bluuebunny/crossref_metadata_2025_split huggingface dataset:
Refining omega‐3 supplementation trials in APOE4 carriers for dementia prevention
Authors: Yassine Hussein N. , Cordova Isabella , He Xulei , Solomon Victoria , Mack Wendy J. , Harrington Michael G. , Braskie Meredith N. , Schneider Lon 
Published: December 2020

AbstractBackgroundDespite the observed association of the omega‐3s docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake or blood levels with Alzheimer’ disease (AD) incidence and cognitive outcomes, omega‐3 clinical trials have largely been negative. Carrying the APOE4 allele is the strongest genetic risk factor for AD. Therefore, identifying how APOE4 affects the response to omega‐3 supplementation can help refine newer and more personalized trials. DHA supplementation increases EPA levels and EPA has strong anti‐inflammatory effects. The ratio of EPA to arachidonic acid (EPA/AA) is a marker of tissue inflammation.MethodWe examined the effect of APOE4 on the change in plasma and cerebrospinal fluid (CSF) EPA/AA in two different clinical trials: the ADCS‐sponsored DHA trial in patients with mild AD (n=402), and the Brain DHA Delivery Pilot trial in cognitively normal participants (n=33). In both trials, participants were randomized to high doses of algal DHA (2 grams per day). A subset of the ADCS‐sponsored study underwent MRIs for measurement of hippocampal volumes (n=86).ResultPlasma EPA/AA was significantly lower in APOE4 carriers compared to non‐carriers after high dose DHA supplementation in both trials. CSF EPA/AA differed by APOE4 genotype in the Brain DHA Delivery Pilot, with APOE4 non‐carriers having two times greater increase in CSF EPA/AA than APOE4 carriers (30 vs. 14% increase, p=0.001) after supplementation. Greater increase in plasma EPA/AA was positively correlated with less decline in the right hippocampal volume (r=0.31, p=0.03) with APOE4 modifying this association (interaction p value, p=0.01, Figure 1).ConclusionAPOE4 appears to limit the conversion of DHA to EPA after DHA supplementation by promoting EPA’s mitochondrial oxidation. These changes start before the onset of dementia. We propose that the plasma EPA/AA can serve as a biomarker for DHA supplementation efficacy. Prospective validation of this biomarker can guide the development of more personalized omega‐3 interventions designed to reduce the increased AD risk with APOE4.
Legacy of a 10‐year multidomain lifestyle intervention on the cognitive trajectories of overweight and obese individuals with type 2 diabetes mellitus
Authors: Hayden Kathleen M. , Luchsinger Jose , Carmichael Owen T. , Dutton Gareth , Johnson Karen C , Kahn Steven , Rapp Stephen R. , Yasar Sevil , Neiberg Rebecca H. , Espeland Mark A. 
Published: December 2020

AbstractBackgroundLook AHEAD MIND was designed to examine whether a randomized clinical trial designed to induce and sustain long‐term weight losses led to cognitive benefit and to determine the role that baseline weight or history of cardiovascular disease (CVD) played in modifying this association.MethodParticipants (N=3,826; 45‐76 years) were randomized to an intensive lifestyle intervention (ILI) or to diabetes support and education (DSE). We derived a cognitive composite score based on standardized scores on the Look AHEAD battery of tests, including: Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, Modified Mini‐Mental State Exam, Trail Making Test (TMT) Parts A&B, and Stroop Color‐Word Test. Mixed effects models were used to determine whether random assignment to ten years of ILI or DSE would leave a legacy of different trajectories of cognitive function over 6‐8 subsequent years. Subgroups identified in our prior work as having potentially different intervention effects including those with BMI >=30 at randomization, and those who had a history of CVD at baseline randomization were studied.ResultThere were no significant differences in cognitive composite scores over time by intervention arm. However, there was a significant difference in performance on the TMT‐A (p<0.05), with individuals randomized to ILI performing better than the DSE group at the first two cognitive assessments. These relationships did not differ by baseline BMI. Analyses to examine interactions between baseline CVD status and intervention arm suggested those with baseline history of CVD randomized to ILI performed worse than the DSE group on the DSST (p=0.023) and the Stroop Test (p=0.003) over time. This trend for worse performance among ILI participants with CVD history was seen across all tests but only significant for the DSST and Stroop.ConclusionThere were no significant differences in long‐term cognitive performance by randomization arm with the exception of TMT‐A. Interactions by baseline CVD history on two tests of executive function were found, although all tests showed similar yet non‐significant results. Participants with a history of CVD at baseline do not appear to have received cognitive benefits from the ILI intervention.
Clonal Hematopoiesis of indeterminate potential and the risk of mild cognitive impairment or probable dementia in the Women’s Health Initiative Memory Study
Authors: Hayden Kathleen M. , Leng Xiaoyan Iris , Manson JoAnn E. , Desai Pinkal , Kitzman Jacob , Jaiswal Siddhartha , Whitsel Eric A. , Reiner Alexander P 
Published: December 2020

AbstractBackgroundClonal Hematopoiesis of Indeterminate Potential (CHIP) occurs when hematopoietic stem cells in bone marrow undergo somatic mutations and yield genetically distinct leukocyte subpopulations with increased expression of inflammatory genes in innate immune cells. Genes commonly mutated in CHIP are associated with DNA methylation, inflammation, generation of reactive oxygen species, and DNA damage response. Factors associated with CHIP, including inflammation, cardiovascular disease (CVD), metabolic disorders, and stroke are risks for Alzheimer’s disease and other dementias, however the association between CHIP and dementia is unknown. We examined the association between CHIP and the incidence of MCI or probable dementia over 22 years of follow‐up in the Women’s Health Initiative Memory Study (WHIMS). We also examined these associations by common driver mutations for CHIP.MethodWomen without a baseline (1993‐1998) history of stroke, who participated in WHIMS and had baseline blood sample, were followed with annual cognitive assessments, adjudication of MCI or probable dementia, and provided self‐report of dementia diagnoses for up to 22 years. CHIP was defined by whole genome sequencing through TOPMed. Proportional hazards models were used to examine survival to onset of cognitive impairment (mild cognitive impairment (MCI), probable dementia, or self‐reported dementia).ResultWe classified 934 women into two groups, CHIP (11%) and no CHIP (89%). A total of 300 women developed cognitive impairment by Year 22. Survival analyses for time to cognitive impairment was adjusted for baseline age, education, 3MS score, hypertension, diabetes, and BMI. There was no difference in risk of cognitive impairment between the women with and without CHIP (p = 0.63). When CHIP was categorized by gene‐specific driver mutations, survival free of impairment among women with DNMT3A mutations was not different from those without CHIP. Risk for impairment was higher among women with TET2 (HR 1.75, p=0.19). Overall results were not statistically significant, however power was limited by low numbers of women with CHIP (see Figure).ConclusionCHIP was not associated with cognitive outcomes overall but when stratified by the primary CHIP mutations (DNMT3A or TET2), different trends emerged. Future work in WHIMS will explore the cognitive performance over time by different CHIP mutations.
Linking electronic dementia care records to national inpatient data in dementia with Lewy bodies: Frequency, duration and cost implications of hospitalization and recording of delirium episodes
Authors: Mueller Christoph , FitzGerald James M , Perera Gayan , Rajamani Anto Praveen Rajkumar , Bhattarai Manorama , Price Annabel , Ballard Clive , Stewart Robert , Aarsland Dag 
Published: December 2020

AbstractBackgroundIncreased hospitalization is a major component of dementia impact on individuals and cost but has rarely been studied in dementia with Lewy bodies (DLB). In particular episodes of delirium and related hospitalizations have been described as a prodrome of dementia with Lewy bodies. Our aims were to harness a novel linkage between dementia/mental health care records and national hospitalization data in England to (1) describe risk and duration of hospital admissions in patients with DLB and (2) to assess the incidence of delirium recording before and after a diagnosis of dementia is established in patients with DLB and compare findings to a matched cohort of patients with Alzheimer’s disease (AD).MethodIn a large database of mental health and dementia care in South London we identified 194 patients with DLB and 1:4 matched these with 776 patients diagnosed with AD on age, gender, and cognitive status.ResultRates of hospital admissions in the year after dementia diagnosis were significantly higher in patients with DLB compared to patients with AD or the catchment population. Patients with DLB had on average almost four additional hospital days per person‐year than patients with AD and incurred higher hospitalization‐related costs. Further, patients with DLB had significantly more episodes of delirium recorded in the year before dementia diagnosis than patients with AD. Whereas the incidence of recording of delirium episodes reduced substantially in patients with DLB after dementia diagnosis, it remained significantly higher than in patients with AD.ConclusionPatients with DLB are more frequently admitted to general hospital and utilize inpatient care to a substantially higher degree than patients with AD. Establishing a diagnosis of dementia reduces episodes classified as delirium in patients with DLB and might lead to fewer potentially harmful interventions as hospitalization or use of antipsychotic medication. These data highlight an opportunity to reduce hospital days and episodes classified (and treated) as delirium by identifying DLB earlier and providing more targeted care focused on the specific triggers for hospitalization and associations of prolonged stay.
ATN classifications in a mixed cohort of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) pathology using cerebrospinal fluid neurofilament light chain (NFL)
Authors: Cousins Katheryn Alexandra Quilico , Phillips Jeffrey S. , Irwin David J. , Lee Eddie B. , Wolk David A. , Shaw Leslie M. , Gibbons Garrett S. , McMillan Corey T. , Trojanowski John Q. , Grossman Murray 
Published: December 2020

AbstractBackgroundThe ATN framework combines cerebrospinal fluid (CSF) amyloidβ 1‐42 (Aβ1‐42), phosphorylated tau (p‐tau), and total tau (t‐tau) to diagnose individuals along the continuum of Alzheimer’s disease (AD). While ATN profiles indicative of AD are highly accurate, profiles indicating normal, non‐AD pathology, or concurrent AD and non‐AD pathology are inconsistent, due in part to the insensitivity of t‐tau to non‐AD pathologies, such as frontotemporal lobar degeneration (FTLD). We test a modified framework that replaces t‐tau with neurofilament light chain (NFL), a CSF marker of axonal degeneration.MethodWe compare ATN classifications using t‐tau (ATNt) and NFL (ATNf) in an pathology‐confirmed autopsy cohort of 72 AD (3 with concurrent FTLD) and 26 FTLD (14 with concurrent low‐high AD). In an independent living sample, receiver operating characteristic (ROC) analyses defined an optimal NFL cut‐point using 18 hereditary FTLD (10 C9ORF72, 3 MAPT, 2 progranulin, and 3 TARDBP) and 27 matched control subjects without cognitive impairment. Published cut‐points (Shaw et al., 2009) defined A (Aβ1‐42<192 pg/mL), T (p‐tau>23 pg/mL), and Nt (t‐tau>93 pg/mL) status, and the above ROC‐threshold (NFL>1003 pg/mL) defined Nf status to create a CSF‐based ATNt and ATNf profile for each patient.ResultATNt and ATNf were equally likely to identify Alzheimer’s continuum disease based on Aβ1‐42. Fisher’s test indicated no difference in Nf‐positivity (41 of 72) and Nt‐positivity (44 of 72) for AD pathology (p=0.73). ATNf correctly identified 25 of 26 FTLD cases as non‐AD pathology; 21 FTLD cases were classified as non‐AD (A‐T‐Nf+/A‐T+Nf+), 4 as non‐AD and concurrent AD (A+T‐Nf+), and 1 misclassified as normal (A‐T‐Nf‐). Fisher’s test showed that ATNf was significantly more likely to identify FTLD as non‐AD pathology than ATNt (OR = 152.9, CI = 16 – 7639, p < 0.001); under ATNt, only 3 FTLD cases were classified as non‐AD (A‐T‐Nt+/A‐T+Nt+), while 19 were misclassified as normal (A‐T‐Nt‐) and 4 as early AD pathologic change (A+T‐Nt‐).ConclusionATNf designations using NFL were more accurate than t‐tau when assessing a mixed AD‐FTLD pathology cohort. Future biomarker strategies to detect both AD and non‐AD neuropathologies, such as FTLD, should consider alternative markers for N.
Theory of Mind in mild cognitive impairment: Relationship with the default mode network (DMN)
Authors: Michaelian Johannes Carapiet , McKinnon Andrew C , Mowszowski Loren , Duffy Shantel L , Guastella Adam , Naismith Sharon L 
Published: December 2020

AbstractBackgroundIt has been well established that older adults presenting with amnestic Mild Cognitive Impairment (aMCI) are not only at a higher risk of developing dementia compared to individuals with non‐amnestic Mild Cognitive Impairment (naMCI) and older adult controls, but also demonstrate impairments in Theory of Mind (ToM) ability, which has been associated with smaller limbic structure volumes. In the present study, we sought to examine any alterations in resting‐state functional connectivity within the brain's default mode network (DMN) in a sample of adults with MCI previously reported to demonstrate poorer ToM abilities.Methods17 adults with aMCI, 26 adults with naMCI and 16 older adult controls completed the Reading the Mind in the Eyes Test, followed by resting‐state functional magnetic resonance imaging.ResultsAfter controlling for age and correcting for multiple comparisons, adults with aMCI demonstrating poorer ToM abilities revealed significantly decreased functional connectivity between the left lateral temporal cortex (LTC) and the right temporal pole (b = .07, t(23) = 3.73, p = .02), as well as between the left LTC and both the left (b = .06, t(23) = 3.32, p = .03) and right (b = .04, t(23) = 2.91, p = .049) temporoparietal junctions ,relative to adults with naMCI.ConclusionsOur findings suggest that deficits in connectivity across a more widely distributed network of brain regions such as the DMN may be contributing to ToM deficits in aMCI, beyond the previously identified changes in limbic structure volumes. Moreover, in a broader clinical sense, these results contribute to a growing body of evidence highlighting that it is important to include measures of social cognitive function in the routine clinical workup of individuals with suspected MCI.
Identification of ADAMTS4 as an APP‐cleaving enzyme at 669 site in the APP669‐711 production pathway
Authors: Tomita Taisuke , Matsuzaki Masaya , Kaneko Naoki , Yokoyama Miyabishara , Yoshizawa Yota , Iwamoto Shinichi , Tanaka Koichi 
Published: December 2020

AbstractBackgroundAmyloid‐β peptide (Aβ) is deposited in the brains of Alzheimer disease (AD) patients, and proteolytically derived from its precursor protein, APP. APP669‐711 (a.k.a. Aβ(‐3)‐40) is a novel APP‐derived peptide detected in the plasma using immunoprecipitation‐matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry (IP‐MS). We have reported that the composite plasma biomarker, which is combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio, surrogates the accumulation of Aβ in brain (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014; Nakamura et al., Nature 2018). However, the mechanism of APP669‐711 production is largely unclear.MethodWe analyzed the effects of several inhibitors and genetic knockouts on the production of APP699‐711 in cultured cells.ResultEndogenous APP669‐711 was detected in the conditioned medium of BE2‐(C), Neuro2a and A549 cells by IP‐MS. Pharmacological experiments revealed that APP669‐711 is generated by sequential cleavages by GM6001‐sensitive metalloprotease at 669 site and γ‐secretase. Based on the preferences of the substrate sequence, we focused on ADAMTS4, which is the secreted metalloprotease with thrombospondin motif. Overexpression of ADAMTS4 resulted in the overproduction of APP669‐711, which was diminished by the catalytically inactivating mutation (i.e., E362A). Furthermore, endogenous APP669‐711 production was decreased in ADAMTS4 knockout cells.ConclusionThese results indicate that ADAMTS4 is involved in the production pathway of APP669‐711, a novel plasma biomarker for Aβ deposition in the brain.
Aquaporin4 facilitator decreases insoluble amyloid b of 5XFAD mouse brain
Authors: Kwee Ingrid L. , Igarashi Hironaka , Huber Vincent J. , Ueki Satoshi , Suzuki Yuji 
Published: December 2020

AbstractBackgroundMost brain degenerative diseases are recognized as pathologic protein accumulating diseases. To date, there have been no established treatments that promote clearance of pathological proteins. Enhancing clearance, and thus preventive reduction of accumulation of pathological proteins is an obvious target for new treatment development for this category of brain diseases. Aquaporin4 (AQP4) is one of the water channel proteins abundant in brain astrocytes, and controls excretion of metabolites from inside the brain parenchyma to the cerebrospinal fluid. It has been reported that a functional decline of AQP4 is one of the causes of intracerebral pathological protein accumulation diseases, such as amyloid‐β in Alzheimer's disease, and tau accumulation in head trauma. Therefore, promotion of AQP4 function can be expected to prevent/ameliorate intracerebral pathological protein accumulation. We administered TGN‐073, a small sized molecule that facilitates AQP4 function developed by our laboratory, to Alzheimer model 5xFAD mice and assessed its effect on Ab accumulation.Method1. Waste clearance disturbance in 5xFAD mice was assessed using the JJVCPE MRI method in 7month old 5xFAD mice and their litter mates. 2. 5xFAD mice were divided into two groups. One group received 400mg/kg TGN‐073 daily through gavage between the ages of 4 to 7months. The second group received the same volume of water. Soluble and insoluble amyloid b 40/42 was subsequently assessed in the hippocampus and cortex of these two groups.ResultTGN‐073 decreases insoluble amyloid b (Ab) 40 and Ab42 in Alzheimer transgenic mouse (5xFAD mice) brain parenchyma, whereas no significant difference was seen in the clearance of soluble Ab40 or Ab42.ConclusionWaste clearance from brain has been found to be reduced in AQP4 knockout mice and APP‐PS1 Alzheimer transgenic mice. The reduction in clearance is further found to be associated with a decrease in aquaporin 4(AQP4) function in an Alzheimer's disease model mouse. Part of Ab accumulation causation is evoked by reduced waste clearance in 5xFAD mouse. Our study shows that the AQP4 facilitator TGN‐073 prevented the insoluble Ab accumulation in 5xFAD mouse through facilitation of AQP4 activity.
Quality of life and disease burden in patients with MCI and dementia
Authors: Moon Woori 
Published: December 2020

AbstractBackgroundUnderstanding of Health Related Quality of Life (HRQoL) and disease burden from Mild Cognitive Impairment (MCI) and dementia is critical to properly manage growing clinical and social burden of cognitive disorder. While each type of cognitive disorders requires different management strategy, studies separately evaluating HRQoL and disease burden of different types of dementia are sparse. Particularly, there is no study estimating disease burden from MCI. Therefore, we investigated 1) the loss of HRQoL from each of MCI, Alzheimer’s Dementia (AD), Vascular Dementia (VD), and dementia total, 2) the disease burden of each disorder in Disability Adjusted Life Year (DALY) with population representative cohort data.MethodEuro‐QoL‐5D index scores and clinical data of 6,520 elderlies are derived from Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) cohort. We built a multiple linear regression model to estimate the adjusted impact of cognitive disorder on HRQoL. For calculation of DALY, disease specific prevalence, mortality, remission rate are obtained from Korean Longitudinal Study on Health and Aging (KLOSHA) and KLOSCAD cohort. The current and future DALY from MCI, AD, VD and total dementia is calculated by standardized method according to the World Health Organization’s guideline.ResultAfter adjustment of covariates, VD causes the most substantial HRQoL loss of ‐0.309, followed by AD (‐0.143) and MCI (‐0.017). Patients with CDR ≥2 experience significantly higher loss of HRQoL (‐0.498) than patient with CDR 1 (‐0.151) or CDR <1 (‐0.096). In 2015, DALY per 100,000 attributed to AD, VD and dementia total is 417, 237, and 931 respectively. The DALY from MCI (412 per 100,000) is almost same with that of AD. The projected DALY from MCI and dementia in 2065 (9,543 per 100,000) is more than seven times bigger than 2015 (1,343 per 100,000).ConclusionCognitive disorders, especially VD, cause significant loss of HRQoL in elderlies. The disease burden from MCI as well as dementia is substantial at present and rapidly grows. From MCI stage, the early efforts should be made to prevent HRQoL loss and to manage increasing disease burden. (Supported by Korean Health Technology R&D Project, Ministry of Health and Welfare, grant number HI15C3206.)
Decreased plasma Aβ levels were not associated with post‐stroke cognitive impairment
Authors: Lu Wenhui , Zhao Yi , Shang Suhang , Chen Chen , Wang Jin , Qu Qiumin 
Published: December 2020

AbstractBackgroundIt has been reported that stroke promotes the deposition of Aβ in the brain, which may be associated with post‐stroke cognitive impairment. Considering plasma Aβ is closely related to Aβ deposition in the brain, in the present study, we investigated the relationship between plasma Aβ levels and cognitive dysfunction after stroke.MethodA total of 138 patients of acute ischemic stroke (within 2 weeks of onset) who were hospitalized in the Neurology Department of the first affiliated hospital of Xi 'an Jiaotong University and 138 age‐matched controls were enrolled between Jan1, 2017, and Oct 30, 2018. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) was used to assess the pre‐existing cognitive status. A validated Chinese version of the Mini‐Mental State Examination was used to assess cognition. Fasting venous blood was taken in the morning and plasma Aβ42, Aβ40, sLRP1, and sRAGE levels were measured by ELISA. The relationship between plasma Aβ and cognitive impairment was analyzed using logistic regression analysis.ResultAmong acute ischemic stroke 138 patients, 37 patients met the criteria for cognitive impairment, the incidence of cognitive impairment was 26.81%. Plasma Aβ42, sLRP‐1 and Aβ42/Aβ40 ratio were decreased in the acute ischemic stroke group. While plasma Aβ40, Aβ42, sLRP‐1, sRAGE levels and Aβ42/Aβ40 ratio had no significant difference between cognitive impairment group and the normal cognitive group. The multivariate analysis showed that plasma Aβ40, Aβ42, sLRP‐1, sRAGE levels and Aβ42/Aβ40 ratio were not associated with post‐stroke cognitive impairment.ConclusionPlasma Aβ42, sLRP‐1 and Aβ42/Aβ40 ratio were decreased after acute ischemic stroke, however, the levels of plasma Aβ and transports were not associated with post‐stroke cognitive impairment.