Brain, Vol. 123, No. 7, 1422-1430,
July 2000
© 2000 Oxford University Press
Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy
1 Autonomic Unit, University Department of Clinical Neurology, Institute of Neurology, University College London, 2 National Hospital for Neurology and Neurosurgery and 3 Neurovascular Medicine Unit, Division of Neuroscience and Psychological Medicine, Imperial College School of Medicine at St Mary's, London, UK
Correspondence to:
Professor C. J. Mathias, Neurovascular Medicine (Pickering) Unit, Imperial College School of Medicine at St Mary's, St Mary's Hospital, Praed Street, London, UK E-mail: cjmathias{at}ic.ac.uk
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Abstract |
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The clinical features of progressive supranuclear palsy (PSP) overlap with other parkinsonian syndromes, including multiple system atrophy (MSA). Autonomic dysfunction is a characteristic of MSA, but has also been described in PSP. We therefore report results from a series of physiological studies of cardiovascular autonomic function in 35 PSP and 20 MSA subjects, and 26 age-matched healthy control subjects. The response to growth hormone–clonidine testing, a neuropharmacological assessment of central adrenoceptor function, was also assessed in 14 PSP and 10 MSA subjects, and compared with 10 controls. None was on medication which may have affected the results. Orthostatic hypotension did not occur in PSP subjects or controls, unlike MSA subjects. Overall there was no evidence of sympathetic vasoconstrictor failure in PSP subjects, unlike MSA subjects, although the pressor response to mental arithmetic was reduced. Cardiac parasympathetic function was affected in only a minority (three of 35) of PSP subjects and was abnormal in MSA subjects. After clonidine administration, growth hormone rose in PSP subjects (median increase 4.3; interquartile range 1.8–7.8 mU/l) and controls, unlike MSA subjects (0.9; 0.3–2.4 mU/l; P < 0.005, Mann–Whitney U-test). In conclusion, in PSP subjects, responses to both physiological and pharmacological tests provided evidence against widespread autonomic dysfunction; this differed markedly from MSA subjects. Thus, cardiovascular autonomic dysfunction should be an exclusionary feature in the diagnosis of PSP.
progressive supranuclear palsy; autonomic function; physiology; neurohormonal; multiple system atrophy; clonidine
BP = blood pressure; GH = growth hormone; GHRH = growth hormone releasing hormone; IGF-1 = insulin-like growth factor-1; MSA = multiple system atrophy; PSP = progressive supranuclear palsy; TSH = thyroid stimulating hormone
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Introduction |
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In patients presenting with parkinsonian features, autonomic dysfunction has significant implications for diagnosis, prognosis and management (Mathias, 1997
). In multiple system atrophy (MSA), autonomic failure is a characteristic feature, as based on numerous physiological, pharmacological and neurochemical studies (Mathias, 1996; Mathias and Williams, 1994; Polinsky, 1999). In progressive supranuclear palsy (PSP), there may be overlapping neurological features with MSA, especially in the early stages, and these include a bilateral akinetic rigid syndrome which is poorly responsive to levodopa (Lees, 1987). Also in PSP, abnormalities of cardiovascular and sudomotor autonomic reflexes have been reported; these include a postural blood pressure fall (Gutrecht, 1992), an impaired heart rate response on standing (van Dijk et al., 1991), a diminished pressor response to isometric exercise (van Dijk et al., 1991; Gutrecht, 1992) and an abnormal skin sympathetic response (Sasaki et al., 1994). Despite these reports of autonomic dysfunction, recent publications of both clinical and neuropathologically based criteria for the diagnosis of PSP (Hauw et al., 1994; Collins et al., 1995; Litvan et al., 1996) list unexplained dysautonomia (including postural hypotension) as a mandatory exclusion criterion. There have been no detailed studies of cardiovascular autonomic function in a large cohort of PSP patients, and we report our observations using a series of physiological tests (Mathias and Bannister, 1999). Additionally, we studied the growth hormone (GH) response to clonidine as an impaired response is an indicator of central autonomic failure, as demonstrated previously in MSA subjects (Kimber et al., 1997). The physiological, pharmacological and neurohormonal responses in PSP subjects have been compared with subjects with MSA and with age- and sex-matched healthy normal subjects. |
Subjects |
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Three groups of subjects were studied. Thirty-five subjects [mean age 65.5 ± 1.3 (SEM) years, male/female ratio 2 : 1] had typical clinical features of PSP (Daniel et al., 1995
; Litvan et al., 1996) were studied. The mean duration of disease was 3.8 ± 0.6 years and mean Hoehn and Yahr score (Hoehn and Yahr, 1967) was 3.1 ± 0.3. None previously had taken neuroleptic drugs, abused alcohol or had more than one family member with parkinsonism. Subjects were neither obese nor underweight and were not clinically depressed at the time of testing. None had pyramidal or cerebellar dysfunction or abnormal reflexes. All had a poor response to anti-parkinsonian treatment and none had taken L-dopa, dopaminergic agonists or anticholinergic medication within 1 month of the study. All female subjects were post-menopausal.
Twenty MSA subjects with parkinsonian and autonomic features (mean age 60 ± 6.7 years, male/female ratio 2 : 1) also were studied. The mean duration of disease was 4.5 ± 1.1 years and mean Hoehn and Yahr score was 3.5 ± 0.5. All had a symptomatic fall in systolic blood pressure (BP) (of >20 mmHg) on standing and an abnormal plasma noradrenaline response to head-up tilt. Also, all had urinary bladder symptoms, impotence (in males), hypohidrosis, and bilateral akinesia and muscular rigidity with minimal or no tremor; the majority had additional cerebellar features. They had a suboptimal clinical response to L-dopa and none had been taking antiparkinsonian medication for >1 month. Secondary causes of autonomic dysfunction (e.g. diabetes mellitus) were excluded (Mathias, 2000).
Twenty-six healthy normal subjects matched for age and sex (mean age 67 ± 5 years, male/female ratio 2 : 1) were studied as controls. None was on drugs. All subjects gave informed consent and the study was approved by the ethics committees at The National Hospital for Neurology and Neurosurgery and St Mary's Hospital
Cardiovascular autonomic testing was performed in each subject. In addition, neuropharmacological challenge with clonidine was carried out in a subgroup of 14 PSP subjects (mean age 65 ± 1.0 years, male/female ratio 3.5 : 1), 10 MSA subjects (mean age 65 ± 1.0, male/female ratio 2.3 : 1) and 10 age- and sex-matched normal controls (mean age 61 ± 1.0, male/female ratio 2.3 : 1).
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Methods |
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Physiological tests of cardiovascular autonomic function
Testing was carried out in a dedicated autonomic laboratory. BP and heart rate were measured intermittently using an automated device (Sentron, Bard Biochemical, USA), which was calibrated against a mercury sphygmomanometer and also continuously recorded using a Finapres device (Ohmeda, USA). The changes with physiological stimuli included head-up tilt for 10 min, standing for 5 min, isometric exercise, cutaneous cold, mental arithmetic, deep breathing and the Valsalva manoeuvre, that were performed as previously described (Mathias and Bannister, 1999
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Neuropharmacological challenge with clonidine
Subjects were studied on a separate occasion, after an overnight fast. BP and heart rate were measured by automated syphgmomanometer (Sentron). An antecubital vein cannula was sited for collection of blood samples and infusion of drugs. After a 15 min supine equilibration period, clonidine (2 µg/kg) was given intravenously over 10 min (Kimber et al., 1997) and blood samples for analysis collected at 15 min intervals, centrifuged at 0°C and stored at –70°C until analysed. Samples from each subject were tested in the same assay run. Plasma catecholamines (noradrenaline, adrenaline and dopamine) were measured using high-performance liquid chromatography with an electrochemical detector (May et al., 1988), plasma glucose by the glucose oxidase method with a Chem Lab autoanalyser (Hornchurch, Essex, UK) and serum GH by 131I-labelled GH immunoradiometric assay kit (Netria, London, UK). Plasma growth hormone releasing hormone (GHRH), thyroid stimulating hormone (TSH), prolactin and insulin-like growth factor-1 (IGF-1) were also measured radioimmmunometrically. The inter- and intra-personal assay variations were, respectively, 4.7 and 4.3% for noradrenaline, 4.6 and 5.1% for adrenaline, 6.4 and 5.8% for dopamine, 4.8 and 3.2% for glucose, 5.4 and 7.4% for GH, 5.5 and 4% for TSH, 2.6 and 2.1% for prolactin, 5 and 7% for IGF-1.
Statistical analysis
Analysis of summary measures of outcome was by Student's t-test for parametric data and Mann–Whitney U-test for non-parametric parameters, using Minitab for Microsoft Windows 95. Unless specified, values are means and (±) standard error of mean. BP is presented in mmHg and heart rate in beats/min.
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Results |
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Physiological tests of cardiovascular autonomic function
Basal values
Mean resting supine levels of BP were similar in all groups (controls 130/75 ± 4/1 mmHg; PSP subjects 139/76 ± 4/3 mmHg; MSA subjects 138/81 ± 8/5 mmHg). Resting heart rate was (68 ± 2 beats/min) in controls and was higher in PSP (75 ± 1.8 beats/min) and MSA subjects (79 ± 3 beats/ min) (P < 0.05 for comparison of both PSP and MSA subjects with controls).
Postural change
On head-up tilt and standing, BP was unchanged in controls and PSP subjects, unlike MSA subjects in whom there was a substantial fall in BP on head-up tilt (–47/27 mmHg) and on standing (–66/33 mmHg) (Table 1). None of the PSP subjects had a fall in BP of >20 mmHg systolic or >10 mmHg diastolic. There was a similar rise in heart rate with tilt in PSP subjects (4 ± 1 beats/min) and controls (4.7 ± 1.1 n.s.).
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Pressor tests
The mean increase in systolic BP during mental arithmetic in controls was 16 ± 2 mmHg; the rise was less in PSP subjects (9 ± 2 mmHg, P < 0.05) and lower still in MSA subjects (–2 ± 3 mmHg, P < 0.01). In PSP subjects, the pressor responses to isometric exercise and cutaneous cold were similar to controls. In MSA subjects, there was a reduced pressor response to isometric exercise, but not to cutaneous cold (Table 1
) There were no significant differences in the heart rate responses to pressor stimuli, except during isometric exercise in MSA subjects when it was significantly lower than in controls.
Heart rate responses to respiratory stimuli
The heart rate change expressed as the Valsalva ratio during and following a Valsalva manoeuvre was similar in controls and PSP subjects, but was lower in MSA subjects (P < 0.05). There were no heart rate variability differences during deep breathing between controls and PSP subjects, unlike MSA subjects in whom it was significantly reduced (P < 0.05). Individual analysis indicated that out of 35 PSP cases, only four had a subnormal Valsalva ratio (<1.15); these subjects also had reduced sinus arrhythmia (<5 beats/min).
Neuropharmacological challenge with clonidine
Cardiovascular
Basal BP was similar in controls (128/79 ± 6/3 mmHg) and PSP subjects (133/76 ± 5/3 mmHg), but higher in MSA subjects (145/86 ± 6/4 mmHg; P < 0.05 for comparison with both controls and PSP subjects). Following clonidine administration there was a fall in BP in controls (mean arterial pressure: 95 ± 4.0 mmHg to 78 ± 2.0 mmHg, P < 0.005), PSP subjects (95 ± 4.0 mmHg to 76 ± 2.0 mmHg, P < 0.05) and MSA subjects (106 ± 4 mmHg to 83 ± 5.0 mmHg, P < 0.05). There was a similar fall in heart rate in each group (controls, –9 ± 1.0 beats/min; PSP subjects, –7 ± 2.0 beats/min; MSA subjects, –9 ± 1.6 beats/min; all non-significant).
Plasma catecholamines
Basal plasma noradrenaline levels were similar in controls and PSP subjects but were lower in MSA subjects (P < 0.005). After clonidine administration, plasma noradrenaline fell to similar levels in controls and PSP subjects, but to lower levels in MSA subjects (P < 0.05). However, there was a similar percentage fall in noradrenaline in each group (controls, –65%; PSP subjects, –61%; MSA subjects, –65%).
Basal plasma adrenaline levels in controls were not statistically different from PSP subjects and levels were lower in MSA subjects (P < 0.05). Following clonidine administration, plasma adrenaline levels fell in each group, with lower values in PSP and MSA subjects compared with controls (P < 0.005 for both).
Basal plasma dopamine levels were statistically similar in controls, and PSP and MSA subjects. After clonidine administration, levels of dopamine fell below the detection limits of the assay in each group.
There was no significant correlation between basal noradrenaline values and the fall in BP after clonidine administration; the Pearson correlation coefficient (r) was 0.18 in controls, –0.09 in PSP subjects and 0.54 in MSA subjects (all non-significant).
Serum GH
Basal serum GH was similar in all groups (Table 2 and Fig. 1A). Following clonidine administration, individual `raw' GH values were distributed non-parametrically and therefore the summary value of maximum increase in GH (as the maximum to baseline) was calculated. The median increase in GH was statistically similar in controls (6.0 ± interquartile range 2.8–7.1 mU/l) and PSP subjects (4.3 ± interquartile range 1.8–7.8 mU/l, non-significant) and was significantly lower in MSA subjects (0.9 ± interquartile range 0.4–2.4 mU/l, P < 0.05) (Fig. 1B).
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Plasma GHRH
Basal levels of plasma GHRH were similar in all groups (Table 2
). Because of individual variance in basal values and non-parametric distribution of GHRH data following clonidine administration, logarithmic (e) transformation of the summary value of maximum increase in GHRH (as maximum to baseline) was calculated. There was a greater increase in controls (3.4 ± 0.3 units), than in PSP subjects (1.9 ± 0.2 units, P < 0.05) and MSA subjects (2.0 ± 0.6 units, P < 0.05 in comparison with both controls and PSP subjects).
IGF-1
There were no differences in basal IGF-1 between controls (151 ± 26 ng/ml), PSP subjects (135 ± 15 ng/ml) and MSA subjects (147 ± 24 ng/ml).
Plasma glucose
Baseline values of glucose were similar in controls, and PSP and MSA subjects (Table 2). After clonidine administration both groups showed a similar rise in glucose compared with baseline (P < 0.05 for each).
Prolactin
Basal levels of prolactin were similar between the three groups (Table 3) and there was no significant change following clonidine administration.
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TSH
Basal levels of TSH were similar between the three groups (Table 3
) and there was no significant change following clonidine administration. |
Discussion |
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This study of PSP patients indicated that none had orthostatic hypotension and the majority of cardiovascular autonomic responses (except to mental arithmetic) were similar to controls. The responses in MSA subjects were markedly different. Pharmacological and neurohormonal testing indicated that the GH–clonidine responses were similar in PSP subjects and controls, but were significantly lower in MSA subjects.
The currently accepted definition of orthostatic hypotension is a fall in BP of >20 mmHg systolic or >10 mmHg diastolic within 3 min of standing or on passive head-up tilting for a similar period (Schatz et al., 1996). None of the PSP subjects had orthostatic hypotension on either head-up tilt or standing. Sandroni and colleagues reported `insignificant orthostatic hypotension' on tilting to 80° for 5 min, although raw data was not provided (Sandroni et al., 1991). In PSP subjects, a greater fall in BP (mean –15/7 mmHg) on standing for 1–2 min compared with controls was reported by van Dijk and colleagues (van Dijk et al., 1991) and Gutrecht (Gutrecht, 1992) (mean fall –8/3 mmHg). Van Dijk and colleagues did not exclude subjects on levodopa, dopaminergic agonists or anticholinergics (van Dijk et al., 1991); some of these drugs may have affected cardiovascular autonomic function or lowered BP through their vasodilatory effects. In our study the confounding effects of drugs were excluded. Furthermore, the severity of disease based on the Hoehn and Yahr scale rating (Hoehn and Yahr, 1967) was similar. Neither of the BP falls reported in the studies by van Dijk and colleagues (van Dijk et al., 1991) and Gutrecht (Gutrecht, 1992) would fulfil current criteria for orthostatic hypotension. Our results in a large cohort of PSP patients clearly exclude orthostatic hypotension on both head-up tilt and standing, thus indicating that the baroreceptor reflex and the response to postural change were functionally intact.
Abnormal pressor responses to isometric exercise in PSP subjects were reported in two previous studies (van Dijk et al., 1991; Gutrecht, 1992). We assessed the pressor responses to three stimuli that increased efferent sympathetic activity by different mechanisms: central command (mental arithmetic), activation of peripheral ergoreceptors combined with central command (isometric exercise) and peripheral nociception (cutaneous cold). There was a diminished pressor response to mental arithmetic in PSP subjects compared with controls. This was unlikely to reflect an impairment of sympathetic vasoconstrictor activity as there were normal pressor responses to isometric exercise and cutaneous cold. A possible explanation was impaired cortical activation due to cognitive deficits, as is known to occur in PSP. Formal tests of neuropsychological function were not undertaken at the time of the study, but bedside testing indicated impaired cognition. Overall the data favours functional preservation of central autonomic networks influencing brainstem cardiovascular autonomic centres and descending sympathetic vasoconstrictor pathways. Whether the impaired pressor responses to isometric exercise observed by van Dijk and colleagues (van Dijk et al., 1991) were due to technical difficulties, including reduced grip strength, or to other factors is unclear.
Previous studies of cardiovagal function in PSP have documented a decreased heart rate response to standing (ratio 30 : 15) (van Dijk et al., 1991; Gutrecht, 1992), but normal responses to respiratory stimuli (heart rate variability during deep breathing and the Valsalva manoeuvre). In our study, the heart rate responses to head-up tilt were similar in PSP subjects and controls. Individual analyses indicated that of the 35 subjects, only four PSP subjects had abnormally low Valsalva ratios (<1.15) and reduced sinus arrythmia (<5 beats/min). None had evidence of other autonomic abnormalities and the reason for the abnormal cardiovagal impairment is not clear. In the majority of PSP subjects, therefore, there was no abnormality of cardiac parasympathetic dysfunction.
Overall, therefore, the cardiovascular responses to physiological tests of autonomic function showed neither orthostatic hypotension nor widespread abnormalities of sympathetic vasconstrictor or cardiac parasympathetic function in PSP subjects. This indicated functional integrity of the baroreflex pathways in PSP subjects, as distinct from MSA subjects in whom there was both orthostatic hypotension and evidence of impairment of sympathetic and parasympathetic pathways. The autonomic abnormalities in MSA patients have been ascribed to involvement of supraspinal cardiovascular centres, including catecholaminergic cells of the ventrolateral medulla (Benarroch et al., 1998), vagal nuclei and loss of preganglionic sympathetic neurons in the intermediolateral columns of the spinal cord (Daniel, 1999). These areas appeared to be functionally spared in our PSP subjects.
We used clonidine as a neuropharmacological probe of central autonomic function, with particular attention on cardiovascular and neurohormonal responses. The basal BP in PSP subjects and controls was similar in the different studies. In MSA subjects there was a higher basal mean arterial pressure in the clonidine study that may reflect increased variability, as has been described previously (Shepherd and Shepherd, 1999). This was not observed in PSP subjects in whom the basal levels of BP were normal; an increased incidence of hypertension has been reported in PSP subjects, although occurring before the development of neurological impairment (Ghika and Bogousslavsky, 1997). The basal levels of plasma noradrenaline, adrenaline and dopamine were similar in PSP subjects and controls. In MSA subjects the noradrenaline levels were lower, although not as low as the values reported in peripheral autonomic failure (Mathias et al., 1990; Thomaides et al., 1992b; Polinsky 1999). Reduced noradrenaline levels have been reported previously in MSA subjects with the `mixed' form of MSA (having parkinsonian, cerebellar and autonomic features) (Kimber et al., 1997), with higher levels in the parkinsonian and cerebellar forms; thus, the mixed form (as observed the majority of MSA subjects in this study) may reflect a more advanced form of MSA. The cardiovascular and catecholamine response to clonidine in PSP subjects was similar to controls. Clonidine exerts these effects predominantly via a central action (Schmitt and Schmitt, 1969; Reid et al., 1977; Kooner et al., 1991). Similar responses occurred in MSA for reasons that are unclear, but may reflect differential effects of clonidine on the splanchnic circulation, which would explain the fall in BP (Thomaides et al., 1992a), and on the spinal cord and sympathetic ganglia, which would explain the fall in noradrenaline (Kooner et al., 1991), as described previously.
The GH response to clonidine was studied as a further dynamic test of the central autonomic network and particularly of hypothalamic-
2-adrenergic function. In MSA subjects there was no GH-response to clonidine, probably due to loss of medullary catecholaminergic neurons innervating the hypothalamus (Spokes et al., 1979). In PSP subjects there was a response similar to that of controls; this response was different from MSA subjects. Although the GH rise in PSP subjects was not significantly different to controls, there appeared to be an altered distribution of responses (see Fig. 1B). The reasons for this are unclear, since basal levels of GH in PSP subjects were similar to controls, as has been previously reported (Gomez et al., 1994). In endogenous depression there is a blunted GH response to clonidine (Matussek et al., 1980; Charney et al., 1983) that is not entirely restored despite successful treatment with antidepressant drugs (Checkley et al., 1981). Depression is more common in PSP subjects than controls (Dubois et al., 1988). None of our PSP subjects was clinically depressed when studied; however, seven of the 14 cases in whom the clonidine-GH test was performed had been treated previously for depression with tricyclic antidepressants, although there was no relationship between GH responses and depression history. Animal and human studies indicate that clonidine acts on the hypothalamus, probably through post-synaptic 2-adrenoceptors (Muller, 1987), to stimulate GH secretion through hypothalamic peptides via stimulation of GHRH or suppression of somatostatin. Plasma levels of GHRH were measured in peripheral venous plasma. In a previous study, the levels following clonidine administration were less in MSA subjects than in controls (Kimber et al., 1997), as also was observed in our study. Levels of GHRH were also subnormal in PSP subjects. Changes in venous plasma GHRH, however, are difficult to interpret because of the extrahypothalamic contribution to peripheral levels from the gastrointestinal tract, pancreas and adrenal glands. In PSP subjects there was no evidence of overall GH deficiency as plasma levels of the peptide IGF-1 (which is generated primarily by the liver in response to circulating GH) were similar to controls. IGF-1 exerts negative feedback effects on GH secretion in both the pituitary and hypothalamus, and as similar levels were observed in all groups, could not have accounted for the different GH responses observed. Levels of TSH and prolactin also were studied as a surrogate measure of hypothalamic somatostatin release since both these hormones are inhibited by IGF-1 (Siler et al., 1974; Enjalbert et al., 1986); there were similar levels of IGF-1 in PSP subjects and controls after clonidine administration, excluding excess release or increased sensitivity to somatostatin.
Decreased numbers of 2-adrenoceptors have been observed using autoradiography in non-hypothalamic brain regions in a single case of PSP (Pascual et al., 1993). This may be explained in part by degeneration of locus coeruleus neurons, as described previously in PSP subjects (Daniel et al., 1995), which project to both cortical and sub-cortical structures. Hypothalamic adrenergic innervation, however, is not primarily from locus coeruleus neurons, but from medullary catecholaminergic neurons (Sawchenko and Swanson, 1982). Lesions of these medullary cells and their hypothalamic projections in MSA patients may be of importance in explaining the impaired GH response (Benarroch et al., 1998). In PSP patients medullary catecholaminergic neurons are preserved (Malessa et al., 1990), which may explain the ability of clonidine to stimulate GH levels. The neuroendocrine responses to clonidine in PSP subjects were different from MSA subjects, but not identical to normal controls; this may indicate selective impairment of central mechanisms that may become apparent as the disease progresses and this warrants further study.
In PSP patients at autopsy, there are tau-positive fibres and neurofibrillary tangles in the brainstem (Daniel et al., 1995) and spinal cord (Kato et al., 1986); these have been a presumed explanation for the abnormal cardiovascular autonomic responses in previous reports. Also, Steele and colleagues, in three of their seven original autopsied cases, described degeneration (gliosis and atypical neurofibrillary tangles) in the dorsal vagal nucleus (Steele et al., 1964). Pathological changes (neurofibrillary tangles) were also reported in the hypothalamus in PSP subjects; however, hypothalamic noradrenaline content, described in later studies, was not affected (Kish et al., 1985). These neuropathological and neurochemical reports reflect the difficulties in relating morphological deficits to functional loss in a progressive neurological disorder, such as PSP, and emphasize the need for in vivo studies, which may be especially important for diagnosis, prognosis and designing strategies for treatment.
In conclusion, in PSP subjects, unlike MSA subjects, standard autonomic function tests did not indicate orthostatic hypotension. The responses to two pressor tests (isometric exercise and cutaneous cold) were preserved, but the response to mental arithmetic was impaired; the latter favours involvement of cortical centres influencing functionally preserved cardiovascular autonomic centres and sympathetic vasoconstrictor efferent pathways. In the majority of subjects, cardiac parasympathetic function to various stimuli was preserved. Cardiovascular autonomic dysfunction should be an exclusion criterion for the clinical diagnosis of PSP, certainly in the early stages of the disease. Whether central autonomic impairment occurs later in the disease (as the responses to clonidine were different from MSA subjects but not identical to controls) is yet to be determined.
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Acknowledgments |
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We wish to thank our colleagues, especially at the National Hospital for Neurology and Neurosurgery and the Imperial College School of Medicine, for referring patients. Lydia Thornley and Laura Judd provided valuable assistance with cardiovascular autonomic testing. L.W. was supported by the Brain Research Trust during part of the study.
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Received July 15, 1999. Revised December 14, 1999. Accepted December 20, 1999.
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