See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/262884528
Autonomic Dysfunction in Alzheimer's
Disease: Tools for Assessment and Review of
the Literature
ARTICLE in JOURNAL OF ALZHEIMER'S DISEASE: JAD · JUNE 2014 Impact Factor: 4.15 · DOI: 10.3233/JAD-140513 · Source: PubMed CITATIONS4
READS194
11 AUTHORS, INCLUDING: Klara Komici 14 PUBLICATIONS 77 CITATIONS SEE PROFILE Gennaro Pagano King's College London 54 PUBLICATIONS 326 CITATIONS SEE PROFILE Dario Leosco University of Naples Federico II 164 PUBLICATIONS 1,840 CITATIONS SEE PROFILE Nicola Ferrara University of Naples Federico II 242 PUBLICATIONS 3,490 CITATIONS SEE PROFILE Available from: Gennaro Pagano Retrieved on: 28 December 2015Uncorrected Author Proof
IOS Press
Review
1Autonomic Dysfunction in Alzheimer’s
Disease: Tools for Assessment and Review
of the Literature
2
3
4
Grazia Daniela Femminella
a, Giuseppe Rengo
b,∗, Klara Komici
a, Paola Iacotucci
a, Laura Petraglia
a,
Gennaro Pagano
a, Claudio de Lucia
a, Vincenzo Canonico
a, Domenico Bonaduce
a, Dario Leosco
aand Nicola Ferrara
a,b5
6 7
aDepartment of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
8
bSalvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy
9
Handling Associate Editor: Patrizia Mecocci 10
Accepted 8 April 2014
Abstract. Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential
diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer’s disease are also implicated in autonomic nervous system regulation, and it has been hypothesized that the deficit in central cholinergic function observed in Alzheimer’s disease could likely lead to autonomic dysfunction. Several feasible tests can be used in clinical practice for the assessment of parasympathetic and sympathetic functions, especially in terms of cardiovascular autonomic modulation. In this review, we describe the different tests available and the evidence from the literature which indicate a definite presence of autonomic dysfunction in dementia at various degrees. Importantly, the recognition of dysautonomia, besides possibly being an early marker of dementia, would help prevent the disabling complications which increase the risk of morbidity, institutionalization, and mortality in these individuals.
11 12 13 14 15 16 17 18 19
Keywords: Alzheimer’s disease, autonomic nervous system, baroreflex, functional recovery, orthostatic hypotension 20
Alzheimer’s disease (AD) is a progressive neurode-21
generative disorder and the leading cause of dementia 22
worldwide. AD affects more than 20% of individuals 23
over 80 years of age, and its prevalence is expected 24
to rise with the increase of life expectancy. How-25
ever, there is still a limited understanding of this 26
disease and its underlying causes, and existing drugs 27
only provide symptomatic benefits but there are no
∗Correspondence to: Giuseppe Rengo, MD, PhD, Salvatore
Maugeri Foundation, IRCCS - Scientific Institute of Telese Terme, Via Bagni Vecchi, 1 - 82037 – Telese Terme (BN), Italy. Tel.: +39 0817463677; Fax: +39 0817462339; E-mail: giuseppe.rengo@ unina.it.
currently available disease-modifying therapies [1]. It 28 is now established that the two major protein abnor- 29 malities in AD brain pathology are amyloid- (A) 30 deposition and tau accumulation. Besides these, other 31 mechanism might contribute to sporadic AD, such 32 as those suggested by the vascular hypothesis, which 33 states that cardiovascular diseases are an important 34 causal or contributing factor in AD, with hyperten- 35 sion regarded as the most powerful vascular risk factor 36 for AD (Fig. 1) [2, 3]. Indeed, cardiovascular fac- 37 tors are commonly recognized as risk factors for AD, 38 however, the relationship between cardiovascular fac- 39 tors and AD-related neurodegeneration is not clearly 40
Uncorrected Author Proof
2 G.D. Femminella et al. / Dysautonomia in Alzheimer’s Disease
-Secretase Cleavage
β -Secretase Cleavage
λ
Fig. 1. Hypothetical model of multifactorial Alzheimer’s disease (AD) pathogenesis. AD is likely to be caused by interactions among mul-tiple factors, including amyloid- protein precursor (APP)/amyloid- (A), tau, apolipoprotein E (ApoE4), and vascular abnormalities. A accumulation in brain results from increased A production from APP, decreased degradation, or reduced clearance across the dysfunctional blood-brain barrier. A accumulation leads to the formation of A oligomers and amyloid plaques, which are toxic to neurons, whereas its accumulation in the perivascular region leads to cerebral amyloid angiopathy, which disrupts vessel function. Vascular injury also induces toxic accumulation and capillary hypoperfusion, leading to early neuronal dysfunction. A aggregation amplifies neuronal dysfunction, impairs synaptic functions, triggers the release of neurotoxic mediators from microglial cells, and contributes to disease propagation. The lipid transport protein ApoE is primarily synthesized by astrocytes and microglia and once lipidated forms lipoprotein particles. Lipidated ApoE binds soluble A and promotes A uptake through cell-surface receptors or thorough the blood-brain barrier. The ApoE4 isoform impairs A clearance and promotes A deposition. Both A and hypoperfusion can induce tau hyperphosphorylation, leading to neurofibrillary tangle formation.
understood [3]. A system that could be implicated 41
in this relationship between vascular disease and AD 42
is the cholinergic system. The cholinergic system is 43
a crucial regulator of the cardiovascular and auto-44
nomic functions, and it is prominently affected in AD, 45
beginning in the pre-clinical phases. Various lines of 46
evidence indicate that in AD the cortical perivascular 47
cholinergic nerve terminals are largely lost, contribut-48
ing to the impairment of the observed reduction in 49
cerebral blood flow: the analysis of this relationship has 50
also led to the cholinergic-vascular hypothesis [4, 5]. 51
Moreover, various central nervous system structures 52
affected in AD are also implicated in autonomic ner- 53 vous system regulation, such as hypothalamus, locus 54 coeruleus, cerebral neocortex, insular cortex, and brain 55 stem [6]. Thus, a deficit in central cholinergic function 56 could likely lead to autonomic dysfunction, suggest- 57 ing that a link between higher cerebral and autonomic 58 neural functions could be reasonably hypothesized in 59 dementia. To date, however, the autonomic involve- 60 ment in AD has received only limited attention even 61 though its investigation could have important clinical 62 potential, because the recognition of autonomic fail- 63 ure in AD might prevent the disabling complications 64
Uncorrected Author Proof
Table 1 Autonomic function tests
Test System explored Advantages Disadvantages
Heart Rate Interval Variability Cardiac sympathovagal balance Simple, non-invasive Unknown
Ewing’s battery tests Cardiac sympathovagal balance Simple, non-invasive Require some degree of collaboration from the subject
Baroreflex Baroreflex function Simple, non-invasive Unknown
Carotid Sinus Massage Carotid sinus reflex sensitivity Simple, non-invasive Should be avoided in patients with ventricular arrythmia events, recent myocardial infarction or
cerebro-vascular events Plasma epinephrine and
norepinephrine measurement
Adrenergic system Simple, non-invasive High variability
Cardiac MIBG scintigraphy Adrenergic innervation of the heart In vivo evaluation of cardiac
innervation
Invasive, expensive, available only in specialized centers
of postural dizziness, syncope and falls, which increase 65
the risk of morbidity, institutionalization, and mortality 66
in these individuals [7]. 67
Thus, in this review, we will focus on the principal 68
tests used to evaluate sympathetic and parasympathetic 69
dysfunction, and we will also report the evidence on 70
autonomic dysfunction in AD from the literature. 71
SYMPATHOVAGAL FUNCTION 72
ASSESSMENT IN AD PATIENTS 73
The sympathetic and parasympathetic nervous sys-74
tem are key regulators of important functions, as blood 75
pressure (BP), heart rate (HR), respiration, gastroin-76
testinal, endocrine, urinary continence, and sexual 77
function [8, 9]. Several autonomic function tests have 78
been developed in order to investigate the severity 79
and distribution of autonomic dysfunction, to evaluate 80
the orthostatic intolerance, to diagnose the autonomic 81
neuropathy, and to monitor the course of autonomic 82
dysfunction and the response to eventual treatment [8]. 83
Furthermore, autonomic function tests are an important 84
tool in research studies investigating cardiovascular 85
and neurological disease pathophysiology. The central 86
nervous system structures related to the sympatho-87
vagal network are hypothalamic structures such as 88
paraventricular nucleus, dorsomedial nucleus, lateral 89
hypothalamic area, posterior hypothalamic nucleus, 90
and mammillary nucleus. These structures control both 91
the sympathetic and parasympathetic outflow. The 92
extra-hypothalamic structures related to sympathetic 93
drive are locus coeroleus, rostral and ventrolateral cau-94
dal medulla, and raphe nuclei, with respect to other 95
extra-hypothalamic structures such as dorsal motor 96
nucleus of vagus, amygdala, and nucleus ambygus 97
that control the parasympathetic drive [10]. Several of 98
these structures like hypothalamus, locus coeroleus, 99
and insular cortex are primarily involved in AD, there-100
fore it is reasonable to think that there should be a 101 connection between AD pathogenesis and sympatho- 102 vagal drive [11]. Here we describe some of the methods 103 used to assess autonomic function in AD (Table 1). 104
Heart rate interval variability 105
After the patient stays calm, in a rest supine position 106 for about 10–15 minutes, a continuous electrocardio- 107 gram (ECG) is recorded for 5 minutes and both the 108 time-domain indexes and frequency-domain indexes 109 are calculated [12]. Time-domain indexes are a statis- 110 tical calculation of consecutive R-R intervals. In this 111 case, during the continuous 5 minutes ECG record- 112 ing all QRS complexes and all normal to normal 113 (NN) intervals are detected. From this information 114 the mean HR, mean NN interval, difference between 115 longer-shorter NN can be calculated. Another statisti- 116 cal variable derived from this analysis is the standard 117 deviation of NN intervals (SDNN). Frequency-domain 118 indexes are a spectral method that analyses the fluc- 119 tuations in the frequency domain. The average of 120 R-R intervals undergoes Fourier transform algorithm 121 to obtain the power spectral density, so the units of 122 cycles/beat are converted in cycles/s (Hz). From the 123 above calculations low frequency (0.04–0.15 Hz) and 124 high frequency bands (0.15–0.4 Hz) are obtained. The 125 low frequency/high frequency bands ratio is used as 126 a marker of sympathovagal balance. This is a simple, 127 non-invasive method and taking advantage on the little 128 cooperation needed, it can be used even in the advanced 129
stage AD patient [13]. 130
Ewing’s battery tests 131
Five simple, noninvasive cardiovascular reflex tests 132 have been used by Ewing and colleagues to assess auto- 133 nomic function in diabetic patients [14]. Thereafter, 134
Uncorrected Author Proof
4 G.D. Femminella et al. / Dysautonomia in Alzheimer’s Disease
their use has been widespread in the evaluation of auto-135
nomic function in several clinical settings, providing 136
accuracy and reliability in the assessment of the auto-137
nomic system. The five tests used in Ewing’s standard 138
battery are: the heart rate responses to the Valsalva 139
maneuver, standing up (30:15 ratio), and deep breath-140
ing (maximum-minimum heart rate); the BP responses 141
to standing up (postural BP change), and sustained 142
handgrip. 143
Valsalva ratio
144
The Valsalva maneuver consists in performing 145
forced expiration for 15 seconds at a pressure of 146
40 mmHg. The Valsalva ratio is calculated dividing the 147
maximal R-R interval during 15 seconds of expiration 148
by the minimal R–R interval during the maneuver [15]. 149
Heart rate response to standing
150
Physiologically, after standing an increase in heart 151
rate occurs; this reaches its maximum at about the 15th 152
beat after standing, followed by a relative bradycardia, 153
maximal around the 30th beat. The ratio of maximum 154
R–R interval at the 30th beat to the minimum R–R 155
interval at the 15th beat represents the 30:15 ratio. 156
R–R interval variation (RRIV) during rest and
157
deep breathing (DB)
158
This method is also performed by ECG recordings 159
after about 5–10 minutes of rest in supine position 160
[16]. In this position the patient is invited to per-161
form forced DB at 6 breaths/minutes (5 seconds for 162
inspiration and 5 seconds for expiration), controlled 163
by ECG recordings. According to the longest and 164
the shortest R-R interval duration (in rest or during 165
forced DB), the mean R-R is calculated. Difference 166
between longest and shortest R-R interval duration is 167
the average between them. The ratio between mean and 168
average R–R interval is considered as the RRIV. The 169
RRIV at rest is a simple method that can be performed 170
in most of the patients with AD [17]. However, per-171
forming this test in advanced stage AD patients can be 172
potentially difficult. 173
Blood pressure variation (BP)
174
Orthostatic hypotension is evaluated by monitor-175
ing BP in supine position after 10 minutes of rest 176
and then after 3 minutes of active standing position. 177
According to other protocols, BP monitoring is also 178
performed during a) Valsalva maneuver, evaluated as 179
the BP response by the difference between the peak 180
systolic BP during the maneuver and the mean sys-181
tolic BP prior to the maneuver. The BP behavior during 182
Valsalva maneuver is described in four phases as the 183 act of blowing induces a transient rise in BP (phase 184 I), thereafter the reduced preload manifests as reduced 185 BP (early phase II), this reduction induces a BP rise 186 as a result of baroreflex activation (late phase II); then 187 the patient stops the maneuver and the BP starts falling 188 (phase III), and in the end the vascular peripheral resis- 189 tance increases and the BP rises (phase IV); b) BP 190 control during isometric exercise (or handgrip): the 191 patient is invited to remain in a sitting position for 192 at least 3 minutes after 10–15 minutes of resting in 193 supine position. In this case the BP response is cal- 194 culated as difference between the mean diastolic BP 195 prior to sitting position and just before the end of sitting 196 exercise; in the handgrip tests, handgrip is maintained 197 at 30% of the maximum voluntary contraction using 198 a dynamometer for up to 5 minutes. The difference 199 between the diastolic BP just before release of hand- 200 grip, and before starting, is taken as the test measure; 201 c) Cold presser test: diastolic BP variation is evaluated 202 after the participant submerges his left hand in cold 203 water at 4◦C [18]. According to the Ewing’s classifi- 204 cation, the subjects cardiovascular autonomic function 205 can be normal (all tests normal or one borderline), early 206 impaired (one of the three heart rate tests abnormal or 207 two borderline), definitely impaired (two or more of 208 the heart rate tests abnormal), severely impaired (two 209 or more of the heart rate tests abnormal plus one or both 210 of the BP tests abnormal or both borderline) or atyp- 211 ical (any other combination). In the Ewing’s battery, 212 the heart rate tests better evaluate the parasympathetic 213 function, while the BP tests measure the sympathetic 214
function. 215
Baroreflex (BR) estimation 216
BR is the mechanism responsible for BP and HR 217 control. Sudden changes of BP activate the BR and, as 218 a result of sympathovagal activation, HR is modulated 219 in order to restore the BP. BR estimation consists of 220 ECG recordings and BP control at the same time [19]. 221 To study the eventual BR modification in AD the casual 222 ARXAR model has been used, which describes the 223 casual relationship between R–R interval and BP [20]. 224
Carotid sinus (CS) massage 225
CS reflex sensitivity is measured by the response 226 of HR and BP after 5–10 seconds of CS massage. 227 After 5 seconds, a fall in HR can be noticed and 228 after 20 seconds, a fall in BP is usually found. How- 229 ever this assessment should be avoided in patients 230
Uncorrected Author Proof
with ventricular arrhythmia events, recent myocardial231
infarction, or cerebrovascular events [21]. 232
Plasma epinephrine and norepinephrine
233
measurement
234
The plasmatic level of cathecolamines is evaluated 235
after 30 minutes in resting supine position and after 5 236
minutes of orthostatic standing. Blood samples should 237
be kept in ice and spun within 1 hour after collection. 238
Plasma should then be stored at−80◦C [22]. Plasmatic 239
levels of cathecolamines have been evaluated also dur-240
ing the cold presser test. In the same conditions also 241
the cortisol and ACTH levels have been evaluated [23]. 242
123I-MIBG scintigraphy 243
Another method to study the sympathetic drive 244
in cardiovascular impairment is iodine-123 meta-245
iodobenzylguanidine (123I-MIBG) imaging. Non-246
invasive imaging with iodinated MIBG can assess 247
efferent adrenergic neuronal functions in the heart, as 248
the MIBG competes with noreadrenaline for neuronal 249
uptake. A reduced MIBG uptake has been correlated 250
to sympathetic dysfunction in heart failure and dia-251
betic neuropathy [24, 25]. Recent studies indicate that 252
sympathetic overdrive, represented by reduced MIBG 253
uptake without cardiac pathology involvement, may 254
indicate also a central nervous system involvement 255
[26, 27]. Indeed, it is now established that altered 256
myocardial MIBG uptake can help in the differential 257
diagnosis between Parkinson disease and secondary 258
parkinsonisms, as well as to differentiate between 259
dementia with Lewy body (DLB) and AD [28, 29]. 260
Other methods described in literature for the eval-261
uation of the autonomic function comprise: Holter 262
ECG recording, autonomic urinary test performed 263
by cistometric studies, gastrointestinal test as gastric 264
scintigraphy, thermoregulatory sweat test, phenyle-265
phrine and pilocarpine eye drop test. 266
In summary, we believe that a proper use of the auto-267
nomic function test would be not only valuable for the 268
research studies in patients with dementia, but could 269
also bring a benefit to the diagnosis, prognosis and to 270
eventual therapy follow-up. 271
CLINICAL EVIDENCE ON ALZHEIMER’S 272
DISEASE AND AUTONOMIC 273
DYSFUNCTION 274
As stated above, autonomic dysfunction, present in 275
all the common dementia subtypes, is believed to be 276
caused by generalized underactivity of the choliner- 277 gic system. According to Perry et al. in dementia the 278 parasympathetic and sympathetic systems are affected 279 by a widespread deficit in cholinergic function and all 280 the common subtypes of dementia have been asso- 281 ciated with cholinergic deficits [30]. Evidence from 282 previous studies has shown alterations in autonomic 283 modulation in AD, either in terms of impaired vagal 284 parasympathetic function or as altered sympathetic 285 response to orthostasis [17, 22]. 286 Braak suggests a sequence of six stages of AD based 287 on progressive involvement of the two main brain 288 structures implicated in autonomic control, insular cor- 289 tex, and brainstem. He speculated that these structures 290 may be affected by neurodegeneration in a “preclin- 291 ical stage” and that the autonomic dysfunction may 292 be present before the onset of clinical symptoms of 293 dementia [6]. Thus, autonomic dysfunction may be 294 a novel biomarker of neurodegeneration. Also Royall 295 et al. suggest that AD is associated with both insu- 296 lar pathology and autonomic dysfunction. Their data 297 indicate that the right hemisphere metabolic changes, 298 showed in the preclinical AD pathology, are signif- 299 icantly associated with mortality in non-demented 300 elderly persons. Furthermore they have measured abso- 301 lute insular cerebral blood flow (CBF) by dynamic 302 contrast MRI. They noticed that the absolute reduc- 303 tions in right insular CBF and relatively reduced right 304 versus left insular CBF are associated with orthosta- 305 sis in the same population. These observations indicate 306 that the prevalence of preclinical AD is probably higher 307 than the number of demented cases and that the tests 308 on the right hemisphere functions may be useful in 309 detecting those at risk. Moreover, AD treatment is 310 essential for delaying the progressions of symptoms 311 and might also have an impact on related autonomic 312 dysfunction [31]. In previous reports, cardiac auto- 313 nomic dysfunction in AD patients, measured by heart 314 rate variability (HRV) assessment, showed a significant 315 correlation with blood levels of acetylcholinesterase 316 activity, suggesting that the presence of autonomic 317 cardiac dysfunction in AD patients might be due to 318 a cholinergic deficit in the peripheral autonomic ner- 319 vous system [32]. Moreover, autonomic tests have also 320 shown significant correlations with specific neuropsy- 321 chiatric deficits in AD, hypothesizing that a lack of 322 cortical modulation can play a role [33]. 323 Collins et al. examined dysautonomia in patients 324 with mild cognitive impairment (MCI). MCI rep- 325 resents the earliest clinical stage of AD and other 326 dementias and is characterized by impairment in mem- 327 ory and/or others cognitive domains but preserved 328
Uncorrected Author Proof
6 G.D. Femminella et al. / Dysautonomia in Alzheimer’s Disease
functional abilities [34]. In this study, all subjects 329
underwent Ewing’s battery tests to examine the auto-330
nomic function and neuropsychological assessment 331
to evaluate the degree of cognitive impairment. MCI 332
patients presented with significant autonomic dysfunc-333
tion compared with controls. The parasympathetic 334
system was mainly involved in the autonomic dysfunc-335
tion as demonstrated by the deficits in the HR responses 336
to cardiovascular reflex tests and reduced high fre-337
quency on HRV. The predominance of parasympathetic 338
dysfunction in MCI suggests that neurodegeneration 339
may be due to an early cholinergic deficiency that 340
involves central autonomic network in dementia [18]. 341
As previously mentioned, cardiovascular factors are 342
now commonly accepted as risk factors for AD and 343
the BR alterations have been considered as a possible 344
link between BP control and AD [35]. The BR is a 345
reflex loop with cardiac, vascular, and cerebral com-346
ponents involved in a short term BP regulation, acting 347
through the autonomic nervous system by restoring 348
sudden changes in BP through the modulation of heart 349
rate and vascular tone. 350
Meel-van den Abeelen et al. compared BR function 351
in patients with AD, MCI, and healthy elderly subjects. 352
In AD, the BR was measured in basal conditions and 353
after cholinesterase inhibitors treatment. They found a 354
close relationship between AD and reduced BR func-355
tion, suggesting that the cholinergic system might play 356
a role. Indeed, cholinesterase inhibitors increased BR 357
function in AD. Moreover, MCI patients showed an 358
intermediate BR function between normal and AD 359
subjects [19]. 360
Van Beek et al. interestingly reported that ortho-361
static tolerance was preserved in AD, probably due 362
to enhanced sympathetic tone, and galantamine did 363
not affect orthostatic tolerance or HR in AD patients 364
[36]. Moreover, a study investigating the association 365
of the hypotensive syndromes orthostatic hypotension, 366
postprandial hypotension, and carotid sinus hypersen-367
sitivity with cognitive impairment has shown that the 368
prevalence of cognitive impairment was similar across 369
the hypotensive syndromes and not significantly differ-370
ent from controls. However, all patients with dementia 371
in this study had higher baseline HR, which could be 372
suggestive of cholinergic function impairment [37]. 373
The majority of studies, using a combination of car-374
diovascular reflex tests and HRV, reported different 375
modifications of the sympathetic and parasympathetic 376
system in dementia. De Vilhena Toledo and Junqueira 377
evaluated AD subjects with mild to severe cognitive 378
dysfunction, assessed by CAMCOG, the cognitive part 379
of the Cambridge Examination for Mental Disorders, 380
and the Mini-Mental State Examination (MMSE). 381 These patients showed subtle, relative, and abso- 382 lute depression of parasympathetic modulation and 383 only relative sympathetic over activity [38]. Positive 384 correlations were found between indexes of cardiac 385 parasympathetic modulation of short-term HRV and 386 the cognitive performance assessed by the CAMCOG 387 and MMSE tests scores, while a trend for negative 388 correlation was reported for the sympathetic activ- 389 ity. The authors conclude that the more deficient the 390 cognitive performance, the less is the parasympathetic 391 modulation, and the higher the trend to sympathetic 392
hyperactivity. 393
Pascualy et al. examined the effects of AD on 394 hypothalamic-pituitary-adrenocortical (HPA) axis and 395 the sympathetic nervous system responses to a stan- 396 dardized aversive stressor. Subjects included AD and 397 cognitively normal elderly. The authors measured 398 plasma adrenocorticotropin hormone (ACTH), corti- 399 sol, norepinephrine, and epinephrine responses to a 400 1-minute cold pressor test. The cortisol response was 401 increased in the AD group but the ACTH response did 402 not differ between groups. Basal norepinephrine con- 403 centrations were higher in the AD group and although 404 norepinephrine responses to cold pressor test did not 405 differ between groups, the BP response was higher in 406 the AD subjects. These results suggest that in AD there 407 is an increased HPA axis responsiveness to cold pressor 408 test at the level of the adrenal cortex and an increase 409 in basal sympathoneural activity and in cardiovascu- 410 lar responsiveness to sympathoneural stimulation [23]. 411 A previous report from our group has also indicated 412 that other possible markers of sympathetic overactivity, 413 as G-protein coupled receptor kinase 2 (GRK2) pro- 414 tein levels in circulating lymphocyte, are upregulated 415 in AD patients with both mild and moderate/severe 416 clinical manifestations of the syndrome and are sig- 417 nificantly correlated with the severity of cognitive 418 impairment [39]. In cardiovascular disease, lympho- 419 cyte GRK2 protein levels are an emerging biomarker 420 of sympathetic dysfunction with important prognostic 421 implications [40] and several lines of evidence suggest 422 that GRK2 could also play a crucial role in AD-related 423
neurodegeneration [41]. 424
Recent studies have compared the prevalence of 425 autonomic dysfunction in different dementia subtypes. 426 In particular, Allan and colleagues evaluated patients 427 with AD, DLB, vascular dementia (VaD), and Parkin- 428 son’s disease dementia (PDD). The authors enrolled 429 elderly patient (>65 years) and clinical autonomic 430 function tests were carried out according to Ewing’s 431 battery [14]. The results emphasized that there were 432
Uncorrected Author Proof
important differences between the four types ofdemen-433
tia, with orthostatic hypotension being prevalent in all 434
patients with dementia, implying the need for further 435
research in orthostatic hypotension as a modifiable risk 436
factor for falls in these patients. Indeed, autonomic dys-437
function occurred in all subtypes of dementia but was 438
especially noticeable in PDD and DLB with important 439
implications for patient management [15]. 440
In a previous study, Allan and colleagues had 441
also examined the prevalence and severity of auto-442
nomic symptoms in patients with different subtypes 443
of dementia and their association with levels of phys-444
ical activity, activities of daily living, depression, and 445
quality of life. They enrolled patients affected by PDD, 446
DLB, VaD, AD, and healthy controls. They noticed, 447
also in this study, that the autonomic symptoms were 448
significantly higher in PDD, DLB, and VaD patients 449
than either controls or AD patients. Moreover the auto-450
nomic symptom scores were associated with poorer 451
outcomes in physical activity, activity of daily living, 452
depression, and quality of life [42]. 453
Recent data point out important therapeutic impli-454
cations, showing that cholinesterase inhibitors can 455
modulate autonomic function in patients with AD. 456
Indeed, treatment with these drugs was associated with 457
functional improvement of the autonomic nervous sys-458
tem behavior and to a decrease orthostatic BP in AD 459
patients [43]. 460
CONCLUSIONS 461
As the elderly population grows, the prevalence of 462
patients with dementia will contextually increase, pos-463
ing a challenge for accurate clinical management not 464
only of the cognitive aspects of these diseases, but also 465
of their associate conditions, among which autonomic 466
dysfunction plays an important role. Autonomic failure 467
may occur as part of the dementing process, as some 468
authors suggest, can be the result of altered response 469
to stress conditions or might be exacerbated by drugs 470
interfering with the autonomic function. Moreover, the 471
existence of modifications of the cardiac sympatho-472
vagal balance toward a higher sympathetic and lower 473
parasympathetic modulation are highly prevalent in 474
elderly and may contribute to disrupted homeostatic 475
adaptive capacity. In any case, it is likely to expect 476
a higher proportion of abnormal autonomic manifes-477
tations and symptoms in patients with dementia, thus 478
a thorough clinical autonomic assessment for elderly 479
demented patient must be performed, taking advan-480
tage of several non-invasive tests available. However, 481
further studies with standard methodologies in larger 482 groups of patients are advisable, in order to improve 483 the benefits of these tests in clinical practice. Moreover, 484 prospective studies are needed, evaluating whether the 485 early detection of autonomic dysfunction in dementia 486 might favorably impact patients clinical management. 487 In addition to that, autonomic derangement itself could 488 be an early biomarker in dementia diagnosis, and could 489 also help in the differential diagnosis among dementia 490
subtypes. 491
Importantly, the impact of autonomic dysfunction 492 on key symptoms such as dizziness, syncope, falls, 493 constipation, and incontinence needs to be carefully 494 investigated in patients with dementia. Future studies 495 should address whether multi-factorial interventions 496 can improve autonomic function in these patients, 497 improving quality of life and preventing the disabling 498 complications which increase the risk of morbidity, 499 institutionalization, and mortality in these individuals. 500
DISCLOSURE STATEMENT 501
Authors’ disclosures available online (http://www.j- 502 alz.com/disclosures/view.php?id=2262). 503
REFERENCES 504
[1] Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB, Edison 505
P, Hagan JJ, Holmes C, Jones E, Katona C, Kearns I, Kehoe 506
P, Mudher A, Passmore A, Shepherd N, Walsh F, Ballard C 507
(2012) Drug repositioning for Alzheimer’s disease. Nat Rev 508
Drug Discov 11, 833-846. 509
[2] Iadecola C (2010) The overlap between neurodegenerative 510
and vascular factors in the pathogenesis of dementia. Acta 511
Neuropathol 120, 287-296. 512
[3] Wiesmann M, Kiliaan AJ, Claassen JA (2013) Vascular 513
aspects of cognitive impairment and dementia. J Cereb Blood 514
Flow Metab 33, 1696-1706. 515
[4] Claassen JA, Jansen RW (2006) Cholinergically mediated 516
augmentation of cerebral perfusion in Alzheimer’s disease 517
and related cognitive disorders: The cholinergic-vascular 518
hypothesis. J Gerontol A Biol Sci Med Sci 61, 267-271. 519
[5] Van Beek AH, Claassen JA (2011) The cerebrovascular role of 520
the cholinergic neural system in Alzheimer’s disease. Behav 521
Brain Res 221, 537-542. 522
[6] Braak H, Braak E (1995) Staging of Alzheimer’s disease- 523
related neurofibrillary changes. Neurobiol Aging 16, 271-278; 524
discussion 278-284. 525
[7] Idiaquez J, Roman GC (2011) Autonomic dysfunction in neu- 526
rodegenerative dementias. J Neurol Sci 305, 22-27. 527
[8] Low PA (1993) Autonomic nervous system function. J Clin 528
Neurophysiol 10, 14-27. 529
[9] Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic 530
nervous system in heart failure: Pathophysiology and therapy. 531
Circ Res 113, 739-753. 532
[10] Critchley HD (2005) Neural mechanisms of autonomic, affec- 533
Uncorrected Author Proof
8 G.D. Femminella et al. / Dysautonomia in Alzheimer’s Disease
[11] Chu CC, Tranel D, Damasio AR, Van Hoesen GW (1997) The
535
autonomic-related cortex: Pathology in Alzheimer’s disease.
536
Cereb Cortex 7, 86-95. 537
[12] (1996) Heart rate variability: Standards of measurement,
538
physiological interpretation and clinical use. Task Force of
539
the European Society of Cardiology and the North
Ameri-540
can Society of Pacing and Electrophysiology. Circulation 93,
541
1043-1065.
542
[13] Toledo MA, Junqueira LF Jr (2010) Cardiac autonomic
modu-543
lation and cognitive status in Alzheimer’s disease. Clin Auton
544
Res 20, 11-17. 545
[14] Ewing DJ, Martyn CN, Young RJ, Clarke BF (1985) The
546
value of cardiovascular autonomic function tests: 10 years
547
experience in diabetes. Diabetes Care 8, 491-498.
548
[15] Allan LM, Ballard CG, Allen J, Murray A, Davidson AW,
549
McKeith IG, Kenny RA (2007) Autonomic dysfunction in
550
dementia. J Neurol Neurosurg Psychiatry 78, 671-677.
551
[16] Shahani BT, Day TJ, Cros D, Khalil N, Kneebone CS (1990)
552
RR interval variation and the sympathetic skin response in the
553
assessment of autonomic function in peripheral neuropathy.
554
Arch Neurol 47, 659-664. 555
[17] Wang SJ, Liao KK, Fuh JL, Lin KN, Wu ZA, Liu CY, Liu HC
556
(1994) Cardiovascular autonomic functions in Alzheimer’s
557
disease. Age Ageing 23, 400-404.
558
[18] Collins O, Dillon S, Finucane C, Lawlor B, Kenny RA (2012)
559
Parasympathetic autonomic dysfunction is common in mild
560
cognitive impairment. Neurobiol Aging 33, 2324-2333.
561
[19] Meel-van den Abeelen AS, Lagro J, Gommer ED, Reulen
562
JP, Claassen JA (2013) Baroreflex function is reduced in
563
Alzheimer’s disease: A candidate biomarker? Neurobiol
564
Aging 34, 1170-1176. 565
[20] Nollo G, Porta A, Faes L, Del Greco M, Disertori M, Ravelli
566
F (2001) Causal linear parametric model for baroreflex gain
567
assessment in patients with recent myocardial infarction. Am
568
J Physiol Heart Circ Physiol 280, H1830-H1839. 569
[21] Kenny RA, Kalaria R, Ballard C (2002) Neurocardiovascular
570
instability in cognitive impairment and dementia. Ann N Y
571
Acad Sci 977, 183-195. 572
[22] Vitiello B, Veith RC, Molchan SE, Martinez RA, Lawlor BA,
573
Radcliffe J, Hill JL, Sunderland T (1993) Autonomic
dys-574
function in patients with dementia of the Alzheimer type. Biol
575
Psychiatry 34, 428-433. 576
[23] Pascualy M, Petrie EC, Brodkin K, Peskind ER, Wilkinson
577
CW, Raskind MA (2000) Hypothalamic pituitary
adreno-578
cortical and sympathetic nervous system responses to the
579
cold pressor test in Alzheimer’s disease. Biol Psychiatry 48,
580
247-254.
581
[24] Paolillo S, Rengo G, Pagano G, Pellegrino T, Savarese G,
582
Femminella GD, Tuccillo M, Boemio A, Attena E, Formisano
583
R, Petraglia L, Scopacasa F, Galasso G, Leosco D, Trimarco
584
B, Cuocolo A, Perrone-Filardi P (2013) Impact of diabetes on
585
cardiac sympathetic innervation in patients with heart failure:
586
A 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic
587
study. Diabetes Care 36, 2395-2401.
588
[25] Rengo G, Perrone-Filardi P, Femminella GD, Liccardo D,
589
Zincarelli C, de Lucia C, Pagano G, Marsico F,
Lymper-590
opoulos A, Leosco D (2012) Targeting the beta-adrenergic
591
receptor system through G-protein-coupled receptor kinase
592
2: A new paradigm for therapy and prognostic evaluation in
593
heart failure: From bench to bedside. Circ Heart Fail 5,
385-594
391.
595
[26] Hanyu H, Shimizu S, Hirao K, Kanetaka H, Iwamoto
596
T, Chikamori T, Usui Y, Yamashina A, Koizumi K, Abe
597
K (2006) Comparative value of brain perfusion SPECT
598
and [(123)I]MIBG myocardial scintigraphy in distinguishing
599
between dementia with Lewy bodies and Alzheimer’s disease. 600
Eur J Nucl Med Mol Imaging 33, 248-253. 601
[27] Horimoto Y, Matsumoto M, Akatsu H, Ikari H, Kojima 602
K, Yamamoto T, Otsuka Y, Ojika K, Ueda R, Kosaka K 603
(2003) Autonomic dysfunctions in dementia with Lewy bod- 604
ies. J Neurol 250, 530-533. 605
[28] Yoshita M, Taki J, Yamada M (2001) A clinical role for 606
[(123)I]MIBG myocardial scintigraphy in the distinction 607
between dementia of the Alzheimer’s-type and dementia 608
with Lewy bodies. J Neurol Neurosurg Psychiatry 71, 583- 609
588. 610
[29] Yoshita M, Taki J, Yokoyama K, Noguchi-Shinohara M, 611
Matsumoto Y, Nakajima K, Yamada M (2006) Value of 123I- 612
MIBG radioactivity in the differential diagnosis of DLB from 613
AD. Neurology 66, 1850-1854. 614
[30] Perry EK, Smith CJ, Court JA, Perry RH (1990) Cholinergic 615
nicotinic and muscarinic receptors in dementia of Alzheimer, 616
Parkinson and Lewy body types. J Neural Transm Park Dis 617
Dement Sect 2, 149-158. 618
[31] Royall DR, Gao JH, Kellogg DL Jr (2006) Insular Alzheimer’s 619
disease pathology as a cause of “age-related” autonomic dys- 620
function and mortality in the non-demented elderly. Med 621
Hypotheses 67, 747-758. 622
[32] Giubilei F, Strano S, Imbimbo BP, Tisei P, Calcagnini G, 623
Lino S, Frontoni M, Santini M, Fieschi C (1998) Cardiac 624
autonomic dysfunction in patients with Alzheimer disease: 625
Possible pathogenetic mechanisms. Alzheimer Dis Assoc Dis- 626
ord 12, 356-361. 627
[33] Idiaquez J, Sandoval E, Seguel A (2002) Association between 628
neuropsychiatric and autonomic dysfunction in Alzheimer’s 629
disease. Clin Auton Res 12, 43-46. 630
[34] Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, 631
Wahlund LO, Nordberg A, Backman L, Albert M, Almkvist 632
O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erk- 633
injuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, 634
Ritchie K, van Duijn C, Visser P, Petersen RC (2004) Mild 635
cognitive impairment–beyond controversies, towards a con- 636
sensus: Report of the International Working Group on Mild 637
Cognitive Impairment. J Intern Med 256, 240-246. 638
[35] Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, 639
Nilsson L, Persson G, Oden A, Svanborg A (1996) 15-year 640
longitudinal study of blood pressure and dementia. Lancet 641
347, 1141-1145. 642
[36] van Beek AH, Sijbesma JC, Olde Rikkert MG, Claassen JA 643
(2010) Galantamine does not cause aggravated orthostatic 644
hypotension in people with Alzheimer’s disease. J Am Geriatr 645
Soc 58, 409-410. 646
[37] Schoon Y, Lagro J, Verhoeven Y, Rikkert MO, Claassen J 647
(2013) Hypotensive syndromes are not associated with cog- 648
nitive impairment in geriatric patients. Am J Alzheimers Dis 649
Other Demen 28, 47-53. 650
[38] de Vilhena Toledo MA, Junqueira LF Jr (2008) Cardiac sym- 651
pathovagal modulation evaluated by short-term heart interval 652
variability is subtly impaired in Alzheimer’s disease. Geriatr 653
Gerontol Int 8, 109-118. 654
[39] Leosco D, Fortunato F, Rengo G, Iaccarino G, Sanzari E, 655
Golino L, Zincarelli C, Canonico V, Marchese M, Koch 656
WJ, Rengo F (2007) Lymphocyte G-protein-coupled receptor 657
kinase-2 is upregulated in patients with Alzheimer’s disease. 658
Neurosci Lett 415, 279-282. 659
[40] Rengo G, Galasso G, Femminella GD, Parisi V, Zincarelli 660
C, Pagano G, De Lucia C, Cannavo A, Liccardo D, Mar- 661
ciano C, Vigorito C, Giallauria F, Ferrara N, Furgi G, Filardi 662
PP, Koch WJ, Leosco D (2014) Reduction of lymphocyte 663
Uncorrected Author Proof
training predicts survival in patients with heart failure. Eur J
665
Prev Cardiol 21, 4-11. 666
[41] Femminella GD, Rengo G, Pagano G, de Lucia C, Komici
667
K, Parisi V, Cannavo A, Liccardo D, Vigorito C, Filardi PP,
668
Ferrara N, Leosco D (2013) beta-adrenergic receptors and G
669
protein-coupled receptor kinase-2 in Alzheimer’s disease: A
670
new paradigm for prognosis and therapy? J Alzheimers Dis
671
34, 341-347.
672
[42] Allan L, McKeith I, Ballard C, Kenny RA (2006) The 673
prevalence of autonomic symptoms in dementia and their 674
association with physical activity, activities of daily living and 675
quality of life. Dement Geriatr Cogn Disord 22, 230-237. 676
[43] da Costa Dias FL, Ferreira Lisboa da Silva RM, de Moraes 677
EN, Caramelli P (2013) Cholinesterase inhibitors modulate 678
autonomic function in patients with Alzheimer s disease and 679
