Adrenomedullin: A vasoactive agent for sporadic and hereditary vascular cognitive impairment

Ihara, Masafumi; Washida, Kazuo; Yoshimoto, Takeshi; Saitô, Satoshi

doi:10.1016/j.cccb.2021.100007

Cited by 5 publications

(6 citation statements)

References 54 publications

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“…50 Higher ADM has been shown to be inversely correlated with lower Word Fluency Test scores and has been proposed as a therapeutic option for vascular cognitive impairment. 51,52 16 Among older adults in the Lothian Birth Cohort 1936, the Horvath epigenetic age acceleration measure was not associated with change in general fluid-type intelligence derived from the Wechsler Adult Intelligence Scale-III over 6 years. 15 These epigenetic age estimators were developed to capture cellular aging processes (IEAA and EAA), phenotypic age (AgeAccel-Pheno), or estimate mortality risk (AgeAccelGrim) and thus may not have adequately captured cognitive aging.…”

Section: Discussionmentioning

confidence: 92%

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study

Nguyen,

McEvoy,

Espeland

et al. 2024

Neurology

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Background and ObjectivesEpigenetic age estimators indicating faster/slower biological aging vs chronological age independently associate with several age-related outcomes; however, longitudinal associations with cognitive function are understudied. We examined associations of epigenetic age estimators with cognitive function measured annually. MethodsThis longitudinal study consisted of older women enrolled in the Women's Health Initiative Memory Study with DNA methylation (DNAm) collected at baseline (1995)(1996)(1997)(1998) from 3 ancillary studies and were followed up to 13 years. Global cognitive function was measured annually by Modified Mini-Mental State Examination (3MS; baseline-2007) and by modified Telephone Interview for Cognitive Status (TICS-m, 2008(TICS-m, -2021. We calculated 5 epigenetic age estimators: extrinsic AgeAccel, intrinsic AgeAccel, AgeAccelPheno, AgeAccelGrim2, Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), and AgeAccelGrim2 components (DNA-based plasma protein surrogates). We estimated longitudinal epigenetic age estimator-cognitive function associations using linear mixedeffects models containing age, education, race or ethnicity, and subsequently alcohol, smoking, body mass index, and comorbidities. We examined effect modification by APOE e4 carriage. ResultsA total of 795 participants were enrolled. The mean baseline age was 70.8 ± 4 years (10.7% Black, 3.9% Hispanic or Latina, 85.4% White), A 1-SD (0.12) increment in DunedinPACE associated with faster annual declines in TICS-m scores in minimally adjusted (β = −0.118, 95% CI −0.202 to −0.034; p = 0.0006) and fully adjusted (β = −0.123, 95% CI −0.211 to −0.036; p = 0.006) models. AgeAccelPheno associated with faster annual declines in TICS-m with minimal adjustment (β = −0.091, 95% CI −0.176 to −0.006; p = 0.035) but not with full adjustment. No other epigenetic age estimators associated with changes in 3MS or TICS-m. Higher values of DNAm-based surrogates of growth differentiation factor 15, beta-2 microglobulin, Cystatin C, tissue inhibitor metalloproteinase 1, and adrenomedullin associated with faster annual declines in 3MS and TICS-m. Higher DNAm log A1c associated with faster annual declines in TICS-m only. DunedinPACE associated with faster annual declines in 3MS among APOE e4 carriers but not among noncarriers (p-interaction = 0.020). DiscussionHigher DunedinPACE associated with faster declines in TICS-m and 3MS scores among APOE e4 carriers. DunedinPACE may help identify older women at risk of future cognitive decline. Limitations include the ancillary studies that collected epigenetic data not designed to study epigenetics and cognitive function. We examined epigenetic age estimators with global cognitive function and not specific cognitive domains. Findings may not generalize to men and more diverse populations.

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Section: Discussionmentioning

confidence: 92%

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study

Nguyen,

McEvoy,

Espeland

et al. 2024

Neurology

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“…However, the safety of AM in cerebrovascular diseases remains uncertain. AM, known for its ability to induce vasodilation and lower blood pressure [7] , may theoretically worsen cerebral hypoperfusion and infarcts. The angiogenic properties of AM may raise concerns about an increased risk of cerebral hemorrhage, which is a common manifestation of CADASIL, particularly in East Asian populations [43] .…”

Section: Discussionmentioning

confidence: 99%

“…Adrenomedullin (AM) is a bioactive peptide initially discovered in human pheochromocytoma [5] . Within the cerebral vasculature, endothelial cells are the primary source of AM secretion, and AM can have multiple sites of action on the neuro-glial-vascular unit [6] by binding to a heterodimer receptor composed of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) type 2 or 3 [7] . Based on these modes of action, AM has exhibited angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties and has shown promise in mitigating WM damage in a mouse model of cerebral hypoperfusion [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Washida,

Saito,

Tanaka

et al. 2024

Cerebral Circulation - Cognition and Behavior

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“…Therefore, it is reasonable to assume that ADM is mainly secreted from ischemic, but not yet infarcted, region of brain tissue, namely the ischemic penumbra. ADM exerts neuroprotective effects by several physiological modes of action: vascular smooth muscle cell‐mediated vasodilation, angiogenesis by acting on vascular endothelium, oligodendrogenesis, and anti‐inflammatory effects by modulating immune cells [ 41 ]. Indeed, in the MCA occlusion model mice, infarct size was reduced by exogenous ADM administration [ 16 ], and conversely, ischemic tolerance was decreased in ADM knock‐out mice [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Plasma mid‐regional pro‐adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke

et al. 2022

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Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (r s = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4. 65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.K E Y W O R D S acute ischemic stroke, adrenomedullin, blood biomarker, ischemic penumbra

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Adrenomedullin: A vasoactive agent for sporadic and hereditary vascular cognitive impairment

Cited by 5 publications

References 54 publications

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Plasma mid‐regional pro‐adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke

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