Autonomic Cardiovascular Responses to Tilting in Patients with Alzheimer's Disease and in Healthy Elderly Women
Summary The cardiovascular responses to tilting and breathing were studied in 24 patients with late-onset Alzheimer's disease (AD) and 54 healthy control women aged between 75 and 96 years in order to study the parasympathetic and sympathetic heart-rate control. The cardiovascular response to tilting and breathing showed no age-associated decrease in the healthy control women. During rest, the AD patients had lower mean systolic and diastolic blood pressure but the same heart rate as the control patients. After tilting, the AD patients had a greater increase in heart rate, and the mean systolic blood pressure fell to 126 mmHg compared with 160 mmHg in the control women (p < 0.001). After the initial acceleration, the following deceleration of the heart rate, an expression of parasympathetic nervous activity, was lower in the AD patients (p < 0.001). The deep-breathing test showed no significant difference between the two groups, but the changes of acceleration and brake indices could indicate a dysfunction of the autonomic nervous system since the AD patients were not recumbent.
Introduction Alzheimer's disease (AD) is characterized by neuronal loss from cortical and subcortical regions. Several neurotransmitter systems including acetylcholine, serotonin, dopamine and noradrenaline are affected. Neuronal losses have also been shown in subcortical nuclei such as the lateral hypothalamus and raphe nuclei, nucleus basalis of Meynert and thalamic nuclei with projections to cerebral cortex [1, 2]. Integration of the autonomic nervous system takes place in the hypothalamus but autonomic reactions can also be elicited from the cerebral cortex. Whether this integration is changed in Alzheimer's disease, thereby affecting cardiovascular responses to tilting has not to our knowledge been previously studied.
The autonomic nervous system plays an important role in the control of blood pressure and activity of the heart. The sympathetic system, in contrast to the parasympathetic system, is characterized by a more or less constant activity with influence from somatic afferents. The cranial part of the parasympathetic system which includes the vagal nerve inhibits the heart rate. The autonomic nervous system is tested by the heart-rate responses to tilting and forced breathing [3, 4]. There is an age-associated decrease of these test indices in healthy controls [5, 6]. This decrease is probably due to impaired function of the receptor organ or parts of the autonomic nervous system [5]. Results from previous studies are not conclusive as to whether there is a more rapid or slower decline after the age of 60 [3, 4]. Age and Ageing 1992,21:301 -307
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
SOLVE ELMSTAHL, MARIE PETERSSON, BO LILJA, SVEN-MARTEN SAMUELSSON, INGMAR ROSEN, LILLEMOR BJUNO
s. ELMSTAHL ET AL.
Subjects and Methods Two groups of women were studied, one consisting of 24 patients with a late-onset AD of mean duration 7.2 ±3.6 years, and one consisting of 54 age-matched healthy control subjects. The AD subjects, born 1894—1914 with a mean age of 85 + 5.3 years, were selected as follows from Varnhem Hospital in Malmo, Sweden, a Geriatric University Hospital with 800 geriatric long-stay patients: all women with a medical history of dementia, confusion or loss of memory were examined and medical records were checked. Patients who fulfilled the inclusion criteria
(see below) were included. The clinical examination included rating scales for the diagnosis of multiinfarct dementia [13] and frontal-lobe dementia of non-Alzheimer type [14]. Patients with a score ^ 7 or ^ 5 on these scales, indicating multi-infarct dementia or frontal-lobe dementia, were excluded. Twentyfour women who were regarded as having probable or possible AD, according to the criteria of NINCDSADRDA [15] participated in an orthostatic test. Fifty-four control subjects, born 1894-1914, were recruited in the following way: a questionnaire was sent to 808 age-matched women living in Malmo, using the Population Register at the City Council. The response rate was 65.6%. The aim was to recruit three age-matched controls, born within the same month and year, for each case. Seventy-four subjects, who denied cardio- and cerebrovascular disease, diabetes or malignancy, were examined. The AD patients and control subjects were examined physically and neurologically and they underwent EEG and neuropsychological assessment including Minimental State Examination [16], spatial tests with Koh's Block design [17] and Memory-for-Designs Test [18], vocabulary tests according to Husen [19], Synonyms [20] and Paired Associates measuring immediate recall and Memory for Objects [21]. The control subjects were interviewed about their medical history and life-style factors. Further exclusion criteria for both groups were: a medical history or signs of stroke; clinical or labora-
Figure I. The blood pressure changes in patients with Alzheimer's disease (D) and controls (A) before, during and after tilt (differences before and during tilt are significant , p < 0.001). Values are means ± SD.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
Several cardiovascular tests have been introduced to measure autonomic nerve function [1, 2, 7, 8]. The heart-rate reactions after tilting, with an initial acceleration followed by a deceleration expressed as acceleration and brake indices, have been used as indicators of the functions of the sympathetic and parasympathetic systems [8, 9]. Variation of the heart rate during deep breathing reflects the parasympathetic nervous system [10—12]. The aim of the present study was to study the autonomic nervous system and the heart-rate reaction in Alzheimer patients and also to obtain reference values for healthy elderly subjects.
AUTONOMIC CARDIOVASCULAR RESPONSES TO T I L T I N G IN AD rate changes (HR) were expressed as follows: the mean R-R interval (A) at rest, 1 min before tilting was measured; after tilting, the shortest R-R interval (B) and then the following longest R-R interval (C) were chosen. Acceleration and brake indices were expressed as A-B/A and C-B/A, respectively [9]. The deep-breathing test with six consecutive maximal expirations (E) and inspirations (I) were performed during continuous ECG recording. The heart-rate E/I ratio was expressed as the ratio between the mean longest R-R interval during expiration and the shortest interval during inspiration [12]. Statistical analysis: Differences between groups were tested by the Mann—Whitney Wilcoxon rank sum test. Data are given as means ± standard deviation. Differences with p < 0.05 were considered significant.
Results During rest, the 24 AD patients had lower mean systolic blood pressure (137 ±19 vs. 167 ± 2 3 mmHg, p < 0.001) and lower diastolic blood pressure (75 ± 10 vs. 84 ± 10 mmHg, p < 0.01) than the 54 control subjects, but the same heart rate (72 ±10.0 vs. 72 ±9.9 beats/min). During the orthostatic test, the mean systolic blood
110 100-
6050 supine 1
2
tilting
3
4
5
Time (min)
1
2
supine
Figure 2. The heart-rate variations in patients with Alzheimer's disease (•) and controls ( A ) before, during and after tilt (differences before and during tilt are significant p < 0.001). Values are means ± SD.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
ton' signs of malignancy, metabolic, hepatic or renal disease; folic acid or cobalamine deficiency, atrial flutter, fibrillation or left bundle branch conduction disturbance on electrocardiogram, alcohol or drug abuse, beta-blocker treatment, inability to stand up and to be fastened to a tilting table. Twenty subjects in the control group were excluded for one or more reasons; six used beta-blockers and six women had atrial flutter or fibrillation detected at ECG. Seven cases of possible dementia according to clinical examination and testing and one case of stroke were excluded. Seventeen of 24 cases were classified as probable AD and eight cases as possible AD. Four of the patients with possible AD had asymmetric brain disorder according to E E C All 24 patients were dependent on help with most of the activities of daily living. All but two had rating IV-VI according to Berger's rating of the severity of 'senility' [22]. The mean index of activity of daily life according to Katz et al. was 4.9 [23]. Biochemical variables, including haemoglobin, cobalamine, folate, glucose and HbAic in blood and electrolytes in serum were determined by routine methods at the Department of Clinical Chemistry, Malmo and they were normal in all cases and controls. The orthostatic test was performed with continuous ECG recording while the subject was tilted from supine to upright position, remaining so for 8 min and then tilted back again. The initial rapid heart
s. ELMSTAHL ET AL.
3°4
Table. Cardiovascular responses with acceleration and brake indices after tilting, and heart-rate expiration/inspiration ratio during deep breathing in patients with Alzheimer's disease (AD) and age-matched controls Age (years)
AD
(n)
>89
—
0
(n)
12.8±6.5 11.2 + 3.5 12.6±6.6 15.0 + 8.1 11.0 ±4.4
54
•••
8 NS 26 *•• 14 NS 6 NS
11.8±7.2 54 • • • 8 •* 11.7±3.7 11.1 +6.7 26 • • 14 NS 11.9±8.6 14.7 ±10.0 6 NS 1.13 + 0.09 51 NS 1.16±0.15 8 NS 1.12 ±0.67 25 NS 1.13 ±0.12 12 NS 1.15±0.60 6 NS
= p89 4 14.7±7.0 Brake index 24 All 5.9 ±4.0 5 4.7 ±3.7 75-79 9 4.7 ±2.5 80-84 6 8.6 ±5.8 85-89 4 >89 6.2 ±1.4 Expirationjinspiration ratio 10 All 1.15±0.12 3 75-79 1.18±0.13 4 80-84 1.15 ±0.18 3 85-89 1.12 + 0.15
Controls
AUTONOMIC CARDIOVASCULAR RESPONSES TO TILTING IN AD
An age-associated decrease of cardiovascular responses mediated by the autonomic nervous system has been shown in healthy subjects [4, 29]. A non-linear decrease of the heart rate
response with age has been reported with a more rapid decline after the age of 60 [3]. Bergstrom et al. have suggested linear equations for the age-associated decrease of the acceleration and brake indices up to 60 years of age [6]. In our study, the mean increase of the heart rate in the healthy control women, 10 beats/min, was in agreement with the findings of Kaijser and Sachs who found a mean increase of 11 beats/min in 60-85-year-old subjects [5]. However, in the healthy women, we found no significant decrease of acceleration and brake indices between ages 75 and 96 years. Instead, the small changes indicated that they had reached a plateau. Therefore linear equations suggested for the age-associated decline in cardiovascular responses cannot be extrapolated to the very old. Instantaneous heart-rate changes with forced breathing and the expiration and inspiration ratio are used to assess vagal function. A decreased response, more pronounced on the parasympathetic nerve functions, has been found in elderly subjects [3]. Wielingei al. [26] found a poor correlation between heart-rate changes after tilting and forced breathing, suggesting the involvement of different mechanisms. T h e response to forced breathing is dependent on efferent and afferent nerve functions as well as the effector organ. In our study, although the heart-rate E/I ratio did not differ between the groups, the small number of subjects in the AD group made it difficult to evaluate any differences in the very old. Smith reported an age-associated decrease of the E/I ratio from 1.62 to 1.16 between the ages of 16 to 80 years [30]. We found the similar E/I ratio, 1.12, in the age interval 80 to 84 years, but no age-associated decline of the E/I ratio was found between 75 and 96 years of age. In summary, we found that Alzheimer patients had a high acceleration index and a low brake index of the heart rate during tilt which could be explained by an imbalance of the autonomic nervous system. The cardiovascular response to tilting and forced breathing showed no age-associated decrease in healthy control women between 75 and 96 years of age. These findings might increase the diagnostic values of the acceleration and brake indices and E/I ratio in elderly subjects.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
The heart rate response to tilt with an initial acceleration followed by a deceleration can be used to study sympathetic and parasympathetic neuropathy [1, 9]. The transient decrease of heart rate, as a measure of the parasympathetic nervous system, is estimated by the brake index. We found a lower brake index in the Alzheimer patients which could indicate a vagal dysfunction but several other possibilities have to be considered. One explanation might be a decreased response from volume receptors during tilt which explains the same heart rate in both groups during rest and the absence of a difference during the deep-breathing test. Also, the primary subcortical nuclei abnormalities which affect the hypothalamus, responsible for the integration of autonomic nervous system, or retrograde changes secondary to cortical degeneration might be responsible for the vagal imbalance during tilt. In Alzheimer's disease, a subcortical degeneration of cholinergic nuclei, such as the nucleus of Meynert, with afferent projections to cortex has been reported [27]. However, the neuropathological changes and reduction in choline-acetyltransferase, as a marker for cholinergic neurons, are most pronounced in the temporal cortex, hippocampus and amygdala [28]. Another explanation to consider is prolonged physical inactivity with bed rest and immobilization known to reduce stroke volume and cardiac output. Resting systolic and diastolic blood pressures during rest generally remain stable although an increase in diastolic blood pressure has been noted and heart rate usually shows a small increase with time [29]. In this study, the mean heart rate was the same in both groups and diastolic blood pressure was numerically lower in the AD patients and opposite to the findings during bed-rest conditions [29]. None of the patients was bedridden and all could participate in the orthostatic test. Although 19 of the patients could not walk independently and needed some assistance none had received prolonged bed rest. Therefore, it seems unlikely that inactivity only could explain the cardiovascular effects of tilt.
3°5
306
s. ELMSTAHL ET AL.
Acknowledgements This study was supported by grants from Pahlsson's Foundation, the Medical Faculty at the University of Lund, and the city of Malmo. We express our appreciation to psychologists Eva Nilsson and Siv Hedstrom, and laboratory assistants Eva Hansson and Margareta Norvik for their assistance.
15.
References
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17. 18. 19. 20.
21.
22. 23.
24.
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26.
27.
28.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
1. Hirano A, Zimmerman HM. Alzheimer's neurofibrillary changes: a topographic study. Arch Neurol 1962;7:227^*2. 2. Ishii T. Distribution of Alzheimer's neurofibrillary changes in the brain stem and hypothalamus of senile dementia. Acta Neuropathol 1966;6:181-7. 3. Ewing DJ, Borsey BQ, Bellavere F, Clarke BF. Cardiac autonomic neuropathy in diabetes: comparison of measures of R-R interval variation. Diabetologia 1981 ;21:18-24. 4. Mackay JD, Page M, Cambridge J, Watkins PJ. Diabetic autonomic neuropathy. The diagnostic value of heart rate monitoring. Diabetologia 1980;18:471-8. 5. Kaijser L, Sachs C. Autonomic cardiovascular responses in old age. Clin Physiol 1985;5:347-57. 6. Bergstrom B, Lilja B, Rosberg K, Sundkvist G. Autonomic nerve functions. Reference values in healthy subjects. Clin Physiol 1986;6:523-8. 7. Clarke BF, Ewing DJ, Campbell IW. Diabetic autonomic neuropathy. Diabetologia 1979; 17:195-212. 8. Ewing DJ, Campbell IVV, Murray A, Neilson JM, Clarke BF. Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes. Br Med J 1978;l:145-7. 9. Sundkvist G, Lilja B, Aimer LO. Abnormal diastolic blood pressure and heart rate reactions to tilting in diabetes mellirus. Diabetologia 1980;19:433-8. 10. Wheeler T, Watkins PJ. Cardiac denervation in diabetes. Br Med J 1973;4:584-6. 11. Bennett T, Farquhar IK, Hosking DJ, Hampton JR. Assessment of methods for estimating autonomic nervous control of the heart in patients with diabetes mellitus. Diabetes 1978;27:116774. 12. Sundkvist G, Aimer LO, Lilja B. Respiratory influence on heart rate in diabetes mellitus. Br MedJ 1979;l:924-5. 13. Hachinski VC, IlifTLD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975;32:632-7. 14. Gustafson L, Nilsson L. Differential diagnosis
of presenile dementia on clinical grounds. Acta Psychiatr Scand 1982,65:194-209. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: Report of the N I N C D S ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:934-44. Folstein MF, Folstein SE, McHugh PR. 'Minimental state': a practical method for grading the cognitive state of patients for the clinician, jf Psychiatr Res 1975;12:189-98. Johansson AM. Psychological evaluation in dementia and depression. Dan Med Bull [Suppl] 1985;l:6O-2. Graham FK, Kendall BS. Memory-for-designs tests: revised general manual. Percept Mot Skills 1960;ll:147-88. Husen T. CVB-skalan, individuell testskala for vuxna. Skandinaviska testforlaget. Lund, 1956 (In Swedish). Dureman I, Salde H. Psykometrisk och experimental-psykologiska metoder for klinisk tilldmpning. Stockholm: Almqvist & Wiksell, 1959 (In Swedish). Cronholm B, Molander L. Memory disturbances after electroconvulsive therapy: conditions 6 hours after electroshock treatment. Acta Psychiatr Neurol Scand 1954;32:280-306. Berger EY. A system for rating the severity of senility. J Am Geriatr Soc 1980;28:234-6. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged—the Index of ADL: a standardized measure of biological and psychosocial function. J Am Med Worn Assoc 1983;185:914-9. Englund E, Brun A, Ailing C. White matter changes in dementia of Alzheimer's type—biochemical and neuropathological correlates. Brain 1988;III: 1425-39. Tuckman J, Shillingford J. Effect of different degrees of tilt on cardiac output, heart rate and blood pressure in normal man. Br Heart J 1966;28:32-9. Wieling W, van Brederode JF, de Rijk LG, Borst C, Dunning AJ. Reflex control of heart rate in normal subjects in relation to age: a data base for cardiac vagal neuropathy. Diabetologia 1982;22:163-6. Esiri M. Patterns of cortical and subcortical pathology in Alzheimer's disease. In: Davies DC, ed. Alzheimer's disease: towards an understanding of the aetiology and pathogenesis. London: John Libbey, 1989;33^1. Perry EK, Perry RH. The cholinergic system in
AUTONOMIC CARDIOVASCULAR RESPONSES TO T I L T I N G IN AD Alzheimer's disease. In: Roberts PJ, ed. Biochemistry of dementia, Chichester: John Wiley & Sons, 1980;135-83. 29. Sandier H. Cardiovascular effects of inactivity. In: Sandier H, Vernikos J, eds. Inactivity: phvsiological effects, New York: Pergamon Press, 1986;ll-48. 30. Smith SA. Reduced sinus arrhythmia in diabetic autonomic neuropathy: diagnostic value of an age-related normal range. Br Med J 1982;285:1599-601.
307
Authors' addresses S. Elmstahl, M. Petersson, S-M. Samuelsson, L. Bjuno Department of Community Health Sciences, Geriatric Medicine, University of Lund, Varnhem Hospital, S-212 16 Malmo, Sweden B. Lilja Department of Clinical Physiology, I. Rosen Department of Clinical Neurophysiology,
Received in revised form 23 December 1991
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
Malmo General Hospital, University of Lund, Malmo, Sweden
Summary The cardiovascular responses to tilting and breathing were studied in 24 patients with late-onset Alzheimer's disease (AD) and 54 healthy control women aged between 75 and 96 years in order to study the parasympathetic and sympathetic heart-rate control. The cardiovascular response to tilting and breathing showed no age-associated decrease in the healthy control women. During rest, the AD patients had lower mean systolic and diastolic blood pressure but the same heart rate as the control patients. After tilting, the AD patients had a greater increase in heart rate, and the mean systolic blood pressure fell to 126 mmHg compared with 160 mmHg in the control women (p < 0.001). After the initial acceleration, the following deceleration of the heart rate, an expression of parasympathetic nervous activity, was lower in the AD patients (p < 0.001). The deep-breathing test showed no significant difference between the two groups, but the changes of acceleration and brake indices could indicate a dysfunction of the autonomic nervous system since the AD patients were not recumbent.
Introduction Alzheimer's disease (AD) is characterized by neuronal loss from cortical and subcortical regions. Several neurotransmitter systems including acetylcholine, serotonin, dopamine and noradrenaline are affected. Neuronal losses have also been shown in subcortical nuclei such as the lateral hypothalamus and raphe nuclei, nucleus basalis of Meynert and thalamic nuclei with projections to cerebral cortex [1, 2]. Integration of the autonomic nervous system takes place in the hypothalamus but autonomic reactions can also be elicited from the cerebral cortex. Whether this integration is changed in Alzheimer's disease, thereby affecting cardiovascular responses to tilting has not to our knowledge been previously studied.
The autonomic nervous system plays an important role in the control of blood pressure and activity of the heart. The sympathetic system, in contrast to the parasympathetic system, is characterized by a more or less constant activity with influence from somatic afferents. The cranial part of the parasympathetic system which includes the vagal nerve inhibits the heart rate. The autonomic nervous system is tested by the heart-rate responses to tilting and forced breathing [3, 4]. There is an age-associated decrease of these test indices in healthy controls [5, 6]. This decrease is probably due to impaired function of the receptor organ or parts of the autonomic nervous system [5]. Results from previous studies are not conclusive as to whether there is a more rapid or slower decline after the age of 60 [3, 4]. Age and Ageing 1992,21:301 -307
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
SOLVE ELMSTAHL, MARIE PETERSSON, BO LILJA, SVEN-MARTEN SAMUELSSON, INGMAR ROSEN, LILLEMOR BJUNO
s. ELMSTAHL ET AL.
Subjects and Methods Two groups of women were studied, one consisting of 24 patients with a late-onset AD of mean duration 7.2 ±3.6 years, and one consisting of 54 age-matched healthy control subjects. The AD subjects, born 1894—1914 with a mean age of 85 + 5.3 years, were selected as follows from Varnhem Hospital in Malmo, Sweden, a Geriatric University Hospital with 800 geriatric long-stay patients: all women with a medical history of dementia, confusion or loss of memory were examined and medical records were checked. Patients who fulfilled the inclusion criteria
(see below) were included. The clinical examination included rating scales for the diagnosis of multiinfarct dementia [13] and frontal-lobe dementia of non-Alzheimer type [14]. Patients with a score ^ 7 or ^ 5 on these scales, indicating multi-infarct dementia or frontal-lobe dementia, were excluded. Twentyfour women who were regarded as having probable or possible AD, according to the criteria of NINCDSADRDA [15] participated in an orthostatic test. Fifty-four control subjects, born 1894-1914, were recruited in the following way: a questionnaire was sent to 808 age-matched women living in Malmo, using the Population Register at the City Council. The response rate was 65.6%. The aim was to recruit three age-matched controls, born within the same month and year, for each case. Seventy-four subjects, who denied cardio- and cerebrovascular disease, diabetes or malignancy, were examined. The AD patients and control subjects were examined physically and neurologically and they underwent EEG and neuropsychological assessment including Minimental State Examination [16], spatial tests with Koh's Block design [17] and Memory-for-Designs Test [18], vocabulary tests according to Husen [19], Synonyms [20] and Paired Associates measuring immediate recall and Memory for Objects [21]. The control subjects were interviewed about their medical history and life-style factors. Further exclusion criteria for both groups were: a medical history or signs of stroke; clinical or labora-
Figure I. The blood pressure changes in patients with Alzheimer's disease (D) and controls (A) before, during and after tilt (differences before and during tilt are significant , p < 0.001). Values are means ± SD.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
Several cardiovascular tests have been introduced to measure autonomic nerve function [1, 2, 7, 8]. The heart-rate reactions after tilting, with an initial acceleration followed by a deceleration expressed as acceleration and brake indices, have been used as indicators of the functions of the sympathetic and parasympathetic systems [8, 9]. Variation of the heart rate during deep breathing reflects the parasympathetic nervous system [10—12]. The aim of the present study was to study the autonomic nervous system and the heart-rate reaction in Alzheimer patients and also to obtain reference values for healthy elderly subjects.
AUTONOMIC CARDIOVASCULAR RESPONSES TO T I L T I N G IN AD rate changes (HR) were expressed as follows: the mean R-R interval (A) at rest, 1 min before tilting was measured; after tilting, the shortest R-R interval (B) and then the following longest R-R interval (C) were chosen. Acceleration and brake indices were expressed as A-B/A and C-B/A, respectively [9]. The deep-breathing test with six consecutive maximal expirations (E) and inspirations (I) were performed during continuous ECG recording. The heart-rate E/I ratio was expressed as the ratio between the mean longest R-R interval during expiration and the shortest interval during inspiration [12]. Statistical analysis: Differences between groups were tested by the Mann—Whitney Wilcoxon rank sum test. Data are given as means ± standard deviation. Differences with p < 0.05 were considered significant.
Results During rest, the 24 AD patients had lower mean systolic blood pressure (137 ±19 vs. 167 ± 2 3 mmHg, p < 0.001) and lower diastolic blood pressure (75 ± 10 vs. 84 ± 10 mmHg, p < 0.01) than the 54 control subjects, but the same heart rate (72 ±10.0 vs. 72 ±9.9 beats/min). During the orthostatic test, the mean systolic blood
110 100-
6050 supine 1
2
tilting
3
4
5
Time (min)
1
2
supine
Figure 2. The heart-rate variations in patients with Alzheimer's disease (•) and controls ( A ) before, during and after tilt (differences before and during tilt are significant p < 0.001). Values are means ± SD.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
ton' signs of malignancy, metabolic, hepatic or renal disease; folic acid or cobalamine deficiency, atrial flutter, fibrillation or left bundle branch conduction disturbance on electrocardiogram, alcohol or drug abuse, beta-blocker treatment, inability to stand up and to be fastened to a tilting table. Twenty subjects in the control group were excluded for one or more reasons; six used beta-blockers and six women had atrial flutter or fibrillation detected at ECG. Seven cases of possible dementia according to clinical examination and testing and one case of stroke were excluded. Seventeen of 24 cases were classified as probable AD and eight cases as possible AD. Four of the patients with possible AD had asymmetric brain disorder according to E E C All 24 patients were dependent on help with most of the activities of daily living. All but two had rating IV-VI according to Berger's rating of the severity of 'senility' [22]. The mean index of activity of daily life according to Katz et al. was 4.9 [23]. Biochemical variables, including haemoglobin, cobalamine, folate, glucose and HbAic in blood and electrolytes in serum were determined by routine methods at the Department of Clinical Chemistry, Malmo and they were normal in all cases and controls. The orthostatic test was performed with continuous ECG recording while the subject was tilted from supine to upright position, remaining so for 8 min and then tilted back again. The initial rapid heart
s. ELMSTAHL ET AL.
3°4
Table. Cardiovascular responses with acceleration and brake indices after tilting, and heart-rate expiration/inspiration ratio during deep breathing in patients with Alzheimer's disease (AD) and age-matched controls Age (years)
AD
(n)
>89
—
0
(n)
12.8±6.5 11.2 + 3.5 12.6±6.6 15.0 + 8.1 11.0 ±4.4
54
•••
8 NS 26 *•• 14 NS 6 NS
11.8±7.2 54 • • • 8 •* 11.7±3.7 11.1 +6.7 26 • • 14 NS 11.9±8.6 14.7 ±10.0 6 NS 1.13 + 0.09 51 NS 1.16±0.15 8 NS 1.12 ±0.67 25 NS 1.13 ±0.12 12 NS 1.15±0.60 6 NS
= p89 4 14.7±7.0 Brake index 24 All 5.9 ±4.0 5 4.7 ±3.7 75-79 9 4.7 ±2.5 80-84 6 8.6 ±5.8 85-89 4 >89 6.2 ±1.4 Expirationjinspiration ratio 10 All 1.15±0.12 3 75-79 1.18±0.13 4 80-84 1.15 ±0.18 3 85-89 1.12 + 0.15
Controls
AUTONOMIC CARDIOVASCULAR RESPONSES TO TILTING IN AD
An age-associated decrease of cardiovascular responses mediated by the autonomic nervous system has been shown in healthy subjects [4, 29]. A non-linear decrease of the heart rate
response with age has been reported with a more rapid decline after the age of 60 [3]. Bergstrom et al. have suggested linear equations for the age-associated decrease of the acceleration and brake indices up to 60 years of age [6]. In our study, the mean increase of the heart rate in the healthy control women, 10 beats/min, was in agreement with the findings of Kaijser and Sachs who found a mean increase of 11 beats/min in 60-85-year-old subjects [5]. However, in the healthy women, we found no significant decrease of acceleration and brake indices between ages 75 and 96 years. Instead, the small changes indicated that they had reached a plateau. Therefore linear equations suggested for the age-associated decline in cardiovascular responses cannot be extrapolated to the very old. Instantaneous heart-rate changes with forced breathing and the expiration and inspiration ratio are used to assess vagal function. A decreased response, more pronounced on the parasympathetic nerve functions, has been found in elderly subjects [3]. Wielingei al. [26] found a poor correlation between heart-rate changes after tilting and forced breathing, suggesting the involvement of different mechanisms. T h e response to forced breathing is dependent on efferent and afferent nerve functions as well as the effector organ. In our study, although the heart-rate E/I ratio did not differ between the groups, the small number of subjects in the AD group made it difficult to evaluate any differences in the very old. Smith reported an age-associated decrease of the E/I ratio from 1.62 to 1.16 between the ages of 16 to 80 years [30]. We found the similar E/I ratio, 1.12, in the age interval 80 to 84 years, but no age-associated decline of the E/I ratio was found between 75 and 96 years of age. In summary, we found that Alzheimer patients had a high acceleration index and a low brake index of the heart rate during tilt which could be explained by an imbalance of the autonomic nervous system. The cardiovascular response to tilting and forced breathing showed no age-associated decrease in healthy control women between 75 and 96 years of age. These findings might increase the diagnostic values of the acceleration and brake indices and E/I ratio in elderly subjects.
Downloaded from http://ageing.oxfordjournals.org/ at University of Sussex on March 26, 2015
The heart rate response to tilt with an initial acceleration followed by a deceleration can be used to study sympathetic and parasympathetic neuropathy [1, 9]. The transient decrease of heart rate, as a measure of the parasympathetic nervous system, is estimated by the brake index. We found a lower brake index in the Alzheimer patients which could indicate a vagal dysfunction but several other possibilities have to be considered. One explanation might be a decreased response from volume receptors during tilt which explains the same heart rate in both groups during rest and the absence of a difference during the deep-breathing test. Also, the primary subcortical nuclei abnormalities which affect the hypothalamus, responsible for the integration of autonomic nervous system, or retrograde changes secondary to cortical degeneration might be responsible for the vagal imbalance during tilt. In Alzheimer's disease, a subcortical degeneration of cholinergic nuclei, such as the nucleus of Meynert, with afferent projections to cortex has been reported [27]. However, the neuropathological changes and reduction in choline-acetyltransferase, as a marker for cholinergic neurons, are most pronounced in the temporal cortex, hippocampus and amygdala [28]. Another explanation to consider is prolonged physical inactivity with bed rest and immobilization known to reduce stroke volume and cardiac output. Resting systolic and diastolic blood pressures during rest generally remain stable although an increase in diastolic blood pressure has been noted and heart rate usually shows a small increase with time [29]. In this study, the mean heart rate was the same in both groups and diastolic blood pressure was numerically lower in the AD patients and opposite to the findings during bed-rest conditions [29]. None of the patients was bedridden and all could participate in the orthostatic test. Although 19 of the patients could not walk independently and needed some assistance none had received prolonged bed rest. Therefore, it seems unlikely that inactivity only could explain the cardiovascular effects of tilt.
3°5
306
s. ELMSTAHL ET AL.
Acknowledgements This study was supported by grants from Pahlsson's Foundation, the Medical Faculty at the University of Lund, and the city of Malmo. We express our appreciation to psychologists Eva Nilsson and Siv Hedstrom, and laboratory assistants Eva Hansson and Margareta Norvik for their assistance.
15.
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Authors' addresses S. Elmstahl, M. Petersson, S-M. Samuelsson, L. Bjuno Department of Community Health Sciences, Geriatric Medicine, University of Lund, Varnhem Hospital, S-212 16 Malmo, Sweden B. Lilja Department of Clinical Physiology, I. Rosen Department of Clinical Neurophysiology,
Received in revised form 23 December 1991
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Malmo General Hospital, University of Lund, Malmo, Sweden
