Jeffrey L. Seeburger

Scales as outcome measures for Alzheimer's disease.

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimers disease (AD) continues to evolve. In addition to assessing drugs for symptomatic relief, an increasing number of trials are focusing on potential disease‐modifying agents. Moreover, participants with AD are being studied earlier in their course of disease. As a result, the limitations of current outcome measures have become more apparent, as has the need for better instruments. In recognition of the need to review and possibly revise current assessment measures, the Alzheimers Association, in cooperation with industry leaders and academic investigators, convened a Research Roundtable meeting devoted to scales as outcome measures for AD clinical trials. The meeting included a discussion of methodological issues in the use of scales in AD clinical trials, including cross‐cultural issues. Specific topics related to the use of cognitive, functional, global, and neuropsychiatric scales were also presented. Speakers also addressed academic and industry initiatives for pooling data from untreated and placebo‐treated patients in clinical trials. A number of regulatory topics were also discussed with agency representatives. Panel discussions highlighted areas of controversy, in an effort to gain consensus on various topics.

Screening for New Biomarkers for Subcortical Vascular Dementia and Alzheimer’s Disease

Background: Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD) and Alzheimer’s disease (AD) at an early stage in the disease process. Methods: In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF) samples from dementia patients and patients at risk of developing dementia (mild cognitive impairment). Results: The levels of several CSF proteins were increased in SVD and its incipient state, and in moderate-to-severe AD compared with the control group. In contrast, some CSF proteins were altered in AD, but not in SVD. The levels of heart-type fatty acid binding protein (H-FABP) were consistently increased in all groups with dementia but only in some of their incipient states. Conclusions: In summary, these results support the notion that SVD and AD are driven by different pathophysiological mechanisms reflected in the CSF protein profile and that H-FABP in CSF is a general marker of neurodegeneration.

Cerebrospinal Fluid Biomarkers Distinguish Postmortem-Confirmed Alzheimer's Disease from Other Dementias and Healthy Controls in the OPTIMA Cohort

Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimers disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9-13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ42 and higher t-tau, p-tau, t-tau/Aβ42, and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.

High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

Non-linear relationships of cerebrospinal fluid biomarker levels with cognitive function: an observational study

IntroductionLevels of cerebrospinal fluid (CSF) β-amyloid (Aβ) and Tau proteins change in Alzheimers disease (AD). We tested if the relationships of these biomarkers with cognitive impairment are linear or non-linear.MethodsWe assessed cognitive function and assayed CSF Aβ and Tau biomarkers in 95 non-demented volunteers and 97 AD patients. We then tested non-linearities in their inter-relations.ResultsCSF biomarkers related to cognitive function in the non-demented range of cognition, but these relations were weak or absent in the patient range; Aβ1-40s relationship was biphasic.ConclusionsMajor biomarker changes precede clinical AD and index cognitive impairment in AD poorly, if at all.

Efficacy and tolerability of rizatriptan for the treatment of acute migraine in sumatriptan non-responders

Objective: The study was carried out to assess the efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treating acute migraine in patients who are non-responders to sumatriptan. Background: Many migraineurs report dissatisfaction with sumatriptan efficacy. It is unclear whether sumatriptan 100 mg non-responders will respond to other triptans. Methods: This was a randomized, placebo-controlled, double-blind study in adults with >1-year history of ICHD-II (International Classification of Headache Disorders, second edition) migraine who reported that they generally do not respond to sumatriptan (≥50% unsatisfactory response). In the baseline phase, participants treated a single moderate/severe migraine attack with open-label generic sumatriptan 100 mg. Those who continued to experience moderate/severe pain at two hours post-dose were eligible to enter the double-blind treatment phase, during which participants treated three migraine attacks in crossover fashion (two with rizatriptan 10-mg ODT, one with placebo) after being randomly assigned to one of three treatment sequences (1 : 1 : 1 ratio). The primary endpoint was two-hour pain relief. Results: A total of 102 (94%) participants treated at least one study migraine. Pain relief at two hours was significantly greater with rizatriptan compared with placebo (51% vs. 20%, p < .001). Response rates also favored rizatriptan on two-hour pain freedom (22% vs. 12%, p = .013) as well as 24-hour sustained pain relief (38% vs. 14%, p < .001) and sustained pain freedom (20% vs. 11%, p = .036). Treatment was generally well tolerated. Conclusion: Rizatriptan 10-mg ODT was superior to placebo at providing two-hour pain relief and two-hour pain freedom in the treatment of acute migraine in those who do not respond to sumatriptan 100 mg. Rizatriptan was generally well tolerated in this population.

Rizatriptan for Treatment of Acute Migraine in Patients Taking Topiramate for Migraine Prophylaxis

Objective.— To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis.

P3-092: Prediction of short-term and long-term cognitive decline in moderate Alzheimer's disease patients in the Oxford project to investigate memory and aging (optima) cohort using CSF biomarkers

Background: Assessment of changes in the rate of cognitive decline of patients with AD is a primary objective of AD clinical trials. However, the heterogeneity in the presentation of the disease reduces the sensitivity of cognitive endpoints for evaluating drug efficacy. Consequently, the potential for CSF markers to predict the rate of cognitive decline was examined as a strategy for mitigating the effects of such variance. Methods: The expression of amyloid (A 40, A 42, sAPP , sAPP ) and tau (t-tau, p-tau-181) markers was measured in baseline visit CSF collected from patients with clinicallydiagnosed AD (n 15), pathologically-confirmed AD (n 29), and agematched controls (n 37) who were part of the OPTIMA natural history cohort. The relationship between CSF marker expression and decline in CAMCOG and MMSE scores over the subsequent year was explored using linear regression analysis, and the relationship to long-term ( 10 years) decline in CAMCOG scores explored using nonlinear mixed effects modeling. Results: The AD regression modeling suggested that high baseline t-tau (log2 pg/ml) was associated with more rapid decline in CAMCOG scores within the first year from baseline (%R 10, m [95%CI] -4.5 [-8.4, -0.7], p 0.023). The ratio of t-tau/A 42 was also associated with short-term CAMCOG decline (%R 21, m [95%CI] -5.7 [-8.8, -2.6], p 0.00067). Examination of other tau/amyloid ratios, and of MMSE decline, produced similar results. By comparison, common demographic variables, as well as CSF A 42/A 40, were not associated with decline in the first year. The nonlinear modeling suggested that high baseline tau was also associated with more rapid long-term CAMCOG decline. The CAMCOG half-life was reduced by approximately 50% for patients with baseline tau levels at the 97.5% quantile compared to those at the 2.5% quantile. Conclusions: These findings indicate that CSF biomarkers can account for some variance in the analysis of cognitive decline in AD and that tau/amyloid expression ratios are stronger predictors of short-term decline than the individual markers. This could be due to a more complete representation of the disease process (pathogenesis by amyloid and degeneration by tau) by the ratios. The tau marker alone, however, appears to be a strong predictor of both short-term and long-term decline.

Differential mass spectrometry identifies candidate markers for Alzheimer's disease in humans

(TMT) A and B, denomination (DO80), digit span tests, battery of frontal function were performed in AD patients. All patients gave their informed consent. CSF biomarkers (Ab 1-42, tau and p181 tau) were assessed after lumbar puncture in the month following cognitive tests. Spearman correlation coefficients between CSF biomarkers and the different cognitive tests were calculated. Generalized linear models adjusted for age, sex and level of education were used for multivariable analysis. Results: MMSE scores were inversely associated with the levels of CSF Ab 1-42 (Spearman’s rho 1⁄4 0.28, p 1⁄4 0.03) and TMT B scores were associated with tau (Spearman’s rho1⁄4 0.37, p1⁄4 0.02) and p181-tau (Spearman’s rho1⁄4 0.45, p1⁄4 0.004) CSF levels. These associations remained after adjustment for age, sex, and level of education in multivariable analysis. No correlation was observed with the other cognitive tests. Conclusions: Our results show that in a cohort of recently diagnosed AD patients, CSF biomarkers levels can correlate with the results of cognitive functions. A b 1-42 levels are linked to MMSE scores reflecting the global cognitive functions and tau and p181 tau CSF levels are correlated with executive functions assessed by the TMT B test.