bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIN1 rs744373 SNP is associated with increased mean diffusivity in non‐demented elderly
Authors: Rubinski Anna , Franzmeier Nicolai , Neitzel Julia , Ewers Michael 
Published: December 2020

AbstractBackgroundThe rs744373 SNP in the bridging integrator‐1 gene (BIN1) is the second most important risk factor of sporadic Alzheimer’s disease (AD) after ApoE genotype. We have recently shown that the BIN1 SNP is associated with higher tau deposition in the brain (Franzmeier et al. Nat Commun 2019). Recent findings indicate that BIN1 protein is highly expressed in the white matter (WM) in the brain. Although WM alterations are common in AD and may contribute to dementia symptoms, it is unclear whether BIN1 risk allele is associated with lower WM integrity. To address this research gap, we tested whether BIN1 rs744373 is associated with WM alterations in non‐demented elderly, independently of amyloid PET.MethodsWe included diffusion tensor imaging (DTI) data, 18‐F AV45 amyloid PET, and AV1451 tau PET from 61 individuals including cognitively normal controls (CN, n=35) and individuals with mild cognitive impaired (MCI, n=26) from ADNI. 14 CN and 15 MCI individuals were BIN1 rs744373 SNP carriers. Global mean diffusivity (MD) and global fractional anisotropy (FA) were mapped within the white matter. In linear voxel‐based regression analyses, we tested the BIN1 rs744373 genotype effect on MD (primary outcome) and FA values, controlled for age, gender, education, diagnosis and global amyloid PET. We further assessed the voxel‐level group differences in MD (BIN1 rs744373 carriers vs. non‐carriers) using TBSS. Tau PET was assessed in projection areas of major fiber tracts.ResultsBIN1 rs744373‐carriage was associated with elevated global white matter MD values (p=0.003, Figure 1), independent of global Aβ PET SUVR, and regional MD predominantly located within the left superior/inferior longitudinal fasciculus, left/right uncinate fasciculus and left inferior fronto‐occipital fasciculus (Figure 2). No significant effect on FA was observed. When stratified by diagnosis, associations between BIN1 rs744373 and elevated global MD were significant in the MCI subgroup (p=0.01). Mediation analyses of the effect of BIN1 on white matter via tau PET in connected areas will be discussed.ConclusionBIN1 rs744373 risk allele is associated with white matter alterations in MCI independent of Aβ, suggesting that BIN1 SNP may enhance the risk of microstructural white matter impairment and thus contribute to dementia symptoms.
Using the Framingham Cardiovascular Disease Risk Score to predict cognitive performance in cognitively normal non‐hispanic whites and Mexican American elders
Authors: Vintimilla Raul , Balasubramanian Kishore , Hall James R. , Johnson Leigh Ann , O'Bryant Sid 
Published: December 2020

AbstractBackgroundPrevalence of cardiovascular disease risk factors (CVRFs) is higher among Mexican Americans (MAs) that non‐Hispanic Whites (NHWs), placing this population at a higher risk of cognitive decline. The purpose of this study was to examine the relationship between the Framingham Cardiovascular Disease 10‐years risk score (FCVDRS) and cognitive performance among MAs and NHWs. This study extends the limited literature about FCVDRS and cognition among MAs.MethodWe studied 518 cognitively normal participants (92 NHWs and 426 MAs) from an epidemiological study of aging. Gender, age, hypertension treatment status, systolic blood pressure (SBP) level, smoking status, diabetes mellitus diagnosis (DM), HDL, and total cholesterol levels were used to calculate the FCVDRS for each individual. A linear regression was conducted to examine the association of FCVDRS with MMSE, logical memory I and II, Trails B, FAS, and digit span scores. A one‐way ANOVA was used to analyze the relationship of FCVDRS categories (low < 10, moderate 10 – 20, high > 20), and test scores, along with Tukey post hoc tests to elucidate the magnitude of differences between the groups. Education was entered as a covariate in the model.ResultMAs had a higher prevalence of DM, higher SBP, and lower HDL values. Linear regression model was significant only for executive function in MAs , F(1,352) = 7.86, p = 0.005. One ‐way ANOVA showed a significant difference for Trails B, F(2,351) = 5.21, p = 0.006, and MMSE, F(2,414) = 3.00, p = 0.005 among MAs. In both cases, post hoc test indicated that MMSE and Trails B mean scores were lower in the high risk group when compared to the low risk group. No significant trends were seen in the Non‐Hispanic White subset.ConclusionOur data has shown that FCVDRS can be used to predict performance on measures of global cognition and executive function in MAs. Although more work has to be done to further understand the predictive power of FCVDRS, there is promise in using this model to develop early intervention programs targeted to MAs.
Development of the mobile cognitive app performance platform for detection of AD‐related cognitive change
Authors: Mechanic‐Hamilton Dawn , Lydon Sean , Halberstadter Kimberly , Lane Jacqueline , Das Sandhitsu R. , Wolk David A. 
Published: December 2020

AbstractBackgroundThis pilot study investigates the psychometric properties of a mobile app‐based memory task, the mobile cognitive app performance platform (mCAPP), to detect memory changes associated with preclinical Alzheimer’s Disease (AD). A mobile, reliable, valid, short, and engaging cognitive assessment is necessary for early detection and tracking change in individuals at risk for AD.MethodParticipants included 30 older adults (60% female; age=70.9±4.1, years of education=16±2.5; 73% Caucasian) with normal cognition who are enrolled in the Penn ADRC cohort. The mCAPP memory task includes learning and then matching hidden card pairs and incorporates increasing memory load, pattern separation features (lure vs. non‐lure), and spatial memory (moving target cards). Participants completed the NACC UDS3 neuropsychological battery and additional cognitive measures, within six months of the mCAPP testing and twenty participants completed a high‐resolution structural MRI scan.ResultAlmost all participants found the difficulty level of the mCAPP game to be “just right” (92%), 65% reported they enjoyed the game and 43% reported they would play it for fun. Higher average number of guesses at higher memory load levels was correlated with lower story learning and memory, digit span, trail making test (TMT) B and olfactory performance (p<0.05). Higher average duration of time on the higher memory load levels was correlated with worse performance on digit span, animal naming, TMT A and B, and olfaction (p<0.05). The number of guesses and duration of time on lure vs. non‐lure trials was significantly different, with more guesses and more time required for the lure trials (requires pattern separation) at higher memory load levels [Guesses: 8 card, t(29)=5.6,p<0.001; 12 cards, t(29)=4.5,p<0.001; Duration: 8 cards, t(29)=6.9,p<0.001; 12 cards, t(29)=5.9,p<0.001]. At some higher memory load levels, longer duration of time on trials correlated with smaller mean thickness of the parahippocampal cortex (p<0.05).ConclusionIn this study, we show feasibility, validity, and utility of multiple memory components of the mCAPP memory task for use in detecting subtle cognitive differences associated with preclinical AD. Future work will include examination of the relationship of mCAPP variables with molecular biomarkers, at‐home and burst testing, and development of additional measures in other domains of cognition.
Regional differences of amyloid PET SUVR induced by spatial smoothing and the role of reference region
Authors: Palombit Alessandro , Manber Richard , Joules Richard , Wolz Robin 
Published: December 2020

AbstractBackgroundSpatial smoothing can be applied to imaging data from Amyloid PET (Ab‐PET) scans in clinical trials with the aim of decreasing the noise level and improve tissue delineation to the ultimate extent of easing the structural registration process. In this study, we quantify regional differences of Ab‐PET attributable to post‐reconstruction spatial smoothing.MethodAmyloid PET ([18F]‐Flutemetamol, Siemens Biograph 64 mCT PET/CT scanner) and structural MRI were collected in 10 participants (3 AD, 4 MCI). Each Ab‐PET dataset was reconstructed as single saturated image (OSEM, 8 iterations, 21 subsets, PSF+TOF), separately with and without spatial smoothing (3D Gaussian kernel, FWHM = 3mm). Bias field‐corrected and skull‐stripped T1w‐MRI images were segmented with LEAP [Ledig;ISBI;2012] and separately registered to the smoothed/unsmoothed Ab‐PET volumes. Regional SUVR, defined as within‐region average with cerebellar grey matter (GC) or whole cerebellum (WHC) as reference region, was separately calculated for smoothed/unsmoothed Ab‐PET and compared between smoothed/unsmoothed Ab‐PET volumes.ResultRegional SUVR was found to significantly differ between smoothed/unsmoothed (Wilcoxon signed‐rank test, p < 0.05) with both reference regions. Quantitative SUVR differences (unsmoothed – smoothed) were nonetheless regionally limited (Figure 1A) with a relative difference of ‐0.149% or +0.988% (averaged across regions/subjects) respectively with GC or WHC reference, and very small size effects with Cohen’s d = ‐0.014 (GC) and 0.046 (WHC). A strong rank correlation (Figure 1B) was found between SUVR with different smoothing levels both regarding GC (r = 0.984, p < 0.05) and WHC (r = 0.985, p < 0.05). SUVR relative differences between smoothing levels did not exceed the 5% threshold with GC (WHC similar thus omitted), differences not reaching significance (Figure 2B) if corrected for multiple‐comparisons across regions.ConclusionSmoothing‐related regional SUVR differences were found to be below the scan‐rescan physiological level [Tolboom;JNM;2009], suggesting minimal impact on the statistical analyses. Nonetheless, spatial smoothing can improve the PET‐MRI registration robustness by improving Ab‐PET tissue delineation and noise content, an essential feature for automatic processing of large cohorts’ data.
Common and rare variants in Alzheimer’s disease genes are associated with episodic memory in South Asians from the LASI‐DAD study
Authors: Zhao Wei , Smith Jennifer A. , Yu Miao , Moorjani Priya , Ganna Andrea , Dey Aparajit Ballav , Lee Jinkook , Kardia Sharon L.R. 
Published: December 2020

AbstractBackgroundMany risk loci for Alzheimer’s disease (AD) have been identified in genome wide association studies (GWAS) conducted primarily in European ancestry (EA). We previously investigated whether SNPs identified in EA were associated with episodic memory in South Asians, and failed to find an association for the majority of SNPs. Due to genetic heterogeneity among different race/ethnic groups, risk SNPs identified in EA GWAS may not be as strongly associated in different ethnicities. Genes, however, have the same function across ethnicities. The goal of this study was to use a gene‐based approach to investigate the association between 39 known risk genes for AD and episodic memory in 937 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD).MethodParticipants were genotyped using the Illumina Global Screening Array and imputed to 1000G Phase 3v5. We used a gene‐based approach, the sequence kernel association test (SKAT and SKAT‐O), to assess the joint effects of all SNPs simultaneously within each risk gene on two episodic memory scores (total and delayed word recall) after controlling for age, gender, and population structure. We used two weighting schemes: equal weight for all SNPs/variants (beta(1,1)), and upweighting of rare variants (beta(1,25)).ResultPreliminary analyses showed that 7 genes (APOE, ADAMTS1, RIN3, IQCK, KAT8, HLA‐DRB5, EPHA1) were associated with total learning score and 2 genes (ADAMTS1, CLU) were associated with delayed recall score using the equal SNP/variant weighting approach at a nominal p‐value (p < 0.05). Using the rare variant weighting approach, 5 genes (APOE, ADAMTS1, KAT8, RIN3, HLA‐DRB5) were associated with total learning score and 2 genes (ADAMTS1 and ABCA7) were associated with delayed recall score.ConclusionGiven that variation in only one gene was associated with both total learning and delayed recall, different biological mechanisms may be involved in these traits. Moreover, the association of the majority of genes was driven by both common and rare variants, whereas only a few associations were driven largely by rare variants. Future work is needed to identify the specific variants that influence episodic memory in South Asians.
Characterization and comparison of memory and affective behavior in common transgenic mouse models of Alzheimer’s disease
Authors: Dong Hongxin , Locci Andrea , Keszycki Rachel M. , Orellana Hector D. , Rodriguez Guadalupe , Fisher Daniel W. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder with cognitive decline, yet over 90% of patients also develop behavioral symptoms during disease progression. While a few studies have identified some aberrant behaviors in transgenic mouse models of AD, rigorous characterization and comparison of AD models for memory and affective behavior has yet to be done.MethodsWe characterized memory and affective behavior in three commonly AD mouse models (5xFAD, APP/PS1, and APPNLGF mice) at 10 months of age. We evaluated working, spatial, and social memory deficits using Y‐maze, novel object recognition (NOR), social recognition, and Morris water maze (MWM). We assayed affective behavior with open field, light‐dark box, social interaction and tail suspension tests. Then, we evaluated the dynamic changes in memory and affective behavior in 5xFAD mice at 6 and 10 months of age.ResultsAll three AD mouse lines demonstrated deficits in working, spatial and social memory compared to WT mice. However, 5XFAD and APPNLGF mice showed more severe working and social memory deficits compared to APP/PS1 mice. In the open field, 5xFAD but not APPNLGF and APP/PS1 mice showed a reduction in the time spent and the number of entries in the center of the arena. In the light/dark box test, both 5xFAD and APPNLGF but not APP/PS1 mice entered land spent less time in the light compartment. Similarly, 5xFAD and APPNLGF mice demonstrated reduced time spent and number of entries around the conspecific in the social interaction test. Finally, 5xFAD and APPNLGF but not APP/PS1 mice had increased immobility in the tail‐suspension test. Interestingly, changes in the affective behavior but not memory deficits were found in 5XFAD mice at 6 months of age, and some of these behavioral alterations worsened at 10 months of age.ConclusionsAlthough 10‐month‐old 5xFAD, APPNLGF, and APP/PS1 mice displayed working, spatial and social memory deficits, only 5xFAD and APPNLGF showed robust anxiety‐ and depressive‐like behaviors at this time point. Importantly, the 5xFAD mice displayed significant deficits in affective behavior but not memory impairment at an early time‐point, suggesting that the AD‐pathology may drive changes in affective behavior before more overt memory deficits.
Targeting of misfolded, pathogenic TDP‐43 with rationally designed antibodies
Authors: Cashman Neil R. , Louadi Sarah , Zhao Beibei , Roman Andrei , Gibbs Ebrima , Dijkstra Anke A. , Plotkin Steven S. , Kaplan Johanne 
Published: December 2020

AbstractBackgroundMisfolded, aggregated TDP‐43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) through direct toxicity, loss of function of normal TDP‐43, induction of misfolding of other neuronal proteins, and prion‐like, cell‐to‐cell propagation of disease. We sought to generate antibodies selectively targeting the misfolded, pathogenic form of TDP‐43 while sparing physiological forms of TDP‐43 important for normal cell function.MethodMice and rabbits were immunized with an unfolded N‐terminal domain (NTD) linear epitope predicted to become exposed in cytosolically mislocalized, aggregated TDP‐43 but otherwise buried in natively folded TDP‐43. Selectivity of polyclonal antibody (pAb) for misfolded NTD was confirmed by studies with denaturing and native gel electrophoresis followed by immunoblotting. Monoclonal antibody (mAb) affinity for the immunizing peptide was measured by surface plasmon resonance (SPR). mAb selectivity for pathogenic, aggregated TDP43 was assessed by immunocytochemistry (ICC) of HEK293FT cells transfected with mutant TDP‐43 lacking a functional nuclear localization signal (DNLS) or upon arsenite stress, and by immunohistochemistry (IHC) on patient samples. The ability of mAbs to inhibit cell‐to‐cell transmission of DNLS TDP‐43 was evaluated in cell culture.ResultAffinity‐purified pAb from immunized animals displayed reactivity with recombinant NTD under denaturing but not native conditions, indicating selectivity for unfolded NTD. mAb clones displayed pM affinity for the NTD epitope by SPR. ICC showed mAb reactivity with cytoplasmic aggregates of DNLS‐TDP‐43 but not wild‐type nuclear TDP‐43. Antibodies also did not recognize TDP‐43 in physiological stress granules in HEK‐293FT cells. IHC of ALS and FTLD CNS sections, but not normal control, confirmed selective immunoreactivity of mAbs with pathogenic TDP‐43. In cell culture, mAbs inhibited transmission of misfolding TDP‐43 from the conditioned medium of donor HEK293FT cells transfected with DNLS‐TDP‐43 to naïve recipient cells.ConclusionImmunization with an NTD epitope of misfolded TDP‐43 gave rise to mAbs selective for pathogenic vs physiologically important forms of TDP‐43. The mAbs were capable of inhibiting cell‐to‐cell propagation of misfolding TDP43 in vitro. Such antibodies may have value against extracellular transmission of misfolding TDP‐43 or as pathogenic TDP43‐specific intrabodies expressed intracellularly.
Gait is associated with age and dementia assessments among individuals with Down syndrome
Authors: Van Pelt Kathryn L. 
Published: December 2020

AbstractBackgroundDown Syndrome (DS), caused by triplication of chromosome 21, is associated with the development of Alzheimer's disease (AD) neuropathology by age 40 years. However, clinical signs of dementia may not develop until up to decades after neuropathology. Neuroimaging studies indicate that the striatum and frontal lobes accumulate beta‐amyloid early in AD progression. Given these regions are involved in motor and cognitive function, we hypothesized that gait would be associated with changes in cognition and prodromal dementia.MethodTwenty‐nine participants (n = 16 male) with DS were recruited into the gait study. The average age of participants was 36 (range: 25‐59). The GaitRite mat was used to spatial and temporal gait measures while participants walked at their self‐selected pace or when completing a dual‐task. The dual‐task was counting aloud, starting from a random integer between 1‐10. Participants also completed the Severe Impairment Battery (SIB) and Brief Praxis Test (BPT) to measure cognitive impairment. Linear mixed models evaluated the relationship between age, condition, and gait metrics. Linear regression was used to assess the relationship between gait and cognition metrics.ResultWith increasing age, gait velocity slowed within the counting condition, but not the self‐paced condition (t(180.29) = 2.69; p = 0.008; Figure 1A). There was a trend for step length to shorten with increasing age across all conditions (t(29.01) = ‐1.81; p = 0.08; Figure 1B). Participants’ base stance was wider with increasing age during the counting condition, but not the self‐paced condition (t(179.70) = ‐2.03; p = 0.04; Figure 1C). Faster normalized velocity was associated with better cognition as measured by the SIB (t = 2.99; p = 0.004; Figure 2A) and BPT (t = 2.02; p < 0.05; Figure 2B) across both self‐paced and counting conditions.ConclusionSlower velocity, shorter step length, and wider base stance on the dual‐task gait paradigm were associated with increasing age and cognitive impairment. A dual‐task gait may serve as a prodromal indicator of dementia in DS. Earlier dementia detection will facilitate research investigating ADS pathogenesis and subsequently may provide novel targets for preventative research.
Sex‐specific changes in amyloidosis and neuro‐immune modulation in response to alterations in the gut microbiome
Authors: Shaik Shabana M. , Dodiya Hemraj B. , Cao Yajun , Boutej Hajer , Olszewski Monica , Sisodia Sangram S. 
Published: December 2020

AbstractBackgroundMicroglia, resident macrophages of CNS constantly screen the brain and engage in pathological processes by changing their morphology, expressing various antigens and become phagocytic. This activation causes the release of a wave of chemical mediators that promote the neuroinflammatory milieu. Thus, microglial homeostasis represents a highly plastic multifaceted response, finely tuned by the nature of the stimulus and the molecular repertoire involved. Studies from Sisodia lab have shown that antibiotic (ABX) mediated alterations of the gut microbiome in Thy1‐APPSwe.PS1L166Pmice (APPPS1‐21), resulted in a significant decrease in amyloidosis and altered microglial phenotypes in male mice. To investigate the influence of gut microbiome in modulating microglial function in a sex‐specific manner, we generated transgenic mice that would allow us to assess microglial RNA‐Protein networks and address the molecular mechanisms of CNS immunomodulation.MethodWe generated ‘Thy1‐APP.PS1‐RiboTag’ by crossing APPPS1‐21 mice to RiboTag mice wherein a CD11b promoter drives expression of ribosomal protein L10a (RpL10) that is fused to FLAG/EGFP at the amino‐terminus. Using our established protocol, we altered the microbiome of male and female mice (n=12) by orally gavaging them with ABX from day 14‐21, followed by low dose ABX in drinking water till they are sacrificed (7 wks). Vehicle treated mice were used as controls along with WT‐RiboTag mice. Immunoprecipitation of cortical homogenates with anti‐FLAG was performed to pull‐down actively translated mRNA and proteome in microglia following histopathology.ResultWe evaluated Aβ pathology and found that ABX‐treatment led to reduced amyloidosis in male mice with no significant changes in the female. Analysis of the mRNAs and the newly synthesized peptides resulted in a snapshot of the dynamic translational state of microglial ribosomes. We observed 21 upregulated and 22 downregulated proteins between the WT‐RiboTag and Th1‐APP.PS1‐RiboTag in male mice and 16 upregulated and 70 downregulated in female. Abx treatment resulted in upregulation of 39 and downregulation of 37 proteins in males while the females showed 51 and 9 respectively.ConclusionWe find marked differences in the mRNA and proteins associated with microglial phenotypes expressed in a sex‐specific manner as a function of changes in the gut microbiome.