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Original Contribution |

Cortical Cholinergic Function Is More Severely Affected in Parkinsonian Dementia Than in Alzheimer Disease:  An In Vivo Positron Emission Tomographic Study FREE

Nicolaas I. Bohnen, MD, PhD; Daniel I. Kaufer, MD; Larry S. Ivanco, BA; Brian Lopresti, BSc; Robert A. Koeppe, PhD; James G. Davis, PhD; Chester A. Mathis, PhD; Robert Y. Moore, MD, PhD; Steven T. DeKosky, MD
[+] Author Affiliations

From the Departments of Neurology (Drs Bohnen, Kaufer, Moore, and DeKosky and Mr Ivanco) and Radiology (Drs Bohnen, Davis, and Mathis and Mr Lopresti), University of Pittsburgh School of Medicine and the Veterans Administration Pittsburgh Healthcare System (Dr Bohnen), Pittsburgh, Pa; and the Department of Radiology, University of Michigan, Ann Arbor (Dr Koeppe).


Arch Neurol. 2003;60(12):1745-1748. doi:10.1001/archneur.60.12.1745.
Text Size: A A A
Published online

Background  Pathology reports have shown that cholinergic forebrain neuronal losses in parkinsonian dementia (PDem) are equal to or greater than those in Alzheimer disease (AD). We hypothesized that patients with PDem would have cholinergic deficits that were similar to or greater than those of patients with AD.

Objective  To determine in vivo cortical acetylcholinesterase (AChE) activity in healthy control subjects and in patients with mild AD, PDem, and Parkinson disease without dementia using AChE positron emission tomography.

Setting  University and Veterans' Administration medical center.

Design and Patients  Group comparison design of patients with AD (n = 12), PDem (n = 14), and Parkinson disease without dementia (n = 11), and controls (n = 10) who underwent AChE imaging between July 1, 2000, and January 31, 2003. Patients with AD and PDem had approximately equal dementia severity.

Main Outcome Measures  Cerebral AChE activity.

Results  Compared with controls, mean cortical AChE activity was lowest in patients with PDem (−20.0%), followed by patients with Parkinson disease without dementia (−12.9%; P<.001). Mean cortical AChE activity was relatively preserved in patients with AD (−9.1%), except for regionally selective involvement of the lateral temporal cortex (−15%; P<.001).

Conclusion  Reduced cortical AChE activity is more characteristic of patients with PDem than of patients with mild AD.

Figures in this Article

SINCE THE INITIAL reports of a profound reduction of cortical choline acetyltransferase and cholinergic neuronal loss in patients with Alzheimer disease (AD),1,2 substantial evidence implicates cholinergic hypofunction as a significant component of this disorder. However, recent evidence indicates that cholinergic deficits are not severe in mild AD and become significant only in more advanced stages of this disorder.35

The development of positron emission tomographic (PET) technology to measure AChE functional activity offers the prospect of studying cholinergic innervation in vivo at the early stages of neurodegenerative disorders.6 Acetylcholinesterase (AChE) activity in the human AD-affected brain has been mapped using PET and 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP) and N-[11C]methylpiperidine-4-yl acetate radioligands.7,8 These PET studies reported in vivo reductions of cortical AChE activity that were less than expected on the basis of postmortem data.79

Dementia in Parkinson disease (PD) is common, but its precise pathophysiological substrates are not well understood.10 Significant loss of cholinergic forebrain neurons has also been reported in PD-affected brains.11,12 Arendt et al13 found greater forebrain neuronal loss in patients with PD than in patients with AD, suggesting that cholinergic deficits may be at least as prominent in (late-stage) PD as in AD. The primary aim of this study was to compare in vivo cerebral AChE activity in patients with mild AD, parkinsonian dementia (PDem), and PD without dementia, and healthy controls (HCs).

SUBJECTS

The study involved 47 subjects (12 with AD, 14 with PDem, 11 with PD, and 10 HCs). There were no significant differences in mean (SD) age among the groups: those with AD, 74.3 (5.80) years; those with PDem, 72.8 (7.9) years; those with PD, 71.2 (7.9) years; and HCs, 70.0 (8.7) years; F = 0.67, P = .51). Mini-Mental State Examination (MMSE) scores (mean [SD]) were decreased in the groups with dementia with those with AD being 22.2 (4.6), those with PDem, 22.8 (5.7), those with PD, 27.3 (2.2), and HCs, 29.4 (0.7); (F = 8.30, P<.001) but the scores were not significantly different between the AD-affected and PDem-affected groups (t = 0.29, P = .56). The AD- and PDem-affected groups did not differ in mean (SD) scores on the Global Deterioration Scale with those with AD scoring 4.9 (0.7) and those with PDem, 5.0 (0.8) (t = 0.27, P.79),14 nor in years of education with those with AD scoring (mean [SD]) 12.8 (2.6) years and those with PDem, 13.5 (3.1) years (t = 0.61, P = .60). Sex distribution was different between groups: those with AD, 8 women and 4 men; those with PDem, 1 woman and 13 men; those with PD, 11 men; and HCs, 7 women and 3 men. However, previous AChE PET studies did not find sex differences in cerebral AChE activity.8

The PDem-affected group was evenly divided between patients classified as having idiopathic PD with dementia (n = 7) and those having dementia with Lewy bodies (n = 7). Idiopathic PD with dementia was diagnosed in patients having a history of idiopathic PD with incident dementia. Dementia with Lewy bodies was clinically diagnosed following the Consortium on Dementia With Lewy Bodies' criteria.15 Mini-Mental State Examination scores were not significantly different between those who had idiopathic PD with dementia and those who had dementia with Lewy bodies (mean [SD], 23.9 [5.5] and 21.7 [6.1], respectively; t = 0.68, P = .46). No subjects were taking anticholinergic drugs. The patients with PDem were taking a variable combination of carbidopa-levodopa, selegeline hydrochloride, or dopamine agonists. Dopaminergic medications were withheld for at least 12 to 18 hours (overnight withdrawal) prior to PET imaging the next morning.

Each subject underwent a comprehensive neurological and neuropsychological examination. Subjects were diagnosed as having dementia if they met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and/or NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association) criteria for dementia.16,17 Patients with AD were recruited from the Alzheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pa. Patients with PD or PDem were recruited from the movement disorders clinics at the University of Pittsburgh School of Medicine and the Veterans Administration Healthcare System, Pittsburgh. The results of the neurological examination of the HCs showed no abnormalities. The study was approved by the institutional review boards of the medical centers.

AChE PET AND MAGNETIC RESONANCE IMAGING

The [11C]PMP radioligand is an acetylcholine analogue that serves as a selective substrate for AChE hydrolysis.6 The hydrolyzed radioligand becomes trapped as a hydrophilic product locally in the brain following the AChE biodistribution. Acetylcholinesterase has been recognized since 1966 as a reliable marker for brain cholinergic pathways including the human brain.18,19 Acetylcholinesterase is localized predominantly in cholinergic cell bodies and axons. In the cortex, AChE is present in axons innervating it from the basal forebrain.19 There also is AChE in intrinsic cortical neurons and low levels of AChE are probably present in the noncholinergic structures postsynaptic to the nucleus basalis innervation.20 These data support the validity of [11C]PMP PET as a reliable marker of the forebrain cholinergic system.

The [11C]PMP was prepared using a previously described method.21 Dynamic PET scanning was performed for 80 minutes following a bolus intravenous injection of 15 mCi (555 MBq) of [11C]PMP. Sequential emission scans were obtained in 3-dimensional imaging mode using an emission computed axial tomograph (ECAT HR+; CTI PET Systems, Knoxville, Tenn), which acquires 63 transaxial slices (slice thickness, 2.4 mm with an in-plane resolution of 4.1 mm). A thermoplastic mask was made for each subject to minimize head movement. The PET emission data were corrected for attenuation, scatter, and radioactive decay.

A volumetric spoiled–echo gradient recall MRI was collected for each subject using a 1.5-T scanner (Signa; GE Medical Systems, Milwaukee, Wis). The MRI data were cropped in preparation for alignment with the PET data using AnalyzeAVW software (Biomedical Imaging Resource; Mayo Foundation, Rochester, Minn).

DATA ANALYSIS

The frames of the dynamic [11C]PMP PET data set were individually aligned to eliminate interframe registration errors attributable to patient movement using the automated image registration algorithm of Woods et al.22 The cropped MRI was registered to the PET data using a modified version of automated image registration.23 The registered MRI and the Co-Planar Stereotaxic Atlas of the Human Brain by Talairach and Tournoux24 were used to identify regions of interest (ROIs). The frontal ROI was drawn on the MRI to include dorsolateral prefrontal association (5 slices), anterior cingulate (7 slices), and orbitofrontal cortices (4-5 slices). The parietal ROI included both superior (4 slices) and inferior posterior (4 slices) lateral parietal association cortices. The lateral temporal ROI included the superior (4 slices) and inferior (3 slices) lateral association cortices. Separate ROIs were drawn over the amygdala (3-4 slices) and hippocampus (3-4 slices). All MRI-drawn ROIs were transferred to the PET data. Average neocortical [11C]PMP k3 (hydrolysis rate) activity was calculated as a composite score from frontal, parietal, and lateral temporal association cortices. A noninvasive kinetic analysis of the k3 hydrolysis rate (AChE activity) was performed using a direct estimation of k3 without use of an arterial input function, based on the shape of the tissue time–activity curve alone.25 The shape analysis method has been compared with the more standard compartmental analysis using arterial input functions and nonlinear least squares estimation, and it showed that the noninvasive shape analysis approach gave similar results to kinetic analysis in the brain cortex.25 Analysis of variance with Duncan post hoc tests was used for statistical group comparison.

Average and regional neocortical AChE activities for the different groups are shown in Table 1. Compared with HCs patients with PDem showed the greatest reductions in average frontal, parietal, and temporal neocortical [11C]PMP k3 hydrolysis rates (−20.0%) in the disease groups, followed by patients with PD without dementia (−12.9%; P<.001). Patients with AD had the smallest cortical reductions (−9.1%), with the exception of the lateral temporal neocortex. Temporal subregion analysis revealed greater reductions in the inferior lateral temporal cortex than the superior regions in all groups compared with HCs: those with PDem, −27.2%; those with PD, −22.5%; and those with AD, −17.6% (F = 8.29, P<.001; Figure 1). There were no significant left-right hemispheric differences observed. Right-sided hippocampal AChE activity was significantly reduced only in PDem-affected patients but tended to be lower in the AD-affected group compared with HCs (Table 1).

Table Graphic Jump LocationAverage and Regional Cortical [11C]PMP k3 Hydrolysis Rates in the Various Patient Groups and Healthy Control Subjects*11
Place holder to copy figure label and caption

Percentage reductions of cerebral acetylcholinesterase (AChE) activity in the various patient groups compared with healthy control subjects.

Graphic Jump Location

Compared with HCs, both patients who had dementia with Lewy bodies and patients who had idiopathic PD with dementia showed significant reductions in mean (SD) neocortical [11C]PMP k3 hydrolysis rates (0.0185 [0.002] and 0.0186 [0.002], respectively; t = 0.5, P = .91). There were no significant differences in average or regional neocortical AChE activity between the dementia with Lewy bodies and idiopathic PD with dementia groups (Table 1). There was a nonsignificant trend toward reduced amygdalar activity in the dementia with Lewy bodies group (t = 1.6, P = .15).

Our in vivo imaging findings that patients with mild AD (most of whom had late-onset disease) do not have severe reductions in cortical AChE activity levels are in agreement with recent AChE PET imaging studies.8,26 Kuhl et al8 found slightly greater cortical AChE activity reductions (−25% to −33%), but these AD-affected patients also had more severe dementia (mean MMSE score, 14). Our findings of more significant reductions in the lateral temporal lobe in the AD-affected group are congruent with results from postmortem data showing marked loss of cholinergic fibers within the temporal lobe, particularly the temporal association areas, in AD-affected brains.9

Dementia in PD has often been attributed to coexistent AD.10 However, cognitive impairment has been found to correlate with cortical choline acetyltransferase levels but not with the extent of plaque or tangle formation in PD.27,28 Therefore, degeneration of the cholinergic system may play a significant role in the cognitive decline in PD. Previous imaging studies have reported cholinergic deficits in patients with PD.29,30 Our study demonstrated that cortical AChE deficits were greatest and more extensive in PDem compared with AD of approximately equal degree of dementia severity. A novel finding was that cortical AChE activity in the patients with PD was intermediate between the PDem- and AD-affected groups. Our findings agree with postmortem evidence suggesting that a primarily basal forebrain cholinergic system degeneration appears early in PD and then worsens with the onset of dementia.31

Findings of reduced radioligand activity in patients with dementia raise questions about the effect of partial volume effects due to cerebral atrophy. Koeppe et al25 have discussed how the shape analysis approach, which inherently is entirely insensitive to the scale of the data, is nearly unaffected by tissue atrophy. In addition, Kuhl et al8 have demonstrated that cortical AChE activity did not change as a result of changes in blood flow and that cerebral atrophy had little influence on the measures of cortical AChE activity. As cortical AChE activity reductions in the patients with PD without dementia were generally greater than in patients with AD, these cholinergic reductions are unlikely to be explained by partial volume effects.8

Although prevailing diagnostic criteria for dementia with Lewy bodies distinguish it from AD and idiopathic PD with dementia, it is unclear whether dementia with Lewy bodies and idiopathic PD with dementia are part of the same disease spectrum or are distinct disorders. Our data show that average neocortical cholinergic denervation does not differ between patients with idiopathic PD with dementia and patients with dementia with Lewy bodies and support the view that idiopathic PD with dementia and dementia with Lewy bodies lie on a common disease spectrum with respect to cholinergic pathophysiology.

In conclusion, these findings support a cholinergic model of dementia that may be more applicable to PDem than prototypical AD.

Corresponding author: Nicolaas I. Bohnen, MD, PhD, University of Pittsburgh, Liliane S. Kaufmann Bldg, Suite 811, 3471 Fifth Ave, Pittsburgh, PA 15213.

Accepted for publication July 24, 2003.

Author contributions: Study concept and design (Drs Bohnen, Moore, and DeKosky); acquisition of data (Drs Bohnen, Kaufer, Koeppe, Davis, and Mathis, and Messrs Ivanco and Lopresti); analysis and interpretation of data (Drs Bohnen, Kaufer, Mathis, Moore, and DeKosky); drafting of the manuscript (Drs Bohnen, Kaufer, and Mathis and Messrs Ivanco and Lopresti); critical revision of the manuscript for important intellectual content (Drs Davis, Koeppe, Moore, and DeKosky); statistical expertise (Dr Bohnen); obtained funding (Drs Bohnen, Kaufer, Moore, and DeKosky); administrative, technical, and material support (Messrs Ivanco and Lopresti and Drs Koeppe and Davis); study supervision (Drs Mathis, Moore, and DeKosky).

This study was supported in part by the Department of Veterans Affairs, Washington, DC; grant AG05133 from the National Institute on Aging, Bethesda, Md; and the Scaife Family Foundation, Pittsburgh.

We thank the PET technologists, cyclotron operators, chemists, and study coordinators for their assistance.

Davies  PMaloney  A Selective loss of central cholinergic neurons in Alzheimer's disease [letter]. Lancet.1976;2:1403.
PubMed
Bowen  DMSmith  CBWhite  PDavison  AN Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain.1976;99:459-496.
PubMed
Davis  KLMohs  RCMarin  D  et al Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA.1999;281:1401-1406.
PubMed
Tiraboschi  PHansen  LAAlford  MMasliah  EThal  LJCorey-Bloom  J The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology.2000;55:1278-1283.
PubMed
DeKosky  STIkonomovic  MDStyren  SD  et al Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol.2002;51:145-155.
PubMed
Irie  TFukushi  KAkimoto  YTamagami  HNozaki  T Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AChE) in vivo. Nucl Med Biol.1994;21:801-808.
PubMed
Iyo  MNamba  HFukushi  K  et al Measurement of acetylcholinesterase by positron emission tomography in the brain of healthy controls and patients with Alzheimer's disease. Lancet.1997;349:1805-1809.
PubMed
Kuhl  DEKoeppe  RAMinoshima  S  et al In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease. Neurology.1999;52:691-699.
PubMed
Geula  CMesulam  MM Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer's disease. Cereb Cortex.1996;6:165-177.
PubMed
Mahler  MECummings  JL Alzheimer disease and the dementia of Parkinson disease: comparative investigations. Alzheimer Dis Assoc Disord.1990;4:133-149.
PubMed
Whitehouse  PJHedreen  JCWhite  CLPrice  DL Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol.1983;13:243-248.
PubMed
Candy  JMPerry  RHPerry  EK  et al Pathological changes in the nucleus of Meynert in Alzheimer's and Parkinson's diseases. J Neurol Sci.1983;59:277-289.
PubMed
Arendt  TBigl  VArendt  ATennstedt  A Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease. Acta Neuropathol (Berl).1983;61:101-108.
PubMed
Reisberg  BFerris  SHde Leon  MJCrook  T The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry.1982;139:1136-1139.
PubMed
McKeith  IGPerry  EKPerry  RHfor the Consortium on Dementia With Lewy Bodies Report of the Second Dementia With Lewy Body International Workshop: diagnosis and treatment. Neurology.1999;53:902-905.
PubMed
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC: American Psychiatric Association; 1994.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology.1984;34:939-944.
PubMed
Shute  CCLewis  PR Electron microscopy of cholinergic terminals and acetylcholinesterase-containing neurones in the hippocampal formation of the rat. Z Zellforsch Mikrosk Anat.1966;69:334-343.
PubMed
Selden  NRGitelman  DRSalamon-Murayama  NParrish  TBMesulam  MM Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain.1998;121:2249-2257.
PubMed
Heckers  SGeula  CMesulam  MM Acetylcholinesterase-rich pyramidal neurons in Alzheimer's disease. Neurobiol Aging. July-August1992;13:455-460.
PubMed
Snyder  SETluczek  LJewett  DMNguyen  TBKuhl  DEKilbourn  MR Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP) for in vivo measurements of acetylcholinesterase activity. Nucl Med Biol.1998;25:751-754.
PubMed
Woods  RPMazziota  JCCherry  SR MRI-PET registration with automated algorithm. J Comput Assist Tomogr.1993;17:536-546.
PubMed
Wiseman  MNichols  TWoods  RSweeney  JMintun  M Stereotaxic techniques comparing foci intensity and location of activation areas in the brain as obtained using positron emission tomography (PET). J Nucl Med.1995;36(suppl 1):39.
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  New York, NY: Thieme Medical & Scientific Publishers; 1988.
Koeppe  RAFrey  KASnyder  SEMeyer  PKilbourn  MRKuhl  DE Kinetic modeling of N-[11C]methylpiperidin-4-yl propionate: alternatives for analysis of an irreversible positron emission tomography tracer for measurement of acetylcholinesterase activity in human brain. J Cereb Blood Flow Metab.1999;19:1150-1163.
PubMed
Rinne  JOKaasinen  VJarvenpaa  T  et al Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease. J Neurol Neurosurg Psychiatry.2003;74:113-115.
PubMed
Mattila  PMRoytta  MLonnberg  PMarjamaki  PHelenius  HRinne  JO Choline acetyltransferase activity and striatal dopamine receptors in Parkinson's disease in relation to cognitive impairment. Acta Neuropathol (Berl).2001;102:160-166.
PubMed
Perry  EKCurtis  MDick  DJ  et al Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry.1985;48:413-421.
PubMed
Kuhl  DMinoshima  SFessler  J  et al In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease. Ann Neurol.1996;40:399-410.
PubMed
Shinotoh  HNamba  HYamaguchi  M  et al Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy. Ann Neurol.1999;46:62-69.
PubMed
Ruberg  MPloska  AJavoy-Agid  FAgid  Y Muscarinic binding and choline acetyltransferase activity in Parkinsonian subjects with reference to dementia. Brain Res.1982;232:129-139.
PubMed

Figures

Place holder to copy figure label and caption

Percentage reductions of cerebral acetylcholinesterase (AChE) activity in the various patient groups compared with healthy control subjects.

Graphic Jump Location

Tables

Table Graphic Jump LocationAverage and Regional Cortical [11C]PMP k3 Hydrolysis Rates in the Various Patient Groups and Healthy Control Subjects*11

References

Davies  PMaloney  A Selective loss of central cholinergic neurons in Alzheimer's disease [letter]. Lancet.1976;2:1403.
PubMed
Bowen  DMSmith  CBWhite  PDavison  AN Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain.1976;99:459-496.
PubMed
Davis  KLMohs  RCMarin  D  et al Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA.1999;281:1401-1406.
PubMed
Tiraboschi  PHansen  LAAlford  MMasliah  EThal  LJCorey-Bloom  J The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology.2000;55:1278-1283.
PubMed
DeKosky  STIkonomovic  MDStyren  SD  et al Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol.2002;51:145-155.
PubMed
Irie  TFukushi  KAkimoto  YTamagami  HNozaki  T Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AChE) in vivo. Nucl Med Biol.1994;21:801-808.
PubMed
Iyo  MNamba  HFukushi  K  et al Measurement of acetylcholinesterase by positron emission tomography in the brain of healthy controls and patients with Alzheimer's disease. Lancet.1997;349:1805-1809.
PubMed
Kuhl  DEKoeppe  RAMinoshima  S  et al In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease. Neurology.1999;52:691-699.
PubMed
Geula  CMesulam  MM Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer's disease. Cereb Cortex.1996;6:165-177.
PubMed
Mahler  MECummings  JL Alzheimer disease and the dementia of Parkinson disease: comparative investigations. Alzheimer Dis Assoc Disord.1990;4:133-149.
PubMed
Whitehouse  PJHedreen  JCWhite  CLPrice  DL Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol.1983;13:243-248.
PubMed
Candy  JMPerry  RHPerry  EK  et al Pathological changes in the nucleus of Meynert in Alzheimer's and Parkinson's diseases. J Neurol Sci.1983;59:277-289.
PubMed
Arendt  TBigl  VArendt  ATennstedt  A Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease. Acta Neuropathol (Berl).1983;61:101-108.
PubMed
Reisberg  BFerris  SHde Leon  MJCrook  T The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry.1982;139:1136-1139.
PubMed
McKeith  IGPerry  EKPerry  RHfor the Consortium on Dementia With Lewy Bodies Report of the Second Dementia With Lewy Body International Workshop: diagnosis and treatment. Neurology.1999;53:902-905.
PubMed
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC: American Psychiatric Association; 1994.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology.1984;34:939-944.
PubMed
Shute  CCLewis  PR Electron microscopy of cholinergic terminals and acetylcholinesterase-containing neurones in the hippocampal formation of the rat. Z Zellforsch Mikrosk Anat.1966;69:334-343.
PubMed
Selden  NRGitelman  DRSalamon-Murayama  NParrish  TBMesulam  MM Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain.1998;121:2249-2257.
PubMed
Heckers  SGeula  CMesulam  MM Acetylcholinesterase-rich pyramidal neurons in Alzheimer's disease. Neurobiol Aging. July-August1992;13:455-460.
PubMed
Snyder  SETluczek  LJewett  DMNguyen  TBKuhl  DEKilbourn  MR Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP) for in vivo measurements of acetylcholinesterase activity. Nucl Med Biol.1998;25:751-754.
PubMed
Woods  RPMazziota  JCCherry  SR MRI-PET registration with automated algorithm. J Comput Assist Tomogr.1993;17:536-546.
PubMed
Wiseman  MNichols  TWoods  RSweeney  JMintun  M Stereotaxic techniques comparing foci intensity and location of activation areas in the brain as obtained using positron emission tomography (PET). J Nucl Med.1995;36(suppl 1):39.
Talairach  JTournoux  P Co-Planar Stereotaxic Atlas of the Human Brain.  New York, NY: Thieme Medical & Scientific Publishers; 1988.
Koeppe  RAFrey  KASnyder  SEMeyer  PKilbourn  MRKuhl  DE Kinetic modeling of N-[11C]methylpiperidin-4-yl propionate: alternatives for analysis of an irreversible positron emission tomography tracer for measurement of acetylcholinesterase activity in human brain. J Cereb Blood Flow Metab.1999;19:1150-1163.
PubMed
Rinne  JOKaasinen  VJarvenpaa  T  et al Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease. J Neurol Neurosurg Psychiatry.2003;74:113-115.
PubMed
Mattila  PMRoytta  MLonnberg  PMarjamaki  PHelenius  HRinne  JO Choline acetyltransferase activity and striatal dopamine receptors in Parkinson's disease in relation to cognitive impairment. Acta Neuropathol (Berl).2001;102:160-166.
PubMed
Perry  EKCurtis  MDick  DJ  et al Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry.1985;48:413-421.
PubMed
Kuhl  DMinoshima  SFessler  J  et al In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease. Ann Neurol.1996;40:399-410.
PubMed
Shinotoh  HNamba  HYamaguchi  M  et al Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy. Ann Neurol.1999;46:62-69.
PubMed
Ruberg  MPloska  AJavoy-Agid  FAgid  Y Muscarinic binding and choline acetyltransferase activity in Parkinsonian subjects with reference to dementia. Brain Res.1982;232:129-139.
PubMed

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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