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Cholinergic Deficits Link Dementia and Olfactory Dysfunction in Parkinson's
Abstract & Commentary
By Claire Henchcliffe, MD, Assistant Professor, Department of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe serves on the speaker's bureau of GlaxoSmithKline, Teva Neuroscience, Boehringer Ingelheim, Novartis, and Allergan.
Synopsis: Olfactory dysfunction is associated with cognitive impairment in Parkinson's disease (PD), and both are linked by cholinergic pathway deficits.
Source: Bohnen N, et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease. Brain 2010;133: 1747-1754.
This study examines the relationship of two common non-motor features of Parkinson's disease (PD) that traditionally are thought to begin early (olfactory dysfunction) or late (cognitive impairment) in the disease process. Subjects with PD (n = 58) were evaluated using tests of odor discrimination (University of Pennsylvania Smell Identification Test, UPSIT), and cognitive performance (verbal and non-verbal memory, executive function and reasoning), along with age-matched healthy controls (n = 26). All subjects underwent brain nuclear imaging with the following ligands: [11C]methyl-4-piperidinyl proprionate to measure acetylcholinesterase (AChE) activity, reflecting cholinergic innervation; and (+)-[11C]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter type 2 (VMAT2) protein, reflecting dopaminergic nigrostrostriatal neuron integrity. All PD patients were studied after overnight withholding of dopaminergic medications. PD subjects comprised 49 men and nine women, with mean age 69.0 ± 7.6 (range 51-83) years, and mean disease duration of 7.0 ± 3.8 years. Anticholinergic and cholinesterase inhibitor drugs were not allowed, and all subjects had a Mini-Mental State Examination score of 25 or above. UPSIT and cognitive test scores were lower in PD patients versus controls. AChE activity was reduced in PD versus controls in the hippocampus, amygdala, and neocortex, and VMAT binding was, as expected, lower in PD. In PD, UPSIT scores correlated with AChE activity in the hippocampus (r = 0.56, p < 0.0001) and amygdala (r = 0.50, p < 0.0001), independent of motor severity, disease duration, and age. Moreover, UPSIT scores were associated with higher composite memory scores (r = 0.26, p < 0.05). A post hoc analysis of milder (Hoehn and Yahr stage ≤ 2, n = 14) versus more advanced (Hoehn and Yahr stage ≥ 2.5, n = 44) PD subjects revealed a significant association of UPSIT scores with AChE activity and VMAT2 binding in milder PD, but only AChE activity, and not VMAT2 binding, in more advanced PD.
Olfactory dysfunction is strongly associated with Parkinson's disease. It may occur years before motor symptoms, and is being investigated as a possible means of identifying "at risk" individuals for further screening. The Braak hypothesis identifies α-synuclein pathology in the olfactory bulb and anterior olfactory nucleus in initial stages of PD. However, other areas likely contribute to olfactory dysfunction, and this study is an important step in dissecting the role of the limbic system and neocortex in both earlier and later stages of PD. Examining cholinergic activity in PD is interesting for a number of reasons. Loss of cholinergic innervation has been linked to cognitive dysfunction, not only in PD, but also in Alzheimer's disease and other disorders. Moreover, rivastigmine, an acetylcholinesterase inhibitor, is indicated for PD dementia treatment, and another such inhibitor, donepezil, was found in one human Alzheimer's disease study to improve odor identification. In this study, the authors not only demonstrate an association between olfactory dysfunction and a composite cognitive score, but also provide a plausible neurophysiologic explanation through a common neurotransmitter, acetylcholine. What is the practical implication of this work? Cognitive decline and dementia are unfortunately common in PD, and dementia is an independent risk factor for nursing home placement. Dementia remains poorly understood, and difficult to treat. We have as yet no way to predict the degree of risk for an individual at the time of PD diagnosis, and therefore counseling about this important and distressing possibility is limited. One hope is that olfactory testing possibly coupled with specific nuclear imaging might help stratify risk for dementia in PD, and these authors' results provide a strong platform for testing in longitudinal studies.