bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cobalt‐Catalyzed Multi‐Substituted Alkene Synthesis from 1,3‐Dithiolanes and Grignard Reagents
Authors: Davidson Timothy A. , Anam Samiha , Shi Heyao , Dixon Darren J. 
Published: June 2023

AbstractThe cobalt‐catalyzed reaction between 1,3‐dithiolanes and Grignard reagents, for the efficient synthesis of multi‐substituted alkene products, is described. The method was applicable to a variety of benzylic dithiolane substrates, affording di‐, tri‐, and tetra‐substituted 1,1‐diaryl alkene products in good to excellent yields. The use of benzylic Grignard reagents with aryl aldehyde‐derived 1,3‐dithiolanes enabled access to natural product‐derived stilbene architectures with exquisite E selectivity. The operational simplicity, low catalyst loadings, and scalability demonstrate the general utility of the method.
Health‐economic innovation headroom in mild cognitive impairment due to Alzheimer’s diseas
Authors: Handels Ron , Jönsson Linus 
Published: June 2023

AbstractBackgroundEstimating health‐economic impact of new therapies for prodromal Alzheimer’s disease (AD) requires extrapolating short‐term effects on surrogate markers of efficacy to long‐term clinically relevant outcomes. This requires assumptions on the nature of the treatment (symptomatic versus disease‐modifying) and depends on the target population (which varies in disease progression associated to biological subtypes). We aim to estimate the innovation headroom (potential value) of AD treatment in mild cognitive impairment (MCI), describe the impact of assumptions on treatment nature (symptomatic/disease‐modifying) and disease progression (fast/slow progressors), and discuss challenges for health‐economic evaluation of future AD treatments; to ensure patients timely access treatment innovations.MethodThe IPECAD open‐source decision‐analytic model was used to estimating time spent with MCI, mild, moderate and severe dementia, discounted quality‐adjusted life years (QALYs) and costs, under different treatment strategies. Innovation headroom was estimated by simulating a usual care strategy, and compare it with a strategy reflecting a fictive disease‐modifying treatment with 100% efficacy, and a strategy reflecting a fictive 100% efficacious symptomatic therapy; in preventing all individuals to progress to dementia.ResultThe innovation headroom analysis resulted in 4.1 additional QALYs and k€13 lower costs of care with disease‐modifying, and 0.8 additional QALYs and k€71 lower costs of care with symptomatic therapy. The higher QALY gain for disease‐modification is mainly explained by an indirect effect on mortality, resulting in a 5.5 year increase in life expectancy. The innovation headroom was about twice as large in the persons with fast progression compared to persons with slow progression in MCI. The disease‐modifying therapy mainly generated improved health (QALY gains), while the symptomatic therapy mainly generated savings in costs of care; which is contingent on their mortality assumptions.ConclusionThe potential health and economic benefit of (non‐)pharmacological interventions in MCI is substantial. However, its dependency on assumptions related to treatment nature argues for research efforts to better understand the relation between surrogate and long‐term outcomes. Its dependency on target population indicates a potential for individualized treatment based on profiles of disease progression. Finally, we recommend incorporating age‐related comorbidities as a result of the relatively large life years gained.
Role of natural herbs in management of psychological disorders prodromal to dementia
Authors: Khan Saara Ahmad Muddasir 
Published: June 2023

AbstractBackgroundDepression is one of the major psychological disorders and a prodromal sign of dementia and may worsen with metabolic disorders like diabetes mellitus. The present study was done to evaluate efficacy of saffron (Saf) and chamomile (Cham) against diabetes associated depression and memory impairment in murine model and through clinical trial in human volunteers visiting psychiatry clinics at the Aga Khan University Hospital, Karachi, Pakistan.MethodIn murine study, 50 old diabetic albino wistar rats divided into 5 groups as healthy control (HC), diabetic control (DC), Saf water decoction (WD) 10mg/kg, Cham water decoction (CWD) 30mg/kg and Saf+Cham WD 5mg/kg+15mg/kg for two weeks. The behavioral analysis was done through and novel object recognition tests (NOR). Afterwards, animals were sacrificed for blood and brain samples collection. ClinicalTrials.gov Identifier: NCT04935671 of 100 depressed patients were given Saf+Cham tea (20mg+1mg) as an adjuvant therapy for depression and were assessed through PHQ9 scale. The tryptophan level was examined through ELISA.ResultIn animals, treatment of Saf and Cham significantly reduced glucose levels (F4, 45 = 9.847, p<0.05). However, tryptophan (F4, 45 = 8.25, p<0.05), acetylcholine (F4, 45 = 69.9, p<0.05) and serotonin levels (F4, 45 = 116.200; p<0.05) in the brain were increased with improved NOR performance (F4, 45 = 55.718, p<0.05).The clinical trial also revealed significant improvement in PHQ 9 scale (F3, 80 = 20.036, p<0.05) with maintenance of tryptophan levels in the serum (F3, 80 = 5, p<0.05).ConclusionThe study was validated through murine model study showing augmentation of insulin and hence tryptophan entry in the brain through saffron and chamomile administration triggering synthesis of serotonin in brain. The other possible route may be the herbal modulation through acetylcholine levels supplementing serotonin levels in brain. The effects of ACh generated by both populations of cholinergic cells are mediated through pre‐ and postsynaptic receptors on a wide range of neuronal subtypes across the brain which contribute to multiple cortical and hippocampal functions. The clinical trial also showed strong modulating effects of herbal tea on metabolic profile and precursor amino acid with alleviation of depression, a prodromal sign of dementia.
Neurological and cognitive impairment in COVID‐19: clinical characterization andepidemiological
Authors: Júnior José Wagner Leonel Tavares , Neto Pedro Braga , Neto Manoel Alves Sobreira , MONTENEGRO RAQUEL CARVALHO , MOREIRA CAROLINE DE FÁTIMA AQUINO , de Oliveira Lais Lacerda Brasil , da Silva Jean Breno Silveira , Gomes Carmem Meyve Pereira , Gaspar Safira de Brito , Cunha Letícia Chaves Vieira , Sousa Artur Victor Menezes , Feitosa Werbety Lucas Queiroz , Oliveira Danilo Nunes 
Published: June 2023

AbstractBackgroundCOVID‐19 neurological manifestations were demonstrated during the pandemic, including cognitive impairment. Objectives: To determine the prevalence of cognitive and behavioral complaints (such as dementia, MCI or SCD) in a outpatient sample with recent SARS‐COV2 infection. Specific: Evaluate the association of cognitive impairment with the presence of the polymorphism found in the APOE gene and with respiratory diseaseMethodObservational, longitudinal, prospective clinical study. Inclusion criteria: patients with confirmed Covid‐19. Patients are evaluated in an outpatient clinic. They are evaluated through a standardized attendance record, with somatic and cognitive neurological assessment. Cognitive assessment involves the application of cognitive (ACER, MMSE and CDR), functional (Pfeffer) and psychiatric (GDS or Beck) screening instruments, in addition to subsequent extensive neuropsychological assessment. In addition, APOE polymorphism is analysed.ResultsTo date, 200 patients were evaluated. The average age is 46.5 years, with 65.4% female, 79.16% with 8 or more years of schooling, in addition to 57.5% of the sample with cognitive complaints.ConclusionsThe results so far in our study demonstrate that cognitive complaints are frequent in patients even in the chronic phase of the disease.
MBI‐apathy, ApoEɛ2, and risk for Alzheimer disease dementia
Authors: Vellone Daniella A , Ghahremani Maryam , Ismail Zahinoor 
Published: June 2023

AbstractBackgroundApathy, characterized by decreased interest, initiative, and emotional reactivity, is amongst the most common neuropsychiatric symptoms in dementia. However, apathy can emerge before dementia and constitutes a domain of mild behavioral impairment (MBI), an at‐risk state for incident cognitive decline and dementia. MBI‐apathy is the de novo emergence of persistent apathy in dementia‐free older adults and may be a driving factor in dementia risk conferred by MBI. Apolipoprotein E (ApoE) is a risk marker for Alzheimer disease (AD) dementia. Compared to ApoEɛ3 homozygotes, ApoEɛ2 carriers are 40% less likely to develop AD while ApoEɛ4 carriers are 3.2‐14.9 times more likely. We investigated the association between MBI‐apathy, ApoE, and incident dementia. We hypothesized that ɛ2 would have protective effects for MBI‐apathy associated risk, compared to ɛ3 and ɛ4.MethodDementia‐free participants in the National Alzheimer’s Coordinating Centre were stratified as MBI‐apathy and no‐NPS until dementia diagnosis, based on Neuropsychiatric Inventory Questionnaire scores at 2 consecutive visits. ApoE genotypes were categorized by ɛ2 (ɛ2/ɛ2, ɛ2/ɛ3), ɛ3 (ɛ3/ɛ3), and ɛ4 (ɛ4/ɛ3, ɛ4/ɛ4) alleles. Group characteristics were contrasted to determine covariate inclusion in regression modelling. Cox regressions assessed risk of incident dementia and included an interaction term for MBI‐apathy and ApoE allele.ResultsOf the 3,644 participants (3,022 Normal‐Cognition); 314 had MBI‐apathy (Table 1). Significant main effects were found for MBI‐apathy and incident dementia (HR:2.51, 95% CI:1.99‐3.17, p<0.001) as well as interaction effects with ApoE. In MBI‐apathy (ɛ3 as reference), the ɛ2 group had a 60% lower dementia risk (adjusted HR:0.40, 95% CI:0.19‐0.85) while ɛ4 had a 16% higher risk (adjusted HR:1.16, 95% CI:0.80‐1.69) (Figure 1). Of the 125 participants with apathy who progressed to dementia, 80.8% had AD. In the no‐NPS group (ɛ3 as reference), ɛ2 individuals had a 17% lower dementia risk (adjusted HR:0.83, 95% CI:0.52‐1.33) while ɛ4 individuals had a 177% higher risk (adjusted HR:2.77, 95% CI:2.13‐3.59) (Figure 2).ConclusionTo our knowledge, this is the first study examining the relationship between MBI‐apathy and ApoE status in determining dementia risk. Results suggest that ApoE modifies the association between MBI‐apathy and incident dementia with the ɛ2 allele acting as a protective factor.
Bidirectional Mendelian randomization analyses reveal APOE status mediates the effects of statin medications on Alzheimer’s disease
Authors: Guo Xingzhi , Chong Li , Zhang Xin , Li Rui 
Published: June 2023

AbstractBackgroundThere is currently no unanimous conclusion on the statin medications and Alzheimer’s disease (AD) risk, which has long been one of the most concerns in lipid‐lowering and anti‐atherosclerosis treatment. We performed a bidirectional Mendelian Randomization (MR) to evaluate whether there were causal links between statin medications and AD.MethodSingle nucleotide polymorphisms (SNPs) identified from genome‐wide association studies (GWAS) were used as instrumental variables. One GWAS of statin medications (N = 462,933) and AD (N = 63,926) with summary statistics available was included in the MR analysis. All statistical analyses were conducted using the TwoSampleMR package with default parameters. Inverse variance weighted (IVW) was used as the primary method to calculate the causal estimates (β), accompanied by two complement methods, MR‐Egger and weighted median. Pleiotropic effects and heterogeneity driving causal association were also assessed.ResultIVW results showed that genetically predicted use of statins was causally associated with increased risk of AD (atorvastatin: β = 33.67, P = 0.048; simvastatin: β = 4.88, P = 0.044). However, after removing SNPs inside the apolipoprotein E (APOE) gene region (CHR19:45,111,942‐45,711,941 based on GRCh37/hg19), the causal links of statin medications on AD disappeared (Figure 1A). Two SNPs, rs429358 (C;C) and rs7412 (C;C) known as APOE4 mainly contributed to the controversial data involved in use of statins and AD risk. The results of reverse causal analysis showed that patients with AD tended to have a higher exposure to statins (atorvastatin: β = 0.005, P = 0.001; simvastatin: β = 0.012, P = 0.004). Consistently, when discarding the SNPs within the APOE gene region, no relationship was found between diagnosis of AD and statins exposure (Figure 1B). The directional horizontal pleiotropy and heterogeneities found in MR‐PRESSO global and MR‐Egger regression test were largely disappeared after excluding SNPs inside APOE cluster region.ConclusionOur results suggested that the inconsistent association between statins use and AD risk observed in previous observational investigations might be mainly attributed to various APOE status (APOE2, APOE3, and APOE4). Thus, it reminds clinicians that statins can be used with confidence in lipid‐lowering and anti‐atherosclerosis and are unlikely to affect AD risk.
Detecting age‐dependent deterioration of spatial working memory with a virtual water maze paradigm in human subjects
Authors: Wang Eileen Han‐Jie , Lai Frank Ho‐yin , Shiu Alice Tsz‐Yan , Wong Hui Yan , Leung Sharifa Wing‐Man , Chan Daniel Ting Hoi , Yee Benjamin K 
Published: June 2023

AbstractBackgroundVirtual‐Morris Water Maze (V‐MWM) has been developed to assess potential hippocampal‐dependent memory decline. Previous attempts showed the V‐MWM was sensitive in detecting age‐related reference memory decline, but our pilot study indicated that elderly often could not complete the tasks within 60s. Therefore, we have investigated further the use of a spatial working memory paradigm to evaluate one‐trial learning task allowing for up to 120s per trial.MethodsThree age groups were recruited from the community with a cross‐sectional design. The Young Adult (YA,n = 22), Young Elderly (YE,n = 30) and older elderly (OE,n = 19) groups defined according to the subjects’ age in years: 18‐45, 60‐69, and 70 or above, respectively. The V‐MWM was programmed using MazeWaker. Subjects navigated in a 3D circular arena, defined by uniform walls and presented on a 14‐inch screen using an arrow key. Eight distal 3D‐cues located outside the arena. A total of 8 possible locations assigned randomly to every two consecutive trials. The two trials were separated by 5s or interspersed by a comic strip for 15s. The target become visible after 120s. Working memory was indexed by more efficient navigation from trial‐1 to trial‐2 in terms of latency or path‐length, indexed by the ratio: T2/(T1+T2) and subjected to a 3×2×3 (AgexInterference typesxLocations) ANOVAs. Two 60s‐nonrevealing probe tests were conducted on trials 8th and 16th. Percent path‐length near the 8 possible target‐zones using separate 2×2×8 (Age groupsxInterference typesxTarget‐zones) ANOVAs.ResultsThe YA group outperformed both the YE and OE groups (F(2,68) = 8.17, p = .001), but no significant group by interference interaction was revealed. However, the 15s‐interference tended to increase the latency in both YA and YE groups (F(1,68) = 9.05, p<.005). An overall preference for the target zone was identified in both percent time and path‐length (F(7,62) = 6.03 and 8.71, respectively, p<.001), together with a significant Age x Zones interaction (F(14,126) = 8.71, p<.001) indicative of reduce target zone preference in the OE relative to YA, with YE performing at an intermediate level.Conclusionsur V‐MWM working test was sensitive to detect age‐related visual‐spatial working memory deterioration, but our interference procedures were insufficient to reduce working memory performance in all groups. Alternative interference may be considered in the future.
Biological risk factors for dementia in India
Authors: Crimmins Eileen M. , Farina Mateo , Wu Qiao , Kim Jung Ki , Zhang Xinyao 
Published: June 2023

AbstractBackgroundMany clinical biomarkers have been associated with dementia. This paper uses a novel data set from an understudied population – a national sample of older Indians ‐ to assess the relative importance of 41 biomarkers using a variety of approaches. The value of these data is the extensiveness of the biomarker collection, the validated classification of dementia, and the uniqueness of the population with low average education. Many approaches to both summarizing and reducing data complexity have been suggested. Some of these are based on theory about biological mechanisms and some are agnostic and based on machine‐learning approaches. The results are informative for others collecting and analyzing biomarker data in population samples.MethodWe use 6 approaches to assessing the value of the biomarkers in explaining variance in dementia diagnosis and cognitive functioning – some traditional social science approaches and some based on machine learning. The aim of the different approaches is to determine how to best characterize the influence of biology as well as how to trim and combine the data. The five approaches to measuring biological risk: 41 individual biomarkers; identification of subsets of biomarkers with elastic net; support vector machine learning; factors developed with factor analysis; a principal components approach; and a factor classification based on a theoretical approach.ResultsResults indicate if the aim is explain variance in dementia, all the biomarkers or a reduced set of biomarkers identified by elastic net do the best job at explaining variability. However, biological markers chosen as most important do not fit well our understanding of biological mechanisms.ConclusionIf the aim is understanding the relative importance of biological systems, traditional social science approaches, e.g. the factor analysis and principal components approach, allow better understanding and interpretation of the biomarkers associated with cognitive performance.
Behavioral interventions for persons with mild cognitive impairment: Longitudinal effect on partners with low adjustment
Authors: Ying Gelan , Chandler Melanie , Shandera‐Ochsner Anne , Smith Glenn E. , McAlister Courtney B. , Locke Dona E. 
Published: June 2023

AbstractBackgroundPartners of persons with mild cognitive impairment (pwMCI) show increased rates of depression and other mental health problems compared to the general population. While dyadic behavioral interventions such as cognitive rehabilitation have shown beneficial effects in reducing caregiver burden, research to date lacks consistent outcome measures and rarely focuses on distressed partners. Therefore, this study explored the longitudinal effect of the Healthy Action to Benefit Independence & Thinking® (HABIT) program on partners with relatively low initial adjustment level. We hypothesized that the HABIT program would improve partner adjustment in those who were distressed.MethodData from 322 pwMCI and partners were utilized from the HABIT IRB research registry. Among them, 240 completed HABIT while 82 served as an untreated control group. Consistent with our previous exploratory factor analysis, a composite partner adjustment score was calculated using the Center for Epidemiologic Studies Depression scale (CES‐D), the REACH Anxiety Inventory Form, and the Quality of Life scale for adults with Alzheimer’s Disease (QOL‐AD). We included partners with an adjustment score below the median of each group to focus on partners with low levels of baseline adjustment. Latent growth curve models were conducted at baseline, 3‐month, 6‐month, and 1‐year follow‐ups to investigate the trajectories of partner adjustment level.ResultIn the low adjustment subsample, no between group difference was found at baseline. An overall improvement in partner adjustment scores was observed only in the treatment group (b = 5.00, p<.001). The slope of change was larger (b = 3.75, p = .016) in the treatment group, indicating a faster improvement in adjustment level in HABIT partners with marginally lower baseline and higher follow‐up scores. This difference in the improvement rates was most evident at the 3‐month follow‐up (t(1, 94) = ‐2.63, p = .010) and gradually reduced in subsequent visits.ConclusionIn partners of those with MCI who have low levels of emotional adjustment, behavioral interventions like HABIT can be beneficial in accelerating improvement in their overall adjustment level and facilitate adaptation to their loved ones’ MCI symptoms compared to untreated controls. Techniques taught in dyadic interventions may serve as protective factors for mental health problems in primary caregivers of pwMCI.
Lateral temporal atrophy is a better visual scale to predict MMSE score than hippocampal atrophy in Alzheimer’s disease: A retrospective cross‐sectional study
Authors: Nguyen Khang Vinh , Tong Trang Mai , Pham Trung Thanh , Tran Son The , Nguyen Truc Thanh Tran , Tran Thang Cong 
Published: June 2023

AbstractBackgroundMini‐Mental State Exam (MMSE) is helpful in the cognitive evaluation and staging of Alzheimer patients (AD), but its score could be affected by acute medical conditions, depression, or anxiety. Conversely, head magnetic resonance imaging (MRI) is an independent diagnostic tool to evaluate specific cerebral pathology in AD patients. Many studies have investigated the correlation between head MRI visual scales such as hippocampal atrophy and baseline MMSE to aid in the diagnosis of AD. However, there has not been a study that evaluates the correlation between a comprehensive head MRI visual scale with baseline MMSE in AD patients.MethodWe retrospectively collected records of outpatients diagnosed as probable AD according to DSM V criteria in two dementia wards. Patients with age of onset before 65 years old were considered early‐onset AD patients. The comprehensive visual rating scale (CVRS) was used to semiquantitative structural lesions, including hippocampal, cortical, subcortical atrophy, and small vessel disease. The relationship between MRI lesions and baseline MMSE was evaluated using Bayesian model averaging (BMA) to control confounders. Data analysis was done using R‐4.0.3.ResultWe collected 65 AD patients with 21 (32.31%) early‐onset AD. Lateral temporal atrophy, level of education, and late age‐onset were the strongest independent predictors of baseline MMSE, while other structural lesions were not significant in the BMA model. Furthermore, hippocampal atrophy was only correlated with delayed recall, while temporal atrophy was correlated with orientations, attentions, language, and visual‐spatial.ConclusionOur study suggests that the lateral temporal atrophy correlates more with the baseline MMSE score in patients with AD than the hippocampal atrophy.