Abstract
Background: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging
and Alzheimer’s disease (AD) could reflect decreased NE clearance from central nervous
system (CNS) extracellular fluid or increased release of NE into CNS extracellular
fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol
(DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid
(DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms.
Methods: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following
yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied.
Results: CSF DOPA following yohimbine was higher in older and AD than in young subjects.
CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in
AD than in young subjects.
Conclusions: During alpha-2 adrenoreceptor blockade in both aging and AD, there are
increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance.
This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory
activation of remaining CNS noradrenergic neurons. Given the marked loss of locus
coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly
prominent compensatory activation of remaining LC neurons in this disorder.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Short and long term changes in tyrosine hydroxylase activity in rat brain after substantial destruction of central noradrenergic neurons.J Neurosci. 1981; 1: 493-504
- Compensatory increase in tyrosine hydroxylase activity in rat brain after intravenous injections of 6-hydroxydopamine.Science. 1980; 207: 537-540
- Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Revised. American Psychiatric Association, Washington DC1987
- Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia.Neurology. 1982; 32: 164-168
- Noradrenergic cell loss in the locus coeruleus in Alzheimer’s disease is related to cognitive but not non-cognitive symptoms.Neurobiol Aging. 1998; 19: S308
- Substantial destruction of central noradrenergic projections increases the firing rate of locus ceruleus neurons.Brain Res. 1983; 264: 123-132
- Sympathetic nervous function in human heart as assessed by cardiac spillover of dihydroxyphenylglycol and norepinephrine.Circulation. 1992; 85: 1775-1785
- Effects of Alzheimer’s disease severity on cerebrospinal fluid norepinephrine concentration.Am J Psychiatry. 1997; 154: 25-30
- Age and alpha-adrenergic regulation of plasma norepinephrine kinetics in humans.J Gerontol. 1987; 42: 271-276
- Increased norepinephrine spillover into the jugular veins in essential hypertension.Hypertension. 1992; 19: 62-69
- Mini-mental state.J Psychiatr Res. 1975; 12: 189-198
- Restoration of ascending noradrenergic projections by residual locus coeruleus neurons.J Comp Neurol. 1992; 321: 421-441
- Skin color, aging, and plasma dopa levels.J Auton Nerv Sys. 1989; 26: 261-263
- Monoaminergic effects of folinic acid, L-DOPA, and 5-hydroxytryptophan in dihydropteridine reductase deficiency.J Neurochem. 1995; 64: 2810-2813
- Patterns of plasma levels of catechols in neurogenic orthostatic hypotension.Ann Neurol. 1989; 26: 558-563
- Neuronal source of plasma dihydroxyphenylalanine.J Clin Endocrinol Metab. 1987; 64: 856-861
- Effect of ganglion blockade on cerebrospinal fluid norepinephrine.J Neurochem. 1987; 49: 1484-1490
- Oral yohimbine increases blood pressure and sympathetic nervous outflow in hypertensive patients.J Cardiovascular Pharm. 1993; 22: 22-26
- Improved assay for plasma dihydroxyphenylacetic acid and other catechols using high-performance liquid chromatography with electrochemical detection.J Chromatogr B Biomed Appl. 1994; 653: 131-138
- Adrenergic receptors in aging and Alzheimer’s disease.J Neurochem. 1989; 53: 1772-1778
- Plasma and cerebrospinal fluid neurochemical pattern in Menke’s disease.Ann Neurol. 1993; 33: 171-175
- Plasma DOPA responses during stress.J Pharmacol Exp Ther. 1992; 261: 899-909
- Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer’s disease.Biol Psychiatry. 1995; 38: 185-188
- Cerebrospinal fluid and plasma disposition of yohimbine and 11-hyroxy-yohimbine in young and older healthy subjects, and Alzheimer’s disease patients.Eur J Clin Pharmacology. 1997; 52: 135-138
- Rat brain norepinephrine metabolism.J Neurochem. 1983; 41: 1065-1071
- Locus ceruleus morphometry in aging and schizophrenia.Acta Psychiatr Scand. 1988; 77: 689-697
- Origins of norepinephrine in rat cerebrospinal fluid.Soc Neurosci Abstr. 1988; 14: 1074
- Changes in the monoamine containing neurones of the human CNS in senile dementia.Br J Psychiatry. 1980; 136: 533-541
- Central amine metabolism in Alzheimer’s disease.Neurobiol Aging. 1981; 2: 57-60
- Clinical diagnosis of Alzheimer’s disease.Neurology. 1984; 34: 939-944
- Tables. Author, New York1983
- Development and plasticity of the locus coeruleus.Prog Neurobiol. 1990; 34: 505-526
- Laboratory examinations correlated with severity of dementia.Ann Clin Lab Sci. 1996; 26: 340-345
- Brain uptake of radiolabeled amino amines and hexoses after arterial injection.Am J Physiol. 1971; 221: 1629-1639
- The Brief Psychiatric Rating Scale (BPRS) in geropsychiatric research, I.J Gerontol. 1983; 39: 187-193
- The Brief Psychiatric Rating Scale.Psychol Rep. 1962; 10: 799-812
- Peripheral sympathectomy and adrenal medullectomy do not alter cerebrospinal fluid norepinephrine.Brain Res. 1986; 367: 258-264
- Effects of Alzheimer’s disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidine.Arch Gen Psychiatry. 1995; 52: 774-782
- Alzheimer’s disease.in: Kupfer D.J Bloom F.E Psychopharmacology The Fourth Generation of Progress. Raven Press, New York1995: 1427-1435
- Norepinephrine and MHPG levels in CSF and plasma in Alzheimer’s disease.Arch Gen Psychiatry. 1984; 41: 343-346
- Increased plasma and cerebrospinal fluid norepinephrine in older men.J Clin Endocrinol Metab. 1988; 66: 438-443
- Adrenergic receptors in Alzheimer’s disease brain.J Neuroscience. 1997; 17: 5573-5580
- Age-related differences in norepinephrine kinetics.Am J Physiol. 1990; 259: E422-E431
- Simultaneous measurement of plasma and brain extracellular fluid concentrations of catechols after yohimbine administration in rats.Brain Res. 1991; 542: 8-14
- Concentrations of monoamines and their metabolites in the cerebrospinal fluid from patients with senile dementia of the Alzheimer’s type and vascular dementia of the Binswanger’s type.J Neural Transm Park Dis Dement Sect. 1992; 4: 69-77
- Psychological, cardiovascular, and endocrine changes during 6 hours of continuous infusion of epinephrine or norepinephrine in healthy volunteers.Psychosom Med. 1993; 55: 61-69
- A quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging.J Comp Neurol. 1979; 38: 490-497
- Autonomic dysfunction in patients with dementia of the Alzheimer’s type.Biol Psychiatry. 1993; 34: 428-433
- The uptake of circulating [H3] norepinephrine by the pituitary gland and various areas of the brain.J Neurochem. 1961; 8: 55-64
- Relationship between norepinephrine in blood and cerebrospinal fluid in the presence of a blood-cerebrospinal fluid barrier for norepinephrine.J Neurochem. 1977; 28: 677-679
- Neuropathologic and neurochemical correlates of psychosis in primary dementia.Arch Neurol. 1991; 48: 619-624
Article info
Publication history
Accepted:
December 22,
1998
Received in revised form:
December 10,
1998
Received:
August 21,
1998
Identification
Copyright
© 1999 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
