Paradigm Shift: Cardiovascular Health in the Elderly-Beware of the Brain.

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Myeloid cells in vascular dementia and Alzheimer's disease: Possible therapeutic targets?

Growing evidence supports the suggestion that the peripheral immune system plays a role in different pathologies associated with cognitive impairment, such as vascular dementia (VD) or Alzheimer's disease (AD). The aim of this review is to summarize, within the peripheral immune system, the implications of different types of myeloid cells in AD and VD, with a special focus on post-stroke cognitive impairment and dementia (PSCID). We will review the contributions of the myeloid lineage, from peripheral cells (neutrophils, platelets, monocytes and monocyte-derived macrophages) to central nervous system (CNS)-associated cells (perivascular macrophages and microglia). Finally, we will evaluate different potential strategies for pharmacological modulation of pathological processes mediated by myeloid cell subsets, with an emphasis on neutrophils, their interaction with platelets and the process of immunothrombosis that triggers neutrophil-dependent capillary stall and hypoperfusion, as possible effector mechanisms that may pave the way to novel therapeutic avenues to stop dementia, the epidemic of our time.Spanish Ministry of Science and Innovation (MCIN), Grant/Award Number: PID2019-106581RB-I00; Leducq Foundation for Cardiovascular Research, Grant/Award Numbers: TNE19CVD01, TNE-21CVD04; Instituto de Salud Carlos III (ISCIII) and cofinanced by the European Development Regional Fund “A Way to Achieve Europe”, Grant/Award Numbers: PI20/00535, RICORSICTUSRD21/0006/0001; Severo Ochoa Center of Excellence, Grant/Award Number: CEX2020-001041-S.S

Role of C/EBPβ Transcription Factor in Adult Hippocampal Neurogenesis

[Background]: The dentate gyrus of the hippocampus is one of the regions in which neurogenesis takes place in the adult brain. We have previously demonstrated that CCAAT/enhancer binding protein β (C/EBPβ) is expressed in the granular layer of the dentate gyrus of the adult mouse hippocampus. Taking into account the important role of C/EBPβ in the consolidation of long term memory, the fact that newborn neurons in the hippocampus contribute to learning and memory processes, and the role of this transcription factor, previously demonstrated by our group, in regulating neuronal differentiation, we speculated that this transcription factor could regulate stem/progenitor cells in this region of the brain. [Methodologu/Principal Findings]: Here, we show, using C/EBPβ knockout mice, that C/EBPβ expression is observed in the subset of newborn cells that proliferate in the hippocampus of the adult brain. Mice lacking C/EBPβ present reduced survival of newborn cells in the hippocampus, a decrease in the number of these cells that differentiate into neurons and a diminished number of cells that are proliferating in the subgranular zone of the dentate gyrus. These results were further confirmed in vitro. Neurosphere cultures from adult mice deficient in C/EBPβ present less proliferation and neuronal differentiation than neurospheres derived from wild type mice. [Conclusions/Significance]: In summary, using in vivo and in vitro strategies, we have identified C/EBPβ as a key player in the proliferation and survival of the new neurons produced in the adult mouse hippocampus. Our results support a novel role of C/EBPβ in the processes of adult hippocampal neurogenesis, providing new insights into the mechanisms that control neurogenesis in this region of the brain.This work was supported by a postdoctoral fellowship of the Consejo Superior de Investigaciones Cientificas (M.C.-C.) Grant Sponsor: Ministerio de Investigación y Ciencia; Grant numbers: SAF2007-62811 and SAF2010-16365. CIBERNED is funded by the Instituto de Salud Carlos III.Peer reviewe

Long-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model

BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment. OBJECTIVES: This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD. METHODS: TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood-brain barrier (BBB) integrity. RESULTS: Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB. CONCLUSIONS: Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.This work was funded by a Proof-of-Concept Award from the Robertson Therapeutic Development Fund (Dr. Cortes-Canteli), The Rockefeller University; NINDS/NIH grant NIS106668 (Drs. Norris and Strickland); European Union’s Seventh Framework Programme (FP7-PEOPLE-2013-IIF), grant agreement n PIIF-GA-2013-624811 (Drs. Cortes-Canteli and Fuster), CNIC, Madrid, Spain; Miguel Servet type I research contract (CP16/00174 and MS16/00174 [Dr. Cortes-Canteli]), Instituto de Salud Carlos III (ISCIII), CNIC; Iniciativa de Empleo Juvenil (PEJ16/MED/TL-1231 [A. Marcos-Diaz] and PEJ-2018-AI/BMD-11477 [C. Ceron]) from Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid; European Regional Development Funds (FEDER “Una manera de hacer Europa”) and European Social Funds (FSE “El FSE invierte en tu futuro”); and with the support of the Marie Curie Alumni Association (Dr. Cortes-Canteli). The CNIC is supported by the ISCIII, the Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). CIC biomaGUNE is a Maria de Maeztu Unit of Excellence (MDM-2017-0720). Dr. Sanchez-Gonzalez is an employee of Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study.

BACKGROUND Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, “la Caixa” Foundation. We thank the PESA participants and the imaging, administrative, and medical PESA teams. The PESA study is equally co-funded by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and Santander Bank (Madrid, Spain) and also receives funding from the Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI15/02019), the European Regional Development Fund (ERDF—A Way to Build Europe), and the European Social Fund (ESF—Investing in Your Future). CNIC is a Severo Ochoa Center of Excellence (CEX2020- 001041-S) and is supported by the ISCIII, the Spanish Ministry for Science and Innovation, and the Pro-CNIC Foundation. CT-P was supported by a “la Caixa” Foundation fellowship (ID 100010434, LCF/BQ/DI19/11730052). MC-C was supported by a Miguel Servet type II research contract (ISCIII, CPII21/00007) and the Fondo de Investigación Sanitaria (ISCIII, PI20/00819). We acknowledge the Sephardic Foundation on Aging and other donors of the Alzheimer’s Disease Research (grant number A2022034S), a programme of the BrightFocus Foundation, for support of this research. This work was also partially produced with the support of a 2021 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation awarded to MC-C (the Foundation takes no responsibility for the opinions, statements, and contents of this project, which are entirely the responsibility of its authors). BI was supported by the European Research Council (ERC-2018-CoG 819775-MATRIX). MS is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine; KAW2014.0363), the Swedish Research Council (2017-02869, 2021-02678, 2021-06545), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF-agreement (ALFGBG-813971, ALFGBG-965326), the Swedish Brain Foundation (FO2021-0311), and the Swedish Alzheimer Foundation (AF-740191). MS-C receives funding from the European Research Council (grant agreement number 948677), project “PI19/00155”, funded by ISCIII and co-funded by the EU, and a fellowship from “la Caixa” Foundation (ID 100010434) and from the EU’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 847648 (LCF/BQ/PR21/11840004). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018), the EU’s Horizon Europe research and innovation programme under grant agreement number 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation, USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the EU’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 860197 (MIRIADE), the EU Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915, #2022-00732), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALFagreement (#ALFGBG-715986, #ALFGBG-965240), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270), Hjärnfonden, Sweden (#FO2017-0243, #ALZ2022-0006), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer’s Association 2022–2025 grant (SG-23-1038904 QC).S

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study

BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation

Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models.

Cerebral blood flow (CBF) reductions in Alzheimer’s disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer’s disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer’s disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer’s disease patients

Alzheimer's Disease and Vascular Aging: JACC Focus Seminar

Alzheimer's disease, the leading cause of dementia in the elderly, is a neurodegenerative condition characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, age-related vascular changes accompany or even precede the development of Alzheimer's pathology, raising the possibility that they may have a pathogenic role. This review provides an appraisal of the alterations in cerebral and systemic vasculature, the heart, and hemostasis that occur in Alzheimer's disease and their relationships to cognitive impairment. Although the molecular pathogenesis of these alterations remains to be defined, amyloid-β is a likely contributor in the brain as in the heart. Collectively, the evidence suggests that vascular pathology is a likely pathogenic contributor to age-related dementia, including Alzheimer's disease, inextricably linked to disease onset and progression. Consequently, the contribution of vascular factors should be considered in preventive, diagnostic, and therapeutic approaches to address one of the major health challenges of our time.Dr. Cortes-Canteli is supported by a Miguel Servet type I research contract (CP16/00174 and MS16/00174); a Fondo de Investigación Sanitaria project (PI17/00590) from the Instituto de Salud Carlos III (ISCIII), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; European Regional Development Funds (FEDER “Una manera de hacer Europa”); and European Social Funds (FSE “El FSE invierte en tu futuro”). The CNIC is supported by the ISCIII, the Spanish Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Iadecola has served on the strategic advisory board for Broadview Ventures; and is supported by the National Institutes of Health (grants R01-NS34179, R37-NS089323, R01-NS100447, R01-NS095441, and R01-NS/HL37853).S

Plasmin Deficiency Leads to Fibrin Accumulation and a Compromised Inflammatory Response in the Mouse Brain

Accepted Article This article is protected by copyright. All rights reserved. ABSTRACT Background -Excess fibrin in blood vessels is cleared by plasmin, the key proteolytic enzym