bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diabetes and stroke potentiate hippocampal inhibitory tone: A link to Alzheimer's disease/vascular dementia
Authors: Buitrago Luna , Li Jei , Neymottin Samuel , Barone Frank , Brickman Adam M. , Luchsinger Jose , Moreno Herman 
Published: December 2020

AbstractBackgroundMice expressing mutated hAPP in the entorhinal cortex (EC) display, hypersynchrony of the EC‐hippocampus circuit, caused by decreased inhibitory tone (Angulo et al., NBD 2017). A similar EC inhibitory failure was also observed in mice expressing hAPOE4, (Nuriel et al., Nat Neursc 2017). Here we evaluated changes in EC‐hippocampus synaptic plasticity and neuronal properties produced by two additional AD risk factors, diabetes and ischemic strokeMethodHippocampal synaptic plasticity and single cell recordings were made from leptin mutant (db/db, diabetes) and normoglicemic (db/+) heterozygous mice 4‐6 m.o. one month following stroke (transient middle cerebral artery occlusion (tMCAo) or sham surgery. tMCAo was produced by a monofilament occluding the origin of MCA for 30 minutes. Recordings were made from horizontal hippocampal slices in aCSF. Schaffer collaterals to CA1 evoked field excitatory postsynaptic potential (fEPSPs) were measured before and after induction of long term potentiation (LTP). Finally, miniature inhibitory post‐synaptic currents (mIPSCs) in CA1 pyramidal neurons were recorded, using the whole cell configuration of patch‐clamp technique.ResultBoth control and diabetic mice developed a paradoxical larger LTP at the CA3‐CA1 synapse after stroke (i.e. db/db‐sham vs. db/db‐stroke,% of slope EPSP change = 180+/−21% vs. 250+/−16% respectively, p < 0.05. Modeling with the program NEURON simulator suggested that this was due to loss of synaptic inhibition. We found that the peak amplitude of mIPSCs was smaller in CA1 neurons in the stroked hemisphere compared to the sham CA1 hemisphere in db/+ mice (db/+ sham vs. db/+ tMCAo = ANOVA; F = 14,99, p = 0.01). By contrast, CA1 mIPSCs frequency, but not amplitude, decreased in db/db tMCAo compared with db/db sham (F = 6.4, p = 0.022). The mean peak amplitude in db/db sham mice were significantly smaller than in db/+ sham mice (F = 6,2, p = 0.021)ConclusionThe data suggest that the observed difference in sham vs. tMCAo mIPSCs amplitude observed in db/+ mice is due to a post‐synaptic change in either GABA‐A receptor number or function. While, in db/db sham mice we observed a post‐synaptic inhibitory alteration, as seen in db/+ mice with stroke. After acute ischemia, an additional presynaptic inhibitory dysfunction in db/db occurs. Modeling suggests that the mechanism occurs via inhibitory synaptic pruning.
Educational intervention for primary care to improve the prevention and detection of dementia in two Latin American countries: The PREDES dementia trial
Authors: Roa‐Rojas Paloma , Martinez‐Ruiz Adrian , Parada Gabriel 
Published: December 2020

AbstractBackgroundThe worldwide prevalence of dementia is increasing, especially in Latin American countries like Mexico and Chile. Prevention and early diagnosis of dementia within primary care is important because it allows those with the disease and their care givers to engage with support services and plan for the future. However, evidence suggests that dementia remains under‐detected and sub‐optimally managed in general practice. Considering this, there are several studies about the effectiveness of educational interventions for improvement of detection rates and management of dementia in primary care, but they have showed mixed results. For example, practice‐based educational workshops are effective for improving rates of detecting dementia but not for changing clinical management. Hence, the challenge still is to find effective educational methods for prevention, detection and management of dementia. In this study, our main goal is to test the effectiveness of an educational intervention developed for general practice, designed to promote prevention detection and management of dementias in both countries, Mexico and Chile. The educational intervention combines practice‐based workshops and on‐line support materials. Its effectiveness will be tested in a two phases unblinded cluster randomised controlled trial with a pre‐post intervention design, with two arms; normal care versus the educational intervention. Primary care practices in both countries will be recruited with the aim of reviewing 400 clinical files. We will examine whether the educational intervention is effective within the primary care setting. Our primary outcome measure will be an increase in the proportion of patients who receive timely detection and propper channeling. We will also examine important secondary outcomes such as improvements in knowledge and attitudes towards dementia in both countries. Also as a secondary outcome, the benefits to patients in terms of quality of life will be evaluated. The PREDES trial builds on previous evidence about the effectiveness of educational interventions in improving timely detection and management of dementia in primary care. However, this intervention is different because it also considers prevention. If this trial is successful it could have implications for the implementation of the National Dementia Strategies in both countries.
Brain atrophy coupled to cognitive decline 3 years after stroke
Authors: Brodtmann Amy , Werden Emilio , Khlif Mohamed Salah , Bird Laura J , Bradshaw Jennifer , Egorova Natalia , Restrepo Carolina , Churilov Leonid , Cumming Toby 
Published: December 2020

AbstractBackgroundCardiovascular risk factors and stroke are associated with increased risk of all‐cause dementia. More than one third of stroke patients will develop dementia, but mechanisms are unclear. Vascular brain burden from accumulated risk factors may contribute to cognitive impairment at the time of stroke, with the stroke being yet another manifestation of vascular disease. We examined total brain volume (TBV) and hippocampal volume (HV) in a group of stroke patients 3 years after their clinical event. We compared those who were cognitively impaired (CI) at 3 months after stroke to those who were cognitively normal (CN). We hypothesized that CI patients would exhibit greater total brain volume loss over the ensuing 3 years than those with normal cognition.MethodThe Cognition And Neocortical Volume After Stroke (CANVAS) study is an observational cohort study of 135 patients with ischemic stroke examining brain volume and cognition over 3 years. All ischemic stroke types and etiologies were included. A history of cognitive impairment was an exclusion criterion. Participants were tested at baseline (within 6 weeks of stroke), 3 months, 1 year and 3 years after stroke. Total brain and hippocampal volume and neuropsychological testing were performed at each time‐point with the primary comparison being brain volume change between 3 months and 3 years. Only participants with usable MRI scans were included in this analysis (n=92). Clinical dementia panels were convened to produce consensus reports for CN, CI, or dementia.ResultAt 3‐months post‐stroke, 67 patients (67.4 years, 15 women) were cognitively normal and 25 were cognitively impaired (74.7 years, 11 women); none had dementia. Total brain volume decline was greater in the CI group (M = 30.67 cm3 n = 25) relative to the CN group (M = 19.63 cm3; SD = 13.84 cm3; n = 67). Hippocampal volume change between 3‐months and 3‐years was comparable in both groups.ConclusionTotal brain volume decline is greater over 3 years in stroke patients who have cognitive impairment at 3‐months post‐stroke. Hippocampal volume loss was not significantly associated with cognitive decline. Cognitive impairment at 3 months is associated with accelerated neurodegeneration in people with stroke.
Vascular risk and physical activity as modulators of cognitive and neurodegenerative trajectories: Independent and interactive effects with beta‐amyloid
Authors: Chhatwal Jasmeer P , Rabin Jennifer S , Yang Hyun‐Sik , Klein Hannah , Scott Matthew R , Kirn Dylan , Pruzin Jeremy J , Yau Wai‐Ying , Schultz Aaron P , Johnson Keith A , Sperling Reisa A 
Published: December 2020

AbstractBackgroundUnderstanding the extent to which vascular and lifestyle factors operate independently and synergistically with Alzheimer’s disease pathology is critical to designing optimized clinical trials and to assessing the efficacy of interventions to delay cognitive impairment. We examined this question by leveraging data from a longitudinal cohort study with detailed cognitive and multi‐modal imaging data (the Harvard Aging Brain Study; HABS).MethodWe used cross‐sectional and longitudinal data from HABS (n = 223; mean age at entry: 72y; mean follow‐up of 5.9y), including 11C‐Pittsburgh‐Compound‐B (PiB) amyloid PET, 18F‐Flortaucipir (FTP) tau PET, MRI, pedometer‐measured physical activity data, cognitive testing (Preclinical Alzheimer Cognitive Composite; PACC), and the Framingham Heart Study Cardiovascular Disease Risk Score (FHS‐CVD). Using linear mixed effects models, we examined the interplay of vascular risk factors, imaging measures of cerebrovascular injury, and physical activity with PET measures of b‐amyloid burden as they relate to longitudinal cognitive performance, neurodegeneration, and tau pathology.ResultWe observed that higher FHS‐CVD at study entry was predictive of poorer longitudinal cognitive performance on the PACC, alone and interactively with PiB‐PET (both p<0.001). Greater baseline physical activity (mean steps) was predictive of better longitudinal cognitive performance when interacted with PiB‐PET (p <0.001). Lower FHS‐CVD and greater physical activity were both predictive of less neurodegeneration (longitudinal MRI measures of hippocampal and gray matter volumes) when interacted with PiB‐PET (all p < 0.01). In the subset of participants with available tau PET, FHS‐CVD but not physical activity interacted with PiB‐PET to significantly predict cross‐sectional and longitudinal tau accumulation (p < 0.05). Diffusion but not FLAIR measures of white matter disruption added to FHS‐CVD in predicting cognitive decline.ConclusionTogether with many prior studies, these data indicate strong additive and/or synergistic effects of vascular risk and physical activity with b‐amyloid in prediction of longitudinal cognition, neurodegeneration, and tau accumulation. These results suggest interventions targeting physical activity and vascular risk in order to delay cognitive decline may be particularly effective in people with elevated β‐amyloid burden. Similarly, consideration of vascular and lifestyle factors may improve our understanding of the potential clinical effectiveness of anti‐amyloid and tau therapies currently in testing.
Cardiovascular and stroke risk, cognitive change, and mild cognitive impairment: Results from the HCHS/SOL and SOL‐INCA
Authors: Tarraf Wassim , Wu Benson , Ramos Alberto R , Gallo Linda , Stickel Ariana , Gonzalez Hector M , Vasquez Priscilla M , Daviglus Martha , Zeng Donglin , Schneiderman Neil , Lipton Richard B , Isasi Carmen R , Lamar Melissa , Smoller Sylvia , Cai Jianwen 
Published: December 2020

AbstractBackgroundCardiovascular and cerebrovascular health problems significantly increase risk for Alzheimer’s Disease and Related Dementias (ADRDs), and Hispanics/Latinos are arguably at higher risk for ADRDs compared to Whites. Middle‐age may be a crucial time in which cardiovascular health starts to notably impact cognition. Most research supporting connections between cardiovascular and cognitive health and ADRDs has been conducted with non‐Hispanic/Latino White samples. Diverse Hispanics/Latinos may differentially benefit from improvements in cardiovascular health to an equal or greater extent than Whites. The purpose of the study was to characterize the associations between mid‐life cardiovascular health and 7‐year change in cognition in diverse Hispanics/Latinos.MethodsWe used prospective data from middle‐age and older Latinos (45‐74 years and older at Visit1; 2008‐2011) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Visit 1) who were cardiovascular disease‐free and stroke/TIA‐free at Visit1 (unweighted n=3,345) to examine relationships between baseline cardiovascular health, assessed using the multiethnic Global Vascular Risk Score (GVRS), and change in cognition from Visit1 to Visit2 (SOL‐INCA; 2016‐2018), an average of 7‐years later, and Mild Cognitive Impairment (MCI) prevalence at Visit2. In addition to MCI, cognitive outcomes included global and domain specific (verbal learning and memory, verbal fluency, executive functioning, attention, and psychomotor speed tasks) cognitive change. We fit survey generalized linear regressions to model the associations between the cardiovascular risk exposure and our cognitive outcomes and examined modifications by sex and age.ResultsAdjusting for covariates, higher GVRS scores (10% increments) were associated with more pronounced decline (SD units) in global (β=‐0.35; SE=0.06; p<0.001) and domain specific cognitive performance. Higher GVRS scores were also associated with higher odds ratio of MCI (OR=1.59; 95% CI=[1.10;2.38]; p=0.023) at Visit 2. We found no statistical evidence to support sex or age modifications in the associations between GVRS, cognitive change, and MCI.ConclusionCardiovascular and stroke risk is associated with accelerated cognitive decline and an increased risk of MCI. Effects did not differ by age. These results raise the possibility that vascular risk factor modification in Hispanics/Latinos may promote successful cognitive aging and reduce the risk for MCI.
The novel omega‐6 fatty acid docosapentaenoic acid positively modulates brain innate immune response for resolving neuroinflammation at early and late stages of humanized APOE‐based Alzheimer’s disease models
Authors: Ma Qiulan‐Ma , Zhu Chansheng , Caoili Kaitlin , Frautschy Sally A. , Cole Gregory M 
Published: December 2020

AbstractBackgroundNeuroinflammation has been well established to play a crucial role in the pathogenesis and progression of Alzheimer’s disease (AD), and strong epidemiological studies have shown clear evidence of nonsteroidal anti‐inflammatory drugs (NSAIDs) for preventing the onset of AD in middle‐aged people, but NSAIDs and all other anti‐inflammatory drugs such as selective cyclooxygenase 2 (COX2) inhibitors have failed to treat moderate to severe or early stage AD in clinical trials. In this study, we report the mechanism and efficacy of omega‐6 fatty acid linoleic acid (LA) on the reduction and resolution of neuroinflammation at early and late stages of humanized APOE‐based AD models. We found that the novel LA metabolite docosapentaenoic acid (DPAn‐6) has robust anti‐inflammatory and neuronal protective effects in old ApoE4x5FAD mice with pre‐existing severe amyloid burden, gliosis, behavior deficits and neurodegeneration.MethodTwo different ages of ApoE4x5FAD animals were used for the study. First, 3 to 4‐month‐old adult ApoE3x5FAD and ApoE4x5FAD were treated by dietary linoleic acid for four months. Secondly, 11 to 14‐month‐old ApoE4x5FAD mice were treated by oral DPAn‐6 for three weeks. Treatment efficacy was analyzed by novel object recognition, ELISA, RNAseq and immunohistochemistry.ResultWe found that dietary LA reduced proinflammatory cytokines and COX2 gene expression and resolved neuroinflammation evidenced by reduced IL1&beta and IL6 but increased anti‐inflammatory IL‐10 in adult ApoE3x5FAD and ApoE4x5FAD mice. In this study, the high LA diet increased its CNS metabolite DPAn‐6 greater with ApoE4. Thus, we further tested DPAn‐6 in old ApoE4x5FAD administering by gavage for three weeks. DPAn‐6 significantly reduced microgliosis, astrogliosis, innate immune inflammatory and caspase gene expression. In parallel, DPAn‐6 coordinately increased BDNF, VGF, ADCYAP1 and neuronal pentraxin 2 expression, indicating increased neurotrophin and plasticity‐related gene expression relevant to novel object memory improvement. In addition, COX expression was also reduced by LA or DPAn‐6 in vivo and in vitro amyloid‐&beta42 oligomer‐challenged microglial BV2 cells.ConclusionTaken together, we demonstrated that a novel n‐6 fatty acid docosapentaenoic acid modulated innate immune responses to resolve neuroinflammation at early and late stages of AD models with or without ApoE4. This was accompanied by synaptic, neuronal and cognitive benefits.
Pre‐clinical development of a blood‐brain barrier (BBB)‐penetrating anti‐amyloid‒β fusion protein
Authors: Chakravarthy Balu , Comas Rosa , Atkinson Trevor , Menard Michel , Brunette Eric , Jiang Susan , Haukenfrers Julie , Charlebois Claudie , Delaney Christie , Dudani Renu , Aylsworth Amy , Tauskela Joseph , Haqqani Arsalan , Rennie Kerry , Pon Robert , Agbayani Gerard , Bihun Craig , Akache Bassel , McCluskie Michael , Guhados Ganesh , Callaway Jim , Gillard John , Yoganathan Nathan , Stanimirovic Danica 
Published: December 2020

AbstractBackgroundWe have developed a blood‐brain barrier (BBB) crossing anti‐amyloid fusion protein KG207 as a potential AD therapeutic. This humanized bi‐functional molecule was generated by fusing an Aß oligomer (AßO)‐ binding peptide (ABP) with a BBB carrier FC5 via IgG‐1 Fc fragment. Present study shows that KG207 crosses the BBB in vitro and in vivo (mouse, rat and dog), penetrates target regions of the brain (cortex and hippocampus) and engages parenchymal Aß. KG207 neutralizes AßO‐induced toxicity in vitro and does not stimulate pro‐inflammatory cytokine production in mouse microglia. Studies demonstrated that KG207 was safe up to 300 mg/kg.MethodRecombinant KG207 was produced in CHO cells. BBB‐permeability was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat, mouse and dog) models. AßO binding was determined by ELISA. Following iv injection, serum, CSF and brain levels of KG207 and Aß were assessed by nanoLC‐ MRM, ELISA and Western blot methods. Aß toxicity studies were done in human neuroblastoma (SH‐SY5Y) cells and rat primary cortical neuronal cells. Following exposure to KG207, cytokine levels in BV2 microglia were measured using Millipore Luminex assay kit. Safety studies were done in Sprague Dawley rats at 30, 100 and 300 mg/kg.ResultKG207 retained both Aß‐oligomer binding activity and BBB‐permeability in vitro. When injected iv into rats and mouse, KG207 rapidly appeared in the CSF and brain parenchyma (cortex and hippocampus) indicating active transport of ABP across BBB by FC5 in vivo. In AD transgenic mice, KG207 treatment showed a significant reduction of brain Aß levels. KG207 significantly reduced AßO‐induced toxicity in both human neuroblastoma cells and primary cortical neurons in vitro. KG207 blocked AßO binding to cellular proteins in vitro. KG207 did not activate BV2 mouse microglia and induce pro‐inflammatory cytokines. No adverse effects were seen in rats injected with up to 300 mg/kg, including neurotoxicity.ConclusionCollectively, these results indicate that KG207 can effectivey cross the blood‐brain barrier, penetrate the brain and facilitate Aß clearance in vivo. In vitro data suggest that KG207 can safely clear Aß without eliciting pro‐inflammatory cytokine secretion by microglia.
Cultural differences in end‐of‐life care planning for persons with dementia: Comparison of U.S. and Korean cases
Authors: Ha Jung‐Hwa , Lee Changsook 
Published: December 2020

AbstractBackgroundProviding good quality care at the end of life is important not only for cognitively‐intact patients but also for people who have dementia. In order to respect the patients’ preferences for end‐of‐life care (EOLC) among persons with dementia (PwD), it is critical to engage in advance care planning before PwDs lose cognitive functioning. However, even if health practitioners perceive such needs, they may be constrained by social and cultural factors in initiating conversations about EOLC. This study examined cultural differences in EOLC planning for PwDs using the case study method. We conducted in‐depth interviews with 7 social workers who work in South Korea, 2 Korean American social workers working with Korean‐American older adults in the US, and 3 American social workers who work in the community and hospice settings serving diverse populations. We asked about participants’ opinion about advance care planning(or EOLC) for PwDs, whether and how they engage in discussions on EOLC, obstacles in their efforts to engage in these discussions, suggestions for improving EOLC and decision making for PwDs. We conducted content analysis and extracted themes relevant to our research questions. Results show that social workers in Korea feel reluctant to engage in advance care planning for PwDs because older adults as well as their caregivers do not want to talk about death. Compared to social workers in Korea, social workers working in the Korean American communities in the US engage in EOLC planning with their clients more frequently, but they wait until they find opportunities to talk about EOLC, such as death of their client’s family of friends. On the other hand, social workers working in the non‐immigrant communities in the US perceived advance care planning as a way to ensure self‐determination and autonomy in EOLC decision making and offered opportunities to prepare for EOLC even when their clients did not bring up the issues. Implications for culturally sensitive practice and ways to improve awareness on the importance of EOLC planning in death‐avoiding cultures are discussed.
Regional variability and solubility of apolipoprotein E in brains from patients with Alzheimer’s and Parkinson’s disease
Authors: Twohig Daniel , Karampatsi Dimitra , Edlund Anna K. , Nielsen Henrietta M. 
Published: December 2020

AbstractBackground
APOEε4 is the strongest genetic risk factor for both Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and increases the severity of Lewy pathology in Parkinson’s disease (PD) and DLB1. Interestingly, nearly all familial PSEN1 mutation‐carrying AD patients exhibit Lewy pathology specifically in the amygdala2 and higher CSF α‐synuclein levels in APOEε4‐carrying asymptomatic familial AD patients were linked to amyloid‐β pathology3. Further, brain‐area specific intraneuronal accumulation of soluble α‐synuclein was previously reported in AD patients4 and an enrichment of ApoE was described in dopaminergic neurons of PD patients5. Together the accumulating evidence suggests an intricate interplay between APOEε4, ApoE and α‐synuclein in both PD/DLB and AD. Here we investigated the levels and molecular size distribution of ApoE4 and total ApoE in three different brain areas from PD and AD patients.MethodFresh‐frozen tissue (Netherlands Brain Bank) from the medial frontal lobe, medial temporal lobe and amygdala of neuropathologically confirmed AD (n=3) and PD (n=3) patients with an APOEε3/ε4 genotype was lysed and fractionated to yield tris‐buffered saline (TBS) soluble and TBS‐Triton X‐100 (TBX) soluble protein fractions. Western blotting, densitometry and statistical analysis were then used to identify, quantify and compare levels of total ApoE and ApoE4 in the two fractions from each brain area.ResultTBS‐soluble levels of monomeric ApoE4 were higher in PD patients versus AD patients specifically within the amygdala (p=0.046), the same fractions also contained high molecular weight ApoE bands (90‐95kDa) that were significantly enriched in the AD patients (p=0.028) The TBX‐soluble fractions from the frontal gyrus of PD patients exhibited lower levels of fragmented (28‐30kDa) ApoE4 (p=0.047) and total ApoE compared to AD patients.ConclusionElevated levels of TBS‐soluble monomeric ApoE4 in the amygdala of PD patients compared to AD patients and increased fragmentation of TBX‐soluble ApoE and specifically ApoE4 in AD patients together suggest an implication of ApoE4‐specific processes that differ between PD and AD.