Lü, Mei

ABSTRACT Parkinson's disease (PD) biomarkers are needed to enhance therapeutics research and to understand PD pathogenesis. Methods that simultaneously measure hundreds of small molecular‐weight compounds—metabolomic analysis–“fingerprint” disease‐specific alterations in individual compounds or metabolic pathways. Beyond a nontargeted search for PD biomarkers, we hypothesized that PD cerebrospinal fluid would show increased formation of the excitotoxin 3‐hydroxykynurenine and diminished concentration of the antioxidant glutathione. Cerebrospinal fluid was collected at <4 hours postmortem from 48 pathologically‐verified PD subjects and 57 comparably‐aged controls. Assays involved ultra‐high‐performance liquid and gas chromatography linked to mass spectrometry. We used univariate techniques to determine fold‐changes in concentrations of biochemicals; false‐discovery rates were calculated to exclude spurious findings. Data was modeled using a Support Vector Machine for analyzing compounds selected by Welch's t test. Classification accuracy was determined by cross‐validation. Of 243 structurally‐identified biochemicals,19 compounds differentiated PD from controls at a 20% false‐discovery level. In PD, mean 3‐hydroxykynurenine concentration was increased by one‐third, and mean oxidized glutathione was decreased by 40% (for each, P < .01). Four of the 19 compounds differentiating PD from controls were N‐acetylated amino acids, suggesting a generalized alteration in N‐acetylation activity. The Support Vector Machine classification model distinguished between groups at 83% sensitivity and 91% specificity for the learning data, and at 65% and 79% from cross‐validation. In this study, the first for metabolomic profiling of PD cerebrospinal fluid, we found several novel biomarkers and offer new directions for recognizing disease‐specific biochemical indicators. The findings support involvement of excitotoxicity and oxidative stress in the pathogenesis of PD. © 2013 International Parkinson and Movement Disorder Society

Background and Purpose —The National Institutes of Health Stroke Scale (NIHSS) is accepted widely for measuring acute stroke deficits in clinical trials, but it contains items that exhibit poor reliability or do not contribute meaningful information. To improve the scale for use in clinical research, we used formal clinimetric analyses to derive a modified version, the mNIHSS. We then sought to demonstrate the validity and reliability of the new mNIHSS. Methods —The mNIHSS was derived from our prior clinimetric studies of the NIHSS by deleting poorly reproducible or redundant items (level of consciousness, face weakness, ataxia, dysarthria) and collapsing the sensory item into 2 responses. Reliability of the mNIHSS was assessed with the certification data originally collected to assess the reliability of investigators in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA (recombinant tissue plasminogen activator) Stroke Trial. Validity of the mNIHSS was assessed with the outcome results of the NINDS rtPA Stroke Trial. Results —Reliability was improved with the mNIHSS: the number of scale items with poor κ coefficients on either of the certification tapes decreased from 8 (20%) to 3 (14%) with the mNIHSS. With the use of factor analysis, the structure underlying the mNIHSS was found identical to the original scale. On serial use of the scale, goodness of fit coefficients were higher with the mNIHSS. With data from part I of the trial data, the proportion of patients who improved ≥4 points within 24 hours after treatment was statistically significantly increased by tPA (odds ratio, 1.3; 95% confidence limits, 1.0, 1.8; P =0.05). Likewise, the odds ratio for complete/nearly complete resolution of stroke symptoms 3 months after treatment was 1.7 (95% confidence limits, 1.2, 2.6) with the mNIHSS. Other outcomes showed the same agreement when the mNIHSS was compared with the original scale. The mNIHSS showed good responsiveness, ie, was useful in differentiating patients likely to hemorrhage or have a good outcome after stroke. Conclusions —The mNIHSS appears to be identical clinimetrically to the original NIHSS when the same data are used for validation and reliability. Power appears to be greater with the mNIHSS with the use of 24-hour end points, suggesting the need for fewer patients in trials designed to detect treatment effects comparable to rtPA. The mNIHSS contains fewer items and might be simpler to use in clinical research trials. Prospective analysis of reliability and validity, with the use of an independently collected cohort, must be obtained before the mNIHSS is used in a research setting.

Background and Purpose —The National Institutes of Health Stroke Scale (NIHSS) is a valid, reproducible scale that measures neurological deficit. Of 42 possible points, 7 points are directly related to measurement of language compared with only 2 points related to neglect. Methods —We examined the placebo arm of the NINDS t-PA stroke trial to test the hypothesis that the total volume of cerebral infarction in patients with right hemisphere strokes would be greater than the volume of cerebral infarction in patients with left hemisphere strokes who have similar NIHSS scores. The volume of stroke was determined by computerized image analysis of CT films and CT images stored on computer tape and optical disks. Cube-root transformation of lesion volume was performed for each CT. Transformed lesion volume was analyzed in a logistic regression model to predict volume of stroke by NIHSS score for each hemisphere. Spearman rank correlation was used to determine the relation between the NIHSS score and lesion volume. Results —The volume for right hemisphere stroke was statistically greater than the volume for left hemisphere strokes, adjusting for the baseline NIHSS ( P <0.001). For each 5-point category of the NIHSS score <20, the median volume of right hemisphere strokes was approximately double the median volume of left hemisphere strokes. For example, for patients with a left hemisphere stroke and a 24-hour NIHSS score of 16 to 20, the median volume of cerebral infarction was 48 mL (interquartile range 14 to 111 mL) as compared with 133 mL (interquartile range 81 to 208 mL) for patients with a right hemisphere stroke ( P <0.001). The median volume of a right hemisphere stroke was roughly equal to the median volume of a left hemisphere stroke in the next highest 5-point category of the NIHSS. The Spearman rank correlation between the 24-hour NIHSS score and 3-month lesion volume was 0.72 for patients with left hemisphere stroke and 0.71 for patients with right hemisphere stroke. Conclusions —For a given NIHSS score, the median volume of right hemisphere strokes is consistently larger than the median volume of left hemisphere strokes. The clinical implications of our finding need further exploration.