Alzheimer's disease-related changes in diseases characterized by elevation of intracranial or intraocular pressure

Authors: Peter Wostyn a, Kurt Audenaert b and Peter Paul De Deyn c, d

In this review, we focus on the coexistence of Alzheimer's disease-related changes in brain diseases, such as normal pressure hydrocephalus and traumatic brain injury, and in glaucoma at the level of the retinal ganglion cells. This is a group of diseases that affect central nervous system tissue and are characterized by elevation of intracranial or intraocular pressure and/or local shear stress and strain. In considering possible mechanisms underlying Alzheimer-type changes in these diseases, we briefly summarize recent evidence indicating that caspase activation and abnormal processing of β-amyloid precursor protein, which are important events in Alzheimer's disease, may play a role both in glaucoma and following traumatic brain injury. With regard to normal pressure hydrocephalus, evidence suggests that changes in cerebrospinal fluid circulatory dynamics ultimately may result in reduced clearance of neurotoxins, such as β-amyloid peptides and tau protein, that play a role in the pathogenesis of Alzheimer's disease. Data presented in this review could be interpreted to suggest that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to increased levels of mechanical stress. Evidence for such a relationship is of major importance because it may support an association between elevated mechanical load and the development of Alzheimer-type lesions. Further studies are warranted, however, especially to elucidate the role of elevated mechanical forces in Alzheimer's disease neuropathogenesis.

a Department of Psychiatry, PC Sint-Amandus, Reigerlostraat 10, 8730 Beernem, Belgium
b Department of Psychiatry, University Hospital Gent, De Pintelaan 185, 9000 Gent, Belgium
c Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA), Lindendreef 1, 2020 Antwerp, Belgium
d Reference Centre for Biological Markers of Memory Disorders, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium

Clin Neurol Neurosurg. 2008 Feb;110(2):101-9. Epub 2007 Dec 3.

1. Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized clinically by a gradual decline in cognition and daily functioning and behavioural alterations . Currently, AD is known to be the most common form of dementia among older people . In addition to synaptic degradation and extensive neuronal cell loss, neuropathological characteristics of AD include extracellular senile plaques containing β-amyloid (Aβ) derived from the β-amyloid precursor protein (APP), and intracellular neurofibrillary tangles (NFTs) caused by abnormally phosphorylated tau protein . Despite decades of intensive research, the precise aetiology of AD remains elusive. In the vast majority of cases, the disease likely results from a combination of factors, including age, genetic causal or risk features, and environmental factors and .

In this review, we focus on the coexistence of AD-related changes in brain diseases, such as normal pressure hydrocephalus (NPH) and traumatic brain injury (TBI), and in glaucoma at the level of the retinal ganglion cells (RGCs). This is a group of diseases that affect central nervous system tissue and are characterized by elevation of intracranial pressure (ICP) or intraocular pressure (IOP) and/or local shear stress and strain. The purpose of this review is to present some relevant data that support the idea that exposure to elevated mechanical load may predispose the central nervous system to accumulation of Alzheimer-type changes.

2. NPH, TBI and glaucoma are diseases often accompanied by elevated mechanical load

It is generally assumed that NPH is a disorder of decreased cerebrospinal fluid (CSF) absorption . During the initial stage of the disease, intracerebroventricular pressure may increase, thereby leading to ventricular enlargement with stretching of the periventricular parenchyma . As the ventricles enlarge, CSF pressure returns to normal so that it is within the normal range at lumbar puncture and . The historical labelling “normal pressure” hydrocephalus was based on the finding that all three patients reported by Hakim and Adams in 1965 showed low CSF pressures at lumbar puncture and . However, the name of this condition is misleading because long-term intracranial pressure monitoring demonstrates intermittently raised ICP at night in association with pressure waves and . The pattern of brain damage in NPH has been explained on the basis of shear stresses . One explanation for NPH predicts that maximal shear stress is greatest in the periventricular region and diminishes steeply with increasing distance from the ventricular wall, and the incremental maximal shear stress remains greatest in the periventricular region as the ventricles enlarge . Numerous studies show that the brain damage in hydrocephalus follows a similar gradient .

During head injury, high ICP associated with impact has been predicted to lead to the generation of regions of high shear stress and tissue strain . ICP changes and high shear levels were generated in several experimental models of TBI , , , and . When an excessive mechanical force is applied to the brain, the brain deforms. The rapid deformation of brain tissue believed to take place during TBI can initiate a cascade of pathological events ultimately leading to neurodegeneration .

Glaucoma is a group of diseases that have in common a characteristic optic neuropathy and visual field defects. Glaucoma is usually associated with elevated intraocular pressure, but a subset of glaucomatous patients has normal IOP and is designated normal tension glaucoma. Mechanical and vascular theories for the pathogenesis of glaucomatous optic neuropathy (GON) have been presented . According to the mechanical theory, GON may be a direct consequence of increased IOP leading to regions of high shear stress and strain in the lamina cribrosa . The lamina cribrosa forms the bottom of the optic cup on the inner surface of the optic nerve head and allows the optic nerve to emerge from the orbit. At this site, increased IOP may result in mechanical forces on retinal ganglion cell axons with subsequent cell injury .

Interestingly, pathological features overlapping with those of AD have been described in all three of the above diseases. In later sections, we will summarize some relevant data with a special focus on AD-related changes in these diseases and possible mechanisms underlying these changes. This data could be interpreted to suggest that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to increased mechanical load. It should be noted that many different factors may be involved in the above diseases. For example, TBI involves direct mechanical damage, which may be aggravated by secondary insults, such as glutamate excitotoxicity, calcium-mediated toxicity, and ischemia . However, in addition to sharing AD-related changes (as discussed below), the three diseases are linked by the common involvement of elevated mechanical load. The immediate following section presents data showing that neuronal injury responses depend on different characteristics of mechanical load.

3. Mechanical load characteristics and injury response

Shear stress and strain are known to affect cell physiology . During a traumatic insult to the brain, tissue is subjected to large stresses at high rates which can induce a complex cascade of molecular and physiological effects which can result in delayed post-traumatic cell death and . The injury response of brain tissue is known to be dependent on both the magnitude and rate of mechanical stress. Rate and magnitude-dependent injury responses have been demonstrated in different in vitro models of neuronal injury which induce mechanical insult via fluid shear stress or elastic membrane stretch , and . Geddes and Cargill , for example, have shown that increases in intracellular free calcium concentration after an insult to cultured neurons depended synergistically on the applied strain rate and magnitude. It has been shown that mechanical stretch to neurons results in a strain rate and magnitude-dependent increase in plasma membrane permeability that likely causes massive influx of calcium through non-specific pores/openings and .

It has also been shown that pulsatile mechanical load has a more dramatic effect on cell physiology than steady mechanical load and . Indeed, there is evidence that repetitive shear stress on neurons is more harmful than steady shear stress . Support for this view came from observations from in vivo injuries and diseases such as glaucoma . Strain rate associated with glaucoma is expected to be much lower than that associated with head injury . During glaucoma, diurnal variations in IOP give rise to cyclic variations in stress and strain in the cells in the optic disk . Large diurnal variations in IOP are correlated with greater vision loss than constant elevated IOP . In vitro, in neuron-like cells, Edwards et al. showed that during cyclical shear stress, which might mimic cell exposure conditions associated with diurnal variations in IOP or repetitive strain injury, the strain rate increased by over an order of magnitude from the first to all subsequent cycles, suggesting that the cell and/or its polymer network became more elastic upon cyclic shear stress application . The authors measured the degree of cytoskeletal polymerization before and after exposure of cells to cyclic shear stress and found that the fraction of polymerized tubulin in the cell relative to total tubulin decreased by a factor of 2 after six cycles of shear stress . This study also demonstrated that the extent of injury, as indicated by the fraction of cells with fragmented DNA, was three times higher for cyclic shear stress than for steady shear stress. This might be related to the change in strain rate and/or cytoskeletal reorganization associated with cyclic stress . In an earlier study, Triyoso and Good showed that application of pulsatile shear stress to a neuron-like cell in vitro induces G protein activation, nitric oxide synthase activation, new protein synthesis, entry of calcium into the cell, and DNA fragmentation without lactate dehydrogenase release immediately after injury.

4. Possible link between TBI and AD

There is considerable evidence linking traumatic brain injury to AD. TBI has been identified as a probable risk factor for AD in several epidemiological studies. Many of these studies take the form of retrospective case-control studies. A common criticism of these studies is the potential of recall bias, because individuals are often asked to recall events that occurred decades earlier . Plassman et al. attempted to prevent recall bias by using a prospective historical cohort design. Using the records of World War II male veterans, they found that head injury in early adult life was associated with increased risk of AD or other dementias in late life, and that this risk increased with severity of the injury . Moreover, a recent systematic review of case-control studies replicated the findings of an older meta-analysis, supporting the association between a history of previous head injury and the risk of developing AD only in men, not in women and . An important genetic risk factor for AD and poor outcome after TBI is the epsilon 4 allele of the apolipoprotein E gene located on chromosome 19 . It has been shown to act synergistically and additively with a previous TBI as risk factors for AD, although research of others has failed to support these findings .

Apart from being considered a risk factor for AD, severe head injury can result in both Aβ protein deposition and tau pathology in the brain . Deposits of Aβ protein can be found in the brains of 30% of fatally head-injured patients and occur in association with increased expression of APP as part of an acute phase response to brain injury , and . Smith et al. assessed tau immunoreactivity in the hippocampus and adjacent temporal lobe in cases of fatal TBI with survival times ranging from less than 24 h up to 1 month. Four patterns of tau immunoreactivity were seen: neuronal perikaryal immunoreactivity, neuropil threads, glial cell immunoreactivity with associated punctate staining in white matter, and diffuse neuropil staining . Glial tau immunoreactivity was seen in some TBI cases but not controls . However, neurofibrillary tangles and neuropil threads did not appear more prevalent after TBI when compared with age-matched controls and . Roberts et al. reported that dementia pugilistica in boxers is associated with large numbers of both neurofibrillary tangles and diffuse Aβ protein plaques. It is also interesting to note that a recent study using a transgenic mouse model of AD-like amyloidosis found that repeated mild TBI accelerated brain Aβ protein accumulation and oxidative stress, which could thus work synergistically to promote the onset or drive the progression of AD . Moreover, in a recent study, Yoshiyama et al. demonstrated enhanced NFT formation in a transgenic tauopathy mouse model after repeated mild TBI. A marked increase of β-amyloid (1-42) and APP was found in ventricular CSF after severe TBI . However, another study showed that β-amyloid (1-42) was significantly decreased in CSF after severe TBI, and also demonstrated an association between low β-amyloid (1-42) and poor early outcome after TBI . In contrast to β-amyloid (1-42), CSF tau was highly elevated when measured at early time points post-trauma . Severity and outcome of TBI did not significantly correlate with tau levels .

Traumatic axonal injury is a complex phenomenon that involves activation of multiple pathologic cascades. A recent study in pigs has suggested that impaired axonal transport caused by brain trauma induces long-term pathological co-accumulation of APP with beta-site APP-cleaving enzyme, presenilin-1, and activated caspase, and that the abnormal concentration of these factors may lead to APP proteolysis and Aβ peptide formation within the axonal membrane compartment . Several studies provide evidence for apoptosis, a genetically predetermined program of cell death, as a mechanism for neuronal cell death both in AD , , , , , and and following TBI . One of the most important stages in apoptosis is the activation of a family of cysteine aspartate proteases known as caspases . Accumulating evidence suggests that multiple caspases are activated after TBI . A recent study found caspase-3 activity in CSF samples from patients with TBI, whereas no caspase-3 activity was found in CSF from controls . Using an impact acceleration rat model that causes TBI, Stone et al. found that caspase-3 cleavage of APP occurs in association with formation of Aβ peptide. Recent studies have demonstrated that the release of the pro-apoptotic protein cytochrome c from mitochondria leads to caspase activation following TBI and . Axonal injury is a common feature of severe TBI . In severe TBI, the axolemma is perturbed focally, allowing for calcium influx triggering local intraaxonal cytoskeletal and mitochondrial damage . This mitochondrial damage may lead to the release of cytochrome c, which then activates caspases .

As noted above, there is accumulating evidence to suggest that apoptotic mechanisms may also play a role in AD pathogenesis , , , , , and . The loss of hippocampal neurons by apoptotic cell death is a prominent feature of AD . Several studies have demonstrated the widespread activation of caspases in the AD brain , , , , , and . Recent research suggests that caspase activation in AD neurons may not immediately lead to cell death, which indicates a slow, apoptotic-like degenerative process that is profoundly different from the rather rapid, classical apoptotic pathway , and . The results of a study by Gervais et al. point to evidence that caspase-3 is the predominant caspase involved in APP cleavage observed in apoptotic cells. Consistent with this is its marked elevation in dying pyramidal neurons of the Alzheimer's brain hippocampus and co-localization of its APP cleavage product with Aβ in senile plaques . This study also found that caspase-mediated proteolysis of APP increases the rate of Aβ peptide formation in neuronal cells . Other in vitro studies also demonstrated a relationship between caspase-mediated cleavage of APP and formation of the Aβ peptide and . The caspase-mediated cleavage of APP appears to be distinct from that mediated by secretases, which is thought to be the primary mechanism for production of Aβ peptides in AD . Caspase proteolysis, however, does not directly account for Aβ excision from APP . It can be questioned, then, how caspase-mediated APP cleavage could give rise to Aβ generation. One possible explanation that has been proposed is that with caspase cleavage of APP, dysregulation of APP proteolytic processing may occur due to the removal of the carboxy-terminus and its associated regulatory proteins . Two neuronal proteins that influence proteolytic cleavage of APP, FE65 and X11, have been shown to bind to the carboxy-terminal cytoplasmic region of APP and . The interaction of APP and FE65 has been shown in vitro to potentiate the translocation of APP to the cell surface and to dramatically increase the secretion of Aβ peptide . X11 seems to have an opposite regulatory role in the Aβ secretion. It has been shown to decrease the proteolytic processing of APP and to promote its cellular retention . As the caspase-3-mediated cleavage of APP removes this carboxy-terminus and its associated regulatory proteins, it is possible that a shift in APP processing toward an amyloidogenic pathway may occur . Considering possible consequences of caspase activation, it is interesting to note that recent studies reported that tau protein is also a substrate for caspase cleavage and . In a recent study by Rissman et al. , it was suggested that Aβ protein accumulation triggers caspase activation, leading to caspase cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology.

5. Possible link between glaucoma and AD

Recent research has also revealed molecular similarities between glaucoma and AD. Studies consistently report decreased levels of β-amyloid (1-42) and increased levels of tau in CSF from AD patients in comparison with healthy subjects and . Recently, Yoneda et al. suggested the possibility of a role for β-amyloid (1-42) and tau in the pathogenesis of glaucoma and diabetic retinopathy having found significantly decreased levels of β-amyloid (1-42) and significantly increased levels of tau in the vitreous fluid from patients with these disorders in comparison with the levels in a control group. Their findings suggested that the neurodegeneration processes in these ocular diseases might share, at least in part, a common mechanism with AD . In an earlier 2003 paper entitled “Glaucoma: ocular Alzheimer's disease?” , McKinnon had already pointed out similarities in the process leading to retinal ganglion cell death in glaucoma and neuronal cell death in AD. Glaucoma and AD are chronic neurodegenerative conditions that involve neuronal death by apoptosis . As noted earlier, activation of caspases and abnormal APP processing, which includes production of Aβ, are important events in AD , , , , , and . McKinnon et al. detected a similar situation in rat glaucoma. Indeed, in their study using a chronic ocular hypertensive rat glaucoma model, the authors found that caspases, specifically caspase-8 and caspase-3, are activated in RGCs, where caspase-3 cleaves APP to produce neurotoxic fragments that include Aβ . This suggested a new hypothesis for RGC death in glaucoma involving chronic Aβ neurotoxicity, mimicking AD at the molecular level . Their findings of caspase-8 activation suggested the involvement of the extrinsic apoptotic cascade in RGCs during exposure to ocular hypertension . Activation of the extrinsic apoptosis pathway, triggered by binding of extracellular ligands to cell membrane-bound receptors of the tumor necrosis factor superfamily, leads to the activation of the initiator caspase-8 via recruitment of the adaptor protein Fas-associating protein with death domain and . Once activated, caspase-8 can induce activation of executioner caspases, such as caspase-3, to trigger cell death and . McKinnon et al. suggested that a second series of events might contribute to RGC death in rat ocular hypertension. APP has been reported to undergo rapid anterograde axonal transport in the optic nerve and . Research evidence suggests that glaucoma obstructs both anterograde and retrograde axonal transport in RGC axons at the optic nerve head and . The authors hypothesized that the obstruction of anterograde axonal transport could lead to local build-up of APP, and that this could represent a potential trigger for caspase activation in RGCs and . In neurons, elevated APP levels are known to activate caspase-3, leading to APP cleavage into fragments that upregulate Aβ levels . Given that increased Aβ potentiates apoptosis in the central nervous system and is capable of activating both caspase-8 and caspase-3 in primary neuronal cultures, a vicious cycle could erupt with further caspase-3 activation, APP cleavage, and Aβ formation . The authors also proposed that activation of caspases in glaucoma does not lead to an immediate and rapid process of RGC death but provokes a protracted form of apoptosis, similar to that seen in AD neuronal cells , and . Evidence in support of this conclusion was the fact that caspase activation in the ocular hypertensive rat model did not immediately kill all RGCs within 2 days . As in AD, glaucoma might involve lower levels of caspase activation that do not immediately induce cell death but result in delayed apoptosis that renders them vulnerable to oxidative stress .

As we noted earlier, the hypothesis of the present review is that exposure to elevated mechanical load may predispose the central nervous system to accumulation of Alzheimer-type changes. In this context, the above findings in ocular hypertension models of rat glaucoma are interesting because they raise the possibility that high intraocular pressure could be a trigger for Aβ production. As noted above, not all patients with glaucoma are found to have a high IOP. Unfortunately, no good animal model for normal tension glaucoma has so far been developed.

6. Possible link between NPH and AD

There is accumulating evidence of a high correlation between NPH and AD neuropathological findings. Indeed, patients with clinical and radiographic evidence of NPH appear to have a higher than expected coincidence of AD pathologic changes involving plaques and tangles, as demonstrated in cortical biopsy samples obtained at shunt implantation and . In a series of 27 cases of NPH, Bech et al. reported on six patients (22%) presenting with AD-like lesions. In another series reported by Savolainen et al. , between 31 and 50% of patients with NPH met the criteria for the neuropathological verification of Alzheimer's disease. In 2000, Golomb et al. reported on 23 patients (41%) with AD in a series of 56 patients biopsied at the time of shunt placement for NPH. In the severely demented NPH patients, 75% were AD positive . Although AD positive patients with NPH were more cognitively impaired and exhibited greater gait dysfunction, their improvement after shunt placement was comparable with patients with negative biopsies . The authors concluded by suggesting that patients with NPH who are good candidates for shunt operations based on accepted clinical and radiographic criteria should not be denied surgery solely because AD may be suspected as a concomitant diagnosis .

Although the primary change in NPH is an increase in CSF outflow resistance, decreased CSF production also has been reported , and . Both events lead to a decrease in CSF turnover and . Reduced CSF production and turnover have also been demonstrated in AD . It has been suggested that both AD and NPH are physiologically related to CSF circulatory failure, resulting in reduced CSF clearance and accumulation of neurotoxins, such as β-amyloid peptides and tau protein, that play a role in the pathogenesis of AD . Higher concentrations of Aβ increase the probability of aggregation and fibril formation and . Hence, reduced CSF clearance of Aβ should facilitate amyloid burden in the brain . In contrast to the 40-amino acid form of Aβ, the longer 42-residue form is more prone to aggregate and form plaques . Interestingly, a very recent study by Kapaki et al. found that total tau was significantly increased in the CSF of idiopathic NPH patients and highly increased in the CSF of AD patients as compared with the control group, whilst β-amyloid (1-42) was decreased in both diseases. Tau phosphorylated at threonine 181 (phospho-tau) was significantly increased only in the CSF of AD patients, but not in the CSF of idiopathic NPH patients as compared with the controls . For the discrimination of AD from NPH, phospho-tau seemed adequate and better than the various combinations . The consistent finding of low CSF concentrations of Aβ (1-42) in patients with AD and idiopathic NPH, the authors noted, could strengthen the hypothesis of CSF dysfunction and decreased cerebral clearance of these peptides into CSF . Silverberg et al. already postulated that the lack of CSF production and turnover would increase the concentration of Aβ (1-42) in the interstitial fluid and thereby increase the probability of deposition in parenchymal aggregates. The aggregated Aβ (1-42) is not then available for measurement in the CSF. As regards total tau, Kapaki et al. demonstrated increased CSF concentration and noted that according to the above hypothesis, this might result from decreased CSF turnover. Phospho-tau, however, might reflect a specific neurodegenerative process, namely neurofibrillary degeneration, and could thus be a more specific marker for AD .

According to the observed decrease in the secretion rate of CSF in patients suffering from NPH, Silverberg et al. postulated that chronic increased ICP causes downregulation of CSF production. CSF is produced mainly by the choroid plexus (CP) which is located in the ventricles of the brain. The epithelial cells which cover these highly vascularised tissues form the blood–CSF barrier. Studies in animals have shown that chronically elevated CSF pressure decreases CSF production and that chronic hydrocephalus damages the choroid plexus secretory epithelium . Hochwald et al. demonstrated a decrease of the average rate of formation of CSF in hydrocephalic cats. This decrease was attributed in part to histological changes in the CP, including flattening of the secretory epithelium. Similar changes in the CP were observed in human hydrocephalus . Johnson and Johnson also described atrophy of the CP in hydrocephalic hamsters. These atrophic changes were assumed to be due to increased intraventricular pressure . As noted above, a decrease in CSF production is also found in AD . CSF production also decreases in association with age . Ageing of the CP is associated with flattening of epithelial cells and basement membrane thickening and . In AD, choroid plexuses present similar, although much more pronounced, abnormalities than those observed in ageing and .

With regard to hydrocephalus, Knuckey et al. studied the function of the CP in rats exposed to increased ICP. Results demonstrated a decrease in the ability of the CP to release chloride following hydrocephalus. This decrease in chloride efflux might reflect a decrease in the water movement by the epithelial cells and hence a decrease in CSF formation . The authors further suggested that decreased function of the CP epithelium might result from neuronal or hormonal regulation of the CP in response to raised ICP . In a recent paper, Johanson et al. proposed that ventriculomegaly and transient elevations in ICP in NPH might elicit a compensatory response in CP to downregulate CSF formation by promoting ion reabsorption via the Na–K–2Cl cotransporter isoform 1 (NKCC1). This ion-translocating protein coupled to CSF formation is highly expressed in the apical membrane of choroid plexus epithelial cells, thereby being strategically positioned to sense physical changes in CSF . Changes in pressure or volume represent potential stimuli for inducing NKCC1 in CP and . Consistent with their idea on the regulation of the CP epithelial function with ventriculomegaly and elevated ICP is the observation of enhanced expression of CP NKCC1 in congenital hydrocephalus rats with ventriculomegaly .

7. No clear link between pseudotumor cerebri and AD

In the context of the present article, the question arises as to whether there is a correlation between pseudotumor cerebri (PTC) and Alzheimer-type changes. Pseudotumor cerebri, also known as idiopathic or benign intracranial hypertension, is a condition of increased ICP in the absence of an intracranial infection, a space-occupying lesion, or hydrocephalus . The pathophysiology of this disorder is unclear. Potential mechanisms underlying PTC include increased CSF production, decreased CSF absorption, idiopathic brain swelling, and idiopathic intracranial venous hypertension . However, unrelated to the pathophysiological mechanism, this condition is associated with an elevation of ICP. Seemingly inconsistent with the idea that elevated mechanical load can contribute to AD neuropathogenesis, there is no evidence in the literature of a correlation between dementia and PTC . Although a possible link between PTC and AD was suggested by a very recent study by Peng et al. , this link was only based on increased ALZ-50 immunoreactivity in the CSF of PTC patients. The lack of clear evidence of an association between PTC and AD, however, is not inconsistent with the idea proposed in this review. With regard to PTC, it has been predicted that the parenchyma experiences no shear stresses or shear stresses which are only mild in comparison with those in hydrocephalus . Moreover, in contrast to TBI, which is known to occur from a high rate deformation of the brain tissue, PTC is not associated with rapid tissue deformation. According to these mechanical loading parameters, injury responses associated with PTC may be quite small and insufficient to contribute to AD neuropathogenesis.

8. Conclusion

Recent research findings provide evidence for AD-related changes in a number of diseases affecting central nervous system tissue, such as NPH, TBI, and glaucoma, which are characterized by elevation of ICP or IOP and/or local shear stress and strain. Recent evidence indicates that caspase activation and abnormal processing of APP, which are important events in AD, may play a role both in glaucoma and following TBI. With regard to normal pressure hydrocephalus, evidence suggests that changes in cerebrospinal fluid circulatory dynamics ultimately may result in reduced clearance of neurotoxins, such as β-amyloid peptides and tau protein, that play a role in the pathogenesis of AD. Data presented in this review could be interpreted to suggest that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to increased levels of mechanical stress, leaving open the possibilities that this may occur by facilitating production and/or by reducing clearance of neurotoxic substances such as Aβ peptides. This leads to the attractive speculation that elevated mechanical load may contribute to the development of Alzheimer-type lesions. Further studies are warranted, however, especially to elucidate the role of elevated mechanical forces in AD neuropathogenesis.

Much appreciation is expressed to Dr. Kathie Vierstraete for her very constructive comments on the manuscript, and also to Carlos Moreau and Carine Vierstraete for their expert secretarial assistance.


  1. R. Bullock and G. Hammond, Realistic expectations: the management of severe Alzheimer disease, Alzheimer Dis Assoc Disord 17 (Suppl. 3) (2003), pp. S80–S85. 
  2. D.A. Evans, H.H. Funkenstein, M.S. Albert, P.A. Scherr, N.R. Cook and M.J. Chown et al., Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported, JAMA 262 (1989), pp. 2551–2556. 
  3. D.J. Selkoe, Alzheimer's disease: genes, proteins, and therapy, Physiol Rev 81 (2001), pp. 741–766. 
  4. P.B. Gorelick, Risk factors for vascular dementia and Alzheimer disease, Stroke 35 (11 Suppl. 1) (2004), pp. 2620–2622. 
  5. A. Rocchi, S. Pellegrini, G. Siciliano and L. Murri, Causative and susceptibility genes for Alzheimer's disease: a review, Brain Res Bull 61 (2003), pp. 1–24. 
  6. B. Kahlon, G. Sundbarg and S. Rehncrona, Comparison between the lumbar infusion and CSF tap tests to predict outcome after shunt surgery in suspected normal pressure hydrocephalus, J Neurol Neurosurg Psychiatry 73 (2002), pp. 721–726. 
  7. O. Kizu, K. Yamada and T. Nishimura, Proton chemical shift imaging in normal pressure hydrocephalus, AJNR Am J Neuroradiol 22 (2001), pp. 1659–1664. 
  8. G.D. Silverberg, M. Mayo, T. Saul, E. Rubenstein and D. McGuire, Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis, Lancet Neurol 2 (2003), pp. 506–511. 
  9. R.D. Adams, C.M. Fisher, S. Hakim, R.G. Ojemann and W.H. Sweet, Symptomatic occult hydrocephalus with “normal” cerebrospinal-fluid pressure. A treatable syndrome, N Engl J Med 273 (1965), pp. 117–126. 
  10. P. Bret, J. Guyotat and J. Chazal, Is normal pressure hydrocephalus a valid concept in 2002? A reappraisal in five questions and proposal for a new designation of the syndrome as “chronic hydrocephalus”, J Neurol Neurosurg Psychiatry 73 (2002), pp. 9–12. 
  11. G.D. Silverberg, Normal pressure hydrocephalus (NPH): ischaemia, CSF stagnation or both, Brain 127 (2004), pp. 947–948. 
  12. D.N. Levine, The pathogenesis of normal pressure hydrocephalus: a theoretical analysis, Bull Math Biol 61 (1999), pp. 875–916. 
  13. D.H. Triyoso and T.A. Good, Pulsatile shear stress leads to DNA fragmentation in human SH-SY5Y neuroblastoma cell line, J Physiol 515 (1999), pp. 355–365. 
  14. K. Engelborghs, J. Verlooy, B. Van Deuren, J. Van Reempts and M. Borgers, Intracranial pressure in a modified experimental model of closed head injury, Acta Neurochir Suppl (Wien) 70 (1997), pp. 123–125. 
  15. K. Engelborghs, J. Verlooy, J. Van Reempts, B. Van Deuren, M. Van de Ven and M. Borgers, Temporal changes in intracranial pressure in a modified experimental model of closed head injury, J Neurosurg 89 (1998), pp. 796–806. 
  16. S. Fujiwara, Y. Yanagida and Y. Mizoi, Impact-induced intracranial pressure caused by an accelerated motion of the head or by skull deformation; an experimental study using physical models of the head and neck, and ones of the skull, Forensic Sci Int 43 (1989), pp. 159–169. 
  17. K. Ueno, J.W. Melvin, L. Li and J.W. Lighthall, Development of tissue level brain injury criteria by finite element analysis, J Neurotrauma 12 (1995), pp. 695–706. 
  18. L. Zhang, K.H. Yang and A.I. King, Comparison of brain responses between frontal and lateral impacts by finite element modeling, J Neurotrauma 18 (2001), pp. 21–30. 
  19. B. Morrison 3rd, H.L. Cater, C.D. Benham and L.E. Sundstrom, An in vitro model of traumatic brain injury utilising two-dimensional stretch of organotypic hippocampal slice cultures, J Neurosci Methods 150 (2006), pp. 192–201. 
  20. J. Flammer, S. Orgul, V.P. Costa, N. Orzalesi, G.K. Krieglstein and L.M. Serra et al., The impact of ocular blood flow in glaucoma, Prog Retin Eye Res 21 (2002), pp. 359–393.
  21. D.C. Engel, J.E. Slemmer, A.S. Vlug, A.I. Maas and J.T. Weber, Combined effects of mechanical and ischemic injury to cortical cells: secondary ischemia increases damage and decreases effects of neuroprotective agents, Neuropharmacology 49 (2005), pp. 985–995. 
  22. M.E. Edwards, S.S. Wang and T.A. Good, Role of viscoelastic properties of differentiated SH-SY5Y human neuroblastoma cells in cyclic shear stress injury, Biotechnol Prog 17 (2001), pp. 760–767. 
  23. M.C. LaPlaca and L.E. Thibault, An in vitro traumatic injury model to examine the response of neurons to a hydrodynamically-induced deformation, Ann Biomed Eng 25 (1997), pp. 665–677. 
  24. M.C. LaPlaca, V.M. Lee and L.E. Thibault, An in vitro model of traumatic neuronal injury: loading rate-dependent changes in acute cytosolic calcium and lactate dehydrogenase release, J Neurotrauma 14 (1997), pp. 355–368. 
  25. D.M. Geddes and R.S. Cargill 2nd, An in vitro model of neural trauma: device characterization and calcium response to mechanical stretch, J Biomech Eng 123 (2001), pp. 247–255. 
  26. D.M. Geddes, R.S. Cargill 2nd and M.C. LaPlaca, Mechanical stretch to neurons results in a strain rate and magnitude-dependent increase in plasma membrane permeability, J Neurotrauma 20 (2003), pp. 1039–1049. 
  27. D.M. Geddes, M.C. LaPlaca and R.S. Cargill 2nd, Susceptibility of hippocampal neurons to mechanically induced injury, Exp Neurol 184 (2003), pp. 420–427. 
  28. B.L. Plassman, R.J. Havlik, D.C. Steffens, M.J. Helms, T.N. Newman and D. Drosdick et al., Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias, Neurology 55 (2000), pp. 1158–1166.
  29. S. Fleminger, D.L. Oliver, S. Lovestone, S. Rabe-Hesketh and A. Giora, Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication, J Neurol Neurosurg Psychiatry 74 (2003), pp. 857–862. 
  30. K.A. Jellinger, Head injury and dementia, Curr Opin Neurol 17 (2004), pp. 719–723. 
  31. K. Horsburgh, M.O. McCarron, F. White and J.A. Nicoll, The role of apolipoprotein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models, Neurobiol Aging 21 (2000), pp. 245–255. 
  32. L. Chamelian, M. Reis and A. Feinstein, Six-month recovery from mild to moderate traumatic brain injury: the role of APOE-epsilon 4 allele, Brain 127 (2004), pp. 2621–2628. 
  33. D.I. Graham, S.M. Gentleman, A. Lynch and G.W. Roberts, Distribution of beta-amyloid protein in the brain following severe head injury, Neuropathol Appl Neurobiol 21 (1995), pp. 27–34. 
  34. G.W. Roberts, S.M. Gentleman, A. Lynch, L. Murray, M. Landon and D.I. Graham, Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease, J Neurol Neurosurg Psychiatry 57 (1994), pp. 419–425. 
  35. G.W. Roberts, S.M. Gentleman, A. Lynch and D.I. Graham, Beta A4 amyloid protein deposition in brain after head trauma, Lancet 338 (1991), pp. 1422–1423. 
  36. C. Smith, D.I. Graham, L.S. Murray and J.A. Nicoll, Tau immunohistochemistry in acute brain injury, Neuropathol Appl Neurobiol 29 (2003), pp. 496–502. 
  37. G.W. Roberts, D. Allsop and C. Bruton, The occult aftermath of boxing, J Neurol Neurosurg Psychiatry 53 (1990), pp. 373–378. 
  38. K. Uryu, H. Laurer, T. McIntosh, D. Pratico, D. Martinez and S. Leight et al., Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis, J Neurosci 22 (2002), pp. 446–454. 
  39. Y. Yoshiyama, K. Uryu, M. Higuchi, L. Longhi, R. Hoover and S. Fujimoto et al., Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model, J Neurotrauma 22 (2005), pp. 1134–1141. 
  40. A. Olsson, L. Csajbok, M. Ost, K. Hoglund, K. Nylen and L. Rosengren et al., Marked increase of beta-amyloid(1-42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury, J Neurol 251 (2004), pp. 870–876.
  41. G. Franz, R. Beer, A. Kampfl, K. Engelhardt, E. Schmutzhard and H. Ulmer et al., Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury, Neurology 60 (2003), pp. 1457–1461.
  42. X.H. Chen, R. Siman, A. Iwata, D.F. Meaney, J.Q. Trojanowski and D.H. Smith, Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma, Am J Pathol 165 (2004), pp. 357–371. 
  43. F.G. Gervais, D. Xu, G.S. Robertson, J.P. Vaillancourt, Y. Zhu and J. Huang et al., Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation, Cell 97 (1999), pp. 395–406. 
  44. C. Stadelmann, T.L. Deckwerth, A. Srinivasan, C. Bancher, W. Bruck and K. Jellinger et al., Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death, Am J Pathol 155 (1999), pp. 1459–1466. 
  45. T.T. Rohn, E. Head, W.H. Nesse, C.W. Cotman and D.H. Cribbs, Activation of caspase-8 in the Alzheimer's disease brain, Neurobiol Dis 8 (2001), pp. 1006–1016. 
  46. T.T. Rohn, E. Head, J.H. Su, A.J. Anderson, B.A. Bahr and C.W. Cotman et al., Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease, Am J Pathol 158 (2001), pp. 189–198. 
  47. J.H. Su, M. Zhao, A.J. Anderson, A. Srinivasan and C.W. Cotman, Activated caspase-3 expression in Alzheimer's and aged control brain: correlation with Alzheimer pathology, Brain Res 898 (2001), pp. 350–357.
  48. T.T. Rohn, R.A. Rissman, M.C. Davis, Y.E. Kim, C.W. Cotman and E. Head, Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain, Neurobiol Dis 11 (2002), pp. 341–354. 
  49. M.C. Gastard, J.C. Troncoso and V.E. Koliatsos, Caspase activation in the limbic cortex of subjects with early Alzheimer's disease, Ann Neurol 54 (2003), pp. 393–398. 
  50. A.G. Yakovlev and A.I. Faden, Caspase-dependent apoptotic pathways in CNS injury, Mol Neurobiol 24 (2001), pp. 131–144. 
  51. S.M. Knoblach, M. Nikolaeva, X. Huang, L. Fan, S. Krajewski and J.C. Reed et al., Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome, J Neurotrauma 19 (2002), pp. 1155–1170. 
  52. L. Harter, M. Keel, H. Hentze, M. Leist and W. Ertel, Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury, J Neuroimmunol 121 (2001), pp. 76–78. 
  53. J.R. Stone, D.O. Okonkwo, R.H. Singleton, L.K. Mutlu, G.A. Helm and J.T. Povlishock, Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury, J Neurotrauma 19 (2002), pp. 601–614. 
  54. A. Buki, D.O. Okonkwo, K.K. Wang and J.T. Povlishock, Cytochrome c release and caspase activation in traumatic axonal injury, J Neurosci 20 (2000), pp. 2825–2834. 
  55. P.G. Sullivan, J.N. Keller, W.L. Bussen and S.W. Scheff, Cytochrome c release and caspase activation after traumatic brain injury, Brain Res 949 (2002), pp. 88–96. 
  56. S.J. McKinnon, Glaucoma: ocular Alzheimer's disease?, Front Biosci 8 (2003), pp. s1140–s1156. 
  57. S.J. McKinnon, D.M. Lehman, L.A. Kerrigan-Baumrind, C.A. Merges, M.E. Pease and D.F. Kerrigan et al., Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension, Invest Ophthalmol Vis Sci 43 (2002), pp. 1077–1087. 
  58. N.Y. Barnes, L. Li, K. Yoshikawa, L.M. Schwartz, R.W. Oppenheim and C.E. Milligan, Increased production of amyloid precursor protein provides a substrate for caspase-3 in dying motoneurons, J Neurosci 18 (1998), pp. 5869–5880. 
  59. A. LeBlanc, H. Liu, C. Goodyer, C. Bergeron and J. Hammond, Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease, J Biol Chem 274 (1999), pp. 23426–23436. 
  60. L. Pellegrini, B.J. Passer, M. Tabaton, J.K. Ganjei and L. D’Adamio, Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and -8, J Biol Chem 274 (1999), pp. 21011–21016. 
  61. S.Y. Guenette, J. Chen, P.D. Jondro and R.E. Tanzi, Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein, Proc Natl Acad Sci USA 93 (1996), pp. 10832–10837. 
  62. J.P. Borg, J. Ooi, E. Levy and B. Margolis, The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein, Mol Cell Biol 16 (1996), pp. 6229–6241.
  63. B. Delatour, L. Mercken, K.H. El Hachimi, M.A. Colle, L. Pradier and C. Duyckaerts, FE65 in Alzheimer's disease: neuronal distribution and association with neurofibrillary tangles, Am J Pathol 158 (2001), pp. 1585–1591. 
  64. J.P. Borg, Y. Yang, M. De Taddeo-Borg, B. Margolis and R.S. Turner, The X11alpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secretion, J Biol Chem 273 (1998), pp. 14761–14766. 
  65. R.A. Rissman, W.W. Poon, M. Blurton-Jones, S. Oddo, R. Torp and M.P. Vitek et al., Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology, J Clin Invest 114 (2004), pp. 121–130.
  66. T.C. Gamblin, F. Chen, A. Zambrano, A. Abraha, S. Lagalwar and A.L. Guillozet et al., Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease, Proc Natl Acad Sci USA 100 (2003), pp. 10032–10037. 
  67. S. Yoneda, H. Hara, A. Hirata, M. Fukushima, Y. Inomata and H. Tanihara, Vitreous fluid levels of beta-amyloid (1-42) and tau in patients with retinal diseases, Jpn J Ophthalmol 49 (2005), pp. 106–108. 
  68. Engelborghs S, De Vreese K, Van de Casteele T, Vanderstichele H, Van Everbroeck B, Cras P, Martin JJ, Vanmechelen E, De Deyn PP. Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia. Neurobiol Aging 2007, doi:10.1016/j.neurobiolaging.2007.02.016.
  69. N.G. Tahzib, N.L. Ransom, H.A. Reitsamer and S.J. McKinnon, Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat model of glaucoma, Brain Res Bull 62 (2004), pp. 491–495.
  70. G.D. Silverberg, M. Mayo, T. Saul, J. Carvalho and D. McGuire, Novel ventriculo-peritoneal shunt in Alzheimer's disease cerebrospinal fluid biomarkers, Expert Rev Neurother 4 (2004), pp. 97–107. 
  71. R.A. Bech, G. Waldemar, F. Gjerris, L. Klinken and M. Juhler, Shunting effects in patients with idiopathic normal pressure hydrocephalus; correlation with cerebral and leptomeningeal biopsy findings, Acta Neurochir (Wien) 141 (1999), pp. 633–639. 
  72. S. Savolainen, L. Paljarvi and M. Vapalahti, Prevalence of Alzheimer's disease in patients investigated for presumed normal pressure hydrocephalus: a clinical and neuropathological study, Acta Neurochir (Wien) 141 (1999), pp. 849–853. 
  73. J. Golomb, J. Wisoff, D.C. Miller, I. Boksay, A. Kluger and H. Weiner et al., Alzheimer's disease comorbidity in normal pressure hydrocephalus: prevalence and shunt response, J Neurol Neurosurg Psychiatry 68 (2000), pp. 778–781. 
  74. G.D. Silverberg, S. Huhn, R.A. Jaffe, S.D. Chang, T. Saul and G. Heit et al., Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus, J Neurosurg 97 (2002), pp. 1271–1275. 
  75. G.D. Silverberg, E. Levinthal, E.V. Sullivan, D.A. Bloch, S.D. Chang and J. Leverenz et al., Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study, Neurology 59 (2002), pp. 1139–1145. 
  76. E.N. Kapaki, G.P. Paraskevas, N.G. Tzerakis, C. Sfagos, A. Seretis and E. Kararizou et al., Cerebrospinal fluid tau, phospho-tau 181 and beta-amyloid 1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer's disease, Eur J Neurol 14 (2007), pp. 168–173. 
  77. M. Czosnyka, Z. Czosnyka, E.A. Schmidt and S. Momjian, Cerebrospinal fluid production, J Neurosurg 99 (2003), pp. 206–207 . 
  78. G.M. Hochwald, A. Sahar, A.R. Sadik and J. Ransohoff, Cerebrospinal fluid production and histological observations in animals with experimental obstructive hydrocephalus, Exp Neurol 25 (1969), pp. 190–199. 
  79. R.T. Johnson and K.P. Johnson, Hydrocephalus following viral infection: the pathology of aqueductal stenosis developing after experimental mumps virus infection, J Neuropathol Exp Neurol 27 (1968), pp. 591–606.
  80. G.D. Silverberg, G. Heit, S. Huhn, R.A. Jaffe, S.D. Chang and H. Bronte-Stewart et al., The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type, Neurology 57 (2001), pp. 1763–1766. 
  81. C. May, J.A. Kaye, J.R. Atack, M.B. Schapiro, R.P. Friedland and S.I. Rapoport, Cerebrospinal fluid production is reduced in healthy aging, Neurology 40 (1990), pp. 500–503. 
  82. J.M. Serot, M.C. Bene, B. Foliguet and G.C. Faure, Morphological alterations of the choroid plexus in late-onset Alzheimer's disease, Acta Neuropathol (Berl) 99 (2000), pp. 105–108. 
  83. J.M. Serot, M.C. Bene and G.C. Faure, Choroid plexus, aging of the brain, and Alzheimer's disease, Front Biosci 8 (2003), pp. s515–s521. 
  84. N.W. Knuckey, J. Preston, D. Palm, M.H. Epstein and C. Johanson, Hydrocephalus decreases chloride efflux from the choroid plexus epithelium, Brain Res 618 (1993), pp. 313–317. 
  85. C. Johanson, P. McMillan, R. Tavares, A. Spangenberger, J. Duncan and G. Silverberg et al., Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease, Cerebrospinal Fluid Res 1 (2004), p. 3.
  86. G. Jiang, F. Akar, S.L. Cobbs, K. Lomashvilli, R. Lakkis and F.J. Gordon et al., Blood pressure regulates the activity and function of the Na–K–2Cl cotransporter in vascular smooth muscle, Am J Physiol Heart Circ Physiol 286 (2004), pp. H1552–H1557. 
  87. C.E. Johanson, H.C. Jones, E.G. Stopa, C. Ayala, J.A. Duncan and P.N. McMillan, Enhanced expression of the Na–K–2Cl cotransporter at different regions of the blood–CSF barrier in the perinatal H-Tx rat, Eur J Pediatr Surg 12 (Suppl. 1) (2002), pp. S47–S49. 
  88. K. Wessel, A. Thron, D. Linden, D. Petersen and J. Dichgans, Pseudotumor cerebri: clinical and neuroradiological findings, Eur Arch Psychiatry Neurol Sci 237 (1987), pp. 54–60. 
  89. J.N. Higgins, C. Cousins, B.K. Owler, N. Sarkies and J.D. Pickard, Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting, J Neurol Neurosurg Psychiatry 74 (2003), pp. 1662–1666. 
  90. G.A. Bateman, Pulse wave encephalopathy: a spectrum hypothesis incorporating Alzheimer's disease, vascular dementia and normal pressure hydrocephalus, Med Hypotheses 62 (2004), pp. 182–187.
  91. J.H. Peng, F.T. Kung, W. Peng and J.C. Parker Jr., Increased ALZ-50 immunoreactivity in CSF of pseudotumor cerebri patients, Ann Clin Lab Sci 36 (2006), pp. 151–156. 
  92. D.N. Levine, Ventricular size in pseudotumor cerebri and the theory of impaired CSF absorption, J Neurol Sci 177 (2000), pp. 85–94.


Source: Science Direct