Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Lukkarinen, Heikki; Tesseur, Ina; Pemberton, Darrel J.; Ark, Peter van der; Timmers, Maarten; Slemmon, Randy; Janssens, Luc; Streffer, Johannes; Nueten, Luc Van; Bottelbergs, Astrid; Rauramaa, Tuomas; Koivisto, Anne M.; Herukka, Sanna‐Kaisa; Korhonen, Ville; Junkkari, Antti; Hiltunen, Mikko; Engelborghs, Sebastiaan; Blennow, Kaj; Zetterberg, Henrik; Kolb, Hartmuth C.; Leinonen, Ville

doi:10.3233/jad-201361

Cited by 11 publications

(28 citation statements)

References 54 publications

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“…Thus, reinforcing the role of NfL as reflecting changes in neurodegeneration independently from T-tau and P-tau 181 . In previous studies, NfL has been stated to be elevated in several neurodegenerative diseases, including iNPH, when compared to healthy individuals, mirroring both acute and subacute changes in brain metabolism [ 26 – 28 ]. Consequently, we believe that our baseline concentrations of lumbar CSF NfL are able to reflect symptoms seen both pre- and postoperatively.…”

Section: Discussionmentioning

confidence: 99%

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Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients

Lukkarinen

Jeppsson

Wikkelsø

et al. 2022

Fluids Barriers CNS

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Background The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid β (Aβ) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. Methods Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ); amyloid-β isoforms of 42, 40 and 38 (Aβ42, Aβ40, Aβ38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). Results Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p < 0.0001). Low CSF T-tau and absence of apolipoprotein E ε4 predicted over 20% gait improvement postoperatively (p = 0.043 and p = 0.008). Preoperative CSF T-tau, P-tau181 and NfL correlated negatively with MMSE scores both pre- (p < 0.01) and post-surgery (p < 0.01). Furthermore, T-tau, NfL and Aβ42 correlated with MMSE outcomes (p < 0.05). Low preoperative CSF P-tau181 (p = 0.001) and T-tau with NfL (p < 0.001 and p = 0.049) best predicted pre- and postoperative MMSE scores greater than or equal to 26. Conclusions CSF biomarkers of neurodegeneration appeared to correlate with pre- and postoperative cognition, providing a window into neuropathological processes. In addition, preoperative CSF neurodegeneration biomarkers may have potential in the prediction of gait and cognitive outcomes after shunt surgery.

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Section: Discussionmentioning

confidence: 99%

“…A possible explanation for the prognostic features of T-tau, P-tau 181 and NfL reported is their ability to reflect acute and subacute neuropathologic processes [ 28 , 29 ]. The natural course of iNPH is reported to be progressive and potentially lethal [ 3 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients

Lukkarinen

Jeppsson

Wikkelsø

et al. 2022

Fluids Barriers CNS

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“…All markers increased notably by 140-810% in lumbar CSF, except beta amyloid that had an erratic behavior. All studied biomarkers (tau, NFL, NRGN and beta amyloid) correlated highly between lumbar and ventricular samples but were systematically lower in ventricular samples [94]. Longitudinal follow-up shoed that after initial postoperative increase, tau and NRGN levels are stable in NPH regardless of brain biopsy amyloid pathology.…”

Section: Lab Testsmentioning

confidence: 82%

“…NFL normalized after surgery to preshunting levels. Amyloid is the less affected by shunting and may be the best predictor of concomitant AD risk in NPH patients [94]. Tau levels (both p-tau and t-tau) have shown a steady increase of 2% per year in AD [95].…”

Section: Lab Testsmentioning

confidence: 99%

Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain

Hakim¹,

Jaramillo-Velásquez²,

Gonzalez³

et al. 2022

Cerebrospinal Fluid

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Normal pressure hydrocephalus syndrome is the most common form of hydrocephalus in the elderly and produces a dementia which can be reversible surgically. It is characterized by ventriculomegaly and the classic triad of symmetric gait disturbance, cognitive decline and urinary incontinence, also known as Hakim’s triad. To date, the exact etiology of the disease has not been elucidated and the only effective treatment is a cerebrospinal fluid shunting procedure which can be a ventriculoatrial, ventriculoperitoneal or lumboperitoneal shunt. The most important problem is the high rate of underdiagnosis or misdiagnosis due to similarities in symptoms with other neurodegenerative disorders, and in some cases, coexistence. Hence, increasing awareness amongst the community and medical professionals in order to increase clinical suspicion, timely diagnosis and treatment are paramount. The best way to achieve this is by having a structured protocol with patient-centered tests that evaluates the entire myriad of alterations a clinician might encounter whenever treating patients with this disorder. Recent advances in imaging technology as well as cerebrospinal fluid biomarkers have given interesting insight into the pathophysiology of the disease and will certainly contribute greatly in diagnostic advancements. We finally present an institutional protocol which has been accredited by international peers with promising results in diagnostic and outcome rates.

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“…In preclinical AD, CSF biomarkers are known to change years before cognitive decline [ 51 ]. A higher prevalence of AD has been shown in females [ 26 – 30 ] and a high comorbidity between AD pathology and iNPH has been found in perioperative brain biopsies [ 52 , 53 ]. With this in mind, one possible explanation for our discrepant findings between the sexes could be a higher prevalence of preclinical AD pathology in the female group.…”

Section: Discussionmentioning

confidence: 99%

Ventricular volume in relation to lumbar CSF levels of amyloid-β 1–42, tau and phosphorylated tau in iNPH, is there a dilution effect?

Lidén

Farahmand

Laurell

2022

Fluids Barriers CNS

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Background Levels of the biomarkers amyloid-β 1–42 (Aβ42), tau and phosphorylated tau (p-tau) are decreased in the cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). The mechanism behind this is unknown, but one potential explanation is dilution by excessive CSF volumes. The aim of this study was to investigate the presence of a dilution effect, by studying the relationship between ventricular volume (VV) and the levels of the CSF biomarkers. Methods In this cross-sectional observational study, preoperative magnetic resonance imaging (MRI) and lumbar CSF was acquired from 136 patients with a median age of 76 years, 89 men and 47 females, selected for surgical treatment for iNPH. The CSF volume of the lateral and third ventricles was segmented on MRI and related to preoperative concentrations of Aβ42, tau and p-tau. Results In the total sample VV (Median 140.7 mL) correlated weakly (rs = − 0.17) with Aβ42 (Median 534 pg/mL), but not with tau (Median 216 pg/mL) nor p-tau (Median 31 pg/mL). In a subgroup analysis, the correlation between VV and Aβ42 was only present in the male group (rs = − 0.22, p = 0.038). Further, Aβ42 correlated positively with tau (rs = 0.30, p = 0.004) and p-tau (rs = 0.26, p = 0.012) in males but not in females. Conclusions The findings did not support a major dilution effect in iNPH, at least not in females. The only result in favor for dilution was a weak negative correlation between VV and Aβ42 but not with the other lumbar CSF biomarkers. The different results between males and females suggest that future investigations of the CSF pattern in iNPH would gain from sex-based subgroup analysis.

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Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Cited by 11 publications

References 54 publications

Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients

Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients

Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain

Ventricular volume in relation to lumbar CSF levels of amyloid-β 1–42, tau and phosphorylated tau in iNPH, is there a dilution effect?

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