Department of Neurosurgery,
#Authors contributed equally.
Correspondence Address: Dr. Jun Yang, Department of Neurosurgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China. E-mail: email@example.com
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Idiopathic normal pressure hydrocephalus (iNPH) is characterized by abnormal cerebrospinal fluid (CSF) flow and consequent cerebral ventricular enlargement due to imbalance of CSF production and absorption. The typical triad symptoms, namely cognitive decline, gait disturbance, and urinary incontinence, are thought to be caused by disruption of CSF circulation. However, some patients may still experience symptomatic progression after functional shunting, suggesting that iNPH is far more complicated than a simple disorder of CSF circulation. Moreover, the diagnostic workup of iNPH can be challenging due to symptomatic and neuroimaging overlaps with other neurological disorders, such as Alzheimer’s disease. Furthermore, accumulating studies indicate that the pathogenesis of iNPH might relate to multiple mechanisms, including abnormalities of brain development, brain extracellular matrix, synaptic function, blood flow, and cerebral metabolism. Therefore, iNPH is not an isolated entity in occurrence and development. Nevertheless, different pathogeneses may result in protein content changes in CSF, and the biomarkers in CSF may reflect the possible mechanisms involving the etiology of iNPH and are potentially useful in assisting the diagnosis and treatment selection. In this review, we summarize the main findings of CSF biomarkers and aim to outline a possible synthetic profile in assisting iNPH diagnosis and therapeutic options.
Idiopathic normal pressure hydrocephalus, cerebrospinal fluid, biomarkers, neurodegenerative diseases
Idiopathic normal pressure hydrocephalus (iNPH) is one of the disabling neurological disorders whose potential treatability is significantly impacted by the timeliness of unequivocal diagnosis. iNPH is characterized by ventriculomegaly that is caused by an imbalance between cerebrospinal fluid (CSF) production and absorption. The characteristic triad symptoms of dementia, gait disturbance, and urinary incontinence are thought to be caused by a disruption of CSF dynamics[1,2]. Therefore, the triad symptoms of iNPH could be surgically treatable with a diversion of CSF into peritoneal cavity or heart. However, the diagnostic workup of iNPH can be a challenge due to neuroimaging and symptomatic overlaps with other neurological disorders, such as Alzheimer’s disease (AD) and subcortical ischemic vascular disease, especially at early stage. Moreover, although the cognitive decline could be proceeded by these diseases, they are not equally responsive to the treatment of CSF shunting. Therefore, further effort to improve the diagnosis of iNPH would benefit the current imaging and symptomatic diagnostic criteria. Increasing studies indicate that the pathogenesis of iNPH involves multiple mechanisms, including abnormalities of brain development, brain extracellular matrix, synaptic function, blood flow, and cerebral metabolism, which could result in protein content changes in CSF. On the other hand, impaired CSF absorption could lead to a pathological flow of CSF into the periventricular tissues to initiate a cascade of pathological processes such as edema and consequent neuronal degenerative changes. Therefore, measurements of different biomarkers in CSF may reflect the underlying neuropathological changes of the brain and could play an important role in revealing the possible etiological mechanisms. Furthermore, its detection may facilitate the timeliness and accuracy of iNPH diagnosis, and thus becomes potentially useful for therapeutic selection and treatment response monitoring. In addition, the biomarkers could help to differentiate iNPH from other neurological disorders, which might mimic iNPH symptomatology but show unsatisfactory outcomes after shunting[5,6]. Despite a growing interest, the CSF biomarker profile in iNPH has not yet been identified definitively. In this review, we summarize the main findings of CSF biomarkers regarding iNPH and outline a rough CSF profile in order to assist iNPH diagnosis and provide adequate treatment. It is notable that, due to the etiological complexity of iNPH, most biomarkers might lack specificity for iNPH diagnosis and are possibly coincidental, confounding with other overlapping neurological diseases. In addition, in comparison with a cortical brain biopsy or neuropsychological testing, biomarkers may also have limitations in distinguishing iNPH from comorbid iNPH plus AD, as well as in predicting clinical cognitive outcome post shunting[6,8,9]. However, a combination of more than one biomarker may enhance the predictive value and provide more viable and accurate solutions. Ideally, the dynamic changes of biomarker measured before and after surgical diversion of CSF would supply useful clinical information for the diagnosis and assistance in monitoring disease progression. The biomarkers could be categorized as AD discrimination, neurodegeneration and demyelination, neuroinflammation, neuropeptides and cerebral metabolites, and as biomarkers in response to cerebral and vascular insulting, among others[1,2,10,11].
Dementia in iNPH is potentially reversible if adequately treated. However, it often resembles the clinical appearance of patients with AD, such as memory decline, as well as attention and executive impairment. Urinary incontinence and gait disturbance may also occur in both diseases due to disturbed subcortical network caused by vascular pathology. Moreover, ventricular enlargement may have been observed in AD patients as a result of cerebral atrophy rather than CSF circulation impairment. Furthermore, the pathological examination of cortical brain biopsies performed during placement of CSF shunts revealed AD neurodegenerative changes in 24% of iNPH patients, suggesting a high comorbidity of both diseases. Thus, cortical brain biopsy may provide a valuable predictive way for outcome evaluation[6,8]. However, cortical brain biopsy is not always available or appropriate in some cases. Moreover, both iNPH and AD diseases may manifest sleep disturbances, which correlate with dysfunction of the glia-lymphatic (glymphatic) system, consequently building-up of brain metabolic wasters, favoring dementia development[14,15]. Therefore, it is always a challenge to discriminate iNPH and AD diseases in clinical practice.
The glymphatic system facilitates cerebral metabolite and brain fluid clearance during sleep via glia-supported perivascular channels. This system facilitates efflux of cerebrospinal and interstitial fluid via the perivascular spaces to the meningeal and cervical lymphatic vessels, assisting the draining/clearing of metabolic wastes from the central nervous. The glymphatic flux is proposed to be driven by cardiac-induced arterial pulsation, and may be possibly manipulated through change of intracranial pressure pulsatility with our cardiac-gated device. Most interestingly, the action of glymphatic flux is predominant during sleep, and up to 90% of iNPH patients are associated with obstructive sleep apnea, a common sleep disorder. Blockage of the airway in obstructive sleep apnea causes increased awakenings and decreased quality of sleep, resulting in glymphatic dysfunction and increased cerebral Aβ aggregation. Patients with obstructive sleep apnea encounter reduced oxygen intake due to intermittent airway obstruction. Excessive breathing against a closed airway induces negative intrathoracic pressure, sufficient to cause atrial distortion and reduced venous return to the heart and ultimately affect arterial pulsation, resulting in dysfunction of glymphatic flux.
Many studies have shown impaired glymphatic function in both iNPH and AD. Furthermore, iNPH and AD patients share multiple clinical and pathologic features such as Aβ deposition, cerebrovascular inflammation, impaired localization of perivascular astrocyte aquaporin-4 (AQP4), and sleep disturbances. Therefore, it is a diagnostic challenge in daily practice for iNPH and AD. Although many biomarkers have been investigated for their discrimination, amyloid-β 42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau) are the most robust candidate markers to discriminate iNPH from AD patients[1,2]. Aβ42 is lower in both iNPH and AD patients compared with healthy control, and Aβ42 does not separate iNPH and AD. Tau protein is a microtubule-associated protein and is a marker for neuronal degeneration. The levels of t-tau and p-tau are higher in AD patients compared with iNPH patients and controls, whereas the levels of t-tau and p-tau are within normal range in iNPH patients. The combination of these biomarkers, i.e., the reduced Aβ42 with concomitant normal or reduced t-tau and p-tau levels in iNPH coupled with reduced Aβ42 with concomitant increased both t-tau and p-tau levels in AD, may significantly improve the accuracy of differential diagnosis between AD and iNPH patients. The mechanism of lower Aβ42 level in iNPH patients is unknown. However, the reduced production of Aβ42 due to a decline in brain metabolism in the periventricular zone in iNPH patients[23,24] and interstitial Aβ deposition due to impaired glymphatic function may be possible reasons. Meanwhile, the low concentrations of CSF t-tau and p-tau do not support the major cortical degenerative process in iNPH[24,25], whereas, in AD patients, the core pathological changes are the accumulation of abnormally folded beta-amyloid and tau proteins in the plaques and neuronal tangles, and the progressive deposition of amyloid plaques lowers Aβ42 level. Moreover, concurrent axonal degenerations and neurofibrillary tangle formation further increase t-tau and p-tau CSF levels in AD patients. The representative information and main biomarkers for assisting differential diagnosis of iNPH and AD are summarized in the attached Table 1.
The representative information and biomarkers in iNPH and AD
|Ventriculomegaly||↑↑||↑||[6,13]||18-42% of iNPH also had AD brain biopsy findings|
|OSA||65%-90%||44%||[15,19]||OSA: obstructive sleep apnea|
|GFD||Yes||Yes||[14-15,18]||GFD: Glymphatic flux dysfunction|
|WMLs||↑||↑||[64-66]||WMLs: cerebral white matter lesions|
|PWMD||↑||↑||[28-30]||PWMD: periventricular white matter damage|
|FSO||↑↑||↑||[1-3]||FSO: favorable surgical outcome|
|*Aβ42||↓||↓||[1-2,22-24]||Amyloid-beta-42. No difference vs. AD, ↓ vs. control|
|*t-tau||↓/-||↑||[1-2,21-24,27]||Total tau. ↓ vs. AD, no difference vs. control|
|*p-tau||↓/-||↑||[1-2,22,27]||Phosphorylated tau. ↓ vs. AD, no difference vs. control|
|NFL||↑||N/A||[12,31-34]||Neurofilament light chains. Correlated with PWMD and FSO|
|MBP||↑||↑||[31-33,39-41]||Myelin basic protein. Correlated with PWMD and FSO|
|TNF-α||↑||N/A||[45-46]||Tumor-necrosis factor α. Correlated with FSO|
|TGF-β1||↑||N/A||[47-49]||Transforming growth factor β1|
|IL-1β||↑||↑||[44,50-52]||Pro-inflammatory cytokines, interleukin-1β|
|IL-6||↑||↑||[50-52]||Pro-inflammatory cytokines, interleukin-6|
|IL-10||↑||↑||[50-52]||Anti-inflammatory cytokine, interleukin-10|
|TFPI-2||↑||↑||[50-52]||Tissue factor pathway inhibitor 2|
|MCP-1||↑||↑||[50-52]||Monocyte chemoattractant protein-1|
|VIP||↓||N/A||[10,54-55,57]||Vasoactive intestinal peptide|
|DSIP||↓||N/A||[10,54-55]||Delta-sleep inducing peptide|
|NGF||↑↑||N/A||[69,70]||Nerve growth factor|
|VEGF||↑||N/A||[59,71-73]||Vascular endothelial growth factor. Correlated with FSO|
|GFAP||↑||N/A||[34,76]||Glial fibrillary acidic protein|
|PGDS||↓||-||||Prostaglandin D synthase|
The disturbance of CSF circulation could lead to a potentially hostile milieu for cerebral structures, especially periventricular areas and subcortical structures, and could result in vascular lesions, destruction of periventricular white matter, and subsequent neurodegeneration and demyelination[28-30]. Such pathological changes could be estimated with the examination of CSF contents, such as neurofilament light chains (NFL), myelin basic protein (MBP), and leucine-rich-α2-glycoprotein (LRG)[31-33]. NFL is a cytoskeletal element in nerve axons and dendrites, and therefore could be considered as a biomarker for axonal damage in patients with iNPH[31,34]. Although some studies did not find difference of CSF NFL levels between iNPH and AD patients[11,32], as well as controls, other studies demonstrated increased CSF NFL levels, and the increase paralleled the degeneration of large myelinated axons in iNPH[31,36]. In addition, some studies observed that the ventricular NFL level directly correlated with altered signals in periventricular white matter in brain MRI. Moreover, one study demonstrated that high preoperative NFL level was associated with favorable surgical outcomes, and suggested that NFL could possibly be used as an indicator for neurodegeneration and a marker of ongoing axonal damage.
Demyelination of the periventricular white matter could occur in hydrocephalus due to the result of mechanical stretching. MBP is an oligodendroglial structural protein of myelin and sulfatide is a glycosphingolipid component of myelin, and they are essential for the maintenance of central nervous system myelin and axon structure[32,39]. Both MBP and sulfatide are well known indicators for ongoing demyelination and therefore are attractive markers for the pathological process. However, the CSF levels of MBP are higher in many different neurologic disorders, including iNPH and cerebrovascular diseases, leading to lack of specification for iNPH diagnosis[32,36], whereas it is demonstrated that changes of MBP levels are correlated with periventricular white matter damage. When comparing the levels of MBP pre- and post-shunting, the results showed that the levels of MBP decreased post-shunting, suggesting that MBP could be used for evaluation of brain damage and shunting effect.
LRG is an astrocytic protein and could be induced by inflammation. The LRG level in CSF increases with age in iNPH and other dementia diseases. It was speculated that the accumulation of LRG in the brains is one of the causes of neurodegeneration, therefore its level in CSF could be an anticipated marker for early diagnosis of iNPH and other dementia diseases[33,43].
Taking together, all these markers allow tracking the integrity of periventricular and subcortical structures. Although they are not disease specific, their changes in CSF directly reflect cerebral damage, and they may be useful indicators in comparative analyses between iNPH and other neurodegenerative diseases.
Cytokines mediate inflammatory response and often correlate with neurodegeneration in neurological diseases. The profile of CSF cytokines provides access to explore the pathogenic mechanisms of different neurological diseases and therapeutic approaches. Abundant CSF cytokines have been investigated in iNPH patients, but a more definite profile still needs to be clarified[32,36].
Tumor-necrosis factor (TNF-α) is a cytokine of inflammatory mediator and its level in CSF is significantly high in iNPH patients[45,46]. Most interestingly, the CSF level of TNF-α returned to the control level in the patients with shunt improvement. Because of its short half-life, the increased CSF TNF-α may be caused by increased production rather than the accumulation due to CSF stagnation, which suggests that TNF-α in CSF might be used as a candidate marker for the evaluation of demyelination and disease progression in iNPH patients. More studies are needed for validation.
Transforming growth factor β1(TGF-β1), one of the three cytokines in the TGF family, plays a role in cell differentiation and tissue modification during brain development. It could be released from microglia and astrocytes in response to cerebral insult to initiate neuroinflammation and neurodegeneration through the induction of fibrosis, vascular hypertrophy, accumulation of extracellular matrix components, and neuronal apoptosis[47-49]. TGF-β level was found to be higher in iNPH patients than controls, and was considered to be a reliable index of cerebral damage in iNPH.
Other increased inflammatory biomarkers measured in iNPH patients include IL-1β and IL-6 (pro-inflammatory cytokines), IL-10 (anti-inflammatory cytokine), tissue factor pathway inhibitor 2 (TFPI-2), chitinase-3-like protein-1 (YKL-40), and monocyte chemoattractant protein (MCP-1)[50-52]. However, as similar changes are also observed in AD and Parkinson’s disease, these changes only reflect an underlying neuroinflammatory processes of pro-inflammatory reaction (IL-1β and IL-6) and compensatory anti-inflammatory reaction (IL-10), rather than disease-specific indicators[44,51,52]. TFPI-2 is involved in inflammatory process by recruiting astrocytes and microglia to the injury site. YKL-40 is then released from astrocyte and/or microglia in response to neuroinflammation. The increased CSF YKL-40 levels seem to be correlated with cognitive decline and therefore to predict progression of dementia. However, more studies are deserved on the clinical use of this novel promising neuroinflammation biomarker[35,48].
Neuropeptides, including somatostatin, vasoactive intestinal peptide, neuropeptide Y, and delta-sleep inducing peptide, have been evaluated by various groups[10,54,55]. Decreased CSF somatostatin levels suggest damage to the hypothalamus and the cortical neurons that normally have high concentrations of somatostatin. Higher level of somatostatin correlates with better visual memory and mental condition in iNPH patients, proposing that somatostatin may have a modulatory role in cognition. Vasoactive intestinal peptide is a potent vasodilator and therefore may play a role in chronic ischemia, and the CSF level is usually higher in iNPH patients with cerebrovascular disease[55-57]. Delta-sleep inducing peptide is a nine-amino acid peptide with a role in sleep-wakefulness regulation. iNPH patients with lower delta-sleep inducing peptide level show worse psychomotor performance. Several studies also reported reduced levels of neuropeptide Y in iNPH patients[54-56].
Cerebral metabolism changes may occur in iNPH patients. iNPH patients were also reported to have altered levels of lactate, an end product of anaerobic glycolysis underlying a presence of chronic ischemia[58,59]. Free-radical peroxidation could result in cellular dysfunction and may therefore be implicated in the pathogenesis of iNPH and dementia. A study showed that the levels of free-radical peroxidation products significantly increased in iNPH patients. The authors implied that peroxidation of cytoplasmic membranes might be involved in the development of cognitive dysfunction in iNPH.
Blood-brain barrier is a physically powerful gateway that strictly monitors and controls the interchange of substances between central nervous system and blood flow. Its function is strictly dependent on the integrity of microvascular endothelium and thus affected by many pathophysiological risk factors, including vascular/hemodynamic changes, inflammation, etc., and in turn affects the homeostasis of central nervous system. The “CSF/blood albumin ratio” represents a reliable index of blood-brain barrier function. Blood-brain barrier impairment was reported in different neurodegenerative diseases, including AD and cerebral vascular disease. Nowadays, it has been scarcely evaluated in iNPH patients, but available reports indicate a substantial preservation of the blood-brain barrier[22,36].
Vascular risk factor may be a component of subcortical neuropathology in the development of iNPH. As key components, cerebral white matter lesions and hypertension were reported to be related to the pathophysiology of iNPH[64-66]. White matter lesions, involved in different cognitive processes and/or clinical outcomes, are associated with small vessel disease and white matter ischemia. The association between iNPH and white matter lesions indicates the involvement of microvascular disturbances in the white matter and in the pathological processes of iNPH. In addition, hypertension increases the risk of iNPH through the mechanisms of involved small vessel diseases, including hypertension induced endothelial damage and resultant extravasation of blood products into white matter, impaired blood flow with reduced metabolism, and direct mechanical effect on ventricular size[66,67]. Therefore, identifications of vascular related risk factors may improve diagnostic accuracy and address the underlying pathology regarding the development of iNPH, and ultimately provide suitable intervention for iNPH management. Overall, the dynamic and morphological alterations in subcortical structure of iNPH brain could be resulted from white matter lesions, hypertension related vascular lesions, destruction of periventricular white matter axons and gliosis, and impaired CSF circulation. Such pathological alterations could affect CSF protein contents and biomarkers in CSF could mirror the underlying pathologic alterations. As markers of subcortical damage, at least three proteins have been measured in iNPH patients, including NFL, LRG, and MBP. The functions and clinical application of these proteins are discussed above. In summary, NFL is a cytoskeletal protein for maintenance of axonal architecture and is considered as a marker for neuronal morphological integrity. Although it has also been assessed as a biomarker for inflammatory and neurodegenerative diseases, it has been observed that ventricular NFL levels in iNPH patients directly correlate with more extensive altered signals in periventricular white matter in brain MRI. LRG is an astrocytic protein and is increased in CSF of iNPH patients, suggesting a potential biomarker for iNPH, but it also changes with aging and non-specific inflammation. MBP is an oligodendroglial structural protein of myelin. Its CSF levels are increased in iNPH patients and other cerebrovascular and neurodegenerative diseases, indicating the damage of periventricular white matter[1,32].
In addition, nerve growth factor (NGF) play an important role in neuro-regeneration in response to brain injury and age-related atrophy. NGF is scarcely detectable in innervated tissues, but denervation of cerebral tissue could lead to the production of NGF and become measurable in the target tissues. The CSF level of NGF was found to be significantly higher in hydrocephalus patients compared with the controls, which suggests the possibility that the increased NGF levels could represent an increased cerebral regeneration after shunting.
Vascular endothelial growth factor plays roles in many cerebral physiological and pathological modifications, and its level in CSF is respondent to ischemic condition involved in different neurological disorders[59,71-73]. Our group demonstrated that the CSF levels of vascular endothelial growth factor in iNPH patients have circadian variations and exercise induced increasing. The higher concentration of vascular endothelial growth factor level in CSF is associated with less response to shunting and worse clinical outcome, suggesting a possible concurrent ischemic or vascular injury in iNPH patients[73,75].
Glial fibrillary acidic protein is a marker for gliosis[34,76]. In iNPH patients, the CSF level of glial fibrillary acidic protein was increased when compared with controls, and correlated with disease progression. The increased glial fibrillary acidic protein level in CSF suggests an irreversible damage to astrocytes, since glial fibrillary acidic protein is not secreted by astrocytes.
All of these markers suggest the involvement of vascular risk factors and consequent subcortical white matter lesions in the development of iNPH; however, further studies are needed to explore their predictive value in clinical application.
The level of prostaglandin D synthase was found to be significantly lower in iNPH patients compared with controls and other dementia patients, such as Lewy body dementia, vascular dementia, and AD. This enzyme is secreted into CSF by the leptomeninges and the trabecular cells of the arachnoid membrane. The authors speculated that the decreased level of prostaglandin D synthase was probably due to a degenerative change of the arachnoid membrane in iNPH patients.
Finally, the methodology of CSF biomarker detection may also affect the ability to reliably evaluate biological biomarkers for the differentiation and prognosis of cognitive impairment diseases. Many factors may affect the reliability and sensitivity of biomarker detection, for example, the systematic difference between different assays, different pre-analytical protocol for sample preparation and storage, analytical variability of measurement procedures, etc.[79,80]. When interpreting measurement results, these factors should be considered. In addition, some biomarkers exhibit periodic concentration patterns. Therefore, the most appropriate time for sample collection must also be considered when designing a protocol.
The overlap of neuroimaging and symptomatic manifestations leads to diagnostic confusion between iNPH and other neurodegeneration diseases, such as AD and subcortical ischemic vascular disease. Despite the absence of definite pathological hallmarks, the biomarkers altered in CSF might serve as targets for diagnosis and therapeutic intervention. Furthermore, the biomarkers in CSF could reflect the adjacent cerebral pathophysiological status, therefore are potentially useful to provide insight into the pathological changes in the brain milieu and underling pathogenesis. Although many CSF biomarkers have been analyzed in iNPH patients, the significant findings include the reduced Aβ42 with concomitant normal or reduced t-tau and p-tau levels in iNPH coupled with reduced Aβ42 with concomitant increased both t-tau and p-tau levels in AD. This characteristic alteration may significantly improve the accuracy of differential diagnosis between AD and iNPH patients. Other biomarkers may lack specification in differential diagnosis, but the definite changes may mirror the underlying pathogenesis mechanisms, such as demyelination, neurodegeneration, and neuroinflammation, and provide valuable information to further explore the pathogenesis mechanisms and optical therapeutic manipulations.
Conceived of the presented idea: Yang J
Underwent literature review and synthesized a draft: Yang J, Zhang XJ, and Guo J
Contributed ideas throughout the process and approved the final draft: Yang J
Looked over and edited draft: Yang J, Zhang XJ, and Guo JAvailability of data and materials
Not applicable.Financial support and sponsorship
None.Conflicts of interest
All authors declared that there are no conflicts of interest.Ethical approval and consent to participate
Not applicable.Consent for publication
© The Author(s) 2020.
1. Schirinzi T, Sancesario GM, Di Lazzaro G, D’Elia A, Imbriani P, et al. Cerebrospinal fluid biomarkers profile of idiopathic normal pressure hydrocephalus. J Neural Transm (Vienna) 2018;125:673-9.DOIPubMed
2. Manniche C, Hejl AM, Hasselbalch SG, Simonsen AH. Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus versus Alzheimer’s disease and subcortical ischemic vascular disease: a systematic review. J Alzheimers Dis 2019;68:267-79.DOIPubMed
3. Ghosh S, Lippa C. Diagnosis and prognosis in idiopathic normal pressure hydrocephalus. Am J Alzheimers Dis Other Demen 2014;29:583-9.DOIPubMed
4. Keong NC, Pena A, Price SJ, Czosnyka M, Czosnyka Z, et al. Imaging normal pressure hydrocephalus: theories, techniques, and challenges. Neurosurg Focus 2016;41:E11.DOIPubMed
5. Savolainen S, Hurskainen H, Paljärvi L, Alafuzoff I, Vapalahti M. Five-year outcome of normal pressure hydrocephalus with or without a shunt: predictive value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir (Wien) 2002;144:515-23.DOIPubMed
6. Pomeraniec IJ, Bond AE, Lopes MB, Jane JA Sr. Concurrent Alzheimer’s pathology in patients with clinical normal pressure hydrocephalus: correlation of high-volume lumbar puncture results, cortical brain biopsies, and outcomes. J Neurosurg 2016;124:382-8.DOIPubMed
7. Graff-Radford NR. Alzheimer CSF biomarkers may be misleading in normal-pressure hydrocephalus. Neurology 2014;83:1573-5.DOIPubMed PMC
8. Pomeraniec IJ, Taylor DG, Bond AE, Lopes MB. Concurrent Alzheimer’s pathology in patients with clinical normal pressure hydrocephalus. J Neurosurg Sci 2018; doi: 10.23736/S0390-5616.18.04350-3.DOIPubMed
9. McGovern RA, Nelp TB, Kelly KM, Chan AK, Mazzoni P, et al. Predicting cognitive improvement in normal pressure hydrocephalus patients using preoperative neuropsychological testing and cerebrospinal fluid biomarkers. Neurosurgery 2019;85:E662-9.DOIPubMed
10. Tarnaris A, Watkins LD, Kitchen ND. Biomarkers in chronic adult hydrocephalus. Cerebrospinal Fluid Res 2006;3:11.DOIPubMed PMC
11. Agren-Wilsson A, Lekman A, Sjöberg W, Rosengren L, Blennow K, et al. CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol Scand 2007;116:333-9.DOIPubMed
12. Saito M, Nishio Y, Kanno S, Uchiyama M, Hayashi A, et al. Cognitive profile of idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Dis Extra 2011;1:202-11.DOIPubMed PMC
13. Espay AJ, Da Prat GA, Dwivedi AK, Rodriguez-Porcel F, Vaughan JE, et al. Deconstructing normal pressure hydrocephalus: ventriculomegaly as early sign of neurodegeneration. Ann Neurol 2017;82:503-13.DOIPubMed
14. Nassar BR, Lippa CF. Idiopathic normal pressure hydrocephalus: a review for general practitioners. Gerontol Geriatr Med 2016;2:2333721416643702.DOIPubMed PMC
15. Reeves BC, Karimy JK, Kundishora AJ, Mestre H, Cerci HM, et al. Glymphatic system impairment in Alzheimer’s disease and idiopathic normal pressure hydrocephalus. Trends Mol Med 2020;26:285-95.DOIPubMed
16. Iliff JJ, Wang MH, Zeppenfeld DM, Venkataraman A, Plog BA, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 2013;33:18190-9.DOIPubMed PMC
17. Luciano MG, Dombrowski SM, Qvarlander S, El-Khoury S, Yang J, et al. Novel method for dynamic control of intracranial pressure. J Neurosurg 2017;126:1629-40.DOIPubMed
18. Xie LL, Kang HY, Xu QW, Chen MJ, Liao YH, et al. Sleep drives metabolite clearance from the adult brain. Science 2013;342:373-7.DOIPubMed PMC
19. Roman 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;19:39.DOIPubMed PMC
20. Ju YE, Zangrilli MA, Finn MB, Fagan AM, Holtzman DM. Obstructive sleep apnea treatment, slow wave activity, and amyloid-beta. Ann Neurol 2019;85:291-5.DOIPubMed PMC
21. Gao Y, Tan L, Yu JT. Tau in Alzheimer’s disease: mechanisms and therapeutic strategies. Curr Alzheimer Res 2018;15:283-300.DOIPubMed
22. Schirinzi T, Sancesario GM, Ialongo C, Imbriani P, Madeo G, et al. A clinical and biochemical analysis in the differential diagnosis of idiopathic normal pressure hydrocephalus. Front Neurol 2015;6:86.DOIPubMed PMC
23. Momjian S, Owler BK, Czosnyka Z, Czosnyka M, Pena A, et al. Pattern of white matter regional cerebral blood flow and autoregulation in normal pressure hydrocephalus. Brain 2004;127:965-72.DOIPubMed
24. Jeppsson A, Wikkelso C, Blennow K, Zetterberg H, Constantinescu R, et al. CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics. J Neurol Neurosurg Psychiatry 2019;90:1117-23.DOIPubMed PMC
25. Moriya M, Miyajima M, Nakajima M, Ogino I, Arai H. Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade. PLoS One 2015;10:e0119973.DOIPubMed PMC
26. Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, et al. Alzheimer’s disease. Lancet 2016;388:505-17.DOIPubMed
27. Blennow K, Biscetti L, Eusebi P, Parnetti L. Cerebrospinal fluid biomarkers in Alzheimer’s and Parkinson’s diseases-from pathophysiology to clinical practice. Mov Disord 2016;31:836-47.DOIPubMed
28. Leinonen V, Koivisto AM, Savolainen S, Rummukainen J, Sutela A, et al. Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature. Neuropathol Appl Neurobiol 2012;38:72-86.DOIPubMed
29. Silverberg GD. Normal pressure hydrocephalus (NPH): ischaemia, CSF stagnation or both. Brain 2004;127:947-8.DOIPubMed
30. Kudo T, Mima T, Hashimoto R, Nakao K, Morihara T, et al. Tau protein is a potential biological marker for normal pressure hydrocephalus. Psychiatry Clin Neurosci 2000;54:199-202.DOIPubMed
31. Magdalinou N, Lees AJ, Zetterberg H. Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions. J Neurol Neurosurg Psychiatry 2014;85:1065-75.DOIPubMed PMC
32. Pyykko OT, Lumela M, Rummukainen J, Nerg O, Seppala TT, et al. Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus. PLoS One 2014;9:e91974.DOIPubMed PMC
33. Miyajima M, Nakajima M, Motoi Y, Moriya M, Sugano H, et al. Leucine-rich alpha2-glycoprotein is a novel biomarker of neurodegenerative disease in human cerebrospinal fluid and causes neurodegeneration in mouse cerebral cortex. PLoS One 2013;8:e74453.DOIPubMed PMC
34. Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 2003;61:1720-5.DOIPubMed
35. Jeppsson A, Höltta M, Zetterberg H, Blennow K, Wikkelsø C, et al. Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS 2016;13:13.DOIPubMed PMC
36. Jeppsson A, Zetterberg H, Blennow K, Wikkelsø C. Idiopathic normal-pressure hydrocephalus: pathophysiology and diagnosis by CSF biomarkers. Neurology 2013;80:1385-92.DOIPubMed
37. Tullberg M, Blennow K, Mansson JE, Fredman P, Tisell M, et al. Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur J Neurol 2007;14:248-54.DOIPubMed
38. Tullberg M, Rosengren L, Blomsterwall E, Karlsson JE, Wikkelso C. CSF neurofilament and glial fibrillary acidic protein in normal pressure hydrocephalus. Neurology 1998;50:1122-7.DOIPubMed
39. Marcus J, Honigbaum S, Shroff S, Honke K, Rosenbluth J, et al. Sulfatide is essential for the maintenance of CNS myelin and axon structure. Glia 2006;53:372-81.DOIPubMed
40. Miller A, Glass-Marmor L, Abraham M, Grossman I, Shapiro S, et al. Bio-markers of disease activity and response to therapy in multiple sclerosis. Clin Neurol Neurosurg 2004;106:249-54.DOIPubMed
41. Lamers KJB, Vos P, Verbeek MM, Rosmalen F, van Geel WJA, et al. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res Bull 2003;61:261-4.DOIPubMed
42. Longatti PL, Canova G, Guida F, Carniato A, Moro M, et al. The CSF myelin basic protein: a reliable marker of actual cerebral damage in hydrocephalus. J Neurosurg Sci 1993;37:87-90.PubMed
43. Nakajima M, Miyajima M, Ogino I, Watanabe M, Miyata H, et al. Leucine-rich alpha-2-glycoprotein is a marker for idiopathic normal pressure hydrocephalus. Acta Neurochir (Wien) 2011;153:1339-46.DOIPubMed PMC
44. Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine 2016;1.PubMed PMC
45. Tarkowski E, Tullberg M, Fredman P, Wikkelso C. Normal pressure hydrocephalus triggers intrathecal production of TNF-alpha. Neurobiol Aging 2003;24:707-14.DOIPubMed
46. Castaneyra-Ruiz L, Gonzalez-Marrero I, Carmona-Calero EM, Abreu-Gonzalez P, Lecuona M, 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.DOIPubMed
47. 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;413:141-4.DOIPubMed
48. Pfanner T, Henri-Bhargava A, Borchert S. Cerebrospinal fluid biomarkers as predictors of shunt response in idiopathic normal pressure hydrocephalus: a systematic review. Can J Neurol Sci 2018;45:3-10.DOIPubMed
49. Zhang X, Huang WJ, Chen WW. TGF-beta1 factor in the cerebrovascular diseases of Alzheimer’s disease. Eur Rev Med Pharmacol Sci 2016;20:5178-85.PubMed
50. Crawley JT, Goulding DA, Ferreira V, Severs NJ, Lupu F. Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2002;22:218-24.DOIPubMed
51. Sosvorova L, Vcelak J, Mohapl M, Vitku J, Bicikova M, et al. Selected pro- and anti-inflammatory cytokines in cerebrospinal fluid in normal pressure hydrocephalus. Neuro Endocrinol Lett 2014;35:586-93.PubMed
52. Sosvorova L, Mohapl M, Vcelak J, Hill M, Vitku J, et al. The impact of selected cytokines in the follow-up of normal pressure hydrocephalus. Physiol Res 2015;64:S283-90.DOIPubMed
53. Kester MI, Teunissen CE, Sutphen C, Herries EM, Ladenson JH, et al. Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer’s disease in a memory clinic cohort. Alzheimers Res Ther 2015;7:59.DOIPubMed PMC
54. Poca MA, Mataró M, Sahuquillo J, Catalán R, Ibañez J, et al. Shunt related changes in somatostatin, neuropeptide Y, and corticotropin releasing factor concentrations in patients with normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 2001;70:298-304.DOIPubMed PMC
55. Tisell M, Tullberg M, Mansson JE, Fredman P, Blennow K, et al. Differences in cerebrospinal fluid dynamics do not affect the levels of biochemical markers in ventricular CSF from patients with aqueductal stenosis and idiopathic normal pressure hydrocephalus. Eur J Neurol 2004;11:17-23.DOIPubMed
56. Wikkelsö C, Ekman R, Westergren I, Johansson B. Neuropeptides in cerebrospinal fluid in normal-pressure hydrocephalus and dementia. Eur Neurol 1991;31:88-93.DOIPubMed
57. Tullberg M, Mansson JE, Fredman P, Lekman A, Blennow K, et al. CSF sulfatide distinguishes between normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy. J Neurol Neurosurg Psychiatry 2000;69:74-81.DOIPubMed PMC
58. Nooijen PT, Schoonderwaldt HC, Wevers RA, Hommes OR, Lamers KJ. Neuron-specific enolase, S-100 protein, myelin basic protein and lactate in CSF in dementia. Dement Geriatr Cogn Disord 1997;8:169-73.DOIPubMed
59. Tarnaris A, Toma AK, Pullen E, Chapman MD, Petzold A, et al. Cognitive, biochemical, and imaging profile of patients suffering from idiopathic normal pressure hydrocephalus. Alzheimers Dement 2011;7:501-8.DOIPubMed
60. Fersten E, Gordon-Krajcer W, Glowacki M, Mroziak B, Jurkiewicz J, et al. Cerebrospinal fluid free-radical peroxidation products and cognitive functioning patterns differentiate varieties of normal pressure hydrocephalus. Folia Neuropathol 2004;42:133-40.PubMed
61. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41-53.DOIPubMed
62. Chow BW, Gu C. The molecular constituents of the blood-brain barrier. Trends Neurosci 2015;38:598-608.DOIPubMed PMC
63. Janelidze S, Hertze J, Nagga K, Nilsson K, Nilsson C, et al. Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol Aging 2017;51:104-12.DOIPubMed PMC
64. Eide PK, Pripp AH. Increased prevalence of cardiovascular disease in idiopathic normal pressure hydrocephalus patients compared to a population-based cohort from the HUNT3 survey. Fluids Barriers CNS 2014;11:19.DOIPubMed PMC
65. Krauss JK, Regel JP, Vach W, Orszagh M, Jungling FD, et al. White matter lesions in patients with idiopathic normal pressure hydrocephalus and in an age-matched control group: a comparative study. Neurosurgery 1997;40:491-5.DOIPubMed
66. Jaraj D, Agerskov S, Rabiei K, Marlow T, Jensen C, et al. Vascular factors in suspected normal pressure hydrocephalus: a population-based study. Neurology 2016;86:592-9.DOIPubMed PMC
67. Graff-Radford NR, Knopman DS, Penman AD, Coker LH, Mosley TH. Do systolic BP and pulse pressure relate to ventricular enlargement? Eur J Neurol 2013;20:720-4.DOIPubMed
68. Miyajima M, Nakajima M, Ogino I, Miyata H, Motoi Y, et al. Soluble amyloid precursor protein alpha in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus. Eur J Neurol 2013;20:236-42.DOIPubMed
69. Mashayekhi F, Salehi Z. Expression of nerve growth factor in cerebrospinal fluid of congenital hydrocephalic and normal children. Eur J Neurol 2005;12:632-7.DOIPubMed
70. Yang JT, Chang CN, Hsu YH, Wei KC, Lin TK, et al. Increase in CSF NGF concentration is positively correlated with poor prognosis of postoperative hydrocephalic patients. Clin Biochem 1999;32:673-5.DOIPubMed
71. Del Bigio MR. Neuropathological changes caused by hydrocephalus. Acta Neuropathol 1993;85:573-85.DOIPubMed
72. Li X, Miyajima M, Mineki R, Taka H, Murayama K, et al. Analysis of cerebellum proteomics in the hydrocephalic H-Tx rat. Neuroreport 2005;16:571-4.DOIPubMed
73. Yang J, Dombrowski SM, Krishnan C, Krajcir N, Deshpande A, et al. Vascular endothelial growth factor in the CSF of elderly patients with ventriculomegaly: variability, periodicity and levels in drainage responders and non-responders. Clin Neurol Neurosurg 2013;115:1729-34.DOIPubMed
74. Yang J, Shanahan KJ, Shriver LP, Luciano MG. Exercise-induced changes of cerebrospinal fluid vascular endothelial growth factor in adult chronic hydrocephalus patients. J Clin Neurosci 2016;24:52-6.DOIPubMed
75. Huang H, Yang J, Luciano M, Shriver LP. Longitudinal metabolite profiling of cerebrospinal fluid in normal pressure hydrocephalus links brain metabolism with exercise-induced VEGF production and clinical outcome. Neurochem Res 2016;41:1713-22.DOIPubMed
76. Bartosik-Psujek H, Stelmasiak Z. Biochemical markers of damage of the central nervous system in multiple sclerosis. Ann Univ Mariae Curie Sklodowska Med 2001;56:389-92.PubMed
77. Mase M, Yamada K, Shimazu N, Seiki K, Oda H, et al. Lipocalin-type prostaglandin D synthase (beta-trace) in cerebrospinal fluid: a useful marker for the diagnosis of normal pressure hydrocephalus. Neurosci Res 2003;47:455-9.DOIPubMed
78. Shaw LM, Hansson O, Manuilova E, Masters CL, Doecke JD, et al. Method comparison study of the Elecsys(R) beta-Amyloid (1-42) CSF assay versus comparator assays and LC-MS/MS. Clin Biochem 2019;72:7-14.DOIPubMed
79. Yang J, Dombrowski SM, Deshpande A, Krajcir N, El-Khoury S, et al. Stability analysis of vascular endothelial growth factor in cerebrospinal fluid. Neurochem Res 2011;36:1947-54.DOIPubMed
80. Schindler SE, Gray JD, Gordon BA, Xiong C, Batrla-Utermann R, et al. Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement 2018;14:1460-9.DOIPubMed PMC
Zhang XJ, Guo J, Yang J. Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus. Neuroimmunol Neuroinflammation 2020;7:109-19. http://dx.doi.org/10.20517/2347-8659.2019.018