Evaluation of Vascular Reactivity in Alzheimer’s Disease via Iontophoresis of Vasoactive Compounds

Jonathan Maltz, Ph.D.William Jagust, M.D.Jamie Eberling, Ph.D.Thomas Budinger, M.D., Ph.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 risk factors.

- risk of demetia 5x in women with myocardial infarction- cerebral hypoperfusion- Apolipoprotein 4 allele predisposes to both atherosclerosis and dementia

2. Cholinergic 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.

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.

Iontophoresis: quantitative drug delivery

Perfusion response to iontophoresis

Laser Doppler imaging: quantitative measurement of perfusion

Laser Doppler perfusion imaging

Laser Doppler imaging of perfusion response to iontophoresis

Typical response to ACh

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.

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 patientsMini-mental state examination (MMSE) scores > 2716 Age-matched controlsSubjects lived at home

Algotsson et al.

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

12 AD patients, age 73 - 88, mean 80.43 not treated with acetylcholinesterase inhibitors (ACHEI’s)6 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

Iontophoretic dose

110 A for 60 secondsAll solutions: 0.5 – 1 mM

Results

Agent Action AD vs Control

Methacholine Muscarinic endothelium dependent vasodilator (EDV)

AD increased 78% p < 0.003

Acetylcholine Cholinergic EDV AD increased 68% p < 0.03

Sodium nitroprusside

NO donor to smooth muscle

AD increased 46% p < 0.05

Mean response vs. time

Time-integrals of perfusion responses

Conclusions

Perfusion response to MCh, ACh and SNP 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.

Results suggest MCh perfusion studies may be useful in monitoring acetylcholinesterase inhibitor therapy.

Proposed explanation

AChEIs delay the metabolic breakdown of cholinergic agonists in cutaneous tissue.

This leads to enhanced and prolonged vasodilation.

Why is response to endothelium independent vasodilator SNP enhanced?

Proposed mechanism behind enhanced endothelium-independent vasodilation

SNP relaxes smooth muscle

Flow increases

Endothelium stimulated

ACh released by endothelial cells

Donepezil preserves endogenous ACh for longer by inhibiting AChE

Prolonged and enhanced dilatory response

Reinterpreting the result of Algotsson et al. (2000)

AD with ApoE4

AD without ApoE4

Controls

On AChEI:

4 of 9

On AChEI:

1 of 8

11

(1 with ApoE4)

Sodium nitroprusside

Perfusion enhanced 30% (p < 0.02)

Not significantly different from controls (NS)

Acetylcholine NS NS

Isoproterenol NS NS

Future plans

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.