bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influenza vaccination is associated with a reduced incidence of Alzheimer’s disease
Authors: Amran Albert , Lin Yaobin , Kim Yejin , Bernstam Elmer , Jiang Xiaoqian , Schulz Paul E 
Published: December 2020

AbstractBackgroundAD is a devastating disease and its pathophysiology is still largely unknown. No treatment has been shown to be efficacious, so prevention remains a very valuable approach. The objective of this work is to statistically test the relationship between influenza vaccination and the incidence of AD to identify a candidate for AD prevention.MethodWe used the Cerner Health Fact EHR dataset and excluded patients less than 60 years of age and included patients with ICD9 code ‘331.0’, i.e. Alzheimer’s disease. From this population, we constructed a cohort (N=311,424) for statistical analysis. Then we did propensity score matching (PMS) on AD with regard to patients’ demographics and then did PMS on influenza vaccine with regard to the age of AD onset and potential confounds such as prescribed medications. We obtained a balanced data set with respect to vaccinated patients and unvaccinated patients with PMS (N=9,066). To analyze the effects of frequency of vaccination, we divided the number of vaccinations by the length of time from the first vaccination timestamp to AD onset or the end of the observation. We performed a survival analysis on the entire cohort where development of AD was the end outcome.ResultWe obtained our results using chi‐square test, uni‐variate analysis, and time‐to‐event analysis. Our main outcomes are three aspects: (1) influenza vaccine significantly decreases AD prevalence (odds ratio 0.8309 with a p‐value < 0.0001). (2) the frequency of influenza vaccine has a significant impact to inhibit AD onset (odds ratio 0.8736 with a p‐value of 0.0342). (3) time‐to‐event analysis shows taking influenza vaccine at an earlier age leads to smaller AD risk than having vaccine at an older age (when the first vaccination age increases by 1, the hazard rate increases by 1.0924, p‐value < 0.0001).ConclusionAnalysis of a large clinical database suggests that there is a strong inverse relationship between AD and influenza vaccination. This result provides evidence that influenza vaccination may be a confounding factor in epidemiological studies of risk factors of Alzheimer’s Disease. Future studies may shed light on biological mechanisms to more deeply understand a promising, readily available candidate for preventing AD.
Imaging profiles of Alzheimer’s disease and behavioural variant frontotemporal dementia based on cortical structural correlation networks
Authors: Vuksanovic Vesna , Staff Roger , Ahearn Trevor , Murray Alison D. , Wischik Claude 
Published: December 2020

AbstractBackgroundReduced cortical structural properties are recognised as potential imaging marker for neurodegenerative disorders. However, networks of correlated fluctuations in cortical structural properties in Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD) have remained elusive. Here, we set out to investigate organisations of structural correlation networks in these patients, and further to show how they become (dis)organised across the cortical lobes.MethodStructural correlation networks are estimated from magnetic resonance images (MRI) in three study groups ‐ AD, bvFTD and healthy controls ‐ each consisting of an equal number of participants (N = 200). Group‐level networks are constructed by cross‐correlating regional structural properties (e.g., thickness, surface area or volume) across all subjects within the group while controlling for confounding variables age, gender and global values.ResultNetwork organisation is evaluated using several network matrices including the node degree, node strength and network density on the whole‐brain and across the brain lobes. We found that the reduced cortical properties in AD and bvFTD alter organization of the corresponding structural cortical networks at the whole brain. We also found that differences in the measured network properties are lobe specific.ConclusionOur results show that understanding patterns of correlated reductions in cortical structures may assist in deciphering how cortical changes underlie cognitive and behavioural processes impaired in AD and bvFTD. Reference: Vuksanović V, Staff RT, Ahearn T, Murray AD, Wischik CM. Cortical Thickness and Surface Area Networks in Healthy Aging, Alzheimer’s Disease and Behavioral Variant Fronto‐Temporal Dementia. Int J Neural Syst. 2019 Aug;29(6):1850055. https://doi.org/10.1142/S0129065718500557. Epub 2018 Nov 14. PubMed PMID: 30638083.
Cellular vulnerability in Lewy body diseases
Authors: Erskine Daniel , Hatton Chris , Perrott Abigail , Lai Nicola , Sidhpura Keval , Turnbull Doug , Attems Johannes 
Published: December 2020

AbstractBackgroundLewy body diseases (LBD) are characterised by Lewy body pathology, cell loss and mitochondrial dysfunction, but the overlap between these three features is not well understood. We have explored the hypothesis that neurodegeneration in LBD is the result of energy failure in cells with high energy demands, such as cortical fast‐spiking interneurons and cholinergic basal forebrain neurons, irrespective of Lewy body accumulation.MethodWe obtained post‐mortem substantia innominata, prefrontal cortex and inferior temporal cortex brain tissue from LBD cases, controls, and disease‐control groups (Alzheimer’s disease and/or mitochondrial disease cases). We conducted stereological analysis of fast‐spiking interneurons, pyramidal neurons and cholinergic neurons; neuropathological analysis of alpha‐synuclein, amyloid‐beta and tau; and immunofluorescent quantification of NDUFB8 (Complex I) and COX4 (Complex IV) normalised to mitochondrial mass.ResultDespite not developing Lewy bodies, we observed a 40% reduction in density of fast‐spiking interneurons, whilst pyramidal neurons that are vulnerable to Lewy bodies had preserved populations. Changes in cell density were not related to any neuropathological feature. Preliminary data suggests Complex I reductions relative to VDAC1 in fast‐spiking interneurons and cholinergic nbM neurons, with more variable changes in Complex IV expression.ConclusionThe present findings demonstrate loss of a cell population that does not develop Lewy bodies alongside preservation of proximal Lewy body‐bearing neurons. This challenges the hypothesis that neurodegeneration in LBD results from Lewy body pathology. Our preliminary findings indicate that mitochondrial impairments in cells with high reliance on energy production may more closely relate to neurodegeneration in LBD than Lewy body formation.
Endoplasmic reticulum stress induces spatial memory deficits by activating GSK‐3 in Alzheimer’s disease
Authors: Wang Xiao‐Ming 
Published: December 2020

AbstractBackgroundEndoplasmic reticulum (ER) stress is involved in Alzheimer’s disease (AD), but the mechanism remains unclear.MethodTunicamycin (TM), a recognized ER stress inducer, was injected into the brain ventricle of Sprague‐Dawley (SD) rats to induce the unfolded protein response (UPR). Rats was divided into 3 groups for the brain lateral ventricle injections with DMSO, TM, or TM + SB, respectively. The behavioural test was conducted after 24 and 48 hours, respectively. Then the rats were sacrificed. Brain samples were collected for further protein analysis and specific stains.ResultTM‐induced UPR was convinced by enhanced phosphorylation of pancreatic ER kinase (PERK), inositol‐requiring enzyme‐1 (IRE‐1), and transcription factor‐6 (ATF‐6) activation. Behavioural test demonstrated UPR induced spatialmemory deficits and impairments of synaptic plasticity in the rats. After TM treatment, GSK‐3β was activated. Phosphorylation of cAMP response element binding protein at Ser129 (pS129‐CREB) was up‐regulated with an increased nuclear co‐localization of pY126‐GSK‐3β and pS129‐CREB. Simultaneous inhibition of GSK‐3β by hippocampal infusion of SB216763 (SB) attenuated TM‐induced UPR, synaptic plasticity, and spatial memory impairment with restoration of pS129‐CREB.ConclusionTM‐induced UPR causes AD‐like spatial memory deficits and synapse impairments by activating GSK‐3b/pS129‐CREB pathway. GSK‐3 inhibition might be a promising therapy in AD treatment.
Education and income might protect the brain differently against white matter lesions in aging
Authors: Rodriguez Francisca S. , Lampe Leonie , Gaebler Michael , Witte A. Veronica , Villringer Arno , Riedel‐Heller Steffi G. 
Published: December 2020

AbstractBackgroundA lower socioeconomic status (SES) is associated with poorer cognitive health in old age and with more white matter lesions in the brain. It is not clear whether education and income, the two major components of SES, contribute differently to cognitive health, given that education is believed to build up a cognitive reserve. Aim of the study was to investigate how education and income independently contribute to cognitive functioning and brain white matter in aging.MethodParticipants (age 40‐80 years) of the representative population‐based LIFE‐Adult study completed the CERAD neurological test battery and underwent MR scanning (n=2,385 without neurological diseases). The association between education and income on cognitive performance and white matter lesions was analyzed via generalized linear regression modelling adjusted for age, gender, APOE e4 allele and household size. We further tested whether health (heart disease, high blood pressure, elevated blood lipids, diabetes, depression) could explain the associations.ResultHigher education as well as higher income were significantly associated with better performance in the CERAD and fewer total white matter hypointensities (WMH). Only higher education was associated with a lower Fazekas scale score, while only higher income was associated with fewer periventricular WMH. With increasing age, the protective effect of both, higher education and higher income, on performance in the Trail Making Test B and the total white matter volume increased. Older age additionally increased the protective effect of higher income on fewer total and periventricular WMH. The age‐related association between income and periventricular WMH was largely explained by high blood pressure.ConclusionOur findings suggest that higher education and higher income may protect cognitive functioning by a smaller loss of white matter in aging. While education is associated with WMH in general, income is specifically associated with periventricular WMH, an ageing‐related association that seems to be related to blood pressure. As none of the other health indicators explained our findings, more research is necessary to investigate what aspects of low educational attainment and low income bring about WMH.
Big data analysis of Korea health insurance review and assessment service for treatment cost of dementia and depression from 2014 to 2018
Authors: Eun Hun Jeong , Choi Mal Rye , Kim Hyun Gi 
Published: December 2020

AbstractBackgroundRecently, Korea has entered the aging society, and the related dementia and depression are increasing rapidly. Therefore, the purpose of this study was to find out the actual situation by using the Big Data Hub of the Korea Health Insurance Review & Assessment Service to find the data registered in Korea Health Insurance.MethodAuthors visited the Big Data Hub at Korea Health Insurance Review & Assessment Service homepage. After extracting data on the number of patients and medical expenses for 5 years from 2014 to 2018 for dementia and depression in Big Data Homepage, the data were analyzed and statistically verified using Microsoft Excel and IBM SPSS version 23.0. Mann‐Whitney test for hypothesis evaluation applicated.ResultNo. for 5yrs(2014‐2018) : Dementia 929,552.571±809112.0384, Depression 1,434,674.429±1006545.7405 Probability of correct significance, p=0.259. Total Cost for 5yrs : Dementia 3,219,859,523.57±3070117355.004(Korean Won), Depression 566,886,256.29±409089339.917(Korean Won), p=0.209, Expenses excluding insurer contribution applicated for data analysis. Total cost for 5yrs/person : Dementia 2,466.0143±791.06624(US dollar), Depression 334.1757±19.28922(US dollar), p=0.001, 1 dollar=1170.24 Korean Won (2020.1.25). Total cost for 1yr/person : Dementia 493.20286±158.21327(US dollar), Depression 66.83514±3.857845(Us dollar), p=0.001. Dementia 64 years below(US dollar) : Men 440.6060 , Women 203.0120, Dementia 65‐80>years(US dollar) : Men 441.9200, Women 639.2740, Depression 64years below(US dollar) : Men 69.0080, Women 63.0420, Depression 65‐80>years(US dollar) : Men 64.2980, Women 61.9620.ConclusionThe results of the above study analyzed data on dementia and depression using big data from the Korea Health Insurance Review and Assessment Service, and proved that the number of cases of dementia was less than that of depression, but the treatment cost was higher. The cost of treatment of dementia was much higher for men before 64, but after 65, the cost burden for women increased.
TMEM97 is a potential amyloid beta receptor in human Alzheimer’s disease synapses
Authors: Colom‐Cadena Martí , Tulloch Jane , Rose Jamie , Smith Colin , Spires‐Jones Tara 
Published: December 2020

AbstractBackgroundSynapse loss correlates strongly with cognitive decline in Alzheimer’s disease (AD), and abundant evidence from animal and cell models implicates soluble amyloid beta in synaptic dysfunction and loss. While many candidate synaptic receptors for amyloid beta have been observed in model systems, the physiologically relevant amyloid beta receptor(s) involved in synapse degeneration in human AD brain remain unknown. Here we tested the hypothesis that TMEM97, recently discovered to be the sigma 2 receptor, binds amyloid beta in synapses in human AD brain.MethodsTo do this, we combined high resolution array tomography with Forster resonance energy transfer (FRET) to examine whether amyloid beta and candidate receptors are in close enough proximity to be interacting in human postmortem brain samples. We examined temporal cortex from AD (n = 9) and age matched control (n = 6) cases. Ribbons of 70 nm serial sections from human brain samples were stained with antibodies to label pre synapses, post‐synapses, amyloid beta, and TMEM97, and images before and after acceptor photobleaching were obtained on a confocal microscope.ResultsWe observe that TMEM97 is present in a higher proportion of post‐synapses in AD brain compared to control brain and that in AD a higher proportion of post‐synapses contain both TMEM97 and amyloid beta. Further, TMEM97 and amyloid beta are in close enough proximity to generate a FRET signal in post‐synaptic densities. Cellular prion protein was also in close proximity to amyloid beta, but as expected, pre synaptic and post‐synaptic markers were too far apart to generate a FRET signal (negative control).ConclusionsThese data support a role for TMEM97 as a synaptic receptor for amyloid beta in human Alzheimer’s disease brain where it may mediate synaptotoxicity.
Single‐cell profiling of circulating and brain‐resident immune cells in a mouse model for amyloidosis and in aged mice
Authors: van Olst Lynn , Verhoeff Jan , Schetters Sjoerd T.T. , Hulshof Lianne A. , van Dijk Roland , van der Pol Susanne M.A. , Schouten Marijn , Vallejo Juan J. Garcia , van Der Flier Wiesje , Teunissen Charlotte E. , Middeldorp Jinte , de Vries Helga E. 
Published: December 2020

AbstractBackgroundEmerging evidence suggests that peripheral immunity plays an important role in the progression of Alzheimer’s disease (AD) (Gate et al., 2020). However, more understanding on how peripheral immune cells respond to AD pathology is needed before utilizing the immune system further for early diagnosis and therapeutic treatment. Here, we aimed to map the immune system in the early stages of amyloidosis. In addition, we aimed to characterize the aged immune system and to study the effect of age‐related circulating immune factors on the immune response.MethodWe used 6‐month‐old APPswe/PS1dE9 (APP/PS1) transgenic and wild type (WT) mice to study the immune response to amyloid‐beta pathology and 20 month‐old WT mice for characterization of the aged immune system. In addition, both 6‐month‐old WT and APP/PS1 mice received multiple injections with aged blood plasma derived from 20‐month‐old WT mice. Next, immunohistochemical and high‐dimensional single‐cell analysis using time‐of‐flight mass cytometry (CyTOF), allowing detection of different immune populations and their activation status, was performed to map the circulating and brain‐resident immune cells in the different conditions (Figure 1).ResultImmunohistochemical analysis revealed that T cell infiltration in the 6‐month‐old APP/PS1 brain coincided with early amyloid‐beta plaque formation. Single cell analysis of circulating and brain‐resident immune cells of APP/PS1 mice showed that especially T cells clustered in different cell‐subsets and had increased expression of activation and cell‐adhesion molecules compared to young WT mice. In contrast, circulating and brain‐resident T cells of aged mice contained more regulatory cell subsets and increasingly expressed molecules involved in immune inhibition. Interestingly, initial analysis revealed that injections with aged WT blood plasma partially reduced the aforementioned differences in T cells between young WT and APP/PS1 mice.ConclusionWe found that circulating and brain‐resident T cells were different in their subsets and expression profile in early amyloid‐beta accumulation and in aging. In addition, the activation status of APP/PS1‐derived T cells was reduced after exposure to aged WT blood plasma resulting in a T‐cell signature more similar to young WT mice. Currently, we are further investigating the peripheral immune response to amyloid‐beta pathology by lipid‐ and RNA profiling of the circulating immune cells.
Machine learning regression analysis predicts brain amyloid‐β burden: A multimodal neuroimaging research study
Authors: Lin Li , Wang Xiaoni , Wang Xiaoqi , Li Xuanyu , Sun Yu , Du Wenying , Chen Guanqun , Han Ying 
Published: December 2020

AbstractBackgroundRecent criteria have unveiled the importance of biomarkers in the continuum of Alzheimer's disease, which greatly enhances the progression of clinical trials of prevention and treatment. However, the expanding cost and resources limit the first‐line brain amyloid measurement techniques.ObjectiveWe aimed to develop an inexpensive and sensitive method to predict brain amyloid‐β burden by integrating machine learning and multimodal MRI.MethodsEighty‐three elders were enrolled from the Xuanwu Hospital. Brain amyloid‐β burden, structural and functional changes were respectively assessed with (18)F‐AV45 amyloid PET, structural and diffusion MRI, functional MRI. Using regression machine implementations, we predicted brain amyloid‐β level by voxel‐based morphometry, fractional anisotropy and fractional amplitude of low frequency fluctuations (fALFF).ResultsWe found that extracted features could predict brain amyloid‐β burden, using voxel‐based morphometry (r=0.55, p=0.001) or/and fractional anisotropy (r=0.36, p=0.002), but not fALFF(r=0.07, p=0.2388). These results were replicated using cross‐validation procedures and these models were statistical significance determined by permutation testing. The brain regions that showed most important to predict amyloid‐β burden were superior temporal gyrus, parahippocampal gyrus, inferior frontal gyrus and hippocampus.ConclusionThe current study showed high correlation between the structural and diffusion MRI indexes and amyloid burden in the elders which opens a new possibility for early diagnosis of AD.
Trajectory of apathy, cognition and neural correlates in the decades before symptoms in frontotemporal dementia
Authors: Malpetti Maura , Kievit Rogier A , Jones P Simon , Rittman Timothy , Tsvetanov Kamen A , van Swieten John C , Borroni Barbara , Galimberti Daniela , Sanchez‐Valle Raquel , Laforce Robert , Moreno Fermin , Synofzik Matthis , Graff Caroline , Masellis Mario , Tartaglia Carmela , Vandenberghe Rik , Finger Elizabeth , Tagliavini Fabrizio , de Mendonca Alexandre , Santana Isabel , Butler Christopher , Ducharme Simon , Gerhard Alexander , Danek Adrian , Levin Johannes , Otto Markus , Frisoni Giovanni B , Ghidoni Roberta , Heller Carolin , Todd Emily , Bocchetta Martina , Convery Rhian S , Peakman Georgia , Moore Katrina M , Rohrer Jonathan D , Rowe James B 
Published: December 2020

AbstractBackgroundIn frontotemporal dementia (FTD), apathy is reported to negatively impact the prognosis and survival of patients. The study of genetic FTD in its pre‐symptomatic period permits the investigation of markers in the early stages of disease progression. Therefore, in pre‐symptomatic gene carriers in the multicentre Genetic FTD Initiative (GENFI), we examined longitudinal apathy changes in association with cognitive decline over time, and baseline measures of atrophy.MethodSix hundred participants from Data Freeze 4 (2019) were included: 304 pre‐symptomatic mutation carriers, and 296 family members without mutations. Clinical assessment and a structural MRI scan were undertaken at baseline, and annually for at least 2‐years. Latent Growth Curve modelling (LGCM) was used to assess: 1) longitudinal changes in apathy, as measured by the apathy subscale of the Revised Cambridge Behavioural Inventory; 2) the relationship with longitudinal changes in executive function; 3) the association with baseline regional grey matter volumes. The time to the expected year of symptom onset was included as a covariate.ResultUnivariate LGCM identified a significant linear increase in apathy scores for pre‐symptomatic carriers (estimate= 0.51, se=0.18, z scores= 2.88, p=0.004), but not in non‐carriers (estimate= 0.08, se=0.08, z scores=1.04, p=0.30). An equality constrained comparison suggested a significant group difference in the progression of apathy (i.e. the slope) ((∆ χ2=10.14; p=0.0015). Pre‐symptomatic carriers also had a significant decline in executive functions (est=‐0.07, se=0.03, z scores=‐2.49, p=0.017), which was predicted by baseline apathy (standard estimate=‐0.40, p=0.008). In pre‐symptomatic carriers only, the annual rate of change in apathy was significantly associated with brain volume in frontal lobe (standard estimate=‐0.47, p=0.008) and cingulate cortex (standard estimate=‐0.29, p=0.05) at the baseline.ConclusionApathy progresses significantly in pre‐symptomatic FTD and predicts a sub‐clinical deterioration of executive performance in gene carriers. Apathy changes over 2 years are associated with volume in the frontal lobe and cingulate gyrus measured at the baseline. We suggest that apathy may be a modifiable factor to protect function and cognition in those with, or at risk of, frontotemporal dementia.