December 2022

AbstractBackgroundHigh concentrations of circulating C‐reactive protein (CRP) have been related to poorer cognition in adults (Lewis et al. Age Ageing. 2021;50:2199). Within the Lifebrain consortium (Walhovd et al. Eur Psychiatry. 2018;50:47), we recently reported overall lifespan associations between increased CRP and smaller hippocampal (HPC) volumes, albeit these could not be observed in one subsample of middle‐aged individuals (Wang et al. Brain Behav Immun. 2022;100:243). Here we hypothesized that functional brain integrity measures would be sensitive to predict CRP levels in this group. We focused on global system segregation (SyS) a graph theory‐based metric which quantifies the extent to which major functional networks are segregated from each other.MethodWe included 336 volunteers (mean age 53.8; SD: 7.1; 47.9% women) from the Barcelona Brain Health Initiative (Cattaneo et al. Front Aging Neurosci. 2018;10:321). High‐sensitive CRP (hsCRP) concentrations were determined through dry blood samples and log10 transformed (Wang et al. Brain Behav Immun. 2022;100:243). Adjusted HPC volumes were estimated from T1‐wheigthed 3T MRI acquisitions (Raz et al. Cereb Cortex 2005;15:1676). SyS values were calculated (Ewers et al. Brain. 2021;144:2176) from 100 nodes defined by the Schaefer‐Yeo atlas (Fig 1a). Multiple linear regression investigated the associations between age, gender, cognitive function (MMSE and episodic memory), HPC volumes, APOE status and SyS as predictor variables and hs‐CRP as the dependent measure.ResultIn the adjusted model only SyS (β= ‐0.56, p<0.05) and APOE (β= ‐0.21, p=0.003) predicted hsCRP concentrations. Global SyS was negatively related to hsCRP (Fig 1b). As in Wang et al (2022), APOE E4 carriers (N=71; mean:‐0.43; SD=0.62) exhibited lower CRP circulating levels than non‐E4 bearers (N=265; mean: ‐0.20; SD=0.51; t=3.23, p<0.001), however there were no differences in SyS according to APOE genotypes (t=0.95, p=0.34).Conclusionhs‐CRP blood concentrations were predicted by global segregation of functional networks in absence of HPC volume or cognitive status effects. As such, blood derived hsCRP levels may represent an early indicator of middle‐age individual variations in a measure recently reported to predict future cognitive decline (Chan et al. Nat Aging 2021;1:1053) and represent a cognitive resilience mechanism in the face of AD pathology (Ewers et al. Brain. 2021;144:2176).
The Effects of Multiple Doses of Lomecel‐B, Longeveron’ s Cell‐based Therapy, on Alzheimer’s disease: Study Design and Rationale of this Phase 2a Multi‐ center Clinical trial.
Authors: Ramdas Kevin N. , Brody Mark , Herskowitz Brad , Agronin Marc , Ruiz Jorge G , Fuquay Ana , Rodriguez Savannah , Mehranfard Danial , McClain‐Moss Lisa , Gincel Dan , Hare Joshua M. , Oliva Anthony A. 
Published: December 2022

AbstractBackgroundLomecel‐B is an allogeneic medicinal signaling cell (MSC) formulation under clinical investigation for Alzheimer’s disease (AD). We have successfully completed a double‐blinded, placebo‐controlled Phase 1 safety trial, in which Lomecel‐B was found to be safe and tolerable in patients with mild AD, and yielded preliminary evidence supporting potential efficacy. Mechanistically, this included evidence of pro‐vascular and anti‐inflammatory activities. Extending upon these promising results, we present the rationale and design of the next‐phase 2a trial in this program.MethodThe primary objective of this double‐blinded, randomized, and placebo‐controlled Phase 2a trial is to evaluate the safety of multiple doses of Lomecel‐B versus a single dose or placebo. Forty‐eight participants will be equally randomized to four study arms, and will receive intravenous infusions at Weeks 0, 4, 8, and 12, and followed up through Week 39 post‐first infusion. Arm 1 will receive four intravenous infusions of placebo. Arm 2 will receive one infusion of low‐dose Lomecel‐B (2.5×107 cells) followed by three infusions of Placebo. Arm 3 will receive four infusions of low‐dose Lomecel‐B. Arm 4 will receive four infusions of high‐dose Lomecel‐B (108 cells). Enrolled subjects will undergo a multi‐tiered screening process (clinical evaluation, blood‐work, MRI, and PET). Major enrollment criteria are mild AD with confirmatory beta‐amyloid tracer PET, 60‐85 years of age, and a MMSE score of 18‐24.Safety will be monitored by examining vital signs, physical and neurological exams, laboratory tests (hematology, coagulation, blood chemistry, and urinalysis), and neuroimaging. The secondary objectives are to assess the effects of Lomecel‐B on the cognitive function, and pro‐vascular and anti‐inflammatory biomarkers. Exploratory objectives include neurocognitive, neuropsychiatric, quality‐of‐life, activities‐of‐daily‐living, frailty status, and biomarkers assessments.ResultThis multicenter phase 2a trial has been allowed to proceed by FDA, is IRB approved, and actively enrolling.ConclusionThis trial is designed to obtain safety and preliminary efficacy data on the effects of a multiple doses of Lomecel‐B on mild AD, with an emphasis on biomarkers related to proposed mechanisms of action (MOAs). We anticipate this trial will have complete enrollment by early 2023, and preliminary safety findings available soon thereafter.
Heart failure associations with cerebral structure: combined analysis from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the SECRET‐II trial of heart failure with preserved ejection fraction
Authors: Schaich Christopher L. , Mujtaba Mohammadtokir , Hugenschmidt Christina E , Jung Youngkyoo , Bertoni Alain G. , Shah Sanjiv J. , Chen Haiying , Kitzman Dalane W. , Hughes Tim M. 
Published: December 2022

AbstractBackgroundHeart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in adults 65 and older, but little is known about its relationship with neurocognitive outcomes. We compared brain magnetic resonance imaging (MRI) markers in older adults across stages of preclinical HF and clinical HFpEF.MethodAll participants completed baseline HF evaluation of risk factors, echocardiography, electrocardiography, and cardiopulmonary exercise by ACC/AHA stages; 3T brain MRI; and cognitive testing using harmonized protocols and teams at Wake Forest School of Medicine (2016‐2021). MESA participants without symptomatic HF were assigned to: Stage 0, no risk factors for HF (n = 30); Stage A, risk factors for HF without cardiac structural abnormalities (n = 111); or Stage B, abnormal cardiac structure or function without HF symptoms (n = 66). Participants with stable clinical HFpEF were recruited from the SECRET‐II trial and assigned to Stage C (n = 43). We compared intracranial volume‐adjusted total gray matter (GM), hippocampal, and white matter hyperintensity lesion (WMH) volumes across HF stages using multivariable linear regression adjusted for age, sex, and race, and report standardized least‐squares (LS) means estimates in SD units with 95% CI and Dunnett‐adjusted p‐values (referent = Stage 0).ResultThe combined sample (N = 250) was aged 72±7 years, 64% female, 47% white, and completed 15±3 years of education. Participants with Stage C HFpEF were younger (69±5 vs. 73±7 years, p<0.001) and more likely to be female (85% vs. 59%, p<0.001) than participants in lower stages. Stage B and Stage C participants had significantly lower GM volume than Stage 0 (0.38 [0.07, 0.69] vs. ‐0.12 [‐0.33, 0.09] in Stage B, p = 0.019; ‐0.36 [‐0.64, ‐0.09] in Stage C HFpEF, p = 0.001; Figure A), and Stages A‐C had non‐significant trends toward lower hippocampal volume (Stage 0 vs. Stage C p = 0.053; Figure B) and greater WMH volume (Stage 0 vs. Stages A‐C combined p = 0.073; Figure C). There were no interactions by sex or race.ConclusionIn this combined analysis from harmonized and diverse cohorts, higher HF stages and clinical HFpEF were associated with significantly lower gray matter volume. Observed trends toward lower hippocampal volume and higher WMH volume in HF Stages A‐C warrant further investigation.
Frequency of TAR DNA‐binding protein 43 (TDP‐43) increases linearly with age in the demented and non‐demented elderly population
Authors: Carlos Arenn F. , Tosakulwong Nirubol , Weigand Stephen D , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Murray Melissa E. , Dickson Dennis W. , Josephs Keith A 
Published: December 2022

AbstractBackgroundTDP‐43 is a nuclear RNA‐binding protein involved in various neurodegenerative diseases, including Alzheimer’s Disease (AD), and normal aging. It strongly affects cognition and memory loss in AD. Concomitant TDP‐43 pathology increases the likelihood of being cognitively impaired at death.MethodMayo Clinic has amassed a large database with 1072 study participants with known TDP‐43 pathology status, who were prospectively recruited and followed in the Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Group. All underwent neurologic, genetic, and neuropathologic evaluations. Amygdala sections immunostained with antibodies against TDP‐43 were screened for TDP‐43‐immunoreactive inclusions and successively staged using the Josephs staging scheme. The frequency of TDP‐43 pathology by age at death was estimated using logistic regression with age modelled using a restricted cubic spline. Models were fit for all cases including the subset of 581 cases with dementia.ResultOur cohort was predominantly White (99%) with median age at death of 87 years (IQR: 80‐92) and relatively even sex distribution (52% female). About 55% had Braak stage V‐VI and 61% had Thal amyloid phase ≥3. Fifty‐two percent met criteria for intermediate‐high probability AD. TDP‐43‐immunoreactivity (TDP‐43+) was detected in 44% with median TDP‐43 stage of 3 (IQR: 1‐5), and in 54% with a median stage of 3 (IQR: 2‐5) in those with dementia. TDP‐43+ frequency increased approximately linearly with age at death. At 70 years at death, an estimated 30% (95% CI: 25–35) of the cohort was TDP‐43+ versus 33% (CI: 27–40) of those with dementia. By 90 years at death, 49% (CI: 45–52) of the overall cohort and 68% (CI:62‐73) of those with dementia were TDP‐43+.ConclusionThe results from our large cohort confirm that TDP‐43 pathology frequency increases in elderly White study participants with age of death, independent of cognitive status. Furthermore, TDP‐43 pathology frequency increases to a greater degree with age in those with dementia. Given the clear links between TDP‐43 and impaired cognition, the contribution of TDP‐43 to an individual’s cognitive impairment is likely to increase with age; a dynamic with significant public health consequences given our aging population.
Leveraging American football helmet accelerometer data to estimate associations between cumulative repetitive head impact exposure and chronic traumatic encephalopathy
Authors: Nair Evan S , Daneshvar Daniel H , Rasch Abigail , Abdolmohammadi Bobak , Saltiel Nicole , Uretsky Madeline , Shah Arsal , Baucom Zachary H. , Martin Brett M , Palmisano Joseph , Cherry Jonathan D , Alvarez Victor E. , Huber Bertrand R. , Alosco Michael L , Tripodis Yorghos , Crary John F. , Stein Thor D. , McKee Ann C. , Mez Jesse B. 
Published: December 2022

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players’ athletic careers and CTE pathology.Method656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors’ career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death.ResultThe mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p’s<.001) and severity of CTE (p’s<.001). Based on ROC analyses, CHII‐R (AUC=0.765, p<.001) and CHII‐G (AUC= 0.758, p<.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2).ConclusionAmong former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology.