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UNLABELLED: Longitudinal studies in nondemented Parkinson disease (PD) subjects offer an opportunity to study the earliest regional cerebral subcortical and cortical metabolic changes underlying incident dementia in this disorder. METHODS: Twenty-three PD subjects without dementia (Hoehn and Yahr stages I-III; age, 61.8 ± 9.7 y; Mini-Mental State Examination, 28.0 ± 1.4) and 27 controls (age, 59.8 ± 11.5 y) underwent (18)F-FDG PET at study entry. PD subjects underwent yearly clinical assessment to determine conversion to dementia. The mean duration of follow-up was 3.9 ± 1.2 y (range, 2.0-6.8 y). Follow-up (18)F-FDG PET was available in a subset of subjects at 2 or more years. Both volume-of-interest and 3-dimensional stereotactic surface projection (3D-SSP) analyses were performed. RESULTS: Six subjects became demented (PDD), with a mean time of 3.8 ± 1.7 y (range, 1.9-6.0 y) to development of dementia. Mean duration of disease before onset of dementia was 9.7 ± 4.2 y (range, 3.1-14 y). There were significant metabolic reductions in the occipital (-11.8% vs. controls, F((2,22)) = 7.0, P = 0.002) and posterior cingulate (-12.1% vs. controls, F((2,22)) = 5.2, P = 0.009) cortices in PDD subjects at baseline, before diagnosis of dementia, compared with controls. Metabolism was most diminished in the visual association cortex (Brodmann area [BA] 18; -20.0% vs. control, F((2,22)) = 8.45, P = 0.0007) of PDD subjects. There was mild hypometabolism in the caudate nucleus (-8.4% vs. control, F((2,22)) = 3.2, P < 0.05). There was no significant hypometabolism in the temporal or frontal lobes. PD subjects who did not become demented (non-PDD), compared with controls, had reduced cerebral metabolism in the primary occipital cortex (BA 17) that was revealed only by 3D-SSP analysis. Follow-up scans in 5 PDD subjects at 2 y after study entry demonstrated a significant interval within-subject change in the thalamus (-11.4%), posterior cingulate (-9%), occipital (-7%), parietal (-7%), and frontal cortices (-7%) and mild reductions in the temporal cortex (-5%) and hippocampus (-3%), compared with study entry scans. CONCLUSION: Incident dementia in idiopathic PD is heralded by decreased metabolism in the visual association (BA 18) and posterior cingulate cortices, with mild involvement also of the caudate nucleus. Two-year follow-up data from 5 PDD converters show that progression to dementia is associated with mixed subcortical and cortical changes that involve the mesiofrontal lobes also. These findings provide insights into early metabolic features of parkinsonian dementia.

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OBJECTIVE: We tested the premise that cholinesterase inhibitor therapy should target butyrylcholinesterase (BuChE) in Alzheimer's disease (AD), not acetylcholinesterase (AChE) alone, because both enzymes hydrolyze acetylcholine, and BuChE is increased in AD cerebral cortex. METHODS: To examine this issue in vivo, we quantified human cerebral cortical BuChE activity using tracer kinetic estimates (k(3)) of 1-[(11)C]methyl-4-piperidinyl n-butyrate ([(11)C]BMP) hydrolysis determined by positron emission tomography. Validation of the putative positron emission tomography method included regional distribution, positive correlation with age, and attenuation by the nonselective cholinesterase inhibitor physostigmine, but no attenuation by the AChE-selective inhibitor donepezil. Positron emission tomography scans in AD patients (n = 15) and control subjects (n = 12) measured both BuChE (using [(11)C]BMP) and AChE activity (using N-[(11)C] methylpiperidin-4-yl propionate, an established method). RESULTS: As expected, AChE activity in AD cerebral cortex was decreased to 75 +/- 13% of normal (p = 0.00001). Contrary to prediction, accompanying BuChE activity also was decreased to 82 +/- 14% of normal (p = 0.001). INTERPRETATION: Failure to observe increased [(11)C]BMP hydrolysis in vivo makes it less likely that incremental BuChE contributes importantly to acetylcholine hydrolysis in AD. The findings do not support the premise that inhibitor therapy should target BuChE so as to prevent increased levels of BuChE from hydrolyzing acetylcholine in AD cerebral cortex.

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Neurochemical imaging is one of the most established "molecular" imaging techniques. There have been tremendous efforts expended to develop radioligands specific to each neurochemical system. Investigational applications of neurochemical imaging in dementing disorders are extensive. Cholinergic, dopaminergic, and serotonergic systems, as well as benzodiazepine receptors, opioid receptors, and glutamatergic receptors have been imaged in Alzheimer disease and other dementing disorders. These investigations have provided important insights into disease processes in living human patients. The clinical diagnostic use of neurochemical imaging for dementing disorders is currently limited, but this technique is used to help develop therapeutic drugs at multiple levels.

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Dementia with Lewy bodies (DLB) is recognized as one of the most common forms of neurodegenerative dementia. Neuroimaging contributes to a better understanding of the pathophysiology of DLB by examining alterations in brain metabolism, neurochemisty, and morphology in living patients. Neuroimaging can provide objective and quantifiable antemortem markers for the presence of and the progression of DLB and permits differentiation from other dementias. This article reviews current neuroimaging findings in DLB with particular attention to occipital hypometabolism, dopaminergic and cholinergic deficits, and medial temporal lobe atrophy as measured by positron emission tomography, single-photon emission computed tomography, and magnetic resonance imaging.

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