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

INTRODUCTION: Levels of cerebrospinal fluid (CSF) β-amyloid (Aβ) and Tau proteins change in Alzheimer's disease (AD). We tested if the relationships of these biomarkers with cognitive impairment are linear or non-linear. METHODS: We 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. RESULTS: CSF biomarkers related to cognitive function in the non-demented range of cognition, but these relations were weak or absent in the patient range; Aβ1-40's relationship was biphasic. CONCLUSIONS: Major biomarker changes precede clinical AD and index cognitive impairment in AD poorly, if at all

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

Scales as outcome measures for Alzheimer's disease

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimer's 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 Alzheimer's 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

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

<div><p>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.</p></div

Receiver-operator curves (ROC) for cross-sectional study (Cohort-1).

<p>Comparison of the AD samples versus the control samples was used to estimate the sensitivity, while the comparisons between two groups comprised of randomly selected but equally balanced AD and control samples were used to estimate specificity.</p

The demographic characteristics of the cross sectional study population, Cohort-1, at the time of CSF collection.

<p>CTL = control; AD = Alzheimer's disease; N, n = number of subjects/patients; SD = standard deviation; MMSE = Mini- mental state examination; ApoE = Apolipoprotein E</p><p>The demographic characteristics of the cross sectional study population, Cohort-1, at the time of CSF collection.</p