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-ß (Aß) 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 Aß plaques in frontal cortical brain biopsy and 13 iNPH patients without Aß pathology. CSF Amyloid-ß42 (Aß42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. RESULTS: All biomarkers but Aß42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aß42 instead showed divergent longitudinal decrease between Aß-positive and -negative patients in L-CSF, and thereafter increase in Aß-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aß42 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 (Aß42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aß42 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 Aß pathology, while NFL normalized toward its pre-shunt levels. Aß42 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.

Copy number loss in SFMBT1 is common among Finnish and Norwegian patients with iNPH.

OBJECTIVE: To evaluate the role of the copy number loss in SFMBT1 in a Caucasian population. METHODS: Five hundred sixty-seven Finnish and 377 Norwegian patients with idiopathic normal pressure hydrocephalus (iNPH) were genotyped and compared with 508 Finnish elderly, neurologically healthy controls. The copy number loss in intron 2 of SFMBT1 was determined using quantitative PCR. RESULTS: The copy number loss in intron 2 of SFMBT1 was detected in 10% of Finnish (odds ratio [OR] = 1.9, p = 0.0078) and in 21% of Norwegian (OR = 4.7, p < 0.0001) patients with iNPH compared with 5.4% in Finnish controls. No copy number gains in SFMBT1 were detected in patients with iNPH or healthy controls. The carrier status did not provide any prognostic value for the effect of shunt surgery in either population. Moreover, no difference was detected in the prevalence of hypertension or T2DM between SFMBT1 copy number loss carriers and noncarriers. CONCLUSIONS: This is the largest and the first multinational study reporting the increased prevalence of the copy number loss in intron 2 of SFMBT1 among patients with iNPH, providing further evidence of its role in iNPH. The pathogenic role still remains unclear, requiring further study.