bluuebunny/crossref_metadata_2025_split huggingface dataset:
The presence of Alzheimer’s disease pathology in dementia with Lewy bodies is related to increased neocortical α‐synuclein load and different α‐synuclein morphology
Authors: Geut Hanneke , van den Berg Emma , Bank Netherlands Brain , Rozemuller Annemieke J.M. , Lemstra Afina W. , van de Berg Wilma 
Published: December 2020

AbstractBackgroundThe presence of Alzheimer’s disease (AD) type pathology in dementia with Lewy bodies (DLB) has been linked to a more rapid disease progression. We aimed to examine the relation between load of AD‐type pathology and load and morphology of α‐synuclein pathology in DLB brains.MethodWe included 50 donors from the Netherlands Brain Bank fulfilling clinical criteria for ‘probable DLB’ and limbic or neocortical Lewy body disease. Levels of AD‐type pathology according to NIA‐AA guidelines were either absent to low (pure DLB, n = 15), or intermediate to high (mixed DLB/AD, n = 35). We visually rated α‐synuclein‐positive and amyloid‐β‐positive morphologies, and we quantitatively measured amyloid‐β, hyperphosphorylated tau (HPF‐tau) and α‐synuclein load in fifteen brain regions. Regional amyloid‐β and HPF‐tau levels in DLB donors were compared to eight AD donors without α‐synuclein pathology (pure AD).ResultMixed DLB/AD compared to pure DLB donors showed a shorter disease duration (6 ± 3 vs. 8 ± 3 years, p = 0.021), more diffuse intraneuronal α‐synuclein positivity (p = 0.002) but not more glial α‐synuclein positivity, and a higher overall α‐synuclein load (F = 25.7, p < 0.001), specifically in the parietal (p = 0.006), temporal (p = 0.002) and occipital cortex (p = 0.006). Mixed DLB/AD was related to more capillary cerebral amyloid angiopathy (CAA) (49% vs. 7%, p < 0.001). Within cortical regions, α‐synuclein load was most strongly related to amyloid‐β and HPF‐tau load in the temporal (Pearson’s r = 0.38 and 0.50 respectively) and occipital cortex (r = 0.43 and 0.42 respectively). While controlling for age at death, mixed DLB/AD compared to pure AD showed lower HPF‐tau load in frontal (p = 0.043) and parietal cortices (p = 0.002), but not in temporal cortex (p = 0.48), and no differences in amyloid‐β load in the frontal (p = 0.57), parietal (p = 0.56) and temporal cortex (p = 0.10).ConclusionThe presence of AD‐type pathology in DLB was related to more diffuse intraneuronal α‐synuclein positivity, a higher neocortical α‐synuclein load and more capillary CAA. This study provides evidence for different neuropathological profiles in DLB, which may contribute to clinical heterogeneity in this disease.
Binding affinity of Hsp90 for tau protein plays a key role in tau protein degradation
Authors: Calzada Jesus Ismael , Tapia Jose Isabel 
Published: December 2020

AbstractBackgroundDeposits of hyperphosphorylated Tau Protein is the main feature of Alzheimer disease and these are closely related with cognitive impairment, aggregates can cause neuronal death. Into cells there are mechanisms responsible for maintaining a balance among synthesis and degradation of proteins, named proteostasis mechanisms, one of them is mediated maily by Hsp90. Due to the presence of intracellular protein deposits in Alzheimer disease it is clear that some of the proteostasis fail or is not too efficient.MethodSH‐SY5Y cells were transfected independently with two distinct plasmids containing two different forms of tau protein, one which contains a tau with 14 aminoacid changed for alanine in order to prevent phosphorylation and the other containing the same aminoacid changed for glutamate to mimic phosphorylation, Tau protein expression was analyzed by western blot at different times.The same genes that codified for Tau proteins that were expressed in cell line, were cloned into an expression vector to be expressed in bacteria as recombinant proteins, then protein expression was carried out in E.coli BL21DE3 induced by IPTG, bacterial cells were lysed and recombinant proteins were purified by nickel columns and then quantified. Afterwards overlay assays were developed, various concentrations of the two different types of purified Tau proteins were spotted onto a nitrocellulose membrane. This membrane was incubated with cellular extracts of SHSH‐5Y containing native form of Hsp90. Subsequently, membrane was washed and the protein still bound was detected by inmmunobloting with an antibody recognizing Hsp90. Additionally, Dynamic light scattering light was performed to evaluate if recombinant proteins could produce fibrillation.ResultWe found that diminishing of Tau expression which has glutamates was less than Tau expression containing alanine, at the time of 48h. Overlay assay showed that cellular Hsp90 presented lower binding affinity for recombinant Tau with glutamates. Finally, in Dynamic Light Scattering assay Tau with glutamates presents higher fibrillation than Tau with alanine.ConclusionThese results suggest that binding affinity of Hsp90 for Tau regulates its degradation, this could be the main reason of its accumulation and agreggation into cell. Moreover, phosphorylation in specific sites is closely related with its fibrillation.
Determinants of caregiver burden in early onset dementia
Authors: Chiari Annalisa , Pistoresi Barbara , Galli Chiara , Tondelli Manuela , Vinceti Giulia , Addabbo Tindara , Zamboni Giovanna 
Published: December 2020

AbstractBackgroundCaregivers of patients with early onset dementia (EOD) experience high levels of burden, which is known to be affected by financial and social variables, as well as by psychological features of the caregiver and patient’s symptoms. However, it is not known how all these factors reciprocally interact in determining the burden of caregivers of EOD patients. We investigated multiple determinants of burden in a comprehensive model.MethodConsecutive eligible patients with EOD and their caregivers were recruited from the Cognitive Neurology Clinic of the Modena University Hospital, Italy. Patients underwent extended clinical, imaging and neuropsychological assessment. Caregivers were interviewed and asked to fill in questionnaires to gain information on patients’ symptoms, caregiver burden (Zarit Burden Interview), caregiver psychological distress (Relative Stress Scale). Patient/caregiver demographics, social and clinical variables were entered in linear multiple regression models and mediation models to explore if the effect on burden is mediated by stress.ResultData from 89 EOD patient‐caregiver dyads were examined. Caregiver burden was positively related to female caregiver sex (b=0.44,p=0.0002), severity of patient’s behavioral symptoms (b=0.32,p=0.0004), diagnostic delay (b=0.18,p=0.017) and financial distress of the family (b=0.28, p=0.0008). Significant factors reducing the burden were caregiver perception of patient’s quality of life (b=‐0.20, p=0.005), disease duration (b=‐0.27,p=0.0003), caregiver age (b=‐0.31,p=0.0017), offspring number (b=‐0.25,p=0.0004), patient’s education (b=‐0.15,p=0.022), region of birth (b=‐0.17,p=0.025) and number of days off work (b=‐0.15, p<0.0001) (adjusted‐R2=0.64). While the effect of financial distress, number of caregiver’s days off‐work, patient’s disease duration, and caregiver sex was entirely mediated by the level of caregiver stress, the effect of diagnostic delay and of proxies of family or social network on burden was direct.ConclusionMost of the effect of the known determinants of the burden of caregivers is mediated by caregivers’ level of stress, in particular for female caregivers. In particular, the number of days off‐work that the caregiver can take is a variable on which action can be taken to reduce the caregivers’ stress, hence their burden. However, as some determinants are independent from stress, direct actions should be aimed at increasing social networks and shortening diagnostic delay to reduce caregiver burden.
Category‐selective semantic deficit for living things in semantic variant primary progressive aphasia
Authors: Henderson Shalom Kim , Cordella Claire , Dev Sheena Isha , Quimby Megan , Wong Bonnie , Ezzo Rania , Collins Jessica A , Dickerson Brad C 
Published: December 2020

AbstractBackgroundStudies of patients with impaired semantic memory have identified cases with a category‐selective semantic deficit (CSSD) for living things—a disproportionate semantic memory loss for animate versus inanimate items. Data are mixed on whether patients with semantic variant primary progressive aphasia (svPPA) exhibit a CSSD, in part because measurement can be confounded by psycholinguistic variables. Furthermore, there exists little consensus regarding the neural substrates of CSSD.Here we examine (1) the effect of animacy on single word comprehension performance in svPPA after accounting for familiarity, frequency, and age of acquisition, and (2) the relationship between cortical atrophy and disproportionate impairment in identifying animate vs. inanimate items.Methods21 individuals with svPPA completed the Cambridge Semantic Battery‐Word Picture Matching (CSB‐WPM) task, which includes 32 animate and 32 inanimate items. Using a multiple regression model, we assessed the effects on CSB‐WBM accuracy of familiarity, frequency, age of acquisition, and animacy (i.e., animate, inanimate). Cohen’s d was used to measure effect size. We then estimated CSSD per individual (% inanimate correct ‐ % animate correct). For each ROI, we ran a linear regression assessing the relationship between cortical thickness and CSSD, covarying for overall semantic impairment.ResultsThe main effect of animacy remained significant (t = 4.6, p < .001) even after including all psycholinguistic variables in the model [F(4,56) = 13.8, p < .001] (Cohen’s d=1.1). After controlling for overall semantic impairment, greater cortical atrophy was associated with greater CSSD in the right posterior superior temporal gyrus (STG) (β = ‐.41, t = ‐2.38, p = .031). Relationships between CSSD and the right entorhinal/perirhinal cortex (β = ‐.39, t = ‐1.88, p = .081) and right posterior fusiform gyrus (β = ‐.39, t = ‐2.08, p = .056) also trended in this direction.ConclusionsResults provide support for an animacy CSSD in svPPA, with individuals showing greater deficits for animate compared with inanimate items even after controlling for familiarity, frequency, and age of acquisition. The right temporal lobe, especially the posterior STG, entorhinal/perirhinal cortex, and the posterior fusiform gyrus, may also play a critical role in the representation of animate items.
Characterizing the cognitive phenotype of Parkinson’s disease
Authors: Tipton Philip W. , Bulbul Nazli G. , Crook Julia E. , Uitti Ryan J. , Wszolek Zbigniew , Ertekin‐Taner Nilufer 
Published: December 2020

AbstractBackgroundParkinson’s disease (PD) is a complex neurodegenerative disease in which combinations of motor and non‐motor symptoms result in a wide range of phenotypic presentations and disease progression. Precise characterization of these clinical endophenotypes can guide clinical practice. Such endophenotypes can also be powerful to identify genetic factors for complex diseases, like PD. Given the prevalence and impact of cognitive impairment in PD, we aimed to characterize cognitive endophenotypes in a cohort of PD patients with longitudinal assessments.MethodWe reviewed the medical records of 1028 individuals diagnosed with PD by a movement disorders specialist at our institution. We extracted scores from all available Mini‐Mental Status Examinations (MMSE). We fit proportional odds models with patient specific random effects to estimate odds ratios for higher versus lower cognition in association with age, sex and follow‐up time.ResultAmong the 237 patients with at least one MMSE, 108 had ≥2 time points and 118 were cognitively impaired (MMSE<27). The mean age was 71 years, 63 (27%) were female and the mean follow‐up time was 2.56 years. Overall, females with PD had higher MMSE scores than males with an odds ratio at age 70 of 2.43 (95% CI: 1.29, 4.97). However, MMSE scores decline with age at a faster rate in females than males (p=0.002) with ORs for a 1 year of 0.85 (0.79, 0.91) and 0.94 (95%CI: 0.91, 0.97), respectively. Within patients, declines in MMSE per year had an OR of 0.76 (0.60, 0.97) for females and 0.85 (0.75, 0.95) for males though this difference was not statistically significant. Corresponding expected MMSE trajectories are shown in the figure.ConclusionOur findings demonstrate sex differences in the cognitive phenotypes of PD. In particular, cognitive scores tend to be higher in females compared to males, but decline faster in females. These findings have clinical implications regarding counseling of patients with PD. We are currently expanding this approach to specific cognitive domains, other validated tests of cognition, and investigating the influence of genetic risk factors, such as APOE on cognitive decline in PD.
Pilot study of MRI white matter tissue properties in Alzheimer’s, vascular and mixed dementias
Authors: Lee Hyunwoo , Wiggermann Vanessa , Rauscher Alexander , Beg Mirza Faisal , Popuri Karteek , Tam Roger , Lam Kevin , Jacova Claudia , Sossi Vesna , Pettersen Jacqueline , Benavente Oscar R. , Hsiung Ging‐Yuek Robin 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) with cerebrovascular disease is known as ‘mixed’ dementia (MixD).[Wang_2012][Langa_2004] MixD can have heterogeneous clinical/imaging presentations. This makes it difficult to distinguish MixD from AD or vascular dementia (VaD) using structural markers such as atrophy or white matter hyperintensity (WMH) volumes. [Suri_2014] We explored whether WM tissue properties on MRI, represented by R2* and diffusion‐tensor (DTI) images, could distinguish MixD from AD or VaD.MethodN=17 participants (cross‐sectional; 7 MixD/5 Subcortical VaD/5 AD; Sex: 11M/6F; Age: 75±8yrs) were scanned on a 3T Philips Achieva. WMHs were segmented on 3D‐Fluid Attenuated Inversion Recovery images. T1‐weighted MP‐RAGE images were segmented into the grey/white‐matters using SPM12. These outputs were combined to construct WMH and normal‐appearing WM (NAWM) masks. DTI images were processed using FSL. R2* images were computed using in‐house software. For each participant, the average R2*, fractional anisotropy (FA) and mean diffusivity (MDf) values were calculated within the WMH and NAWM masks.ResultAverage WMH volumes were (mean±SD) AD: 5191±4693mm3, MD: 34680±17059mm3 (p<.05 compared to AD), SVaD: 20896±14920mm3 (p>.05 compared to MixD or AD). A linear model was used to predict the measured R2*, FA or MDf values from the diagnosis subtypes, adjusting for age and sex. R2* results: Pairwise t‐tests revealed significantly lower R2* values within the WMHs compared to NAWM (all subtypes p<0.0005). MixD had significantly lower WMH R2* values compared to AD (p=0.01) or VaD (p=0.02) subgroups. DTI results: Pairwise t‐tests revealed significantly higher MDf values within the WMHs compared to NAWM (all subtypes p<0.009). FA values were significantly lower within the WMHs compared to NAWM for the MixD (p=0.0002) and VaD (p=0.03) but not the AD (p=0.09) subtype.ConclusionOur MixD cohort was characterized by potentially disrupted fiber integrity (represented by decreased FA) and increased water content (represented by lower R2*) within the WMH areas. These abnormalities likely represent etiologies caused by both neurodegenerative and cerebrovascular factors. Future studies that incorporate measures of neurodegeneration or neuroinflammation, such as biofluid markers, may help to further characterize WM tissue abnormalities in MixD compared to those found in ‘pure’ AD or VaD.
Deletion of neuronal BACE1 causes mice memory deficits
Authors: Hu Xiangyou , Darboe Mabintou , Yan Riqiang 
Published: December 2020

AbstractBackgroundThe β‐site APP cleaving enzyme 1 (BACE1) was initially identified as a transmembrane aspartyl protease cleaving amyloid precursor protein.MethodsBehavioral test (open field, water maze, Y‐maze and fear conditioning test), western blotting and LTP.ResultsWe crossed Thy1‐cre line with BACE1 conditional knockout (BACE1fl/fl) mice to obtain Thy1‐cre;BACE1fl/fl mice to delete BACE1 in neurons. These mice at 8 months were conducted behavioral tests which includes open field, Y maze, water maze, and fear conditioning. In the open field, we found that the total moving distance were similar between Thy1‐cre;BACE1fl/fl and BACE1fl/fl controls. However, the Thy1‐cre;BACE1fl/fl
mice spent more time in the corner area and less time in the center area. In the Y maze test, we found that the spontaneous alteration was significantly reduced in Thy1‐cre;BACE1fl/fl
mice, suggesting deleting neuronal BACE1 affects mice spatial working memory. In water maze test, we found that Thy1‐cre;BACE1fl/fl
mice spent more time to reach the platform compared to the age‐matched controls, which indicates that deleting neuronal BACE1 also causes mice reference memory deficit. This phenomenon was only observed in the male Thy1‐cre;BACE1fl/fl
mice. In fear conditioning test, the freeze time (%) was significantly reduced in day 2 for contextual memory test and day 3 for cue memory test in male Thy1‐cre;BACE1fl/fl
mice, but not in the females. To explore what reason causing gender difference in the cognition deficit in both water maze and fear conditioning tests, we did western bolt and found that BACE1 level was significantly reduced in the hippocampus and the cerebral cortex in Thy1‐cre;BACE1fl/fl
mice, and the BACE1 level was ever lower in the males than in the females. We also conducted LTP recording on Thy1‐cre;BACE1fl/fl
hippocampal slices, and found that the amplitudes of field excitatory postsynaptic potentials (fEPSPs) were significantly reduced in Thy1‐cre;BACE1fl/fl
mice compared to age‐matched BACE1fl/fl
mice.ConclusionThese data reveal that only deletion of BACE1 in neurons affects mice learning and memory.
Glucose metabolism mainly reflects local atrophy and tau pathology at symptomatic stages of Alzheimer’s disease
Authors: Strom Amelia , Iaccarino Leonardo , Edwards Lauren , Lesman‐Segev Orit H. , Soleimani‐Meigooni David N. , Jagust William J. , Miller Bruce L. , Rabinovici Gil D. , Joie Renaud La 
Published: December 2020

AbstractBackgroundWe assessed the relative contributions of four potential mechanisms associated with [18F]‐Fluorodeoxyglucose (FDG)‐PET hypometabolism in the posterior cingulate cortex (PCC) and inferior parietal (IP) lobe, two primary regions of hypometabolism in AD: 1) local (amyloid and tau) pathology and atrophy, 2) pathology in functionally connected regions, 3) deafferentation from the degenerating medial temporal lobe (MTL), and 4) vascular injury in the white matter (Figure 1).MethodEighty‐five patients with MCI or AD dementia underwent MRI and PET with FDG for glucose metabolism, [11C]‐Pittsburgh Compound B (PIB) for amyloid, and [18F]‐Flortaucipir (FTP) for tau within one year (Table 1). SUVR were calculated using tracer‐specific reference regions: pons for FDG, cerebellar cortex for PIB, and inferior cerebellar cortex for FTP. ROIs and volume of white matter hyperintensities (WMH) were defined in native space using FreeSurfer. Regions with high or low connectivity to PCC/IP were defined based on task‐free fMRI data from cognitively normal participants from neurosynth.org (Figure 2). Imaging variables were transformed into age‐adjusted z‐scores using demographic‐matched modality‐specific control groups (Table 1). Multiple regression analyses were run to identify variables associated with FDG‐SUVR, using a composite disease severity score combining Mini‐Mental State Examination and Clinical Dementia Rating scores as a covariate.ResultLocal gray matter volume (GMV) and FTP‐SUVR, but not PIB‐SUVR, were independently associated with FDG‐SUVR in PCC (R2=.603, βGMV=0.353, βFTP=‐0.374) and IP (R2=.702, βGMV=0.419, βFTP=‐0.361) in a model that included disease severity (Table 2). Models including PIB/FTP in connected regions did not outperform models with disease severity and local GMV/FTP alone. Results were similar when including measures of pathology in non‐connected regions. Similarly, models including MTL volume did not outperform models with disease severity and local GMV/FTP alone. Volume of WMH was weakly associated with FDG‐SUVR in PCC but not IP.ConclusionHypometabolism reflected local atrophy and tau pathology. A weak association between WMH volume and PCC hypometabolism was seen, suggesting that white matter damage may also be a driver of hypometabolism. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or MTL volume in the symptomatic stage of AD.
Alzheimer's disease GWAS weighted by multi‐omics and endophenotypes identifies novel risk loci
Authors: Ma Yiyi , Vardarajan Badri N. ,   CHARGE ADSP FUS, Bennett David A. , Fornage Myriam , Seshadri Sudha , Destefano Anita L. , De Jager Philip L. 
Published: December 2020

AbstractBackgroundWe have increasing information on the role of certain genetic variants in a wide variety of molecular traits and endophenotypes of Alzheimer’s disease (AD), but their impacts on the prioritization of AD risk gene are unknown.MethodBased on the summary statistics of the genome‐wide association study (GWAS) of AD published by the International Genomics of Alzheimer’s Project (IGAP) consortium (Kunkle et al., 2019), we have weighted each SNP by their associations with traits of eQTL (RNA expression), mQTL (DNA methylation), haQTL (histone acetylation), brain phosphorylated tangles (TAU), β‐amyloid protein (Aβ), and cognitive decline derived from the ROS‐MAP samples of postmortem dorsal‐lateral prefrontal cortex of AMP‐AD. Then, we collapsed all of the weighted SNPs found in each gene using the SKATO test, based on the 1000 reference genome.Result38∼43% of genes (n = 12,899) have an increase in their statistical significance level after incorporating the weights of their genetic effects on omic molecular traits and AD endophenotypes. A subset of these gene‐level assessments reach the trait‐specific Bonferroni corrected genome‐wide significance threshold (P < 0.05/number of genes for each trait). The burden of TAU pathology has the strongest effect with RASGRF2, FCF1, ZCWPW1, C6orf10, VAC14, ADGRF2, ACP2, DDB2, and CR1L being prioritized. Similarly, we have results prioritized by weighting by (1) Amyloid β: FCF1, NRXN1, PLCB1, and DLG2; (2) cognitive decline: AKAP13, CR1L, KIAA1671, and CR2; and (3) eQTL: TRIT1, RAPSN, and C6orf10. The latter also emerges from the haQTL analysis, and no results emerge from the mQTL analysis.ConclusionWeighting by omic molecular traits and endophenotypes leading to AD is able to prioritize additional genes that could contribute to AD susceptibility. Functional validation is ongoing.