Parametric in vivo brain imaging during activation to examine pathological mechanisms of functional failure in Alzheimer disease.

Alzheimer disease (AD) patients demonstrate reduced "resting state" regional cerebral metabolic rates for glucose (rCMRglc) and reduced regional cerebral blood flow (rCBF) in cortical association areas, early and throughout the course of disease. In this paper, we hypothesize that parametric cognitive or passive stimulation, during in vivo brain imaging, can be used to elucidate the pathological basis of these flow and metabolic abnormalities in individual AD patients. Experimental data suggest that sigmoidal relations (nonliner monotonically increasing relations reaching a horizontal asymptote) exist in the normal brain between rCBF or rCMRglc, and a function F(D,P) of task difficulty D (intensity, duration, pattern complexity) and subject performance P (reaction time, accuracy, effort, attention). Pathological mechanism I, under some conditions reversible and involving neural (including synaptic) element dropout or modification with retained capacity for full activation at high values of F(D,P), is expected early in AD and should shift the rising phase of the normal sigmoidal curve to the right. Observed rCBF responses in a face-matching task in mildly-moderately demented AD patients are consistent with mechanism I. Pathological mechanisms II and III, both irreversible and involving neural element dropout with loss of capacity for maximum activation, should alter the sigmoidal brain response at all values of F(D,P), and are expected late in disease. Our hypothesis predicts that activation paradigms with a wide range of F(D,P) values could help to distinguish among the reversible and irreversible pathological mechanisms in AD, and to evaluate drug action on these mechanisms.