Research article| Volume 119, ISSUE 1, P110-118, October 1993

Frequency analysis of catecholamine axonal morphology in human brain

II. Alzheimer's disease and hippocampal sympathetic ingrowth
  • Rosemarie M. Booze
    Correspondence to: Rosemarie M. Booze, Ph.D., Department of Pharmacology, University of Kentucky College of Medicine, MS-305 UKMC, Lexington, KY 40536-0084, USA. Tel.: (606) 233-6507; Fax: (606) 258-1981.
    Department of Pharmacology and College of Pharmacy, University of Kentucky Medical Center, Lexington, KY 40536-0084, USA
    Search for articles by this author
  • Charles F. Mactutus
    Department of Pharmacology and College of Pharmacy, University of Kentucky Medical Center, Lexington, KY 40536-0084, USA
    Search for articles by this author
  • Catherine R. Gutman
    Department of Medicine (Neurology), Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA

    Department of Pharmacology, Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA
    Search for articles by this author
  • James N. Davis
    Department of Medicine (Neurology), Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA

    Department of Pharmacology, Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.


      We have examined the various diverse morphologies of catecholamine axons in the brains of patients with Alzheimer's disease. Alzheimer's disease and aged control brain tissue were obtained by a rapid autopsy protocol (mean postmortem delay < 1 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus, and the calcarine cortex (Brodmann area 17) were processed for identification of catecholamine axons using tyrosine hydroxylase immunocytochemistry. A total of 1275 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct axon-type categories. The axon classification from patients with Alzheimer's disease significantly differed from those of an age-matched control population in the hippocampus. The Alzheimer's disease brains were decreased in the frequency of very long, thin, tyrosine hydroxylase immunoreactive axons (type 1) and had an increased frequency of shorter, tortuous, axons (type 3). These selective quantitative shifts in hippocampal catecholaminergic axon morphology are consistent with the hypothesis that sympathetic noradrenergic axons invade the hippocampus of patients with Alzheimer's disease. Multivariate modeling of the frequency sampling data found that the axon type classification scheme successfully predicted the presence of Alzheimer's disease. In particular, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to have errorless predictive ability with respect to late onset (> 75 years) Alzheimer's disease. In summary, the use of quantitative neuroanatomical measures of catecholamine axonal morphologies in Alzheimer's disease brain tissue identified a specific frequency shift which may represent hippocampal sympathetic ingrowth and this unique measure was found to have predictive utility with respect to Alzheimer's disease.


      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 access
      One-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 to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ayyagari V.
        • Harrell L.E.
        • Parsons D.S.
        Interaction of neurotransmitter systems in the hippocampus: a study of some behavioral effects of hippocampal sympathetic ingrowth.
        J. Neurosci. 1991; 11: 2848-2854
        • Ball M.J.
        Topographical distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of ageing and demented patients — a quantitative study.
        Acta Neuropathol. 1978; 42: 73-80
        • Berger B.
        • Tassin J.P.
        • Rancurel G.
        • Blanc G.
        Catecholaminergic innervation of the human cerebral cortex in presenile and senile dementia — histochemical and biochemical studies.
        in: Usdin E. Sourkes T.L. Youdim M.B.H. Enzymes and Neurotransmitters in Mental Disease. John Wiley and Sons, Chichester1980: 317-328
        • Bird T.D.
        • Stranahan S.
        • Sumi S.M.
        • Raskind M.
        Alzheimer's disease: choline acetyltransferase activity in brain tissue from clinical and pathological subgroups.
        Ann. Neurol. 1983; 14: 284-293
        • Blessed G.
        • Tomlinson B.E.
        • Roth M.
        The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects.
        Br. J. Psychiat. 1968; 114: 797-811
      1. BMDP Statistical Software. University of California Press, Berkeley, CA1987
        • Bondareff W.
        • Mountjoy C.Q.
        • Roth M.
        Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia.
        Neurology. 1982; 32: 164-168
        • Booze R.M.
        • Davis J.N.
        Persistence of sympathetic ingrowth in the hippocampus of aging rats.
        Neurobiol. Aging. 1987; 8: 213-218
        • Booze R.M.
        • Hall J.A.
        • Cress N.M.
        • Miller G.D.
        • Davis J.N.
        Abnormal tyrosine hydroxylase immunoreactive fibers in rat hippocampus following administration of the noradrenergic neurotoxin, DSP-4.
        Exp. Neurol. 1988; 101: 75-86
        • Booze R.M.
        • Laforet G.
        • Davis J.N.
        Hippocampal sympathetic ingrowth in rats and guinea pigs: quantitative morphometry and topographical differences.
        Brain Res. 1986; 375: 251-258
        • Booze R.M.
        • Mactutus C.F.
        • Gutman C.R.
        • Davis J.N.
        Frequency analysis of catecholamine axonal morphology in human brain. I. Effects of postmortem delay interval.
        J. Neurol. Sci. 1993; 119: 99-109
        • Braak H.
        Architectonics as seen by lipofuscin stains.
        in: Peters A.A. Jones E.G. Cerebral Cortex, Vol. 1, Cellular Components of the Cerebral Cortex. Plenum Press, New York1984: 59-104
        • Cervera P.
        • Duyckaerts C.
        • Ruberg M.
        • Hirsch E.
        • Ransmayr G.
        • Hauw J-J.
        • Agid Y.
        Tyrosine hydroxylase-like immunoreactivity in senile plaques is not related to the density of tyrosine hydroxylase-positive fibers in patients with Alzheimer's disease.
        Neurosci. Lett. 1990; 110: 210-215
        • Chan-Palay V.
        • Asan E.
        Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson's disease with and without dementia and depression.
        J. Comp. Neurol. 1989; 287: 373-392
        • Crain B.J.
        • Burger P.C.
        The laminar distribution of neuritic plaques in the fascia dentata of patients with Alzheimer's disease.
        Acta Neuropathol. 1988; 76: 87-93
        • Crutcher K.A.
        Sympathetic sprouting in the central nervous system: a model for studies of axonal growth in the mature mammalian brain.
        Brain Res. Rev. 1987; 12: 203-233
        • Crutcher K.A.
        • Brothers L.
        • Davis J.N.
        Sympathetic noradrenergic sprouting in response to central cholinergic denervation: a histochemical study of neuronal sprouting in the rat hippocampal formation.
        Brain Res. 1981; 210: 115-128
        • Davies P.
        • Maloney A.J.F.
        Selective loss of central cholinergic neurons in Alzheimer's disease.
        Lancet. 1976; 2: 1403
        • Gaspar P.
        • Berger B.
        • Alvarez A.
        • Vigny A.
        • Henry J.P.
        Catecholaminergic innervation of the septal area in man: immunocytochemical study using TH and DBH antibodies.
        J. Comp. Neurol. 1985; 241: 12-33
        • Geddes J.W.
        • Monaghan D.T.
        • Cotman C.W.
        • Lott I.T.
        • Kim R.C.
        • Chui H.C.
        Plasticity of hippocampal circuitry in Alzheimer's disease.
        Science. 1985; 230: 1179-1181
        • Harrell L.E.
        • Parsons D.S.
        The role of gender in the behavioral effects of peripheral sympathetic ingrowth.
        Exp. Neurol. 1988; 99: 315-325
        • Harrell L.E.
        • Goyal M.
        • Parsons D.S.
        • Peagler A.
        The effect of gonadal steroids on the behavioral and biochemical effects of hippocampal sympathetic ingrowth.
        Physiol. Behav. 1990; 48: 507-513
        • Hausman L.
        Atlases of the Spinal Cord and Brainstem and Forebrain.
        Charles C Thomas, Springfield, IL1969
        • Hyman B.T.
        • Kromer L.J.
        • VanHoesen G.W.
        Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease.
        Ann. Neurol. 1987; 21: 259-267
        • Hsu S.M.
        • Raine L.
        • Fanger H.
        Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures.
        J. Histochem. Cytochem. 1981; 29: 577-580
        • Ichimiya Y.
        • Arai H.
        • Kosaka K.
        • Iizuka R.
        Morphological and biochemical changes in the cholinergic and monoaminergic systems in Alzheimer-type dementia.
        Acta Neuropathol. 1986; 70: 112-116
        • Iverson L.L.
        • Rossor M.N.
        • Reynolds G.P.
        • Hills R.
        • Roth M.
        • Mountjoy C.Q.
        • Foote S.L.
        • Morrison J.H.
        • Bloom F.E.
        Loss of pigmented dopamine-β-hydroxylase positive cells form locus coeruleus in senile dementia of the Alzheimer's type.
        Neurosci. Lett. 1983; 39: 95-100
        • Katzman R.
        • Terry R.
        • DeTeresa R.
        • Brown T.
        • Davies P.
        • Fuld P.
        • Renbing X.
        • Peck A.
        Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques.
        Ann. Neurol. 1988; 23: 138-144
        • Khachaturian Z.S.
        Diagnosis of Alzheimer's disease.
        Arch. Neurol. 1985; 42: 1097-1105
        • Loy R.
        • Moore R.Y.
        Anomalous innervation of the hippocampal formation by peripheral sympathetic axons following mechanical injury.
        Exp. Neurol. 1977; 57: 645-650
        • Mann D.M.A.
        • Lincoln J.
        • Yates P.O.
        • Stamp J.E.
        • Toper S.
        Changes in the monoamine containing neurones of the human CNS in senile dementia.
        Br. J. Psychiat. 1980; 136: 533-541
        • Mann D.M.A.
        • Marcyniuk B.
        • Yates P.O.
        • Neary D.
        • Snowden J.S.
        The progression of the pathological changes of Alzheimer's disease in frontal and temporal neocortex examined both at biopsy and autopsy.
        Neuropathol. Appl. Neurobiol. 1988; 14: 177-195
        • Marcyniuk B.
        • Mann D.M.A.
        • Yates P.O.
        Loss of nerve cells from locus coeruleus in Alzheimer's disease is topographically arranged.
        Neurosci. Lett. 1986; 64: 247-252
        • Perry E.K.
        • Tomlinson B.E.
        • Blessed G.
        • Bergmann K.
        • Gibson P.H.
        • Perry R.H.
        Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia.
        Br. Med. J. 1978; 2: 1457-1459
        • Perry E.K.
        • Tomlinson B.E.
        • Blessed G.
        • Perry R.H.
        • Cross A.J.
        • Crow T.J.
        Neuropathological and biochemical observations on the noradrenergic system in Alzheimer's disease.
        J. Neurol. Sci. 1981; 51: 279-287
        • Powers R.E.
        • Struble R.G.
        • Casanova M.F.
        • O'Connor D.T.
        • Kitt C.A.
        • Price D.L.
        Innervation of human hippocampus by noradrenergic systems: normal anatomy and structural abnormalities in aging and Alzheimer's disease.
        Neurosci. 1988; 25: 401-417
        • Rogers J.
        • Morrison J.H.
        Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer's disease.
        J. Neurosci. 1985; 5: 2801-2808
        • Saper C.B.
        Chemical neuroanatomy of Alzheimer's disease.
        in: Iverson L.L. Iverson S.D. Snyder S.H. Psychopharmacology of the Aging Nervous System. Plenum Press, New York1988: 131-156
        • Schwartz P.
        Amyloid degeneration and tuberculosis in the aged.
        Gerontologia. 1972; 18: 321-362
        • Siegel S.
        Nonparametric Statistics for the Behavioral Sciences.
        McGraw-Hill, New York1956
        • Terry R.D.
        • Peck A.
        • DeTeresa R.
        • Schechter R.
        • Horoupian D.S.
        Some morphometric aspects of the brain in senile dementia of the Alzheimer type.
        Ann. Neurol. 1981; 10: 184-192
        • Tomlinson B.E.
        • Irving D.
        • Blessed G.
        Cell loss in the locus coeruleus in senile dementia of Alzheimer type.
        J. Neurol. Sci. 1981; 49: 419-428
        • Torack R.M.
        • Morris J.C.
        Tyrosine hydroxylase-like (TH) immunoreactivity in Parkinson's disease and Alzheimer's disease.
        J. Neural Transm. 1992; 4: 165-171
        • Whitehouse P.J.
        • Price D.L.
        • Struble R.G.
        • Clark A.W.
        • Coyle J.T.
        • Delong M.R.
        Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.
        Science. 1982; 215: 1237-1239
        • Wilcock G.K.
        • Esiri M.M.
        Plaques, tangles, and dementia: a quantitative study.
        J. Neurol. Sci. 1982; 56: 343-356
        • Winer B.J.
        Statistical Principles in Experimental Design.
        McGraw-Hill, New York1972 (1972)