Cerebral injury in patients on haemodialysis and dementia: the effects of cerebral perfusion and embolisation

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Abstract

Thesis title: Cerebral injury in patients on haemodialysis and dementia: the effects of cerebral perfusion and embolisation.Introduction: Stroke and cognitive impairment are types of cerebral injuries (CI) that occur in patients on haemodialysis (HD) and in Alzheimer’s disease (AD) and vascular dementia (VaD). Vascular causes of CI include embolisation and defective perfusion. Emboli consisting of particles, clots or bubbles arise from: extracorporeal circulations (EC) during HD and infused intravenously in HD and the arterial tree in AD and VaD. Intravenous emboli during HD may pass into the arterial circulation paradoxically in the presence of a venous to arterial circulation shunt (v-aCS) usually through a patent foramen ovale (PFO). Cerebral embolic signals (CES) are potentially preventable or treatable and perfusion deficits are amenable to appropriate cardiovascular drug modification. The aim of this thesis is to study the interplay of embolisation and haemodynamic factors causing CI and potential ways of treating CI in two seemingly different but closely linked subsets of patients.Methods: I investigated a) paradoxical dialysis induced CES in 54 consecutive patients; b) sources of embolic signals from the extracorporeal circuit in11 patients on HD; c) cerebral haemodynamics and acute changes in cognition during a single HD session in 9 patients d) cerebral blood flow haemodynamics of executive dysfunction in 19 patients with dementia and 19 matched controls; e) the efficacy of potential therapies (Atorvastatin and Clopidogrel) to inhibit CES in 33 patients with AD and VaD and its effects on neuroinflammation.Results: a) embolic signals were detected in the subclavian vein continuously during HD with a median (per 10 min) of 26 at the end of the first hour, rising to 33.5 and 69 at the end of the 2nd and 3rd hours respectively(p<0.001, Wilcoxon’s signed ranks test). CES were detected in 13(24%) and 15(27.7%) CI+ve and CI-ve patients respectively. V-aCS (PFO) were detected in 19/30 CI +ve patients compared to 14/21 CI-ve patients (p=0.087, Fisher’s exact test). Significant v-aCS likely to be a PFO were detected in 11/30 CI+ve and 7/ 28 CI-ve patients (p=0.380). b) embolic signals were detected throughout the EC; most numbers being detected beyond the roller pump following the infusion of heparin (p=0.01) c) deficits of executive function and attention were common post HD compared to pre HD, and correlated with duration of HD and age (p<0.05); these deficits reflected a similarity in the cognitive profile of HD patients with patients with vascular cognitive impairment thus proving the theory that potentially preventable vascular risk factors can cause CI in patients on HD. Multivariate analysis of variance with post hoc Bonferroni corrections did not reveal any significant correlations between haemodynamic parameters and tests of cognitive dysfunction d) Executive dysfunction was again common in patients with dementia compared to controls. Multivariate analysis of variance with post hoc Bonferroni corrections did not reveal any significant correlations between haemodynamic parameters and tests of cognitive dysfunction e) CES were detected in 39/133 patients with dementia. Atorvastatin and Clopidogrel were effective in reducing the numbers of CE (p=0.022 and p=0.036) respectively when compared to no additional treatment.Conclusions: CES are commonly detected on TCD in dementia and in HD. In HD, emboli are generated in the extracorporeal circuit and infused continuously into patients but can only reach the brain in the presence of a v-aCS and in significant numbers in patients with a PFO. Patients on HD and dementia have marked executive dysfunction and this is related to vascular risk factors and possible cerebral small vessel disease. Patients on HD have fluctuations in cognition during dialysis, which may contribute to CI. HD may thus present an in-vivo model of accelerated CI. Cerebral emboli, detectable as CES are perhaps a preventable or treatable cause of CI: targeted therapy with atorvastatin and clopidogrel are effective in reducing the numbers of CES in dementia.

Layman's Abstract

Introduction: Stroke and memory loss are types of cerebral injuries (CI) that occur in patients on haemodialysis (HD) and in Alzheimer’s disease (AD) and vascular dementia (VaD). Causes of CI include embolisation and inadequate perfusion. Emboli consisting of particles, clots or bubbles arise from the machine/tubes (extracorporeal) in the machine during HD and enter the venous circulation during HD and into arteries in AD and VaD. In HD, emboli may pass into the arterial circulation 'paradoxically' in the presence of a communication between the right and left sides of the heart, a venous to arterial circulation shunt (v-aCS) usually through a patent foramen ovale (PFO). Cerebral embolic signals (CES) are potentially preventable or treatable and defective blood flow is amenable to appropriate cardiovascular drug modification. This thesis studies the interplay of embolisation and blood flow related factors causing CI and potential ways of treating CI in two seemingly different but closely linked subsets of patients.Methods: I investigated a) paradoxical dialysis induced CES in 54 consecutive patients; b) sources of embolic signals from the extracorporeal circuit in11 patients on HD; c) cerebral blood flow and acute changes in memory during a single HD session in 9 patients d) changes in cerebral blood flow during memory tasks in 19 patients with dementia and 19 matched controls; e) the efficacy of potential therapies (Atorvastatin and Clopidogrel) to inhibit CES in 33 patients with AD and VaD and its effects on inflammation in the brain.Results: a) embolic signals were detected in the subclavian vein continuously during HD with a median (per 10 min) of 26 at the end of the first hour, rising to 33.5 and 69 at the end of the 2nd and 3rd hours respectively(p<0.001, Wilcoxon’s signed ranks test). CES were detected in 13(24%) and 15(27.7%) CI+ve and CI-ve patients respectively. V-aCS (PFO) were detected in 19/30 CI +ve patients compared to 14/21 CI-ve patients (p=0.087, Fisher’s exact test). Significant v-aCS likely to be a PFO were detected in 11/30 CI+ve and 7/ 28 CI-ve patients (p=0.380). b) embolic signals were detected throughout the EC; most numbers being detected beyond the roller pump following the infusion of heparin (a blood thinning agent) (p=0.01) c) deficits of executive function and attention were common post HD compared to pre HD, and correlated with duration of HD and age (p<0.05); these deficits reflected a similarity in the cognitive profile of HD patients with patients with vascular cognitive impairment thus proving the theory that potentially preventable vascular risk factors can cause CI in patients on HD. d) Executive dysfunction ( memory loss) was again common in patients with dementia compared to controls. e) CES were detected in 39/133 patients with dementia. Atorvastatin and Clopidogrel were effective in reducing the numbers of CE (p=0.022 and p=0.036) respectively when compared to no additional treatment.Conclusions: CES are commonly detected on TCD in dementia and in HD. In HD, emboli are generated in the extracorporeal circuit and infused continuously into patients but can only reach the brain in the presence of a v-aCS and in significant numbers in patients with a PFO. Patients on HD and dementia have marked executive dysfunction and this is related to vascular risk factors and possible cerebral small vessel disease. Patients on HD have fluctuations in cognition during dialysis, which may contribute to CI. HD may thus present a human model of accelerated CI. Cerebral emboli, detectable as CES are perhaps a preventable or treatable cause of CI: targeted therapy with atorvastatin and clopidogrel are effective in reducing the numbers of CES in dementia.

Keyword(s)

Alzheimer's disease; Atorvastatin; Clopidogrel; cerebral emboli; dementia; embolic signals; haemodialysis; patent foramen ovale; transcranial Doppler; vascular dementia

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