bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau spreads through episodic memory networks in the aging brain
Authors: Jagust William J. , Adams Jenna N. , Ziontz Jacob , Cassady Kaitlin , Maass Anne 
Published: December 2020

AbstractBackgroundEpisodic memory involves an anterior temporal (AT) network specialized for object memory and a posteromedial (PM) network specialized for spatial memory. Tau arises in transentorhinal cortex, in the AT system. These observations suggest that (1) targets of anterolateral entorhinal cortex (alEC) in the AT network should contain more tau than targets of posteromedial entorhinal cortex (pmEC) in the PM network, and (2) patterns of connectivity from the medial temporal lobe may explain tau spread into the medial parietal lobe.MethodOlder cognitively normal participants (mean age 76, sample sizes from 87‐123 depending on the analysis) in the Berkeley Aging Cohort Study (BACS) underwent resting state fMRI on a Siemens 3T Trio system, tau‐PET with [18F]flortaucipir and Aβ PET with [11C]PIB. Young adults (mean age 25, N = 55) were studied with fMRI but not PET. fMRI data was analyzed with seed‐to‐voxel and ROI‐to‐ROI approaches to define networks which were related to protein aggregates measured with PET.ResultsFunctional connectivity patterns from alEC and pmEC reflected known AT and PM memory networks. Cortical targets of alEC demonstrated greater tau deposition than targets of pmEC; this effect was greater with higher Aβ and stronger connectivity. Retrosplenial cortex (RSC) showed stronger connectivity to the hippocampus than to alEC or pmEC, and stronger hippocampal‐RSC connectivity was associated with more tau deposition in medial parietal lobe (MPL). Higher hippocampal‐RSC connectivity and more MPL tau associated with poorer episodic memory performance. In comparison to younger individuals, older people showed de‐differentiation of these networks with evidence of alEC aberrantly connected to RSC. Segregation of AT and PM networks, measured as the scaled difference of within‐network correlations minus between‐network connections decreased as tau increased in older adults, reflecting greater functional connectivity between AT and PM networks.ConclusionsThese results indicate that neocortical tau preferentially arises in brain regions strongly connected to alEC as part of the AT system. Aβ potentiation may reflect early AD. MPL tau does not appear to arise directly from entorhinal cortex but from spread via the hippocampus. Functional consequences of these events included reduced network segregation and episodic memory impairment.
Plasma P‐tau immunoassays, methodological aspects and clinical performance
Authors: Blennow Kaj 
Published: December 2020

AbstractBackgroundThe promise of novel disease‐modifying therapies for Alzheimer’s disease (AD) calls for simple and widely available screening tests for AD‐type pathophysiology, specifically brain amyloidosis (A), tau pathology (T) and neurodegeneration (N). Technical developments have given analytical tools to measure AD protein biomarkers in blood samples. The plasma Aβ42/40 ratio shows high concordance with amyloid PET and blood neurofilament light (NFL) is a sensitive marker for neurodegeneration. CSF P‐tau181 is a well‐established and disease‐specific AD biomarker, but in addition, blood biomarkers for brain tau pathology is urgently needed.MethodImmunoassays with analytical sensitivity in the low pg/mL range has been developed for P‐tau181 in both plasma and serum samples, with blood levels correlating tightly with corresponding CSF levels in paired samples. Immunoprecipitation mass spectrometry (IP‐MS) experiments verify that the P‐tau181 Simoa assay specifically measure tau phosphorylated at Threonine 181.ResultResults from several clinical cohorts show that P‐tau181 is markedly increased along the whole AD continuum, from Aβ‐positive cognitively unimpaired elderly to AD dementia cases (p<0.0001). Plasma p‐tau181 also distinguishes AD from other tauopathies and neurodegenerative disorders, e.g. FTD, PSP/CBD, PD and vascular dementia, with AUC values of 83‐100%. Importantly, plasma p‐tau181 is associated with tau (MK‐6240) PET positivity (AUC>90%), but is also increased in the very early phase of AD, in amyloid PET positive but tau PET negative (Braak stage 0) individuals.ConclusionPlasma p‐tau181 is a novel promising blood biomarker for AD‐type tau pathophysiology. Blood p‐tau181 may be developed into a simple, cost‐effective and scalable test for screening and diagnosis of AD.
The effectiveness of a self‐administered acupressure intervention in caregivers of Alzheimer's disease patients: A systematic review
Authors: Almeida Jose Roberto , Almeida Maysa Cunha , Cunha Maria Eduarda , Silva Ana Gabriela Correia 
Published: December 2020

AbstractBackgroundCaregiving for people with Alzheimer's disease (AD) is highly stressful and has significant negative consequences, such as anxiety and depression. Although a variety of pharmacological and psychosocial interventions have been developed to alleviate caregiver stress, there is a need to find interventions that are effective and acceptable to caregivers. Acupressure, defined as an application of pressure an acupoints using the hands, fingers or thumbs, is a non invasive technique based on the meridian theory of traditional Chinese Medicine (TCM). TCM theory holds that meridians, which are channels in a network of energy pathways through the body, regulate the flow of QI (vital energy) and the unbalanced flow of QI results in disease. By applying external pressure to acupoints and has been successfully used for management of multiple symptoms without adverse effects.MethodA systematic review was undertaken using the Cochrane library and Medline reporting guidelines. twenty six databases and relevant websites were searched. Two reviewers appraised the quality of the studies and carried out data extraction.ResultMany studies showed that caregivers are at risk of emotional, mental and physical health problems. Fatigue is often the initial and most difficult problem resulting from the stressful caregiving process and leads to sleep disturbance, anxiety and depression. The emotional and physical strain of caregiving and its adverse impact on family caregivers health and well‐being is recognized as a serious public health problem. Studies have reported positive effects and safety of self‐administration acupressure for this symptoms. This technique has a number of advantages including flexibility, low cost and empowerment.ConclusionThis results provide evidence for the effectiveness of self‐administered acupressure in reduce stress and improving symptoms of fatigue, insomnia, depression and health‐related quality of life in caregivers of people with AD. It is necessary to provide support to caregivers, to enhance caregivers' feelings of positive emotions. Acupressure may be useful for treatment intervention and thus reduces caregivers anxiety and depression.
Co‐occurring mutations of optineurin (OPTN) and colony‐stimulating factor‐1 receptor (CSF1R) genes in a family with familial frontotemporal dementia
Authors: Yu Jeryl T. , Dominguez Jacqueline C. , Daroy Maria Luisa , Ng Adeline Su Lyn , Tan Yi Jayne 
Published: December 2020

AbstractBackgroundWe report the clinical profiles and genetics of multiple family members from Samar, Philippines presenting with varying phenotypes of frontotemporal dementia. Literature studies report three gene mutations associated with a majority of fFTD cases, namely the microtubule associated protein tau gene (MAPT), and progranulin gene (PGRN), chromosome 9 open reading frame 72 (C9ORF72). These were all excluded in our case.MethodsClinical examination, Cranial MRI, and FDG‐PET were done. Genomic DNA was extracted from blood samples and analyzed via targeted exome sequencing.ResultA frameshift mutation in the Optineurin (OPTN Chr 10:13166090 G>GA) was identified in multiple family members. This mutation is absent in public large international databases. Clinical and genetic studies show that frontotemporal dementia and motor neuron disease, in particular amyotrophic lateral sclerosis, are part of a disease spectrum with a common pathogenesis. However, there was no clinical or diagnostic evidence of motor neuron disease in family members with Optineurin mutations. A second mutation‐ missense mutation in the Colony‐Stimulating Factor‐1R V235G genes was seen in several family members. Colony‐Stimulating Factor‐1R gene mutations are associated with leukodystrophies when occurring singly. Clinical presentation and diagnostic tests did not support any of these findings.ConclusionAt present, this is the only reported family with such combined mutations and genotype‐phenotype discordance. We are further investigating this family by conducting whole exome sequencing.
High molecular weight amyloid β1‐42 oligomers induce neurotoxicity via plasma membrane damage
Authors: Yasumoto Taro , Takamura Yusaku , Tsuji Mayumi , Nakayama Takahiro , Imamura Keiko , Inoue Haruhisa , Nakamura Shiro , Inoue Tomio , Kimura Atsushi Michael , Yano Satoshi , Nishijo Hisao , Kiuchi Yuji , Teplow David B. , Ono Kenjiro 
Published: December 2020

AbstractBackgroundAmyloid β protein (Aβ) molecules that may contribute to Alzheimer's disease (AD) form low molecular weight (LMW‐Aβ), high molecular weight oligomer (HMW‐Aβ) such as protofibrils, and ultimately fibrils. Recent evidence suggests that oxidative stress and plasma membrane damage induced by soluble Aβ oligomers elicit neurotoxicity and play an initiating role in the development of AD pathology. But the precise mechanisms still remain unclear. In this study, we focused on clarifying the detailed mechanism of the HMW‐Aβ neurotoxicity.MethodThe elution of LMW‐Aβ and HMW‐Aβ was carried out using size exclusion chromatography. SH‐SY5Y cells (Human glioblastoma) were exposed to 5 μM of LMW‐Aβ and HMW‐Aβ for 30 min. To detect cytotoxicity, Aβexposed‐cells were measured mitochondrial activity and release of lactate dehydrogenase. Oxidative stress biomarkers (reactive oxygen species and phospholipid peroxidation of plasma membrane) were assessed. We also assayed intracellular Ca2+ ([Ca2+]i) level and membrane fluidity, and membrane electrical resistance by whole‐cell patch‐clamp.ResultSH‐SY5Y cells exposed to Aβ oligomers had significantly increased cytotoxicity and oxidative stress compared to untreated cells. The damaging effects of HMW‐Aβ were significantly greater than those of LMW‐Aβ. Exposure of SH‐SY5Y cells to LMW‐Aβ or HMW‐Aβ triggered an elevation in [Ca2+]i. [Ca2+]i levels in SH‐SY5Y cells exposed to HMW‐Aβ rose and maintained high level of [Ca2+]i , while pretreatment with nicardipine and memantine suppressed this continuous rising. Furthermore, both HMW‐Aβ and LMW‐Aβ significantly reduced SH‐SY5Y cell membrane fluidity compared with untreated control cell while, HMW‐Aβ produced a larger decrease in fluidity than did LMW‐Aβ. The resting potential was significantly elevated in SH‐SY5Y cells exposed to HMW‐Aβ compared with untreated control cells and LMW‐Aβ exposed cells and the input resistance was significantly lower following HMW‐Aβ exposure.ConclusionThese results suggest that HMW‐Aβchanged the structure of lipid bilayer due to cell membrane phospholipid peroxidation and disrupted the homeostasis of ions across the cell membrane. It was speculated that HMW‐Aβ induced neurotoxicity was induced by membrane structural changes such as the formation of small pores in the cell membrane. Accordingly, we propose that the therapeutic reduction of HMW‐Aβ has important implications for the development of AD therapies.
Long longitudinal tract lesion contributes to progression of Alzheimer’s disease
Authors: Xu Yun , Zhao Hui , Luo Cai Mei 
Published: December 2020

AbstractBackgroundThe pattern of degenerative changes in white matter (WM) microstructure and its relationship with cognitive function have not been clarified yet in the course of Alzheimer’s disease (AD). The present research aimed to explore the alterations of WM microstructure and its relationship with clinical features in amnestic mild cognitive(aMCI) and AD patients.MethodNeuropsychological data and diffusion tensor imaging (DTI) images were collected from 28 AD subjects, 31 aMCI subjects, and 27 normal controls (NC). Tract‐based spatial statistics (TBSS) were used to investigate fractional anisotropy (FA) and mean diffusivity (MD) among groups. Relationship between diffusion metrics and cognitive functions was examined. A support vector machine (SVM) classification was performed to determine the discriminative ability of DTI metrics in separating aMCI and AD patients from controls.ResultThe values of diffusion metrics in aMCI group presented intermediately between NC and AD groups. As compared to controls or aMCI patients, AD patients displayed widespread WM lesions, including the inferior longitudinal fasciculus, inferior fronto‐occipital fasciculi, superior longitudinal fasciculus and so on. However, no significant FA/MD differences were detected between NC and aMCI groups. Significant relationships between FA/MD metrics of long longitudinal tract and AVLT‐DR scores were found in aMCI and AD groups, respectively. The accuracy of DTI metrics in differentiating controls and AD patients were highly reached 89% and 85% according to SVM.ConclusionWM microstructure is extensively disrupted in AD. Long longitudinal tract integrity is closely related to memory and would hold potential value for monitoring the course of Alzheimer's disease.
Hypertension and Alzheimer's disease pathology at autopsy: A systematic review
Authors: Abdulrahman Hanna , den Brok Melina , van Dalen Jan Willem , Richard Edo 
Published: December 2020

AbstractBackgroundHypertension is an important risk factor for all‐cause dementia and Alzheimer’s disease (AD). Reports about the relation between mid‐life hypertension and AD‐related neuropathology are sparse and inconsistent. We conducted a systematic review to collate and synthesize the literature on the relation between hypertension and AD neuropathology.MethodsSearch terms included dementia, Alzheimer’s disease, hypertension, autopsy, obduction and neuropathology. The main outcome was AD‐related neuropathological changes at autopsy (including amyloid plaques and neurofibrillary tangles) with hypertension as exposure, either collected retrospectively from medical records or prospectively measured at clinical evaluation(s). We included prospective and retrospective cohort studies with individuals from general and selected (e.g. memory clinic) populations. We excluded case‐control studies.ResultsWe found 10 studies (total N = 3054, median 231 participants, range 50‐1288) that were very heterogeneous concerning populations, methodological approach and statistical analysis. Most studies reported no association between midlife hypertension and AD‐changes at autopsy. Two studies (total n = 1531) reported an association between hypertension and elevated numbers of neurofibrillary tangles and neuritic plaques. Of those studies, one reported that both a low and a high BP in late‐life was associated with an increased burden of amyloid plaques and tangles (U‐shape).ConclusionsOur study shows no consistent association between blood pressure and AD‐neuropathology. However, based on our results, we speculate that the association between hypertension and AD‐neuropathology is age‐dependent, and that U‐shaped relations may have been obscured in linear analyses. Future studies could take this phenomenon into account when investigating the relation between hypertension and AD neuropathology.
Putative role of β‐arrestin 2 in regulating TNF signalling to NFκB pathway
Authors: Salai Kaung Htet Tun , Lee Jasinda , Dawe Gavin Stewart , Lai Mitchell Kim Peng 
Published: December 2020

AbstractBackgroundNeuroinflammation is one of the features observed in neurodegenerative diseases, and inflammatory cytokines and chemokines are two of the important players in the neuroinflammatory responses. β‐arrestin 2 has also been reported to play a crucial role in regulating cytokines and chemokines release as the loss of β‐arrestin 2 leads to an increase in the sepsis‐induced inflammation. However, the role of β‐arrestin 2 in regulating the TNF mediated cytokines and chemokines production is poorly understood.MethodStable β‐arrestin 2 knockdown (KD) and negative control (NC) SH‐SY5Y clone cells were used for this study. Subcellular fractionation was used to investigate the cell surface TNF‐R1, and co‐immunoprecipitation (co‐IP) was performed to determine for the possible interaction between TNF‐R1 and β‐arrestin 2. Immunoblotting was used to investigate P65 phosphorylation status. Lastly, cytokines and chemokines mRNA expressions were quantified using Real Time‐PCR after TNF treatment.ResultSubcellular fractionation showed significantly more TNF‐R1 remained on the cell membrane fraction of KD compared to NC. Using NC cells, co‐IP showed the possible interaction between TNF‐R1 and β‐arrestin 2. KD also demonstrated significant increase in P65 phosphorylation compared to NC, along with significantly higher mRNA expressions of cytokines and chemokines.ConclusionThese results suggest that prolong TNF‐R1 on the membrane, possibly due to the lack of desensitization by β‐arrestin 2, may have led to an increase in the P65 phosphorylation, and resulting in a significant increase in the cytokines and chemokines mRNA expressions. Hence, our findings established the important role of β‐arrestin 2 in the TNF mediated NFκB pathway, and cytokines and chemokines production.
Race but not sex differences in incidence of dementia diagnosis among older veterans
Authors: Kornblith Erica S , Peltz Carrie , Xia Feng , Barnes Deborah E , Byers Amy L , Yaffe Kristine 
Published: December 2020

AbstractBackgroundAlthough the U.S. military is increasingly diverse, the impact of sex and race on incidence of dementia diagnosis among older Veterans is unknown.MethodWe compared incidence of dementia diagnosis among self‐reported race groups (Non‐Hispanic White, Non‐Hispanic Black, Hispanic, and Asian) and by sex among a random sample of all Veterans > 65 years in the Veterans Health Administration between 10/1/2003 and 9/30/2015. We included Veterans without baseline prevalent dementia (over a 2‐year baseline) with >1 visit during the follow‐up period (< 12 years). Dementia was defined as inpatient/ outpatient diagnoses using International Classification of Disease 9th Edition (ICD‐9) codes recommended by the VA Dementia Steering Committee, dementia medication prescription, or both. We calculated crude incidence by age, sex, and race; and conducted Cox models adjusted for age and sex/race. We further adjusted models for education, income, cardiac/metabolic, and military (post‐traumatic stress disorder, traumatic brain injury) risk factors.ResultThe analytic cohort included 497,127 Veterans (mean age 75.4) after excluding 18,314 with baseline dementia and 11,058 without follow‐up. About eight percent (n=40,352) were diagnosed with dementia during follow‐up. Overall incidence increased by age (50/1000 people, ages 65‐74; 112/1000 for 75‐84, and 116/1000 among 85+; p<0.001). Across all ages, males’ incidence (81/1000) was similar to females’ (77/1000; p=0.10); adjusted Hazard ratio (HR) for females vs. males: 0.96, 95% Confidence Interval (CI) 0.89‐1.03. Hispanic Veterans had highest incidence (154/1000), while Asian veterans had lowest (71/1000); incidence for white Veterans was 79/1000, and 101/1000 for Black Veterans. Compared to white Veterans, Asian Veterans had borderline lower risk of dementia diagnosis (HR: 0.87, 95% CI 0.76‐1.01), and Black (HR: 1.61, 95% CI 1.55‐1.66) and Hispanic Veterans (HR: 1.80, 1.68‐1.93) had increased risk. The pattern of results was similar after full adjustment (Hispanic HR 1.59, 95% CI 1.48‐ 1.71; Black HR 1.49, 95% CI 1.44‐1.54; Asian HR 0.89, 95% CI 0.77‐1.04).ConclusionAmong older U.S. Veterans, there were differences in incidence of dementia diagnosis by race: Black and Hispanic Veterans had almost two‐fold greater risk compared to white Veterans. Asian Veterans had lower risk. Females and males had similar incidence. These results highlight health disparities requiring further study.
Quality of life scores predict incidence of dementia: Results from PREADViSE
Authors: Ding Xiuhua , Abner Erin L , Schmitt Frederick A , Kryscio Richard J 
Published: December 2020

AbstractBackgroundThe Medical Outcomes Study Questionnaire Short Form 36 health survey (SF‐36) measures health‐related quality of life (QOL) from the patient’s point of view and is an indicator of overall health status. QOL measures may show differential changes over time prior to dementia onset.MethodsWe analyzed data from the Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non‐demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF‐36 assessments at annual visits were included in the current analysis. Two summary scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean 50 with standard deviation of 10. Linear mixed models (LMM) were applied to determine how SF‐36 scores varied over time and by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline SF‐36 scores were associated with dementia incidence, adjusting for baseline age, race, APOE‐4 status, diabetes, and self‐reported memory complaint at baseline.ResultsThe mean of MCS at baseline for subjects with dementia diagnosis later (mean± SD: 53.86±9.47) was significantly lower than for subjects without dementia diagnosis (mean± SD: 56.42±6.48) (p = 0.005), while the means of PCS at baseline (Dementia: 49.31±7.93 vs. Non‐dementia: 49.77±7.81) were not significantly different (p = 0.54). The LMM analysis showed a significant effect only for time in PCS. For MCS, the indicator for dementia was significantly associated with poorer self‐reported mental health after adjusting baseline age, black race, and memory complaint. Given adjustments for other risk factors, results from the Cox model showed that a 10‐unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%‐55%).ConclusionThe SF‐36 MCS summary score may be a predictor for future dementia and could be useful in longitudinal dementia research.