Antihypertensive Therapy and Cerebral Hemodynamics in Executive Mild Cognitive Impairment: Results of a Pilot Randomized Clinical Trial

Abstract

Background The comparative effects of antihypertensive therapy on cerebral hemodynamics in the contest of cognitive decline related to hypertension are unknown. Objectives To compare antihypertensive medicationsthat modulate the renin angiotensin system in cerebral hemodynamic and cognitive effects in hypertensive individuals with executive dysfunction. Design double-blind randomized clinical trial. Setting Community-dwelling Participants Subjects were ≥60 years with hypertension and executive dysfunction. Intervention lisinopril, candesartan, or hydrochlorothiazide for 1 year Measurements Cerebral blood flow velocity (Transcranial Doppler ultrasonography during rest, sitting, standing, hypercapnia, and hypocapnia), cognition and blood pressure were measured at baseline, 6 and 12 months. Linear mixed models were used to compare the3 groups. Results Of the 53 enrolled, 47 had successful insonation (mean age=72 years; 70% white; 57% women). There was a tendency for increased blood flow velocity (BFV) in the candesartan groupcompared to a decline in the lisinopril or HCTZ groups (between group p-value =0.57). This was significant in those with relative low BFV at baseline (<median 27.6 cm/sec, between group p-value =0.03). The candesartan group also had the greatest improvement in executive function (Trail Making Test, part B improved by 17.1 seconds vs HCTZ improved by 4.2 seconds and lisinopril worsened by 14.4 seconds, p=0.008). CO2-vasoreactivity and vasomotor range significantly declined in the lisinopril (within-group p-value=0.001 and 0.02 for vasoreactivity and vasomotor range) and HCTZ groups (within-group p-value=0.10 and 0.009 respectively) but not in the candesartan group (within-group p-value=0.25 and 0.38 respectively; between-group p-values= 0.3 and 0.46 respectively). Conclusion This pilot study suggests that angiotensin receptor blockers may preferentially preserve cerebral hemodynamics and improved executive function in those with executive dysfunction. These findings warrant further investigation in a larger trial.

Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

“…However, further analysis suggested that there remained limitations to this conclusion including assessment of cognitive function as a secondary outcome measure, short duration time of study, low dosage and undistinguished forms of dementia (AD was not distinguished from VaD). Indeed, the need for further exploration of ARBs is supported by findings from a number of studies, including the anti-hypertensives and vascular, endothelial and cognitive function trial that showed how people on ARBs had improved executive function [52], which may relate to ARBs preserving cerebral haemodynamics [53], and which when combined with the findings that ARBs are associated with lower levels of AD [54], all point to ARBs having particular benefits when looked at in isolation and in specific patient groups. Indeed, in very elderly hypertensive patients losartan (ARB) [55] and telmisartan (ARB) in combination with hydrochlorothiazide (diuretic) [56] showed significant improvements on cognitive function compared to atenolol (b-adrenergic blocker) and lisinopril (ACE-I), respectively.…”

“…While the mechanisms by which these ARBs exert such effects on Ab-induced brain injury are unknown, the results support the suggested protective nature of ARBs on cognition. Indeed, more recently, the suggested protective effects of ARBs on human cognition were found with their reported beneficial effects on executive cognitive function, cerebral haemodynamics and in terms of the levels of AD pathology [52][53][54].…”

Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia

“…47,48 Another small trial assessing the effect of 1-year lisinopril versus candesartan versus hydrochlorothiazide found no significant between-group differences in vasoreactivity or vasomotor range. 49 Future observational and experimental studies should investigate potential beneficial drug classes, based on aforementioned mechanism in relation to cognition and markers of cerebrovascular permeability, in addition to lacunar stroke. Also, nonmedicinal interventions such as physical activity, diet, and other lifestyle factors may contribute to maintaining vasoreactivity.…”

Elevated LDL-C combined with hypertension worsens subclinical vascular impairment and cognitive function

“…Importantly, the early cognitive deficit of young hypertensive individuals can be reversed with an appropriate antihypertensive therapy, as suggested by previous findings. 24,[57][58][59] The association between high BP and anxiety is supported by a large number of case-control studies, which compared either psychological symptoms in hypertensive and control subjects, or BP in patients with a variety of psychiatric disorders and controls. 60 When examining anxiety disorder, Vetere et al 61 found a higher prevalence in hypertensive individuals compared with controls.…”

“…17 The applied tests, previously used by several authors, [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] can reveal such minor alterations of the cognitive function, which are not necessarily evident during everyday activity. All tests were carried out and scored by a trained psychologist.…”