Akiyo Aotsuka

Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study.

We measured brain acetylcholinesterase activity in 30 patients with Alzheimers disease (AD) and 14 age‐matched controls by positron emission tomography (PET) and using a carbon 11–labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three‐compartment analysis using the metabolite corrected arterial input function. Twenty‐eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini‐Mental State Examination scores, supporting the cholinergic hypothesis in AD. Ann Neurol 2000;48:194–200

Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET.

Acetylcholinesterase (AChE) activities in the brain of three patients with AD were measured once before and once during donepezil treatment (5 mg/d in two patients, 3 mg/d in one patient) using PET and N-[11C]methylpiperidin-4-yl acetate. Donepezil reduced k3 values, an index of AChE activity, in the cerebral cortex by 39 ± 5%. All patients showed some degree of symptomatic improvement, and it was concluded that this improvement was likely caused by improved cholinergic activity by inhibition of AChE in the brain.

The Amygdala and Alzheimer's Disease

Abstract: The primary transmitter deficit is cholinergic in Alzheimers disease (AD), and the amygdala receives a major cholinergic projection from the nucleus basalis of Meynert (Ch4), which may play an important role in the retention of affective conditioning and/or memory consolidation. We measured brain acetylcholinesterase (AChE) activity in 54 patients with AD and in 22 normal controls by positron emission tomography and N‐[11C]methylpiperidin‐4‐yl acetate to characterize the cholinergic pathology in AD. The k3 values were calculated as an index of AChE activity in a three‐compartment model analysis using the metabolite‐corrected arterial input function. The k3 values were highly significantly reduced by 20% in the cerebral neocortex (P <0.0001 in the two‐tailed t test), 14% in the hippocampus (P <0.001), and 33% in the amygdala (P <0.0001) in AD patients compared with normal controls. The k3 values were significantly correlated with the Mini‐Mental State Examination scores in both the cerebral cortex (P <0.001) and the amygdala (P <0.05) in AD patients, supporting the cholinergic hypothesis of cognitive dysfuncion in AD. Further studies are required, however, to elucidate the specific role of the cholinergic deficit in the amygdala in the emotional and behavioral symptoms in AD.

Kinetic analysis of [11C]MP4A using a high-radioactivity brain region that represents an integrated input function for measurement of cerebral acetylcholinesterase activity without arterial blood sampling

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [11C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [11C]MP4A through AChE (k3; an AChE index) are calculated by using Blomqvists linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k3 with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k3 values. The authors then applied these methods to [11C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k3 estimates between RLS and NLS analyses (456 cerebral regions, [RLS k3] = 0.98 × [NLS k3], r = 0.92, P < 0.001). Significant reductions were observed in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices (P < 0.001, single-tailed t-test), and hippocampus (P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) Fin these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [11C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [11C]MP4A studies.

Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia.

Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.

Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography

Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k 3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (−30%) and parietal cortices (−31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.

Positron Emission Tomographic Measurement of Brain Acetylcholinesterase Activity Using N-[11C]methylpiperidin-4-yl Acetate Without Arterial Blood Sampling: Methodology of Shape Analysis and its Diagnostic Power for Alzheimer's Disease

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is a radiotracer that has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET) using a standard compartment model analysis and a metabolite-corrected arterial input function. In the current study, the authors evaluated the applicability of a simple kinetic analysis without blood sampling, namely shape analysis. First, the authors used computer simulations to analyze factors that affect the precision and bias of shape analysis, then optimized the shape analysis procedure for [11C]MP4A. Before shape analysis execution, the later part of dynamic PET data except for the initial 3 minutes were smoothed by fitting to a bi-exponential function followed by linear interpolation of 8 data points between each of adjacent scan frames. Simulations showed that shape analysis yielded estimates of regional metabolic rates of [11C]MP4A by AChE (k3) with acceptable precision and bias in brain regions with low k3 values such as neocortex. Estimates in regions with higher k3 values became progressively more inaccurate. The authors then applied the method to [11C]MP4A PET data in 10 healthy subjects and 20 patients with Alzheimers disease (AD). There was a highly significant linear correlation in regional k3 estimates between shape and compartment analyses (300 neocortical regions, [shape k3] = 0.93 × [NLS k3], r = 0.89, P < 0.001). Significant reductions in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral cortices in patients with AD as compared with controls were observed when using shape analysis (P < 0.013, two-tailed t-test), although these reductions (17% to 20%) were somewhat less than those obtained by compartment analysis (22% to 27%). The sensitivity of shape analysis for detecting neocortical regions with abnormally low k3 in the 20 patients with AD (92 out of 200 regions, 46%) also was somewhat less than compartment analysis (136 out of 200 regions, 68%). However, taking its simplicity and noninvasiveness into account, the authors conclude that quantitative measurement of neocortical AChE activity with shape analysis and [11C]MP4A PET is practical and useful for clinical diagnosis of AD.

PET study of brain acetylcholinesterase in cerebellar degenerative disorders.

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA‐C), 7 patients with spinocerebellar ataxia type‐3 (SCA‐3), 3 patients with SCA‐6, and 13 healthy age‐matched volunteers participated in this study. Brain AChE activity was measured by [11C] N‐methylpiperidin‐4‐yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (−27%) and the posterior lobe of cerebellar cortex (−36%) in patients with MSA‐C and in the thalamus (−23%) in patients with SCA‐3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA‐3 patients were negatively correlated with the unified Parkinsons disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA‐3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.

Brain acetylcholinesterase activity in FTDP-17 studied by PET

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant tauopathy. To date, 33 distinct mutations in the tau gene have been reported.1 The clinical features of the N279K tau mutation include parkinsonism, personality changes, and supranuclear gaze palsy.2 Occasionally, cognitive impairment resembling Alzheimer disease (AD) can occur in FTDP-17. In AD, acetylcholinesterase (AChE) activities are depleted in the cerebral cortex. Although impairment of the nigrostriatal dopaminergic pathway has been demonstrated in FTDP-17,3 functional imaging of the cholinergic system in FTDP-17 has not been reported. Using PET and 11C-labeled N -methylpiperidin-4-yl acetate ([11C]MP4A),4 we measured AChE activity in the brains of two patients with FTDP-17 carrying the N279K tau mutation. ### Patients and control subjects. A 50-year-old man with congenital nystagmus began having neck and right arm rigidity and a shuffling gait at age 44. His symptoms improved with trihexyphenidyl and levodopa. During the next several years, however, he began to fall frequently and became forgetful and depressed. A half year before the PET study, he scored 17 of 30 points (cut-off …

Evaluation of simplified kinetic analyses for measurement of brain acetylcholinesterase activity using N-[11C]methylpiperidin-4-yl propionate and positron emission tomography

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvists equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.