Vestibular loss as a contributor to Alzheimer’s disease

Medical Hypotheses 80 (2013) 360–367

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Vestibular loss as a contributor to Alzheimer’s disease Fred H. Previc ⇑ Texas A&M University – San Antonio, One University Way, San Antonio, TX 78224, United States

a r t i c l e

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Article history: Received 1 August 2012 Accepted 25 December 2012

a b s t r a c t Alzheimer’s disease is a complex disorder whose etiology is still controversial. It is proposed that vestibular loss may contribute to the onset of Alzheimer’s disease, which initially involves degeneration of cholinergic systems in the posterior parietal-temporal, medial-temporal, and posterior-cingulate regions. A major projection to this system emanates from the semicircular canals of the vestibular labyrinth, with vestibular damage leading to severe degeneration of the medial-temporal region. The vestibular loss hypothesis is further supported by the vestibular symptoms found in Alzheimer’s patients as well as in various diseases that are major risk factors for Alzheimer’s disease. Ó 2013 Elsevier Ltd. All rights reserved.

Alzheimer’s disease (AD) is the leading cause of dementia and a disease that is increasing rapidly as the elderly population in the industrialized nations continues to rise. It is projected that over 13 million Americans will suffer from it by 2050 [1]. For several decades, the leading theory of the cause of AD focused on the buildup of beta-amyloid protein, which contributes to the breakdown of tau neurofilament protein and the formation of plaques and neurofibrillary tangles that are hallmarks of the disease. While the buildup of beta-amyloid protein is undoubtedly a feature of the disease process in most cases, there is accumulating evidence that it may not be the major cause of AD. Alternative theories have more recently centered on general health-risk factors such as cerebrovascular deficiency, lack of exercise, head trauma, and diabetes in the etiology of AD [2]. By contrast, I propose a more specific relationship between vestibular loss and AD that accounts for the many key neuroanatomical and behavioral features of AD as well as the contributions of general health-risk factors and even potentially the association with amyloid protein disturbances. The need for alternative theories to explain AD is due to the failures or limitations of the current ones. The leading theory based on amyloid plaques is problematic because amyloid buildup occurs after the initiation of the disease, can occur in the absence of the disease altogether, and is not well-correlated with neuronal loss in key areas [3]. Moreover, over one dozen large clinical trials with anti-amyloid drugs have failed in humans, sometimes with serious side effects [4], including two highly publicized recent Phase III clinical trials [5]. Also, the amyloid theory has difficulty explaining

the behavioral and neuroanatomical specificity of AD, at least in its earliest stage. In contrast to the widespread neural and behavioral failure seen in later stages of disease, the initial symptoms are most salient in the area of memory, particularly topographical memory [6], and are accompanied by specific degeneration of the hippocampal and parahippocampal regions of the medial-temporal cortex and hypoperfusion of the parietal-temporal and posteriorcingulate cortices [7]. Why these particular areas should be most affected is not only a problem for the amyloid and tau hypotheses but also for more general ‘‘health-risk’’ theories, as there are no compelling reasons for believing that aging, cerebrovascular insufficiency, hypoxia, diabetes, head trauma, lack of exercise, and many other general risk factors should preferentially affect these regions. Indeed, one disorder that does attack the medial-temporal cortex more than other brain areas is epilepsy, which often originates in this area and can lead chronically to degeneration of it but is not a risk factor per se for AD.1 The vestibular hypothesis of AD is consistent with the important role of the vestibular system in cognition (by virtue of its involvement in body, head and eye movements and the many visuospatial functions associated with them) and emotion (by virtue of its influence over the major sympathetic neurotransmitters norepinephrine and serotonin) [8,9]. The vestibular system, more than any other sensory system, diffusely projects to a variety of cortical and subcortical structures [10]. Although the largest vestibular projection zone lies in the posterior Sylvian region containing the parietal-insular and parietal-temporal cortex, there is also an important and specific vestibular projection to the medial-temporal cortex, including the hippocampus and

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[2].

Introduction

0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.12.023

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Indeed, AD may to a greater extent be a risk factor for epilepsy than the vice versa

F.H. Previc / Medical Hypotheses 80 (2013) 360–367

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Fig. 1. Areas of reduced metabolic activity/hypoperfusion in Alzheimer’s patients using positron emission tomography. Sagittal, coronal, and horizontal views are shown from left to right. Highlighted areas included the posterior parietal-temporal region and cingulate cortex. Although the medial-temporal region does not show hypoperfusion, it is the most severely atrophied early in AD. From Mosconi [7], with permission of author.

parahippocampal gyrus (see Fig. 1). This latter projection is believed to emanate primarily from the horizontal semicircular canals and appears to be a cholinergically dominated one, with both the medial vestibular nucleus (to which the horizontal canals project) and the hippocampus very rich in acetylcholine [11]. The parietal-temporal, posterior-cingulate, and medial-temporal regions are the major components of the topographical or ‘‘topokinetic’’ orientation and memory systems [12], which are highly analogous to the ‘‘action-extrapersonal’’ system described by Previc [13] and the ‘‘navigation network’’ described by Maguire et al. [14]. This system receives signals from various senses concerning the position and motion of the head in space, which are then used to detect our location and direction in topographical space (hence, the use of the term ‘‘heading’’ for the latter).2 This neural system is responsible for spatial episodic memory, receives substantial vestibular inputs [13], and not only declines in normal aging [16] but is the first to functionally and anatomically degenerate in Alzheimer’s patients [7]. Indeed, the specific loss of the above cortical regions allows >90% diagnostic specificity of AD relative to other dementias [7]. The hypothesized contribution of vestibular loss to degeneration of the topographical cortical system would be an example of anterograde degeneration, in which destruction of lower structures leads to degeneration of their higher projection zones. Anterograde degeneration occurs following damage to many types of sensory organs and can occur transneuronally, with neurons several synapses removed from the end-organ being affected and suffering apoptotic cell death [17]. It is known to occur following damage to the olfactory bulb, which also projects to the medial temporal region; indeed, anosmia (loss of smell) is one of the many behavioral symptoms that can occur in association with AD [18]. A more general rationale for an external cause of the degeneration of the topographical cortical system is based on the fact that the telencephalon is not prone to degenerate on its own. Contrary to early notions, the brain typically does not decline unless exposed to serious disease, such as diabetes, cardiovascular decline, sensory system loss, major nutritional deficiency, or external toxins [19–22]. Major neurological disorders, such as Parkinson’s disease and vascular dementia and Wernicke–Korsakoff’s syndrome (the second and third-most prevalent dementias) involve specific causal agents, sometimes in conjunction with susceptibility genes. Vascular dementia is caused by specific cerebrovascular insults 2 The horizontal nature of the ‘‘topokinetic’’ or ‘‘action-extrapersonal’’ systems is due to the fact that heading changes primarily along the horizontal surface of the earth. It has been shown that ‘‘head-direction’’ cells in the anterior thalamus and parahippocampal gyrus respond almost exclusively to movements of the head in the horizontal plane [15]. When postural and other adjustments must be made in response to off-vertical body and head movements in pitch and roll, other neurovestibular systems are responsible — e,g., those that comprise the ambientextrapersonal system described by Previc [13].

such as stroke, while Wernicke–Korsakoff’s syndrome is mainly caused by thiamine deficiency in conjunction with excessive chronic alcohol use [21]. In Parkinson’s disease, the second-most common neurodegenerative disease of any sort after AD, pesticides and other environmental toxins are believed to play an important etiological role, often in association with genes that render the patient more susceptible [22]. When I first discussed the topographical orientation and memory functions of the action-extrapersonal system and its possible involvement in AD [13], there were only a few references suggesting an important contribution of vestibular inputs to this system. Since then, however, a substantial literature has arisen documenting various aspects of this relationship—over 130 references on ‘‘vestibular–hippocampus’’ in Medline since 1998 as well as major reviews by Smith et al. [9,23,24]. The remainder of this paper will briefly review the role of vestibular inputs to the hippocampal area, which lies at the heart of the topographical memory system and is the earliest region to degenerate anatomically during the course of AD. I will then review the evidence for specific vestibular impairment in AD and show how many of the leading health-risk factors for AD are accompanied by degeneration/dysfunction of the vestibular system. Vestibular inputs to the hippocampus The vestibular system is the phylogenetically oldest of all of the sensory systems and the earliest to mature during development. It is composed of two major types of end-organs: the otolith organs and semicircular canals. The two otolith organs—the utricle and saccule—respond to linear acceleration in the three cardinal axes and are known as the graviceptors. They are primarily responsible for the control of posture, orientation relative to gravity, and changes in sympathetic arousal to compensate for shifting of the orthostatic column relative to gravity during movements and positioning of the body [25]. By contrast, the semicircular canals respond to angular motions in pitch, roll and yaw and are primarily designed to signal head movements in generating, among things, the vestibular–ocular reflex (VOR). They are believed to mainly increase parasympathetic activity, partly through cholinergic mechanisms [25]. Of the three semicircular canals in each labyrinth, the horizontal or lateral canal—which forms the major projection to the medial vestibular nucleus [26]—responds to head movements in the horizontal plane, which are most important in detecting our head movements and orientation in topographical space. The two sets of vertical canals (the posterior and superior) respond to movements relative to gravity and assist the otolith organs in the control of vertical eye movements and posture. While there is some evidence that utricular stimulation may excite the hippocampus [27] and that mutant mice deprived of specific otolith inputs may suffer from spatial memory deficits

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[28], the dearth of neurons that respond to pitch and roll movements of the head in the hippocampus and other parts of the cortical topographical system point to a lesser role of otoliths and/or vertical canals in the higher neural centers controlling our interactions in topographical space.3 Prior to the mid-1990s, there were only a few hints that the vestibular system may project in a significant way to the hippocampus and other medial temporal structures. Douglas et al. [30] and later Potegal [31] documented the role of vestibular inputs on hippocampally mediated spatial learning, while Frederickson et al. [32] showed that the hippocampal EEG was abnormal in rats with congenital vestibular loss. Arnolds et al. [33] showed that vestibularly mediated whole-body and eye movements alter hippocampal EEG, and Matthews et al. [34] showed that animals with fornix lesions disrupting hippocampal transmission could not overcome large passive rotations to improve spatial learning performance. Horii et al. [35] first demonstrated the specificity of the vestibular inputs to the hippocampus by demonstrating that hot caloric stimulation—which excites the semicircular canals—increased acetylcholine (ACh) release in the hippocampus. Moreover, this effect could be blocked by glutamatergic antagonists in the medial vestibular nucleus, whereas blocking auditory inputs had no effect on hippocampal ACh release. This was quickly followed by studies that showed vestibular influences on (1) the firing of hippocampal cells that signal the animal’s location in the environment (‘‘place cells’’) [36], (2) hippocampal theta EEG rhythms [37], and (3) the firing of head-direction cells in the subiculum adjacent to the hippocampus [15]. Subsequent studies showed that vestibular stimulation—and not the eye or head movements that accompany it—is responsible for the changes in hippocampal activity [27,38] and that passive rotation-induced (Type 2) theta is mediated by a muscarinic cholinergic synapses because it can be blocked by atropine [39,40]. Vestibular loss leads to major atrophy of the hippocampus in humans that correlates with impairments on spatial memory tasks, such as a virtual version of the Morris water maze [41]. The magnitude of this loss – about 17% – is intermediate to that found in mild cognitive dementia (13%) and AD (24%) [42] and cannot be attributed to reduced motor activity since hyperactivity accompanies bilateral vestibular damage [41]. Because of the bilateral central projections of the vestibular system and its extensive efferent control, resulting in an effective compensation for unilateral damage [43], the behavioral and anatomical effects on hippocampal systems are much greater for bilateral as compared to unilateral labyrinthectomies [23,44]. This may explain why unilateral labyrinthectomies frequently performed to treat Meniere’s disease have yet to be linked to a greater risk of spatial memory deficits and AD. The vestibular projection appears to be greatest in the anterior hippocampus, which is profoundly damaged in AD [45], whereas visual inputs are integrated primarily in the posterior hippocampus [46]. Vestibular lesions also disrupt single-neuronal firing related to spatial location in the hippocampus [47], similar to the effect observed with head-direction cells in other components of the topographic memory system [15]. Numerous studies have also shown a relationship between chemically induced lesions of the vestibular system and hippocampally mediated spatial learning, following administration of such drugs as sodium arsanilate [48] and 3,30 iminodipropionitrile (IDPN) [49,50]. The latter compound is highly ototoxic, with the hair cells of the crista ampullaris (the transduction zone of the

3 Cuthbert et al. [27] showed that stimulation of the utricle, as well as the canals, can also elicit field potentials in the hippocampus. However, it is not clear whether the utricular potentials may indirectly result from stimulation of the semicircular canals, given extensive otolith–canal interactions in the inertial reorganization of head signals [29].

semicircular canals) being most affected, followed by those in the utricle and saccule. Various vestibular functional deficits are found after injections of sodium arsanilate and IDPN, including disruption of righting reflexes, hyperactivity, circling, and abnormal head movements. In addition, many spatial learning deficits exist in animals treated with sodium arsanilate and IDPN, including performance decrements on the Morris water maze and radial-arm maze [48,49], both of which are sensitive to hippocampal damage. The IDPN cognitive deficits have been shown, at least in some cases, to be independent of co-existing postural and movement impairments. Intriguingly, IDPN also destroys neurofilament proteins, although it is not highly damaging to tau, the neurofilament protein most affected in AD. It is suggested that the axonopathies and vestibular loss creased by IDPN may involve different mechanisms, although a relationship cannot be ruled out [50]. The vestibular projection to the hippocampus is believed to be indirect. Some candidates include transmission through (1) the posterior thalamus to the inferior parietal cortex, (2) the dorsal tegmental nucleus, the lateral mammillary nucleus, and the anterior dorsal nucleus of the thalamus, and (3) the pedunculopontine tegmental nucleus, the supramammillary nucleus and the medial septal nucleus [24]. All of these are extensively connected with the hippocampus or parahippocampal gyrus, with the septal nucleus in particular having been shown to exert a major influence over the hippocampal theta rhythm that is activated by vestibular stimulation and movement [51]. It is noteworthy that the dorsal tegmental nucleus receives most of its vestibular projections from the medial vestibular nucleus [52]. The above brief review demonstrates that vestibular inputs— especially those emanating from the horizontal semicircular canals and medial vestibular nucleus and coursing through brainstem and limbic cholinergic pathways—appear to have a major influence on the function and integrity of those pathways most affected early on in AD. Although other neurotransmitters, such as glutamate, may be involved in vestibular stimulation of the hippocampus and in treating AD [53], the cholinergic dominance of this system is consistent with the abolition of vestibularly induced long-term potentiation in the hippocampus by specific lesions of the septohippocampal cholinergic pathways [51] and by the fact that anticholinesterase drugs (e.g., donezepil/Aricept) are the treatments of choice in AD [54]. The severity of the neuroanatomical, neurochemical, electrophysiological and behavioral degradations to the topographical orientation and memory systems following vestibular loss alone is especially impressive given that visual, olfactory and other sensory inputs also feed into these systems.

Vestibular symptoms in AD The existence of actual vestibular system impairment in AD is suggestive but limited. Many subtle vestibular signs have been shown in Alzheimer’s patients, including problems in maintaining fixation and tracking objects and in using vestibular cues for postural control in conflict with discrepant visual and somatosensory inputs. Direct tests of vestibular function are almost entirely lacking, however, and neuroanatomical studies of the vestibular organ and primary vestibular pathways have shown only subtle (though potentially important) alterations. While the vestibular signs in AD could result from abnormalities in many areas of the brainstem and not just the vestibular organ itself, no evidence to date indicates that hippocampal or other cortical damage per se is the cause of them. The ability to maintain an upright posture and avoid falling is impaired significantly in patients with AD relative to the normal elderly, who themselves show declines in postural control [55–58]. This is true even when other problems not specific to AD, such as extrapyramidal motor signs, are ruled out [58]. Indeed, walking

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and balance problems are some of the most important predictors of later cognitive decline in dementia [59]. Several studies that have investigated postural control with reduced or discrepant sensory inputs have shown Alzheimer’s patients to have special problems in using vestibular inputs to maintain a stable posture [56,57]. For example, using the Sensory Organization Test with swayreferenced support to eliminate somatosensory cues, Alzheimer’s patients fall significantly more than age-matched normals when visual cues are either absent or discrepant [56,57]. The relationship between balance problems and major functional deficits in AD is complex, in that postural deficits do not always correlate with the degree of cognitive impairment [59,60]. Hence, the vestibularly mediated balance impairment may be associated with, but not causal to, the cognitive deficits. This would be expected if the initial cognitive deficits are due primarily to loss of (horizontal) semicircular canal function and the balance problems are due more to impaired otolith and vertical-canal function. While in most cases vestibular loss would involve the horizontal canals as well as other parts of the vestibular organ, this would not necessarily be the case. What is certainly true is that the balance problems in Alzheimer’s patients are not due to the medial-temporal atrophy in AD, since damage to this region alone does not produce postural deficits. There has been only one study that directly examined horizontal semicircular canal function in Alzheimer’s patients [61]. While this study is often-cited as indicating a normal VOR in AD, it excluded patients with disorders that are known to be risk factors for both vestibular dysfunction and AD, such as cerebrovascular deficiency, head trauma, and mental retardation. Moreover, it obtained analyzable data from only one patient with mild dementia, and it did not specify whether the VOR gain even in this patient was measured in the light (where optokinetic nystagmus, or OKN, would have affected the VOR) or in darkness. By contrast, indirect measures of semicircular canal function are more suggestive of abnormalities in AD. One universally reported finding is deranged smooth pursuit tracking, which is interrupted by saccadic intrusions (see [62,63]). This coincides with deficits in the smooth phase of OKN, which must be suppressed in order to pursue a moving object against a background. While smooth-pursuit deficits can be caused by damage to a number of areas, the most important region is the vestibulocerebellum containing the flocculus. Also, vestibular lesions severely disrupt pursuit, OKN, and other smooth eye movements [64]. Conversely, the hippocampus and surrounding areas do not play an important role in smooth eye movements, so deficits to them in AD cannot be attributed to direct loss of these areas. Evidence for anatomical abnormalities in the vestibular pathways of Alzheimer’s patients is also sparse. While it was once believed that the vestibular brainstem pathways are fairly wellpreserved in Alzheimer’s patients—and there is certainly no evidence of the large numbers of plaques and neurofibrillary tangles found in other areas of the brain—it has recently been argued that brainstem pathology is fairly widespread in these patients and precedes the cortical pathologies [65]. For example, Baloyannis et al. [66] found extensive loss of dendritic contacts and synapses within both the cerebellum and brainstem vestibular pathways as well as other synaptic abnormalities. This finding suggests that, although most vestibulocerebellar cell bodies may be intact, they may be effectively deafferented in terms of their upstream transmission, thereby creating the opportunity for severe anterograde degeneration to occur.

Vestibular loss and major risks for AD As mentioned in the Introduction section, there are a number of general risk factors for AD, many pertaining to the health of the individual. The most prominent one is aging, but others include

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cerebrovascular deficiencies, diabetes and other metabolic disorders, traumatic brain injury, and Down syndrome. Most, if not all, of these risk factors are also risk factors for vestibular disease. Other risk factors such as heavy-metal exposures, fumigant exposures, and low education level that may influence the likelihood of both AD and vestibular disorders [67,68] will not be reviewed here because they are less well-documented or their relationships are not specific. Inflammation is another nonspecific risk factor for both AD and vestibular dysfunction that will not be discussed here because it may be exacerbated by a variety of vascular, trauma, and metabolic insults [69]. Finally, depression is an important manifestation of vestibular dysfunction [70] and a possible risk factor for AD [71], but the causal relationship between depression and AD at this point is too poorly understood to invite speculation concerning vestibular mechanisms. The purpose if this section is not to review every purported risk factor for AD or to claim that vestibular loss is the only or even major causal factor in those conditions believed to accompany the development of AD. Rather, I merely put forth a perspective that highlights these risk factors from the standpoint of the vestibular loss hypothesis of this paper. Age The effect of age on AD has been well-documented, with a prevalence of less than 5% for 60 year-olds to almost 30% for 85 yearolds [1]. Not surprisingly, elderly persons also are believed to suffer from a wide variety of vestibular-related problems, although as noted earlier it is often too difficult to even carry out any careful testing in individuals with dementia. Some of the vestibular changes observed with age include decreases in postural control, greater incidence of falls, and deficits in the canal-mediated VOR, and the odds-ratio for having a vestibular disorder rises from 1.0 at age 40 to 25 at age 80 [67]. Baloh et al. [72] studied the horizontal VOR longitudinally and found abnormalities in the VOR time-constant and gain, particularly at low-frequencies of rotation. Agrawal et al. [73] showed vestibular degeneration in tests of all three semicircular canals (using dynamic visual acuity to head thrusts) and both otolith organs by means of the evoked myogenic potential. The declines observed were greatest for the semicircular canals and then the saccule and utricle, consistent with the greater canal hair cell loss during aging [74]. Although auditory loss also occurs during aging, there is no evidence that peripheral auditory loss is greater in AD patients than in normal individuals, although central auditory disturbances may occur [75]. This is consistent with animal evidence that vestibular damage is much more significant than auditory damage in altering hippocampal function [23]. Cardiovascular insufficiency Cardiovascular insufficiency in the form of hypertension, atherosclerosis (thickening of the arteries) and hypoxia are all considered risk factors for AD, as with other dementias [2,76]. In a recent study [77], only 32% of patients with mild cognitive impairment and no cardiovascular risk factors later developed dementia, while 60% of those with mild cognitive impairment and cardiovascular risks did so. While vascularly induced oxidative stress is believed to increase output of beta-amyloid protein [76], it may also have an important effect on vestibular function. For example, atherosclerosis is known to be in high prevalence in certain disorders of vestibular organ, including benign paroxysmal positional vertigo (BPPV) [78,79]. More generally, insufficiency and other abnormalities of blood flow in the vertebrobasilar artery feeding the cerebellum and vestibular organs may be responsible for many vestibular symptoms, including abnormal rotatory and caloric-induced nystagmus [80]. Basilar artery abnormalities are also known to lead

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to migraines, which have been reported in some but not all studies to be associated with AD [68]. Hypertension has been linked to vestibular disorders in some studies [78,81] but more marginally so in others [67,82]. By contrast, moderate physical exercise of at least 20–30 min two or three times per week has been shown to improve cognitive function in the elderly [83] and to reduce substantially the risk of AD [84,85]. This effect is observed even when controlling for vascular disorders, locomotory disorders, and other AD risk factors that could be associated with exercise. The beneficial effects of exercise in delaying or preventing AD are paralleled by increased blood flow to the vestibular nucleus and higher vestibular processing centers but not the cochlear nucleus or any other hearing centers [86]. Physical exercise has also been shown to improve various vestibulospinal and vestibulo-ocular reflexes [87]. It is noteworthy that physical exercise specifically increases the volume of the anterior hippocampus that receives vestibular input and is most affected in AD but does not alter caudate nucleus or thalamic volumes [88]. Diabetes and other metabolic disorders A variety of metabolic disorders affect the vestibular system, including hypothyroidism, elevated lipids, altered levels of sex hormones, and diabetes [89]. Most of these disorders may also be risk factors for AD [76]. Of all of the metabolic risk factors, diabetes has been the most clearly linked to both AD and vestibular loss. Alzheimer’s patients have a two-to-threefold greater risk of Type 2 diabetes [90], but it is not clear exactly what mediates this risk—insulin resistance, vascular effects, or brain-selective insulin-regulation effects. Vestibular deficits have also been linked to diabetes, although the evidence is not as consistent. Diabetes is clinically observed in association with balance and other vestibular disorders [91], and one recent large-scale study reported that vestibular disorders are 70% more likely among those with diabetes [67]. De Reuck [78] also found a high percentage of diabetes in his sample (12.5% for Meniere’s disease and 20% for BPPV), although Neuhauser et al., [81] and Warninghoff et al. [82] found less than 10% prevalence of diabetes in their samples. Potential mechanisms underlying the association between diabetes and vestibular disorders include disturbances in blood flow to the vestibular organ or alterations in glucose metabolism. Traumatic brain injury Although the data are complex and not always consistent, especially for mild head trauma such as low-grade concussions, the general finding from studies of traumatic brain injury is that severe brain trauma increases the risk of AD or least hastens its onset [92]. The risk of traumatic brain injury on AD may be dependent on a genetic susceptibility involving apolipoprotein E, which promotes amyloid formation. Some postulated mechanisms for the effect of brain trauma on AD include inflammation, excitotoxicity, axonal shear, microhemmorhages and ischemia, and oxidative stress [2]. One factor that has not been implicated in the effects of traumatic brain injury on AD is vestibular dysfunction, even though complaints of dizziness and other vestibular symptoms are quite common in those suffering from blast injuries and concussions. In a recent review and study, Akin and Murnane [93] showed extensive impairment of both horizontal semicircular canal and otolith organ functions in military blast victims. As might be expected, given that they respond to linear acceleration and would be subjected to more destructive hair-cell shearing, the otoliths were impaired in 84% of patients while 29% of patients showed semicircular deficits. While canal damage occurs in far fewer blast

victims than does otolith damage, it is still quite substantial and capable of contributing to AD in a large number of patients suffering from traumatic brain injury. Down syndrome Down syndrome, caused by a trisomy of chromosome 21, shares many key features in common with AD, including medial-temporal atrophy, cholinergic failure, and beta-amyloid plaques. The increase in amyloid production and plaques in Down’s patients may be partly due to the locus of the amyloid precursor protein on chromosome 21 [94]. It is generally recognized that the vast majority of Down’s patients who live to middle age will develop AD [2]. Vestibular dysfunction has long been known to occur in Down syndrome [8]. In addition to actual malformations of the vestibular system, individuals with Down syndrome have difficulties with balance, ocular tracking, and motor coordination [8]. They exhibit disturbances of OKN similar to those of Alzheimer’s patients, with saccadic intrusions accompanying the slow pursuit phase [95]. The VOR in those with Down syndrome is also characterized by a number of abnormalities, especially a reduced number of beats and reduced gains and time-constants [96]. The vestibular deficits are consistent with the many audio-vestibular deficits found in mouse trisomy 16, which is homologous to trisomy 21 in humans. Hence, one of the major implications of Down syndrome findings is there may exist a chromosomal/genetic confluence of vestibular deficits, amyloid abnormalities, and AD. It is worth noting in this regard that mice with genetically engineered loss of amyloid precursor and precursor-like proteins show ataxia, head tilt, spinning, and other vestibular symptoms [97]. It is also intriguing that, in the frog labyrinth, beta-amyloid fragments can alter firing in the ampullary nerve, leading from the semicircular canals [98]. While it is conceivable beta-amyloid plays a role in actually creating the vestibular loss and thereby indirectly could promote the onset of symptoms in AD, the role of beta-amyloid as the major cause of AD remains problematic, as described in the Introduction section [3]. Summary The preceding review highlights the clear vestibular symptoms in many of the diseases/processes considered major risk factors for AD. Most of these risk factors were previously related to genetic or other abnormalities of the amyloid system or to more general bioeffects, such as oxidative stress or inflammation. The peripheral damage to the vestibular organ may be different across the various disorders—e.g., hair-cell loss is likely in aging and traumatic brain injury (possibly due to excessive shearing), neuronal death in brainstem vestibular pathways due to ischemia is likely in many vascular and metabolic disorders, and actual vestibular malformation may be present in Down syndrome. Nevertheless, a common result of all of these vestibular deficits may be the deafferentation of higher vestibular and integrative centers. It should be cautioned that no evidence exists that the comorbid vestibular dysfunction in any of the above disorders actually differentiates those patients who develop AD from those who do not. Nor is there any evidence that the vestibular loss is the direct causal agent in the development of AD in specific patients, even though vestibular damage can produce deficits similar to many of those found in AD. But, it is even less likely that the auditory hair cell deafferentation that frequently accompanies vestibular damage produces the AD [23], especially given that chronic noise exposure may actually protect against AD [68].

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Conclusion The hypothesis put forth here that vestibular loss may contribute to AD is supported by many findings in both normal individuals and in AD patients as well as animals. The horizontal semicircular canals, in particular, send an indirect cholinergic projection to the hippocampus and parahippocampal gyrus and associated regions such as the posterior parietal-temporal and posterior-cingulate cortices that are important in topographical memory and comprise the neural system most devastated early on in AD. Due to anterograde degeneration, vestibular damage (especially if it is bilateral) can result in atrophy of this system and a severe impairment of topographical memory. In addition, Alzheimer’s patients show indirect symptoms of vestibular dysfunction and also tentative evidence of synaptic loss in brainstem vestibular pathways. Finally, vestibular deficits are more frequently found in diseases that are major risk factors for AD. This hypothesis does not posit that vestibular deficits are the only cause of AD or even the only source of anterograde degeneration in AD. Olfactory loss may also produce anterograde degeneration in the medial-temporal area [18], and even glucocorticoid elevation due to stress may turn out to be a factor responsible for specific damage to this area [99]. Also, this hypothesis is directed mainly at the early phases of AD, when a relatively specific impairment of the topographical memory and orientation system occurs. The role of vestibular dysfunction is less clear in the later stages of AD, when widespread atrophy of the brain occurs. However, the vestibular system is a widely projecting and diffuse system that could affect much of the brain if damaged, and some evidence indicates that vestibular dysfunction can affect general memory [23]. Moreover, the caudate nucleus also receives vestibular inputs [31] and is important in the motoric aspects of navigation [14]; functional loss in the caudate could, because of its extensive connections with the dorsolateral prefrontal cortex [100], explain the subsequent degeneration of the latter and the more general intellectual decline found in later stages of AD. What this hypothesis does offer is a different perspective on many major findings in AD and suggests that vestibular loss should receive much more attention as a potential causal agent in the development of AD. More research is clearly needed to document the progression of AD in specific individuals with vestibular dysfunction and to determine the specific vestibular mechanisms that are most associated with the loss of topographical memory in early AD. If vestibular loss does, indeed, turn out to be a major contributor to AD, then vestibular prevention and therapeutic strategies may eventually prove crucial in preventing or slowing the progression of this disease. Such strategies could eventually include targeted vestibular exercises, vestibular implants to stimulate the semicircular canals [101], galvanic vestibular stimulation (which improves general memory function in humans [23], caloric stimulation of the semicircular canals (which activates the hippocampus in humans) [102], and still-experimental hair-cell restoration [103]. Conflict of interest statement None. Acknowledgment I would like to thank Dr. Wes Krueger for reviewing aspects of this theory and for sharing some of his clinical observations. References [1] Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119–22.

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