Buscar en
Neurología (English Edition)
Toda la web
Inicio Neurología (English Edition) Current concepts on the pathophysiology of idiopathic chronic adult hydrocephalu...
Journal Information
Vol. 33. Issue 7.
Pages 449-458 (September 2018)
Visits
1941
Vol. 33. Issue 7.
Pages 449-458 (September 2018)
Review article
DOI: 10.1016/j.nrleng.2016.03.013
Open Access
Current concepts on the pathophysiology of idiopathic chronic adult hydrocephalus: Are we facing another neurodegenerative disease?
Actualización en la fisiopatología de la hidrocefalia crónica del adulto idiopática: ¿nos enfrentamos a otra enfermedad neurodegenerativa?
Visits
...
R. Martín-Láeza,
Corresponding author
rmlaez@yahoo.es

Corresponding author.
, N. Valle-San Románb, E.M. Rodríguez-Rodríguezc, E. Marco-de Lucasb, J.A. Berciano Blancoc, A. Vázquez-Barqueroa
a Servicio de Neurocirugía, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
b Servicio de Radiología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
c Servicio de Neurología, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria IDIVAL, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Universidad de Cantabria, Santander, Cantabria, Spain
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Figures (5)
Show moreShow less
Abstract
Introduction

Since its description five decades ago, the pathophysiology of idiopathic chronic adult hydrocephalus (iCAH) has been traditionally related to the effect that ventricular dilatation exerts on the structures surrounding the ventricular system. However, altered cerebral blood flow, especially a reduction in the CSF turnover rate, are starting to be considered the main pathophysiological elements of this disease.

Development

Compression of the pyramidal tract, the frontostriatal and frontoreticular circuits, and the paraventricular fibres of the superior longitudinal fasciculus have all been reported in iCAH. At the level of the corpus callosum, gliosis replaces a number of commissural tracts. Cerebral blood flow is also altered, showing a periventricular watershed region limited by the subependymal arteries and the perforating branches of the major arteries of the anterior cerebral circulation. The CSF turnover rate is decreased by 75%, leading to the reduced clearance of neurotoxins and the interruption of neuroendocrine and paracrine signalling in the CSF.

Conclusions

iCAH presents as a complex nosological entity, in which the effects of subcortical microangiopathy and reduced CSF turnover play a key role. According to its pathophysiology, it is simpler to think of iCAH more as a neurodegenerative disease, such as Alzheimer disease or Binswanger disease than as the classical concept of hydrocephalus.

Keywords:
Cerebrospinal fluid clearance
Pathophysiology
Cerebral blood flow
Idiopathic chronic adult hydrocephalus
Cerebrospinal fluid turnover
Diffusion tractography
Resumen
Introducción

Desde la descripción hace 5 décadas de la hidrocefalia crónica del adulto idiopática (HCAi), su fisiopatología ha sido considerada básicamente relacionada con el efecto que la dilatación ventricular ejerce sobre las estructuras adyacentes al sistema ventricular. Sin embargo, las alteraciones en el flujo sanguíneo cerebral (FSC) y, sobre todo, la reducción en el recambio licuoral parecen emerger como componentes fisiopatológicos principales de esta enfermedad.

Desarrollo

En la HCAi se observa una compresión del tracto piramidal, de los circuitos cortico-subcorticales fronto-estriatales y fronto-reticulares, y de las fibras profundas del fascículo longitudinal superior. En el cuerpo calloso se objetiva un descenso en el número de fibras comisurales, que son reemplazadas por gliosis. El FSC se encuentra alterado, con un patrón de última pradera en la región subcortical adyacente a los ventrículos, correspondiente a la intersección entre las arterias subependimarias y las arterias perforantes dependientes de los grandes troncos arteriales de la circulación anterior. El recambio diario del LCR se ve disminuido en un 75%, lo que conlleva una reducción del aclaramiento de neurotóxicos y la interrupción de las señalizaciones neuroendocrinas y paracrinas que ocurren a través del LCR.

Conclusiones

La HCAi emerge como una entidad nosológica compleja, en la que los efectos de la microangiopatía subcortical y la disminución del recambio de LCR desempeñan un papel fundamental. Esta base fisiopatológica aleja la HCAi del concepto clásico de hidrocefalia y la acerca al perfil de otras enfermedades neurodegenerativas, como la enfermedad de Alzheimer o la enfermedad de Binswanger.

Palabras clave:
Aclaramiento licuoral
Fisiopatología
Flujo sanguíneo cerebral
Hidrocefalia crónica del adulto idiopática
Recambio licuoral
Tractografía por tensor de difusión
Full Text
Introduction

Idiopathic normal-pressure hydrocephalus (iNPH) is a nosological entity characterised by the clinical triad of gait disturbance, cognitive impairment, and urinary incontinence, with neuroimaging findings of ventricular dilatation (Fig. 1) and in the absence of any other cause that may explain clinical findings.

Figure 1.

Preoperative MR image of a patient with idiopathic normal-pressure hydrocephalus who responded well to ventriculoperitoneal shunting. (A) Axial T1-weighted sequence. Moderate dilatation of the lateral ventricles and the third ventricle. (B) Axial T2-weighted sequence. CSF flow artefacts in the third ventricle; absence of hyperintensity at the periventricular and subcortical levels. (C) Sagittal T1-weighted sequence. Descent of the third ventricle floor, rounding of the third ventricle, and decreased mamillopontine distance. The image shows no obstruction in the aqueduct of Sylvius that may explain ventricular dilatation. (D) Coronal FLAIR sequence. Typical pattern of effacement of convexity sulci, especially in the midline. The CSF flow signal void on the T2-weighted sequence extends towards both Monro foramina, reaching the lower and middle portions of the ventricular cavities. Absence of periventricular and subcortical hyperintensities.

(0.36MB).

Although this clinical syndrome had previously been described in the literature1–5 (particular emphasis should be placed on the descriptions made by French neurologist Etienne Mouline6 in 1819 and German pathologist Friedrich Dörner7 in 1826), it was the late Colombian neurosurgeon Salomón Hakim Dow who provided a systematic description of the clinical and radiological features of iNPH in his doctoral thesis, written over 50 years ago.8 Hakim, together with 2 renowned neurologists from the Massachusetts General Hospital, Raymond D. Adams and Charles M. Fisher, disclosed his findings in 2 articles, which were published simultaneously in the New England Journal of Medicine9 and the Journal of Neurological Sciences.10

The classic triad of symptoms has traditionally been thought to be caused by the effect of ventricular dilatation on periventricular nerves11–17 and vessels.18–25 However, recent studies also suggest an inability of the CSF to remove waste products from the extracellular fluid as a causal factor for iNPH.26–29

We provide updated information on the pathophysiology of the disease, placing special emphasis on decreased CSF turnover, a novel factor which may have an impact on long-term prognosis. These findings challenge the classic concept of hydrocephalus, suggesting that iNPH is a neurodegenerative disease.

DevelopmentCompression of periventricular subcortical fibres

Compression of the frontal projections descending close to the frontal horns of the lateral ventricles alters the function of the projections. These alterations may be completely reversible when dysfunction is caused by slowing or interruption of axonal transport at that level, or permanent in the case of demyelination or loss of axonal integrity.16,17 Different MRI techniques have increased our knowledge of the fascicles affected in patients with iNPH, including the cortical and subcortical projections of these fascicles, and help determine whether lesions are reversible. Diffusion-weighted imaging and diffusion tensor imaging (DTI) are the forms of MRI most frequently used to assess these patients. The former evaluates the presence of free interstitial water by calculating apparent diffusion coefficient (ADC) values (these values are higher in the extracellular oedema). However, axon regeneration by gliosis, which invariably occurs in the chronic phase of axonal damage, may cause an even greater increase in ADC values. DTI, including fibre tractography, is much more sensitive than ADCs for evaluating the integrity, density, and potential displacement of nerve fascicles, as it detects anisotropic changes in water molecules due to the unidirectional propagation of action potentials. Mean diffusivity (MD) may be analogous to ADC values, whereas fractional anisotropy (FA) decreases significantly when axonal disruption occurs (even in the areas where ADC maps show no significant increase of ADC coefficients or where these are normal due to the artefact generated by residual gliosis), and increases with axon density, for example as a consequence of axon compaction due to the effect of a force perpendicular to the axons’ trajectory. Consequently, an increase in ADC or MD values in the presence of normal or increased FA values suggests interstitial oedema, whereas a decrease in FA values is suggestive of axonal damage regardless of MD or ADC values.30

The most important studies conducted to date using these techniques are consistent in that increased ADC and/or MD values are observed both in the corpus callosum and in the internal capsule. FA, however, increases in the internal capsule, especially in its anterior limb, and decreases in the corpus callosum, especially at the level of the genu.11–14,31 Other findings reported in the literature include increases in FA in the caudate nucleus,11,31 increases in MD with no FA changes in the white matter associated with the precentral cortex,15 and increased axonal density in the corticospinal tract at the paraventricular level, as a consequence of compaction in the areas adjacent to the ventricle.32 In the light of these findings, we may conclude that iNPH involves compression of the pyramidal tract and the frontostriatal and frontoreticular cortico-subcortico-cortical circuits (Fig. 2), in addition to dysfunction of the deep fibres of the superior longitudinal fascicle. In the corpus callosum, decreased FA and increased ADC and/or MD values are suggestive of a reduced number of commissural fibres, which would have been replaced by gliosis.

Figure 2.

Tractography reconstruction of DTI sequences of the patient shown in the previous figure. The image shows the distortion generated by ventricular dilatation along the pyramidal tract (1) and in the corticostriatal and corticoreticular connections (3). The corticostriatal and corticoreticular tracts are considerably thinner than normal; thinning is also observed in the cingulate fasciculus (2) and, to a lesser extent, in the pyramidal tract (1).

(0.33MB).
Reduced cerebral blood flow

Multiple studies have shown reduced cerebral blood flow (CBF) in patients with iNPH, although global involvement is rather discreet, with CBF decreases ranging from 20% to 30%.18–25,33 A recent study conducted at Osaka University found patients with confirmed iNPH and those with ventricular dilatation displaying the radiological signs but no symptoms of iNPH to have lower CBF than do healthy controls.25 The literature reports conflicting results regarding the severity of clinical symptoms and its association with CBF; most studies do not show a direct relationship,18,22,25 whereas some do suggest a correlation between clinical severity and a progressive decrease in CBF.19,21,34

The mechanisms underlying CBF alterations are yet to be understood. If decreases in CBF were due only to the distortion caused by ventricular dilatation and the forces exerted on cerebral microcirculation, we may expect to observe a negative correlation between decreases in CBF and the distance to the ventricular system, with greater CBF decreases in the most internal and inferior portion of the centrum semiovale, in the thalamus, and in the head and tail of the caudate nucleus. Some recent studies have overcome the limitations of poor spatial resolution of traditional techniques for measuring CBF by co-registering H215O-PET images onto MRI images, demonstrating a CBF gradient from the periventricular region to the cortex; the relationship between changes in CBF and distance is not proportional, however.18,19 The study by Momjian et al.18 is particularly interesting: the researchers located the area of maximal CBF decrease in the subcortical white matter, 1cm from the ventricular wall, observing a 50% decrease in the cerebrovascular reserve (CVR) in that location (Fig. 3). These findings are compatible with the concept of last meadow in the subcortical region adjacent to the ventricles. This phenomenon has a coherent microanatomical basis, since the tissue closest to the ependyma is irrigated by subependymal arteries and the tissue farthest from the ependyma by perforating branches of the major arteries of the anterior circulation (Fig. 4).35,36 The area of greatest sensitivity to ischaemia is the area where both vascular territories intersect and where CBF and CVR alterations are most marked. In any case, basal ganglia alterations seem to be a constant in most clinical studies of iNPH.19,34,37

Figure 3.

Vascularisation of periventricular structures. The basal ganglia and internal capsule are located in a last meadow area (a) between the territory of the perforating branches (2) of the middle cerebral artery (1) and the branches of the subependymal arteries (5). The corpus callosum is irrigated mainly by the short callosal arteries (4) from the pericallosal artery (3), which belong to the terminal circulation.

(0.25MB).
Figure 4.

Cerebral blood flow (CBF) in the periventricular region in patients with idiopathic normal-pressure hydrocephalus. (A) The relationship between CBF and distance to the ependymal surface of the ventricle follows a logarithmic curve.18 (B) When patients experience fluid overload, CBF drops in the subependymal last meadow area, located 5-15mm from the ventricular surface.

(0.46MB).

Other studies have also detected cortical alterations which may not be explained by a merely mechanical phenomenon, given the relative distance from the ventricular system. Hypoperfusion is more marked in the anterior and inferior mesial regions of the frontal lobe than in other structures.22,34 Several studies have also described alterations in such areas as the left anterior temporal cortex,22 the hippocampus and parahippocampus,37 the frontal lobe white matter corresponding to the superior longitudinal fasciculus,34 and parietal association areas.34

Cerebrovascular involvement associated with iNPH is considerable, also affecting cerebral vasoreactivity, which is reduced as a result of exhaustion of the CVR. To evaluate the CVR, Chang et al.21 studied CBF in 167 patients diagnosed with iNPH using 99mTc-HMPAO SPECT before and after administering 1g acetazolamide. The researchers found that the CBF increased by 50%-80% less in patients with iNPH than in healthy individuals after the infusion of acetazolamide; this may reflect decreased vasoreactivity in response to increased partial pressure of CO2 in arterial blood or a significant decrease in the CVR. Fortunately, these changes are not accompanied by alterations in the metabolic coupling of the areas involved, since the cerebral metabolic rate decreases in line with decreases in CBF, and the oxygen extraction fraction remains within normal limits.38,39

Decreased CSF turnover

As occurs with the lymph in the rest of the body, CSF excretes the macromolecules present in the interstitial fluid that cannot be reabsorbed by venous capillaries. Under normal circumstances, CSF contains over 2000 different proteins, which amount to less than 4‰ of its weight.40 Reabsorption of CSF water may be unrelated to macromolecule excretion: the former takes place in the venous ends of the capillaries, whereas the latter occurs in arachnoid granulations or in extracranial lymphatic vessels. Alterations in macromolecule excretion may persist even in the case of volumetric balance in the production and absorption of CSF water (Fig. 5).

Figure 5.

Pathophysiological consequences of decreased CSF clearance: accumulation of neurotoxins and inflammatory mediators, and exposure of the neuropeptides responsible for neuroendocrine signalling to the activity of hydrolytic enzymes.

Aβ-42: 42-residue fragment of amyloid-β peptide; ACT: antichymotrypsin; APP: amyloid precursor protein; LRG: leucine-rich glycoprotein; NPY: neuropeptide Y; TGF: transforming growth factor; TNF: tumour necrosis factor; VIP: vasoactive intestinal peptide.

(0.42MB).

In patients with iNPH, the CSF production rate may drop to 0.25±0.08mL/min, which represents a decrease of over 30%.41 Furthermore, increased ventricle size results in a 30% increase in distribution volume (an increase of over 200mL in most patients). This, combined with impaired CSF reabsorption, results in a 75% decrease in the CSF turnover rate. Adaptive changes in the choroid plexus and the vascular feet of the astrocytes prevent CSF production-absorption imbalances. Aquaporin-1 expression decreases in the choroid plexus42–44 as a result of the activation of the natriuretic peptide system of the circumventricular organs and hypothalamic nuclei45,46; this results in decreased water transport in the apical membrane of the choroid epithelium and, consequently, reduced CSF production. On the other hand, aquaporin-4 expression increases in white matter astrocytes42,43,47–49 probably in order to increase CSF water reabsorption into the venous capillaries.42,50 However, increased absorption into venous capillaries may reduce periventricular interstitial fluid pressure, promoting the appearance of a pressure gradient between the interstitium and the ventricle and maintaining ventricular dilatation.51,52 There is insufficient evidence for conclusions to be drawn on how this situation affects protein clearance in patients with iNPH, although it may be hypothesised that CSF turnover involves at least 2 processes: the reduction of neurotoxin clearance and the interruption of neuroendocrine and paracrine signalling in the CSF.53

Although there is no direct evidence of decreased neurotoxin clearance in patients with iNPH, this may be observed indirectly in the results from biomarker studies and CSF proteomic analysis. Most studies report decreased concentration of the majority of metabolites of the amyloid proteolytic processing pathway, including amyloid precursor protein (APP) and amyloid-β–42 peptide (Aβ-42).54–58 Total and phosphorylated tau protein levels remain within normal ranges or are lower than normal.54,57,59 Decreased CSF turnover results in deficient APP clearance from the interstitial space: APP would therefore be processed by β-secretase and then by γ-secretase, resulting in Aβ-42 aggregation into amyloid plaques, and decreasing the concentration of these 2 components in the CSF.26–29 A study by Fagan et al.,60 including patients without dementia, provides evidence in support of this hypothesis. The researchers found that patients with cerebral amyloid deposition in 11C-PiB PET images had lower CSF Aβ-42 levels. Pyykö et al.61 confirmed these results in patients with iNPH, observing a linear, inversely proportional relationship between APP levels in brain biopsy samples and Aβ-42 concentrations in both ventricular and lumbar intrathecal CSF. Moriya et al.62 and Jeppsson et al.58 report increased Aβ-42 levels in the CSF of patients with iNPH after shunt implantation; this increase was correlated with the patients’ neurological improvements. These findings suggest that normalisation of CSF flow dynamics after shunting promotes a shift from oligomeric to monomeric Aβ as a result of increased concentration of Aβ-38, an isomer with low aggregability.62

The inflammatory profile provides additional data: an excess of acute-phase reactants in the CSF (in the absence of abnormal cellularity according to biochemical analysis or of microglial activation in the periventricular region, which may point to an inflammatory process as the cause of these findings) suggests that decreased CSF clearance is responsible for the accumulation of astrocytic proinflammatory mediators. Several studies have reported increased levels of leucine-rich α-2-glycoprotein,63,64 α-1-antichymotrypsin,63,65 haptoglobin,63 transferrin,66 α-1-β glycoprotein,65 and tumour necrosis factor α.67 Other researchers have also observed an increase in free-radical peroxidation products, which may also be associated with decreased CSF turnover.68

Li et al.69 described an increase in TGF-β–dependent signalling. Although excessive TGF-β may be partially due to deficient TGF-β clearance, this mechanism does not explain TGF-β type II receptor upregulation, another finding reported by these researchers. These findings may be explained by the presence of an adaptive mechanism in response to the increasing levels of inflammatory mediators and acute-phase reactants, since this cytokine has a protective effect, blocking inflammatory response in glial and endothelial cells.70–72

The potential impact of abnormal accumulation of these proteins is evident:

  • Reduced APP clearance promotes amyloid deposition in blood vessels and tissues, promoting the development of intercurrent neurodegenerative processes or accelerating their progression (e.g. Alzheimer disease).53

  • The diffusion of proinflammatory proteins, especially TNF-α (which promotes aggregation and cell adhesion in capillaries), in the periventricular region may alter microvascular dynamics, compounding the mechanical effect of ventricular dilatation in the periventricular region.18

  • Free radicals damage neurons, glial cells, and endothelial cells, and their effects at the molecular level have been associated with the pathophysiology of a wide range of neurological diseases; it is therefore very likely that they play a role in tissue damage in iNPH.68

  • TGF-β induces neuronal and oligodendrocytic apoptosis.73,74 Delayed programmed cell death may explain the progressive clinical deterioration frequently seen in these patients despite initially successful shunting.

Alterations in neuroendocrine signalling in the CSF constitute another possible mechanism, despite the lack of objective evidence of the existence of this neuroendocrine signalling pathway. Over 100 neuropeptides are described in the literature as potentially using CSF circulation to reach distant regions of the CNS; these neuropeptides are similar in terms of their synthesis, release, and regulation, and their functions are radically different from those of conventional neurotransmitters.75

Patients with iNPH have been found to have low CSF levels of somatostatin (SOM),76–80 vasoactive intestinal peptide (VIP),59,79,81 neuropeptide Y (NPY),59,79,80,82 cholecystokinin,83 δ sleep-inducing peptide,79,84 and corticotropin-releasing hormone.80 The interpretation of these findings is not straightforward: they may result from a nearly global dysfunction of peptidergic neurotransmission secondary to iNPH, or may reflect the action of an active mechanism by which deficient CSF turnover would result in the exposure of peptides to the action of neuropeptidases, decreasing CSF peptide levels and interrupting neurotransmission in the CSF.85,86

SOM is probably the peptide that has been studied most extensively in this context. This peptide is diffusely located throughout the brain, although it is mainly produced in the preoptic, paraventricular, arcuate, and ventromedial nuclei of the hypothalamus. In addition to its involvement in regulating the endocrine system, acting as a growth hormone–releasing hormone antagonist, SOM promotes dopaminergic transmission in the striatum and contributes to normal neuronal function in ageing.87 The latter function is linked to the proteolytic activity of neprilysin; this protease is involved in Aβ-42 catabolism and its activity induces SOM expression.88 Reduced SOM expression secondary to impaired CSF turnover may promote Aβ-42 accumulation, worsening clinical symptoms. NPY is also diffusely distributed throughout the brain, including in such areas as the amygdala, hippocampus, basal ganglia, and of course the hypothalamus, where NPY colocalises with SOM-producing neurons in the paraventricular and arcuate nuclei.87 A recent article shows that NPY balances the toxic effects of Aβ, promoting neurotrophin synthesis in cells.89 Decreased NPY levels in patients with iNPH may therefore promote neuronal loss, especially due to the synergistic effect of SOM. VIP has a similar effect: in addition to its function in vasodilation and the synthesis of neurotrophin-3 and activity-dependent neurotrophic factor in glial cells, the peptide inhibits the inflammatory response in the neuroglia, mainly by blocking the production of TNF-α and free radicals in the microglia.90

Conclusions

Compression of the periventricular subcortical fibres is not the only pathophysiological mechanism in iNPH. The characteristic, long-term clinical progression of this type of hydrocephalus may also be explained by CBF alterations in the last meadow areas between the perforating branches of the major arteries of the anterior circulation and the subependymal arteries, and by reduced CSF turnover, which leads to reduced neurotoxin clearance and altered neuroendocrine signalling in the CSF.

Conflicts of interest

The authors have no conflicts of interest to declare.

References
[1]
G.B. Morgagni.
De sedibus et causis morborum per anatomen indagatis libri quinque. Dissectiones, et animadversiones, nunc primum editas, complectuntur propemodum innumeras, medicis, chirurgis, anatomicis profuturas. Multiplex pr‘fixus est index rerum, et nominum accuratissimus.
Typographia Remondiniana, (1761),
[2]
L.A. Gölis.
Kranfengeschichte vom Wasserschlage und von der hizigen Gehirnhöhlen wassersucht.
Praktische Abhandlungen über die vorzüglicheren Krankheiten des kindlichen Alters, pp. 268-270
[3]
G. Riddoch.
Progressive dementia without headaches or changes in the optic disks due to tumors of the third ventricle.
Brain, 59 (1936), pp. 225-233
[4]
H. Roger, J. Paillas, J. Roger, J. Tamalet.
Grande hydrocéphalie latente du vieillard chez une démente artérioscléreuse.
Rev Neurol (Paris), 82 (1950), pp. 437-438
[5]
P.R. McHugh.
Occult hydrocephalus.
Q J Med, 33 (1964), pp. 297-308
[6]
E. Moulin.
Hydrocèphale passive ou chronique.
Décrite pour la premère fois, pp. 117-215
[7]
F. Dörner.
De hydrocephalo chronico senili.
University of Würzburg, (1826),
[thesis]
[8]
S. Hakim.
Algunas observaciones sobre la presión del LCR. Síndrome hidrocefálico del adulto con presión normal del LCR.
Pontificia Universidad Javeriana, (1964),
[Tésis doctoral]
[9]
R.D. Adams, C.M. Fisher, S. Hakim, R.G. Ojemann, W.H. Sweet.
Symptomatic occult hydrocephalus with normal cerebrospinal-fluid pressure, a treatable syndrome.
N Engl J Med, 273 (1965), pp. 117-126
[10]
S. Hakim, R.D. Adams.
The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. Observations on cerebrospinal fluid hydrodynamics.
J Neurol Sci, 2 (1965), pp. 307-327
[11]
S. Osuka, A. Matsushita, T. Yamamoto, K. Saotome, T. Isobe, Y. Nagatomo, et al.
Evaluation of ventriculomegaly using diffusion tensor imaging: correlations with chronic hydrocephalus and atrophy.
J Neurosurg, 112 (2010), pp. 832-839
[12]
Y. Assaf, L. Ben-Sira, S. Constantini, L.C. Chang, L. Beni-Adani.
Diffusion tensor imaging in hydrocephalus: initial experience.
AJNR Am J Neuroradiol, 27 (2006), pp. 1717-1724
[13]
E. Hattingen, A. Jurcoane, J. Melber, S. Blasel, F.E. Zanella, T. Neumann-Haefelin, et al.
Diffusion tensor imaging in patients with adult chronic idiopathic hydrocephalus.
Neurosurgery, 66 (2010), pp. 917-924
[14]
E.L. Air, W. Yuan, S.K. Holland, B.V. Jones, K. Bierbrauer, M. Altaye, et al.
Longitudinal comparison of pre- and postoperative diffusion tensor imaging parameters in young children with hydrocephalus.
J Neurosurg Pediatr, 5 (2010), pp. 385-391
[15]
N. Lenfeldt, A. Larsson, L. Nyberg, R. Birgander, A. Eklund, J. Malm.
Diffusion tensor imaging reveals supplementary lesions to frontal white matter in idiopathic normal pressure hydrocephalus.
Neurosurgery, 68 (2011), pp. 1586-1593
[16]
M.R. Del Bigio.
Neuropathology and structural changes in hydrocephalus.
Dev Disabil Res Rev, 16 (2010), pp. 16-22
[17]
M.R. Del Bigio.
Pathophysiologic consequences of hydrocephalus.
Neurosurg Clin N Am, 12 (2001), pp. 639-649
vii
[18]
S. Momjian, B.K. Owler, Z. Czosnyka, M. Czosnyka, A. Pena, J.D. Pickard.
Pattern of white matter regional cerebral blood flow and autoregulation in normal pressure hydrocephalus.
Brain, 127 (2004), pp. 965-972
[19]
B.K. Owler, S. Momjian, Z. Czosnyka, M. Czosnyka, A. Pena, N.G. Harris, et al.
Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values.
J Cereb Blood Flow Metab, 24 (2004), pp. 17-23
[20]
B.K. Owler, J.D. Pickard.
Normal pressure hydrocephalus and cerebral blood flow: a review.
Acta Neurol Scand, 104 (2001), pp. 325-342
[21]
C.C. Chang, H. Asada, T. Mimura, S. Suzuki.
A prospective study of cerebral blood flow and cerebrovascular reactivity to acetazolamide in 162 patients with idiopathic normal-pressure hydrocephalus.
J Neurosurg, 111 (2009), pp. 610-617
[22]
P.M. Klinge, D.J. Brooks, A. Samii, E. Weckesser, J. van den Hoff, H. Fricke, et al.
Correlates of local cerebral blood flow (CBF) in normal pressure hydrocephalus patients before and after shunting – a retrospective analysis of [(15)O]H(2)O PET-CBF studies in 65 patients.
Clin Neurol Neurosurg, 110 (2008), pp. 369-375
[23]
K. Mori, M. Maeda, S. Asegawa, J. Iwata.
Quantitative local cerebral blood flow change after cerebrospinal fluid removal in patients with normal pressure hydrocephalus measured by a double injection method with N-isopropyl-p-[(123)I] iodoamphetamine.
Acta Neurochir (Wien), 144 (2002), pp. 255-262
[24]
F. Hertel, C. Walter, M. Schmitt, M. Morsdorf, W. Jammers, H.P. Busch, et al.
Is a combination of Tc-SPECT or perfusion weighted magnetic resonance imaging with spinal tap test helpful in the diagnosis of normal pressure hydrocephalus?.
J Neurol Neurosurg Psychiatry, 74 (2003), pp. 479-484
[25]
M. Takaya, H. Kazui, H. Tokunaga, T. Yoshida, Y. Kito, T. Wada, et al.
Global cerebral hypoperfusion in preclinical stage of idiopathic normal pressure hydrocephalus.
J Neurol Sci, 298 (2010), pp. 35-41
[26]
G.D. Silverberg, A.A. Messier, M.C. Miller, J.T. Machan, S.S. Majmudar, E.G. Stopa, et al.
Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging.
J Neuropathol Exp Neurol, 69 (2010), pp. 1034-1043
[27]
G.D. Silverberg, M.C. Miller, J.T. Machan, C.E. Johanson, I.N. Caralopoulos, C.L. Pascale, et al.
Amyloid and Tau accumulate in the brains of aged hydrocephalic rats.
Brain Res, 1317 (2010), pp. 286-296
[28]
G.D. Silverberg, M.C. Miller, A.A. Messier, S. Majmudar, J.T. Machan, J.E. Donahue, et al.
Amyloid deposition and influx transporter expression at the blood–brain barrier increase in normal aging.
J Neuropathol Exp Neurol, 69 (2010), pp. 98-108
[29]
Y. Nonaka, M. Miyajima, I. Ogino, M. Nakajima, H. Arai.
Analysis of neuronal cell death in the cerebral cortex of H-Tx rats with compensated hydrocephalus.
J Neurosurg Pediatr, 1 (2008), pp. 68-74
[30]
P. Hagmann, L. Jonasson, P. Maeder, J.P. Thiran, V.J. Wedeen, R. Meuli.
Understanding diffusion MR imaging techniques: from scalar diffusion-weighted imaging to diffusion tensor imaging and beyond.
Radiographics, 26 (2006), pp. S205-S223
[31]
S. Osuka, A. Matsumura, E. Ishikawa, A. Matsushita.
Diffusion tensor imaging in patients with adult chronic idiopathic hydrocephalus.
Neurosurgery, 67 (2010), pp. E1474
[32]
K. Kamiya, M. Hori, M. Miyajima, M. Nakajima, Y. Suzuki, K. Kamagata, et al.
Axon diameter and intra-axonal volume fraction of the corticospinal tract in idiopathic normal pressure hydrocephalus measured by q-space imaging.
[33]
H.L. Mamo, P.C. Meric, J.C. Ponsin, A.C. Rey, A.G. Luft, J.A. Seylaz.
Cerebral blood flow in normal pressure hydrocephalus.
Stroke, 18 (1987), pp. 1074-1080
[34]
M. Mataro, M.A. Poca, P. Salgado-Pineda, J. Castell-Conesa, J. Sahuquillo, M.J. Diez-Castro, et al.
Postsurgical cerebral perfusion changes in idiopathic normal pressure hydrocephalus: a statistical parametric mapping study of SPECT images.
J Nucl Med, 44 (2003), pp. 1884-1889
[35]
S. Marinkovic, H. Gibo, B. Filipovic, V. Dulejic, I. Piscevic.
Microanatomy of the subependymal arteries of the lateral ventricle.
Surg Neurol, 63 (2005), pp. 451-458
[36]
S. Marinkovic, H. Gibo, M. Milisavljevic, V. Djulejic, V.T. Jovanovic.
Microanatomy of the intrachoroidal vasculature of the lateral ventricle.
Neurosurgery, 57 (2005), pp. 22-36
[37]
E. Küstermann, M. Ebke, K. Dolge, G. Schwendemann, D. Leibfritz, M. Herrmann.
Neural correlates of movement disorders in normal pressure hydrocephalus.
Topics in advance imaging, pp. 171-174
[38]
J. Miyamoto, Y. Imahori, K. Mineura.
Cerebral oxygen metabolism in idiopathic-normal pressure hydrocephalus.
Neurol Res, 29 (2007), pp. 830-834
[39]
J. Miyamoto, K. Tatsuzawa, Y. Inoue, Y. Imahori, K. Mineura.
Oxygen metabolism changes in patients with idiopathic normal pressure hydrocephalus before and after shunting operation.
Acta Neurol Scand, 116 (2007), pp. 137-143
[40]
J. Xu, J. Chen, E.R. Peskind, J. Jin, J. Eng, C. Pan, et al.
Characterization of proteome of human cerebrospinal fluid.
Int Rev Neurobiol, 73 (2006), pp. 29-98
[41]
G.D. Silverberg, S. Huhn, R.A. Jaffe, S.D. Chang, T. Saul, G. Heit, et al.
Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus.
J Neurosurg, 97 (2002), pp. 1271-1275
[42]
A.S. Filippidis, M.Y. Kalani, H.L. Rekate.
Hydrocephalus and aquaporins: lessons learned from the bench.
Childs Nerv Syst, 27 (2011), pp. 27-33
[43]
L. Paul, M. Madan, M. Rammling, S. Chigurupati, S.L. Chan, J.V. Pattisapu.
Expression of aquaporin 1 and 4 in a congenital hydrocephalus rat model.
Neurosurgery, 68 (2011), pp. 462-473
[44]
K. Oshio, H. Watanabe, Y. Song, A.S. Verkman, G.T. Manley.
Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1.
FASEB J, 19 (2005), pp. 76-78
[45]
C.E. Johanson, J.E. Donahue, A. Spangenberger, E.G. Stopa, J.A. Duncan, H.S. Sharma.
Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation.
Acta Neurochir Suppl, 96 (2006), pp. 451-456
[46]
J.E. Preston, P.N. McMillan, E.G. Stopa, J.R. Nashold, J.A. Duncan, C.E. Johanson.
Atrial natriuretic peptide induction of dark epithelial cells in choroid plexus: consistency with the model of CSF downregulation in hydrocephalus.
Eur J Pediatr Surg, 13 (2003), pp. S40-S42
[47]
A.D. Skjolding, I.J. Rowland, L.V. Sogaard, J. Praetorius, M. Penkowa, M. Juhler.
Hydrocephalus induces dynamic spatiotemporal regulation of aquaporin-4 expression in the rat brain.
Cerebrospinal Fluid Res, 7 (2010), pp. 20
[48]
A.D. Skjolding, A.V. Holst, H. Broholm, H. Laursen, M. Juhler.
Differences in distribution and regulation of astrocytic aquaporin-4 in human and rat hydrocephalic brain.
Neuropathol Appl Neurobiol, 39 (2013), pp. 179-191
[49]
B.K. Owler, T. Pitham, D. Wang.
Aquaporins: relevance to cerebrospinal fluid physiology and therapeutic potential in hydrocephalus.
Cerebrospinal Fluid Res, 7 (2010), pp. 15
[50]
T. Tourdias, I. Dragonu, Y. Fushimi, M.S. Deloire, C. Boiziau, B. Brochet, et al.
Aquaporin 4 correlates with apparent diffusion coefficient and hydrocephalus severity in the rat brain: a combined MRI-histological study.
Neuroimage, 47 (2009), pp. 659-666
[51]
K.P. Wilkie, G. Nagra, M. Johnston.
A mathematical analysis of physiological and molecular mechanisms that modulate pressure gradients and facilitate ventricular expansion in hydrocephalus.
Int J Numer Anal Model B, 316 (2012), pp. 65-81
[52]
A. Pena, N.G. Harris, M.D. Bolton, M. Czosnyka, J.D. Pickard.
Communicating hydrocephalus: the biomechanics of progressive ventricular enlargement revisited.
Acta Neurochir Suppl, 81 (2002), pp. 59-63
[53]
G.D. Silverberg, M. Mayo, T. Saul, E. Rubenstein, D. McGuire.
Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis.
Lancet Neurol, 2 (2003), pp. 506-511
[54]
A. Agren-Wilsson, A. Lekman, W. Sjoberg, L. Rosengren, K. Blennow, A.T. Bergenheim, et al.
CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus.
Acta Neurol Scand, 116 (2007), pp. 333-339
[55]
A. Tarnaris, A.K. Toma, E. Pullen, M.D. Chapman, A. Petzold, L. Cipolotti, et al.
Cognitive, biochemical, and imaging profile of patients suffering from idiopathic normal pressure hydrocephalus.
Alzheimers Dement, 7 (2011), pp. 501-508
[56]
B. Ray, P.F. Reyes, D.K. Lahiri.
Biochemical studies in normal pressure hydrocephalus (NPH) patients: change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Abeta) peptide and phospho-tau.
J Psychiatr Res, 45 (2011), pp. 539-547
[57]
H. Lins, I. Wichart, C. Bancher, C.W. Wallesch, K.A. Jellinger, N. Rosler.
Immunoreactivities of amyloid beta peptide ([1-42]) and total tau protein in lumbar cerebrospinal fluid of patients with normal pressure hydrocephalus.
J Neural Transm, 111 (2004), pp. 273-280
[58]
A. Jeppsson, H. Zetterberg, K. Blennow, C. Wikkelso.
Idiopathic normal-pressure hydrocephalus: Pathophysiology and diagnosis by CSF biomarkers.
Neurology, 80 (2013), pp. 1385-1392
[59]
M. Tullberg, K. Blennow, J.E. Mansson, P. Fredman, M. Tisell, C. Wikkelso.
Cerebrospinal fluid markers before and after shunting in patients with secondary and idiopathic normal pressure hydrocephalus.
Cerebrospinal Fluid Res, 5 (2008), pp. 9
[60]
A.M. Fagan, M.A. Mintun, A.R. Shah, P. Aldea, C.M. Roe, R.H. Mach, et al.
Cerebrospinal fluid tau and ptau (181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease.
EMBO Mol Med, 1 (2009), pp. 371-380
[61]
O.T. Pyykko, M. Lumela, J. Rummukainen, O. Nerg, T.T. Seppala, S.K. Herukka, et al.
Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus.
[62]
M. Moriya, M. Miyajima, M. Nakajima, I. Ogino, H. Arai.
Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade.
PLoS ONE, 10 (2015), pp. e0119973
[63]
X. Li, M. Miyajima, R. Mineki, H. Taka, K. Murayama, H. Arai.
Analysis of potential diagnostic biomarkers in cerebrospinal fluid of idiopathic normal pressure hydrocephalus by proteomics.
Acta Neurochir (Wien), 148 (2006), pp. 859-864
[64]
M. Nakajima, M. Miyajima, I. Ogino, M. Watanabe, H. Miyata, K.L. Karagiozov, et al.
Leucine-rich alpha-2-glycoprotein is a marker for idiopathic normal pressure hydrocephalus.
Acta Neurochir (Wien), 153 (2011), pp. 1339-1346
[65]
A. Scollato, A. Terreni, A. Caldini, B. Salvadori, P. Gallina, S. Francese, et al.
CSF proteomic analysis in patients with normal pressure hydrocephalus selected for the shunt: CSF biomarkers of response to surgical treatment.
Neurol Sci, 31 (2010), pp. 283-291
[66]
S. Futakawa, K. Nara, M. Miyajima, A. Kuno, H. Ito, H. Kaji, et al.
A unique N-glycan on human transferrin in CSF: A possible biomarker for iNPH.
Neurobiol Aging, 33 (2012), pp. 1807-1815
[67]
E. Tarkowski, M. Tullberg, P. Fredman, C. Wikkelso.
Normal pressure hydrocephalus triggers intrathecal production of TNF-alpha.
Neurobiol Aging, 24 (2003), pp. 707-714
[68]
E. Fersten, W. Gordon-Krajcer, M. Glowacki, B. Mroziak, J. Jurkiewicz, Z. Czernicki.
Cerebrospinal fluid free-radical peroxidation products and cognitive functioning patterns differentiate varieties of normal pressure hydrocephalus.
Folia Neuropathol, 42 (2004), pp. 133-140
[69]
X. Li, M. Miyajima, C. Jiang, H. Arai.
Expression of TGF-betas and TGF-beta type ii receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus.
Neurosci Lett, 413 (2007), pp. 141-144
[70]
C.E. Finch, N.J. Laping, T.E. Morgan, N.R. Nichols.
Pasinetti GM. TGF-beta 1 is an organizer of responses to neurodegeneration.
J Cell Biochem, 53 (1993), pp. 314-322
[71]
I. Tesseur, T. Wyss-Coray.
A role for TGF-beta signaling in neurodegeneration: Evidence from genetically engineered models.
Curr Alzheimer Res, 3 (2006), pp. 505-513
[72]
I. Tesseur, K. Zou, L. Esposito, F. Bard, E. Berber, J.V. Can, et al.
Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology.
J Clin Invest, 116 (2006), pp. 3060-3069
[73]
P. Salins, Y. He, K. Olson, G. Glazner, T. Kashour, F. Amara.
TGF-beta1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis.
Neurosci Lett, 430 (2008), pp. 81-86
[74]
N. Schuster, H. Bender, O.G. Rossler, A. Philippi, N. Dunker, G. Thiel, et al.
Transforming growth factor-beta and tumor necrosis factor-alpha cooperate to induce apoptosis in the oligodendroglial cell line OLI-neu.
J Neurosci Res, 73 (2003), pp. 324-333
[75]
D.N. Irani.
Propierties and composition of normal cerebrospinal fluid.
Cerebrospinal fluid in clinical practice, pp. 69-89
[76]
A. Molins, R. Catalan, J. Sahuquillo, J.M. Castellanos, A. Codina, R. Galard.
Somatostatin cerebrospinal fluid levels in dementia.
J Neurol, 238 (1991), pp. 168-170
[77]
H. Cramer, D. Schaudt, K. Rissler, D. Strubel, J.M. Warter, F. Kuntzmann.
Somatostatin-like immunoreactivity and substance-P-like immunoreactivity in the CSF of patients with senile dementia of Alzheimer type, multi-infarct syndrome and communicating hydrocephalus.
J Neurol, 232 (1985), pp. 346-351
[78]
K. Rissler, H. Cramer, D. Schaudt, D. Strubel, W.F. Gattaz.
Molecular size distribution of somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with degenerative brain disease.
Neurosci Res, 3 (1986), pp. 213-225
[79]
C. Wikkelso, R. Ekman, I. Westergren, B. Johansson.
Neuropeptides in cerebrospinal fluid in normal-pressure hydrocephalus and dementia.
Eur Neurol, 31 (1991), pp. 88-93
[80]
M.A. Poca, M. Mataro, J. Sahuquillo, R. Catalan, J. Ibanez, R. Galard.
Shunt related changes in somatostatin, neuropeptide Y, and corticotropin releasing factor concentrations in patients with normal pressure hydrocephalus.
J Neurol Neurosurg Psychiatry, 70 (2001), pp. 298-304
[81]
C. Wikkelso, J. Fahrenkrug, C. Blomstrand, B.B. Johansson.
Dementia of different etiologies: vasoactive intestinal polypeptide in CSF.
Neurology, 35 (1985), pp. 592-595
[82]
R. Catalan, J. Sahuquillo, M.A. Poca, A. Molins, J.M. Castellanos, R. Galard.
Neuropeptide Y cerebrospinal fluid levels in patients with normal pressure hydrocephalus syndrome.
Biol Psychiatry, 36 (1994), pp. 61-63
[83]
R. Galard, M.A. Poca, R. Catalan, M. Tintore, J.M. Castellanos, J. Sahuquillo.
Decreased cholecystokinin levels in cerebrospinal fluid of patients with adult chronic hydrocephalus syndrome.
Biol Psychiatry, 41 (1997), pp. 804-809
[84]
A. Ernst, H. Cramer, D. Strubel, F. Kuntzmann, G.A. Schoenenberger.
Comparison of DSIP- (delta sleep-inducing peptide) and P-DSIP-like (phosphorylated) immunoreactivity in cerebrospinal fluid of patients with senile dementia of Alzheimer type, multi-infarct syndrome, communicating hydrocephalus and Parkinson's disease.
J Neurol, 235 (1987), pp. 16-21
[85]
S.M. Waters, T.P. Davis.
Alterations of peptide metabolism and neuropeptidase activity in senile dementia of the Alzheimer's type.
Ann N Y Acad Sci, 814 (1997), pp. 30-39
[86]
T. Saito, Y. Takaki, N. Iwata, J. Trojanowski, T.C. Saido.
Alzheimer's disease, neuropeptides, neuropeptidase, and amyloid-beta peptide metabolism.
Sci Aging Knowledge Environ, 2003 (2003), pp. PE1
[87]
T.D. Geracioti, J.R. Strawn, N.N. Ekhator, M. Wortman, J. Kasckow.
Neuroregulatory peptides of central nervous system origin: from laboratory to clinic.
Hormones, brain and behavior, pp. 2541-2596
[88]
T. Saito, N. Iwata, S. Tsubuki, Y. Takaki, J. Takano, S.M. Huang, et al.
Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.
Nat Med, 11 (2005), pp. 434-439
[89]
N. Croce, V. Dinallo, V. Ricci, G. Federici, C. Caltagirone, S. Bernardini, et al.
Neuroprotective effect of neuropeptide Y against beta-amyloid 25-35 toxicity in SH-SY5Y neuroblastoma cells is associated with increased neurotrophin production.
Neurodegener Dis, 8 (2011), pp. 300-309
[90]
A.S.P. Dedja, J.Z. Nowak.
Neuroprotective potencial of three peptides: PACAP, VIP and PHI.
Pharmacol Rep, 57 (2005), pp. 307-320

Please cite this article as: Martín-Láez R, Valle-San Román N, Rodríguez-Rodríguez EM, Marco-de Lucas E, Berciano Blanco JA, Vázquez-Barquero A. Actualización en la fisiopatología de la hidrocefalia crónica del adulto idiopática: ¿nos enfrentamos a otra enfermedad neurodegenerativa? Neurología. 2018;33:449–458.

Copyright © 2016. Sociedad Española de Neurología
Article options
Tools
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos

es en pt
Política de cookies Cookies policy Política de cookies
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.