bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel P75‐neurotrophin receptor antagonist, EVT901, reduces neuroinflammation in the TGFAD344 rat model of Alzheimer’s disease
Authors: Kang Min Su , Singleton Thomas A , Aliaga Arturo Aliaga , Massarweh Gassan , Gauthier Serge , Soucy Jean‐Paul , Kostikov Alexey , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundp75‐neurotrophin receptor (p75NTR) plays an important role in cell death in adults and has been associated with age‐related basal forebrain degeneration and in Alzheimer’s disease (AD). A recent study demonstrated the reduced pro‐inflammatory response and improvement of the functional outcome by blocking p75NTR following traumatic brain injury. Here, we aimed to test whether a novel p75NTR antagonist, EVT901, reduces neuroinflammation caused by AD pathology in the TgFAD344 rat model (Tg). We hypothesized that chronic administration of EVT901 will reduce the neuroinflammation caused by amyloidosis and hyperphosphorylated tau in the AD rat model.MethodTwo parallel longitudinal studies were conducted to characterize the progression of amyloidosis and neuroinflammation in TgFAD344 rat models (WT = 15 & Tg = 22) and the effect of EVT901 on neuroinflammation (Tg = 6). In the first study, animals underwent 60‐minute dynamic PET scans using [18F]AZD4694 for amyloid‐beta and [11C]PBR28 for neuroinflammation at 15 and 22 months. During the intervention study, animals received 1 mg/kg of EVT901 for 7 days via tail vein injection at 22 months. These animals also underwent [11C]PBR28 PET one day before and after the intervention. The 1 mg/ml drug was prepared in a 10% PEG‐400/90% saline solution. All PET images were matched to the respective MRI and normalized to the average template. [18F]AZD4694 BPND and [11C]PBR28 BPND were quantified based on the SRTM method using pons and midbrain as a reference region, respectively.ResultThe first study demonstrated a significant increase in [18F]AZD4694 and [11C]PBR28 uptake in both the hippocampus and neocortex in Tg compared to WT at baseline and follow‐up. TgFAD344 rats showed a longitudinal increase in [18F]AZD4694 and [11C]PBR28 binding in similar regions. Our second study demonstrated a significant reduction in [11C]PBR28 binding following the intervention in the hippocampus and parietotemporal cortex.ConclusionThis study demonstrated the amyloid pathology and neuroinflammation in the TgFAD344 rat model is captured by [18F]AZD4694 and [11C]PBR28 in vivo. Furthermore, a novel p75NTR antagonist, EVT901, reduces the neuroinflammation induced by AD pathophysiology. Blocking p75NTR can be considered a novel therapeutic target to reduce neuroinflammation in AD.
Neurocognitive mechanisms of spatial pattern separation in older adults with and without subclinical memory impairment
Authors: Márquez Freddie , Larson Myra S , Smith Anna , Miranda Blake A , McMillan Liv , Sathishkumar Mithra , Yassa Michael A. 
Published: December 2020

AbstractBackgroundDecline in episodic memory is a hallmark feature of Alzheimer’s disease (AD). Episodic memories can be operationalized as detailed conjunctions of items and their spatiotemporal context. Our past work has uncovered deficits in pattern separation of similar object memories in nondemented older adults. However, separation of similar spatial locations was only slightly impaired in this population. We hypothesized that these deficits may be more readily observable in individuals with subclinical memory impairment (assessed by verbal list recall). We also sought to determine the neural mechanisms by which spatial pattern separation deficits may manifest in older adults, focusing on the posterior parietal network which is involved in spatial processing and implicated in AD.MethodsTwo cohorts were included in this analysis. The first is a group of older adults with subclinical memory impairment (aged impaired – AI, age range: 61‐91; mean MMSE: 28.3 ± 1.50; mean RAVLT delayed recall: 9.66 ± 4.05). The second is a group of non‐demented older adults without memory impairment (aged unimpaired – AU; age range: 61‐86; mean MMSE: 28.1 ± 1.59; RAVLT delayed recall: 11.4 ± 3.01). Participants underwent whole brain high‐resolution resting state functional magnetic resonance imaging (1.5 × 1.5 × 2 mm resolution). They were also administered a battery of neuropsychological tests including tests of object and spatial pattern separation. We used performance on the RAVLT as the outcome predicted by performance on the discrimination tests. Specifically, we used delayed recall (DR), retroactive interference (RI), and percent forgetting (PF).ResultsBehaviorally, spatial, but not item, pattern separation performance predicted RAVLT DR, RI and PF scores in the AI group, but not the AU group. Functional connectivity analyses revealed that the connectivity of regions involved in spatial processing was significantly related to spatial pattern separation performance in the AI group, but not the AU group.ConclusionThese results validate the neurobiological basis of spatial pattern separation and suggest that such tasks can be used to detect early stages of AD, which has important implications for future diagnostics and treatment approaches.
Physical performance and cognition in an ethnically diverse cohort of oldest‐old individuals: The LifeAfter90 study
Authors: Whitmer Rachel A , Kawas Claudia H , Gilsanz Paola , Glymour M Maria , Mungas Dan M , DeCarli Charles , Mayeda Elizabeth Rose , Peterson Rachel , George Kristen M , Corrada Maria MM 
Published: December 2020

AbstractBackgroundIn prior studies of oldest‐old, poor physical performance is associated with cognitive impairment and risk of incident dementia, though this was in highly educated Caucasians. There is limited data on physical performance in diverse cohorts of oldest‐old. Identification of how physical performance is emblematic of frailty, health, and underlying pathology in representative populations is essential. Here we examine the cross‐sectional association between physical performance and cognitive function among the first 610 participants enrolled in LifeAfter90, an ongoing multiethnic oldest‐old cohort.MethodLifeAfter90 participants are long‐time members of the Kaiser Permanente Northern California Health Care System without a dementia diagnosis in their medical record at the time of recruitment. Evaluations are every six months and include a neuropsychological tests with the Spanish and English Neuropsychological Assessment Scales (SENAS) and physical performance measures (4‐meter walk and hand grip). The SENAS assesses domains of episodic memory, semantic memory, and executive function. 4‐meter walk was measured twice and averaged, handgrip was measured 3 times in the dominant hand and averaged. Using linear regression, we studied the cross‐sectional associations between the two physical performance measures and SENAS cognitive domains across racial/ethnic groups adjusted for age, gender and education.ResultAt baseline, participants were on average 92.6 years of age, 62% were women, 45% had a college education, and 68% were racial/ethnic minorities (Table 1). Overall, those with better grip strength and shorter walk time had better cognitive scores overall, and across all three domains. However, when stratifying by race these associations were not ubiquitous across all groups (Table 2). Namely, physical performance was only associated with executive function in Whites (Table 2); while physical performance was consistently associated with all three domains in Black, Latino, and Asian oldest‐old individuals.ConclusionIn this oldest‐old, racially/ethnically diverse cohort, physical performance is associated with better executive function, semantic memory and verbal episodic memory. Markers of frailty and health may have different meaning in diverse populations. Understanding differences in the association between physical performance and cognitive performance is crucial as they could reflect racial/ethnic differences on burden of pathology.
Insulin‐like growth factor‐1 (IGF‐1) is a biomarker of objective cognitive impairment but not subjective cognitive complaint in cerebral palsy
Authors: Ng Ted Kheng Siang , Tagawa Alex , Carollo James , Heyn Patricia C. 
Published: December 2020

AbstractBackgroundCognitive impairments are common in cerebral palsy (CP), however the evidence on the biological underpinnings of these impairments in CP has been scarce. Although insulin‐like growth factor‐1 (IGF‐1) is involved in cognitive deficits, its roles in cognitive functions in CP is unknown. We aimed to examine whether IGF‐1 is a biomarker of objective and self‐reported cognitive functions in CP.MethodBased on a priori screening criteria, we recruited 72 adults with CP for a cross‐sectional study conducted in an accredited clinical motion analysis laboratory at Children’s Hospital Colorado. Subtests of the Wechsler Adult Intelligence Scale (WAIS) were administered to assess multiple cognitive functions. We used The Patient‐Reported Outcomes Measurement Information System (PROMIS) to measure multiple domains of self‐reported health, including cognitive complaints. Biomarkers were measured by fasting blood tests. All biomarkers measured were log‐transformed to conform to statistical normality.ResultCP patients recruited had mean age=20 (SD=5.3), Male=47.2% and female=52.8%. Controlling for covariates, IGF‐1 correlated significantly with multiple cognitive domains, including delayed recall and recognition (declarative memory), block design (visual‐spatial and motor skills), and symbol search (processing speed). Furthermore, IGF‐1 correlated significantly with two other biomarkers, IL‐6 and IGF‐BP3, suggesting a network of insulin signaling and inflammatory biomarkers contributing to the objective cognitive impairment in multiple domains in CP patients. No association was found with subjective memory complaint, although IGF‐1 associated significantly with social roles and activities and physical function domains of PROMIS.ConclusionIn CP patients, IGF‐1 is a useful biomarker for objective cognitive impairment and other self‐reported functions, but not subjective cognitive complaint.
Longitudinal changes in A/T/N imaging biomarkers in early‐onset and late‐onset Alzheimer’s disease
Authors: Baek Min Seok , Cho Hanna , Kim Hankyeol , Lee Jae Hoon , Ryu Young Hoon , Lyoo Chul Hyoung 
Published: December 2020

AbstractBackgroundTo investigate the effect of onset‐age on the baseline and longitudinal changes in A/T/N imaging biomarkers in the Alzheimer’s disease (AD) spectrum.Method71 Aβ‐positive cognitively impaired (CI+) individuals and 67 Aβ‐negative cognitively unimpaired (CU‐) individuals completed longitudinal two PET scans (18F‐florbetaben for Aβ and 18F‐flortaucipir for tau) and magnetic resonance (MR) imaging studies with a mean follow‐up duration of two years. Based on the onset‐age of cognitive impairment, baseline and the annual change in standardized uptake value ratio (SUVR) values and regional volumes were compared between 15 early‐onset (EOCI+, onset < 65 yrs) and 56 late‐onset (LOCI+, onset ≥ 65 yrs) CI+ groups.ResultBaseline Aβ burden and its accumulation rate were not different between the EOCI+ and LOCI+ groups. When compared to LOCI+, EOCI+ group showed greater baseline tau burden and its accumulation rate in widespread cortical regions except for the medial temporal regions. Baseline volume of the entorhinal cortex was smaller in the LOCI+ group than that in the EOCI+ group, while the volume atrophy rates in the parietal cortex and precuneus were higher in the EOCI+ group although these regions did not survive correcting for region‐wise multiple comparisons.ConclusionEarly‐onset AD patients have greater tau burden and are more likely to be vulnerable to progressive tau accumulation in the widespread neocortex, and thereby may be more vulnerable to the progressive neurodegeneration than the late‐onset AD.
Rostro‐caudal locus coeruleus integrity differences vary with age and sex using ultra‐high field imaging
Authors: Riphagen Joost M. , van Hooren Roy W.E. , Pagen Linda H.G. , Poser Benedikt A. , Jacobs Heidi I.L. 
Published: December 2020

AbstractBackgroundAutopsy studies reported that the locus coeruleus (LC) is one of the initial regions to accumulate tau early in life. With every increase in Braak stage, LC volumes declines with approximately 8%. In addition, animal studies have reported a sexual differentiation of the locus coeruleus (LC), reflecting a higher number of neurons in women. Given the reported sexual dimorphism in subcortical volumes and cortical tau deposition, indicating a higher vulnerability in women, we sought to examine age and sex‐differences along the rostro‐caudal axis of the LC by using dedicated novel structural ultra‐high field imaging methods.MethodInclusion: 89 participants 20‐85 yrs (45F/41M,Age females 49(sd19.29), males 51(sd22.2) p=0.65). Imaging was done at 7T, including MP2RAGE anatomical scans and our previously validated MT‐TFL sequence that enables imaging the length of the LC at 0,4mm3. Structural scans were bias‐field corrected and we generated a common template using an iterative diffeomorphic warp estimate with Advanced Normalization Tools (ANTs http://stnava.github.io/ANTs/) and LC templates were constructed by manual tracing the average projection map (RWEvH, Figure 1A). The segmented LC was then projected to each high‐resolution MT‐TFL to extract the voxel‐intensity along the rostro‐caudal length. Linear mixed effects models examined age differences in LC intensity along this axis (age by z‐coordinate) as well as the modulation of sex (age by sex by z‐coordinate), implementing a random slope for position and random intercept for each subject.ResultWe found an age‐related quadratic gradient of the voxel intensity, in which lower voxels intensities were observed in the central section, not rostral or caudal section, in older individuals (Figure 1B; df1480, t=2.91,p= 0.0036). This gradient is sex dependent and shows that this effect is driven by lower intensities in older males compared to females in the central LC (df 1476, t=2.20, p=0.0274, Figure 1C).ConclusionWe demonstrated a male vulnerability for lower medial LC structural properties. The medial LC is one of the regions initially affected by tau. Other studies reported a female vulnerability to tau. Further analyses including hormonal and biomarker data will help to elucidate the biological underpinnings of the sex‐differences in Alzheimer’s disease processes.
Association of ventricular size on executive function and attention is modified by Apolipoprotein E and moderated by pulse pressure in Alzheimer's disease
Authors: Sapkota Shraddha , McFall G. Peggy , Dixon Roger A. , Masellis Mario , Black Sandra E. 
Published: December 2020

AbstractBackgroundGenetic, structural imaging, and vascular risk factors are key determinants of cognitive differences in Alzheimer’s disease (AD). We investigated synergistic associations between three risk factors from each domain on cognition in AD. We focused on (1) whether structural imaging predicts cognitive performance, (2) and is differentially represented by genetic risk and (3) further moderated by vascular risk. Specifically, whether ventricular enlargement predicts EF and attention and whether this is differentially represented by Apolipoprotein E(APOE) and further moderated by pulse pressure (PP).MethodsWe used AD patients (n=321; mean age=71.6(9.6) years; %female=53) from the Sunnybrook Dementia Study (SDS). First, we performed a confirmatory factor analysis to build EF and attention latent factors using five standardized cognitive tests (EF:Wisconsin card sorting test, digit symbol substitution, phonemic fluency, attention:forward and backward digit span). Second, we tested whether ventricular size predicts EF and attention performance at baseline. Third, we tested an APOE effect modification where a different relationship is observed for ventricular size on EF and attention in context of APOE stratification. Fourth, we tested whether PP moderates any effect modification by APOE risk on ventricular size and EF and attention. PP was calculated using systolic minus diastolic blood pressure and divided into low and high groups using the mean PP.ResultsThe best fitting model was observed with a two factor EF and attention model (χ2(df)= 4.059(4),p=0.3981; RMSEA (90% CI)=0.007(0.000‐0.085); CFI=1.000; SRMR= 0.023). Increase in ventricular size predicted lower EF (β=‐10.743, SE=4.538, p=0.018) and attention (β=‐13.342, SE=4.762, p=0.005) performance only in the APOE ɛ4+ risk group. This APOE effect modification was further moderated by PP where only APOE ɛ4+ risk carriers with low PP had poorer EF (β=‐16.553, SE=6.002, p=0.006) and attention (β=‐17.054, SE=6.225, p=0.006) performance with higher ventricular size.ConclusionsEF and attention risk associated with ventricular enlargement was only present in AD patients carrying the APOE ɛ4 allelic risk and further magnified in adults with low PP. Genetic risk stratification in combination with structural imaging and modifiable vascular risk factors may identify AD patients at magnified risk for accelerated decline with potential opportunities for novelinterventions and precision medicine.
The Spanish and english NIH Toolbox in autosomal dominant Alzheimer’s disease: A preliminary report
Authors: Montoya Lucy , Mora Livier , Barrera Lillibeth , Ringman John M. 
Published: December 2020

AbstractBackgroundAutosomal dominant Alzheimer’s disease (ADAD), in which the future development of AD can be reliably predicted, allows one to sensitively exam cognitive changes occurring in the earliest stages of the disease. The NIH Toolbox (NIHTB) is a standardized battery that comprehensively assesses multiple aspects of neurological function. In the current study we applied the English and Spanish versions of the cognitive and motor tests from the NIHTB to persons with and at‐risk for ADAD to assess its sensitivity to detecting changes occurring in this form of the disease.MethodWe performed the cognitive, motor, and olfactory tests in the NIHTB in 22 persons with or at‐risk for inheriting ADAD mutations. T‐tests were performed comparing raw scores for non‐carriers to asymptomatic carriers (CDR = 0), mildly affected carriers (CDR = 0.5), and mildly demented carriers (CDR = 1). P values less than 0.05 were considered significant.ResultHalf of the participants were evaluated in Spanish. Three persons were asymptomatic carriers, 4 carriers had CDR scores of 0.5, 6 carriers had CDR scores of 1, and 9 were non‐carriers. No differences favoring non‐carriers over asymptomatic carriers were found. Mildly affected carriers (CDR = 0.5) performed worse on the picture sequence memory tests (p values < 0.02) and the olfactory identification test (5.8 vs. 7.4, p = 0.02). Carriers with CDR scores of 1.0 performed more poorly on the list sorting test (7 vs. 16.9, p = 0.02), the picture sequence memory test (p’s < 0.007), the dimensional change card test (14.2 vs. 29.6, p = 0.01), the fluid cognition composite score (82 vs. 108, p = 0.02), the odor identification test (6 vs. 7.4, p < 0.05) and walked more slowly on the 4 meter gait test (5.0 vs. 4.2, p = 0.033).ConclusionThough we were limited by our small sample size, the NIHTB preliminarily demonstrated utility in detecting deficits in memory and executive function (fluid cognition) and in motor and olfactory abilities in early ADAD. Further studies will better define its utility in detecting early cognitive deficits in AD in both its English and Spanish forms.
Synergistic underpinning of global amyloid and cingulate neuroinflammation underlies tau propagation in Alzheimer’s disease
Authors: Kang Min Su , Ottoy Julie , Savard Mélissa , Mathotaarachchi Sulantha , Pascoal Tharick A. , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundUnderstanding the underling pathophysiology of tau burden and its propagation through Braak stages is imperative in Alzheimer’s disease (AD) and its clinical trial strategy. This multimodal PET study aimed to reveal the Aβ ([18F]AZD4694) and activated microglia ([11C]PBR28) converges to potentiate the NFTs ([18F]MK6240) deposition in AD in Braak stages. We hypothesized that the NFTs deposition driven by Aβ and neuroinflammation leads to cognitive.MethodA total of 108 participants (70 CN, 25 MCI, and 13 AD) with a high‐affinity binder for TSPO underwent 3 PET scans, MMSE and CDR‐SB. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. A total of 35 anatomical based regions including Braak stage 1 – 6 and its combination, 23 anatomical regions, and local‐to‐local interactive region were used to evaluate the important regional effect of amyloid and neuroinflammation on tau. All analyses were corrected for age, sex, education, APOE, and multiple correction using FDR.ResultWe showed a significant synergistic local‐to‐local effect between Aβ and neuroinflammation on NFTs in Precuneus/PCC, basolateral temporal, and medial frontal cortices. Moreover, 3D cross‐regional regressions showed signification interactions between amyloid and neuroinflammation on tau on all Braak stages. Importantly, neuroinflammation in cingulate /precuneus demonstrated the greatest number of interactive effects on tau in the presence of amyloid. Last, global amyloid, cingulate neuroinflammation, and Braak stage 4 tau together led to worse MMSE (p = 0.03) while global amyloid and Braak stage 4 tau together led to worse CDR‐SB (p = 0.003).ConclusionThis study demonstrated the imperative role of microglia on tau propagation in the presence of amyloid. The microglial activation in the cingulate/precuneus, epicenter of the archetypical brain network, showed the most frequent effect together with global amyloid on tau loads on all Braak stages. Last, all 3 major targets of AD clinical trials led to worse cognitive score compared to its independent effect. This study underscores the local and distal effects of neuroinflammation and amyloid on Braak staging in AD, and shows molecular underpinnings for a promising combination therapy in AD.