Background
Cortical dysfunction in Alzheimer's disease (AD) has cortical (plaque, tangle, cell death) and subcortical (neural modulators, i. e., cholinergic cell loss) causes. One hypothesis for the modest effect of anticholinesterase (AChE) drugs in AD is that augmenting cholinergic function cannot overcome the disruption from local cortical pathology. This hypothesis predicts that AChE drugs should have a profound restorative effect on cortical brain function in an area of brain that has minimal local pathology. The primary striate cortex is relatively free of local pathology. In healthy controls, its response to a pattern flash stimulus is augmented by endogenous muscarinic activity (Mentis et al. Neuropsychopharmacology, 2001). Therefore, if cholinergic deficiency is the major cause of dysfunction, AChE drugs should cause marked normalization of function in primary striate cortex of AD patients.
Methods
Seven AD patients (mini-mental state exam (MMS) 10.0 ± 5) were compared to 19 healthy controls (MMS 29.0 ± 5). Each subject watched the pattern flash stimulus at various frequencies during Positron Emission Tomography, first off drug and then again while IV physostigmine was infused.
Results
Replicating many studies, and indicative of integrated striate neural activity, the healthy controls showed a biphasic regional blood flow (rCBF) response as flash frequency increased. Compared to controls, the AD group before drug administration had a significantly smaller, but still biphasic rCBF response. After drug, the size of the rCBF response increased toward control levels, however, its biphasic nature (indicative of neural integration) was abolished.
Conclusion
The AChE induced increase in primary striate rCBF rather than indicating a return of function toward normal, appeared to represent increased but dysregulated neural activity in the AD group. Thus, even with minimal cortical pathology, cholinergic augmentation alone was unable to markedly improve cortical function. Other neuromodulators (serotonin, norepinephrine, dopamine) are impaired in AD. Perhaps a strategy replacing multiple modulators simultaneously would more successfully restore cortical function in AD.