Cerebral Cortex Advance Access published online on November 4, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp232
Reduction of Basal Forebrain Cholinergic System Parallels Cognitive Impairment in Patients at High Risk of Developing Alzheimer's Disease
1 Laboratory of Functional Neuroscience, Spanish Network of Excellence in Neurodegenerative Diseases (CIBERNED), University Pablo de Olavide, 41013 Seville, Spain, 2 Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ 07102, USA, 3 Dementia Unit, Neurology Service, University Hospital Virgen del Rocio, 41013 Seville, Spain, 4 Neurorradiology Unit, Radiodiagnostic Service, University Hospital Virgen del Rocio, 41013 Seville, Spain, 5 Department of Psychiatry, University of Rostock, 18147 Rostock, Germany, 6 Institute of Neuroscience and Biophysics, Research Center Juelich, 52425 Juelich, Germany
Address correspondence to Jose L. Cantero, PhD, Laboratory of Functional Neuroscience, University Pablo de Olavide, Ctra. de Utrera, Km. 1, 41013 Seville, Spain. Email: jlcanlor{at}upo.es.
Neuropathological studies suggest that the basal forebrain cholinergic system (BFCS) is affected in Alzheimer's disease (AD), but there is no in vivo evidence of early damage to this system in subjects at high risk of developing AD. Here, we found that mild cognitive impairment (MCI) patients exhibited significant volume reduction of the nucleus basalis of Meynert (NbM) using recently developed probabilistic maps of the BFCS space. In addition, volumes of different magnocellular compartments varied significantly with regional gray matter atrophy in regions known to be affected by AD and were found to correlate with cognitive decline in MCI patients. Bilateral reductions of the horizontal nucleus of the diagonal band of Broca (Ch3) and frontal lobe (medial frontal, orbital, subcallosal gyrus, anterior cingulate, and middle frontal gyrus) were significantly associated with a global decline in cognitive status, whereas volume reduction of the posterior compartment of Ch4 (NbM) and temporal lobe (including hippocampus, entorhinal cortex, and amygdala) were associated with impaired delayed recall in MCI patients. These findings establish, for the first time, a link between degeneration of specific cholinergic compartments of the BFCS and cognitive-related deficits in subjects at high risk of developing AD.
Key Words: Alzheimer's disease • basal forebrain • cerebral aging • cholinergic system • mild cognitive impairment