Elsevier

The Lancet Neurology

Volume 2, Issue 8, August 2003, Pages 506-511
The Lancet Neurology

Personal View
Alzheimer's disease, normal‐pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis

https://doi.org/10.1016/S1474-4422(03)00487-3Get rights and content

Summary

There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-β peptide (Aβ) from the interstitial‐fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimer's disease (AD) or as normal‐pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Aβ in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Aβ. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH–AD may cover an important subset of patients who carry the diagnosis of either AD or NPH.

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.381–42 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

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

References (63)

  • S Savolainen et al.

    Prevalence of Alzheimer's disease in patients investigated forpresumed normal pressure hydrocephalus: a clinical and neuropathological study

    ActaNeurochir(Wien)

    (1999)
  • J Golomb et al.

    Alzheimer's disease comorbidity in normal pressure hydrocephalus: prevalence and shunt response

    JNeurol Neurosurg Psychiatry

    (2000)
  • SS Mirra et al.

    The Consortium to Establish a Registry for Alzheimer's Disease (CERAD): part II–standardization of the neuropathologic assessment of Alzheimer's disease

    Neurology

    (1991)
  • JH Masserman

    Cerebrospinal fluid hydrodynamics IV: clinical experimental studies

    Arch Neurol Psychiatry

    (1934)
  • C May et al.

    Cerebrospinal fluid production is reduced in healthy aging

    Neurology

    (1990)
  • GD Silverberg et al.

    The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type

    Neurology

    (2001)
  • RW Cutler et al.

    Formation and absorption of cerebrospinal fluid in man

    Brain

    (1968)
  • RC Rubin et al.

    The production of cerebrospinal fluid in man and its modification by acetazolamide

    J Neurosurg

    (1966)
  • P Gideon et al.

    Cerebrospinal fluid production and dynamics in normal aging: a MRI phase-mapping study

    Acta Neurol Scand

    (1994)
  • RA Fishman
  • GD Silverberg et al.

    Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus

    J Neurosurg

    (2002)
  • S Shuangshoti et al.

    Human choroid plexus: morphologic and histochemical alterations with age

    Am J Anat

    (1970)
  • JE Preston

    Ageing choroid plexus-cerebrospinal fluid system

    Microsc Res Tech

    (2001)
  • JM Serot et al.

    Morphological alterations of the choroid plexus in late-onset Alzheimer's disease

    Acta Neuropathol (Berl)

    (2000)
  • C Madhavi et al.

    Light and electron microscopic structure of choroid plexus in hydrocephalic guinea pig

    Indian J Med Res

    (1995)
  • JB Mackic et al.

    Cerebro-vascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer's amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy

    J Neurochem

    (1998)
  • DA Snowdon et al.

    Brain infarction and the clinical expression of Alzheimer's disease

    JAMA

    (1997)
  • WH Oldendorf et al.

    Brain extracellular space and the sink action of cerebrospinal fluid: measurement of rabbit brain extracellular space using sucrose labeled with carbon 14

    Arch Neurol

    (1967)
  • ML Rennels et al.

    Rapid solute transport throughout the brain via paravascular fluid pathways

    Adv Neurol

    (1990)
  • C Johanson

    Ventricles and cerebrospinal fluid

  • H Davson et al.

    Symposium on membrane transport: transport in the central nervous system

    Proc R Soc Med

    (1967)
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