J Neurol (2012) 259:921–928 DOI 10.1007/s00415-011-6279-3
ORIGINAL COMMUNICATION
Microcirculation response to local cooling in patients with Huntington’s disease Ziva Melik • Jan Kobal • Ksenija Cankar Martin Strucl
•
Received: 5 May 2011 / Revised: 3 October 2011 / Accepted: 4 October 2011 / Published online: 20 October 2011 Ó Springer-Verlag 2011
Abstract Altered autonomic nervous system (ANS) functioning in early stages of Huntington’s disease (HD) has been suggested, presumably due to distorted high-order autonomic control. ANS functioning in the early stages of HD was further investigated. Laser-Doppler (LD) flux in the skin of the fingertips, heart rate (HR), HR variability, systolic and diastolic blood pressure were measured during rest and during a 6 min cooling of one hand at 15°C. Data of 15 presymptomatic gene mutation carriers (PHD), 15 early symptomatic HD patients (EHD), and two groups of 15 age- and sex-matched controls were compared. The area under the low frequency (LF) and high frequency (HF) bands of the HR variability spectrum were calculated. An augmented reduction of cutaneous LD flux was found in response to the direct cooling in the PHD group (37.5 ± 8.5% of resting value) compared to the PHD controls (67.27 ± 8.4%) (p \ 0.05). In addition, the PHD group had higher (LF/(LF ? HF) index of primary sympathetic modulation of the HR at rest (53.6 ± 3.3) compared to the EHD patients (39.7 ± 4.2) (p \ 0.05). In the EHD group, a significantly smaller change of HR during cooling (100.26 ± 1.2%) was found compared to the EHD controls (95.9 ± 1.0%) (p \ 0.05). The results are in line with the hypothesis that ANS dysfunction occurs even in PHD subjects. Further, they support the hypothesis that dysfunction of the high-order autonomic centres are involved in HD. Z. Melik (&) K. Cankar M. Strucl Medical Faculty, Institute of Physiology, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia e-mail:
[email protected] J. Kobal Department of Neurology, University Medical Centre Ljubljana, Zaloska 2, 1000 Ljubljana, Slovenia
Keywords Huntington’s disease Central autonomic network Heart rate variability Microcirculation Local cooling Laser-Doppler flow
Introduction Huntington’s disease (HD) is a neurodegenerative disorder leading to the progressive death of neurons in various brain regions. There is a triad of movement, behavioural, and cognitive disorders. There are also some other clinical features associated with the disease. Symptoms suggestive of autonomic nervous system (ANS) dysfunction have been reported. Patients with HD experience significantly more gastrointestinal, urinary, cardiovascular and sexual problems [1]. Accordingly, clinical testing has revealed hypofunction of the ANS in mid and advanced HD patients [2–4]. Moreover, there are signs of ANS dysfunction even in early symptomatic HD patients (EHD) and presymptomatic HD gene mutation carriers (PHD). A recent study [5] found a significantly attenuated heart rate response during a cognitive stress test (mental arithmetic) and an exaggerated response during a sensory stressor with aversive characteristics (cold pressure test) in EHD and in PHD individuals. The neural basis for the progression of the autonomic nervous system dysfuction is largely unknown [6]. The evidence of cerebral cortical and hypothalamic pathology [7–11] in the early stages of HD might suggest distorted activity in cortical and subcortical structures that are involved in the higher order central autonomic network (CAN) [12–14]. Recent research has suggested that the cortical parts of CAN are involved very early in PHD subjects [15]. There are some interesting reports of hypothalamic involvement at the beginning of the clinical disease in EHD patients [10, 11, 16–19] that could imply the
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successive involvement of the higher order parts of CAN during progress of the disease. We, therefore, hypothesized that the changes in the cardiovascular ANS functioning could be detected as early as in the presymptomatic phase of the disease due to the successive involvement of the higher order parts of CAN. The common cardiovascular tests like the Valsalva manoeuvre, deep breathing and orthostatic test did not confirm the differences between PHD and EHD subjects [5, 20]. In the present study we introduced new tests that could show more subtle differences in ANS function in PHD and EHD subjects. For this purpose skin microcirculation was examined with laserDoppler flowmetry [21, 22] during the local cooling of one hand, along with cardiovascular autonomic testing. The differences between PHD and EHD individuals were examined with regard to their microcirculatory responses during local cooling that triggers ANS partially through the thermoregulation centre in the hypothalamus [23–26]. Skin microcirculation in humans is under the complex control of neural reflexes and local factors [27–30]. At the cooling site (direct response of skin vessels) cold decreases the amount of norepinephrine released from nerve-endings [31], reduces the enzymatic breakdown of norepinephrine within the vessel wall [32], decreases smooth muscle contractility, diminishes the affinity of alpha1 adrenoceptors for norepinephrine [33–35], and stimulates the mobilization of alpha2c adrenoceptors from the Golgi apparatus to the vascular smooth muscle plasma membrane [36–38]. In contrast, at the site remote from the cooling (indirect response) the response mediated by the sympathetic vasomotor reflexes prevails [39]. The skin is a suitable site for the evaluation of microvascular dysfunction due to the ease and harmlessness of access [27]. Moderate local cooling of the skin was used to avoid pain as individual cold pain perception has important influence on the parameters of cardiovascular reactivity [40]. Furthermore, lower temperatures induce stronger sympathetic stimulation which results in maximum response in all groups of subjects and the disappearance of eventual differences between PHD and EHD subjects.
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diagnostic process and when suggested by the consulting clinical psychologist. Participants were evaluated clinically not more than a week before the study entry. The exclusion criteria were strict: they included diseases and/or conditions that may influence ANS function; medical disorders like cardiac insufficiency, arrhythmia, arterial hypertension requiring treatment, renal and/or liver disease, obstructive pulmonary disease requiring treatment with bronchodilators, endocrine disorders (e.g. diabetes mellitus, thyroid dysfunction). All the PHD subjects were free from regular drug abuse. We tolerated oral contraceptives or occasional intake of nonsteroidal anti-inflammatory drugs. In EHD patients we tolerated all of the above mentioned plus short acting selective serotonin reuptake inhibitors (SSRI). None of the patients were taking drugs with known major and/or long term effect on ANS [43]. Five of our 15 EHD patients were taking low dose of escitalopram (up to 10 mg daily). As SSRI inhibitors might have a mild short term anticholinergic effects, a 48 h wash out period was considered before testing, as recommended [44]. None of the patients presented signs of neurological disorders other than HD nor did they suffer from peripheral neuropathy or psychiatric disease such as schizophrenia, major depressive and/or anxiety disorder as defined by ‘‘Diagnostic and statistical manual of mental disorders - fourth edition’’ criteria. Because cardiovascular parameters highly depend on age and sex, two distinct age- and sex-matched healthy control groups for the PHD and EHD group were selected. Each patient or premanifest subject had a control subject of the same age and sex. Control subjects were healthy, without acute or chronic disease and without regular drug therapy. All the PHD/EHD as the controls were students or employees, originated from similar social environments, and lived a similar life style. We calculated body mass index (BMI) from obtained subjects’ data. There was no statistically significant difference in BMI index values among groups of subjects. Table 1 present the basic data of the study sample. The study was approved by the national medical ethics committee, and written informed consent was obtained from each subject.
Subjects and methods Methods Subjects Clinical evaluation The study enrolled 15 PHD and 15 EHD subjects. HD gene mutation was confirmed by an expanded number of CAG triplets [41]. Predictive testing in PHD subjects was performed according to the IHA/WFN HD committee guidelines [42]. PHD subjects were treated according to IHA/ WFN proposals during the genetic consultation. They were enrolled to study at least 6 months after the presymptomatic
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Before entering the study, participants were examined by a neurologist experienced in HD and a neuropsychiatrist to rule out neurological and/or psychiatric disorders aside from HD. The PHD subjects were carefully observed clinically to detect motor symptoms that may precede the obvious signs of extrapyramidal dysfunction. Clinical
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Table 1 Basic details of the study groups (mean values ± SE) PHD (N = 15)
EHD (N = 15)
PHD control (N = 15)
EHD control (N = 15)
Statistical test Dunnett’s test
Age (years)
34.0 ± 1.9
39.9 ± 2.4
33.9 ± 2.2
40.0 ± 2.3
Age range (years)
24–50
23–55
24–52
26–54
BMI index
23.8 ± 0.7
23.3 ± 0.7
24.1 ± 0.6
24.0 ± 0.7
Dunnett’s test
Male
9 (60.0%)
7 (46.7%)
9 (60.0%)
7 (46.7%)
v2 test
Female
6 (40.0%)
8 (53.3%)
6 (40.0%)
8 (53.3%)
CAG
44.3 ± 0.9
44.7 ± 0.9
Not defined
Not defined
CAG range
40–51
40–51
Not defined
Not defined
UHDRS
1.0 ± 0.4
14.9 ± 1.7a
0b
0c
UHDRS range
0–4
6–25
0
0
a
Dunnett’s test Dunnett’s test
Statistical significant difference between PHD and EHD (p \ 0.05)
b
Statistical significant difference between PHD and PHD controls (p \ 0.05)
c
Statistical significant difference between EHD and EHD controls (p \ 0.05)
status of PHD/EHD individuals was evaluated by the Unified Huntington’s Disease Rating Scale (UHDRS) [45] motor score. No subject receiving more than 4 points was enrolled to PHD group and patients with 5–25 points were enrolled to EHD group. Physical examination, resting electrocardiogram (ECG) and complete routine laboratory tests were performed in all cases. ANS experimental protocol Testing was performed in the morning after abstaining from smoking, alcohol, and caffeine for at least 8 h. The experiment took place in a quiet and comfortable atmosphere with a room temperature of 23–25°C after 15 min of acclimatization. Tests were performed in a supine position. The patients were asked not to perform major voluntary movements during the measurements in order to avoid movement artefacts. Continuous finger arterial blood pressure was measured by 2300 Finapres monitor (Ohmeda, USA), providing values of systolic (SBP), diastolic (DBP) and mean arterial pressure. The surface electrocardiogram was monitored through the standard lead II using a conventional ECG apparatus to determine the average R–R interval at rest and during the cooling period. Laser-Doppler (LD) flux was measured with two Periflux P4001 Master/4002 Satellite LD monitors (Perimed, Sweden). The flux was calculated as the product of concentration of moving blood cells and velocity of moving blood cells. The principle governing measurement of skin perfusion has been described elsewhere [46]. LD flux, blood pressure and ECG were measured for 6 min of rest and during the 6 min of local cooling of one hand. The LD probes (PF401) were attached to the pulp of the index finger of both hands. Cooling was achieved with
flexible cold packs (Comfort Pack, 3 M USA, 200 9 300 mm) at 15°C; the hand was placed between two packs. Heart rate variability analysis Individual R–R intervals were used for spectral analysis of the 5 min recordings at rest. The Autoregressive Transform method was employed. Results are expressed in Power Spectral Density, the squared amplitude calculated for each frequency. The area under the power spectrum curves of the high frequency band (HF 0.15–0.4 Hz) and the low frequency band (LF 0.04–0.15 Hz) was determined, the former being an indicator of parasympathetic nervous system activity [47–49] and the latter being particularly sensitive to cardiac sympathetic nerve activity. The coefficients LF/HF (sympathovagal balance), LF/(LF ? HF) (primary sympathetic modulation of the heart rate) [50], and baroreflex sensitivity (BRS) during rest were calculated. BRS was determined by the sequence method, based on the computer identification in the time domain of spontaneously occurring sequences of four or more consecutive beats characterized by either a progressive rise in SBP and lengthening in R–R interval or by a progressive decrease in SBP and shortening in R–R interval [51, 52]. Nevrokard software was used for the analysis of the gathered data (Medistar, Slovenia). Statistical analysis In the resting precooling condition, the average of 6 min LD flux, blood pressures and heart rate (HR) were calculated and used for the statistics. During cooling, we calculated average values of all parameters for each 2 min intervals of 6 min cooling period. For HRV analysis, 5 min recording of R–R intervals were used during resting period.
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All values obtained during cooling were compared to the resting values before the cooling by a one way ANOVA on repeated measurements (Dunnett’s test). We performed a one-way ANOVA (Dunnett’s test) to test the differences between both groups of patients and the groups of control subjects in the relative changes of LD flux, arterial blood pressure and HR during cooling. All results are expressed in mean values and standard errors of means (SE) with the significance criterion p \ 0.05.
Results All data had normal distribution. The resting values of SBP, DBP, HR, and LD flux are shown in Table 2. The PHD group exhibited a significantly higher DBP compared to the EHD group (Dunnett’s test, p \ 0.05). The resting LD flux was nearly the same in all four groups (one way ANOVA). In the EHD group the HF power was significantly higher, thus their LF/HF and LF/(LF ? HF) coefficients were significantly lower than those of the PHD group (Dunnett’s test, p \ 0.05). The BRS of the EHD and the PHD subjects did not differ. See Table 3. No patient or healthy control subject perceived cold packs as painful. In response to direct cooling (direct response) LD flux decreased during the entire cooling period for all four test groups (Fig. 1a) (Dunnett’s test, p \ 0.05). The LD flux decrease in the PHD group was significantly greater compared to their control. There was no difference in the direct response between the EHD patients and their controls or between the EHD and PHD groups except during the last 2 min of cooling (paired t test, p \ 0.05).
In the contralateral hand (indirect response) the LD flux decreased in the PHD and EHD groups during the entire cooling period (Dunnett’s test, p \ 0.05). However, in the PHD and EHD control groups LD flux increased after a significant fall during first 2 min of cooling (Fig. 1b) (Dunnett’s test, p \ 0.05). There was no significant difference in the indirect response among the groups. SBP increased significantly during cooling in all groups (Dunnett’s test, p \ 0.05) (Fig. 2a). In contrast, DBP increased in the EHD patients and in both control groups (Fig. 2b) but not in the PHD subjects. During first 2 min of cooling significantly lower SBP and DBP was found in the PHD subjects compared to their controls (paired t test, p \ 0.05). The difference between the PHD and EHD patients and that between the EHD patients and their controls was not significant. While the PHD subjects and the PHD and EHD controls demonstrated a significant decrease in HR during the entire cooling period (Fig. 2c) (Dunnett’s test, p \ 0.05), the EHD patients did not, resulting in a significant difference between the EHD patients and their controls during the last 4 min of cooling (paired t test, p \ 0.05).
Discussion The main findings of this study are: (1) the PHD group responded to direct cooling with a significantly greater reduction of cutaneous LD flux than their controls; (2) the PHD subjects responded to cooling with smaller changes of SBP and DBP than their controls; (3) PHD individuals at rest and during cooling had higher SBP, DBP and HR, although not always significantly; (4) at rest the PHD group had a significantly greater LF and lower HF component of
Table 2 Resting values of systolic (SBP), diastolic blood pressure (DBP), heart rate (HR) and laser-Doppler (LD) flux (mean values ± SE) PHD
EHD
PHD control
EHD control
114.8 ± 4.0
117.2 ± 3.2
116.2 ± 3.8
SBP (mmHg)
125.6 ± 5.1
DBP (mmHg)
80.5 ± 3.7
71.3 ± 1.8a
73.2 ± 2.3
71.5 ± 2.5
HR (beats/min)
74.9 ± 3.3
67.8 ± 2.7
68.3 ± 2.3
68.3 ± 2.3
236.1 ± 39
218.8 ± 28
243.3 ± 24
227.0 ± 21
LD flux (PU) a
Statistically significant difference between PHD subjects (N = 15) and EHD patients (N = 15) at p \ 0.05
Table 3 Resting heart rate variability values and values of baroreflex sensitivity (mean values ± SE) PHD
EHD
PHD control
EHD control
HF power (N.U.)
38.1 ± 3.6
59.2 ± 5.0a
50.7 ± 5.4
50.9 ± 4.7
LF/(LF ? HF)
53.6 ± 3.3
39.7 ± 4.2a
45.4 ± 3.9
43.9 ± 4.1
LF/HF
2.70 ± 0.3
1.31 ± 0.4
a
BRS
17.3 ± 2.5
14.5 ± 1.8
a
2.31 ± 0.6
2.12 ± 0.5
21.6 ± 4.4
16.4 ± 2.8
Statistically significant difference between PHD subjects (N = 15) and EHD patients (N = 15) at p \ 0.05
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Fig. 1 Relative changes in laser-Doppler (LD) flux (percentage of resting values) measured on cooling hand (a) and on the contralateral hand (b) in PHD subjects, EHD patients, and their controls (asterisk indicates statistically significant difference between PHD and EHD at p \ 0.05; dagger indicates statistically significant difference between PHD and their control at p \ 0.05)
HRV than the EHD group; (5) the EHD patients responded to cooling with a significantly smaller change in HR than their controls. The physiological effects of local cooling have been established elsewhere [27–39]. It is generally known that the response to moderate local cooling is normally characterised by a decrease in skin blood flow, an increase of blood pressure, and a fall in HR. The decrease of skin blood flow is observable everywhere but is most pronounced at the site of cooling [53]. In the present study the augmented direct response to local cooling in the PHD group may result from local or central factors. Altered interactions of mutant huntingtin with its associated partners could contribute to affected exocytotic processes that are involved in the translocation of alpha2c receptors that participate in the direct microvascular response to cold exposure [36–38, 54, 55]. This would result in attenuated rather than augmented response to cooling and could not explain our results. An alternative explanation would be the central ANS modification of the microvascular response. Preganglionic sympathetic and parasympathetic neurons have been proved to be under the control of CAN [12]. The insular, medial, and other regions of the prefrontal cortex are shown to be involved in high-order autonomic control [12]. Consequently, the emotional mental state of the PHD
subjects with possible anxious reaction could have also contributed to the higher sympathetic activity in spite of the previous psychological treatment and attenuated heart rate response to mental stress [5]. This mechanism could be at least partially challenged by the fact that, during cooling PHD subjects respond with lesser increase of SBP and DBP than controls which suggests that PHD subjects were not more anxious as healthy controls. Another possible explanation of the obtained results would be progressive degeneration of various parts of the CNS, from the cortex through the hypothalamus to the brainstem [7, 8, 56, 57] during HD. After initial neuronal loss, cerebral cortical activity decreases, hypothalamic nuclei become disinhibited and sympathetic activity might rise. Later, the disease also involves hypothalamic nuclei and sympathetic activity might decrease. Similar findings were observed by Feigin et al. 2007 [6], who found in PHD elevated thalamic metabolism that fell to subnormal levels in those subjects who developed symptoms. Ghilardi et al. 2008 [58] also found improved explicit learning in PHD when attentional demands decrease. In the present study, higher LF component of HRV was obtained in the PHD group, suggesting predominantly higher sympathetic activity and this is the most plausible reason for higher SBP, DBP and HR. However, changes in our present study are too subtle to prove the disinhibition theory of ANS dysfunction.
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Fig. 2 Relative changes in systolic pressure (a), diastolic pressure (b), and heart rate (c) (percentage of resting values) measured during local cooling in PHD, EHD and control groups (dagger indicates statistically significant difference between PHD subjects and their control at p \ 0.05; double dagger indicates statistically significant difference between EHD patients and their control at p \ 0.05)
In advanced HD patients clinical testing of autonomic function has revealed a hypofunction of the parasympathetic and sympathetic parts of the ANS [2, 3]. In addition, autonomic dysfunction in mid-stage patients has been found [4]. Nevertheless, only a few studies on ANS function in presymptomatic and early symptomatic HD patients have been performed. Sympathetic predominance was found in presymptomatic and mildly and moderately affected HD patients [20], but another study [5] found no difference in LF and HF values between control, PHD and EHD group. Reasons for the discrepancies might be subtle ANS changes, different clinical methods of evaluation, differences in sample size and individual differences in disease onset and progression. However, it does seem noteworthy that the HF and LF components of HRV of both control groups in the
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present study were between the values of the PHD and EHD groups. We assume that measured values of the HF and LF components of HRV vary with age and the stage of the disease and at one point match those of healthy controls. The results of the present study are in line with recent observations suggesting that brain degeneration in HD extends beyond the striatum to involve nucleus caudatus, putamen, nucleus accumbens, pallidum and cortical regions in the presymptomatic and early stages of the disease [8–11, 17, 55, 59, 60]. The results are also consistent with the concept of CAN, suggesting an intimate connection of the cortical parts of CAN to each other and to the hypothalamus [12]. Conclusions about underlying mechanisms cannot be made on the basis of this study alone, which is limited by a
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lack of information about the functional-structural changes in CNS over the course of the disease. Further studies are necessary to confirm the ANS activity pattern.
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Conclusions The results confirm the hypothesis that ANS dysfunction appears in subjects with a HD gene mutation even before the motor symptoms of the disease manifest. The results support the possibility that a dysfunction of high-order autonomic centres is involved in HD. The present study appears to be the first to evaluate microcirculation in patients with HD. The study demonstrates altered functioning of microcirculation in response to local cooling, especially in the group of PHD subjects. The use of such a harmless test would then seem appropriate for further evaluation of ANS dynamics in PHD. Further cross sectional and longitudinal studies are suggested in combination with structural/functional studies. Acknowledgments The study was supported by Ministry of Higher Education, Science and Technology (Grant No.: PO-510-381), Slovenia. Conflict of interest
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