bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lifespan diffusion MRI reveals structural abnormalities in the 5xFAD model of Alzheimer’s Disease
Authors: Noarbe Brenda P , Jullienne Amandine , Silvola Rebecca , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Persohn Scott C , Territo Paul R , Obenaus Andre , AD MODEL 
Published: December 2022

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium has been established to develop the next generation of Alzheimer’s disease (AD) models based on human genomic findings. As new models are developed, phenotypic data are compared to established models, including the 5xFAD mouse model. We undertook measurements of diffusion metrics to characterize the temporal alterations in brain structure in male and female 5xFAD mice, including connectivity analysis between the hippocampus and infralimbic prefrontal cortex (PFC).Method5xFAD mice were compared to age‐matched littermates (C57BL/6J, WT) at 4, 8, and 12 months (mo). Mice underwent high resolution diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) at 9.4T (5 B0, 30 directions b=3000 mm2/sec) to assess regional white and gray matter. Regional tissue features were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps. Tractography was performed based on the AMBMC mouse atlas. 18F‐AV45 PET was performed in a separate cohort at 4, 6, and 12mo to quantitate amyloid β (Aβ) load.ResultElevated FA within hippocampal CA1 was first observed in 5xFAD males at 8mo, but at 12mo 5xFAD females had increased FA in bilateral CA1 compared to WT mice. Connectivity between CA1 and PFC found 12mo 5xFAD females had significantly increased RD along the tract with concomitant increases in MD and AxD. AV45‐PET uptake was increased at 6mo (∼20%) and remained elevated at 12mo (∼25%) in the PFC in male and female 5xFAD compared to WT. In the hippocampus there was a ∼20% increase in AV45 binding at 6mo, that then declines by 12mo in 5xFAD mice.ConclusionPhenotyping of mouse models using DTI identifies altered brain connectivity and regional tissue modifications that may be indicative of increasing Aβ deposition. These data support that increasing Aβ deposition results in altered DTI metrics and connectivity using clinically relevant imaging modalities.
Assessment of High Risk for Alzheimer’s Disease Using Plasma Biomarkers in Subjects with Normal Cognition in Taiwan: A Preliminary Study
Authors: Hu Chaur‐Jong , Yang Shieh‐Yueh 
Published: December 2022

AbstractBackgroundIn Alzheimer’s disease (AD), cognitive impairment begins 10‐15 years later than neurodegeneration in the brain. Plasma biomarkers are promising candidates for assessing neurodegeneration in people with normal cognition. It has been reported that subjects with the concentration product of plasma amyloid β 1‐42 and total Tau protein, i.e. Aβ1‐42 x T‐Tau, higher than 455 pg2/ml2 are assessed as having a high risk of amnesic mild impairment (aMCI) or AD, denoted as high risk of AD (HRAD). The prevalence of high‐risk for dementia in cognitively normal controls is explored by assaying plasma biomarkers.MethodIn this work, 422 subjects aged 20 to 89 years were enrolled in seven cities around Taiwan. All enrolled subjects were clinically diagnosed with normal cognition. Plasma Aβ1‐40, Aβ1‐42 and T‐Tau levels were assayed for each subject using immunomagnetic reduction to assess the risk of dementia.ResultThe results in this study showed that 4.6% of young adults (age: 20‐44 years), 8.5% of middle‐aged adults (age: 45‐64 years) and 7.3% of elderly adults (age: 65‐90 years) had HRAD. The percentage of individuals with HRAD dramatically increased in middle‐aged and elderly adults compared to young adults.ConclusionThe percentage of HRAD in cognitively normal subjects are approximately 10%, which reveals that the potentially public‐health problem of AD in normal population. Although the subject having abnormal levels of Aβ or Tau is not definitely going on to develop cognitive declines or AD, the risk of suffering cognitive impairment in future is relatively high. Suitable managements are suggested for these high‐risk cognitively normal population. Worth noting, the attention should be paid to preventing cognitive impairment due to AD, not only in elderly adults but also middle‐aged adults. More subjects should be enrolled in the future to validate the percentage of people with normal cognition with HRAD.
SUVN‐I7016031: A Novel M1‐receptor Positive Allosteric Modulator (M1‐PAM) for the treatment of Parkinson's Disease Associated Dementia
Authors: Grandhi Venkata Ramalingayya , Ganuga Narender , Medapati Rajesh Babu , Tadiparthi Jayaprakash , Jayarajan Pradeep , Shinde Anil K , Badange Rajesh Kumar , Nirogi Ramakrishna 
Published: December 2022

AbstractBackgroundParkinson's disease (PD) patients experience progressive cognitive decline over the time and as the disease progresses. Drug‐induced Parkinsonism (DIP) is the second‐most‐common etiology of parkinsonism in the elderly after Parkinson's disease. DIP is indistinguishable from pathological PD as the symptoms are similar for both conditions. Haloperidol is a classical antipsychotic, known for its propensity to cause parkinsonism, which can be accompanied with the cognitive impairment, due to the blockade of striatal dopamine D2 receptors and further the downstream antagonism of M1 receptors in the signaling cascade. Therapeutic potential of SUVN‐I7016031 was evaluated in an animal model reflecting PD associated dementia.MethodHaloperidol was supplied in water feeder bottles at 2 mg/kg, p.o. to induce PD associated dementia. Following one week of haloperidol supplementation, treatment with either SUVN‐I7016031 (0.3, 1, 3 and 10 mg/kg, p.o.) or rivastigmine (0.3 mg/kg, s.c.) was began and the treatments were continued up to 37 days. Social recognition task (SRT) was conducted on day‐13 and day‐37. In SRT, familiarization and recognition trials were conducted with a trial delay of 30 min. Social investigation time by adult rat with either familiar or novel juvenile rat was assessed during recognition trial and compared, along with discriminative index. Statistical analysis is carried out using GraphPad Prism software (Version 7.02).ResultAnimals treated with haloperidol did not discriminate the novel juvenile from the familiar juvenile and showed cognitive impairment on day‐13 and day‐37. Rivastigmine reversed haloperidol‐induced PD dementia on day‐13 and day‐37. SUVN‐I7016031 at 10 mg/kg, p.o., reversed haloperidol‐induced PD dementia on day‐13 of testing. However, on day‐37, SUVN‐I7016031 reversed haloperidol‐induced PD dementia at 1, 3 and 10 mg/kg, p.o. which resulted in dose‐dependent positive efficacy. Further, rivastigmine and SUVN‐I7016031 treatment also resulted in significant improvement of discriminative index relative to haloperidol control on day‐37. Effects observed with SUVN‐I7016031 are more prominent on day‐37 relative to day‐13.ConclusionSUVN‐I7016031 showed positive efficacy in an animal model reflecting PD associated dementia, which could be a future promising therapeutic strategy in improving health related quality of life (hQOL) in PD patients.
A Trait‐like Component of Subjective Memory Concern in Men from Average Age 38 to 67 Years
Authors: Bell Tyler Reed , Beck Asad , Franz Carol E , Gillespie Nathan A. , Reynolds Chandra A. , Williams McKenna E. , Kremen William S. 
Published: December 2022

AbstractBackgroundSubjective memory concern is a risk factor for dementia in older adults, yet it also appears to be stable over time. Few studies examine memory concern starting in midlife in cognitively normal adults or the role of genetic influences on memory concern. We focused on the stability of subjective memory concern from early midlife into older adulthood and its association with objectively assessed episodic memory and depressive symptoms. Using a classical twin design, we assessed genetic and environmental influences on longitudinally‐assessed subjective concern and its overlap with episodic memory and depressive symptoms.MethodWe examined 1,334 community‐dwelling men assessed in the Survey of Health and the Vietnam Era Twin Study of Aging, who were assessed for subjective memory concern at average ages 38, 56, 62, and 67. Objective episodic memory and depressive symptoms were assessed at 56, 62, and 67. Biometric twin models were used to estimate genetic and environmental influences over time, and correlated genetic and environmental influences between measures.ResultSubjective memory concern was highly stable after average age 38 and not significantly associated with age. Phenotypic models showed that subjective memory concern was more related to depressive symptoms (β = .46) than with episodic memory (β = ‐.12) within timepoint, as shown by non‐overlapping confidence intervals. There were no significant lagged associations of subjective memory concern with episodic memory or depressive symptoms. Heritability of subjective memory concern was 51% and remained stable over time; 49% of the variation was attributed to unshared environmental influences. There were also significant genetic correlations between subjective memory concern and both episodic memory and depressive symptoms.ConclusionSubjective memory concern was stable from age 38 to age 67, and over half of the variance was explained by genetic influences. There was also significant genetic overlap with depressive symptoms and episodic memory. The stability and heritability results provide strong support for a trait‐like component of subjective memory concern. To be most useful as an indicator of imminent cognitive decline and increased risk for dementia, it will be important to differentiate dynamic aspects of subjective concern from its trait‐related dimension.
Sex‐specific mediational effects of microglial activation on Alzheimer’s disease proteinopathy in older adults
Authors: Casaletto Kaitlin B , Nichols Emma , Aslanyan Vahan , Simone Stephanie M. , Rabin Jennifer S. , La Joie Renaud , Brickman Adam M. , Dams‐O'Connor Kristen , Palta Priya , Kumar Raj G. , George Kristen M. , Satizabal Claudia L , Schneider Julie A , Pa Judy 
Published: December 2022

AbstractBackgroundWomen show disproportionate burden of Alzheimer’s disease (AD) pathology and higher AD dementia prevalence compared to men, yet the mechanism(s) driving these vulnerabilities are unknown. There is sexual dimorphism in immunologic functioning and neuroimmune processes are implicated in AD genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex.Method187 decedents (64% female; 89 years‐old at death; 62% non‐demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid‐β, and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA‐DP‐DQ‐DR) and morphological staging (stage I, II, or III). Amyloid and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modeling, we estimated the mediational effect of microglial activation on the amyloid to tau relationship in the whole sample and stratified by sex (amyloid→ microglial activation→ tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation→ amyloid→ tau).ResultMicroglial activation significantly mediated 67% (95%CI 32‐90) of the relationship between amyloid and tau in the whole sample; however, stratified analyses suggested this effect was stronger and only statistically significant in women. 57% (95%CI 20‐100) of the effect of amyloid‐β on tau was mediated through microglial activation in women, compared to 19% (95%CI 0‐62) in men. Secondary models suggested that mediational effects were driven by cortical versus subcortical microglial activation. Alternative models suggested that in women, microglial activation was a significant exposure both preceding the amyloid‐β to tau relationship (50%, 95%CI 22‐89) and directly related to tau burden (50%, 95%CI 11‐78). In contrast, in men, only the direct effect of microglial activation to tau reached significance (74%, 95%CI 34‐99) (mediational effect: 25%, 95%CI 1‐66).ConclusionOur models suggest a reciprocal, bidirectional relationship between amyloid‐β and microglial activation that accounts for tau burden in women. In men, direct independent (non‐mediational) relationships between microglial activation or amyloid‐β with tau were observed. Microglial activation may be disproportionately important for AD pathogenesis in women.
Sex Differences in the Effects of High Fat Diet on Neuroinflammation in a Mouse Model of VCID
Authors: Salinero Abigail E , Abi‐Ghanem Charly , Mansour Febronia , Kordit David , Riccio David , Venkataganesh Harini , Kelly Richard D , Robison Lisa S , Gannon Olivia J , Kopec Ashley , Zuloaga Kristen L 
Published: December 2022

AbstractBackgroundNeuroinflammation plays a central role in the progression of vascular contributions to cognitive impairment and dementia (VCID). Unfortunately, anti‐inflammatory therapeutics have proven insufficient so far at ameliorating the progression of VCID. This may be because broadly suppressing inflammation prohibits its beneficial functions. Instead, supporting endogenous inflammation resolving programs may prove more effective. Mid‐life metabolic disease is a major risk factor for VCID, particularly in women. Therefore, we examined neuroinflammation at middle‐age in both males and females with VCID. We modeled metabolic disease via long‐term administration of a high fat (HF) diet, and VCID via unilateral carotid artery occlusion surgery which results in chronic cerebral hypoperfusion. We hypothesized that metabolic disease would lead to more adverse cognitive and neuroinflammatory effects in middle‐aged females compared to males in a mouse model of VCID.Method8.5 month old male and female C57BL/6J mice were placed on a HF or control diet for 7 months. At month 3, they received VCID or sham surgery. At month 6, cognitive function was assessed. Half of the brains were collected for histology while the other half were flash frozen for qPCR analysis of pro‐inflammatory and pro‐resolving mediators.ResultHippocampal‐dependent spatial memory was impaired in VCID males, regardless of diet; however, in females, both HF diet and VCID (or a combination of the two) impaired spatial memory. In males, HF diet increased microglial activity in the hippocampus. Additionally, HF diet in combination with VCID surgery increased expression of pro‐inflammatory markers as well as pro‐resolving mediators in males. However, females on a HF diet experienced a suppression of microglia activity in the hippocampus. HF‐fed females, regardless of surgery, had decreased expression of both pro‐inflammatory markers as well as pro‐resolving mediators.ConclusionIn line with clinical findings, these data suggest that metabolic disease increases cognitive deficits to a greater extent in middle‐aged females than males. Further, our data suggest VCID with metabolic disease increases neuroinflammation and its resolution in males, while metabolic disease suppresses neuroinflammation and its resolution in females. This highlights the need for a better understanding of the sex differences in neuroinflammation following vascular injury.
The Utilization of Nature‐Based Virtual Reality (VR) Practice for the Wellbeing of Older Adults with Dementia
Authors: Kim Yongseop , Lee Jungjoo , Nuseibeh Betsey Zenk , Jung Miyeon J , Kim Junhyoung 
Published: December 2022

AbstractBackgroundDespite abundant evidence supporting the health benefits of nature‐based programs and activities, older adults with dementia experience practical limitations to their participation in these nature‐based activities. Utilizing a Nature‐based Virtual Reality (VR) Program can be a good alternative to outdoor nature activities by minimizing physical and structural barriers that older adults with dementia often encounter. Thus, the purpose of this study was to assess the changes in the emotional health and health‐related quality of life among older adults with dementia after the Nature‐based VR program participation.MethodThis study used a single‐group pre‐post design. Six participants were contacted for recruitment from a memory care unit and five were enrolled. Inclusion criteria were as follows: (a) clinically diagnosed with dementia, (b) have no prior VR experience, (c) basic communication skills, and (d) age between 65‐90 years old. Five participants engaged in the Nature‐based VR program which was offered twice a week for 20‐30 mins during the 5 weeks for a total of 10 sessions. Emotional health and health‐related quality of life were assessed at baseline and immediate‐post intervention. Emotional health was assessed using the Observed Emotion Rating Scale. Caregiver‐observer assessed the levels of five emotions by marking one of six pre‐defined time intervals. Health‐related quality of life was assessed using Alzheimer’s disease‐related quality of life. These items constitute four domains, physical health, mental health, social, and financial domains, and are measured with a 4‐point scale. The summed score of the scale ranges from 13 to 52, and a higher score indicates a higher quality of life for the care recipients.ResultFrom paired t‐test analysis, increased emotional wellbeing was detected. Specifically, the mean score of alertness increased from 4.50 points in pre‐intervention to 5.00 in post‐intervention while anger decreased from 1.67 to 1.00 and anxiety scores decreased from 1.50 to 1.00 points, respectively. Health‐related quality of life improved after the intervention. The QOL‐AD mean scores changed from 38.8 to 41.2 and median value was shifted from 38.5 to 44.0.ConclusionThis study provides preliminary evidence that the Nature‐based VR program may improve emotional health and health‐related quality of life.
Visualization of tau oligomers in TauP301L‐BiFC transgenic mice exhibits the progression of tauopathy
Authors: Lim Sungsu , Pae Ae Nim , Kim Yun Kyung 
Published: December 2022

AbstractBackgroundAccumulation of abnormal tau aggregates in the brain is a pathological hallmark of multiple neurodegenerative disorders including Alzheimer’s disease (AD). Increasing evidence suggests that soluble tau aggregates play a key role in tau pathology as neurotoxic species causing neuronal cell death and act as prion‐like seeds mediating tau propagation. Despite the pathological relevance, there is a paucity of methods to monitor tau oligomerization in the brain. Therefore, we have developed a novel tau transgenic mouse model as a tool to monitor tau self‐assembly in the brain.MethodWe introduced bimolecular fluorescence complementation (BiFC) technique to human tau containing a P301L mutation to generate a novel tau transgenic mouse, named TauP301L‐BiFC. Tau self‐assembly, represented by BiFC fluorescence was monitored and quantified in the brain of transgenic TauP301L‐BiFC mice. Behavior and biochemical differences were assessed between 3 and 12 months for the characterization of TauP301L‐BiFC mice. In vivo efficacy of methylene blue, a tau aggregation inhibitor, was evaluated for further validation of TauP301L‐BiFC mice as an in vivo model of tauopathy.ResultsTauP301L‐BiFC mice showed soluble tau oligomerization from 3 months, showing significantly enriched BiFC fluorescence in the brain. Then, massive tau fragmentation occurred at 6 months showing dramatically decreased TauP301L‐BiFC fluorescence. The fragmented tau species served as a seed for insoluble tau aggregation. In a result, insoluble TauP301L‐BiFC aggregates co‐aggregated with endogenous mouse tau accumulated in the brain, showing subsequently increased BiFC fluorescence from 9 months. Neuronal degeneration and cognitive deficits were observed from 12 months of age. Administration of methylene blue significantly reduced tau‐BiFC fluorescence in the brain of TauP301L‐BiFC mice, presenting a significant decrease in the level of matured tau‐BiFC complexes in the soluble brain lysates. TauP301L‐BiFC mouse model demonstrated that methylene blue reduced the amount of soluble tau oligomers in the brain, resulting in the prevention of cognitive impairments.ConclusionThe tau oligomerization was able to monitor and quantify in the brain of TauP301L‐BiFC mice. Thus, we assure that TauP301L‐BiFC mice are a bonafide animal tool to monitor pathological tau oligomerization in AD and other tauopathies.
Characterising the prodromal phase of dementia with Lewy bodies
Authors: Jensen Clara Mellergaard , Waldemar Gunhild , Vogel Asmus , Frederiksen Kristian Steen 
Published: December 2022

AbstractBackgroundThree subtypes of prodromal dementia with Lewy bodies (DLB) have recently been proposed. This study investigates the frequency of symptoms in the prodromal phase of DLB.MethodPatients diagnosed with DLB between the 1st of February 2017 and 1st of February 2021 were retrospectively identified and matched to a group of patients with Alzheimer’s disease (AD). Patient case files were reviewed identifying the first symptoms and symptoms in the prodromal phase (cognitive impairment, psychiatric symptoms, delirium/acute confusional episodes, RBD, motorsymptoms indicative of Parkinson’s disease, anosmia, and autonomic dysfunction).ResultsA retrospective cohort of 166 DLB patient and 168 AD patients were included. Of the proposed subtypes in patients diagnosed with DLB, 30% presented with cognitive impairment at onset in isolation, 6% with psychiatric symptoms, and 2% with delirium/acute confusional episodes (Figure). Eighty‐three percent of DLB patients had two or more non‐cognitive symptoms in the prodromal phase. Further, 82 % had at least one psychiatric symptom, and 33 % had an episode with delirium/acute confusional episode in the prodromal phase. Of other possible subtypes, Rapid eye movement sleep Behaviour Disorder was found at onset in 22% with a mean prodromal length of 8.4 years (as opposed to 4.3 years in DLB generally)ConclusionWe found no supportive evidence of the proposed clinical subtypes of prodromal DLB. Our findings indicate that RBD subtypes may exist, but further research is needed.