bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subjective cognitive decline and comorbid chronic conditions among United States veterans, 2015‐2018
Authors: Gupta Sangeeta 
Published: December 2020

AbstractBackgroundSubjective Cognitive Decline (SCD) is the self‐reported persistent decline in cognitive performance not detected objectively by neuropsychological tests (1). Epidemiological data have shown that individuals with SCD are at increased risk of progression to Alzheimer’s disease (AD) and related dementia (1). Veterans are at higher risk for Alzheimer’s as a consequence of traumatic brain injury, post‐traumatic stress disorder, and/or service‐related injuries (2). Co‐morbid chronic conditions create additional issues related to cost, medical care, and care giving. Some chronic conditions (diabetes, obesity, myocardial infarction, stroke, high cholesterol and high blood pressure) may further increase the risk for developing AD (1‐3). The objective of this study was to use data from the Behavioral Risk Factor Surveillance System (BRFSS) to examine the prevalence of SCD; functional limitations and comorbidity with chronic conditions in US veterans.MethodCombined BRFSS data for 2015 through 2018 (n= 1815211) were analyzed. 10.6% self‐identified as veterans (n=235683). Multiple chronic conditions (MCC) were defined as 2 or more chronic conditions that affect a person at the same time (4). 12 chronic conditions: angina, arthritis, asthma, cancer, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, high blood pressure, high cholesterol, heart attack, obesity, and stroke were used in the analyses.ResultAmong veterans, 12.9 % reported SCD. Of the veterans reporting SCD: 93.3% were males; 79.4% White Non‐Hispanics and 52.4% reported functional difficulties. SCD prevalence increased with age, from 17.6% among veterans aged 45–54 years to 60.2% among those aged ≥65 years and was lower among college graduates (19.5%) compared to those with less than college education (80.5%). More than fifty percent veterans (51.8%) reporting SCD had not talked to a health care professional. Burden of co‐morbid diabetes, smoking, obesity, myocardial infarction, stroke, high cholesterol and high blood pressure had a significant association with SCD. 77.5% of veterans reporting SCD had MCC.ConclusionAs a precursor to dementia, including Alzheimer’s, early assessment of cognitive issues in veterans is critical. Significant association of chronic conditions with SCD is disturbing. Identifying the burden of associated chronic conditions can further support veteran health providers in ensuring appropriate and timely case management.
Deep phenotyping of the 5xfAD mouse model by MODEL‐AD
Authors: Forner Stefania ,   MODEL‐AD
Published: December 2020

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODELAD) has been established as a consortium consisting of University of California Irvine, University of Indiana, University of Pittsburgh, Jackson Laboratory and Sage Bionetworks to develop the next generation of Alzheimer’s disease (AD) models and institute a standardized and rigorous process for characterization of animal models. One of the goals is to further characterize and deep phenotype well utilized early onset AD models, such as the 5xfAD model. This model is known for recapitulating many AD‐related phenotypes and have a relatively early and aggressive presentation.MethodBehavioral assays, Long‐term potentiation (LTP) recordings from acute hippocampal slices, RNA‐seq, immunofluorescent histology, and biochemical assays were performed in male/female 5xfAD mice and compared to age‐matched littermates (C57BL/6J) mice at 4, 8, 12 and 18 months.Result5xfAD mice exhibit robust plaque deposition, present throughout the brain by 4 months of age, with plaque numbers and sizes increasing with age, alongside increases in detergent soluble and insoluble Aβ38, Aβ40 and Aβ42 levels in both hippocampus and cortex. Concomitant with plaque deposition are increases in microglia densities, and expression of GFAP by astrocytes. Reductions in NeuN+ neurons are seen from 4 months of age in the cortex. Female mice show increased plaque and Aβ burden, and associated changes in glial cells, compared to male mice, but this may be due to observed increased transgene expression from the Thy1 promoter in female mice. Strong behavioral deficits are seen in the elevated plus maze from 4 months of age, compared to wild‐type controls, as well as robust LTP deficits.ConclusionIn summary, 5xfAD mice have a range of cognitive and motor deficits and severe amyloid pathology. All data sets and protocols will be made widely available to the scientific community. For more information, see model‐ad.org.
Subjective cognitive decline, anxiety symptoms, and the risk of mild cognitive impairment and dementia
Authors: Liew Tau Ming 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) and anxiety symptoms both predict neurocognitive disorders, but the two correlate strongly with each other. It is unclear whether they reflect two independent disease processes in the development of neurocognitive disorders, and hence deserve separate attention. This cohort study examined whether SCD and anxiety symptoms demonstrate independent risks of mild cognitive disorder and dementia (MCI/dementia).MethodThe study included 11,522 participants aged ≥60 years and diagnosed with normal cognition at baseline, recruited from Alzheimer’s Disease Centers across USA. The participants were evaluated for SCD and anxiety symptoms at baseline, and followed‐up almost annually for incident MCI/dementia (median follow‐up 4.5 years; interquartile range 2.3–7.4 years). SCD and anxiety symptoms were included in Cox‐regression to investigate their independent risks of MCI/dementia.ResultSCD and anxiety symptoms demonstrated independent risks of MCI/dementia, with HR 1.3 (95% CI 1.1–1.6) and 1.9 (95% CI 1.7–2.1) respectively. Co‐occurring SCD and anxiety symptoms demonstrated the highest risk (HR 2.6, 95% CI 2.0–3.4) – half of the participants in this group developed MCI/dementia within 6.2 years of follow‐up (95% 4.4–8.1), compared to 12.3 years in participants without SCD or anxiety (95% CI 12.1–12.6).ConclusionThe findings suggest that clinicians should not dismiss one over the other when patients present with both SCD and anxiety, and that both constructs may potentially be useful to identify high‐risk populations for preventive interventions and trials. The findings also point to the need for further research to clarify on the neurobiological distinctions between SCD and anxiety symptoms, which may potentially enrich our understanding on the pathogenesis of neurocognitive disorders.
Elucidating the role of the AD risk factor Pyk2 in tau‐induced neuronal dysfunction
Authors: Brody Alex Harrison , Strittmatter Stephen M. 
Published: December 2020

AbstractBackgroundGenetic deletion of the AD risk factor Pyk2 exacerbates tau‐associated phenotypes in PS19 (MAPT P301S) animals, a well described mouse model for tauopathy.MethodAging studies and assessment of spatial memory impairment were conducted on PS19;Pyk2 knockout mice. Histological assessment of tau pathology and hippocampal cell layer thickness was also conducted. Pyk2's role in phosphorylating disease relevant residues of tau was assessed through pharmacological inhibition of Pyk2 in acute hippocampal slice preparations from PS19 animals.ResultGenetic deletion of Pyk2 results in the exacerbation of early death phenotype and spatial memory impairment observed in PS19 animals. Genetic deletion of Pyk2 also results in the exacerbation of tau pathology as well as reduction in dentate gyrus cell layer thickness in PS19 animals. Pharmacological inhibition of Pyk2 results in an increase in tau phosphorylation (pTau S202/T205).ConclusionPyk2 is protective against tau‐associated phenotypes in PS19 mice, and basal Pyk2 activity limits tau phosphorylation at disease relevant residues.
Nutritional status and structural brain changes in MCI, AD and controls: The NUDAD project
Authors: Verhaar Barbara JH 
Published: December 2020

AbstractBackgroundWeight loss has been shown to be detectable more than ten years prior to Alzheimer disease (AD) diagnosis and is associated with higher morbidity, mortality and progression of cognitive decline. We aimed to investigate associations between nutritional status, including weight loss and body composition, and MRI measures of cerebral atrophy and cerebrovascular pathology in patients with mild cognitive impairment (MCI), AD dementia and controls.MethodsWe included 412 patients from the NUDAD project, comprising 129 patients with AD dementia (68±8 years, 48%F, MMSE 24[21‐26]), 107 patients with MCI (67±8 years, 63%F, MMSE 27[25‐28]), and 176 controls (61±8 years, 62;54%F, MMSE 29[27‐29]). Body mass index (BMI), fat mass (FM), fat free mass index (FFMI), waist circumference and mini nutritional assessment (MNA) scores were measured as indicators of nutritional status and transformed to Z‐scores. On MRI, we performed visual ratings (medial temporal atrophy (MTA, 0‐4), global cortical atrophy (GCA, 0‐3), white matter hyperintensities (WMH, 0‐4), microbleeds (0; 1‐2; 3‐5; >5)). Associations between nutritional status and MRI measures were analyzed using linear regression, adjusted for age, sex, syndrome diagnosis and cardiovascular risk factors.ResultsMCI and AD patients had lower BMI, FM and total MNA scores than controls. Lower BMI (ß ‐0.09 (‐0.16; ‐0.01), p<0.05) and lower FFMI (ß ‐0.11 (‐0.22; 0.00), p<0.05) were associated with higher MTA scores, but not with GCA, WMH or microbleeds. Lower FM (ß ‐0.13 (‐0.24;‐0.02), p<0.05) and lower waist circumference (ß ‐0.14 (‐0.25;‐0.02), p<0.05) were associated with more microbleeds, but not with MTA, GCA or WMH scores. Stratification by syndrome diagnosis showed that the observed associations of FM and waist with microbleeds were only significant in MCI patients.ConclusionIn our memory clinic cohort, lower indicators of nutritional status were associated with more MTA and microbleeds, two MRI markers indicative of underlying AD pathology; with strongest associations in MCI and amyloid‐positive controls. Our findings indicate that nutritional status has a role in the development of AD, either as early consequence of the underlying pathology or as an aggravating factor.
Resistance to tau and amyloid pathology supports super‐aging
Authors: Hönig Merle C , Willscheid Niclas , Bischof Gerard N , van Eimeren Thilo , Drzezga Alexander ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundNot much is known about the aging‐associated in vivo accumulation of proteinopathies such as amyloid‐β and tau‐pathology in super‐agers (i.e. individuals performing cognitively above the norm even at high age). Here, we examined the intracerebral amyloid and tau burden in a group of super‐agers (SA), normal‐agers (NA) and patients with mild cognitive impairment (MCI) using PET imaging.MethodData used for analysis were retrieved from the Alzheimer’s Disease Neuroimaging Initiative database and included three age‐ and education‐matched groups of 26 SA, 25 NA and 25 MCI patients, all above 80 years of age. SA were defined as individuals performing above average on the ADNI memory score over a 4‐year period including the time point of the PET scan acquisition. NA presented average and MCI patients below average cognitive performance in this time period. In addition, a group of younger cognitively‐normal, amyloid‐negative controls (YA; M(Age)= 63.2 years) was included as reference. [18F]AV‐1451 (tau) and [18F]AV‐45 (amyloid) PET scans were available for all individuals. The PET scans were pre‐processed including normalization to MNI space, smoothing and intensity standardization to the cerebellum. For statistical analysis, voxel‐wise comparisons (p < .001, uncorr.) and a region‐of‐interest analysis (p<.05, FDR corr.) were conducted, comparing tau and amyloid burden between the four groups, respectively.ResultNo significant difference were observed between SA and YA in terms of tau and amyloid burden. The NA group exhibited higher tau burden in inferior temporal and precuneal areas and no significant differences in amyloid burden, when compared to the YA group. The MCI patients showed both relatively higher amyloid and tau pathology burden.ConclusionThe phenomenon of super‐aging appears to be associated with the resistance to tau and amyloid pathology accumulation, which likely permits maintenance of high cognitive performance despite advanced age.
Longitudinal changes in FAQ scores by informant relationship
Authors: Culhane Jessica E. , Teylan Merilee , Gauthreaux Kathryn , Chen Yen‐Chi , Chan Kwun Chuen Gary , Mock Charles , Kukull Walter A. 
Published: December 2020

AbstractBackgroundInformant reports are assumed to reduce bias associated with self‐report of patients’ neurocognitive conditions, aiding clinicians in diagnosis. Prior studies have indicated that bias in informant reports may exist depending on relationship to the participant (spouse vs child). The Functional Assessment Questionnaire (FAQ) is an informant report of subjects’ functional ability in several domains. We investigated whether there are differences in FAQ score by informant relationship.MethodWe included participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) who had at least three visits with the same informant (spouse or child) and completed the FAQ. Using general linear and linear mixed models, we estimated the cross‐sectional difference in FAQ scores by informant relationship as well as the difference in the slope of FAQ scores over time, adjusting for participant and informant demographics, participant cognition, and participant residence type. We also evaluated whether there were differences in objective cognitive test scores over time by informant relationship using the Mini‐Mental State Exam (MMSE).ResultOf the 6,815 participants that met inclusion criteria, 77% had a spouse informant. At their initial visit, participants with a spouse informant were more likely to be younger, male, white, more educated, and living at home. In adjusted cross‐sectional analysis, spouse informants reported worse functional ability (higher FAQ score) than child informants (1.12 points, 95% CI: 0.74–1.51). In the adjusted longitudinal model, FAQ score increased 1.34 points per year (95% CI: 1.13– 1.55), and the FAQ score was an additional 0.15 points higher per year (95% CI: 0.02– 0.28) for participants with a spouse informant. However, participants with a spouse informant also had MMSE scores that were worse (0.26 points lower per year) compared to those with a child informant.ConclusionThe relationship of the informant to the participant may affect reporting on the FAQ. Cross‐sectionally, spouses of participants report higher FAQ scores (worse functional ability) than children, adjusted for cognition. Spouses also report higher increases in FAQ scores over time compared to children, although this difference may be due to changes in cognitive ability as measured by the MMSE rather than bias.
Nanostructured lipid‐loaded nerolidol ameliorate cyclophosphamide‐induced neuronflammation and cognitive dysfunction
Authors: Iqubal Ashif , Syed Mansoor Ali , Najmi Abul Kalam , Ali Javed , Haque Syed Ehtaishamul 
Published: December 2020

AbstractBackgroundCyclophosphamide‐induced neurotoxic manifestations (neuronal oxidative stress, neuroinflammation, apoptosis and dementia) is major limitation for clinicians and reduce the quality of life of patients. However, to date, there are no approved adjuvant therapy available to attenuate these neurotoxic manifestations. Therefore, in the current study we explored the neuroprotective effect of nanostructured lipid loaded nerolidol nanoformulation, which is a naturally occurring lipophilic sesquiterpene having potent anti‐oxidant and anti‐inflammatory potential.MethodMolecular docking study was performed to assertain the binding affinity of nerolidol with p65 subunit of NF‐kB. Nerolidol nanoformulation and nerolidol suspension were administered at the dose of 200 mg/kg, p.o for 14 days and neurotoxicity was induced in Swiss Albino mice by administrating a single dose of cyclophosphamide 200 mg/kg, i.p on 7th day. Forced Swim test, step down latency and Passive Avoidance test were formed. On 15th days animals were sacrificed, brain was removed and proceeded for the biochemical, histological and immunohistochemical study.ResultMolecular docking study showed significant binding of nerolidol with NF‐kB. Neurobehavioural study showed significant cognitive derailment, biochemical study showed increased oxidative stress, nitrative stress and neuroinflammatory markers. Histopathological study revealed significant damage to CA1, CA2, CA3 regions of hippocampus and frontal cortex. Immunohistochemical study showed increased expression of p‐NF‐kB p65 and cleaved caspase‐3. These neurotoxic effects were reduced by administrating nerolidol nanoformulation at the dose of 200 mg/kg where as nerolidol suspension at the dose of 200 mg/kg was found to be ineffective.ConclusionThe finding of the current study showed that cyclophosphamide induced significant neurotoxicity which was very well reversed by the nerolidol nanoformulation at the dose of 200 mg/kg. Nerolidol, thus, can be a future therapeutic molecule to counteract cyclophosphamide‐induced neuronal oxidative stress, neuroinflammation, apoptosis and dementia.
Genetic associations in Alzheimer’s disease: A systematic review and meta‐analysis
Authors: Hema Sree G.N.S , Marisse Lakshmi Prasanna , K Mamatha , Vithal Abhigjyna , Satish Kshreeraja S. , Rajalekshmi Saraswathy Ganesan , K. Radhika , Burri Raghunath R. 
Published: December 2020

AbstractBackgroundElucidation of genetic associations underlying Alzheimer’s Disease (AD) pathogenesis and progression is of prime importance in early diagnosis and drug discovery. Despite existence of innumerable studies to comprehend the genetic hallmarks of AD, inconsistencies amongst the studies in ascertaining specific genes involved in AD risk prompted this Systematic Review and Meta‐analysis.MethodThe review protocol was registered in Prospero (CRD42019127482). AD related Boolean search strategy was generated to retrieve case‐control studies evaluating genetic associations in AD patients from Pubmed/MEDLINE, Cochrane library, Proquest, Europe PMC, Grey literature, HuGE navigator, Latin American and Carribean Health Sciences literature published till March‐2019. Case‐control studies that defined AD diagnosis through standard diagnostic criteria were included. Preclinical and in‐silico studies were excluded. The shortlisted studies were critically appraised through New Castle Ottawa Scale (NOS) and Q‐Genie tool and the resultant data was extracted. Meta‐analysis was performed for Single Nucleotide Polymorphisms (SNPs) that were reported to be replicated in two different ethnicities by at‐least two studies through random effects model using Revman 5.3. Publication bias was assessed using Egger’s test, funnel plot, Begg and Mazumdar rank correlation test. Later, Interim Venice assessment and sensitivity analysis were executed to evaluate the credibility and versatility of the selected studies respectively.ResultAmong 352 285 studies retrieved, only 793 studies that met the eligibility criteria were critically appraised. This ultimately resulted in 118 studies for systematic review out of which, 23 SNPs corresponding to 15 genes were prioritized for meta‐analysis. The following SNPs were found to be significantly associated with AD risk: rs3865444 (CD33) (p = 0.04; I2 = 40%; OR [CI] = 0.88 [0.78‐0.99]), rs7561528 (BIN1) (p = 0.03; I2 = 46%; OR [CI] = 0.86 [0.76‐0.98]) and rs1801133 (MTHFR) (p = 0.007; I2 = 18%; OR [CI] = 0.73 [0.61‐0.88]). Interim Venice criteria revealed moderate credibility for seven SNPs and weak credibility for 16 SNPs. Further, sensitivity analysis confirmed the versatility of the selected studies.ConclusionOur findings acknowledged significant associations of three SNPs: rs3865444, rs7561528 and rs1801133 with Alzheimer’s risk. This evidence has to be replicated further to substantiate the role of aforesaid SNPs in AD.
Homocysteic acid in blood can detect mild cognitive impairment (MCI) and MCI due to Alzheimer disease (AD) pathological change
Authors: Hasegawa Tohru , Kosoku Yoshinori , Sano Yuka , Yoshida Hiroshi , Kudoh Chiaki , Tabira Takeshi 
Published: December 2020

AbstractBackgroundRecent our findings present a new early diagnostic marker for mild cognitive impairment (MCI), a pre‐stage of Alzheimer’s disease (AD). It may be a causative substance of AD and a therapeutic target. In the treatment of AD, it is thought to be most effective to intervene at the earliest and mildest stages. So it is desirable to use a biomarker that can be detected by a minimally invasive, cost‐effect technique.MethodThe participants of our study were between 60 to 90 years. The data set consisted of 12 participants with AD, 12 with MCI, and 9 cognitively normal individuals as Negative Control (NC) (33 in total).The study was approved by the research ethics committee of Kudoh Chiaki Neurosurgery Clinic. In the study, we measured TNF‐α, cortisol and ACTH by ELISA, and measured HCA, tau and phosphorylated tau by CLEIA.ResultWe evaluated which items were useful as diagnostic markers for MCI and AD by Receiver Operating Characteristic (ROC) analysis. In ROC analyses, for distinguishing diagnostic markers between NC and MCI, the ROC curve of HCA showed very high areas under the ROC curves (AUC). When 0.116 μM of HCA is chosen as the cut‐off, the sensitivity is 91.7% and the specificity is 77.8 %. In our results, the item of HCA was the most useful as a diagnostic marker for MCI. In ROC analyses, in distinguishing diagnostic markers between MCI and AD, the ROC curve of tau and p‐tau showed a very high AUC. When 17.0 pg/mL of tau and 5.9 pg/mL of p‐tau are chosen as the cut‐off, the sensitivity is 83.3%, 91.7% and the specificity is 91.7%, 75.0%, respectively.ConclusionOur results suggested that plasma HCA level is useful as early diagnostic markers of AD. This is because measured values of HCA increase in the stage of MCI, and are thus useful as a diagnostic marker for MCI. On the other hand, our results suggested that plasma tau and p‐tau are useful diagnostic markers for confirming disease progression, because their measured values are linked to cognitive decline and, thus, they are useful as diagnostic markers for AD.