Animals models of normal pressure hydrocephalus

Abstract

Normal Pressure Hydrocephalus (NPH) is a syndrome of dementia, gait disturbances, and urinary incontinence affecting the elderly population. Neuroimaging shows ventriculomegaly, and from the 70s to the early 90s invasive testing of intracranial pressure (ICP) and cerebrospinal fluid (CSF) dynamics supported the concept of a disturbed CSF circulation in those patients. Implantation of ventricular shunts has shown considerable symptomatic improvement in individuals; however, age-related comorbidity and coexisting dementias, such Alzheimer's disease (AD) and subcortical arteriosclerotic encephalopathy (SAE), have conflicted both clinical diagnosis of the syndrome and outcome to treatment. Moreover, a pathological continuum co-existing in the dementias of SAE, AD, and NPH has been proposed more recently, as blood flow and CSF biomarker studies as well as brain biopsies taken at the time of shunt implantation have evidenced the role of chronic ischemia and white-matter disease in NPH patients and biopsies were classified as "Probable AD" according to the Consortium to establish a registry of Alzheimer's disease (CERAD). Aging has shown to be a main risk factor to NPH, but also to AD and SAE, and as the population is aging in both the developed and developing countries, the prevalence of NPH dementia is very likely to increase. As such, research aspects aim at an understanding of the comorbidity, and how it impacts the diagnosis, pathophysiology, and the outcome of NPH. Certainly, NPH has to be seen from the multi- and transdisciplinary perspective, and experimental models are needed to model the interaction of hydrocephalus with risk factors of aging, and the coexisting dementias. The kaolin-induced hydrocephalus model allows preselection of age, manipulation of the disease progress in animals, and modeling of a chronic and long-term hydrocephalus condition, as existing in NPH. Kaolin, an inert silica derivate, creates a CSF malabsorption through scar formation, when injected into the subarachnoidal cisterns. A progressive ventricular enlargement follows a transient increase in ICP, ventricles remain enlarged while ICP normalized, similar to the human condition. Kaolin hydrocephalus induced in the aging 12-months-old rat has supported both, AD- and SAE-pathological correlates the longer the hydrocephalus existed in the animals: a mild but chronic "sublethal" ischemia has been evidenced by C-14-Jodo-Autoradiographic blood flow studies, and intracerebral and perivascular accumulation of Aβ 1-40, Aβ 1-42 peptides and hyperphosphorylated TAU proteins were observed through qualitative and quantitative histology. An age-related CSF circulatory dysfunction and reduced CSF turnover with a subsequent failure to clear Aβ 1-40, Aβ 1-42, and other toxic metabolites out from the brain interstitial fluid was therefore suggested as a common pathological element in NPH and NPH coexisting with AD and SAE. Further evidence to a common element of metabolic failure existing in those dementias was supported by significant breakdown of blood-brain-barrier (BBB) receptors in the aging Kaolin-rat, the best characterized being the low-density-lipoprotein-related protein 1 (LRP-1), which allows Aβ to escape the brain through the capillary border. With aging, Aβ LRP-1 transport is reduced by 50%. Finally, shunt treatment in Kaolin-hydrocephalus has shown that "irreversibility" in the hydrocephalic brain lies in the damage of "ischemia vulnerable" brain regions, such as the CA1 sector of the hippocampus. Changes in synaptophysin and neurofilament immunohistochemistry of CA1 have correlated with histological changes of "delayed neuronal death" and occurred early in the course of hydrocephalus. This warrants a timely shunting of patients. The studies in aging kaolin-induced hydrocephalus might allow insight into late-life disturbances in CSF circulation, CSF turnover, and BBB transport underlying several age-related dementias, including AD. This reconsiders the traditional concept of "shunts for dementia"; however, both clinical and experimental hydrocephalus research should embrace the multidisciplinary aspect as it might allow and bring further insight into the interaction of ICP, impaired CSF circulation, blood flow, and metabolic breakdown in the various dementias. © 2011 Springer Science+Business Media, LLC.