Development of Biomarkers for the Early Detection of Alzheimer's Disease

Organizer: Mony de Leon, New York University

The Neurodegenerative Diseases Discussion Group focuses broadly on the theme of neurodegenerative diseases in an interdisciplinary fashion. Meetings cover a single issue as it relates to neurodegenerative diseases, in general, including cell death, mitochondrial function, protein misfolding, glial cell function, motor neuron deficiencies, and synaptic integrity. In addition, each meeting features talks covering basic, clinical, and translational aspects of research into neurodegenerative diseases.

Program

Kaj Blennow, University of Göteborg, Sweden, "Use of CSF Biomarkers to Identify Early Alzheimer's Disease, and to Monitor Treatment Effects."

Mony de Leon, New York University, "Imaging and CSF Biomarkers in the Early and Specific Diagnosis of Alzheimer's Disease

Domenico Pratico, University of Pennsylvania, "Biomarkers of Oxidative Stress in Neurodegenerative Diseases: An Update."

Leslie Shaw, University of Pennsylvania, Department of Pathology and Laboratory Medicine, "Validation of Biomarkers for Early Disease Detection in the Alzheimer's Disease Neuroimaging Initiative Multicenter Study: A Progress Report."

Abstracts

"Use of CSF Biomarkers to Identify Early Alzheimer's Disease, and to Monitor Treatment Effects"
Kaj Blennow, University of Göteborg, Sweden
The CSF is in direct contact with the extracellular space of the brain, and may thus reflect biochemical changes in the brain. The CSF biomarkers total tau (T-tau), phosphorylated tau (P-tau) and beta-amyloid_1-42 (A-Beta42), have in numerous studies been found to have a high sensitivity as diagnostic markers for AD. Researchers have not set the focus on early diagnosis of AD, especially to evaluate if these CSF biomarkers may be of use to identify which patients with mild cognitive impairment (MCI) that will progress to AD, i.e. have incipient AD, and which will not progress, since they have a benign form of MCI. Recent data also show that these CSF biomarkers can discriminate incipient AD from benign MCI with high certainty. We suggest that CSF biomarkers will be of great use in clinical trials on new therapeutic compounds in MCI cases, since it will allow identification of MCI cases with incipient AD, with progressive symptoms. In contrast, inclusion also of non-progressive MCI cases may reduce the possibility to identify a clinical effect of the drug. CSF biomarkers may also be valuable tools to identify and monitor the biochemical effect of new candidate drugs in AD patients. A large number of treatment strategies, e.g. A-Beta vaccination regimes and anti-aggregation compounds, have been shown to reduced A-Beta plaque load in AD transgenic mouse models. Small Phase IIa studies using CSF biomarkers may be valuable to verify a biochemical effect also in patients with AD.

"Imaging and CSF Biomarkers in the Early and Specific Diagnosis of Alzheimer's Disease"
Mony de Leon
It is well known that MRI and FDG-PET neuroimaging are informative in the mild cognitive impairment (MCI) stage for predicting future Alzheimer's disease (AD). We recently extended this predictive capacity by reporting on their utility for detecting preclinical AD in normal elderly (NL). These advanced image analysis techniques enable precise evaluation of the hippocampal formation for evidence of glucose metabolic (PET) or structural atrophic (MRI) changes. Our data also show that tissue imaging techniques appear to be informative for longitudinal disease progression. Unfortunately, these imaging measures are not specific for AD. Several CSF measurements including P-tau231 and CSF isoprostane (IP) offer the potential for improved specificity and good cross-sectional MCI to AD prediction data, however we observed that without CSF volume correction, only the longitudinal performanc