COMPETITIVE GRANT AWARDS

ERPs as markers of early AD across ethnic groups in MCI

Aims:  1) To test the sensitivity and predictive value of abnormal ERP word repetition effects in patients with MCI.  We will test the predictive value of ERP word repetition effects across all MCI patients, and within subgroups of interest (e.g. minority MCI and non-amnestic MCI). We predict that reduced ERP word repetition effects will be associated with subsequent conversion to AD across and within all these subgroups. 

         2) To test how well “preclinical” abnormalities of the P600 and N400 word repetition effects predict subsequent decline in the cognitive domains of memory and language, respectively.  Prior work suggests that the loss of the P600 word repetition effect indicates dysfunction of neural circuits critical for explicit/declarative memory, while N400 repetition effects appear to reflect implicit memory processes which are related to semantic priming and language comprehension. (Olichney et al Brain 2000).

This study will test a few compounds for their effects in reducing the amount of aggregates of amyloid-b protein (Ab) in the brain. Ab is the major protein component of the amyloid plaques in the brains of patients with Alzheimer's disease (AD).

Ab also exists in small aggregates that are present in early stages of the disease, either inside or outside the neurons in the brain. Many lines of studies strongly support the toxic effects of various Ab aggregates, which may cause dementia in AD. Methods to reduce the levels of Ab, prevent Ab aggregation or eliminate existing Ab aggregates have been proposed for AD therapies. In this proposal, we focus on discovering small molecule, "drug-like" compounds targeting those small Ab aggregates (oligomers) inside the neurons, which have been shown to be an early lesion and causally related to some cognitive deficits and neurodegeneration in AD animal models.

This group of compounds comes from well characterized amyloid ligands, originally developed for use as specific tracers for positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging of brain amyloid. The wish is that these compounds will locate and interact with the small Ab aggregates in the brain and somehow eliminate them. We have some evidence in the test tubes and cultured cells that this might work in living beings. Since animal experiments are a necessary step toward finding effective compounds, we will subject a new and robust AD transgenic model called 5XFAD mice to various regimens of treatments with the candidate compounds.

We will examine whether the compounds are able to reduce the levels of neuronal Ab deposits, and by doing so, ameliorate the synaptic and neuronal loss which are features similar to AD. The proposed experiments would help us to understand the causal relationship of various lesions in the brain of AD patients, and therefore might reveal the fundamental cause of AD. They would also help us to validate or reject our candidate compounds that may have a potential in reducing an early neurotoxic event in AD.

FTLD Diagnostic Study

FTLD is one of the most common presenile neurodegenerative diseases, representing around 15% of early-onset dementia cases (Ikeda). However, diagnostic accuracy is well below what has been achieved for AD, and misdiagnosis is common even at centers specializing in dementia.  Current diagnostic criteria have been criticized for being cumbersome and difficult to use, not designed for use by non-specialists, low inter-rater reliability, and an unacceptably high rate of misdiagnoses.  To address these concerns, international groups of experts have convened to develop new, empirically-based criteria that reflect the recent major advances in our understanding of this group of diseases.  The purpose of this three-year consortium application is to test the inter-rater reliability and validity of these new criteria and develop training modules that will efficiently translate this knowledge to the state ARCCs and to community health care providers. 

The following specific aims will be addressed:

Specific Aim 1:   Assess the inter-rater reliability of the new FTLD diagnostic criteria

Specific Aim 2:   Assess the validity of the new FTLD diagnostic criteria by collecting pathologically-confirmed cases of FTLD and AD and retrospectively applying the diagnostic criteria 

Specific Aim 3:  Assess the validity of the new FTLD diagnostic criteria by prospectively following new cases of FTLD diagnosed with the new criteria.  Subjects will be studies with PIB and, in some instances, pathological confirmation of diagnosis will be possible. 

Specific Aim 4:   To develop educational materials for translate these improved diagnostic criteria to other ARCCs and to community health care providers.