Use of Vitamin K Antagonists and Brain Morphological Changes in Older Adults: An Exposed/Unexposed Voxel-Based Morphometric Study

2018 ◽  
Vol 45 (1-2) ◽  
pp. 18-26 ◽  
Author(s):  
Antoine Brangier ◽  
Sébastien Celle ◽  
Frédéric Roche ◽  
Olivier Beauchet ◽  
Guylaine Ferland ◽  
...  
Keyword(s):  
Older Adults ◽  
White Matter ◽  
Vitamin K ◽  
Morphological Changes ◽  
Vitamin K Antagonists ◽  
Statistical Parametric Mapping ◽  
Morphometric Study ◽  
Intracranial Volume ◽  
Brain Physiology ◽  
Vitamin K Cycle

Background: Vitamin K antagonists (VKAs) are commonly used for their role in haemostasis by interfering with the vitamin K cycle. Since vitamin K also participates in brain physiology, this voxel-based morphometric study aimed to determine whether the duration of exposure to VKAs correlated with focal brain volume reduction in older adults. Methods: In this exposed/unexposed (1: 2) study nested within the GAIT (Gait and Alzheimer Interactions Tracking) cohort, 18 participants exposed to VKA (mean age 75 ± 5 years; 33.3% female; mean exposure 2,122 ± 1,799 days) and 36 matched participants using no VKA (mean age 75 ± 5 years; 33.3% female) underwent MRI scanning of the brain. Cortical grey and white matter volumes were automatically segmented using statistical parametric mapping. Age, gender, educational level, history of atrial fibrillation, type of MRI, and total intracranial volume were included as covariables. Results: The duration of exposure to VKA correlated inversely across the whole brain with the subvolumes of two clusters in the grey matter (right frontal inferior operculum and right precuneus) and one cluster in the white matter (left middle frontal gyrus). In contrast, the grade of white matter hyperintensities did not differ according to the use of VKA. Conclusion: We found focal atrophies in older adults exposed to VKA. These findings provide new insights elucidating the effects of VKAs on brain health and function in older adults.

scholarly journals Volumetric Brain Changes in Older Fallers: A Voxel-Based Morphometric Study

2021 ◽  
Vol 9 ◽  
Author(s):  
Maxime Le Floch ◽  
Pauline Ali ◽  
Marine Asfar ◽  
Dolores Sánchez-Rodríguez ◽  
Mickaël Dinomais ◽  
...  
Keyword(s):  
Older Adults ◽  
White Matter ◽  
Caudate Nucleus ◽  
Statistical Parametric Mapping ◽  
Cognitive Status ◽  
Morphometric Study ◽  
Intracranial Volume ◽  
Psychoactive Drugs ◽  
Cross Sectional ◽  
History Of

BackgroundFalls are frequent and severe in older adults, especially among those with cognitive impairments due to altered motor control. Which brain areas are affected among fallers remains yet not elucidated. The objective of this cross-sectional analysis was to determine whether the history of falls correlated with focal brain volume reductions in older adults.MethodsParticipants from the MERE study (n = 208; mean, 71.9 ± 5.9 years; 43% female; 38% cognitively healthy, 41% with mild cognitive impairment and 21% with dementia) were asked about their history of falls over the preceding year and received a 1.5-Tesla MRI scan of the brain. Cortical gray and white matter subvolumes were automatically segmented using Statistical Parametric Mapping. Age, gender, use of psychoactive drugs, cognitive status, and total intracranial volume were used as covariates.ResultsFifty-eight participants (28%) reported history of falls. Fallers were older (P = 0.001), used more often psychoactive drugs (P = 0.008) and had more often dementia (P = 0.004) compared to non-fallers. After adjustment, we found correlations between the history of falls and brain subvolumes; fallers exhibiting larger gray matter subvolumes in striatum, principally in bilateral caudate nucleus, than non-fallers. By stratifying on cognitive status, these neuroanatomical correlates were retrieved only in participants with MCI or dementia. There were no correlations with the subvolumes of white matter.ConclusionOlder fallers had larger subvolumes in bilateral striatum than non-fallers, principally within the caudate nucleus. This suggests a possible brain adaptative mechanism of falls in people with neurocognitive decline.

scholarly journals Structural Basis of Vitamin K Antagonism

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 482-482
Author(s):  
Weikai Li ◽  
Shixuan Liu ◽  
Shuang Li
Keyword(s):  
Vitamin K ◽  
Conformational Changes ◽  
Conflicts Of Interest ◽  
Bone Mineralization ◽  
Vitamin K Antagonists ◽  
Membrane Surface ◽  
Warfarin Dose ◽  
Binding Pocket ◽  
Structural Basis ◽  
Vitamin K Cycle

The vitamin K cycle supports blood coagulation, bone mineralization, and vascular calcium homeostasis. A key enzyme in this cycle, vitamin K epoxide reductase (VKOR), is the target of vitamin K antagonists (VKAs). Despite their extensive clinical use, the dose of VKAs (e.g., warfarin) is hard to regulate and overdose can lead to fatal bleeding. Improving the dose regulation requires understanding how VKAs inhibit VKOR, which is a membrane-embedded enzyme difficult to characterize with structural and biochemical studies. Here we achieve a long-standing goal of obtaining crystal structures of human VKOR with warfarin, which represents coumarin-based VKAs; with phenindione, which represents indandione-based VKAs; with superwarfarins, the most commonly used rodenticides; and with vitamin K epoxide in a reaction intermediate state. We have also solved structures of a VKOR-like homolog with warfarin, with vitamin K substrates, and without ligand. These structures show that human VKOR adopts an overall fold with four transmembrane helices (TM) and a large ER-luminal region. VKAs are bound at the active site of HsVKOR, which is formed by the surrounding four-TM bundle and a cap domain on top. The cap domain is stabilized by a linked anchor domain that interacts with the membrane surface. VKOR binds specifically to VKAs through hydrogen bonding to their diketone groups. Mutating VKOR residues recognizing the diketones render strong warfarin resistance. Except the hydrogen bonds, the binding pocket is largely hydrophobic. This pocket is incompatible with warfarin metabolite, explaining the inactivation of warfarin through CYP2C9 metabolism; CYP2C9 and VKOR genotypes can explain 30-50% of the patient variability in warfarin dose. In addition, the high potency of superwarfarins is due to the interaction of their side group with a tunnel where the isoprenyl chain of vitamin K is bound. For VKOR catalysis, the same residues affording the VKA-binding specificity also facilitate substrate reduction Initiation of the catalysis requires a reactive cysteine to form a substrate adduct. Interactions from this stably bound adduct induces a closed conformation, thereby triggering electron transfer to reduce the substrate. Importantly, the open to closed conformational change during catalysis similar to that induced by the binding of VKAs. Taken together, VKAs achieve inhibition through mimicking key interactions and conformational changes required for VKOR catalytic cycle. Understanding of these mechanisms will enable improved strategy to regulate warfarin dose and have a broad impact on thromboembolic diseases and bone disorders. Disclosures No relevant conflicts of interest to declare.

scholarly journals Association Between Brain Volumes and Patterns of Physical Activity in Community-Dwelling Older Adults

2020 ◽  
Author(s):  
Amal A Wanigatunga ◽  
Hang Wang ◽  
Yang An ◽  
Eleanor M Simonsick ◽  
Qu Tian ◽  
...  
Keyword(s):  
Physical Activity ◽  
Older Adults ◽  
White Matter ◽  
Brain Structure ◽  
Community Dwelling ◽  
Sensitivity Analyses ◽  
Intracranial Volume ◽  
Accelerometer Data ◽  
Brain Volumes ◽  
Cognitively Normal

Abstract Background Larger brain volumes are often associated with more free-living physical activity (PA) in cognitively normal older adults. Yet, whether greater brain volumes are associated with more favorable (less fragmented) PA patterns, and whether this association is stronger than with total PA, remains unknown. Methods Brain magnetic resonance imaging and wrist-worn accelerometer data were collected in 301 participants (mean age = 77 [SD = 7] years, 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Linear regression models were fit to examine whether brain volumes (cc) were cross-sectionally associated with: (a) total daily PA minutes and (b) activity fragmentation (mean number of PA bouts / total PA minutes × 100). Sensitivity analyses were conducted by adjusting for counterpart PA variables (eg, fragmentation covariate included in the PA minutes model). Results Greater white matter volumes in the parietal and temporal lobes were associated with higher daily PA minutes (2.6 [SE = 1.0] and 3.8 [0.9] min/day, respectively; p < .009 for both) after adjusting for demographics, behavioral factors, medical conditions, gait speed, apolipoprotein E e4 status, and intracranial volume. Greater temporal white matter volume was associated with lower fragmentation (−0.16% [0.05], p = .003). In sensitivity analyses, observed associations between brain volumes and daily PA minutes remained significant while associations with fragmentation no longer remained significant. Conclusions Our results suggest white matter brain structure in cognitively normal older adults is associated with the total amount of PA and, to a lesser extent, the PA accumulation patterns. More work is needed to elucidate the longitudinal relationship between brain structure and function and PA patterns with aging.

scholarly journals Head circumference as a useful surrogate for intracranial volume in older adults

2015 ◽  
Vol 28 (1) ◽  
pp. 157-162 ◽  
Author(s):  
Tammy T. Hshieh ◽  
Meaghan L. Fox ◽  
Cyrus M. Kosar ◽  
Michele Cavallari ◽  
Charles R. G. Guttmann ◽  
...  
Keyword(s):  
Older Adults ◽  
Head Circumference ◽  
Large Scale ◽  
Brain Size ◽  
Statistical Parametric Mapping ◽  
Correlation Coefficients ◽  
Epidemiologic Studies ◽  
Cognitive Outcomes ◽  
Intracranial Volume ◽  
Simple Method

ABSTRACTBackground:Intracranial volume (ICV) has been proposed as a measure of maximum lifetime brain size. Accurate ICV measures require neuroimaging which is not always feasible for epidemiologic investigations. We examined head circumference as a useful surrogate for ICV in older adults.Methods:99 older adults underwent Magnetic Resonance Imaging (MRI). ICV was measured by Statistical Parametric Mapping 8 (SPM8) software or Functional MRI of the Brain Software Library (FSL) extraction with manual editing, typically considered the gold standard. Head circumferences were determined using standardized tape measurement. We examined estimated correlation coefficients between head circumference and the two MRI-based ICV measurements.Results:Head circumference and ICV by SPM8 were moderately correlated (overall r = 0.73, men r = 0.67, women r = 0.63). Head circumference and ICV by FSL were also moderately correlated (overall r = 0.69, men r = 0.63, women r = 0.49).Conclusions:Head circumference measurement was strongly correlated with MRI-derived ICV. Our study presents a simple method to approximate ICV among older patients, which may prove useful as a surrogate for cognitive reserve in large scale epidemiologic studies of cognitive outcomes. This study also suggests the stability of head circumference correlation with ICV throughout the lifespan.

scholarly journals Vitamin K Antagonists and Cognitive Function in Older Adults: The Three-City Cohort Study

2015 ◽  
Vol 71 (10) ◽  
pp. 1356-1362 ◽  
Author(s):  
Guylaine Ferland ◽  
Catherine Feart ◽  
Nancy Presse ◽  
Simon Lorrain ◽  
Fabienne Bazin ◽  
...  
Keyword(s):  
Older Adults ◽  
Cohort Study ◽  
Cognitive Function ◽  
Vitamin K ◽  
Vitamin K Antagonists

scholarly journals Thromboembolism in Older Adults

2021 ◽  
Vol 7 ◽  
Author(s):  
Peter L. Gross ◽  
Noel C. Chan
Keyword(s):  
Older Adults ◽  
Venous Thromboembolism ◽  
Vitamin K ◽  
Older Patients ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Very Elderly ◽  
Direct Acting ◽  
Risk And Benefit ◽  
Direct Acting Oral Anticoagulants

Arterial and venous thromboembolism are both more common in older adults. The use of anticoagulants, the mainstay to prevent thromboembolism, requires consideration of the balance between risk and benefit. Such consideration is even more important in the very elderly in whom the risk of anticoagulant-related bleeding and thrombosis are higher. This review will focus on the challenges of implementing and managing anticoagulant therapy in older patients in an era when the options for anticoagulants include not only vitamin K antagonists (VKAs), but also direct-acting oral anticoagulants (DOACs).

Intracranial calcifications under vitamin K antagonists or direct oral anticoagulants: Results from the French VIKING study in older adults

Maturitas ◽  
2020 ◽  
Vol 132 ◽  
pp. 35-39 ◽  
Author(s):  
Gaëlle Annweiler ◽  
Mathieu Labriffe ◽  
Pierre Ménager ◽  
Guylaine Ferland ◽  
Antoine Brangier ◽  
...  
Keyword(s):  
Older Adults ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Intracranial Calcifications

Use of Vitamin K Antagonists and Brain Volumetry in Older Adults: Preliminary Results From the GAIT Study

2015 ◽  
Vol 63 (10) ◽  
pp. 2199-2202 ◽  
Author(s):  
Cedric Annweiler ◽  
Soraya Denis ◽  
Guillaume Duval ◽  
Guylaine Ferland ◽  
Robert Bartha ◽  
...  
Keyword(s):  
Older Adults ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Preliminary Results ◽  
Brain Volumetry ◽  
Gait Study
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