Standardized regression-based clinical change score cutoffs for normal pressure hydrocephalus.

BACKGROUND: Presently, for patients presenting with suspected Normal Pressure Hydrocephalus (NPH) who undergo temporary drainage of cerebrospinal fluid (CSF) there is no defined model to differentiate chance improvement form clinical significance change at the individual patient level. To address this lack of information we computed standard regression based clinical change models for the 10 Meter Walk Test, Timed Up & Go, Dual Timed Up & Go, 6-Minute Walk Test, Mini-Balance Evaluation Systems Test, Montreal Cognitive Assessment, and Symbol Digit Modalities using data from patients with suspected NPH that underwent temporary drainage of CSF. These clinically significant change modes can classify clinically significant improvement following temporary drainage of CSF at the individual patient level. This allows for physicians to differentiate a clinically significant improvement in symptoms from chance improvement. METHODS: Data was collected from 323 patients, over the age of 60, with suspected NPH that underwent temporary drainage of CSF with corresponding gait and cognitive testing. McSweeney Standardized Regression Based Clinical Change Models were computed for standard gait and cognitive measures: Timed Up & Go, Dual Timed Up & Go, 10 Meter Walk Test, MiniBESTest, 6-Minute Walk Test, Montreal Cognitive Assessment, and Symbol Digit Modalities Test. To assess the discriminate validity of the measures we used correlations, Chi2, and regression analyses. RESULTS: The clinical change models explained 69-91.8% of the variability in post-drain performance (p <  0.001). As patient scores became more impaired, the percent change required for improvement to be clinically significant increased for all measures. We found that the measures were not discriminate, the Timed Up & Go was highly related to the 10 Meter Walk Test (r = 0.85, R2 = 0.769-0.738, p <  0.001), MiniBESTest (r = - 0.67, R2 = 0.589-0.734, p <  0.001), and 6 Minute Walk Test (r = - 0.77, R2 = 0.71-0.734, p <  0.001). CONCLUSION: Standardized Regression Based Clinically Significant Change Models allow for physicians to use an evidence-based approach to differentiate clinically significant change from chance improvement at the individual patient level. The Timed Up & Go was shown to be predictive of detailed measures of gait velocity, balance, and endurance.

Assessment of Preanalytical Cerebrospinal Fluid Handling and Storage Factors on Measurement of Aß1-42, Aß1-40, and pTau181 Using an Automated Chemiluminescent Platform.

BACKGROUND: Standardizing cerebrospinal fluid (CSF) laboratory protocols will improve the reliability and availability of clinical biomarker testing required for prescription of novel Alzheimer disease (AD) therapies. This study evaluated several preanalytical handling and storage factors common to ß-amyloid1-42 (Aß1-42), ß-amyloid1-40 (Aß1-40), and phosphorylated tau (pTau181) concentrations including storage at different temperatures, extended cap contact, various mixing methods, and multiple freeze-thaw cycles. METHODS: Aß1-42, Aß1-40, and pTau181 concentrations were measured using LUMIPULSE G1200 automated assays. Samples were collected in polypropylene tubes of various volumes. Sample cap-contact was evaluated by storing samples in upright and inverted positions at either 4°C for 1 week or -80°C for 1 month. To assess mixing methods, samples were freeze-thawed and mixed by inversion, vortex, horizontal roller, or unmixed prior to assay sampling. The impact of successive freeze-thaw cycles was assessed through freezing, thawing, and analyzing CSF samples. RESULTS: Short-term storage at 4°C did not affect Aß1-42, Aß1-40, or pTau181 measurements in any tube type. Tube cap contact affected Aß1-42 in 2.5 mL tubes and pTau181 levels in 10 mL tubes. No difference was observed between mixing methods. After 4 freeze-thaw cycles, Aß1-42 significantly decreased but Aß1-40 remained unchanged. Utilizing the Aß1-42/Aß1-40 ratio, Aß1-42 values normalized, maintaining ratio values within ±5% of baseline measurements. CONCLUSIONS: Storage of CSF at 4°C for 1 week or -80°C for 1 month did not significantly affect Aß1-42, Aß1-40, pTau181, or associated ratio measurements. Tube cap-contact impacted pTau181 and pTau181/Aß1-42 values in larger tubes. Mixing methods are equivalent. The Aß1-42/Aß1-40 ratio compensates for freeze-thaw variability up to 4 cycles.

CSF Biomarkers Predict Gait Outcomes in Idiopathic Normal Pressure Hydrocephalus.

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), ß-amyloid 42 (Aß1-42), ß-amyloid 40 (Aß1-40), 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 Aß1-40 were individually predictive of long-term improvement in gait outcomes after shunt surgery. A multivariate model of these biomarkers and MRI Evans index, adjusted for age, improved prediction (area under the receiver operating curve 0.76, 95% confidence interval 0.66-0.86). tTau, pTau181, and Aß1-40 levels were statistically different in those whose gait improved after CSF TT compared with those who did not. Using a multivariate model, combining these markers with Evans index and transependymal flow did not significantly improve prediction of an immediate response to CSF TT. Discussion: A combination of CSF biomarkers can predict improvement following shunt surgery for iNPH. However, these measures only modestly discriminate responders from nonresponders following CSF TT. The findings further suggest that abnormal CSF biomarkers in nonresponders may represent comorbid neurodegenerative pathology or a predegenerative phase that presents with an iNPH phenotype.

Effect of Patient-Specific Preanalytic Variables on CSF Aß1-42 Concentrations Measured on an Automated Chemiluminescent Platform.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly used to confirm the accuracy of a clinical diagnosis of mild cognitive impairment or dementia due to Alzheimer disease (AD). Recent evidence suggests that fully automated assays reduce the impact of some preanalytical factors on the variability of these measures. This study evaluated the effect of several preanalytical variables common in clinical settings on the variability of CSF ß-amyloid 1-42 (Aß1-42) concentrations. METHODS: Aß1-42 concentrations were measured using the LUMIPULSE G1200 from both freshly collected and frozen CSF samples. Preanalytic variables examined were: (1) patient fasting prior to CSF collection, (2) blood contamination of specimens, and (3) aliquoting specimens sequentially over the course of collection (i.e., CSF gradients). RESULTS: Patient fasting did not significantly affect CSF Aß1-42 levels. While assessing gradient effects, Aß1-42 concentrations remained stable within the first 5 1-mL aliquots. However, there is evidence of a gradient effect toward higher concentrations over successive aliquots. Aß1-42 levels were stable when fresh CSF samples were spiked with up to 2.5% of blood. However, in frozen CSF samples, even 0.25% blood contamination significantly decreased Aß1-42 concentrations. CONCLUSIONS: The preanalytical variables examined here do not have significant effects on Aß1-42 concentrations if fresh samples are processed within 2 h. However, a gradient effect can be observed on Aß1-42 concentrations after the first 5 mL of collection and blood contamination has a significant impact on Aß1-42 concentrations once specimens have been frozen.