Cerebrospinal Fluid Biomarkers Predict Gait Outcomes in Idiopathic Normal Pressure Hydrocephalus (original) (raw)
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CSF Biomarkers Predict Gait Outcomes in Idiopathic Normal Pressure Hydrocephalus
Neurology: Clinical Practice, 2022
Background and Objectives The assessment of biomarkers in selecting patients with idiopathic normal pressure hydrocephalus (iNPH) for shunt surgery has been limited to small cohort studies and those with limited follow-up. We assessed the potential for CSF biomarkers in predicting immediate response to CSF tap test (TT) and long-term response after shunt surgery. Methods CSF was obtained from patients with iNPH referred for CSF TT after baseline assessment of cognition and gait. CSF neurofilament light (NfL), β-amyloid 42 (Aβ1–42), β-amyloid 40 (Aβ1–40), total tau (tTau), and phosphorylated tau 181 (pTau181) and leucine-rich alpha-2-glycoprotein-1 (LRG1) were measured by ELISA. The ability of these measures to predict immediate improvement following CSF TT and long-term improvement following shunt surgery was compared by univariate and adjusted multivariate regression. Results Lower NfL, pTau181, tTau, and Aβ1–40 were individually predictive of long-term improvement in gait outcomes...
Fluids and barriers of the CNS, 2016
To improve the diagnostic performance of the cerebrospinal fluid (CSF) tap test (TT), early and delayed assessments of gait were performed after the removal of 30 ml of CSF in patients with probable idiopathic normal pressure hydrocephalus. Assessments of gait included the 3-m timed up and go test (TUG), and the 10-m walk in time (10Ti) and in step (10St) tests. Quantitative data for the TUG, the 10Ti, and the 10St were obtained before CSF removal and on days 1 and 4 after removal of 30 ml CSF. CSF shunt surgery was performed in 61 patients within one month after the TT. The gait outcome was assessed 3 months after surgery. The area under the curve (AUC), sensitivity, specificity, and cutoff values were computed for the TUG, the 10Ti, and the 10St on day 1 and day 4 using receiver operating characteristic (ROC) curve analysis. The positive response rate in three measures on day 4 was equal to or higher than the values on day 1. Times were reduced significantly in the TUG and the 10m...
Journal of Alzheimer's disease : JAD, 2018
Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated. To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual ...
Alzheimer’s disease pathology and shunt surgery outcome in normal pressure hydrocephalus
PLOS ONE
We aimed to determine whether presence of AD neuropathology predicted cognitive, gait and balance measures in patients with idiopathic normal pressure hydrocephalus (iNPH) after shunt surgery. This is a prospective study of gait and balance measured by Timed Up and Go (TUG) and Tinetti tests, and cognitive function measured by Mini Mental Status Exam (MMSE), before and after shunt surgery in participants 65 years and older with iNPH at the Johns Hopkins University. Random effects models were used and adjusted for confounders. 88 participants were included in the analysis with a median (IQR) time of 104 (57-213) days between surgery and follow-up. 23 (25%) participants had neuritic plaques present (NP+) and were significantly older [76.4 (6.0) years], but were otherwise similar in all demographics and outcome measures, when compared to the group without neuritic plaques (NP-). NP-and NP+ participants equally improved on measures of TUG (β =-3.
Journal of Alzheimer's Disease, 2021
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), neurofilamen...
Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus
Adult Hydrocephalus, 2014
The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau 181 , Aβ 42 , NFL, TNF-α, TGFβ1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result-that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-α concentration was low in iNPH patients.
Journal of Clinical Neuroscience, 2014
Keywords: b amyloid Biomarker Cerebrospinal fluid Normal pressure hydrocephalus Phosphorylated-tau Predictive value of tests a b s t r a c t Cerebrospinal fluid (CSF) biomarkers, including soluble amyloid b-42 (Ab-42) and phosphorylated-tau (P-tau), reflect core pathophysiological features of Alzheimer's disease (AD). AD is frequently a concomitant pathology in older patients with idiopathic normal-pressure hydrocephalus (iNPH), and somewhat similar altered CSF dynamics exist in both AD and iNPH. We therefore investigated relationships between lumbar CSF biomarkers Ab-42 and P-tau and clinical parameters in iNPH patients, along with differences in these biomarkers between CSF tap test (CSFTT) responders and non-responders. Thirty-one iNPH patients (14 CSFTT responders and 17 CSFTT non-responders) were included in the final analysis. We found lower CSF Ab-42 correlated with poor cognitive performance (r = 0.687, p < 0.001 for Korean Mini Mental State Examination; r = 0.568, p = 0.001 for Frontal Assessment Battery; r = À0.439, p = 0.014 for iNPH grading scale [iNPHGS] cognitive score; r = À0.588, p = 0.001 for Clinical Dementia Rating Scale), and lower CSF P-tau correlated with gait dysfunction (r = À0.624, p < 0.001 for Timed Up and Go Test; r = À0.652, p < 0.001 for 10 meter walking test; r = À0.578, p = 0.001 for Gait Status Scale; r = À0.543, p = 0.002 for iNPHGS gait score). In subgroup analysis, CSF P-tau/Ab-42 ratios were significantly higher in CSFTT non-responders compared to responders (p = 0.027). Two conjectures are suggested. One, CSF biomarkers may play different and characteristic roles in relation to different iNPH symptoms such as cognition and gait. Two, comorbid AD pathology in iNPH patients may affect the response to the CSFTT. Larger studies using combinations of other biomarkers associated with AD would be necessary to evaluate these hypotheses.
Journal of Alzheimer's Disease, 2019
Background: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. Objective: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. Methods: We analyzed CSF concentrations of tau, amyloid- (A) 42 and 40, and leucine rich ␣-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). Results: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, A 42 (LD/FD = 0.80, p < 0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p < 0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau (p = 0.02) and LRG (p = 0.04), respectively. Conclusions: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness.
Movement Disorders Clinical Practice, 2016
Background: Idiopathic normal pressure hydrocephalus (INPH) is a treatable cause of gait disturbance, cognitive impairment, and urinary incontinence. This clinical triad of symptoms occurs in association with ventriculomegaly and normal cerebrospinal fluid (CSF) pressure. Although the treatment outcomes after CSF shunting for INPH have improved significantly since its first description in 1965, shortcomings in our understanding still remain. Not all INPH patients exhibit clinical improvement after shunting, and it is challenging to identify patients who are more likely to benefit from shunting. Methods: The Cochrane Library, Medline, Embase, and PubMed databases were searched for Englishlanguage publications between 1965 and October 2015. Reference lists of publications were also manually searched for additional publications. Results: The findings of this review indicate that, despite efforts to improve patient selection, the degree of clinical improvement after shunting continues to demonstrate significant variability both within and between studies. These discrepancies in treatment outcomes are the result of controversies in 3 distinct but interrelated domains: the underlying pathophysiology of INPH, the diagnosis of INPH, and the identification of likely shunt-responders. Conclusions: This review focuses on these 3 areas and their relation to surgical treatment outcomes. Despite the limitations of published outcome studies and limitations in our understanding of INPH pathophysiology, shunting is a safe and effective means of achieving meaningful clinical improvement in most patients with INPH. Normal pressure hydrocephalus (NPH) was first reported in 1965 as a triad of dementia, gait disturbance, and urinary incontinence, with associated ventricular dilatation and normal cerebrospinal fluid (CSF) pressure. 1 NPH can be classified as idiopathic NPH (INPH) or secondary NPH (SNPH), the latter of which occurs most commonly after subarachnoid hemorrhage, trauma, or meningitis. 2 Although CSF diversion via a shunt is the mainstay of NPH management, surgical outcomes in INPH have been consistently less successful than those in SNPH. 3-5 In addition, the reported rates of postoperative clinical improvement in INPH patients have varied from 24% to 96%. 6,7 These discrepancies in treatment outcomes are the result of controversies in 3 domains: the underlying pathophysiology of INPH, the diagnosis of INPH, and the identification of likely shunt-responders. This review focuses on these 3 areas of controversy and their relation to surgical outcomes. The Cochrane Library, Medline, Embase, and PubMed were searched for English-language publications between 1965 and October 2015 using a combination of medical subject headings and free text key words such as: "normal pressure hydrocephalus," "treatment," "outcome," and "cerebrospinal fluid shunt." Reference lists of publications
2020
Background The amyloid-beta (Aβ) oligomer has strong neurotoxicity and is associated with cognitive impairment in Alzheimer’s disease (AD). However, its role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood. We hypothesised that cerebrospinal fluid (CSF) stagnation leads to Aβ oligomer accumulation in patients with iNPH. We measured CSF Aβ oligomer levels before and after CSF shunting in patients with iNPH. Methods We evaluated two iNPH cohorts: an analysis cohort (cohort-1) with 52 patients and a validation cohort (cohort-2) with 13 patients. For comparison cohorts, we recruited 27 neurologically normal controls (NCs), 16 patients with AD, 15 patients with Parkinson’s disease (PD), and 14 patients with progressive supranuclear palsy (PSP). We measured CSF Aβ oligomer levels and assessed participants’ neurological statuses. We then compared the iNPH cohorts’ pre-shunting measurements with the comparison groups’ measurements and compared cohort-1’...