Data for this personal view were generated by the authors in their published studies of CSF dynamics in ageing and in the dementias associated with AD and NPH. Other publications cited in support of this hypothesis were identified by searches of Medline (1980–2003) with the search terms “Alzheimer's disease”, “normal pressure hydrocephalus”, and “cerebrospinal fluid production, turnover and clearance”. Articles were also identified through searches of the extensive files of the authors on
Personal ViewAlzheimer's disease, normal‐pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis
Section snippets
CSF physiology
Functions of the CSF include buoyancy, acid‐base buffering, and delivery of electrolytes, signalling molecules, transport molecules, and micronutrients to the brain parenchyma. We concentrate here on CSF production, turnover, and clearance.
Clinical syndrome
NPH is a common form of adult-onset, chronic hydrocephalus characterised by a triad of signs and symptoms: apractic (“magnetic”) gait, urinary incontinence, and dementia. All three are present at diagnosis only in a minority of cases. CSF pressure is typically within the normal range when measured by lumbar puncture; hence the term normal‐pressure hydrocephalus.28 However, studies with long‐duration recordings of CSF pressure and infusion tests have shown significantly altered CSF dynamics in
Pathogenesis
Age is unequivocally the most important risk factor for development of non‐familial (sporadic) AD. Age‐related impairment of the CSF circulation, along with genetic factors such as apolipoprotein E4, may lead to accumulation of neurotoxins, such as Aβ and MAP-τ, that have roles in the pathogenesis of AD.18, 37 An increase in the steady‐state cerebral concentration of Aβ (particularly of Aβ1–42 derived from processing of amyloid precursor protein), has a causal role in AD.38 Aβ1–42 aggregates
Interpretation of the data
The available data presented above are consistent with the prevailing concept that the pathological changes associated with AD are due to an increase in the steady‐state concentration of Aβ in the interstitial‐fluid space of the brain, and that this increase is caused by an inability of the ageing brain to clear Aβ.38 In NPH, Aβ accumulation in arachnoid membranes, including arachnoid granulations, could substantially increase resistance to absorption, resulting in reduced CSF clearance of
Potential drug inhibition of CSF production
If the underlying pathophysiology of the dementia in both AD and NPH is, at least partly, an inability to clear toxins from the CSF, approaches to optimise or restore CSF circulation are reasonable. Physicians must consider, for example, the effects of drugs on CSF production. Various drugs commonly prescribed to elderly people decrease CSF production.11, 49 Although each drug may have only a small effect individually, the effect of a daily dose of a cardiac glycoside, a diuretic, and a
Search strategy and selection criteria
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