Cingulate cortex in Parkinson's disease.

Once a diagnosis of Parkinson's disease (PD) has been made, even in its earliest prodromal form of subjective memory impairment, cognitive impairment has begun and involves anterior cingulate cortex (ACC). While the Braak staging scheme showed mid- to later-stage PD progression from cingulate allocortex adjacent to the corpus callosum and progressing into its neocortical moieties, the last decade has produced substantial information on the role of cingulate cortex in multiple symptoms, not just global measures of cognition. Voxel-based morphometry has been used in many studies of mild cognitive impairment (MCI) in PD to show reduced thickness in ACC and posterior cingulate cortex (PCC). Regional cerebral blood flow is altered in association with verbal IQ in all the PCC and anterior midcingulate cortex and executive impairments in ACC. Diffusion tensor imaging shows reduced fractional anisotropy throughout the entire cingulum bundle. Amnestic MCI is associated with reduced dopamine-2 receptor binding in ACC and, even in cognitively normal PD cases, dopaminergic pathways in ACC are impaired early in association with executive and language functions. The cholinergic system also has substantial changes in nicotinic and muscarinic receptor binding, and therapy with donepezil improves Mini-Mental State Exam scores and metabolism in pACC and dPCC. Cingulate cortex is also engaged in two critical symptoms: apathy and visual hallucinations. Finally, one can be optimistic that cingulate cortex will play an important role in developing new biomarkers of early PD. These methods have already been shown to be useful in cingulate cortex and include magnetic resonance spectroscopy, next-generation gene expression, and the new α-synuclein proximity ligation assay that specifically recognizes α-synuclein oligomers. Thus the future is bright for developing multivariate, multimodal biomarkers that include cingulate cortex.