Vol 58, No 1 (2024)
Research Paper
Published online: 2024-02-23

open access

Page views 392
Article views/downloads 327
Get Citation

Connect on Social Media

Connect on Social Media

Neuronal pentraxin 2 correlates with neurodegeneration but not cognition in idiopathic normal pressure hydrocephalus (iNPH)

Megha Patel1, Yifan Zhang2, Mei-Fang Xiao3, Paul Worley13, Abhay Moghekar1
Pubmed: 38393959
Neurol Neurochir Pol 2024;58(1):47-53.


Aim of the study. Neuronal pentraxin-2 (NPTX2) is a synaptic protein responsible for modulating plasticity at excitatory synapses. While the role of NPTX2 as a novel synaptic biomarker in cognitive disorders has been elucidated recently, its role in idiopathic normal pressure hydrocephalus (iNPH) is not yet understood. Clinical rationale for study. To determine if NPTX2 predicts cognition in patients with iNPH, and whether it could serve as a predictive marker for shunt outcomes.

Material and methods. 354 iNPH patients underwent cerebrospinal fluid drainage (CSF) as part of the tap test or extended lumbar drainage. Demographic and clinical measures including age, Evans Index (EI), Montreal Cognitive Assessment (MoCA) score, Functional Activities Questionnaire (FAQ) score, and baseline and post-shunt surgery Timed Up and Go (TUG) test scores were ascertained. CSF NPTX2 concentrations were measured using an ELISA. CSF β-amyloid 1–40 (Aβ1–40), β-amyloid 1–42 (Aβ1–42), and phosphorylated tau-181 (pTau-181) were measured by chemiluminescent assays. Spearman’s correlation was used to determine the correlation between CSF NPTX2 concentrations and age, EI, MoCA and FAQ, TUG, Aβ1–40/Aβ1–42 ratio, and pTau-181 concentrations. Logistic regression was used to determine if CSF NPTX2 values were a predictor of short-term improvement post-CSF drainage or long-term improvement post-shunt surgery.

Results. There were 225 males and 129 females with a mean age of 77.7 years (± 7.06). Average CSF NPTX2 level in all iNPH patients was 559.97 pg/mL (± 432.87). CSF NPTX2 level in those selected for shunt surgery was 505.61 pg/mL (± 322.38). NPTX2 showed modest correlations with pTau-181 (r = 0.44, p < 0.001) with a trend for Aβ42/Aβ40 ratio (r = –0.1, p = 0.053). NPTX2 concentrations did not correlate with age (r = –0.012, p = 0.83) or MoCA score (r = 0.001, p = 0.87), but correlated negatively with FAQ (r = –0.15, p = 0.019).

Conclusions. While CSF NPTX2 values correlate with neurodegeneration, they do not correlate with cognitive or functional measures in iNPH. CSF NPTX2 cannot serve as a predictor of either short-term or long-term improvement after CSF drainage.

Clinical implications. These results suggest that synaptic degeneration is not a core feature of iNPH pathophysiology.

Article available in PDF format

View PDF Download PDF file


  1. Chapman G, Shanmugalingam U, Smith PD. The role of neuronal pentraxin 2 (NP2) in regulating glutamatergic signaling and neuropathology. Front Cell Neurosci. 2019; 13: 575.
  2. Lin CH, Huang YJ, Lin CJ, et al. NMDA neurotransmission dysfunction in mild cognitive impairment and Alzheimer's disease. Curr Pharm Des. 2014; 20(32): 5169–5179.
  3. Libiger O, Shaw LM, Watson MH, et al. Alzheimer's Disease Neuroimaging Initiative (ADNI), Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, Longitudinal CSF Proteomics Project Team. Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease. Alzheimers Dement. 2021; 17(12): 1976–1987.
  4. Ende Ev, Xiao M, Xu D, et al. Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia. Journal of Neurology, Neurosurgery & Psychiatry. 2020; 91(6): 612–621.
  5. Boiten WA, van Steenoven I, Xiao MF, et al. Pathologically decreased CSF levels of synaptic marker NPTX2 in DLB are correlated with levels of alpha-synuclein and VGF. Cells. 2020; 10(1).
  6. Nassar BR, Lippa CF. Idiopathic normal pressure hydrocephalus: a review for general practitioners. Gerontol Geriatr Med. 2016; 2.
  7. Feletti A, d'Avella D, Wikkelsø C, et al. Ventriculoperitoneal shunt complications in the european idiopathic normal pressure hydrocephalus multicenter study. Oper Neurosurg (Hagerstown). 2019; 17(1): 97–102.
  8. Giordan E, Palandri G, Lanzino G, et al. Outcomes and complications of different surgical treatments for idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis. J Neurosurg. 2018 [Epub ahead of print]: 1–13.
  9. Owler BK, Pickard JD. Normal pressure hydrocephalus and cerebral blood flow: a review. Acta Neurol Scand. 2001; 104(6): 325–342.
  10. Xiao H, Hu F, Ding J, et al. Cognitive Impairment in Idiopathic Normal Pressure Hydrocephalus. Neurosci Bull. 2022; 38(9): 1085–1096.
  11. Wang Z, Zhang Y, Hu F, et al. Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus. CNS Neurosci Ther. 2020; 26(12): 1230–1240.
  12. Tan C, Wang X, Wang Y, et al. The pathogenesis based on the glymphatic system, diagnosis, and Treatment of Idiopathic Normal Pressure Hydrocephalus. Clin Interv Aging. 2021; 16: 139–153.
  13. Xiao MF, Xu D, Craig MT, et al. NPTX2 and cognitive dysfunction in Alzheimer's disease. Elife. 2017; 6.
  14. Bae YJ, Choi BSe, Kim JM, et al. Altered glymphatic system in idiopathic normal pressure hydrocephalus. Parkinsonism Relat Disord. 2021; 82: 56–60.
  15. Torretta E, Arosio B, Barbacini P, et al. Novel insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) biomarker discovery in CSF. Int J Mol Sci. 2021; 22(15).
  16. Leinonen V, Koivisto AM, Savolainen S, et al. Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature. Neuropathol Appl Neurobiol. 2012; 38(1): 72–86.
  17. Wesner E, Etzkorn L, Bakre S, et al. The clinical utility of the MOCA in iNPH assessment. Front Neurol. 2022; 13.
  18. Cabral D, Beach TG, Vedders L, et al. Frequency of Alzheimer's disease pathology at autopsy in patients with clinical normal pressure hydrocephalus. Alzheimers Dement. 2011; 7(5): 509–513.
  19. Larsson J, Israelsson H, Eklund A, et al. Falls and fear of falling in shunted Idiopathic Normal Pressure Hydrocephalus-the idiopathic normal pressure hydrocephalus comorbidity and risk factors associated with hydrocephalus study. Neurosurgery. 2021; 89(1): 122–128.
  20. Darrow JA, Lewis A, Gulyani S, et al. CSF biomarkers predict gait outcomes in Idiopathic Normal Pressure Hydrocephalus. Neurol Clin Pract. 2022; 12(2): 91–101.
  21. 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(1): 3–10.
  22. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009; 302(4): 385–393.
  23. Graff-Radford NR. Alzheimer CSF biomarkers may be misleading in normal-pressure hydrocephalus. Neurology. 2014; 83(17): 1573–1575.
  24. Belbin O, Xiao MF, Xu D, et al. Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer's disease-related inhibitory circuit dysfunction in adults with Down syndrome. Mol Neurodegener. 2020; 15(1): 46.
  25. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 1995; 38(4): 643–648.
  26. Ray B, Reyes PF, Lahiri DK. Biochemical studies in Normal Pressure Hydrocephalus (NPH) patients: change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Aβ) peptide and phospho-tau. J Psychiatr Res. 2011; 45(4): 539–547.
  27. Harrison IF, Ismail O, Machhada A, et al. Impaired glymphatic function and clearance of tau in an Alzheimer's disease model. Brain. 2020; 143(8): 2576–2593.
  28. Qiu T, Liu Q, Chen YX, et al. Aβ42 and Aβ40: similarities and differences. J Pept Sci. 2015; 21(7): 522–529.
  29. Kumar-Singh S, Theuns J, Van Broeck B, et al. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006; 27(7): 686–695.
  30. Brean A, Eide PK. Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol Scand. 2008; 118(1): 48–53.
  31. Malm J, Eklund A. Idiopathic normal pressure hydrocephalus. Practical Neurology. 2006; 6(1): 14–27.
  32. Alexandre TS, Meira DM, Rico NC, et al. Accuracy of timed up and go test for screening risk of falls among community-dwelling elderly. Rev Bras Fisioter. 2012; 16(5): 381–388.
  33. Kear B, Guck T, McGaha A. Timed Up and Go (TUG) Test. Journal of Primary Care & Community Health. 2016; 8(1): 9–13.
  34. Scully AE, Lim EC, Teow PP, et al. A systematic review of the diagnostic utility of simple tests of change after trial removal of cerebrospinal fluid in adults with normal pressure hydrocephalus. Clin Rehabil. 2018; 32(7): 942–953.

Neurologia i Neurochirurgia Polska