Dissecting molecular mechanisms in the living brain of dementia patients.
Understanding the molecular mechanisms associated with the development of dementia is essential for designing successful interventions. Dementia, like cancer and cardiovascular disease, requires early detection to potentially arrest or prevent further disease progression. By the time a neurologist begins to manage clinical symptoms, the disease has often damaged the brain significantly. Because successful treatment is the logical goal, detecting the disease when brain damage is still limited is of the essence. The role of chemistry in this discovery process is critical. With the advent of molecular imaging, the understanding of molecular mechanisms in human neurodegenerative diseases has exploded. Traditionally, knowledge of enzyme and neurotransmitter function in humans has been extrapolated from animal studies, but now we can acquire data directly from both healthy and diseased human subjects. In this Account, we describe the use of molecular imaging probes to elucidate the biochemical and cellular bases of dementia (e.g., Alzheimer's disease) and the application of these discoveries to the design of successful therapeutic interventions. Molecular imaging permits observation and evaluation of the basic molecular mechanisms of disease progression in the living brains of patients. 2-Deoxy-2-[(18)F]fluoro-d-glucose is used to assess the effect of Alzheimer's disease progression on neuronal circuits projecting from and to the temporal lobe (one of the earliest metabolic signs of the disease). Recently, we have developed imaging probes for detection of amyloid neuropathology (both tau and beta-amyloid peptide deposits) and neuronal losses. These probes allow us to visualize the development of pathology in the living brain of dementia patients and its consequences, such as losses of critical neurons associated with memory deficits and other neuropsychiatric impairments. Because inflammatory processes are tightly connected to the brain degenerative processes, inflammation is now emerging as an important target for new molecular imaging probes. The combination of molecular probes targeting various processes of dementia is a useful tool for detailed monitoring of disease mechanism, progression, and diagnosis, as well as for the development of rational strategies for promising therapeutic interventions.
Barrio
Jorge R
JR
Department of Molecular and Medical Pharmacology, UCLA David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. jbarrio@mednet.ucla.edu
Satyamurthy
Nagichettiar
N
Huang
Sung-Cheng
SC
Petric
Andrej
A
Small
Gary W
GW
Kepe
Vladimir
V
D000544:Alzheimer Disease / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D018450:Disease Progression; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D006801:Humans; D009570:Nitriles / Q000737:chemistry*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry*; D016875:tau Proteins / Q000378:metabolism
C444520:2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile; D016229:Amyloid beta-Peptides; D009570:Nitriles; D019275:Radiopharmaceuticals; D016875:tau Proteins; D019788:Fluorodeoxyglucose F18