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Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form.

Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease., Author(s): Axel Montagne [1, 2]; Angeliki M Nikolakopoulou [1, 2]; Zhen Zhao [1, 2]; Abhay P Sagare [1, 2]; Gabriel Si [1]; Divna Lazic [1, 2, 3]; Samuel R Barnes [...]

Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although longterm phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic-polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood-brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte-endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Polyunsaturated fatty acids (PUFAs) are the precursors of various lipid mediators of inflammation. Brain imaging techniques for monitoring the brain's uptake of PUFAs would not only uncover the effects of risk factors for excessive neuroinflammation associated with Alzheimer's disease (AD) and related dementia but also direct the development of methods to prevent or treat AD. Radiosynthesized 11C‐docosahexaenoic acid (DHA) and 11C‐arachidonic acid (AA) have already been utilized in positron emission tomography (PET) studies in humans [1, 2]. Because 18F has a longer half‐life than 11C, fluorinated PUFA derivatives would be more favorable alternatives for PET studies of brain uptake. Methods: We prepared 18F‐fluorinated analogues of DHA (18F‐FDHA) and AA (18F‐FAA) as PUFA PET tracers. Radiosynthesis was performed via a nucleophilic fluorination scheme using the tosylate ester derivatives as precursors. We then performed bolus injection of each tracer into 16‐month‐old APOE4 knock‐in mice and scanned them by dynamic PET‐MRI over 45 min to assess region‐specific uptake. PUFA uptake kinetics in the cerebral region was evaluated using the time‐dependent activity in the lumen of the right ventricle as the image‐derived input function and using an irreversible two‐tissue compartment model to calculate the incorporation coefficient (Ki). Results: Both 18F‐FDHA and 18F‐FAA were successfully synthesized in high radiochemical purity (≥98%) and were found to be stable in the formulation and mouse serum for 2 hr. The mean Ki values for the cerebral region were determined to be 6.31 ± 0.98 µL mL‐1 min‐1 for 18F‐FDHA (n = 4) and 6.75 ± 0.68 µL mL‐1 min‐1 for 18F‐FAA (n = 5). Conclusion: Using an image‐based method with 18F‐fluorinated PUFA tracers, we were able to determine Ki values for both AA and DHA. The use of these PUFA PET tracers has the potential to elucidate deleterious changes in PUFA metabolism during various phases of AD as well as effects due to dietary interventions and drug treatment. References 1. Yassine, H.N. et al. (2017). DHA brain uptake and APOE4 status: a PET study with [1‐11C]‐DHA. Alzheimers Res Ther 9, 23. 2. Zanderigo, F. et al. (2018). [11C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use. Synapse 72. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) affects the basic ability to function and has imposed an immense burden on the community and health care system. Focused ultrasound (FUS) has recently been proposed as a novel noninvasive therapeutic approach for AD. However, systematic reviews on the FUS application in AD treatment have not been forthcoming. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria to summarize the techniques associated with safety and efficacy, as well as possible underlying mechanisms of FUS effects on AD in animal and human studies. Animal studies demonstrated FUS with microbubbles (FUS-MB) induced blood-brain-barrier (BBB) opening that could facilitate various therapeutic agents entering the brain. Repeated FUS-MB and FUS stimulation can relieve AD pathology and improve cognitive and memory function. Human studies showed repeated FUS-MB are well tolerated with few adverse events and FUS stimulation could enhance local perfusion and neural function, which correlated with cognitive improvement. We conclude that FUS is a feasible and safe therapeutic and drug delivery strategy for AD. However, FUS treatment on humans is still in the early stages and requires further optimization and standardization. [ABSTRACT FROM AUTHOR]