Jump to comment:

• The utility of CSF biomarkers in idiopathic normal pressure hydrocephalus?
  Halil Onder
  Published on: 10 July 2019

• Published on: 10 July 2019

  The utility of CSF biomarkers in idiopathic normal pressure hydrocephalus?

  • Halil Onder, Neurology Specialist Neurology Clinic, Yozgat City Hospital, Yozgat, Turkey, Telephone number: 3544442066

  Dear Editor,
  The original article by Jeppsson et al. provides substantial perspectives regarding the diagnostic
  significance of cerebrospinal fluid (CSF) biomarkers in discriminating patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. 1 They have found that patients with iNPH had, compared with healthy individuals, lower concentrations of P-tau and APP-derived proteins in combination with elevated MCP-1 1. Moreover, compared with the non-iNPH disorders group, iNPH was characterized by the same significant change; low concentration of tau proteins and APP-derived proteins, and elevated MCP-1. I sincerely appreciate the authors for conducting such a large-scale study of a strictly interesting topic. However, I would like to make some comments hoping to provide a better understanding of some points and some perspectives to be kept in mind while planning future related studies
  In my opinion, the investigation of CSF biomarkers in patients with iNPH may provide several insights in addition to discriminating the iNPH patients from other neurodegenerative diseases. Certainly, these study results may give the opportunity to understand the unknown pathophysiological aspects of iNPH, thereby, even leading to new classifications of the disease. Actually, there may be many questions to be clarified regarding diagnostic approach, evaluation of the iNPH patients and even identification of the disease. 2,3...

  Show More

  Dear Editor,
  The original article by Jeppsson et al. provides substantial perspectives regarding the diagnostic
  significance of cerebrospinal fluid (CSF) biomarkers in discriminating patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. 1 They have found that patients with iNPH had, compared with healthy individuals, lower concentrations of P-tau and APP-derived proteins in combination with elevated MCP-1 1. Moreover, compared with the non-iNPH disorders group, iNPH was characterized by the same significant change; low concentration of tau proteins and APP-derived proteins, and elevated MCP-1. I sincerely appreciate the authors for conducting such a large-scale study of a strictly interesting topic. However, I would like to make some comments hoping to provide a better understanding of some points and some perspectives to be kept in mind while planning future related studies
  In my opinion, the investigation of CSF biomarkers in patients with iNPH may provide several insights in addition to discriminating the iNPH patients from other neurodegenerative diseases. Certainly, these study results may give the opportunity to understand the unknown pathophysiological aspects of iNPH, thereby, even leading to new classifications of the disease. Actually, there may be many questions to be clarified regarding diagnostic approach, evaluation of the iNPH patients and even identification of the disease. 2,3 For instance, the diagnosis of iNPH may be a considerably challenging issue knowing that the full triad of NPH is present in under 60% of patients and the individual components of this triad are nonspecific as they may be encountered in many other neurodegenerative disorders. 2 Nevertheless, the gold standard of the diagnosis has been indicated as the short-term response to CSF drainage. 3,4 On the other hand, although a substantial rate of patients with iNPH improve by shunt surgery (80%), a crucial topic of discussion may be that why some subgroup of patients do not benefit from shunt surgery? Some authors have suggested that the presence of a possible underdiagnosed neurodegenerative disease might the main cause of shunt unresponsiveness in this patient subgroup. Arrestingly, in patients with iNPH, the high rates of the neurodegenerative comorbidities have been reported, several times. 3,5 Besides, it is acknowledged that although the presence of comorbidities does not exclude the possibility of iNPH; comorbidities do influence the prognosis after shunt surgery. 5 More interestingly, Espay et al. preferred to identify some subgroup of patients as the hydrocephalic presentations of neurodegenerative disorders (rather than NPH). 3 However, I believe that many of these discussions may be elucidated in the era of CSF biochemical investigations. Considering the various unknown aspects about the pathophysiology and pathogenesis of iNPH, the sufficiency of the current diagnostic criteria basing on the clinical triad, neuroimaging and short-term response to CSF diversion may also be interrogated. Based on the rationale of that treatment response is a critical clue providing insights about the underlying pathophysiology, I think that the response to shunt surgery may potentially be a crucial criteria to be kept in mind while diagnosing and classifying the patients with the current diagnosis of iNPH. 6 Hence, the use of CSF biomarkers may give promising conclusions for a better understanding of the iNPH pathophysiology and provide possible new classification criteria of the disease. Besides, it is remarkable to state that iNPH has been basically explained via mechanisms of CSF dynamic disturbance, mechanical stretching of periventricular tissue by the enlarging ventricles, impairment of blood-brain barrier, impaired periventricular blood flow associated to interstitial edema, ependyma disruption, microvascular infarctions, gliosis. However, there is no notable clue to classify iNPH as a primary neurodegenerative disease. On the other hand, secondary mechanisms including disturbed elimination of neurotoxic substances such as β-amyloid, tau-protein, and pro-inflammatory cytokines (basically associated with disturbed CSF turnover) have been hypothesized to be involved in the deterioration of iNPH clinic. 7,8 Ergo, investigations of CFS biomarkers in patients with iNPH may also give substantial perspectives regarding the pathophysiological features of iNPH which might be significantly varying among iNPH patients according to the current diagnostic criteria. 6 Furthermore, although it was not investigated in this study, 1 I think that analyzing the differentiating features of CSF biomarkers in iNPH patients benefiting and non-benefiting by shunt surgery would give substantial perspectives about the discussions mentioned above. The authors refer to the previous two reports 9,10 and indicate that there have not been any promising investigations on the use of CSF biomarkers to separate responders from non-responders. Nevertheless, I would like to remind that the mentioned reports included a limited number of patients and, actually, in the report by Miyajima et al., sAPPa was found as a suitable biomarker for also the prognosis of iNPH. 9 Therefore, in my opinion, the investigation of the significance of CSF biochemical pattern in distinguishing the NPH patients of shunt responders and non-responders, certainly constitutes a crucial topic of interest. The CSF biochemical patterns may also be investigated in patients with the current diagnosis of secondary NPH which have been acknowledged to have higher treatment (shunt) response rates in comparison to patients with iNPH. 11,12 In addition, the results of these mentioned studies may provide clues about the critical question of that what extent of the reversibility of the disease is due to the mechanical factors or a possible recovery of an underlying neurodegenerative process, thereby providing crucial insights about the primary underlying pathophysiology.
  Abbreviations: CSF; Cerebrospinal fluid, APP; amyloid precursor protein, MCP-1; monocyte chemoattractant protein 1
  Acknowledgments: None.
  Funding: None.
  Conflict of interests: None.

  References
  1. Jeppsson A, Wikkelso C, Blennow K, et al. CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics. J Neurol Neurosurg Psychiatry. Jun 5 2019.
  2. Marmarou A, Young HF, Aygok GA, et al. Diagnosis and management of idiopathic normal-pressure hydrocephalus: a prospective study in 151 patients. J Neurosurg. Jun 2005;102(6):987-997.
  3. Espay AJ, Da Prat GA, Dwivedi AK, et al. Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration. Ann Neurol. Oct 2017;82(4):503-513.
  4. Ishikawa M, Guideline Committe for Idiopathic Normal Pressure Hydrocephalus JSoNPH. Clinical guidelines for idiopathic normal pressure hydrocephalus. Neurol Med Chir (Tokyo). Apr 2004;44(4):222-223.
  5. Williams MA, Malm J. Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus. Continuum (Minneap Minn). Apr 2016;22(2 Dementia):579-599.
  6. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery. Sep 2005;57(3 Suppl):S4-16; discussion ii-v.
  7. Kudo T, Mima T, Hashimoto R, et al. Tau protein is a potential biological marker for normal pressure hydrocephalus. Psychiatry Clin Neurosci. Apr 2000;54(2):199-202.
  8. Kondziella D, Sonnewald U, Tullberg M, Wikkelso C. Brain metabolism in adult chronic hydrocephalus. J Neurochem. Aug 2008;106(4):1515-1524.
  9. Miyajima M, Nakajima M, Ogino I, Miyata H, Motoi Y, Arai H. Soluble amyloid precursor protein alpha in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus. Eur J Neurol. Feb 2013;20(2):236-242.
  10. Jeppsson A, Holtta M, Zetterberg H, Blennow K, Wikkelso C, Tullberg M. Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS. Jul 29 2016;13(1):13.
  11. Borgesen SE. Conductance to outflow of CSF in normal pressure hydrocephalus. Acta Neurochir (Wien). 1984;71(1-2):1-45.
  12. Daou B, Klinge P, Tjoumakaris S, Rosenwasser RH, Jabbour P. Revisiting secondary normal pressure hydrocephalus: does it exist? A review. Neurosurg Focus. Sep 2016;41(3):E6.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top