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Evaluation of Vascular Reactivity in Alzheimer’s Disease via Iontophoresis of Vasoactive Compounds
Thomas Budinger, M.D., Ph.D.Jonathan Maltz, Ph.D.William Jagust, M.D.Jamie Eberling, Ph.D.Bruce Miller, M.D.
Hypothesis
Altered dilatory response of brain vasculatureis an important factor in the development of AD.This altered response is systemic and affects theperipheral circulation as well as the brain.
Hypothesis suggested by
1. Increased incidence of AD in patients with cardiovascular disease.
2. Acetylcholine and nitric oxide (NO) biochemistry issignificantly altered in the AD brain. These agentsare important mediators of vasodilation throughout the body.
Objective
To test the hypothesis that peripheral vasoactivity is altered in AD by evaluating the cutaneous vasodilatory response to vasoactive agents.
We are studying the effects of
- Acetylcholine (ACh)- Methacholine (MCh)- Sodium nitroprusside (SNP)on the cutaneous vasculature of the human forearm.
All elicit vasodilation via the relaxing action of NO on smooth muscle.
ACh, MCh and SNP
ACh: - Relaxes vascular smooth muscle primarily viareceptor stimulation of endothelial cells, which then release NO.
MCh: - Same mode of action as ACh. - More stable. Seems to act directly on smooth
muscle as well as on endothelial cells. - Preferential muscarinic agonist.
SNP: - Releases NO on decomposition. - Acts by directly relaxing smooth muscle.
Review of previous work
Two studies have investigated cutaneous vasoactivity in AD:
Hörnqvist et al., Gerontology 33(6), 1987
Algotsson et al., Neurobiology of Aging 16(4), 1995
Hörnqvist et al. (1987): Subject selection
12 AD/SDAT patientsAge: 52-84, mean 71Severe dementia, hospitalized
13 controls with various dermatosesAge: 52-82, mean 70
Nicotine and caffeine allowed
Hörnqvist et al.: Results
Agent Action AD vs Control
Phenylephrine 1-agonist AD slightly reduced
Isoproterenol 1-agonist AD reduced
p<0.001
Methacholine Muscarinic agonist
Not significant
Algotsson et al. (1995): Subject selection
15 AD patientsMMSE > 2716 Age-matched controlsSubjects lived at home
Algotsson et al.: Results
Agent Action AD vs Control
Sodium nitroprusside
NO donor to smooth muscle
AD reduced
(not significant)
Isoproterenol 1-agonist AD reduced
p < 0.01
Acetylcholine Endothelium dependent vasodilator
AD reduced
p < 0.05
Our study: Subject selection
9 AD patients, age 73 - 88, mean 80.46 on donepezil (Aricept) 5 mg3 on donepezil 10 mgMMSE range: 2 - 28, mean 19.4
8 controls, age 71 - 84, mean 78.6
12 hour fastLipid panel performedSubjects lived at home
Results
Agent Action AD vs Control
Methacholine Muscarinic agonist
AD increased 42% p < 0.05
Acetylcholine Endothelium dependent vasodilator
AD increased 41% p < 0.16
Sodium nitroprusside
NO donor to smooth muscle
AD increased 35% p < 0.14
Conclusion
Perfusion response to MCh significantly increased in AD under donepezil therapy. Enhanced response to cholinergic agonists is opposite of what Algotsson et al. observed.
It is impossible to evaluate original hypothesis in this patient population.
Weak negative correlation observed between donepezil dose and response to MCh.
Proposed explanation
AChEis delay the metabolic breakdown of cholinergic agonists in cutaneous tissue.This leads to enhanced and prolonged vasodilation.
Results suggest MCh perfusion studies may be useful in monitoring acetylcholinesterase inhibitor therapy.
Future plans
New UCSF-study, monitoring AChEi-therapy in AD/IVD.
Study of recently diagnosed, untreated subjects.
Acknowledgements
We thank Matthew Darmalingum for assisting in these experiments and in the preparation of this presentation.
This study was performed under NIH grant AG 05890-15 and DOE OBER contract DE-AC03-76SF0098.