Tracking Alzheimer’s Disease in the Living Patient: MRI and Cerebrospinal Fluid Measures of Disease Progression

Hypothesis

Hypothesis

Hypothesis:
The neurodegenerative process in Alzheimer's disease (AD) can be objectively monitored with serial volumetric brain MRI and reliably predicted by cerebrospinal fluid (CSF) markers of neuronal death, glial activation, and inflammation.

Goals:
1. To define two groups of AD patients distinguished by "rate of atrophy" in relevant regions (hippocampus, temporal lobe, total brain volume, ventricular volume) on serial brain MRI scans.

2. To demonstrate a relationship between "rate of atrophy" and CSF measures of disease activity, specifically beta amyloid 1-42, tau, neurofilament, GFAP, S100, F2-isoprostanes, protein carbonyls, prostaglandin E2, and nitrite.

Methods:
Sixty subjects (45 AD subjects and 15 healthy controls) will undergo serial brain MRI scans separated by a year. Volumes calculated will include total brain, temporal lobe, ventricular, and hippocampal volumes. Annual rates of volume change will be calculated for each region.

All subjects will have cerebrospinal fluid (CSF) sampled at the onset of the study. Cell count, glucose, total protein, and albumen index will be measured in the OHSU clinical laboratory. The balance of the CSF will be divided and frozen for future studies.

A panel of CSF markers will be examined in order to determine which biochemical markers of disease activity best predict the rate of brain atrophy. Mechanisms and markers of interest include beta amyloid metabolism (beta amyloid 1-42), tau metabolism (tau), neuronal degeneration (tau, neurofilament), astrocytic activation (GFAP, S100), oxidative stress (F2-isoprostanes, protein carbonyls), inflammation (prostaglandin E2), and nitric oxide metabolism (nitrite and nitrate).

Novel markers and mechanisms will also be sought by comparing CSF from "rapid atrophy" and "slow atrophy" cases with proteomic approaches.

CSF and plasma or serum specimens will be made available to collaborating investigators with compelling hypotheses and methods.

Findings:
The rate of brain atrophy in Alzheimer's disease is predicted by the degree of brain atrophy at baseline.

The cerebrospinal fluid markers which are most promising as outcome measures in clinical trials are tau protein and F2 isoprostanes.

We recently reviewed some data on the CSF albumen index, a marker of blood brain barrier integrity, in these subjects. We found a significant minority (20-25%) of subjects had evidence of BBB impairment, and those subjects had a more rapid rate of brain atrophy and clinical decline.