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Journal of Alzheimer’s Disease 47 (2015) 681–689 DOI 10.3233/JAD-150169 IOS Press

Autonomic Dysfunction in Patients with Mild to Moderate Alzheimer’s Disease Christina Jensen-Dahma,∗ , Gunhild Waldemara , Troels Staehelin Jensenb , Lasse Malmqvistc , Michelle Mai Moellerc , Birgitte Bo Andersena , Peter Høghd and Martin Ballegaardc a Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark b Danish

Pain Research Center, Department of Neurology, Aarhus University Hospital, Denmark of Clinical Neurophysiology, Rigshospitalet, University of Copenhagen, Denmark d Regional Dementia Research Centre, Department of Neurology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark c Department

Handling Associate Editor: Walter Struhal

Accepted 5 May 2015

Abstract. Background: Autonomic function has received little attention in Alzheimer’s disease (AD). AD pathology has an impact on brain regions which are important for central autonomic control, but it is unclear if AD is associated with disturbance of autonomic function. Objective: To investigate autonomic function using standardized techniques in patients with AD and healthy age-matched controls. Method: Thirty-three patients with mild to moderate AD and 30 age- and gender-matched healthy controls, without symptoms of autonomic dysfunction, underwent standardized autonomic testing with deep breathing, Valsalva maneuver, head-up tilt, and isometric handgrip test. Brachial pressure curve and electrocardiogram were recorded for off-line analysis of blood pressure and beat-to-beat heart rate (HR). Results: AD patients had impaired blood pressure responses to Vasalva maneuver (p < 0.0001) and HR response to isometric contraction (p = 0.0001). A modified composite autonomic scoring scale showed greater degree of autonomic impairment in patients compared to controls (patient: 2.1 ± 1.6; controls: 0.9 ± 1.1, p = 0.001). HR response to deep breathing and Valsalva ratio were similar in the two groups. Conclusion: We identified autonomic impairment ranging from mild to severe in patients with mild to moderate AD, who did not report autonomic symptoms. Autonomic impairment was mainly related to impairment of sympathetic function and evident by impaired blood pressure response to the Vasalva maneuver. The clinical implications of this finding are that AD may be associated with autonomic disturbances, but patients with AD may rarely report symptoms of autonomic dysfunction. Future research should systematically evaluate symptoms of autonomic function and characterize risk factors associated with autonomic dysfunction. Keywords: Alzheimer’s disease, autonomic function, orthostatic hypotension, tilt test, Valsalva maneuver

INTRODUCTION ∗ Correspondence

to: Christina Jensen-Dahm, MD, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9 # 6911, 2100 Copenhagen, Denmark. Tel.: +45 35456922 / +45 28895017; Fax: +45 35452446; E-mail: [email protected].

Autonomic function has received little attention in Alzheimer’s disease (AD) and the literature is inconsistent with respect to presence or absence of autonomic dysfunction [1, 2]. In other neurodegenerative

ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved

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disorders such as Parkinson’s disease, Lewy body dementia, and multi system atrophy, autonomic disturbances are frequent [3] and it might be questioned why AD should be a neurodegenerative disorder without autonomic disturbances. At early stages AD pathology impacts on brain areas that are important for central autonomic control [4–7]. Furthermore, in a case-study of a patient with autosomal dominant AD caused by an amyloid-␤ protein precursor (A␤PP) mutation, asymptomatic orthostatic hypotension was reported [8]. Autonomic disturbances are associated with significantly increased morbidity as it may cause dizziness, syncope, and falls [9], and it is therefore important to know whether patients with AD have autonomic failure. Examination of autonomic function requires a range of tests in order to investigate sympathetic and parasympathetic function. A frequently used standard battery for testing autonomic function consists of heart rate response to deep breathing, Valsalva maneuver, head-up tilt, and isometric contraction (Ewing Battery) [10]. This set of tests is relatively easy to perform also in patients with cognitive impairment and reflects parasympathetic as well as sympathetic function and was recently recommended for testing autonomic function in patients with AD [11]. Importantly, the battery allows for grading of autonomic function [12]. Thus, the aim of this study was to investigate autonomic function using the Ewing battery in patients with mild to moderate AD compared to age- and gender-matched healthy controls. MATERIALS AND METHODS Ethical approval The protocol was approved by the Regional Committees on Health Research Ethics of the Capital Region of Denmark (protocol: H-2-2011-122) and the Data Protection Agency (journal nr: 2007-58-0015). The study was performed in accordance with the ethical standards of the Regional Committees on Health Research Ethics of the Capital Region of Denmark and in accordance with the Helsinki Declaration of 1975.

Subjects Thirty-three patients were recruited among outpatients from the Memory Clinic at Rigshospitalet, University of Copenhagen, Copenhagen, Denmark and the Memory Clinic at Roskilde Hospital, Roskilde, Denmark. All patients fulfilled the ICD-10 and DSMIV criteria for dementia and had a diagnosis of probable AD according to the NINCDS-ARDA criteria [13], which was given as a consensus diagnosis by a group of memory disorder specialists. Patients were able to give informed consent and all had a caregiver who was willing to participate in order to obtain information about activities of daily living (ADL) and disease staging. Patients were included if they had mild to moderate AD with a Mini-Mental State Examination (MMSE) [14] score between 16 and 26 and a Clinical Dementia Rating score of 0.5-2. Furthermore, the patients should be able to cooperate to the autonomic tests. We included 30 age- and gender-matched healthy controls, which were recruited from a group of elderly, who had previously participated in studies on cognitive testing at the Memory Clinic and did not show signs of cognitive impairment, i.e., none of the subjects fulfilled the ICD-10 criteria for dementia or mild cognitive impairment. All participants gave informed consent to the study protocol. In order to assure that both patients and healthy controls did not suffer from comorbidity, which could potentially impair autonomic function or would impair their ability to cooperate with the test, we applied a number of exclusion criteria. Exclusion criteria for all participants were: significant psychiatric comorbidity, prior or present alcohol abuse, diabetes, peripheral or central neuropathy, significant medical comorbidity, previous transient ischemic attack or stroke, treatment with a ␤-adrenergic antagonists or calcium-channel-antagonist, signs of conductance abnormalities in their electrocardiogram (ECG), were reporting dizziness, or had experienced syncope within the past year. Patients with a mixed diagnosis of vascular dementia and AD were excluded. At baseline, both patients and controls underwent a neurological examination and were excluded if they had signs or symptoms of neurological or inflammatory disease which could lead to autonomic disturbances.

Study design

Baseline characteristics

The study was performed as a case-control study including patients with AD and healthy elderly control (please see below). Analysis of the results of the testing was done blinded to disease status.

To evaluate the patient’s cognitive status, we administered Addenbrooke’s Cognitive Examination (ACE) test which includes the MMSE, but expands on cognitive domains such as memory, language, and

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visuospatial functions and includes test of verbal fluency. ADL function was evaluated in the patients using the Functional Activities Questionnaire and the Instrumental Activities of Daily Living Scale (FAQ–IADL) [15], which is a questionnaire evaluating 10 different instrumental ADL with a maximum score of 30 (dependent of help). All participants were screened for signs of a major depression with the Geriatric Depression Scale (GDS) 15 items, which is a self-reported questionnaire specifically developed as a screening instrument for the presence of depressive symptoms in older populations [16]. In the controls, a MMSE was applied as part of the inclusion criteria. Autonomic testing (Ewing Battery) All participants were tested by the same trained examiner (CJD) with standardized autonomic testing included deep breathing, Valsalva maneuver, head-up tilt, and isometric handgrip test (in the order mentioned) [10]. This set of test was chosen as they are easy to perform and was recently recommended for testing autonomic function in patients with AD [11]. The test were performed in accordance with laboratory standard (please see description below). All subjects were tested in an autonomic reflex laboratory between 1 pm and 5 pm. The participants had been instructed not to exercise 24 h before the testing and not to eat, drink coffee/tea, or smoke 3 h before the testing. The participants were further instructed not to use compressive clothing such as compression stockings on the day of the examination. Participants initially rested for a minimum of 10 min before starting the testing. Monitoring of respiration, heart rate (HR), and blood pressure (BP) HR was monitored continuously as beats per min (bpm) using a 3 lead ECG. Beat-to-beat BP was monitored using a FMS Finometer, model 1 (Finapres Medical Systems, Amsterdam, The Netherlands). Additionally, brachial sphygomanometric BP was obtained every 3 min on the left arm using a Dinamap Vital Signs Monitor 1846sx (Criticon, Tampa, Florida, USA). Heart rate response to deep breathing The test examines the HR responses to deep breathing, which is regarded as a test of parasympathetic or cardiovagal function [17–19]. The participants were lying supine and after relaxing for 10 min they were instructed to breathe at a rate of 6 breaths per minute (inhale for 5 s and exhale for 5 s). The examiner

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continuously instructed the participant when to inhale and exhale for 1 min. After the first cycle, there was a 2-3 min break after which the test was repeated. Respiratory sinus arrhythmia (RSA) amplitude, defined as the difference between HR at the end of expiration and end of inspiration, for 5 consecutive breaths was averaged. Results were compared to age-corrected normal values of the laboratory collected from 399 normal persons (unpublished). Valsalva maneuver The Valsalva maneuver was performed with the participant in the supine position and consists of forced expiration against resistance. The participant was instructed to blow through an open container from a 5 ml syringe connected to a pressure gauge, which allowed measurement of the expiratory pressure. The Valsalva maneuver was performed with an expiratory pressure of 40 mmHg for 15 s. The test was repeated three times in order to assure reproducibility and compliance. The response to Valsalva maneuver typically consists of 4 phases. Phase 1 starts at the onset of the deep breath, where there is a transient rise in BP due to increased intrathoracic and intra-abdominal pressure, which causes mechanical compression of the aorta (2–4 s duration). Phase 2 starts when the maximal expiratory pressure is reached (40 mmHg), which leads to a decrease in BP, which activates the baroreflex. In normal subjects baroreflex activation leads to increased sympathetic activity and a BP increase in late phase 2 (phase 2b). Phase 3 is the first 1-2 s after release of expiratory strain, where there is a passive decline in BP and increase in HR. In phase 4, there is a BP overshoot due to increase in peripheral resistance. The BP response to Valsalva maneuver is thought to primarily reflect sympathetic adrenergic function [17, 20]. Valsalva ratio, which is thought to primarily reflect cardiovagal function [17, 20], was calculated as maximum HR during expiration divided by minimum HR within 20 s after release of strain. Head-up tilt test After resting for minimum 20 min, the participant was tilted to 70◦ from horizontal position. HR and BP were monitored continuously before and during the tilt test and in the recovery period with ECG and Finometer. The test included 8 min of tilting to 70◦ . The participants were repeatedly asked for symptoms such as dizziness, chest pain, and shortness of breath and other signs of discomfort. HR and BP were analyzed by averaging data 20 s before the tilt and by identifying

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the lowest BP and the highest HR within the first 3 min (by averaging minimum 5 s). Last, 20 s of data were averaged at the end of the tilt. The orthostatic response to head-up tilt was graded as 0 = normal response; 1 = mild adrenergic impairment; 2 = moderate adrenergic impairment or postural orthostatic tachycardia syndrome; and 3 = severe autonomic impairment [17]. Orthostatic hypotension was defined as a reduction in systolic BP ≥20 mmHg or diastolic BP of ≥10 mmHg [21], which was evaluated within the first 3 min and after 8 min.

Isometric handgrip test The subject was asked to perform a maximal hand grip using a JAMAR hydraulic hand dynamometer (Fabrication Enterprises Inc., Irvington, NY, US) with the left hand. A mean of three trials were considered maximal grip strength. The participant was then asked to maintain a handgrip of one third of maximum for 3 min. The test leads to an increase in HR and BP [22, 23]. The test was analyzed off-line calculating mean values during 30 s periods from the start of the test and compared to resting values 30 s before the test.

Modified Composite Autonomic Scoring Scale (CASS) score The CASS score is used to grade the degree of autonomic failure and consists of a sudomotor index (grading 1–3), adrenergic index (grading 1–4), and cardiovascular HR index (grading 1–3) [12]. As we did not perform a quantitative sudomotor axon reflex test, a modified CASS score was calculated based on the adrenergic and cardiovascular HR index [12].

Statistical analysis All data were tested for normal distribution using Shapiro-Wilk test of normality and histograms. In case of non-normal distribution log-transformations were tried and, if unsuccessful the numbers were given as median (25–75% interquartile range) otherwise as mean [95% CI]. Differences between groups were compared using Fisher’s exact test (frequencies), t-test, or Mann-Whitney tests as appropriate. For the isometric handgrip test, changes over time were compared using a mixed-model analysis for repeated measures (unstructured covariance matrix) as the subsequent measurements were not independent of the previous. A significance level of p < 0.05 was used. All data was analyzed using SAS 9.1.3 (SAS Institute Inc., USA). RESULTS Clinical characteristics Baseline characteristics are shown in Table 1. Patients and healthy controls were similar with respect to age and sex. Patients used more drugs than the controls mainly due to use of antidementia drugs and selective serotonin reuptake inhibitors (SSRI). Patients had a lower MMSE, but also slightly more depressive symptoms according to mean GDS score, though none of the participants had clinical significant depression. Autonomic testing Deep breathing Table 2 shows the results from the autonomic testing. There was no significant difference between patients and controls for RSA amplitude (p = 0.072). Seven out of 13 patients (54%) with a RSA amplitude below

Table 1 Baseline characteristics of the population Age (years), mean [95% CI] Gender, % female Blood pressure, mmHG – Systolic, mean [95% CI] – Diastolic, mean [95% CI] Heart rate, beats per minute Number of drugs, median (iqr) – Antihypertensive treatment Assessment of cognitive function MMSE, median (iqr) ACE, mean [95% CI] Depressive symptoms (GDS), median (iqr) Activities of Daily Living (FAQ-IADL), mean [95% CI]

Patients (n = 33)

Healthy controls (n = 30)

p

67.5 [65.4 to 69.7] 17 (51.5%)

68.9 [66.9 to 70.9] 17 (56.7%)

0.36 0.8

141.8 [134.9–148.6] 75.3 [71.4] 58.5 [55.6–61.3] 2 (2-3) 9 (27.3%)

129.0 [121.2–136.8] 69.4 [65.0–73.9] 62.2 [58.8–65.6] 1 (0 to 2) 10 (33.3%)

0.015 0.047 0.088 0.0001 0.78

23 (20 to 25) 65.7 [61.0 to 70.4] 1 (0 to 2) 12.9 [10.6 to 15.2]

30 (29 to 30) – 0 (0 to 1) –

Autonomic Dysfunction in Patients with Mild to Moderate Alzheimer's Disease.

Autonomic function has received little attention in Alzheimer's disease (AD). AD pathology has an impact on brain regions which are important for cent...
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