Can chronic increased intracranial pressure or exposure to repetitive intermittent intracranial pressure elevations raise your risk for Alzheimer’s disease?

Author: Wostyn P

Over a decade ago, I formulated the hypothesis that cumulative effects of exposure to high intracranial pressure (ICP) may contribute to the development of Alzheimer's disease (AD), though not necessarily in an exclusive way. In addition to individual ICP characteristics (high 'physiological' ICP) and diseases causing ICP elevation, various activities with significant Valsalva effort, such as weightlifting and wind instrument playing, can generate very high ICPs. Recent studies of normal-pressure hydrocephalus (NPH), glaucoma and Alzheimer's disease provide supportive evidence for this hypothesis. A number of studies have shown a high incidence of AD related lesions in patients with NPH, which is known to be associated with prolonged elevation of ICP in a majority of cases. In both NPH and AD, an important decrease in cerebrospinal fluid (CSF) production was calculated. According to researchers in the US, the resulting CSF stagnation with impaired clearance and accumulation of neurotoxic substances may play an important role in the onset and progression of AD. They tested the hypothesis that improving CSF turnover by means of an investigational low-flow ventriculoperitoneal shunt will delay the progression of dementia in patients with Alzheimer's disease. With regard to the observed decrease in CSF production in patients suffering from NPH, it was postulated that chronic increased ICP causes downregulation of CSF production. It is hypothesized here that repetitive intermittent ICP elevations also may lead to downregulation of CSF production due to long-term cumulative effects. If the latter proves to be true, then both chronic increased ICP and repeated exposures to increased ICP (e.g., repetitive Valsalva maneuvers) may cause a similar cascade of CSF circulatory failure events leading to AD over time. Furthermore, AD may be causally related to increased ICP through other pathomechanisms. Additional supportive evidence for the role of a pressure factor in the pathogenesis of AD comes from studies concerning glaucoma. Elevated intraocular pressure (IOP) is a hallmark of glaucoma. Recently, similarities in pathophysiology between glaucoma and AD have been noted, with increased processing of amyloid precursor protein (APP) and up-regulation of beta-amyloid protein expression in retinal ganglion cells (RGCs). Given this link between AD and glaucoma, evidence for a causal relationship between repetitive intermittent ICP elevations and AD is gained from research indicating that high resistance wind instrument playing raises IOP and may result in glaucomatous damage. To test the validity of the hypothesis that exposure to repetitive but nonsustained ICP elevations may predispose to AD a non-invasive, epidemiological study is proposed in this paper.

Med Hypotheses. 2004;62(6):925-30.

Introduction

Alzheimer’s disease was first described in 1907 by Alois Alzheimer, a German neurologist. AD is the most common form of irreversible dementia. Histologically, it is characterized by the coexistence of senile plaques and neurofibrillary tangles in the brain. There is a strong age-dependence of the disease. Its prevalence doubles every 4.5 years of age. As the proportion of elderly people greatly increases, Alzheimer’s disease will become one of the most frequent, major public health problems. In spite of intensive research, the pathogenesis remains obscure. Most researchers agree that there is no one cause of Alzheimer’s disease. Rather, many factors, both genetic and environmental, probably contribute to the disorder in varying degrees in different individuals. Currently, there are no effective ways to prevent or treat the disease.
Various hypotheses have been proposed to explain the epidemiological and neuropathological features of Alzheimer’s disease. In an earlier paper of mine , it was postulated that cumulative effects of exposure to high intracranial pressure may increase the probability of developing AD. According to data from recent research, there is more scientific evidence for this hypothesis nowadays.

Shunting may be of clinical benefit in AD

Whether cerebrospinal fluid changes, either increased intracranial pressure or CSF stagnation, play a role in the progression of AD remains unclear, though some researchers have suggested that ventriculoperitoneal shunting may slow or stop the progression of dementia in AD. This practice is supported by a pilot study, described by Dr. Gerald Silverberg, from Stanford University in California, and colleagues . In their small trial, 29 patients with mild to moderate AD were randomly selected to shunt implantation or no active treatment.
The use of CSF shunts for senile and presenile dementia was first described in 1969 . Despite early optimism, it was abandoned after producing mixed results and an unacceptably high level of side effects. With regard to normal-pressure hydrocephalus, shunting is the most common and usually the only available treatment. NPH is an accumulation of cerebrospinal fluid that causes the ventricles in the brain to become enlarged. The name of this condition is misleading, however, because many patients have elevated ICP. Sahuquillo et al. analyzed and described ICP profiles in a series of patients with NPH. The majority of the patients, some 70%, presented continuous or intermittently raised ICP.
The idea behind the use of CSF shunts in Alzheimer patients stemmed from observations that cerebral tissue biopsy samples in patients with NPH frequently show AD-like lesions . According to Serot and colleagues the association between NPH and AD cannot be due to chance. In both conditions, Silverberg et al. have reported an important decrease in the secretion rate of cerebrospinal fluid. Cerebrospinal fluid is formed by the choroid plexus of the ventricles. The epithelial cells which cover these highly vascularized tissues, form the blood–cerebrospinal fluid barrier. The principle function of these cells is to produce and maintain the cerebrospinal fluid. Studies in animals show that chronically elevated CSF pressure downregulates the production of CSF and that chronic hydrocephalus damages the choroid plexus secretory epithelium . Degenerative changes of the plexuses also were found in AD. The choroid plexus shows an association of epithelial atrophy, epithelial basement membrane thickening, and stroma fibrosis .
According to the observed decrease in the secretion rate of cerebrospinal fluid in patients suffering from normal-pressure hydrocephalus, Silverberg et al. postulated that chronic increased intracranial pressure causes downregulation of CSF production. Reduced CSF production and turnover may contribute to impaired clearance of extracellular fluids in the brain and subsequent accumulation of neurotoxic substances. Silverberg et al. tested the hypothesis that improving cerebrospinal fluid turnover will delay the progression of Alzheimer’s disease by enhancing clearance of these potential neurotoxins. An investigational low-flow ventriculoperitoneal shunt was designed to slowly drain away toxins from fluid bathing the brain and spinal cord. Subjects were screened and randomized into test and control groups. After a year of monitoring and evaluation, the shunted patients showed a trend towards stability, compared to a decline in the control group. There were no deaths and no subject had symptoms of excessive drainage. The study also found lower CSF levels of potentially neurotoxic proteins such as MAP-Tau and β-amyloid in shunted patients.

Do chronic increased ICP and repetitive but nonsustained ICP elevations predispose to Alzheimer’s disease?

As noted above, Silverberg et al. have reported an important decrease in the secretion rate of cerebrospinal fluid in patients suffering from normal-pressure hydrocephalus. They postulate that chronic increased intracranial pressure causes downregulation of CSF production . Several studies indicate a rather high incidence of AD pathology in NPH . According to Silverberg and colleagues’ data, Serot et al. propose that NPH induces not only macroscopic and microscopic brain tissue lesions but also alterations of choroid plexus functions, notably a decrease of CSF turnover. In patients with NPH, AD-like lesions could thus be directly related to CSF volume and turnover disturbances.
The postulation of a relationship between prolonged elevation of intracranial pressure and downregulation of CSF production is of major importance because it may provide a clue to the underlying mechanism for AD. As AD associated pathologies are more common in subjects with NPH and a decrease in CSF formation is also calculated in patients with AD , then there is some scientific rationale for considering increased ICP, at least in some cases, as the primary determinant of AD. If it is believed that the decrease of CSF turnover in NPH is due to chronic increased ICP, then this raises the possibility that repetitive but nonsustained intracranial pressure elevations also would lead to downregulation of CSF production. The crucial question then is whether or not there are long-term degenerative changes of the choroid plexus of conditions with repeated exposures to increased ICP. As degenerative changes of the plexuses may be one of the earliest manifestations of Alzheimer’s disease , this could shed light on its pathogenesis. If plexus alterations could be found in subjects with a history of repetitive intermittent ICP elevations, then both chronic increased intracranial pressure and repeated exposures to increased ICP might cause a similar cascade of events (plexus alterations, reduced CSF production, decreased CSF turnover and impaired clearance of CSF neurotoxic substances) leading to AD ( Fig. 1). Although Silverberg et al. have noted no lowering of the rate of CSF production in association with acute hydrocephalus, repeated exposures to increased ICP may result in downregulation of CSF production due to long-term cumulative effects, reflecting a time-dependent mechanism as in chronic hydrocephalus. Furthermore, increased ICP, either chronic increased ICP or repetitive intermittent ICP elevations, may also contribute to AD through other pathomechanisms (see Fig. 1).

Fig. 1. Schematic representation of the proposed hypothesis of AD.

 

Elevated ICP is brought about by a variety of conditions. We know, for example, that weightlifters, glassblowers and wind instrument musicians can generate very high intracranial pressures due to repeated Valsalva maneuvers (elevated subglottic pressures), which impair venous return from the head . The cerebral venous system does not have valves as do other venous vessels in the body. Any condition that obstructs or compromises the venous outflow may also increase cerebral blood volume because more blood is backed up in the intracranial cavity.
Evidence that a pressure factor may be involved in AD pathogenesis comes from another area of research, especially from data concerning glaucoma. Glaucoma is an ocular disorder embodying a group of conditions that have in common optic nerve damage. The disease is usually brought about and made worse by elevated intraocular pressure. Both IOP and ICP have similar physiologic pressure ranges and similar responses to changes in intra-abdominal, intra-thoracic and aortic pressure . In his paper entitled “Glaucoma: ocular Alzheimer’s disease?” , McKinnon points to similarities between glaucoma and AD. Both disorders are chronic neurodegenerative conditions. Features of neuronal dysfunction in AD suggest parallels to those detected in retinal ganglion cells in glaucoma. RGCs have been shown to die by apoptosis. Central to apoptosis is the activation of specific proteases, termed caspases. Activation of caspases and abnormal processing of amyloid precursor protein are important events in AD. In rat glaucoma models McKinnon et al. showed that caspase-3 is activated in RGCs and cleaves APP to produce neurotoxic fragments that include β-amyloid. Caspase-3 activity colocalizes with APP cleavage products and β-amyloid in senile plaques . McKinnon suggests a new hypothesis for RGC death in glaucoma involving chronic β-amyloid neurotoxicity, mimicking AD at the molecular level.
The suggestion that repeated exposures to increased ICP may contribute to AD development is supported by a two-part study, described by Schuman et al. , in order to determine whether the playing of high resistance wind instruments increases intraocular pressure, and whether high resistance players have a higher incidence of glaucomatous changes than other musicians. IOP elevation was seen in players dependent on the force of blowing. Visual field testing was increasingly abnormal in high resistance players with more lifetime hours of playing. The authors speculated that cumulative effects of repetitive intermittent IOP elevations might result in glaucomatous damage.

Hypothesis: increased ICP may be an important predisposing factor in the pathogenesis of AD

The research findings mentioned above, also seem to correlate with my previous hypothesis of AD. In an earlier paper , several neuropathological and epidemiological data on Alzheimer’s disease were considered in relation to data from other scientific sources. In light of these considerations, it was hypothesized that high ICP might play a role in the pathogenesis of AD, though not necessarily in an exclusive way. The proposed hypothesis provides a framework for explaining different phenomena of AD.
Alzheimer’s disease is characterized by innumerable senile plaques and neurofibrillary tangles in the brain. These changes also occur to some extent in the brains of non-demented elderly people . The distribution of cognitive impairment in the population also shows a continuum of severity . Thus, from these observations it appears that AD is on a continuum with normal aging. This may result from a single underlying process that varies in magnitude. With regard to ICP, there is considerable variation in the cerebrospinal fluid pressure amongst healthy human subjects. Study of cerebrospinal fluid pressure in normal volunteers showed values ranging from 80 to 240 mm H20 . In a relatively small number of cases, the CSF pressure exceeded 200 mm H2O (=subgroup with high ‘physiological’ pressure). In each subject the pressure tended to fluctuate around a characteristic individual level. There was considerably more variation in the observations from subject to subject than on the same subject. Thus, everyone seems to be exposed to a rather individual level of ICP.
This might explain why the histological features of AD also occur to varying degrees in normal aging. This interindividual variability in ICP may also account for the distribution of cognitive impairment in the population. Indeed, on the one extreme, both pathological increased ICP and high ‘physiological’ ICP may facilitate the formation of neuropathological changes that lead to AD. On the other extreme, people with low physiological ICP may escape development of AD because too little damage occurs to exhibit memory impairment or dementia before death. In addition to activities or diseases causing ICP elevation, constitutional intracranial pressure characteristics (long-standing high ‘physiological’ pressure) may predispose a person to developing AD.
Further, the present hypothesis may also explain the age-specific pattern of prevalence of AD. Advanced age is the strongest risk factor for AD: the prevalence doubles every 4.5 years of age . Exposure to ICP occurs during the entire lifetime of the individual. Simply on the basis of increasing age, pathological changes may accumulate to some threshold beyond which dementia appears. This may also account for the degenerative changes of the choroid plexuses and decrease of CSF secretion, as seen in normal aging and AD . Furthermore, pathological conditions such as heart failure, chronic obstructive pulmonary disease and sleep apnea are quite frequent in the elderly and may, in turn, give rise to elevation of ICP , further increasing the likelihood of AD development. This might explain the high prevalence of AD in older age groups. From this point of view, it is not the ageing process per se which leads to AD but the pressure factor, predominantly giving rise to AD over time.
Some comments can be made on the hypothesis. Firstly, it should be stressed that high ICP eventually accounts only for a subgroup of Alzheimer patients. Several other processes may also contribute to the disease (Fig. 1). Moreover, a small proportion of AD cases is known to have a genetic basis. Secondly, according to the hypothesis, Alzheimer patients of this ‘high ICP subgroup’ may have a normal ICP in the course of their disease. Indeed, repetitive intermittent ICP elevations, as in wind instrument playing, may have given rise to AD development. Elevations of ICP here only occur during blowing on the instruments. Furthermore, conditions with raised intracranial pressure may have precipitated the disease many years before the onset of the typical clinical picture. As a consequence, pathological increased ICP may be missing at the time of measurement.
To test the hypothesis that cumulative effects of repetitive intermittent ICP elevations may result in an increased risk for AD a non-invasive, epidemiological study can be proposed. One way of further analyzing this relationship is to compare the incidence of Alzheimer’s disease in subjects whose occupations or hobbies are associated with repeated exposures to increased ICP versus a control group. Repetitive intermittent ICP elevations may be the case for glassblowers, wind instrument musicians and weightlifters. Their activities require frequent Valsalva maneuvers, which are known to increase ICP by impeding venous drainage from the brain. The finding of an increased frequency of AD in these groups would strongly support this hypothesis. If this study finds that AD is more common among these individuals then more invasive studies will have to be done.

Conclusion

Ten years ago, at the time of publication, it seemed rather premature to speculate on the possible role of increased ICP in the pathogenesis of AD. Now, recent research findings provide more evidence for a link between ICP and AD. In agreement with this hypothesis there are studies of NPH and glaucoma suggesting similarities with AD. This may point to the involvement of a pressure factor in dementia of the Alzheimer type, though not necessarily in an exclusive way. Further study is needed into the risk of developing the clinical features of AD, for those with a history of repetitive intermittent ICP elevations.

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