Molecular Brain Research 84 (2000) 135–140

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Tyrosine hydroxylase and norepinephrine transporter mRNA

expression in the locus coeruleus in Alzheimer’s disease
a,b,c , a,c,d a,b,c e
Patricia Szot *, James B. Leverenz , Elaine R. Peskind , Elizabeth Kiyasu ,
Kirsten Rohde a , Margaret A. Miller c , Murray A. Raskind a,c
a
Northwest Network Mental Illness Research, Education and Clinical Center ( MIRECC), Veterans Administration Puget Sound Health Care System,
Seattle, WA 98108, USA
b
Geriatric Research, Education and Clinical Center ( GRECC), Veterans Administration Puget Sound Health Care System, 1660 S. Colombian Way,
Seattle, WA 98108, USA
c
Department of Psychiatry and Behavioral Science, University of Washington, Seattle, WA 98195, USA
d
Department of Neurology, University of Washington, Seattle, WA 98195, USA
e
Department of Medicine, University of Washington, Seattle, WA 98195, USA

Accepted 9 May 2000

Abstract

Despite the loss of locus coeruleus (LC) noradrenergic neurons in Alzheimer’s disease (AD), cerebrospinal fluid norepinephrine (NE)
levels are normal or increased in AD. This paradox suggests compensatory upregulation of NE synthetic capacity or downregulation of the
NE transporter (NET) in the remaining LC neurons. LC tyrosine hydroxylase (TH) mRNA expression in the LC was measured in AD
subjects (n55) and in age and gender comparable non-demented subjects (n56). When AD subjects were divided into those still
ambulatory prior to death (CDR 3 / 4) and those in a prolonged ‘vegetative’ state prior to death (CDR 5), differences among groups
became apparent at specific levels of the LC. In CDR 3 / 4 AD subjects there was increased TH mRNA expression per neuron compared to
non-demented subjects in the caudal half of the LC. However, expression of NET mRNA in the same subjects was not significantly
different at any level of the LC. These preliminary results suggest an upregulation of NE biosynthetic capacity in at least some LC
neurons in AD prior to the very late stage of the disease.  2000 Elsevier Science B.V. All rights reserved.

Theme: Disorders of the nervous system

Topic: Degenerative disease: Alzheimer’s – other

Keywords: Aging; Alzheimer’s disease; Locus coeruleus; Tyrosine hydroxylase; Norepinephrine transporter; In situ; Locus coeruleus lesion

In Alzheimer’s disease (AD), a substantial loss of
noradrenergic cell bodies has been documented in post-
mortem brain tissue in the locus coeruleus (LC), the major
source of noradrenergic projections to the whole brain
[2,3,11,17,19,31]. However, indices of central nervous
system (CNS) noradrenergic activity in living patients with
AD are difficult to reconcile with the postmortem neuro-
histological findings. Cerebrospinal fluid (CSF) concen-
trations of norepinephrine (NE) and its metabolites do not
differ in the early stages of AD from those of healthy older
individuals, and may increase as AD progresses [7,18,25];
*Corresponding author. Tel.: 11-206-764-2308; fax: 11-206-764-
2569.
E-mail address: szot@u.washington.edu (P. Szot).
these observations suggest a compensatory upregulation of
LC noradrenergic neurons in AD. The objective of this
study was to determine if the mRNA expression for either
tyrosine hydroxylase (TH), the rate limiting enzyme in the
synthesis of NE or NE transporter (NET), the protein
responsible for removing NE from the synaptic cleft, are
altered in AD LC compared to similar age and gender
non-demented comparison subjects.
Subjects included five neuropathologically confirmed
AD cases (one male and four females, ages 65 to 88 years
with a mean6S.E.M. of 74.463.8 years) and six similar
gender and age non-demented comparison subjects (two
males and four females, ages 60 to 86 years with a
mean6S.E.M. of 74.764.1 years). AD subjects met neuro-
pathological criteria for definite AD [1] and met antemor-

0169-328X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0169-328X( 00 )00168-6
136 P. Szot et al. / Molecular Brain Research 84 (2000) 135 – 140
tem National Institute of Neurological and Communicative
Disorders and Stroke (NINDS /ADRDA) [20] criteria for
probable AD. Comparison subjects had no history of
dementia or cognitive decline, and both antemortem and
neuropathologic examination revealed no neurologic dis-
orders. Mean postmortem interval for AD and non-de-
mented comparison subjects was 10.364 and 11.263 h,
respectively.
AD subjects’ clinical records were reviewed to estimate
their clinical status during the year prior to death. All AD
subjects were in advanced stages of the disease, and had
resided in an institution or had received 24-h per day care
at home for at least 1 year. All had become too cognitively
impaired to be evaluated psychometrically by instruments
such as the Mini-Mental State Exam [9]. However, differ-
ences in disease state were still clearly apparent among
these AD subjects which were reflected in their Clinical
Dementia Rating (CDR) scores [21]. One group of three
subjects was ambulatory, had some residual language and
could perform at least one activity of daily living function
with minimal assistance, and were scored as CDR 3 / 4.
The second group of two subjects had been in a mute,
non-ambulatory, ‘vegetative’ state during the year prior to
death and were scored as CDR 5.
Tissue for this study was specifically accessed at auto-
psy using a protocol that provided the complete LC
bilaterally in snap frozen blocks of caudal midbrain and
rostral brainstem. The block included the region between
the third nerve in the midbrain to the trigeminal nerve in
the pons. The block was then dissected into three horizon-
tal blocks, snap frozen in isopentane, cooled with liquid
nitrogen and stored at 2708C. Serial horizontal sections
(20 mm) from each of the three blocks were cut on a
cryostat, thaw mounted onto FisherSuper frost slides and
stored at 2708C. The rostral to caudal distance of the LC
was determined for each case by examining sections every
500 mm with thionin. The rostral pole (or 0 percentile) was
defined as the beginning of the trochlear nucleus and the
caudal pole (or 100 percentile) ended at the rostral level of
the trigeminal motor nucleus [15]. After the rostral to
caudal distance of the LC was determined for each case,
sections were systematically taken to include the 10th,
30th, 50th, 70th and 90th percentile.
In situ hybridization procedures were performed as
described in detail elsewhere [28]. A cDNA TH and NET
clone containing the entire nucleotide sequence for either
the human TH or NET gene was provided by Dr. Karen
O’Malley (Washington University School of Medicine;
GenBank accession number X05290) [22] or Dr. Susan
Amara (Vollum Institute, Oregon Health Sciences Uni-
versity, Portland, OR). A fragment of the TH sequence was
cut with Pst (Promega, Madison, WI) and the vector
ligated to form a 153 base pair TH clone (nucleotides
56–209) in a Bluescript vector. Plasmid for TH was
linearized with HindIII (Promega, Madison, WI) and
transcribed using T7 RNA polymerase (Promega,
Madison, WI) as described in detail elsewhere [28]. NET
sequence was subcloned as previously described [28]. The
final hybridization mix contained either the TH or NET
ribonucleotide probe in a concentration of |1 pmol / ml and
contained 24.5310 6 cpm / 50 ml or 3.2310 6 cpm / 50 ml.
Fifty ml of the labeled ribonucleotide probe was applied
to each tissue with silanized (Sigma, St. Louis, MO)
coverslips. The coverslipped slides were placed in a moist
chamber and incubated overnight at 608C for both TH and
NET ribonucleotide probes. Following incubation the
coverslips were removed and sections were washed for 30
min in 13 SSC. The slides then went through an RNase A
treatment at 378C for 30 min followed by a series of
washes in 0.13 SSC at 658C for both TH and NET.
Sections were then dehydrated through a graded series of
alcohol containing 300 mM ammonium acetate.
Slides hybridized with TH or NET [ 35 S] ribonucleotide
probes were coated with NTB2 Nuclear Track Emulsion
(undiluted) and stored at 2208C for 14 days for TH and 21
days for NET. The slides were developed in Kodak D-19
Developer (diluted 1:1 with water) at 178C, rinsed in water,
and fixed in Kodak General Fixer. The slides were stained
with cresyl violet acetate, dehydrated (70, 95 and 100%
alcohol), allowed to air dry, and mounted with coverslips.
For quantification of either TH or NET hybridization
signal of the ribonucleotide probes, sections through the
LC of both control and Alzheimer’s subjects were pro-
cessed, hybridized, washed, emulsion coated and de-
veloped in the same session. To quantitate TH or NET
mRNA expression in the LC, the density of labeling per
cell was determined by analyzing the amount of silver
grains over a cell body at a threshold value approximately
threefold higher than background under dark-field illumi-
nation with side mounted lighting with a 203 objective.
The number of cells that achieved this criteria were
recorded and totaled bilaterally at each level of the LC and
expressed as number of positively labeled cells. Grain
intensity was measured as pixels using the MicroComputer
Imaging Device (MCID; Imaging Research Inc., Ont.
Canada). Two to three consecutive sections were measured
in each subject at each level. Bilateral readings were made
for each subject, yielding 4–6 readings for each subject at
each level which were then averaged to determine a single
value of grains / cell for each subject at each level. The data
are represented as the mean6S.E.M. of the number of
grains localized over cell bodies in the LC. Data were
analyzed with Student’s t-test (two groups) and / or ana-
lyzed with analysis of variance (ANOVA) (three groups)
followed by a post hoc Fisher test; statistical significance
was taken at P,0.05.
The number of TH positive neurons tended to be
reduced in the rostral LC of AD subjects with a significant
reduction at the 50th percentile (Fig. 1 top left histogram).
Although unbiased stereological technique was not used to
count neurons, the extent and pattern of LC neuron
reduction was similar to that described by others [3,11,20].
TH mRNA expression did not differ significantly between
all AD subjects combined and non-demented comparison
 P. Szot et al. / Molecular Brain Research 84 (2000) 135 – 140 137

Fig. 1. Top left histogram: TH positive labeled cells in the LC at five different levels in non-demented comparison subjects (n56) and in ambulatory AD
CDR 3 / 4 (n53) and vegetative AD CDR 5 (n52) subjects. The data were compared by factorial analysis of variance (ANOVA) followed by post-hoc
Fisher test; P,0.05 was considered statistically significant. The F values at the 50th and 90th percentile were 7.4 and 3.5, respectively. Top right
histogram: TH mRNA expression per cell (grains / cell) in the LC at five different levels in non-demented comparison subjects (n56) and in ambulatory
AD CDR 3 / 4 (n53) and vegetative AD CDR 5 (n52) subjects. The data were compared by factorial analysis of variance (ANOVA) followed by post-hoc
Fisher test; P,0.05 was considered statistically significant. The F values at the 70th and 90th percentile for AD CDR 3 / 4 subjects were 8.7 and 13.7,
respectively. Bottom left histogram: NET positive labeled cells in the LC at five different levels in non-demented comparison subjects (n55) and in AD
subjects (n56). The data were compared by unpaired Student’s t-test. Bottom right histogram: NET mRNA expression per cell (grains / cell) in the LC at
five different levels in non-demented comparison subjects (n56) and in AD subjects (n55). The data were compared by unpaired Student’s t-test.

subjects. However, a large amount of variability was
observed in the amount of TH mRNA expression per cell
at the 70th and 90th percentile. When AD subjects were
divided into an antemortem ambulatory CDR 3 / 4 group
and an antemortem vegetative CDR 5 group, TH mRNA
expression per cell was significantly greater in CDR 3 / 4
subjects than in non-demented comparison subjects at both
the 70th and 90th percentile levels (Fig. 1 top right
histogram). In contrast, CDR 5 subjects’ TH mRNA
expression per cell did not differ from non-demented
comparison subjects. Fig. 2 shows dark field photomicrog-
raphs of TH mRNA expression in the LC at the 70th (A
and C) and 90th (B and D) percentile in a representative
CDR 3 / 4 subject (C and D) and a representative non-
demented comparison subject (A and B).
The number of NET positive neurons was significantly
reduced in AD subjects at the 30th, 50th and 70th
percentile (Fig. 1 bottom left histogram). However, NET
mRNA expression did not differ significantly between AD
and non-demented subjects at any level in the LC (Fig. 1
bottom right histogram). There was also no difference in
NET mRNA expression in the LC at any level between the
two groups of AD subjects. Fig. 3 shows dark field
photomicrographs of NET mRNA expression in the LC at
the 70th (A and C) and 90th (B and D) percentile in the
same subjects where TH mRNA expression was shown in
Fig. 2.
These preliminary data suggest that noradrenergic neu-
rons in specific regions of the LC in AD CDR 3 / 4 subjects
may have an increased capacity to synthesize NE. Such an
increase in NE biosynthetic capacity in AD subjects would
be consistent with the compensatory upregulation demon-
strated in surviving LC neurons following partial neuro-
toxin-induced LC lesion in rats [6,10,27]. This elevation in
138 P. Szot et al. / Molecular Brain Research 84 (2000) 135 – 140

Fig. 2. Dark-field photomicrographs of TH mRNA expression per cell at the 70th (A and C) and 90th (B and D) percentile in a representative
non-demented comparison subject (A and B) and a representative AD CDR 3 / 4 subject (C and D). Scale bar: 200 mm.

LC TH mRNA expression may also explain the normal to
elevated CSF NE levels observed in AD patients [7,25,30].
Several postmortem brain tissue studies suggest that
surviving noradrenergic neurons may compensate for LC
neuronal loss in AD. Although unchanged or reduced NE
levels have been reported in neocortex and hippocampus in
AD [18,26], concomitant measurements of NE and its
metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG)
demonstrated a substantially increased MHPG / NE ratio in
AD subjects [12,15,23,25,30]. These increased MHPG / NE
ratios suggest an increase in NE turnover and compensat-
ory upregulation of remaining LC neurons in AD. Another
marker for noradrenergic terminals, dopamine beta-hy-
droxylase (DBH) is modestly reduced in AD [4,24].
However, the DBH reduction was less than expected given
the marked loss of LC neurons in the AD subjects studied,
and some of the highest DBH concentrations were ob-
served in AD subjects with the lowest LC neuronal counts
[24]. These investigators interpreted their data as con-
sistent with increased noradrenergic innervation from
surviving LC neurons in some AD subjects.
Although increased TH mRNA expression per neuron
was largely restricted to the caudal LC in CDR 3 / 4 AD
subjects, animal studies indicate that caudal LC neurons
broadly project to innervate multiple areas in the brain
including the forebrain [8,16]. This is observed particularly
in the dorsal portion of the caudal LC. Such dorsal caudal
LC neurons demonstrated increased TH mRNA expression
in CDR 3 / 4 AD subjects in the current study.
It remains unclear why the elevation in TH mRNA was
not observed in the advanced vegetative CDR 5 AD
subjects. There were no systematic differences among the
AD groups in medications during the month prior to death
or in cause of death. The duration of vegetative state in the
CDR 5 AD subjects may have affected the level of TH
mRNA expression. Terminal coma may reduce the level of
certain mRNAs [13,14]; however, it is unclear if TH
mRNA is among these.
NET mRNA expression in noradrenergic neurons in the
LC indicates a significant loss in the number of positively
labeled noradrenergic neurons in AD subjects specifically
at the 30th, 50th and 70th percentile; however, the
remaining neurons in AD subjects express similar levels
(grains / cell) as non-demented age matched controls. This
loss of positively labeled neurons in AD subjects is
supported by [ 3 H]nisoxetine binding. Tejani-Butt et al.
[29] demonstrated a significant reduction in [ 3 H]nisoxetine
binding sites (a ligand which specifically binds to NET
sites) in the LC at the middle and caudal regions in AD
subjects, but not at the rostral region. The loss of NET
 P. Szot et al. / Molecular Brain Research 84 (2000) 135 – 140
Fig. 3. Dark-field photomicrographs of NET mRNA expression per cell at the 70th (A and C) and 90th (B and D) percentile in a representative
non-demented comparison subject (A and B) and a representative AD CDR 3 / 4 subject (C and D). Scale bar: 200 mm.
binding sites by this ligand corresponds to where a
significant loss of positively labeled neurons occur in the
LC in AD. These data and others [5,28,32] indicate the
concentration of NE in the CNS noradrenergic neurons
does not regulate the level of NET mRNA expression.
These data suggest that AD subjects in the advanced but
still ambulatory stage of the disease have an elevation of
TH mRNA expression in at least some LC neurons. This
enhanced capacity to synthesize NE may contribute to the
unexpectedly high levels of CSF NE observed in AD
subjects [7,25,30] and to increased MHPG / NE ratio in
forebrain areas in several AD postmortem studies
[12,15,23]. Further investigation with larger numbers of
AD and non-demented subjects is necessary to confirm and
extend these preliminary findings.
Acknowledgements
We would like to thank Ms. Sylvia White and Ms.
Lynne Greenup for their technical assistance. These studies
were supported by the Department of Veterans Affairs
Research and Development Service, Northwest Network
Mental Illness Research, Education and Clinical Center
(MIRECC) and Geriatric Research, Education and Clinical
139
Center (GRECC), VA Puget Sound Health Care System;
the National Alliance for Research on Schizophrenia and
Depression and the University of Washington Alzheimer’s
Disease Research Center (AGO5136); the Geriatric Aca-
demic program (AGO0503); and the Alhadeff Alzheimer’s
Research Fund.
References
[1] American Psychiatric Association, in: Revised 3rd Edition, Diag-
nosis and Statistical Manual of Mental Disorders, American Psychiat-
ric Association, Washington, DC, 1987.
[2] M. Bondareff, C.Q. Mountjoy, M. Roth, Loss of neurons of origin of
the adrenergic projection to cerebral cortex (nucleus locus coeruleus)
in senile dementia, Neurology 32 (1982) 164–168.
[3] V. Chan-Palay, E. Asan, Alterations in catecholamine neurons of the
locus coeruleus in senile dementia of the Alzheimer’s type and in
Parkinson’s disease with and without dementia and depression, J.
Comp. Neurol. 287 (1989) 373–392.
[4] A.J. Cross, T.J. Crow, E.K. Perry, R.H. Perry, G. Blessed, B.E.
Tomlinson et al., Reduced dopamine-b-hydroxylase activity in
Alzheimer’s disease, Br. Med. J. 282 (1981) 93–94.
[5] J.F. Cubells, K.S. Kim, H. Baker, B.T. Volpe, Y. Chung, T.A. Houpt
et al., Differential in vivo regulation of mRNA encoding the
norepinephrine transporter and tyrosine hydroxylase in rat adrenal
medulla and locus ceruleus, J. Neurochem. 65 (1995) 502–509.
140 P. Szot et al. / Molecular Brain Research 84 (2000) 135 – 140
[6] C. Dyon-Laurent, S. Romand, A. Biegon, S.J. Sara, Functional
reorganization of the noradrenergic system after partial fornix
section: a behavioral and autoradiographic study, Exp. Brain Res. 96
(1993) 203–211.
[7] R. Elrod, E.R. Peskind, L. DiGiacomo, K.L. Brodkin, R.C. Veith,
M.A. Raskind et al., Effects of Alzheimer’s disease severity on
cerebrospinal fluid norepinephrine concentration, Am. J. Psychiatry
154 (1997) 25–30.
[8] J.H. Fallon, S.E. Longhlin, Monoamine innervation of the forebrain:
collateralization, Brain Res. Bull. 9 (1982) 295–307.
[9] M.F. Folstein, S.E. Folstein, P.R. McHugh, Mini-Mental State: a
practical method for grading the cognitive state of patients for the
clinician, J. Psychiatr. Res. 12 (1975) 189–198.
[10] J.M. Fritschy, R. Grzanna, Restoration of ascending noradrenergic
projections by residual locus coeruleus neurons: compensatory
response to neurotoxin-induced cell death in the adult rat brain, J.
Comp. Neurol. 321 (1992) 421–441.
[11] D.C. German, K.F. Manaye, C.L. White, D.J. Woodward, D.D.
McIntire, W.K. Smith et al., Disease-specific patterns of locus
coeruleus cell loss, Ann. Neurol. 32 (1992) 667–676.
[12] C.G. Gottfries, R. Adolfsson, S.M. Aquilonius, A. Carlsson, S.A.
Eckernas, A. Nordberg et al., Biochemical changes in dementia
disorders of Alzheimer type (AD/ SDAT), Neurobiol. Aging 4
(1983) 261–271.
[13] P.J. Harrison, P.R. Heath, S.L. Eastwood, P.W. Burnet, B. McDonald,
R.C. Pearson et al., The relative importance of premortem acidosis
and postmortem interval for human brain gene expression studies:
selective mRNA vulnerability and comparison with their encoded
proteins, Neurosci. Lett. 200 (1995) 151–154.
[14] P.J. Harrison, A.W. Procter, A.J.L. Barton, S.L. Lowe, A. Naj-
lerahim, P.H.F. Bertolucci et al., Terminal coma affects messenger
RNA detection in postmortem human temporal cortex, Mol. Brain
Res. 9 (1991) 161–164.
[15] W.J.G. Hoogendijk, M.G.P. Feenstra, M.H.A. Botterblom, J. Gilhuis,
I.E.C. Sommer, W. Kamphorst et al., Increased activity of surviving
locus ceruleus neurons in Alzheimer’s disease, Ann. Neurol. 45
(1999) 82–91.
[16] S.E. Loughlin, S.L. Foote, J.H. Fallon, Locus coeruleus projections
to cortex: topography, morphology and collateralizations, Brain Res.
Bull. 9 (1982) 287–294.
[17] D.M.A. Mann, J. Lincoln, P.O. Yates, J.E. Stamp, S. Toper, Changes
in the monoamine containing neurons of the human CNS in senile
dementia, Br. J. Psychiatry 136 (1980) 533–541.
[18] J.J. Mann, M. Stanley, A. Neophytides, M.J. de Leon, S.H. Ferris, S.
Gershon et al., Central amine metabolism in Alzheimer’s disease: in
vivo relationship to cognitive deficit, Neurobiol. Aging 2 (1981)
57–60.
[19] B. Marcyniuk, D.M.A. Mann, P.O. Yates, Loss of nerve cells from
locus coeruleus in Alzheimer’s disease is topographically arranged,
Neurosci. Lett. 64 (1986) 247–252.
[20] G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price,
E.M. Stadian et al., Clinical diagnosis of Alzheimer’s disease: report
of the NINCDS-ADRDA Work Group under the auspices of
Department of Health and Human Service Task Force on Alzheim-
er’s disease, Neurology 34 (1984) 939–944.
[21] J.C. Morris, C. Ernesto, K. Schafer, M. Coats, S. Leon, M. Sano et
al., Clinical dementia rating training and reliability in multicenter
studies: the Alzheimer’s Disease Cooperative Study experience,
Neurology 48 (1997) 1508–1510.
[22] K.L. O’Malley, M.J. Anhalt, B.M. Martin, J.R. Kelsoe, S.L.
Winfield, E.J. Ginns et al., Isolation and characterization of the
human tyrosine hydroxylase gene: identification of 59 alternative
splice sites responsible for multiple mRNAs, Biochemistry 26
(1987) 6910–6914.
[23] A.M. Palmer, G.K. Wilcock, M.M. Esiri, P.T. Francis, D.M. Bowen,
Monoaminergic innervation of the frontal and temporal lobes in
Alzheimer’s disease, Brain Res. 401 (1987) 231–238.
[24] E.K. Perry, B.E. Tomlinson, G. Blessed, R.H. Perry, A.J. Cross, T.J.
Crow et al., Neuropathological and biochemical observations on the
noradrenergic system in Alzheimer’s disease, J. Neurol. Sci. 51
(1981) 279–287.
[25] M.A. Raskind, E.R. Peskind, J.B. Halter, D.C. Jimerson, Norepi-
nephrine and MHPG levels in CSF and plasma in Alzheimer’s
disease, Arch. Gen. Psychiatry 41 (1984) 343–346.
[26] K.J. Reinikainen, L. Paljarvi, M. Huuskonen, H. Soininen, M.
Laakso, P. Reikkinen et al., A post-mortem study of noradrenergic,
serotonergic and GABAergic neurons in Alzheimer’s disease, J.
Neurol. Sci. 84 (1988) 101–116.
[27] S.J. Sara, C. Dyon-Laurent, B. Guibert, V. Leviel, Noradrenergic
hyperactivity after partial fornix section: role in cholinergic depen-
dent memory performance, Exp. Brain Res. 89 (1992) 125–132.
[28] P. Szot, S.S. White, R.C. Veith, Effect of pentylenetetrazol on the
expression of tyrosine hydroxylase mRNA and norepinephrine and
dopamine transporter mRNA, Mol. Brain Res. 44 (1997) 46–54.
[29] S.M. Tejani-Butt, J. Yang, H. Zaffar, Norepinephrine transporter
sites are decreased in the locus coeruleus in Alzheimer’s disease,
Brain Res. 631 (1993) 147–150.
[30] H. Tohgi, M. Ueno, T. Abel, S. Takahashi, Y. Nozaki, Con-
centrations of monoamines and their metabolites in the cerebrospinal
fluid from patients with senile dementia of the Alzheimer type and
vascular dementia of the Binswanger’s type, J. Neurol. Transm.
Park. Dis. Dement. Sect. 4 (1992) 69–77.
[31] B.E. Tomlinson, D. Irving, G. Blessed, Cell loss in the locus
coeruleus in senile dementia of the Alzheimer type, J. Neurol. Sci.
49 (1981) 419–428.
[32] M.Y. Zhu, G.A. Ordway, Down-regulation of norepinephrine trans-
porters on PC12 cells by transporter inhibitors, J. Neurochem. 68
(1997) 134–141.