Abstract
Idiopathic normal pressure hydrocephalus (iNPH), the most common type of adult‐onset hydrocephalus, is a potentially reversible neuropsychiatric entity characterized by dilated ventricles, cognitive deficit, gait apraxia, and urinary incontinence. Despite its relatively typical imaging features and clinical symptoms, the pathogenesis and pathophysiology of iNPH remain unclear. In this review, we summarize current pathogenetic conceptions of iNPH and its pathophysiological features that lead to neurological deficits. The common consensus is that ventriculomegaly resulting from cerebrospinal fluid (CSF) dynamics could initiate a vicious cycle of neurological damages in iNPH. Pathophysiological factors including hypoperfusion, glymphatic impairment, disturbance of metabolism, astrogliosis, neuroinflammation, and blood‐brain barrier disruption jointly cause white matter and gray matter lesions, and eventually lead to various iNPH symptoms. Also, we review the current treatment options and discuss the prospective treatment strategies for iNPH. CSF diversion with ventriculoperitoneal or lumboperitonealshunts remains as the standard therapy, while its complications prompt attempts to refine shunt insertion and develop new therapeutic procedures. Recent progress on advanced biomaterials and improved understanding of pathogenesis offers new avenues to treat iNPH.
Keywords: cerebrospinal fluid dynamics, idiopathic normal pressure hydrocephalus, pathogenesis, pathophysiology
In this review, we summarized the pathogenesis of idiopathic normal pressure hydrocephalus (iNPH) and its pathophysiological features that lead to neurological deficits. We also reviewed the current treatment strategies for iNPH and discussed prospective future therapies.
1. INTRODUCTION
First defined in 1965, idiopathic normal pressure hydrocephalus (iNPH)is a surgically reversible neurological disorder in adults. It is characterized by dementia, gait disturbance, and urinary incontinence (known as Hakim's triad). 1 , 2 INPH is not a rare clinical entity. The prevalence of iNPH has been estimated to be 10 per 100 000 to 22 per 100 000 overall, with 1.30% in those aged ≥65 years and 5.9% in those aged ≥80 years. 3 , 4 One of the core features of iNPH is that the cerebrospinal fluid (CSF) pressure of an iNPH patient is within normal ranges. 2 Typical brain imaging of iNPH displays ventriculomegaly, periventricular hyperintensities, wide Sylvian fissures, narrowed subarachnoid space, and cortical sulci at the high convexity. 5 In contrast to the secondary normal pressure hydrocephalus with known etiology, the exact cause of iNPH is unknown. 6 Its specific pathogenesis also remains elusive, although several mechanisms have been proposed to contribute to the development of iNPH. 7 Treatment of ventricular shunting, mostly the ventriculoperitoneal shunting, was proved to be successful in alleviating symptoms in approximately 60%‐80% patients. 8 , 9 This review updates on the pathogenesis and pathophysiology of iNPH, including abnormal CSF dynamics and neurological deficits, and recent advances in the treatment strategies for iNPH.
2. METHODS
We searched Medline/PubMed database for the relevant literature using the using the Medical Subject Headings (MeSH) terms “Hydrocephalus, Normal Pressure,” and following keywords “pathogenesis,” “pathophysiology”. The titles and abstracts were reviewed. And 78 articles pertaining to the INPH were included. Non‐English language articles; gray literature publications; editorials and commentaries were excluded. Additional references were obtained from bibliography of selected articles.
3. ABNORMAL CSF
In the physiological condition, CSF flow has both bulk and pulsatile components. Driven by the continuous production of CSF, the CSF bulk flow moves from lateral ventricles to the third ventricle through the interventricular foramen. It continues to flow across the aqueduct of Sylvius down to the fourth ventricle. Further, through the foramen of Magendie and foramen of Luschka, CSF flows to the subarachnoid space where it is reabsorbed into blood circulation. 10 On the contrary, CSF pulsatile flow is driven by arterial pulsatility and intracranial blood inflow. It is most prominent in the aqueduct of Sylvius, representing a rapid CSF oscillation. 11 Closely regulated by cardiovascular pulsation, CSF pulsatile flow moves through aqueduct from the third ventricle to the fourth ventricle during systole and flows backward during the diastole. 12
Abnormal CSF dynamics has been a major research focus in the etiology of iNPH. 11 It was believed to be the initiating factor that contributes to the subsequent ventriculomegaly and neurological deficits in iNPH. 6 , 13 Mechanisms concerning the disturbance of CSF pulsatility and normal CSF drainage have been proposed.
3.1. Increased CSF pulsatility
It has long been observed on MRI images of iNPH patients that the aqueduct flow voids might be an indicator of hyperdynamic CSF flow through the aqueduct. 5 Later application of phase‐contrast (PC)‐MRI enables the observation and quantitation of CSF flow within a cardiac cycle without the injection of tracers. 14 Using PC‐MRI, the measurement of aqueduct stroke volume (ASV), which is defined as the average of flow volume through the aqueduct during diastole and systole, may represent the CSF pulsatility. 15 , 16 There are various PC‐MRI studies showing increased ASV in iNPH patients compared to healthy controls. 17 , 18 , 19 , 20 Luetmer et al 21 demonstrated that elevation of ASV assisted the diagnosis of iNPH and distinguished iNPH from other types of dementia. In a serial PC‐MRI study, Scollato et al 22 found a progressive increase of ASV for 18 to 20 months along with the progression of iNPH symptoms. Also, comparison between shunt responders and shunt non‐responders revealed that patients with higher ASV may benefit more from shunting operation. 22 Similarly, other flow‐related parameters such as CSF velocity, pressure gradient, and rotation also significantly elevated in iNPH patients, demonstrating a hyperdynamic state of CSF motion. 11 , 20 , 23 , 24 Increased CSF pulsatility may associate with reduced arterial pulsatility and decreased intracranial compliance. 19 , 25 , 26 , 27 The aqueduct pulsatility reflects capillary expansion, which is mainly influenced by the pulsatile dampening from the artery according to the Windkessel mechanism. 13 , 28 In the aging process, the loss of arterial pulsatility due to atherosclerosis would significantly increase the pulsatility of aqueduct. 25 In the meantime, intracranial compliance decreases with aging and neurodegeneration, which would restrict the CSF motion in rigid CSF places including subarachnoid space and convexity. 29 , 30 , 31 As a result, the pressure gradient elevated evidently in the aqueduct, turning the CSF flow into a hyperdynamic state. 20 Intriguingly, the direction of hyperdynamic CSF flow is frequently reversed, which tends to flow into the ventricles. 32 Yin et al studied the CSF flow separately in the systole and diastole phase and found that the increased pulsatile flow though the aqueduct in two phases was not equally matched. The rise of CSF flow in diastole phase exceeds that of systole phase, causing a reversed aqueductal CSF net flow in the direction of caudal‐cranial. 18 The retrograde aqueductal flow could generate a sustained pressure gradient, leading to compressive stress and shearing forces to the ependyma. It may further contribute to the dilation of ventricles, which is a core anatomical feature of iNPH. 5 , 20 Indeed, the causal relationship between ASV and ventricular volume has been confirmed. 33
3.2. Reduced CSF drainage
To fully understand the role of abnormal CSF dynamics in the pathogenesis of iNPH, the concept of abnormal CSF drainage should not be overlooked. It has long been acknowledged that in the normal condition, the CSF in the subarachnoid space is reabsorbed through the arachnoid granulations and taken up into the superior sagittal sinus due to the pressure gradientforce. 30 , 34 Recent reports demonstrated that a considerable proportion of CSF could be drained into cervical lymphatic systems. 30 The disturbance of normal CSF drainage is observed in patients with iNPH. In these patients, the resistance to CSF outflow (Rout) is pathologically elevated and has been widely used for the diagnosis of iNPH and the selection of candidates for shunting surgery. 35 Boon et al 36 showed that over 83% iNPH patients had the Rout over 12 mm Hg/mL/min, while the values of healthy controls never exceed 10 mm Hg/mL/min. A meta‐analysis revealed that a Rout of 12 mm Hg/mL/min is a suitable threshold for predicting shunt responsiveness. 37
Studies about abnormal CSF drainage in iNPH mostly focus on the venous‐related route. Bateman et al 38 compared the venous outflow volumes between iNPH patients and age‐matched controls. The results reveal significantly reduced venous outflow in iNPH. The authors further showed that this reduction was due to sinuses stenosis and subsequent elevation in venous pressure in iNPH patients. 39 It is reported that 3‐4 mm Hg rise of sagittal sinus pressure could cease the CSF absorption via the granulations. 40 The retrograde jugular venous flow found in iNPH could induce transmission of high venous pressure, possibly leading to lower flow velocity at the superior sagittal sinus. 41 Furthermore, abnormal activation of transependymal CSF absorption in perivascular white matter (PVWM) may serve as a parallel pathway to compensate the resistance of CSF outflow, which may contribute to periventricular white matter hyperintensities. 6 , 13 The CSF outflow channels (eg, subarachnoid space and veins) and conductivity are major contributing factors of the CSF outflow resistance. 42 As aforementioned, aging has a significant influence on the intracranial compliance. 23 Intracranial compliance gradually reduces with the progress of aging, resulting in more rigid CSF circulatory channels and the elevation of venous pressure. Therefore, it is conceivable that the Rout increases with aging. 43 Lack of sufficient CSF absorption caused by outflow resistance could lead to the accumulation of CSF, and further facilitate the ventricular dilatation driven by high CSF pulsatility. Meanwhile, elevated venous pressure also reduces intracranial compliance and has considerable influence on the CSF hyperdynamics. 44
4. HYPOPERFUSION LEADS TO NEUROPHYSIOLOGICAL CHANGES IN iNPH
Ventricular enlargement induced by abnormal CSF dynamics increases mechanical stress on the parenchyma and blood vessels, causing hypoperfusion and consequent hypoxia in iNPH.
Multiple imaging modalities including MRI, computed tomography, single photon emission computed tomography, or positron emission tomography (PET) indicate both global and regional CBF reduction in the PVWM, gray matter, and basal ganglia in iNPH patients. 45 , 46 , 47 , 48 Such reduced CBF in different regions might account for different symptoms of iNPH. For example, it is reported that CBF reduction in the basal ganglia correlated with the severity of gait abnormality. 49 Right frontal hypoperfusion closely related with urinary dysfunction. 50
Hypoperfusion could further leads to a series of pathophysiological changes of brain tissue including alterations of metabolism, gliosis, neuroinflammation, and blood‐brain barrier impairments.
4.1. Alterations of metabolism
It is generally acknowledged that hypoperfusion and hypoxia could disturb the normal cellular homeostasis, especially the oxygen‐related energy metabolism. 51 , 52 Attention has been payed to the metabolic alterations in iNPH. 53 , 54 , 55 It is found using PET imaging that not only the regional cerebral metabolic rate of oxygen, but also the overall glucose metabolism declined significantly in the basal ganglia. 47 , 56 As the basal ganglia plays a key role in voluntary motor control and gait regulation, it is speculated that decreased oxygen metabolism and glucose utilization contribute to the gait disturbance in iNPH. 47 , 56 Lactate, the end product of anaerobic metabolism, is a sensitive marker of hypoperfusion and hypoxia. 53 Pathologically high lactate values could be observed in CSF samples from iNPH patient, 53 which was in line with a study showing that lactate accumulated within the ventricular system after the reduction of periventricular CBF. 55 However, magnetic resonance spectroscopy did not show any difference in the level of lactate between iNPH patients and controls. 54 These conflicting results may be attributed to different detecting methods or heterogenous patient groups.
Some metabolites that have been analyzed in iNPH could serve as valuable biomarkers. In iNPH patients, the value of N‐acetylaspartate (NAA)/creatine was correlated with the MMSE score, and concentrations of NAA and total N‐acetylaspartate (tNA) were significantly declined in thalamus compared to healthy controls. 54 Metabolic changes could also predict prognosis after shunt surgery in iNPH. For example, increased total choline level and decreased myo‐inositol level in the frontal deep white matter indicate clinical improvement in iNPH patients. 57
4.2. Astrogliosis and neuroinflammation
Astrogliosis is evident in iNPH patients. GFAP (glial fibrillary acidic protein) is commonly used as a marker for reactive astrocytes. 58 Larger GFAP‐stained areas have been observed in the brain tissue specimens collected from iNPH patients compared to those from healthy controls. 58 , 59 GFAP levels also elevated in the CSF samples from iNPH patients. 55 Astrogliosis may worsen the abnormal CSF dynamics by increasing parenchymal stiffness and decreasing the compliance of the brain. 60 , 61
Neuroinflammatory responses, which are characterized by the release of inflammatory mediators, such as cytokines and chemokines, 62 , 63 are prominent during iNPH. Altered levels of inflammatory cytokines in the CSF, as summarized in Table 1, have been reported. 64 , 65 , 66 , 67 , 68 , 69 , 70 Among them, TNF‐α is the most extensively studied. 64 , 67 , 70 One study measured TNF‐α level in the CSF before and after shunt operation in iNPH individuals and detected higher intrathecal TNF‐α level in iNPH patients, which could be reversed completely following the shunt surgery. 70 Furthermore, TNF‐α level was correlated with clinical symptoms, especially the cognitive function decline. 70 A positive correlation was also observed between the expression of TNF‐α and sulfatide, a group of glycosphingolipids that are highly expressed in the myelin sheath, in the CSF, suggesting detrimental effect of TNF‐α on white matter integrity. 70 Several other groups confirmed higher CSF levels of TNF‐α in iNPH patients compared with healthy controls or non‐iNPH disease controls. 64 , 67 TGF‐β1 level is also elevated in the CSF of iNPH patients compared to patients with tension‐type headache. 68 TGF‐β1 is known to be upregulated in endothelial cells and connective tissue cells in response to tissue injury or fibrosis. 71 TGF‐β‐mediated subarachnoid fibrosis is involved in the hydrocephalus after brain hemorrhage. 72 , 73 It is unknown whether this subarachnoid fibrosis also contributes to the development of iNPH. Other inflammation modulators, such as monocyte chemoattractant protein‐1 (MCP‐1) and IL‐6, were also changed in the CSF after iNPH 66 , 67 , 68 , 69 , 74 , 75 (Table 1). The exact roles of each inflammatory factor and their interactions in the pathogenesis and pathophysiology of iNPH await further elucidation.
Table 1.
Cytokines in the pathophysiology of iNPH
Sample | Study design | Sample types | Cytokines | Key findings | Preoperative and postoperative differences | Authors & Year |
---|---|---|---|---|---|---|
16 iNPH, 25 HC | Retrospective | CSF | TNF‐α | Higher CSF levels of TNF‐α in iNPH patients compared to HC. | TNF‐α levels decrease after shunt operation. |
Tarkowski E, 70 2003 |
6 iNPH, 11 HC, 7 MCI | Retrospective | CSF | TNF‐α | Higher CSF levels of TNF‐α in iNPH patients compared to HC and MCI. | / |
Castañeyra‐Ruiz L, 64 2016 |
8 iNPH, 10 SAH‐induced hydrocephalus, 6 non‐hemorrhagic obstructive hydrocephalus | Retrospective | CSF | TNF‐α | Higher CSF levels of TNF‐α in iNPH patients compared to non‐hemorrhagic obstructive hydrocephalus. | / |
Lee JH, 67 2012 |
20 iNPH, 20 non‐iNPH DC | Retrospective | CSF, plasma | IL‐1β | Higher CSF levels of IL‐1β in iNPH patients compared to DC. | / |
Sosvorová L, 69 2014 |
20 iNPH, 20 non‐iNPH DC | Retrospective | CSF, plasma | IL‐6 | Higher CSF levels of IL‐6 in iNPH patients compared to DC. | / |
Sosvorová L, 69 2014 |
5 INPH, 2 non‐iNPH DC | Retrospective | CSF | IL‐6 | Higher CSF levels of IL‐6 in iINPH patients compared to DC. | / |
Czubowicz, 77 2017 |
5 iNPH, 2 non‐iNPH DC | Retrospective | CSF | IL‐8 | Higher CSF levels of IL‐8 in iNPH patients compared to DC. | / |
Czubowicz, 77 2017 |
20 iNPH, 20 non‐iNPH DC | Retrospective | CSF, plasma | IL‐10 | Higher CSF levels of IL‐10 in iNPH patients compared to DC. | / |
Sosvorová L, 81 2014 |
28 iNPH, 20 HC | Retrospective | CSF | MCP‐1 | Higher CSF levels of MCP‐1 in iNPH patients compared to HC. | MCP‐1 levels increase after shunt operation. |
Jeppsson A, 78 2013 |
8 iNPH, 10 SAH‐induced hydrocephalus, 6 non‐hemorrhagic obstructive hydrocephalus | Retrospective | CSF | TGF‐β1 | Higher CSF levels of TGF‐β1 in iNPH patients compared to non‐hemorrhagic obstructive hydrocephalus. | / |
Lee JH, 67 2012 |
21iNPH and 14 tension‐type headache | Retrospective | CSF | TGF‐β1 | Higher CSF levels of TGF‐β1 in iNPH patients compared to tension‐type headache. | / |
Li X, 80 2007 |
Abbreviations: CSF, cerebrospinal fluid; DC, disease controls; HC, healthy controls; IL, interleukin; iNPH, idiopathic normal pressure hydrocephalus; MCI, mild cognitive impairment; MCP‐1, monocyte chemoattractant protein 1; SAH, subarachnoid hemorrhage; TGF, transforming growth factor; TNF, tumor necrosis factor.
4.3. Loss of Blood‐brain Barrier integrity
Blood‐brain barrier (BBB) refers to the barrier between the blood and the brain parenchyma, forming mainly by tight junction‐sealed brain endothelial cells. 76 , 77 , 78 These endothelial cells interact with other cell types within the neurovascular unit, including astrocytes and pericytes to maintain the homeostatic state of the brain microenvironment. 79 , 80 BBB leakage results in the entry of blood‐borne substances into the brain parenchyma. 81 BBB disruptions have been shown to play a key role in the neurological dysfunction after CNS disorders. 82 , 83 , 84 Eide et al 81 measured the fibrinogen extravasation, an indicator of BBB leakage, in cortical brain tissue specimens from 45 iNPH patients and 14 reference subjects. The results show more pronounced fibrinogen extravasation in iNPH specimens, indicating severe breach of BBB integrity in iNPH compared to control subjects. Moreover, it is discovered that increased BBB leakage is associated with the extent of astrogliosis. 81 Distorted and thickened capillary basement membranes, as well as increased number of degenerating pericytes, are also observed in biopsy samples of iNPH patients. 81 , 85 These pathological alterations might all contribute to BBB leakage in iNPH. In contrast, CSF‐based research suggests relative preservation of the BBB integrity in iNPH subjects using the CSF/blood albumin ratio as an index of BBB function. 77 No marked difference in CSF/blood albumin ratio was found between iNPH patients and healthy controls. 66 Such discrepancy might be due to the difference in the molecular mass between fibrinogen and albumin or the variance in the sensitivity among different methods for BBB leakage assessments. Further investigations with more sensitive and reliable markers of BBB leakage are warranted.
5. GLYMPHATIC IMPAIRMENT INCREASES BRAIN DAMAGE IN iNPH
The recently discovered glymphatic system facilitates the bulk flow of CSF into the brain along the para‐arterial space, the interstitial space and eventually into the para‐venous space. This pathway is mediated by Aquaporin‐4 (AQP4) channels at astrocytic perivascular endfeet. 86 It promotes the clearance of excess fluid and waste metabolites from CNS. 86 Normal function of glymphatic system relies on appropriate arterial pulsation, intact AQP4 channels and adequate sleep. 86
Impaired glymphatic system is observed in iNPH individuals. Using contrast‐enhanced MRI, delayed removal of the intrathecal CSF tracer gadobutrol was observed in iNPH. 87 , 88 Since clearance of gadobutrol resembles glymphatic clearance of other metabolites, this result provides compelling evidence for the impaired glymphatic function. 87 , 88 The underlying mechanisms are diverse. First of all, excessive CSF might stagnate in the dilated perivascular spaces (PVS), which compresses on the penetrating arteries to reduce their pulsatility. 89 Secondly, decreased AQP4 density in the astrocytic perivascular endfeet is reported in iNPH patients. 90 In addition, the progressive AQP4 depolarization with aging further exacerbates the abnormal perivascular fluid flow in aged iNPH patients. 91 , 92 , 93 , 94 Thirdly, sleep disorders are frequently diagnosed among iNPH patients. A study among 31 iNPH subjects revealed that all iNPH patients suffered from sleep abnormality to different extent. 95 Over 90.3% of iNPH patients had an obstructive sleep apnea. 95 Sleep abnormality could promote the overnight accumulation of metabolites in the interstitial space. It is hypothesized that repeated inspiratory movements against tongue‐blocked airway lead to elevated intrathoracic negative pressure and reduced venous return, which ultimately cause intracranial venous hypertension and iNPH. 95
A direct consequence of the glymphatic system disturbance is the reduced clearance of neurotoxic substances, such as beta amyloid (Aβ) and hyperphosphorylated tau (HP tau). 53 , 87 Accumulation of these neurotoxic substances could not only impair physiological functions of neurons, but also trigger astrogliosis and neuroinflammation. 96 Several studies reported the aggregation of Aβ and HP tau in brain biopsy samples from iNPH patients. 97 This Alzheimer's disease (AD)‐related pathology is related to cognitive decline in iNPH. 98 Since human studies also implicated impaired glymphatic function in AD, it is speculated that AD and iNPH share common pathogenesis to some extent. 99
6. WHITE MATTER INJURY IN iNPH
Hypoperfusion, glymphatic impairment, and other aforementioned pathophysiological changes in iNPH culminate in brain lesion and functional deficits. White matter lesions are prominent in iNPH. 6 Symptoms of iNPH could be attributed, at least partially, to the compression and stretch of white matter. When the motor nerve fibers of corticospinal tract are inflicted, gait disturbance may occur. The stretch of sacral fibers of the corticospinal tract may disrupt bladder contractions, resulting in urinary incontinence, which is the second most common symptom of iNPH. 100 , 101
White matter lesions in iNPH could be characterized by hyperintensities on T2‐Fluid‐attenuated inversion recovery (FLAIR) MRI imaging, especially the periventricular white matter hyperintensities (PVH). 99 DTI‐MRI is another useful technique to assess the white matter lesion. Mean diffusivity (MD) and fractional anisotropy (FA) are two commonly analyzed DTI parameters. 96 MD increases when more free water diffuses in the extracellular space. FA describes the degree of anisotropy of a diffusion process and reflects the structural integrity of the white matter. 102 Generally, higher MD and lower FA are observed in most white matter‐enriched regions in iNPH patients, displaying white matter edema and the loss of integrity. 103 Links between DTI indices and clinical manifestations have been reported. For instance, low FA in the frontal and parietal subcortical white matter is related to cognitive dysfunction. Low FA in the anterior limb of the left internal capsule, corpus callosum and below the left supplementary motor area is associated with gait disturbance in iNPH. 103 In addition, a strong positive correlation between MD in the corticospinal tract and gait abnormalities has been documented. 104 DTI may also help differentiating iNPH from other neurodegenerative diseases based on the FA and MD values in different white matter regions (eg,Internal capsule and corticospinal tract). 105 , 106
Pathologically, damages on both myelin and myelin‐sheathed axons have been detected in iNPH. Neurofilament light chain (NFL) is a protein that functions to maintain axonal architecture. Myelin basic protein (MBP) is a vital structural protein of myelin. 107 , 108 NFL and MBP are commonly used to assess axonal and myelin integrity, respectively. In iNPH, many studies observed increased levels of NFL and MBP in CSF samples and revealed positive correlations between the upregulation of NFL and MBP in the CSF and the severity of PVH on MRI. 66 , 99 High level of NFL in the CSF is associated closely with clinical symptoms and can be used as a biomarker to measure the severity of axonal loss in iNPH. 99 Elevated level of MBP in CSF might be used as a biomarker for myelin damage in iNPH. 66
7. GRAY MATTER INJURY IN iNPH
It is known that the axon of an unhealthy neuron may progressively dies back over weeks, beginning distally and spreading proximally toward the cell body. 109 Therefore, gray matter lesions are also observed in iNPH patients. Ishii et al 110 reported remarkably decreases in gray matter density in the insula, caudate and thalamus in iNPH patients, as measured by voxel‐based morphometry analysis. They speculated that such gray matter lesions might due to the transmantle pressure that originated from the ventricular dilation to these regions.
The structural and functional organizations in gray matter have been analyzed in iNPH. In a structural network study, larger global network modularity and network decentralization of frontal, temporal, posterior cingulate and insula cortices were observed in iNPH patients compared to controls. 111 Functional network studies with resting‐state functional MRI showed that the connectivity of default mode network reduced in iNPH, which was associated with clinical symptoms, particularly, cognitive and urinary dysfunctions. 112 Transcranial magnetic stimulation is commonly used in the functional network studies. Reduced corticospinal excitability and intracortical inhibitory connectivity in frontal and primary motor cortices are thought to be the culprits of gait disturbances in iNPH. 113
8. CURRENT AND PROSPECTIVE TREATMENT STRATEGIES
Cerebrospinal fluid diversion with ventriculoperitoneal or lumboperitoneal shunts is currently the first‐line and standard therapy for iNPH. 8 , 114 Efficacy does not differ significantly between two types of shunting procedures. Approximately 60%‐80% patients are reported to reduce gait disturbance, one of the most shunt‐responsive symptoms. Ventriculoperitoneal shunts have relatively low shunt failure rate, while lumboperitoneal shunts have the advantage of less invasiveness. 115
The reversal of abnormal CSF dynamics could be the principal mechanism underlying the therapeutic effect of CSF diversion. Drainage of excessive CSF restores normal CSF pulsatility and directly compensates for the insufficient CSF absorption in iNPH patients. 116 Therefore, it is not a surprise to find out that different CSF flow parameters, such as ASV, Rout, and CSF waveforms, are used to predict the clinical response to the shunting operation. 15 , 117 , 118 For instance, aqueduct stroke volume greater than or equal to 42 L is applied to identify patients who might benefit from the shunt surgery. 119 Ventricular decompression after CSF diversion further leads to the restoration of regional and global blood perfusion and the normalization of subsequent pathophysiological changes. Besides, CSF diversion increases the pulsatility of penetrating arteries by decompression, improving the glymphatic function. 89 When surgical intervention is not indicated for a patient, repeated large volume lumbar puncture is an alternative treatment of CSF drainage. 25
There are currently no FDA‐approved pharmacological treatments for iNPH. Clinical trials suggest that acetazolamide, a carbonic anhydrase inhibitor, can reduce periventricular white matter hyperintensities and improve symptoms in iNPH. 120 However, the small sample size, retrospective, and open‐label study design confounded their conclusions. Prospective, double‐blind, and placebo‐controlled trials with larger numbers of subjects are warranted to assess the therapeutic effect and safety of acetazolamide.
Recent years have witnessed a better understanding of iNPH pathogenesis and pathophysiology accompanied by bioengineering advances in medical devices. Novel treatment strategies are on the horizon. Shunt obstruction and infection remain critical concerns in iNPH patients with shunt surgery. 115 According to a recent meta‐analysis, 9%‐16% patients inserted with an adjustable valve and 26%‐38% patients inserted with a fixed‐pressure valve received an additional surgery. 115 Therefore, novel shunt catheters made with advanced biomaterials are needed to prevent cell and bacterial adhesion. Concomitantly, development of “smart” shunts with telemetry, incorporated monitors, and auto‐regulated valves has the potential to improve the treatment outcome. 121 To avoid the permanent implantation of shunts, endoscopic third ventriculostomy (ETV), a procedure formerly demonstrated to be effective in obstructive hydrocephalus, is gaining attention as a surgical treatment of iNPH. 122 In some studies, the ETV had similar or even superior efficacy and lower complication rates comparing to the shunting procedures. 122 However, due to the small number of patients and lack of randomized controlled trials, the generalizability of ETV in iNPH is still limited. Future studies are warranted to determine if ETV could be used for iNPH treatment to a broader population.
Heterogeneous clinical outcomes after surgical treatments clearly indicate that it is not enough merely to drain the excessive CSF. This procedure does not address all pathophysiological problems underlying iNPH. 115 , 123 Novel pharmacological agents could serve as supplementary or alternative therapies in iNPH. According to the pathogenesis of iNPH, pharmacological interventions could be used to normalize CSF hyperdynamics, such as decreasing CSF production, pulsatility and outflow resistance; restoring blood perfusion, promoting clearance of waste metabolites, alleviating neuroinflammation, and providing neuroprotection. Meanwhile, prospective studies using multimodal techniques are needed to identify objective imaging or CSF biomarkers for the quantitative assessments of drug efficacy. In addition, the development of new animal models that better recapitulate the clinical and radiological features of iNPH will definitely pave the way for preclinical screening of potential drugs.
9. CONCLUSION
Here, we provide a comprehensive review on the pathogenesis of iNPH and various mechanisms leading to neurological deficits. Instead of being totally idiopathic, etiologic factors and pathophysiological changes might constitute a vicious, deregulating loop that eventually result in clinical symptoms of iNPH (Figure 1). We also updated the current and prospective treatment strategies for iNPH. Despite the heterogeneous responses and possible complications of CSF diversion, it prevents the development of irreversible neurodegeneration and remains to be the first‐line treatment for iNPH. Improved understanding of the iNPH pathogenesis and its relevant neurological deficits, together with the advances in bioengineering, will offer new avenues to refine current treatments and develop novel surgical and pharmacological therapeutic strategies for iNPH.
Figure 1.
Schematic diagram of pathogenesis and related pathophysiological changes of iNPH. Abnormal CSF dynamics including increased CSF pulsatility and reducedCSF drainage contribute to the chronic development of ventriculomegaly. The subsequent transmantle pressure that originates from the ventricular dilation further leads to regional and global hypoperfusion/hypoxia. This vital pathophysiology initiates a cascade of serial brain damages including disturbance of metabolism, astrogliosis, neuroinflammation, and BBB disruption. Besides, glymphatic impairment, possibly caused by CSF stagnation and other risk factors, contributes to the Alzheimer disease‐like pathology in iNPH. All these factors culminate in white matter and gray matter lesions, which are the basis of clinical manifestations in iNPH. BBB, blood‐brain barrier; CSF, cerebrospinal fluid; IL‐10, interleukin 10; IL‐1β, interleukin 1beta; IL‐6, interleukin 6; IL‐8, interleukin 8; iNPH, Idiopathic normal pressure hydrocephalus; MCP‐1, monocyte chemoattractant protein‐1; NAA: N‐acetylaspartate; TGF‐β1, transforming growth factor‐beta1; TNF‐α, tumor necrosis factor‐alpha
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
This work was supported by project grants from the National Key Research and Development Program of China (No 2018YFC1312900).
Wang Z, Zhang Y, Hu F, Ding J, Wang X. Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus. CNS Neurosci Ther. 2020;26:1230–1240. 10.1111/cns.13526
Contributor Information
Jing Ding, Email: ding.jing@zs-hospital.sh.cn.
Xin Wang, Email: wang.xin@zs-hospital.sh.cn.
REFERENCES
- 1. Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH. Symptomatic occult hydrocephalus with normal cerebrospinal‐fluid pressure. A treatable syndrome. N Engl J Med. 1965;273:117‐126. [DOI] [PubMed] [Google Scholar]
- 2. Lu VM, Kerezoudis P, Patel NP, et al. Our efforts in understanding normal pressure hydrocephalus: learning from the 100 most cited articles by bibliometric analysis. World Neurosurg. 2020;137:429‐434.e13. [DOI] [PubMed] [Google Scholar]
- 3. Martín‐Láez R, Caballero‐Arzapalo H, López‐Menéndez L, Arango‐Lasprilla JC, Vázquez‐Barquero A. Epidemiology of idiopathic normal pressure hydrocephalus: a systematic review of the literature. World Neurosurg. 2015;84(6):2002‐2009. [DOI] [PubMed] [Google Scholar]
- 4. Andersson J, Rosell M, Kockum K, Lilja‐Lund O, Söderström L, Laurell K. Prevalence of idiopathic normal pressure hydrocephalus: a prospective, population‐based study. PLoS One. 2019;14(5):e0217705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Capone PM, Bertelson JA, Ajtai B. Neuroimaging of normal pressure hydrocephalus and hydrocephalus. Neurol Clin. 2020;38(1):171‐183. [DOI] [PubMed] [Google Scholar]
- 6. Skalický P, Mládek A, Vlasák A, De Lacy P, Beneš V, Bradáč O. Normal pressure hydrocephalus‐an overview of pathophysiological mechanisms and diagnostic procedures. Neurosurg Rev. 2019;42(1):1‐14. [DOI] [PubMed] [Google Scholar]
- 7. Bräutigam K, Vakis A, Tsitsipanis C. Pathogenesis of idiopathic Normal Pressure Hydrocephalus: a review of knowledge. J Clin Neurosci. 2019;61:10‐13. [DOI] [PubMed] [Google Scholar]
- 8. Mori E, Ishikawa M, Kato T, et al. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurol Med Chir. 2012;52(11):775‐809. [DOI] [PubMed] [Google Scholar]
- 9. Reddy GK, Bollam P, Caldito G. Long‐term outcomes of ventriculoperitoneal shunt surgery in patients with hydrocephalus. World Neurosurg. 2014;81(2):404‐410. [DOI] [PubMed] [Google Scholar]
- 10. Yamada S, Kelly E. Cerebrospinal fluid dynamics and the pathophysiology of hydrocephalus: new concepts. Semin Ultrasound CT MR. 2016;37(2):84‐91. [DOI] [PubMed] [Google Scholar]
- 11. Wagshul ME, Eide PK, Madsen JR. The pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. Fluids Barriers CNS. 2011;8(1):5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Scollato A, Gallina P, Di Lorenzo N, Bahl G. Is aqueductal stroke volume, measured with cine phase‐contrast magnetic resonance imaging scans useful in predicting outcome of shunt surgery in suspected normal pressure hydrocephalus? Neurosurgery. 2008;63(6):E1209. [DOI] [PubMed] [Google Scholar]
- 13. Chrysikopoulos H. Idiopathic normal pressure hydrocephalus: thoughts on etiology and pathophysiology. Med Hypotheses. 2009;73(5):718‐724. [DOI] [PubMed] [Google Scholar]
- 14. Bradley WG Jr. CSF flow in the brain in the context of normal pressure hydrocephalus. AJNR Am J Neuroradiol. 2015;36(5):831‐838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM. The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal‐pressure hydrocephalus. Neurosurgery. 2005;57(3 Suppl):S17‐S28. discussion ii–v. [DOI] [PubMed] [Google Scholar]
- 16. Vivas‐Buitrago T, Lokossou A, Jusué‐Torres I, et al. Aqueductal cerebrospinal fluid stroke volume flow in a rodent model of chronic communicating hydrocephalus: establishing a homogeneous study population for cerebrospinal fluid dynamics exploration. World Neurosurg. 2019;128:e1118‐e1125. [DOI] [PubMed] [Google Scholar]
- 17. Tawfik AM, Elsorogy L, Abdelghaffar R, Naby AA, Elmenshawi I. Phase‐contrast MRI CSF flow measurements for the diagnosis of normal‐pressure hydrocephalus: observer agreement of velocity versus volume parameters. AJR Am J Roentgenol. 2017;208(4):838‐843. [DOI] [PubMed] [Google Scholar]
- 18. Yin LK, Zheng JJ, Zhao L, et al. Reversed aqueductal cerebrospinal fluid net flow in idiopathic normal pressure hydrocephalus. Acta Neurol Scand. 2017;136(5):434‐439. [DOI] [PubMed] [Google Scholar]
- 19. Qvarlander S, Ambarki K, Wåhlin A, et al. Cerebrospinal fluid and blood flow patterns in idiopathic normal pressure hydrocephalus. Acta Neurol Scand. 2017;135(5):576‐584. [DOI] [PubMed] [Google Scholar]
- 20. Hayashi N, Matsumae M, Yatsushiro S, Hirayama A, Abdullah A, Kuroda K. Quantitative analysis of cerebrospinal fluid pressure gradients in healthy volunteers and patients with normal pressure hydrocephalus. Neurol Med Chir. 2015;55(8):657‐662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Luetmer PH, Huston J, Friedman JA, et al. Measurement of cerebrospinal fluid flow at the cerebral aqueduct by use of phase‐contrast magnetic resonance imaging: technique validation and utility in diagnosing idiopathic normal pressure hydrocephalus. Neurosurgery. 2002;50(3):534‐543; discussion 543–534.11841721 [Google Scholar]
- 22. Scollato A, Tenenbaum R, Bahl G, Celerini M, Salani B, Di Lorenzo N. Changes in aqueductal CSF stroke volume and progression of symptoms in patients with unshunted idiopathic normal pressure hydrocephalus. AJNR Am J Neuroradiol. 2008;29(1):192‐197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Takizawa K, Matsumae M, Hayashi N, Hirayama A, Yatsushiro S, Kuroda K. Hyperdynamic CSF motion profiles found in idiopathic normal pressure hydrocephalus and Alzheimer's disease assessed by fluid mechanics derived from magnetic resonance images. Fluids and barriers of the CNS. 2017;14(1):29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Yamada S, Ishikawa M, Ito H, et al. Cerebrospinal fluid dynamics in idiopathic normal pressure hydrocephalus on four‐dimensional flow imaging. Eur Radiol. 2020;30(8):4454‐4465. [DOI] [PubMed] [Google Scholar]
- 25. Oliveira LM, Nitrini R, Román GC. Normal‐pressure hydrocephalus: a critical review. Dement Neuropsychol. 2019;13(2):133‐143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Greitz D, Hannerz J, Rähn T, Bolander H, Ericsson A. MR imaging of cerebrospinal fluid dynamics in health and disease. On the vascular pathogenesis of communicating hydrocephalus and benign intracranial hypertension. Acta Radiol. 1994;35(3):204‐211. [PubMed] [Google Scholar]
- 27. Alperin NJ, Lee SH, Loth F, Raksin PB, Lichtor T. MR‐Intracranial pressure (ICP): a method to measure intracranial elastance and pressure noninvasively by means of MR imaging: baboon and human study. Radiology. 2000;217(3):877‐885. [DOI] [PubMed] [Google Scholar]
- 28. Greitz D, Wirestam R, Franck A, Nordell B, Thomsen C, Ståhlberg F. Pulsatile brain movement and associated hydrodynamics studied by magnetic resonance phase imaging. The Monro‐Kellie doctrine revisited. Neuroradiology. 1992;34(5):370‐380. [DOI] [PubMed] [Google Scholar]
- 29. Miyati T, Mase M, Kasai H, et al. Noninvasive MRI assessment of intracranial compliance in idiopathic normal pressure hydrocephalus. J Mag Resonance Imaging: JMRI. 2007;26(2):274‐278. [DOI] [PubMed] [Google Scholar]
- 30. Bothwell SW, Janigro D, Patabendige A. Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids Barriers CNS. 2019;16(1):9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Leinonen V, Vanninen R, Rauramaa T. Cerebrospinal fluid circulation and hydrocephalus. Handb Clin Neurol. 2017;145:39‐50. [DOI] [PubMed] [Google Scholar]
- 32. Ringstad G, Emblem KE, Eide PK. Phase‐contrast magnetic resonance imaging reveals net retrograde aqueductal flow in idiopathic normal pressure hydrocephalus. J Neurosurg. 2016;124(6):1850‐1857. [DOI] [PubMed] [Google Scholar]
- 33. Ringstad G, Emblem KE, Geier O, Alperin N, Eide PK. Aqueductal stroke volume: comparisons with intracranial pressure scores in idiopathic normal pressure hydrocephalus. AJNR Am J Neuroradiol. 2015;36(9):1623‐1630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Khasawneh AH, Garling RJ, Harris CA. Cerebrospinal fluid circulation: what do we know and how do we know it? Brain circulation. 2018;4(1):14‐18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Malm J, Jacobsson J, Birgander R, Eklund A. Reference values for CSF outflow resistance and intracranial pressure in healthy elderly. Neurology. 2011;76(10):903‐909. [DOI] [PubMed] [Google Scholar]
- 36. Boon AJ, Tans JT, Delwel EJ, et al. Dutch normal‐pressure hydrocephalus study: randomized comparison of low‐ and medium‐pressure shunts. J Neurosurg. 1998;88(3):490‐495. [DOI] [PubMed] [Google Scholar]
- 37. Kim DJ, Kim H, Kim YT, et al. Thresholds of resistance to CSF outflow in predicting shunt responsiveness. Neurol Res. 2015;37(4):332‐340. [DOI] [PubMed] [Google Scholar]
- 38. Bateman GA. The pathophysiology of idiopathic normal pressure hydrocephalus: cerebral ischemia or altered venous hemodynamics? Am J Neuroradiol. 2008;29(1):198‐203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Bateman GA, Siddique SH. Cerebrospinal fluid absorption block at the vertex in chronic hydrocephalus: obstructed arachnoid granulations or elevated venous pressure? Fluids Barriers CNS. 2014;11:11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Benabid AL, De Rougemont J, Barge M. Cerebral venous pressure, sinus pressure and intracranial pressure. Neurochirurgie. 1974;20(7):623‐632. [PubMed] [Google Scholar]
- 41. Kuriyama N, Tokuda T, Yamada K, et al. Flow velocity of the superior sagittal sinus is reduced in patients with idiopathic normal pressure hydrocephalus. J Neuroimaging. 2011;21(4):365‐369. [DOI] [PubMed] [Google Scholar]
- 42. Bateman GA, Levi CR, Schofield P, Wang Y, Lovett EC. The pathophysiology of the aqueduct stroke volume in normal pressure hydrocephalus: can co‐morbidity with other forms of dementia be excluded? Neuroradiology. 2005;47(10):741‐748. [DOI] [PubMed] [Google Scholar]
- 43. Albeck MJ, Skak C, Nielsen PR, Olsen KS, Børgesen SE, Gjerris F. Age dependency of resistance to cerebrospinal fluid outflow. J Neurosurg. 1998;89(2):275‐278. [DOI] [PubMed] [Google Scholar]
- 44. Jacobsson J, Qvarlander S, Eklund A, Malm J. Comparison of the CSF dynamics between patients with idiopathic normal pressure hydrocephalus and healthy volunteers. J Neurosurg. 2018;131(4):1018‐1023. [DOI] [PubMed] [Google Scholar]
- 45. Owler BK, Pickard JD. Normal pressure hydrocephalus and cerebral blood flow: a review. Acta Neurol Scand. 2001;104(6):325‐342. [DOI] [PubMed] [Google Scholar]
- 46. Takeuchi T, Goto H, Izaki K, et al. Pathophysiology of cerebral circulatory disorders in idiopathic normal pressure hydrocephalus. Neurol Med Chir (Tokyo). 2007;47(7):299‐306. discussion 306. [DOI] [PubMed] [Google Scholar]
- 47. Miyamoto J, Imahori Y, Mineura K. Cerebral oxygen metabolism in idiopathic‐normal pressure hydrocephalus. Neurol Res. 2007;29(8):830‐834. [DOI] [PubMed] [Google Scholar]
- 48. Larsson A, Bergh AC, Bilting M, et al. Regional cerebral blood flow in normal pressure hydrocephalus: diagnostic and prognostic aspects. Eur J Nucl Med. 1994;21(2):118‐123. [DOI] [PubMed] [Google Scholar]
- 49. Owler BK, Momjian S, Czosnyka Z, et al. Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values. J Cereb Blood Flow Metab. 2004;24(1):17‐23. [DOI] [PubMed] [Google Scholar]
- 50. Sakakibara R, Uchida Y, Ishii K, et al. Correlation of right frontal hypoperfusion and urinary dysfunction in iNPH: a SPECT study. Neurourol Urodyn. 2012;31(1):50‐55. [DOI] [PubMed] [Google Scholar]
- 51. Glenn TC, Kelly DF, Boscardin WJ, et al. Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism. J Cereb Blood Flow Metab. 2003;23(10):1239‐1250. [DOI] [PubMed] [Google Scholar]
- 52. Göttler J, Preibisch C, Riederer I, et al. Reduced blood oxygenation level dependent connectivity is related to hypoperfusion in Alzheimer's disease. J Cereb Blood Flow Metab. 2019;39(7):1314‐1325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Kondziella D, Sonnewald U, Tullberg M, Wikkelso C. Brain metabolism in adult chronic hydrocephalus. J Neurochem. 2008;106(4):1515‐1524. [DOI] [PubMed] [Google Scholar]
- 54. Lundin F, Tisell A, Dahlqvist Leinhard O, et al. Reduced thalamic N‐acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled 1H‐magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification. J Neurol Neurosurg Psychiatry. 2011;82(7):772‐778. [DOI] [PubMed] [Google Scholar]
- 55. Tarnaris A, Toma AK, Pullen E, et al. Cognitive, biochemical, and imaging profile of patients suffering from idiopathic normal pressure hydrocephalus. Alzheimers Dement. 2011;7(5):501‐508. [DOI] [PubMed] [Google Scholar]
- 56. Miyazaki K, Hanaoka K, Kaida H, Chiba Y, Ishii K. Changes in cerebral glucose metabolism caused by morphologic features of prodromal idiopathic normal pressure hydrocephalus. EJNMMI Res. 2019;9(1):111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Lundin F, Tisell A, Leijon G, et al. Preoperative and postoperative 1H‐MR spectroscopy changes in frontal deep white matter and the thalamus in idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry. 2013;84(2):188‐193. [DOI] [PubMed] [Google Scholar]
- 58. Zhou B, Zuo YX, Jiang RT. Astrocyte morphology: diversity, plasticity, and role in neurological diseases. CNS Neurosci Ther. 2019;25(6):665‐673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59. Eide PK, Hansson HA. Astrogliosis and impaired aquaporin‐4 and dystrophin systems in idiopathic normal pressure hydrocephalus. Neuropathol Appl Neurobiol. 2018;44(5):474‐490. [DOI] [PubMed] [Google Scholar]
- 60. Lu YB, Iandiev I, Hollborn M, et al. Reactive glial cells: increased stiffness correlates with increased intermediate filament expression. FASEB J. 2011;25(2):624‐631. [DOI] [PubMed] [Google Scholar]
- 61. Fattahi N, Arani A, Perry A, et al. MR elastography demonstrates increased brain stiffness in normal pressure hydrocephalus. AJNR Am J Neuroradiol. 2016;37(3):462‐467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Li Y, Zhu ZY, Huang TT, et al. The peripheral immune response after stroke‐A double edge sword for blood‐brain barrier integrity. CNS Neurosci Ther. 2018;24(12):1115‐1128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Wang X, Xuan W, Zhu ZY, et al. The evolving role of neuro‐immune interaction in brain repair after cerebral ischemic stroke. CNS Neurosci Ther. 2018;24(12):1100‐1114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Castañeyra‐Ruiz L, González‐Marrero I, Carmona‐Calero EM, et al. Cerebrospinal fluid levels of tumor necrosis factor alpha and aquaporin 1 in patients with mild cognitive impairment and idiopathic normal pressure hydrocephalus. Clin Neurol Neurosurg. 2016;146:76‐81. [DOI] [PubMed] [Google Scholar]
- 65. Czubowicz K, Głowacki M, Fersten E, Kozłowska E, Strosznajder RP, Czernicki Z. Levels of selected pro‐ and anti‐inflammatory cytokines in cerebrospinal fluid in patients with hydrocephalus. Folia Neuropathol. 2017;55(4):301‐307. [DOI] [PubMed] [Google Scholar]
- 66. Jeppsson A, Zetterberg H, Blennow K, Wikkelsø C. Idiopathic normal‐pressure hydrocephalus: pathophysiology and diagnosis by CSF biomarkers. Neurology. 2013;80(15):1385‐1392. [DOI] [PubMed] [Google Scholar]
- 67. Lee JH, Park DH, Back DB, et al. Comparison of cerebrospinal fluid biomarkers between idiopathic normal pressure hydrocephalus and subarachnoid hemorrhage‐induced chronic hydrocephalus: a pilot study. Med Sci Monit. 2012;18(12):PR19‐PR25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Li X, Miyajima M, Jiang C, Arai H. Expression of TGF‐betas and TGF‐beta type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neurosci Lett. 2007;413(2):141‐144. [DOI] [PubMed] [Google Scholar]
- 69. Sosvorova L, Vcelak J, Mohapl M, Vitku J, Bicikova M, Hampl R. Selected pro‐ and anti‐inflammatory cytokines in cerebrospinal fluid in normal pressure hydrocephalus. Neuro Endocrinol Lett. 2014;35(7):586‐593. [PubMed] [Google Scholar]
- 70. Tarkowski E, Tullberg M, Fredman P, Wikkelsö C. Normal pressure hydrocephalus triggers intrathecal production of TNF‐alpha. Neurobiol Aging. 2003;24(5):707‐714. [DOI] [PubMed] [Google Scholar]
- 71. Verrecchia F, Mauviel A. Transforming growth factor‐beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol. 2002;118(2):211‐215. [DOI] [PubMed] [Google Scholar]
- 72. Botfield H, Gonzalez AM, Abdullah O, et al. Decorin prevents the development of juvenile communicating hydrocephalus. Brain. 2013;136(Pt 9):2842‐2858. [DOI] [PubMed] [Google Scholar]
- 73. Douglas MR, Daniel M, Lagord C, et al. High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus. J Neurol Neurosurg Psychiatry. 2009;80(5):545‐550. [DOI] [PubMed] [Google Scholar]
- 74. Jeppsson A, Höltta M, Zetterberg H, Blennow K, Wikkelsø C, Tullberg M. Amyloid mis‐metabolism in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS. 2016;13(1):13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75. Jeppsson A, Wikkelsö C, Blennow K, et al. CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics. J Neurol Neurosurg Psychiatry. 2019;90(10):1117‐1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76. Abbott NJ. Blood‐brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437‐449. [DOI] [PubMed] [Google Scholar]
- 77. Yao Y. Basement membrane and stroke. J Cereb Blood Flow Metab. 2019;39(1):3‐19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Liu WY, Wang ZB, Zhang LC, Wei X, Li L. Tight junction in blood‐brain barrier: an overview of structure, regulation, and regulator substances. CNS Neurosci Ther. 2012;18(8):609‐615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79. Abbott NJ, Friedman A. Overview and introduction: the blood‐brain barrier in health and disease. Epilepsia. 2012;53:1‐6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80. Banks WA, Kovac A, Morofuji Y. Neurovascular unit crosstalk: pericytes and astrocytes modify cytokine secretion patterns of brain endothelial cells. J Cereb Blood Flow Metab. 2018;38(6):1104‐1118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81. Eide PK, Hansson HA. Blood‐brain barrier leakage of blood proteins in idiopathic normal pressure hydrocephalus. Brain Res. 2020;1727:146547. [DOI] [PubMed] [Google Scholar]
- 82. Daneman R, Prat A. The blood‐brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83. Zhang W, Zhu L, An C, Wang R, Gao Y. The blood brain barrier in cerebral ischemic injury – disruption and repair. Brain Hemorrhages. 2020;1(1):34‐53. [Google Scholar]
- 84. Liu Q, Radwanski R, Babadjouni R, et al. Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood‐brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab. 2019;39(2):240‐250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Eidsvaag VA, Hansson HA, Heuser K, Nagelhus EA, Eide PK. Brain capillary ultrastructure in idiopathic normal pressure hydrocephalus: relationship with static and pulsatile intracranial pressure. J Neuropathol Exp Neurol. 2017;76(12):1034‐1045. [DOI] [PubMed] [Google Scholar]
- 86. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018;17(11):1016‐1024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87. Eide PK, Ringstad G. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: a glymphatic magnetic resonance imaging study. J Cereb Blood Flow Metab. 2019;39(7):1355‐1368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88. Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain. 2017;140(10):2691‐2705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89. Gallina P, Porfirio B, Lolli F. iNPH as a '2‐hit' Intracranial Hydrodynamic Derangement Disease. Trends Mol Med. 2020;26(6):531‐532. [DOI] [PubMed] [Google Scholar]
- 90. Reeves BC, Karimy JK, Kundishora AJ, et al. Glymphatic system impairment in Alzheimer's disease and idiopathic normal pressure hydrocephalus. Trends Mol Med. 2020;26(3):285‐295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92. Hasan‐Olive MM, Enger R, Hansson HA, Nagelhus EA, Eide PK. Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus. Glia. 2019;67(1):91‐100. [DOI] [PubMed] [Google Scholar]
- 93. Haj‐Yasein NN, Vindedal GF, Eilert‐Olsen M, et al. Glial‐conditional deletion of aquaporin‐4 (Aqp4) reduces blood‐brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci USA. 2011;108(43):17815‐17820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94. Vindedal GF, Thoren AE, Jensen V, et al. Removal of aquaporin‐4 from glial and ependymal membranes causes brain water accumulation. Mol Cell Neurosci. 2016;77:47‐52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95. Román GC, Jackson RE, Fung SH, Zhang YJ, Verma AK. Sleep‐disordered breathing and idiopathic normal‐pressure hydrocephalus: recent pathophysiological advances. Curr Neurol Neurosci Rep. 2019;19(7):39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96. Angelucci F, Čechová K, Průša R, Hort J. Amyloid beta soluble forms and plasminogen activation system in Alzheimer's disease: consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications. CNS Neurosci Ther. 2019;25(3):303‐313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97. Bech‐Azeddine R, Høgh P, Juhler M, Gjerris F, Waldemar G. Idiopathic normal‐pressure hydrocephalus: clinical comorbidity correlated with cerebral biopsy findings and outcome of cerebrospinal fluid shunting. J Neurol Neurosurg Psychiatry. 2007;78(2):157‐161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98. Chen Z, Liu C, Zhang J, Relkin N, Xing Y, Li Y. Cerebrospinal fluid Aβ42, t‐tau, and p‐tau levels in the differential diagnosis of idiopathic normal‐pressure hydrocephalus: a systematic review and meta‐analysis. Fluids Barriers CNS. 2017;14(1):13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99. Tullberg M, Blennow K, Månsson JE, Fredman P, Tisell M, Wikkelsö C. Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur J Neurol. 2007;14(3):248‐254. [DOI] [PubMed] [Google Scholar]
- 100. Md J, Biagioni MC. Normal pressure hydrocephalus. In: StatPearls. Treasure Island, FL: StatPearls Publishing; Copyright © 2020, StatPearls Publishing LLC.; 2020. [Google Scholar]
- 101. Gleason PL, Black PM, Matsumae M. The neurobiology of normal pressure hydrocephalus. Neurosurg Clin N Am. 1993;4(4):667‐675. [PubMed] [Google Scholar]
- 102. Basser PJ, Jones DK. Diffusion‐tensor MRI: theory, experimental design and data analysis ‐ a technical review. NMR Biomed. 2002;15(7–8):456‐467. [DOI] [PubMed] [Google Scholar]
- 103. Kanno S, Abe N, Saito M, et al. White matter involvement in idiopathic normal pressure hydrocephalus: a voxel‐based diffusion tensor imaging study. J Neurol. 2011;258(11):1949‐1957. [DOI] [PubMed] [Google Scholar]
- 104. Hattingen E, Jurcoane A, Melber J, et al. Diffusion tensor imaging in patients with adult chronic idiopathic hydrocephalus. Neurosurgery. 2010;66(5):917‐924. [DOI] [PubMed] [Google Scholar]
- 105. Kim MJ, Seo SW, Lee KM, et al. Differential diagnosis of idiopathic normal pressure hydrocephalus from other dementias using diffusion tensor imaging. AJNR Am J Neuroradiol. 2011;32(8):1496‐1503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106. Ivkovic M, Liu B, Ahmed F, et al. Differential diagnosis of normal pressure hydrocephalus by MRI mean diffusivity histogram analysis. AJNR Am J Neuroradiol. 2013;34(6):1168‐1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107. Schirinzi T, Sancesario GM, Di Lazzaro G, et al. Cerebrospinal fluid biomarkers profile of idiopathic normal pressure hydrocephalus. J Neural Transm (Vienna). 2018;125(4):673‐679. [DOI] [PubMed] [Google Scholar]
- 108. Agren‐Wilsson A, Lekman A, Sjöberg W, et al. CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol Scand. 2007;116(5):333‐339. [DOI] [PubMed] [Google Scholar]
- 109. Raff MC, Whitmore AV, Finn JT. Axonal self‐destruction and neurodegeneration. Science. 2002;296(5569):868‐871. [DOI] [PubMed] [Google Scholar]
- 110. Ishii K, Kawaguchi T, Shimada K, et al. Voxel‐based analysis of gray matter and CSF space in idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Disord. 2008;25(4):329‐335. [DOI] [PubMed] [Google Scholar]
- 111. Yin L‐K, Zheng J‐J, Tian J‐Q, et al. Abnormal gray matter structural networks in idiopathic normal pressure hydrocephalus. Front Aging Neurosci. 2018;10:356. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112. Khoo HM, Kishima H, Tani N, et al. Default mode network connectivity in patients with idiopathic normal pressure hydrocephalus. J Neurosurg. 2016;124(2):350‐358. [DOI] [PubMed] [Google Scholar]
- 113. Chistyakov AV, Hafner H, Sinai A, Kaplan B, Zaaroor M. Motor cortex disinhibition in normal‐pressure hydrocephalus. J Neurosurg. 2012;116(2):453‐459. [DOI] [PubMed] [Google Scholar]
- 114. Tullberg M, Jensen C, Ekholm S, Wikkelsø C. Normal pressure hydrocephalus: vascular white matter changes on MR images must not exclude patients from shunt surgery. AJNR Am J Neuroradiol. 2001;22(9):1665‐1673. [PMC free article] [PubMed] [Google Scholar]
- 115. Giordan E, Palandri G, Lanzino G, Murad MH, Elder BD. Outcomes and complications of different surgical treatments for idiopathic normal pressure hydrocephalus: a systematic review and meta‐analysis. J Neurosurg. 2018;131(4):1024‐1036. [DOI] [PubMed] [Google Scholar]
- 116. McAllister JP 2nd, Williams MA, Walker ML, et al. An update on research priorities in hydrocephalus: overview of the third National Institutes of Health‐sponsored symposium "Opportunities for Hydrocephalus Research: Pathways to Better Outcomes". J Neurosurg. 2015;123(6):1427‐1438. [DOI] [PubMed] [Google Scholar]
- 117. Woodworth GF, McGirt MJ, Williams MA, Rigamonti D. Cerebrospinal fluid drainage and dynamics in the diagnosis of normal pressure hydrocephalus. Neurosurgery. 2009;64(5):919–926; discussion 925–916. [DOI] [PubMed] [Google Scholar]
- 118. Qvarlander S, Lundkvist B, Koskinen LO, Malm J, Eklund A. Pulsatility in CSF dynamics: pathophysiology of idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry. 2013;84(7):735‐741. [DOI] [PubMed] [Google Scholar]
- 119. Bradley WG Jr, Scalzo D, Queralt J, Nitz WN, Atkinson DJ, Wong P. Normal‐pressure hydrocephalus: evaluation with cerebrospinal fluid flow measurements at MR imaging. Radiology. 1996;198(2):523‐529. [DOI] [PubMed] [Google Scholar]
- 120. Alperin N, Oliu CJ, Bagci AM, et al. Low‐dose acetazolamide reverses periventricular white matter hyperintensities in iNPH. Neurology. 2014;82(15):1347‐1351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121. Lutz BR, Venkataraman P, Browd SR. New and improved ways to treat hydrocephalus: pursuit of a smart shunt. Surgical Neurol Int. 2013;4(Suppl 1):S38‐S50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Tudor KI, Tudor M, McCleery J, Car J. Endoscopic third ventriculostomy (ETV) for idiopathic normal pressure hydrocephalus (iNPH). Cochrane Database Syst Rev. 2015;(7):CD010033 10.1002/14651858.CD010033.pub2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123. Bergsneider M, Black PM, Klinge P, Marmarou A, Relkin N. Surgical management of idiopathic normal‐pressure hydrocephalus. Neurosurgery. 2005;57(3 Suppl):S29‐S39. discussion ii–v. [DOI] [PubMed] [Google Scholar]