Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.
BACKGROUND
Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.


OBJECTIVE
To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.


METHODS
L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.


RESULTS
All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.


CONCLUSION
Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.
['Lukkarinen|Heikki|H|', 'Tesseur|Ina|I|', 'Pemberton|Darrel|D|', 'Van Der Ark|Peter|P|', 'Timmers|Maarten|M|', 'Slemmon|Randy|R|', 'Janssens|Luc|L|', 'Streffer|Johannes|J|', 'Van Nueten|Luc|L|', 'Bottelbergs|Astrid|A|', 'Rauramaa|Tuomas|T|', 'Koivisto|Anne M|AM|', 'Herukka|Sanna-Kaisa|SK|', 'Korhonen|Ville E|VE|', 'Junkkari|Antti|A|', 'Hiltunen|Mikko|M|', 'Engelborghs|Sebastiaan|S|', 'Blennow|Kaj|K|', 'Zetterberg|Henrik|H|', 'Kolb|Hartmuth C|HC|', 'Leinonen|Ville|V|']
D000368:Aged D000369:Aged, 80 and over D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D015415:Biomarkers D002557:Cerebrospinal Fluid Shunts D005260:Female D006801:Humans D006850:Hydrocephalus, Normal Pressure D008297:Male D008875:Middle Aged D016900:Neurofilament Proteins D010446:Peptide Fragments D010766:Phosphorylation D012044:Regression Analysis D018570:Risk Assessment D016875:tau Proteins
biomarkers idiopathic normal pressure hydrocephalus Aβ42 T-tau neurofilament light neurogranin P-tau