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Blood pressure regulation in alzheimer's disease
Journal of the
Autonomic Nervous
System ELSEVIER
Journal of the Autonomic Nervous System 48 (1994) 65 71
Blood pressure regulation in Alzheimer's disease William J. Burke a,* Pedro G. Coronado a, Catherine A. Schmitt ~, Kathleen M. Gillespie c, Hyung D. Chung a,b Departments of a Neurology, b Pathology and c School of Public Health, Saint Louis Unit~ersity Medical School and Veterans Administration Medical Center, 3635 Vista at Grand, St. Louis, MO 63110, USA
(Received 26 April 1993; revised 27 September 1993; accepted 27 September 1993)
Abstract Brain neurons which regulate blood pressure (BP), including the C-1 tonic vasomotor neurons, degenerate in Alzheimer's disease (AD). This study determines whether BP is decreased in AD. We reviewed records of three autopsy proven AD patients. Medical causes for decreased BP were investigated. Yearly averages for systolic (SBP), diastolic (DBP), mean arterial (AP) blood pressure and pulse pressure (PP) were calculated. BP in the year ot diagnosis was compared to the sum of all BP in subsequent years. In addition, each yearly measurement through the course of AD was compared to its counterpart in the year of diagnosis. Three BP measurements were significantly decreased by from 6.9% to 15.9% in all patients when BP in the year of diagnosis was compared to the sum of each pressure in subsequent years. Sustained BP declines started in the third to fourth year after diagnosis of AD and continued for up to 9 years. The PP was decreased by 19.9% in one patient. There was a strong correlation between the number of C-1 neurons in these cases and their AP and SBP in the years after diagnosis. Hypothalamic phenylethanolamine N-methyltransferase activity was decreased by 63% in AD compared to control cases. Neurofibrillary tangles were found in the paraventricular nucleus of the hypothalamus in an AD case. We postulate that BP is altered in AD as neurons which regulate it degenerate. Key words: Blood pressure; Dementia; Epinephrine neuron
1. Introduction T h e b r a i n plays an i m p o r t a n t role in m a i n t a i n ing a r t e r i a l p r e s s u r e [18]. R e c e n t l y , r e s e a r c h e r s have d e l i n e a t e d the n e u r a l s u b s t r a t e s for b r a i n c o n t r o l o f b l o o d p r e s s u r e (BP) [2,3,16,18-20,23, 24,27,30]. B r a i n r e g i o n s involved in t h e c e n t r a l
* Corresponding author. Tel.: (314) 577-8026; Fax: (314) 2685101.
c o n t r o l of BP i n c l u d e t h e a m y g d a l a [20], h y p o t h a l a m u s [3], r a p h e nuclei [16], locus c e r u l e u s [24] a n d t h e C-1 n u c l e u s in the r o s t r a l v e n t r a l lateral m e d u l l a [19,23]. T h e C-1 n u c l e u s c o n t a i n s e p i n e p h r i n e ( E p i ) n e u r o n s which a r e the tonic v a s o m o t o r c e n t e r o f the b r a i n [18,20] a n d which a r e i d e n t i f i e d by t h e specific r a t e limiting e n z y m e in E p i synthesis, p h e n y l e t h a n o l a m i n e N - m e t h y l t r a n s f e r a s e ( P M N T ) [21]. T h e s e n e u r o n s m e d i a t e t h e b a r o r e c e p t o r reflex a n d are critical for m a i n t a i n i n g resting b l o o d p r e s s u r e [18-20]. Projec-
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W.J. Burke et aL /Journal q[ the Autonomic Nerrous System 48 (1994) 05- 71
tions of Epi neurons to both spinal cord and hypothalamus are important in BP regulation [3, 18,19,21,22,24]. In addition to Epi [18-20,23], neurotransmitters which mediate BP control include glutamate [27], acetylcholine [2], serotonin [30] and norepinephrine [24]. Neuronal degeneration in Alzheimer's disease (AD) affects brain regions [1,7, 25,28,31] and neurotransmitters [6,9,12] which control BP. The present study is a chart review of AD patients to determine whether arterial pressure is altered during the disease. In addition, we examine C-1 neurons in the same AD patients to determine whether the number of neurons in this BP center correlate with BP changes in these patients. Finally, we measure hypothalamic P N M T activity in AD and controls and examine the hypothalamus for the characteristic changes of AD.
2. Materials and methods
Patients. Charts of the 121 AD cases in our brain bank were reviewed. O f these, three were chosen for this study. The rest were rejected for one or more of the following reasons: (1) lack of data for diagnosis or yearly blood pressure measurements (93 cases); (2) history of diabetes (4 cases) or hypertension (24 cases). The charts of two women and one man, age 71.3 + 2.4 years, with clinical and autopsy [15] established AD were studied. Patients had clinical A D from 4 years to 13 years prior to death. The diagnosis was confirmed at autopsy according to established criteria [14]. In addition to A D patient A had subarachnoid and right thalamic hemorrhage and patient C had perivascular calcification and mild gliosis in the globus pallidus. The patients had no evidence of hypovolemia, neuropathy or other disease which may cause autonomic nervous system dysfunction. All hospital, nursing home and clinical records were reviewed for BP, medicationS, length of institutionalization and weight. Patients were ambulatory throughout most of the course of their disease. Patients A and B were ambulatory until 1 year and patient C until 1.5 months prior to death. Patients' BP were
recorded from the date of diagnosis or earlier, if available, until death, when they were alert, afebrile and not acutely ill (e.g., from pneumonia, acute urinary tract infection, or sepsis). The time at which blood pressures were taken was variable. By using all measurements recorded when the patient was not acutely ill, we calculated yearly averages for diastolic (DBP), systolic (SBP), mean arterial blood pressure (AP), pulse pressure (PP), and heart rate (HR). We compared each BP parameter in the year of diagnosis with the sum of all BP in subsequent years using Student's t-test computed with separate variances. In addition, we compared the annual average for each year after diagnosis to the average value in the year of diagnosis for each variable. The one-tailed tests were selected because the hypothesis of interest was that each variable declined after diagnosis. Cell counts. The C-1 nucleus from the patients described above was dissected from AD brains as previously described [7]. Tissue was fixed in 10% formalin, dehydrated in graded alcohol and xytene, embedded in paraffin and sectioned at 10 tzm thickness. Every fifth section was stained with hematoxylin-eosin. All neurons in at least 21 sections were counted [8]. The AP and SBP in years after the diagnosis was correlated to the number of neurons in C-1 for the three AD patients using Pearson correlation coefficients. Hypothalamic studies. In order to determine whether P N M T projections to the hypothalamus are involved in A D we measured PNMT activity in five AD patients (age: 69.4 + 1.9 years; postmortem interval: 15.6 + 3.9 h) and four control patients without clinical or pathological evidence of AD (age: 69.5 + 3.0 years; postmortem interval: 16.4 + 5.1 h) using our previously described assay [9]. One unit of P N M T activity is 1 pmol of [3H]epinephrine formed per hour. In addition, we looked for neurofibrillary tangles in the paraventricular nucleus by staining hypothalamus with thioflavin S. Hypothalami from a control and an AD case were fixed in 10% buffered formalin, dehydrated in graded alcohol and xylene, embedded in paraffin, sectioned at 10 mm thickness and stained with thioflavin S. Slides were viewed and photographs taken under a Nikon Optiphot fluo-
W.J. Burke et aL /Journal of the Autonomic Nercous System 48 (1994) 65- 7I
67
Table l Blood pressure changes during the course of Alzheimer's disease Patient
Time of m e a s u r e m e n t
Blood pressures (mmHg) Systolic
Diastolic
Mean arterial
Pulse
A
Year of diagnosis Years after diagnosis
142.9 ± 2.7 120.5 + 1.9 ÷+
81.8 ± 2,7 72.1 + 0.8 +
102.1 + 2.4 87.7 _+ 1.1 ++
61.1 ± 2.4 48.4 ± 1.6 + ~
99.3 + 7,8 79.9 +_ 1.1 **
B
Year of diagnosis Years after diagnosis
127.3 ± 3.5 118.2 ± 1.0 ***
76.0 ± 2.8 70.2 ± 0.7 **
51.3 ± 4.1 48.0 + 0.9 *
83.6 ± 3,9 77.5 + 1.8 *
C
Year of diagnosis Years after diagnosis
137.7 ± 3.5 128.0 ± 2.8 ***
83.2 ± 2.1 76.7 ± 2.1 ***
54.5 ± 2.3 51.3 _+ 13.6 *
80.0 + 2.2 82.0 +_ 4.4 *
H e a rt rate
93.1 ± 2.4 86.2 ± 0.7 *** 101.4 ± 2.4 93.8 ± 2.1 ***
Blood pressures and heart rate were measured in three A D patients at times when they were not acutely ill. The mean +_ SE arc shown for all m e a s u r e m e n t s in the year the patient was diagnosed or earlier if available, and in all subsequent years till death. Significance was d e t e r m i n e d comparing blood pressure or heart rate in year of diagnosis to that in all subsequent years using Student's t-test. Deg rees of significance are indicated as follows: * P = NS; ** P < 0.05; *** P < 0.025; + P < 0.002: ++ P < 0.001
105
A
105 100
100
95
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Year Fig. 1. Change in mean arterial pressure during the course of AD. Me a n arterial pressure (AP) was measured in three A D pa t i e ms when not acutely ill from date of diagnosis to death. Blood pressures prior to diagnosis were obtainable for patient C. Bars indicate the average of all AP in mmHg in the year designated. The numbe r of blood pressures taken each year is given in each bar. Statistical significance was d e t e r m i n e d using Student's t-test comparing AP in year of diagnosis with that in each subsequent year. Degrees of significance are indicated as follows: (a) P = NS; (b) P < 0.05; (c), P < 0.025; (d), P < 0.001; (e), P < 0.0005.
(~q
I¥.,L Burke et al. /.Iournal ol the .~lutonomic Nerrous ,~vstem 48 (1994) 05-71
rescence microscope (Nikon Inc., Garden City, NY).
3. ResuLts Three of the four BP m e a s u r e m e n t s were significantly decreased in all three A D patients during the course of the disease (Table 1). SBP was decreased by 15.9%, 6.9% and 7.1%, respectively, in patients A through C. DBP was decreased by 12.9%, 7.2% and 7.6%. AP was decreased by 14.3%, 7.1% and 7.4%. The PP was decreased by 19.9% only in patient A. The H R was also decreased by 19.5% in this patient but not in patients B or C. Persistent decreases in AP occurred in the third to fourth year after diagnosis and remained decreased for up to 9 years (Fig. 1).
A similar time course of BP change was found for SBP and DBP but not for PP or H R (data not shown). Patient C had a diagnosis of borderline hypertension but did not require treatment, and none of the patients were on antihypertensivc medications. Antipsychotic and antidepressant medications which could potentially lower blood pressure were also reviewed. Patients A and C were not on these medications during years when BP was decreased. Patient B was on these medications both in years of normal and low BP levels. Thus there was no correlation between these medications and BP. There was also no correlation between length of institutionalization and onset of decreased BP. There was no consistent relationship between weight and BP. All patients lost weight during the course of AD. Comparing weights in the first year of persistent BP drop
Fig. 2. Paraventricular nucleus of the hypothalamus stained with thioflavin S. Photograph taken under a fluorescent microscope shows a neurofibillary tangle (arrow).
W.J. Burke et al. / Journal of the Autonomic Nert,ous System 48 (1994) 65-71
with those in the year preceding the drop, patients A (8.9 lbs) and C (22.1 Ibs) lost weight. However, patient B (2.9 lbs) gained weight. Up to 30% of C-1 neurons were atrophic in sections from these same AD cases. There was a wide range in the number of C-1 neurons from 21,699 in patient B and 23,474 in patient A to 27,761 in C. The number of C-1 neurons in these AD patients correlated strongly with their AP (r = 0.995, P = 0.065) and SBP (r = 0.998, P = 0.04) in the years after diagnosis. Hypothalamic P N M T activity was sigificantly decresaed by 63% in the five AD patients (AD: 0.037 + 0.015 units/hypothalamus vs controls: 0.100 _+ 0.016; P < 0.025). Hypothalamic PNMT from cases B and C were 0.016 and 0.097 units/hypothalamus, respectively. The hypothalamus from patient A was not available. The paraventricular nucleus from the AD but not the control case showed neurofibrillary tangles (Fig. 2).
4. Discussion
The brain plays an important role in maintaining BP and in adjusting BP in response to environmental stimuli [3,18,20]. The C-1 region of the rostral ventral lateral medulla, amygdala and hypothalamus are some of the regions important in BP regulation [3,18,20,24]. The C-1 Epi neurons are a relay station in the baroreceptor reflex [3,18,20,23]. These neurons monitor BP information from baroreceptors via inputs from the nucleus tractus solitarius and regulate sympathetic outflow of neurons in the intermediolateral cell column of the thoracic cord [3,18-20,23]. Stimulation of C-1 neurons increases BP and lesions decrease BP [22]. These neurons constitute the brain's tonic vasomotor center which is critical in maintaining resting BP levels [18-20,22,23]. Superimposed on these tonic resting levels are BP responses to environmental stimuli [20] which are mediated in part by the amygdala and hypothalamus [20,24]. The dorsal medial region of the medulla also appears important in blood pressure regulation [26]. Both ventral lateral and dorsal medial catecholamine neurons project to the
69
amygdala [14,17] and hypothalamus [14]. We now report for the first time that BP decreases during the course of AD. This decreased BP was not attributable to medical conditions. Contrariwise there are significant deficits in AD central nervous system in the regions which regulate BP including C-1, C-2, the amygdala and the hypothalamus [6,7,10-12,25,28]. Our results support the notion that these brain regions are important in BP regulation in man. These findings do not preclude the possibility that BP could increase in some AD cases if appropriate brain regions were affected. However, results presented here and elsewhere [5-8] provide an explanation for the decreased prevalence of hypertension in AD [29]. The physiological mechanisms by which BP was decreased in these patients is not known. However, the fact that H R was decreased in one AD case suggests that control of H R may be important. However, in the other cases H R was not affected; therefore, alterations in stroke volume or peripheral resistance may also play a role. Our findings suggest that BP changes occur relatively late in the course of AD. This result is consonant with our previous report that changes in C-1 and C-2 cell bodies occur relatively late in AD [7,8]. These results do not imply that BP decreases in all cases of AD; rather they supporl the view that there is a subset of AD patients whose BP is altered as neurons which regulate BP are affected by AD. A larger prospective study would be needed to determine the number of AD patients whose BP is affected. Earlier studies showed the importance of C-1 neurons in maintaining BP in a variety of mammalian species such as rats, cats and dogs [18-20,23]. We found that in AD, C-1 perikarya undergo changes typical of the disease: decreased numbers and atrophy of neurons, neurofibrillary tangles and positive staining with Alz-50 antibody [8,11]. Here we show evidence of neurofibrillary degeneration in the paraventricular nucleus of the hypothalamus. a region which regulates BP and which is a target for Epi neurons [10,18,19,24]. Additionally in AD. the projection terminals of these Epi neurons to areas important for BP regulation including hypothalamus, amygdala and locus ceruleus, arc deficient [6,10]. Although case C did not have a
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Pv~J. Burke et al. /Journal of the Autonomic Nercous System 48 (1994) 65- 71
decrease in hypothalamic PNMT, we have previously reported a significant decrease in P N M T in the amygdala and LC for this case [6]. Our findings of a strong correlation between AP and SBP and the number of C-1 neurons in A D patients supports the importance of these neurons in regulation of BP in man. However, our results do not prove that degeneration of these neurons in AD is the primary cause of the decreased BP. Alternatively, degeneration of these neurons may reflect loss of their target neurons which control BP. Finally, we have hypothesized that loss of target neurons in one brain region could affect the output of Epi neurons to a relatively normal target in another brain region [5]. In this regard, loss of cortical and subcortical targets could trigger degenerative changes in Epi neurons and thereby alter their output to the spinal sympathetic neurons or other neurons which regulate BP [5,14,21].
5. Acknowledgment We acknowledge support from: PHS grants AG 09188 and AG 0032; Veterans Administration Merit Review Program and the Saint Louis University Brain Bank.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
6. References [1] Bondareff, W., Mountjoy, C.Q. and Roth, M., Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus eeruleus) in senile dementia, Neurology, 32 (1982) 164-168. [2] Brezenoff, H.E., Vargas, H. and Xiao, Y-F., Blockade of brain M2 muscarinie receptors lowers blood pressure in spontaneously hypertensive rats. Pharmacology, 36 (1988) 101-105. [3] Brody, M.J., Central nervous system mechanisms of arterial pressure regulation, Fed. Proc., 45 (1986) 2700-2706. [4] Burke, W.J., Hanson, D.M. and Chung, H.D., A highly sensitive assay for phenylethanolamine N-methyltransferase in human brain, Proc. Soc. Exp. Biol. Med., 181 (1986) 66-70. [5] Burke, W.J., Chung, H.D., Strong, R., Mattammal, M.B., Marshall, G.L., Nakra R., Grossberg, G.T., Haring, J.G. and Joh, T.H., Mechanism of degeneration of epinephrine neurons in Alzheimer's disease. In: R. Strong, W.G.
[15] [16]
[17]
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[19]
[20]
Woods and W.J. Burke (Eds.), Central Nervous System Disorders of Aging, Raven Press, New York, 1987~ pp. 41-70. Burke, W.J., Marshall, G.L, Chung, H.D., Nakra, R., Grossberg, G.T. and Joh, T.H., Phenylethanolamine Nmethyltransferase is decreased in Alzheimer's disease brains, Ann. Neurol., 22 (1987) 278-280. Burke, W.J., Chung, H.D., Huang, J.S., Huang, S.S., Haring, J.H., Strong, R. and Joh, T.H., Evidence for retrograde degeneration of epinephrine neurons in Alzheimer's disease, Ann. Neurol., 24 (1988) 532-536. Burke, W.J., Chung, H.D., Marshall, G.L., Gillespie, K.N. and Joh, T.H., Evidence for decreased transport of PNMT protein in advanced Alzheimer's disease, J. Am. Geriatr. Soc., 38 (1990) 1275-1282. Burke, W.J., Park, D.H., Chung, H.D., Marshall, G.L., Haring, J.H. and Joh, T.H., Evidence for decreased transport of tryptophan hydroxylase in Alzheimer's disease, Brain Res., 537 (1990) 83-87. Burke, W.J., Coronado, P.G. and Chung, H.D., Blood pressure regulation in Alzheimer's disease (Abstract), Neurology, 42 (Suppl. 3) (1990) 140. Burke, W.J., Galvin, N.J., Chung, H.D., Gillespie, K.N., Cataldo, A.M. and Nixon, R.A., Pathology of epinephrine neurons in Alzheimer's (Abstract), Soc. Neurosci., 18 (1992) 557. Hardy, J., Adolfsson, R., Alafuzoff, I., Bucht, G., Marcusson, J., Nyberg, P., Perdahl, E.J., Wester P. and Windblad, B., Transmitter deficits in Alzheimer's disease, Neurochem. Int., 7 (1985) 545-563. Hokfelt, T., Johansson, O. and Goldstein, M., Central catecholamine neurons as revealed by immunohistochemistry with special reference to adrenaline neurons. In: A. Bjorklund and T. Hokfelt (Eds.), Handbook of Chemical Neuroanatomy, Elsevier, Amsterdam, 1984, pp. 157-276. Hokfelt, T., Johansson, D. and Goldstein, M., Chemical anatomy of the brain, Science, 225 (1984) 1326-1334. Khachaturian, Z.S., Diagnosis of Alzheimer's disease, Arch. Neurol., 42 (1985) 1097-1105. Kushiro, T., Kurumatani, H., Ishii, T., Yokoyama, H., Koike, J., Hatayama, Y., Kobayashi, Y. and Kajiwara, N., Role of serotonergic (5-HT2) receptor in blood pressure regulation in rats, Clin. Exp. Theory Pract., 10 (SuppL 1) (1988) 339-345. Otterson O.P., Afferent connections to the amygdaloid complex of the rat with some observations in the cat. Iti. Afferents from the lower brain stem, J. Comp. Neurot., 202 (1981) 335-356. Reis, D.J., The brain and hypertension: reflections on 35 years of inquiry into the neurobiology of the circulation, Circulation, 70 (Suppl. III) (1984) 31-45. Reis, D.J., Brain-stem mechanisms governing resting and reflex tone of precapillary vessels, J. Cardiovascular Pharmacol., 7 (Suppl. 3) (1985) 160-166. Reis, D.J. and LeDoux. J,E,. Some central neural mechanisms governing resting and behaviorally coupled control of blood pressure, Circulation, 76 (Suppl. I) (1987) 2-9.
W.J. Burke et aL /Journal of the Autonomic NerL,ous System 48 (1994) 65-71 [21] Ross, C.A., Ruggiero, D.A., Job, T.H., Park, D.H. and Reis. D.J., Rostral ventrolateral medulla: selective projection to the thoracic autonomic cell column from the region containing C1 adrenaline neurons, J. Comp. Neurol., 228 (1984) 168-185. [22] Ross, C.A., Ruggiero, D.A., Park, D.H., Job, T.H., Sved, A.F., Fernandez-Pardal, J., Saavedra, J.M. and Reis, D.J., Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C-1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin, J. Neurosci., 4 (1984) 474-494. [23] Ross, C.A., Ruggiero, D.A. and Reis, D.J., Projections from the nucleus tractus solitarii to the rostral ventrolateral medulla, J. Comp. Neurol., 242 (1985) 511-534. [24] Sawchenko, P.E. and Swanson, L.W., The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat, Brain Res. Rev. 4 (1982) 275-325. [25] Scott, S.A., Dekosky, S.T. and Scheff, S.W., Volumetric atrophy of the amygdala in Alzheimer's disease: quantitative serial reconstruction, Neurology, 41 (1991) 351-356.
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[26] Talman, W.T., Snyder, D.W. and Reis, D.J., Chronic lability of arterial pressure produced by destruction of A2 catecholamine neurons in rat brainstem, Circ. Res., (1980) 842-853. [27] Talman, W.T., Granata, A.R. and Reis, D.J., Glutamatergic mechanisms in the nucleus tractus solitarius in blood pressure control, Fed. Proc., 43 (1984) 39-44. [28] Terry, R.D., Alzheimer's disease. In R.L. Davis and D.M. Robertson (Eds.), Textbook of Neuropathology, Williams & Wilkins, Baltimore, 1985, pp. 824-841. [29] Tresch, D.D., Folstein, M.F., Rabins, P.V. and Hazzard, W.R., Prevalence and significance of cardiovascular disease and hypertension in elderly patients with dementia and depression, J. Am. Geriatr Soc., 33 (1985) 530 537. [30] Trolliet, M.R., Kurnjek, M.L., Mikulic, L., Basso, N. and Taquini, A.C., Development of renovascular hypertension after central serotonin depletion, Hypertension, 15 (Suppl. 1) (1990) 166-169. [31] Yamamoto, T. and ttirano, A., Nucleus raphe dorsalis in Alzheimer's disease: Neurofibrillary tangles and loss of large neurons, Ann. Neurol., 17 (1985) 573-577.
Autonomic Nervous
System ELSEVIER
Journal of the Autonomic Nervous System 48 (1994) 65 71
Blood pressure regulation in Alzheimer's disease William J. Burke a,* Pedro G. Coronado a, Catherine A. Schmitt ~, Kathleen M. Gillespie c, Hyung D. Chung a,b Departments of a Neurology, b Pathology and c School of Public Health, Saint Louis Unit~ersity Medical School and Veterans Administration Medical Center, 3635 Vista at Grand, St. Louis, MO 63110, USA
(Received 26 April 1993; revised 27 September 1993; accepted 27 September 1993)
Abstract Brain neurons which regulate blood pressure (BP), including the C-1 tonic vasomotor neurons, degenerate in Alzheimer's disease (AD). This study determines whether BP is decreased in AD. We reviewed records of three autopsy proven AD patients. Medical causes for decreased BP were investigated. Yearly averages for systolic (SBP), diastolic (DBP), mean arterial (AP) blood pressure and pulse pressure (PP) were calculated. BP in the year ot diagnosis was compared to the sum of all BP in subsequent years. In addition, each yearly measurement through the course of AD was compared to its counterpart in the year of diagnosis. Three BP measurements were significantly decreased by from 6.9% to 15.9% in all patients when BP in the year of diagnosis was compared to the sum of each pressure in subsequent years. Sustained BP declines started in the third to fourth year after diagnosis of AD and continued for up to 9 years. The PP was decreased by 19.9% in one patient. There was a strong correlation between the number of C-1 neurons in these cases and their AP and SBP in the years after diagnosis. Hypothalamic phenylethanolamine N-methyltransferase activity was decreased by 63% in AD compared to control cases. Neurofibrillary tangles were found in the paraventricular nucleus of the hypothalamus in an AD case. We postulate that BP is altered in AD as neurons which regulate it degenerate. Key words: Blood pressure; Dementia; Epinephrine neuron
1. Introduction T h e b r a i n plays an i m p o r t a n t role in m a i n t a i n ing a r t e r i a l p r e s s u r e [18]. R e c e n t l y , r e s e a r c h e r s have d e l i n e a t e d the n e u r a l s u b s t r a t e s for b r a i n c o n t r o l o f b l o o d p r e s s u r e (BP) [2,3,16,18-20,23, 24,27,30]. B r a i n r e g i o n s involved in t h e c e n t r a l
* Corresponding author. Tel.: (314) 577-8026; Fax: (314) 2685101.
c o n t r o l of BP i n c l u d e t h e a m y g d a l a [20], h y p o t h a l a m u s [3], r a p h e nuclei [16], locus c e r u l e u s [24] a n d t h e C-1 n u c l e u s in the r o s t r a l v e n t r a l lateral m e d u l l a [19,23]. T h e C-1 n u c l e u s c o n t a i n s e p i n e p h r i n e ( E p i ) n e u r o n s which a r e the tonic v a s o m o t o r c e n t e r o f the b r a i n [18,20] a n d which a r e i d e n t i f i e d by t h e specific r a t e limiting e n z y m e in E p i synthesis, p h e n y l e t h a n o l a m i n e N - m e t h y l t r a n s f e r a s e ( P M N T ) [21]. T h e s e n e u r o n s m e d i a t e t h e b a r o r e c e p t o r reflex a n d are critical for m a i n t a i n i n g resting b l o o d p r e s s u r e [18-20]. Projec-
0165-1838/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0165-1 838(93)E0130-W
66
W.J. Burke et aL /Journal q[ the Autonomic Nerrous System 48 (1994) 05- 71
tions of Epi neurons to both spinal cord and hypothalamus are important in BP regulation [3, 18,19,21,22,24]. In addition to Epi [18-20,23], neurotransmitters which mediate BP control include glutamate [27], acetylcholine [2], serotonin [30] and norepinephrine [24]. Neuronal degeneration in Alzheimer's disease (AD) affects brain regions [1,7, 25,28,31] and neurotransmitters [6,9,12] which control BP. The present study is a chart review of AD patients to determine whether arterial pressure is altered during the disease. In addition, we examine C-1 neurons in the same AD patients to determine whether the number of neurons in this BP center correlate with BP changes in these patients. Finally, we measure hypothalamic P N M T activity in AD and controls and examine the hypothalamus for the characteristic changes of AD.
2. Materials and methods
Patients. Charts of the 121 AD cases in our brain bank were reviewed. O f these, three were chosen for this study. The rest were rejected for one or more of the following reasons: (1) lack of data for diagnosis or yearly blood pressure measurements (93 cases); (2) history of diabetes (4 cases) or hypertension (24 cases). The charts of two women and one man, age 71.3 + 2.4 years, with clinical and autopsy [15] established AD were studied. Patients had clinical A D from 4 years to 13 years prior to death. The diagnosis was confirmed at autopsy according to established criteria [14]. In addition to A D patient A had subarachnoid and right thalamic hemorrhage and patient C had perivascular calcification and mild gliosis in the globus pallidus. The patients had no evidence of hypovolemia, neuropathy or other disease which may cause autonomic nervous system dysfunction. All hospital, nursing home and clinical records were reviewed for BP, medicationS, length of institutionalization and weight. Patients were ambulatory throughout most of the course of their disease. Patients A and B were ambulatory until 1 year and patient C until 1.5 months prior to death. Patients' BP were
recorded from the date of diagnosis or earlier, if available, until death, when they were alert, afebrile and not acutely ill (e.g., from pneumonia, acute urinary tract infection, or sepsis). The time at which blood pressures were taken was variable. By using all measurements recorded when the patient was not acutely ill, we calculated yearly averages for diastolic (DBP), systolic (SBP), mean arterial blood pressure (AP), pulse pressure (PP), and heart rate (HR). We compared each BP parameter in the year of diagnosis with the sum of all BP in subsequent years using Student's t-test computed with separate variances. In addition, we compared the annual average for each year after diagnosis to the average value in the year of diagnosis for each variable. The one-tailed tests were selected because the hypothesis of interest was that each variable declined after diagnosis. Cell counts. The C-1 nucleus from the patients described above was dissected from AD brains as previously described [7]. Tissue was fixed in 10% formalin, dehydrated in graded alcohol and xytene, embedded in paraffin and sectioned at 10 tzm thickness. Every fifth section was stained with hematoxylin-eosin. All neurons in at least 21 sections were counted [8]. The AP and SBP in years after the diagnosis was correlated to the number of neurons in C-1 for the three AD patients using Pearson correlation coefficients. Hypothalamic studies. In order to determine whether P N M T projections to the hypothalamus are involved in A D we measured PNMT activity in five AD patients (age: 69.4 + 1.9 years; postmortem interval: 15.6 + 3.9 h) and four control patients without clinical or pathological evidence of AD (age: 69.5 + 3.0 years; postmortem interval: 16.4 + 5.1 h) using our previously described assay [9]. One unit of P N M T activity is 1 pmol of [3H]epinephrine formed per hour. In addition, we looked for neurofibrillary tangles in the paraventricular nucleus by staining hypothalamus with thioflavin S. Hypothalami from a control and an AD case were fixed in 10% buffered formalin, dehydrated in graded alcohol and xylene, embedded in paraffin, sectioned at 10 mm thickness and stained with thioflavin S. Slides were viewed and photographs taken under a Nikon Optiphot fluo-
W.J. Burke et aL /Journal of the Autonomic Nercous System 48 (1994) 65- 7I
67
Table l Blood pressure changes during the course of Alzheimer's disease Patient
Time of m e a s u r e m e n t
Blood pressures (mmHg) Systolic
Diastolic
Mean arterial
Pulse
A
Year of diagnosis Years after diagnosis
142.9 ± 2.7 120.5 + 1.9 ÷+
81.8 ± 2,7 72.1 + 0.8 +
102.1 + 2.4 87.7 _+ 1.1 ++
61.1 ± 2.4 48.4 ± 1.6 + ~
99.3 + 7,8 79.9 +_ 1.1 **
B
Year of diagnosis Years after diagnosis
127.3 ± 3.5 118.2 ± 1.0 ***
76.0 ± 2.8 70.2 ± 0.7 **
51.3 ± 4.1 48.0 + 0.9 *
83.6 ± 3,9 77.5 + 1.8 *
C
Year of diagnosis Years after diagnosis
137.7 ± 3.5 128.0 ± 2.8 ***
83.2 ± 2.1 76.7 ± 2.1 ***
54.5 ± 2.3 51.3 _+ 13.6 *
80.0 + 2.2 82.0 +_ 4.4 *
H e a rt rate
93.1 ± 2.4 86.2 ± 0.7 *** 101.4 ± 2.4 93.8 ± 2.1 ***
Blood pressures and heart rate were measured in three A D patients at times when they were not acutely ill. The mean +_ SE arc shown for all m e a s u r e m e n t s in the year the patient was diagnosed or earlier if available, and in all subsequent years till death. Significance was d e t e r m i n e d comparing blood pressure or heart rate in year of diagnosis to that in all subsequent years using Student's t-test. Deg rees of significance are indicated as follows: * P = NS; ** P < 0.05; *** P < 0.025; + P < 0.002: ++ P < 0.001
105
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95
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Year Fig. 1. Change in mean arterial pressure during the course of AD. Me a n arterial pressure (AP) was measured in three A D pa t i e ms when not acutely ill from date of diagnosis to death. Blood pressures prior to diagnosis were obtainable for patient C. Bars indicate the average of all AP in mmHg in the year designated. The numbe r of blood pressures taken each year is given in each bar. Statistical significance was d e t e r m i n e d using Student's t-test comparing AP in year of diagnosis with that in each subsequent year. Degrees of significance are indicated as follows: (a) P = NS; (b) P < 0.05; (c), P < 0.025; (d), P < 0.001; (e), P < 0.0005.
(~q
I¥.,L Burke et al. /.Iournal ol the .~lutonomic Nerrous ,~vstem 48 (1994) 05-71
rescence microscope (Nikon Inc., Garden City, NY).
3. ResuLts Three of the four BP m e a s u r e m e n t s were significantly decreased in all three A D patients during the course of the disease (Table 1). SBP was decreased by 15.9%, 6.9% and 7.1%, respectively, in patients A through C. DBP was decreased by 12.9%, 7.2% and 7.6%. AP was decreased by 14.3%, 7.1% and 7.4%. The PP was decreased by 19.9% only in patient A. The H R was also decreased by 19.5% in this patient but not in patients B or C. Persistent decreases in AP occurred in the third to fourth year after diagnosis and remained decreased for up to 9 years (Fig. 1).
A similar time course of BP change was found for SBP and DBP but not for PP or H R (data not shown). Patient C had a diagnosis of borderline hypertension but did not require treatment, and none of the patients were on antihypertensivc medications. Antipsychotic and antidepressant medications which could potentially lower blood pressure were also reviewed. Patients A and C were not on these medications during years when BP was decreased. Patient B was on these medications both in years of normal and low BP levels. Thus there was no correlation between these medications and BP. There was also no correlation between length of institutionalization and onset of decreased BP. There was no consistent relationship between weight and BP. All patients lost weight during the course of AD. Comparing weights in the first year of persistent BP drop
Fig. 2. Paraventricular nucleus of the hypothalamus stained with thioflavin S. Photograph taken under a fluorescent microscope shows a neurofibillary tangle (arrow).
W.J. Burke et al. / Journal of the Autonomic Nert,ous System 48 (1994) 65-71
with those in the year preceding the drop, patients A (8.9 lbs) and C (22.1 Ibs) lost weight. However, patient B (2.9 lbs) gained weight. Up to 30% of C-1 neurons were atrophic in sections from these same AD cases. There was a wide range in the number of C-1 neurons from 21,699 in patient B and 23,474 in patient A to 27,761 in C. The number of C-1 neurons in these AD patients correlated strongly with their AP (r = 0.995, P = 0.065) and SBP (r = 0.998, P = 0.04) in the years after diagnosis. Hypothalamic P N M T activity was sigificantly decresaed by 63% in the five AD patients (AD: 0.037 + 0.015 units/hypothalamus vs controls: 0.100 _+ 0.016; P < 0.025). Hypothalamic PNMT from cases B and C were 0.016 and 0.097 units/hypothalamus, respectively. The hypothalamus from patient A was not available. The paraventricular nucleus from the AD but not the control case showed neurofibrillary tangles (Fig. 2).
4. Discussion
The brain plays an important role in maintaining BP and in adjusting BP in response to environmental stimuli [3,18,20]. The C-1 region of the rostral ventral lateral medulla, amygdala and hypothalamus are some of the regions important in BP regulation [3,18,20,24]. The C-1 Epi neurons are a relay station in the baroreceptor reflex [3,18,20,23]. These neurons monitor BP information from baroreceptors via inputs from the nucleus tractus solitarius and regulate sympathetic outflow of neurons in the intermediolateral cell column of the thoracic cord [3,18-20,23]. Stimulation of C-1 neurons increases BP and lesions decrease BP [22]. These neurons constitute the brain's tonic vasomotor center which is critical in maintaining resting BP levels [18-20,22,23]. Superimposed on these tonic resting levels are BP responses to environmental stimuli [20] which are mediated in part by the amygdala and hypothalamus [20,24]. The dorsal medial region of the medulla also appears important in blood pressure regulation [26]. Both ventral lateral and dorsal medial catecholamine neurons project to the
69
amygdala [14,17] and hypothalamus [14]. We now report for the first time that BP decreases during the course of AD. This decreased BP was not attributable to medical conditions. Contrariwise there are significant deficits in AD central nervous system in the regions which regulate BP including C-1, C-2, the amygdala and the hypothalamus [6,7,10-12,25,28]. Our results support the notion that these brain regions are important in BP regulation in man. These findings do not preclude the possibility that BP could increase in some AD cases if appropriate brain regions were affected. However, results presented here and elsewhere [5-8] provide an explanation for the decreased prevalence of hypertension in AD [29]. The physiological mechanisms by which BP was decreased in these patients is not known. However, the fact that H R was decreased in one AD case suggests that control of H R may be important. However, in the other cases H R was not affected; therefore, alterations in stroke volume or peripheral resistance may also play a role. Our findings suggest that BP changes occur relatively late in the course of AD. This result is consonant with our previous report that changes in C-1 and C-2 cell bodies occur relatively late in AD [7,8]. These results do not imply that BP decreases in all cases of AD; rather they supporl the view that there is a subset of AD patients whose BP is altered as neurons which regulate BP are affected by AD. A larger prospective study would be needed to determine the number of AD patients whose BP is affected. Earlier studies showed the importance of C-1 neurons in maintaining BP in a variety of mammalian species such as rats, cats and dogs [18-20,23]. We found that in AD, C-1 perikarya undergo changes typical of the disease: decreased numbers and atrophy of neurons, neurofibrillary tangles and positive staining with Alz-50 antibody [8,11]. Here we show evidence of neurofibrillary degeneration in the paraventricular nucleus of the hypothalamus. a region which regulates BP and which is a target for Epi neurons [10,18,19,24]. Additionally in AD. the projection terminals of these Epi neurons to areas important for BP regulation including hypothalamus, amygdala and locus ceruleus, arc deficient [6,10]. Although case C did not have a
70
Pv~J. Burke et al. /Journal of the Autonomic Nercous System 48 (1994) 65- 71
decrease in hypothalamic PNMT, we have previously reported a significant decrease in P N M T in the amygdala and LC for this case [6]. Our findings of a strong correlation between AP and SBP and the number of C-1 neurons in A D patients supports the importance of these neurons in regulation of BP in man. However, our results do not prove that degeneration of these neurons in AD is the primary cause of the decreased BP. Alternatively, degeneration of these neurons may reflect loss of their target neurons which control BP. Finally, we have hypothesized that loss of target neurons in one brain region could affect the output of Epi neurons to a relatively normal target in another brain region [5]. In this regard, loss of cortical and subcortical targets could trigger degenerative changes in Epi neurons and thereby alter their output to the spinal sympathetic neurons or other neurons which regulate BP [5,14,21].
5. Acknowledgment We acknowledge support from: PHS grants AG 09188 and AG 0032; Veterans Administration Merit Review Program and the Saint Louis University Brain Bank.
[6]
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[8]
[9]
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[26] Talman, W.T., Snyder, D.W. and Reis, D.J., Chronic lability of arterial pressure produced by destruction of A2 catecholamine neurons in rat brainstem, Circ. Res., (1980) 842-853. [27] Talman, W.T., Granata, A.R. and Reis, D.J., Glutamatergic mechanisms in the nucleus tractus solitarius in blood pressure control, Fed. Proc., 43 (1984) 39-44. [28] Terry, R.D., Alzheimer's disease. In R.L. Davis and D.M. Robertson (Eds.), Textbook of Neuropathology, Williams & Wilkins, Baltimore, 1985, pp. 824-841. [29] Tresch, D.D., Folstein, M.F., Rabins, P.V. and Hazzard, W.R., Prevalence and significance of cardiovascular disease and hypertension in elderly patients with dementia and depression, J. Am. Geriatr Soc., 33 (1985) 530 537. [30] Trolliet, M.R., Kurnjek, M.L., Mikulic, L., Basso, N. and Taquini, A.C., Development of renovascular hypertension after central serotonin depletion, Hypertension, 15 (Suppl. 1) (1990) 166-169. [31] Yamamoto, T. and ttirano, A., Nucleus raphe dorsalis in Alzheimer's disease: Neurofibrillary tangles and loss of large neurons, Ann. Neurol., 17 (1985) 573-577.