Current Topics in Research
The Peripheral Sympathetic Neuron is Intact in Alzheimer’s Disease and Behavioral Variant of Frontotemporal Dementia
American Journal of Alzheimer’s Disease & Other Dementias® 2015, Vol. 30(4) 400-404 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514552319 aja.sagepub.com
Walter Struhal, MD1, Andrija Javor, MD1, Thomas Benesch, MMBA MPA MA2, Milan R. Vosko, MD, PhD1, and Gerhard Ransmayr, MD1
Abstract Introduction: The study was undertaken to evaluate the postganglionic sympathetic sudomotor function employing the quantitative sudomotor axon reflex test (QSART) in tauopathies Alzheimer’s disease (AD) and behavioral variant of frontotemporal dementia (bvFTD). Methods: Patients were recruited in a prospective pilot study. A structured history was taken and QSART was recorded. Results: In all, 15 patients with AD (7 female) and 14 patients with bvFTD (9 female) were included. Mean age (+standard deviation) of patients with AD and bvFTD was 74 + 9 and 71 + 10 years, respectively. Severe sudomotor dysfunction (Composite Autonomic Severity sudomotor score 3) was present in 3 (20%) patients with AD and 0 (0%) patients with bvFTD (P ¼ .037). The upper extremity was only involved in 1 patient with AD and 1 patient with bvFTD. Sweat results of the 4 recording sites did not differ between both groups. Patients’ history correlated with severe autonomic symptoms as assessed with QSART. Conclusion: Postganglionic sudomotor involvement in AD and bvFTD is most likely not part of the disease. Keywords autonomic nervous system, sudomotor function, sympathetic, postganglionar cholinergic system, Alzheimer’s dementia, frontotemporal, dementia
Introduction Autonomic dysfunction in Alzheimer’s disease (AD) was in focus of interest in a number of studies. These studies mainly focused on cardiovascular autonomic dysfunction. Allan and coworkers in 2007 reported, that in 39% of patients with AD pathologic cardiovascular autonomic tests were observed, 34% suffering from orthostatic hypotension (OH).1 A relationship between cognitive impairment and OH was reported, although the causal relationship remained unclear.2 A number of authors have found signs of cardiovascular dysfunction in patients with AD such as reduced 30/15 ratio,3 impaired sympathetic response to standing,4 or depressed baroreceptor reflex sensitivity.5 In contrast to cardiovascular autonomic studies, until recently, there was little attention paid to the sudomotor autonomic nervous system in tauopathies. In fact, there is evidence that amyloid b may directly impair cholinergic transmission.6 In addition, an AD mice model, more vulnerable to amyloid b by additional p75 deficiency, proved severe sudomotor dysfunction and reduction in sympathetic postganglionar target organ innervation.7 In humans, data are lacking on whether deficits in sympathetic function are of central or peripheral origin.7
Recently, the sympathetic sudomotor function was investigated in patients with AD using the Sympathetic Skin Response (SSR) test; a research article by Zakrzewska-Pniewska et al8 observed a pathologic SSR latency in 26% of their patients with AD. Negami et al reported an abnormal SSR in a small minority of their cohort, although only the amplitude of the SSR was evaluated and the latency was not reported.9 The SSR is a polysynaptic reflex with a suprabulbar, bulbar, spinal, and peripheral components.10 Articles employing the SSR are methodically unable to identify the anatomical site of lesion (central or peripheral sympathetic neurons). The SSR in addition is a surrogate measure, and patients with congenital absence of sweat glands (ectodermal anhidrotic dysplasia) show SSR responses.11
1 Autonomic Unit, Department of Neurology and Psychiatry, Johannes Kepler University, Linz, Austria 2 Department of Medical Statistics, Vienna Medical University, Vienna, Austria
Corresponding Author: Walter Struhal, MD, Department of Neurology and Psychiatry, General Hospital of the City of Linz (Allgemeines Krankenhaus der Stadt Linz), Krankenhausstr, 9, A 4020, Linz, Austria. Email: [email protected]
Downloaded from aja.sagepub.com at CMU Libraries - library.cmich.edu on October 4, 2015
Struhal et al
401
Given the current data on sudomotor dysfunction in patients with AD, the question arises whether the peripheral sympathetic neurons or sweat function might be involved in tauopathies in analogy to the in vitro mouse model.7 A method to evaluate the postganglionic sympathetic sudomotor function is the quantitative sudomotor axon reflex test (QSART).12 A pathologic QSART reveals postganglionic sympathetic dysfunction. Current data are limited to AD and do not include other tauopathies. For behavioral variant of frontotemporal dementia (bvFTD), there is no sudomotor data available so far but preganglionic sudomotor dysfunction was demonstrated in a kindred having pallidopontonigral degeneration with N279K mutation.13 This is to our knowledge the first pilot study to evaluate the sympathetic postganglionic sudomotor neuron in patients with tauopathies AD and bvFTD.
Methods and Participants Patients Autonomic function tests were performed in a prospective pilot study at the Autonomic Unit, Department of Neurology and Psychiatry, Johannes Kepler University, Linz. Alzheimer’s disease was diagnosed according to the McKhann criteria.14 Behavioral variant of frontotemporal dementia was diagnosed according to the revised criteria by Neary et al.15 Patients and their relatives gave written informed consent to be enrolled in this study. The study was approved by the Ethical Committee of the province of Upper Austria.
the Q-Sweat device (WR Medical Electronics Co Maplewood, MN, USA). It was routinely recorded from the following 4 sites: medial forearm three-fourths of the distance from the ulnar epicondyle to the pisiform bone; proximal lateral leg, 5 cm distal to the fibular head; medial distal leg, 5 cm proximal to the medial malleolus; and proximal foot over the extensor digitorum brevis muscle. A multicompartment chamber was filled with 10% acetylcholine. The acetylcholine compartment is separated from a second compartment continuously measuring humidity.12 Iontophoresis of acetylcholine into the skin was performed by passing a 2 mA of constant current across the skin. The postganglionic sympathetic sudomotor axon terminal is consecutively activated by the acetylcholine and the impulse travels antidromically, reaches a branch point, and then travels orthodromically to release acetylcholine from the nerve terminals, evoking the sweat response. Sweat production below the sweat compartment was continuously measured by circulating air connected to a high precision hygrometer (Figure 1). Medications, which might have an influence on autonomic test results (eg, b-blockers and antidepressant drugs), were stopped at least for duration of the double half-life before testing. Sudomotor volume results were interpreted according to the sudomotor score of the Composite Autonomic Severity Score (CASS),18 including the interpretation of lengthdependent patterns as pathological if the foot volume was one-third or less of the proximal leg volume.
Exclusion Criteria Tests showing artifacts (eg, sweat compartment leakage) were excluded.
Clinical Assessments All patients received an extensive medical assessment including medical history, indirect history, and investigation of concomitant diseases; clinical neurological examination including Unified Parkinson’s Disease Rating Scale, Tandem-walk performance, Timed Get Up & Go, and Tinetti Test; full neuropsychological assessment including Frontal Assessment Battery, CERAD-Plus, Stroop Word-Colour Test, aphasia status; and cerebral imaging employing 1.5 Tesla MRI. Significant medical causes for secondary dementia were excluded. Clinical follow-up was performed every 6 months. Patients and caregivers were asked to fill out an autonomic symptoms scale16 Results to question 5 (‘‘Is sweating in your feet decreased compared to the rest of your body?’’) and 6 (‘‘Is sweating in your feet decreased or absent (for example, after exercise or during hot weather?’’) were compared to QSART results. In addition, if these data were not provided, a standard autonomic history chart was applied including the question ‘‘Is sweating reduced in feet?’’17 Patients were rested in supine position 15 to 20 minutes before the test. Recordings were performed in an acclimatized room kept on a stable controlled temperature of 23 C. The QSART, which quantitatively evaluates the postganglionic sympathetic cholinergic sudomotor axon, was measured with
Statistical Analysis Single factor variance analysis or independent t test was used to compare differences across groups in normally distributed data. Fisher’s exact test was employed to detect the presence of differences across groups in the categorical baseline characteristics. All statistical tests were performed with SPSS version 20 (SPSS Inc, Chicago, IL, USA).
Results In all, 15 patients with AD and 14 with bvFTD were included. No patient had to be excluded due to artifacts. Demographic characteristics are summarized in Table 1. In total, 3 cases with AD and 1 case with bvFTD were having diabetes mellitus (DM). A positive sudomotor score was found in 7 patients with AD (3 ¼ severe, 1 ¼ moderate, and 3 ¼ mild) and 4 patients with bvFTD (0 ¼ severe, 2 ¼ moderate, and 2 ¼ mild). One female patient with AD (aged 69) with a long-standing history of DM had all sweat recording sites but the hand reduced. All other cases with diabetes had no signs for autonomic neuropathy and a normal QSART.
Downloaded from aja.sagepub.com at CMU Libraries - library.cmich.edu on October 4, 2015
American Journal of Alzheimer’s Disease & Other Dementias® 30(4)
402
Figure 1. A, Normal QSART and (B) pathologic QSART with length-dependent decrease in sudomotor function. First green triangle: iontophoresis start, second green triangle: iontophoresis stop, red trace: arm, blue trace: proximal leg, green trace: medial distal leg, yellow trace foot.
Sweat production in the forearm was reduced in 1 patient with AD (85% of normal value) and 1 patient with bvFTD (45% of normal value). All other patients had no reduction in sweat production in the forearm. There was no significant difference between sudomotor values of the 4 recording sides between both groups (Table 1). There was a significant difference between males and females in the hand and the foot. In the hand, this effect was also influencing a group difference analyzed by multivariate variance analysis (diagnosis and gender). History taking with patient and caregiver was severely aggravated by AD and bvFTD employing structured autonomic history taking.16,17 Only 67% of patients with AD and 71% of the patients with bvFTD were able to present a sound history on autonomic symptoms. In patients providing information for an autonomic history, data did not show significant group differences with the occurrence of sudomotor dysfunction of all grades but with the occurrence of severe sudomotor dysfunction (CASS sudomotor score 3; Table 2).
Discussion Severe sympathetic postganglionic sudomotor dysfunction is present only in a minority of patients with AD, sparing the hand, and absent in patients with bvFTD. Autonomic involvement is not a predominant clinical feature in AD and bvFTD. Nevertheless, sudomotor dysfunction in AD was recently reported in some patients employing the SSR.8,9 A clear age dependency on SSR was previously demonstrated. The SSR declines with age and might not be seen in a number of patients older than 50 years.19 Skin atrophy accompanies normal aging resulting in loss of skin small nerve fibers and sympathetic sweat glands innervation.20 Sudomotor dysfunction might therefore be well expected in elderly patients. In contrast to the sudomotor surrogate measure SSR, QSART is a method to measure sweat production directly. QSART, like SSR, shows a clear age decline in sudomotor response in the leg but unlike SSR not in the arm.21 Therefore, QSART testing of the arm is a valuable measure
Downloaded from aja.sagepub.com at CMU Libraries - library.cmich.edu on October 4, 2015
Struhal et al
403
Table 1. Comparison of Demographic Characteristics and Quantitative Sudomotor Axon Reflex Tests in Individuals With AD and bvFTD.a
Age, years Sex Severe sudomotor dysfunction (sudomotor score 3) Sudomotor dysfunction (sudomotor score 1-3) Sudomotor dysfunction arm Arm sudomotor, mL
AD (n ¼ 15)
bvFTD (n ¼ 14)
P (sign: < .05)
74.2 + 9.4 7 f, 8 m 3 (20.0%)
70.8 + 9.9 9 f, 5 m 0 (0.0%)
ns ns .037
7 (47%)
4 (29%)
ns
1 (7%) 1.14 + 0.85 (f: 0.64 + 0.46;m: 1.59 + 0.88)
1 (7%) 0.74 + 0.48 (f: 0.64 + 0.37; m: 0.92 + 0.58) 0.60 + 0.45 (f: 0.63 + 0.43; m: 0.55 + 0.46) 0.58 + 0.56 (f: 0.62 + 0.61; m: 0.52 + 0.42) 0.62 + 0.59 (f: 0.45 + 0.23; m: 0.92 + 0.85)
ns ns (gender difference:
The Peripheral Sympathetic Neuron is Intact in Alzheimer’s Disease and Behavioral Variant of Frontotemporal Dementia
American Journal of Alzheimer’s Disease & Other Dementias® 2015, Vol. 30(4) 400-404 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514552319 aja.sagepub.com
Walter Struhal, MD1, Andrija Javor, MD1, Thomas Benesch, MMBA MPA MA2, Milan R. Vosko, MD, PhD1, and Gerhard Ransmayr, MD1
Abstract Introduction: The study was undertaken to evaluate the postganglionic sympathetic sudomotor function employing the quantitative sudomotor axon reflex test (QSART) in tauopathies Alzheimer’s disease (AD) and behavioral variant of frontotemporal dementia (bvFTD). Methods: Patients were recruited in a prospective pilot study. A structured history was taken and QSART was recorded. Results: In all, 15 patients with AD (7 female) and 14 patients with bvFTD (9 female) were included. Mean age (+standard deviation) of patients with AD and bvFTD was 74 + 9 and 71 + 10 years, respectively. Severe sudomotor dysfunction (Composite Autonomic Severity sudomotor score 3) was present in 3 (20%) patients with AD and 0 (0%) patients with bvFTD (P ¼ .037). The upper extremity was only involved in 1 patient with AD and 1 patient with bvFTD. Sweat results of the 4 recording sites did not differ between both groups. Patients’ history correlated with severe autonomic symptoms as assessed with QSART. Conclusion: Postganglionic sudomotor involvement in AD and bvFTD is most likely not part of the disease. Keywords autonomic nervous system, sudomotor function, sympathetic, postganglionar cholinergic system, Alzheimer’s dementia, frontotemporal, dementia
Introduction Autonomic dysfunction in Alzheimer’s disease (AD) was in focus of interest in a number of studies. These studies mainly focused on cardiovascular autonomic dysfunction. Allan and coworkers in 2007 reported, that in 39% of patients with AD pathologic cardiovascular autonomic tests were observed, 34% suffering from orthostatic hypotension (OH).1 A relationship between cognitive impairment and OH was reported, although the causal relationship remained unclear.2 A number of authors have found signs of cardiovascular dysfunction in patients with AD such as reduced 30/15 ratio,3 impaired sympathetic response to standing,4 or depressed baroreceptor reflex sensitivity.5 In contrast to cardiovascular autonomic studies, until recently, there was little attention paid to the sudomotor autonomic nervous system in tauopathies. In fact, there is evidence that amyloid b may directly impair cholinergic transmission.6 In addition, an AD mice model, more vulnerable to amyloid b by additional p75 deficiency, proved severe sudomotor dysfunction and reduction in sympathetic postganglionar target organ innervation.7 In humans, data are lacking on whether deficits in sympathetic function are of central or peripheral origin.7
Recently, the sympathetic sudomotor function was investigated in patients with AD using the Sympathetic Skin Response (SSR) test; a research article by Zakrzewska-Pniewska et al8 observed a pathologic SSR latency in 26% of their patients with AD. Negami et al reported an abnormal SSR in a small minority of their cohort, although only the amplitude of the SSR was evaluated and the latency was not reported.9 The SSR is a polysynaptic reflex with a suprabulbar, bulbar, spinal, and peripheral components.10 Articles employing the SSR are methodically unable to identify the anatomical site of lesion (central or peripheral sympathetic neurons). The SSR in addition is a surrogate measure, and patients with congenital absence of sweat glands (ectodermal anhidrotic dysplasia) show SSR responses.11
1 Autonomic Unit, Department of Neurology and Psychiatry, Johannes Kepler University, Linz, Austria 2 Department of Medical Statistics, Vienna Medical University, Vienna, Austria
Corresponding Author: Walter Struhal, MD, Department of Neurology and Psychiatry, General Hospital of the City of Linz (Allgemeines Krankenhaus der Stadt Linz), Krankenhausstr, 9, A 4020, Linz, Austria. Email: [email protected]
Downloaded from aja.sagepub.com at CMU Libraries - library.cmich.edu on October 4, 2015
Struhal et al
401
Given the current data on sudomotor dysfunction in patients with AD, the question arises whether the peripheral sympathetic neurons or sweat function might be involved in tauopathies in analogy to the in vitro mouse model.7 A method to evaluate the postganglionic sympathetic sudomotor function is the quantitative sudomotor axon reflex test (QSART).12 A pathologic QSART reveals postganglionic sympathetic dysfunction. Current data are limited to AD and do not include other tauopathies. For behavioral variant of frontotemporal dementia (bvFTD), there is no sudomotor data available so far but preganglionic sudomotor dysfunction was demonstrated in a kindred having pallidopontonigral degeneration with N279K mutation.13 This is to our knowledge the first pilot study to evaluate the sympathetic postganglionic sudomotor neuron in patients with tauopathies AD and bvFTD.
Methods and Participants Patients Autonomic function tests were performed in a prospective pilot study at the Autonomic Unit, Department of Neurology and Psychiatry, Johannes Kepler University, Linz. Alzheimer’s disease was diagnosed according to the McKhann criteria.14 Behavioral variant of frontotemporal dementia was diagnosed according to the revised criteria by Neary et al.15 Patients and their relatives gave written informed consent to be enrolled in this study. The study was approved by the Ethical Committee of the province of Upper Austria.
the Q-Sweat device (WR Medical Electronics Co Maplewood, MN, USA). It was routinely recorded from the following 4 sites: medial forearm three-fourths of the distance from the ulnar epicondyle to the pisiform bone; proximal lateral leg, 5 cm distal to the fibular head; medial distal leg, 5 cm proximal to the medial malleolus; and proximal foot over the extensor digitorum brevis muscle. A multicompartment chamber was filled with 10% acetylcholine. The acetylcholine compartment is separated from a second compartment continuously measuring humidity.12 Iontophoresis of acetylcholine into the skin was performed by passing a 2 mA of constant current across the skin. The postganglionic sympathetic sudomotor axon terminal is consecutively activated by the acetylcholine and the impulse travels antidromically, reaches a branch point, and then travels orthodromically to release acetylcholine from the nerve terminals, evoking the sweat response. Sweat production below the sweat compartment was continuously measured by circulating air connected to a high precision hygrometer (Figure 1). Medications, which might have an influence on autonomic test results (eg, b-blockers and antidepressant drugs), were stopped at least for duration of the double half-life before testing. Sudomotor volume results were interpreted according to the sudomotor score of the Composite Autonomic Severity Score (CASS),18 including the interpretation of lengthdependent patterns as pathological if the foot volume was one-third or less of the proximal leg volume.
Exclusion Criteria Tests showing artifacts (eg, sweat compartment leakage) were excluded.
Clinical Assessments All patients received an extensive medical assessment including medical history, indirect history, and investigation of concomitant diseases; clinical neurological examination including Unified Parkinson’s Disease Rating Scale, Tandem-walk performance, Timed Get Up & Go, and Tinetti Test; full neuropsychological assessment including Frontal Assessment Battery, CERAD-Plus, Stroop Word-Colour Test, aphasia status; and cerebral imaging employing 1.5 Tesla MRI. Significant medical causes for secondary dementia were excluded. Clinical follow-up was performed every 6 months. Patients and caregivers were asked to fill out an autonomic symptoms scale16 Results to question 5 (‘‘Is sweating in your feet decreased compared to the rest of your body?’’) and 6 (‘‘Is sweating in your feet decreased or absent (for example, after exercise or during hot weather?’’) were compared to QSART results. In addition, if these data were not provided, a standard autonomic history chart was applied including the question ‘‘Is sweating reduced in feet?’’17 Patients were rested in supine position 15 to 20 minutes before the test. Recordings were performed in an acclimatized room kept on a stable controlled temperature of 23 C. The QSART, which quantitatively evaluates the postganglionic sympathetic cholinergic sudomotor axon, was measured with
Statistical Analysis Single factor variance analysis or independent t test was used to compare differences across groups in normally distributed data. Fisher’s exact test was employed to detect the presence of differences across groups in the categorical baseline characteristics. All statistical tests were performed with SPSS version 20 (SPSS Inc, Chicago, IL, USA).
Results In all, 15 patients with AD and 14 with bvFTD were included. No patient had to be excluded due to artifacts. Demographic characteristics are summarized in Table 1. In total, 3 cases with AD and 1 case with bvFTD were having diabetes mellitus (DM). A positive sudomotor score was found in 7 patients with AD (3 ¼ severe, 1 ¼ moderate, and 3 ¼ mild) and 4 patients with bvFTD (0 ¼ severe, 2 ¼ moderate, and 2 ¼ mild). One female patient with AD (aged 69) with a long-standing history of DM had all sweat recording sites but the hand reduced. All other cases with diabetes had no signs for autonomic neuropathy and a normal QSART.
Downloaded from aja.sagepub.com at CMU Libraries - library.cmich.edu on October 4, 2015
American Journal of Alzheimer’s Disease & Other Dementias® 30(4)
402
Figure 1. A, Normal QSART and (B) pathologic QSART with length-dependent decrease in sudomotor function. First green triangle: iontophoresis start, second green triangle: iontophoresis stop, red trace: arm, blue trace: proximal leg, green trace: medial distal leg, yellow trace foot.
Sweat production in the forearm was reduced in 1 patient with AD (85% of normal value) and 1 patient with bvFTD (45% of normal value). All other patients had no reduction in sweat production in the forearm. There was no significant difference between sudomotor values of the 4 recording sides between both groups (Table 1). There was a significant difference between males and females in the hand and the foot. In the hand, this effect was also influencing a group difference analyzed by multivariate variance analysis (diagnosis and gender). History taking with patient and caregiver was severely aggravated by AD and bvFTD employing structured autonomic history taking.16,17 Only 67% of patients with AD and 71% of the patients with bvFTD were able to present a sound history on autonomic symptoms. In patients providing information for an autonomic history, data did not show significant group differences with the occurrence of sudomotor dysfunction of all grades but with the occurrence of severe sudomotor dysfunction (CASS sudomotor score 3; Table 2).
Discussion Severe sympathetic postganglionic sudomotor dysfunction is present only in a minority of patients with AD, sparing the hand, and absent in patients with bvFTD. Autonomic involvement is not a predominant clinical feature in AD and bvFTD. Nevertheless, sudomotor dysfunction in AD was recently reported in some patients employing the SSR.8,9 A clear age dependency on SSR was previously demonstrated. The SSR declines with age and might not be seen in a number of patients older than 50 years.19 Skin atrophy accompanies normal aging resulting in loss of skin small nerve fibers and sympathetic sweat glands innervation.20 Sudomotor dysfunction might therefore be well expected in elderly patients. In contrast to the sudomotor surrogate measure SSR, QSART is a method to measure sweat production directly. QSART, like SSR, shows a clear age decline in sudomotor response in the leg but unlike SSR not in the arm.21 Therefore, QSART testing of the arm is a valuable measure
Downloaded from aja.sagepub.com at CMU Libraries - library.cmich.edu on October 4, 2015
Struhal et al
403
Table 1. Comparison of Demographic Characteristics and Quantitative Sudomotor Axon Reflex Tests in Individuals With AD and bvFTD.a
Age, years Sex Severe sudomotor dysfunction (sudomotor score 3) Sudomotor dysfunction (sudomotor score 1-3) Sudomotor dysfunction arm Arm sudomotor, mL
AD (n ¼ 15)
bvFTD (n ¼ 14)
P (sign: < .05)
74.2 + 9.4 7 f, 8 m 3 (20.0%)
70.8 + 9.9 9 f, 5 m 0 (0.0%)
ns ns .037
7 (47%)
4 (29%)
ns
1 (7%) 1.14 + 0.85 (f: 0.64 + 0.46;m: 1.59 + 0.88)
1 (7%) 0.74 + 0.48 (f: 0.64 + 0.37; m: 0.92 + 0.58) 0.60 + 0.45 (f: 0.63 + 0.43; m: 0.55 + 0.46) 0.58 + 0.56 (f: 0.62 + 0.61; m: 0.52 + 0.42) 0.62 + 0.59 (f: 0.45 + 0.23; m: 0.92 + 0.85)
ns ns (gender difference:
