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Original Article |

Early and Widespread Cholinergic Losses Differentiate Dementia With Lewy Bodies From Alzheimer Disease FREE

Pietro Tiraboschi, MD; Larry A. Hansen, MD; Michael Alford, BA; Annette Merdes, MD; Eliezer Masliah, MD; Leon J. Thal, MD; Jody Corey-Bloom, MD, PhD
[+] Author Affiliations

From Neurologia, Ospedale San Paolo, Milano, Italy (Dr Tiraboschi); the Department of Neurosciences, University of California– San Diego, La Jolla (Drs Hansen, Merdes, Masliah, Thal, and Corey-Bloom and Mr Alford); and the Neurology Service, San Diego Veterans Affairs Medical Center, San Diego, Calif (Drs Thal and Corey-Bloom).


Arch Gen Psychiatry. 2002;59(10):946-951. doi:10.1001/archpsyc.59.10.946.
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Background  Reductions in cholinergic function occur in Alzheimer disease (AD) and dementia with Lewy bodies and correlate with cognitive decline. However, whether such alterations appear in early-stage disease is unclear.

Objective  To examine the timing of cholinergic deficits in AD and dementia with Lewy bodies.

Methods  Autopsy series of 89 patients with AD and 50 patients with the Lewy body variant of AD (LBV). Stage of disease was stratified according to results of the last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. We analyzed choline acetyltransferase (ChAT) activity in the midfrontal, superior temporal, and inferior parietal cortices.

Results  Although compared with a normal control group ChAT activity was decreased in the AD and LBV cohorts, ChAT activity reduction for the LBV cohort was much greater. Moreover, although the decline in ChAT activity in the AD cohort compared with the normal control group was significant only for patients in later stages of the illness, the decline in the LBV cohort was significant for those who died with mild-stage disease. When less impaired patients in each cohort (MMSE, ≥10) underwent separate analysis, the relationship of ChAT activity with the MMSE score was strong and significant for the LBV cohort alone.

Conclusions  Although cholinergic deficits are seen in both AD and LBV, loss of ChAT activity is less severe and occurs later in the clinical course of AD. Conversely, in LBV, loss of ChAT activity is already prominent in the earliest stages of the illness, suggesting that cholinergic replacement therapy may be more effective in LBV than in AD, especially in mild-stage disease.

ALZHEIMER DISEASE (AD) is the most common form of primary degenerative dementia in the elderly, characterized by gradually worsening memory in association with aphasia, apraxia, agnosia, and disturbances of visuospatial perception. Although research in AD has focused on the functional role of multiple neurotransmitter systems, the cholinergic basal forebrain has been the most thoroughly studied. In AD, in which memory impairment is prominent, cholinergic function has been found to be markedly decreased, mainly as a result of neuronal loss in the basal forebrain, especially in the nucleus basalis of Meynert.1 The activity of choline acetyltransferase (ChAT), the presynaptic synthetic enzyme for acetylcholine, has been shown to be reduced by 50% to 90% in patients with AD compared with age-matched normal control (NC) subjects.2,3 Changes in other cholinergic markers have also been reported, including a decline in high-affinity nicotinic receptors4 and a reduction in presynaptic muscarinic receptor activity.5

Several studies have correlated decrements in ChAT activity with clinical indices of dementia severity.2,6,7 However, recent studies have reported that cholinergic enzyme activity is significantly reduced only in brains of severely demented patients with AD, suggesting that cholinergic dysfunction is not present until relatively late in the course of the illness.8,9

Dementia with Lewy bodies (DLB) has been recognized as another common cause of cognitive deterioration in the elderly. Much attention has focused on identifying reliable criteria that allow discrimination between DLB and AD.1012 In addition to cognitive impairment, the core clinical features of DLB are visual hallucinations, fluctuating attention, and parkinsonism.11,12 Neuropsychologically, patients with DLB may display a different pattern of cognitive decline, with worse performance on tests of visuospatial activity, initiation, and perseveration.13 Furthermore, the progression of their deterioration on global measures of dementia (eg, the Mini-Mental State Examination [MMSE]14 and the Mattis Dementia Rating Scale)15 may be faster than that observed in patients with AD.16 Neuropathologically, in most brains of patients with DLB, accompanying AD pathologic changes in the form of neocortical diffuse plaques, neuritic plaques, and modest numbers of neurofibrillary tangles are found in the medial temporal lobe (ie, the Lewy body variant of AD [LBV]).10 A few brains, however, have no more AD pathologic changes than do age-matched controls. Neurochemically, although the decline of ChAT activity has been shown to be much greater in patients with DLB than in those with AD,17 the strength of its association with cognitive decline has been more controversial.1820

Apart from a small number of autopsy studies that included cases with mild impairment,8,21,22 descriptions of neurochemical changes in AD and DLB have been generally based on findings in patients with late-stage disease. Moreover, few studies have been performed using biopsy specimens of living patients with mild to moderate dementia.22,23 Finally, most of these studies considered mixed populations of patients with AD and DLB, since they were performed before DLB had been well defined. Consequently, how early in the course of each of these diseases neurochemical alterations occur remains relatively unclear.

In the present study, we sought to determine whether cholinergic dysfunction was an early event in AD and LBV by examining the activity of ChAT in autopsy specimens of these prospectively observed cohorts who died at different stages of their illness (classified clinically as mild, moderate, severe, and very severe). In addition, we investigated the relationship between the decline in ChAT activity and dementia severity in AD and LBV.

PATIENTS

The patients included in the present study were observed clinically at the University of California–San Diego Alzheimer's Disease Research Center, Seniors Only Care, San Diego, or in the private practices of its senior clinicians. They represent all patients who underwent autopsy between 1985 and the present with a clinical diagnosis of AD or LBV or normal control (NC) for whom ChAT activity was available, and where cognitive testing was administered within 24 months prior to death.

Eighty-nine patients with AD and 50 with LBV met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition for a clinical diagnosis of dementia24 or of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association for probable or possible AD.25 In addition, they met the criteria of the National Institute on Aging for a pathological diagnosis of AD26 and of the Consortium to Establish a Registry for Alzheimer's Disease for a diagnosis of probable or definite AD.27 Patients with LBV also met the criteria of the Consortium on DLB for a pathological diagnosis of DLB.11,12 All patients with AD and LBV were stratified according to their last MMSE score before death as having mild (MMSE score, ≥20; n = 14 for the AD cohort and n = 7 for the LBV cohort), moderate (MMSE score, 10-19; n = 20 for the AD cohort and n = 10 for the LBV cohort), severe (MMSE score, 1-9; n = 29 for the AD cohort and n = 11 for the LBV cohort), and very severe disease(MMSE score, 0; n = 26 for the AD cohort and n = 22 for the LBV cohort).

The NC group consisted of 18 patients with no evidence of cognitive impairment or any other neurologic or psychiatric disorder. Twelve of these patients were also considered neuropathologically normal. The remaining 6 patients had only sufficient senile plaques to meet the National Institute on Aging criteria for AD or neuritic plaques to meet the criteria of the Consortium to Establish a Registry for Alzheimer's Disease for possible AD, but did not display any cognitive impairment on results of extensive neuropsychological testing administered in these cases less than 1 year before death.

NEUROPSYCHOLOGICAL EXAMINATION

Mean scores are reported for the following 3 commonly used measures of global cognitive status: the MMSE, the Blessed Information-Memory-Concentration test,28 and the Mattis Dementia Rating Scale. Most of the patients had also received the comprehensive neuropsychological battery administered through the Alzheimer's Disease Research Center as part of their annual evaluation.29

NEUROPATHOLOGICAL EXAMINATION

Pathological assessment was performed by one of us (L.A.H.). Autopsy was performed within 12 hours of death using a protocol described by Terry et al.30 The left half of the brain was fixed by means of immersion in 10% formalin for 5 to 7 days, at which time blocks were taken for paraffin embedding from the midfrontal (MF), rostral superior temporal (ST), and inferior parietal (IP) areas of the neocortex, hippocampus, entorhinal cortex, basal ganglia/substantia innominata, mesencephalon, and pons. The neocortical areas correspond to Brodmann areas 46, 38, and 39. The paraffin blocks of neocortex were cut at 7-µm thickness for hematoxylin-eosin and thioflavine S staining. Total plaque, neuritic plaque, and neurofibrillary tangle counts were determined by the same examiner (L.A.H.) using the same criteria consistently. Lewy bodies were detected using hematoxylin-eosin and/or anti-ubiquitin immunostaining, as recommended by the Consortium on Dementia with Lewy Bodies.11,12 Specifically, to receive a pathological diagnosis of LBV, 1 or more Lewy bodies had to be present in both the neocortex and brainstem in addition to significant AD pathologic changes.

NEUROCHEMISTRY

Samples were taken from the MF, ST, and IP areas of frozen, unfixed cortex from the right half of the brain and homogenized in 1mM EDTA (pH, 7.0) containing 0.1% Triton X-100 (Sigma-Aldrich Corp, St Louis, Mo). Analysis of ChAT activity was performed by means of the modified Fonnum technique.31,32 The coefficient of variation was 3%, with an intra-assay variability of 7.9%.

STATISTICAL ANALYSIS

Mean values among groups (AD vs NC and LBV vs NC) were compared using 1-way analysis of variance (ANOVA). In case of unequality of group variances(P<.05, Bartlett test), the ANOVA was preceded by logarithmic transformation of raw data. When a significant global result(overall P<.05) was obtained, the ANOVA was followed by the Tukey-Kramer multiple comparisons test to compare each pair of means. Correlation analyses were performed by means of Pearson product moment correlations.

The mean values for the demographics, clinical indices, and biochemical results are summarized in Table 1and Table 2. As expected, disease duration increased and cognitive performance worsened with disease stage in both cohorts. Compared with the NC group, ChAT activity was significantly decreased in the AD and LBV groups. However, loss of ChAT activity for the LBV cohort was much greater than that for the AD cohort, despite comparable mean ages at death, test-death intervals, and disease severity. Although decline of ChAT activity in AD compared with the NC group was statistically significant only for patients who died in the later stages of the disease, decline of ChAT activity in the LBV cohort was statistically significant in the earliest stages of the illness.

Table Graphic Jump LocationTable 1. Demographic, Neuropsychological, and Neurochemical Variables in AD*
Table Graphic Jump LocationTable 2. Demographic, Neuropsychological, and Neurochemical Variables in LBV*

Unlike the LBV group, for whom ChAT activity was significantly reduced(almost maximally) in all brain areas beginning in the mildest stages of the disease (MMSE, ≥20), the AD cohort displayed region-specific differences, with decrements of ChAT activity occurring relatively earlier in the ST cortex(moderate AD) than in the MF and IP cortices (severe AD). Specifically, compared with the NC group, ST ChAT activity was significantly decreased in patients with moderate AD at death (MMSE, 10-19), whereas MF and IP ChAT activities were significantly reduced only in the AD cohort with more severe impairment(MMSE, <10). This pattern of ChAT activity decline in LBV and AD did not change, even when the NC group was limited to the patients with neuropathologically normal findings (n = 12).

The correlations of ChAT activity with the MMSE are shown in Table 3. Correlations between the last MMSE score before death and ChAT activity were most robust for AD when the entire AD cohort (including many patients with severe and very severe AD) was considered. However, when only less impaired patients (with mild and/or moderate AD) in each cohort were included in the analyses, the relationship between the last MMSE before death and ChAT activity was considerably stronger for the LBV cohort in all neocortical regions examined.

Table Graphic Jump LocationTable 3. Correlations Between MMSE Scores and ChAT Activity in AD and LBV*

The present study investigated the timing and distribution of ChAT activity decline during the course of AD and LBV and the relationship between reduction of ChAT activity and dementia severity in these illnesses. To explore this, we used (1) large and well-characterized cohorts of patients with AD and LBV with the last neuropsychological assessment reasonably close to death, and(2) tissue samples from multiple neocortical areas of the patients.

Although definite conclusions about longitudinal changes occurring in individual patients can hardly be drawn from a cross-sectional study, our data strongly support the view that the integrity of cholinergic neurotransmission is affected at different points in the course of these diseases. Cholinergic dysfunction appears to occur early in LBV, whereas in AD, it is seemingly severely reduced only in the later stages of the illness. Furthermore, although this neurochemical deficit may be fairly generalized beginning with early-stage disease in LBV, there may be region-specific differences, with the temporal cortex more susceptible to the loss of ChAT activity than the frontal and parietal cortices, in AD. In fact, ST ChAT activity was significantly decreased in patients with moderate AD at death, whereas MF and IP ChAT activities were significantly reduced only in the AD cohort with more severe impairment. This is in contrast to a recent study by Davis et al,8 in which no regional differences in ChAT activity decline were observed, and suggests that the progression of deterioration in AD may depend on the involvement of an increasing number of specific neocortical regions as the disease advances.

In contrast to AD, the pattern of ChAT activity decline in LBV—early and more extensive, involving all neocortical regions—may contribute to its characteristic clinical profile. In particular, the higher prevalence of psychotic symptoms (visual hallucinations and delusions), severe visuospatial dysfunction, and prominent deficits in executive function, attention, and literal fluency reported for patients with mild- to moderate-stage LBV1113 may be related to earlier and greater reductions of ChAT activity in the temporal, parietal, and frontal cortices, respectively.

Loss of ChAT activity has been shown to correlate with cognitive decline in patients with AD by several investigators,2,68 who reported correlation coefficients ranging from 0.467 to 0.82.2 Although these discrepancies across studies may have several explanations, such as heterogeneity of populations(demented patients alone vs mixtures of patients with and without cognitive impairment), tissue samples (biopsy vs autopsy specimens), and brain regions considered for biochemical assay (eg, allocortical vs neocortical areas), different disease severity of the cohorts examined was likely the most important reason. In our AD sample, the strength of correlation between ChAT activity decline and cognitive impairment increased with increasing severity of dementia of the patients included in the analyses. When the whole AD cohort and the NC group were considered, our results (r = 0.52 [MF and IP cortices]; r = 0.59 [ST cortex]) were quite consistent with those found by other investigators.7,8

The relationship between ChAT activity and cognitive performance has been more controversial in DLB, in which reported correlation coefficients range from 0.2520 to 0.90.18 The same reasons raised for discrepancies in studies of AD and, in particular, the different disease severity of the patients examined, might have contributed to this great variability, since the magnitudes of correlation coefficients in previous studies were considerably reduced when more deteriorated patients were included.20 Moreover, the present study clearly shows that in LBV, unlike AD, the relationship between ChAT activity decline and cognitive impairment weakens as the severity of dementia of the patients included in the analyses increases.

Our findings may have several therapeutic implications. First, our data may provide a rationale for the greater responses reported for patients with more advanced AD in experimental trials of cholinesterase inhibitors, implying that even patients with severe AD retain the capacity to respond to cholinergic treatment. Second, and more important, these results suggest that cholinergic replacement therapy may be particularly effective in LBV, beginning with the earliest stages. Cholinergic replacement therapy has been postulated to play an important role in the treatment of LBV after 3 patients with combined LB-AD pathology and very low neocortical ChAT activity were reported to show a substantial response to tacrine hydrochloride treatment.33 Evidence has also shown that cholinesterase inhibitors may have neuropsychiatric benefits,34 including reduction of agitation, delusions, and hallucinations, which are highly prevalent in LBV.11,12 Although a recent pharmacological trial35 has only partially supported these findings, the present study strongly suggests that cholinergic replacement therapy may have greater benefits, especially early, for patients with LBV than for those with AD. This observation should be further assessed in well-designed, randomized clinical trials.

Submitted for publication May 31, 2001; final revision received December 11, 2001; accepted December 17, 2001.

This study was supported by grant AG05131 from the National Institutes of Health, Bethesda, Md.

We thank Katherine Foster and Barbara Reader for the technical assistance they provided in this study.

Corresponding author and reprints: Jody Corey-Bloom, MD, PhD, Neurology Service (Mail Code 9127), San Diego Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161-3064 (e-mail: jcoreybl@vapop.ucsd.edu).

Whitehouse  PJPrice  DLStruble  RGClark  AWCoyle  GTDeLong  MR Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;2151237- 1239
Perry  EKTomlinson  BEBlessed  GBergman  KGibson  PHPerry  RH Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ. 1978;21457- 1459
Davies  P Neurotransmitter-related enzymes in senile dementia of the Alzheimer type. Brain Res. 1979;171319- 327
James  JRNordberg  A Genetic and enviromental aspects of the role of nicotinic receptors in neurodegenerative disorders: emphasis on Alzheimer's disease and Parkinson's disease. Behav Genet. 1995;25149- 159
Nordberg  AWimblad  B Brain nicotinic and muscarinic receptors in normal aging and dementia. Fisher  AHanin  ILachman  Ceds. Alzheimer's and Parkinson's Disease: Strategies for Research and Development NewYork, NY Plenum Publishing Corp1986;95- 108
Wilcock  GKEsiri  MMBowen  DMSmith  CC Alzheimer's disease: correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci. 1982;57407- 417
Bierer  LMHaroutunian  VGabriel  SKnott  PJCarlin  LSPurohit  DPPerl  DPSchmeidler  JKanof  PDavis  KL Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64749- 760
Davis  KLMohs  RCMarin  DPurohit  DPPerl  DPLantz  MAustin  GHaroutunian  V Cholinergic markers in elderly patients with early signs of Alzheimer's disease. JAMA. 1999;2811401- 1406
Tiraboschi  PHansen  LAAlford  MMasliah  EThal  LJCorey-Bloom  J The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology. 2000;551278- 1283
Hansen  LASalmon  DGalasko  DMasliah  EKatzman  RDe Teresa  RThal  LJPay  MMHofstetter  RKlauber  M The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990;401- 8
McKeith  IGGalasko  DKosaka  KPerry  EKDickson  DWHansen  LASalmon  DPLowe  JMirra  SSByrne  EJLennox  GQuinn  NPEdwardson  JAInce  PGBergeron  CBurns  AMiller  BLLovestone  SCollerton  DJansen  ENBallard  Cde Vos  RAWilcock  GKJellinger  KAPerry  RH Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB International Workshop. Neurology. 1996;471113- 1124
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;53902- 905
Connor  DJSalmon  DSandy  TJGalasko  DHansen  LAThal  LJ Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer's disease. Arch Neurol. 1998;55994- 1000
Folstein  MFFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Mattis  S Mental status examination for organic mental syndrome in the elderly patient. Bellack  LKarasu  Teds.Geriatric Psychiatry New York, NY Grune & Stratton Inc1976;77- 121
Olichney  JMGalasko  DSalmon  DHofstetter  CRHansen  LAKatzman  RThal  LJ Cognitive decline is faster in the Lewy body variant of Alzheimer's disease. Neurology. 1998;51351- 357
Tiraboschi  PHansen  LAAlford  MSabbagh  MNSchoos  BMasliah  EThal  LJCorey-Bloom  J Cholinergic dysfunction in diseases with Lewy bodies. Neurology. 2000;54407- 411
Perry  EKMarshall  EPerry  RHIrving  DSmith  CJBlessed  GFairbairn  AF Cholinergic and dopaminergic activities in senile dementia of the Lewy body type. Alzheimer Dis Assoc Disord. 1990;487- 95
Samuel  WAlford  MHofstetter  CRHansen  LA Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol. 1997;56499- 508
Sabbagh  MNCorey-Bloom  JTiraboschi  PThomas  RMasliah  EThal  LJ Neurochemical markers do not correlate with cognitive decline in the Lewy body variant of Alzheimer's disease. Arch Neurol. 1999;561458- 1461
Bowen  DMBenton  JSSpillane  JASmith  CCTAllen  SJ Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci. 1982;57191- 202
Neary  DSnowden  JSMann  DMBowen  DMSims  NRNorthen  BYates  PODavison  AN Alzheimer's disease: a correlative study. J Neurol Neurosurg Psychiatry. 1986;49229- 237
DeKosky  STScheff  SW Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27457- 464
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
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;34939- 944
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105
Mirra  SSHeyman  AMcKeel  DSumi  SMCrain  BJBrownlee  LMVogel  FSHughes  JPvan Belle  GBerg  L The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), II: standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991;41479- 486
Blessed  GTomlinson  BERoth  M The association between quantitative measures of dementia and of senile change in the cerebral gray matter of elderly subjects. Br J Psychiatry. 1968;114797- 811
Salmon  DButters  N Neuropsychological assessment of dementia in the elderly. Katzman  RRowe  Jeds.Principles of Geriatric Neurology Philadelphia, Pa FA Davis Co Publishers1992;144- 153
Terry  RDPeck  ADeTeresa  RSchecter  RHoroupian  DS Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol. 1981;10184- 192
Fonnum  F A rapid radiochemical method of determination of choline acetyltransferase. J Neurochem. 1975;24407- 409
Hansen  LADeTeresa  RDavies  PTerry  RD Neocortical morphometry, lesion counts, and choline acetyltransferase levels in the age spectrum of Alzheimer's disease. Neurology. 1988;3848- 54
Levy  REagger  SAGriffiths  MPerry  EHonavar  MDean  ALantos  P Lewy bodies and response to tacrine in Alzheimer's disease [letter]. Lancet. 1994;343176
Cummings  JL Changes in neuropsychiatric symptoms as outcome measures in clinical trials with cholinergic therapies for Alzheimer's disease. Alzheimer Dis Assoc Disord. 1997;114S1- S9
McKeith  IDel Ser  TSpano  PFEmre  MWesnes  KAnand  RCicin-Sain  AFerrara  RSpiegel  R Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double-blind, placebo-controlled international study. Lancet. 2000;3562031- 2036

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic, Neuropsychological, and Neurochemical Variables in AD*
Table Graphic Jump LocationTable 2. Demographic, Neuropsychological, and Neurochemical Variables in LBV*
Table Graphic Jump LocationTable 3. Correlations Between MMSE Scores and ChAT Activity in AD and LBV*

References

Whitehouse  PJPrice  DLStruble  RGClark  AWCoyle  GTDeLong  MR Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;2151237- 1239
Perry  EKTomlinson  BEBlessed  GBergman  KGibson  PHPerry  RH Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ. 1978;21457- 1459
Davies  P Neurotransmitter-related enzymes in senile dementia of the Alzheimer type. Brain Res. 1979;171319- 327
James  JRNordberg  A Genetic and enviromental aspects of the role of nicotinic receptors in neurodegenerative disorders: emphasis on Alzheimer's disease and Parkinson's disease. Behav Genet. 1995;25149- 159
Nordberg  AWimblad  B Brain nicotinic and muscarinic receptors in normal aging and dementia. Fisher  AHanin  ILachman  Ceds. Alzheimer's and Parkinson's Disease: Strategies for Research and Development NewYork, NY Plenum Publishing Corp1986;95- 108
Wilcock  GKEsiri  MMBowen  DMSmith  CC Alzheimer's disease: correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci. 1982;57407- 417
Bierer  LMHaroutunian  VGabriel  SKnott  PJCarlin  LSPurohit  DPPerl  DPSchmeidler  JKanof  PDavis  KL Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64749- 760
Davis  KLMohs  RCMarin  DPurohit  DPPerl  DPLantz  MAustin  GHaroutunian  V Cholinergic markers in elderly patients with early signs of Alzheimer's disease. JAMA. 1999;2811401- 1406
Tiraboschi  PHansen  LAAlford  MMasliah  EThal  LJCorey-Bloom  J The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease. Neurology. 2000;551278- 1283
Hansen  LASalmon  DGalasko  DMasliah  EKatzman  RDe Teresa  RThal  LJPay  MMHofstetter  RKlauber  M The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990;401- 8
McKeith  IGGalasko  DKosaka  KPerry  EKDickson  DWHansen  LASalmon  DPLowe  JMirra  SSByrne  EJLennox  GQuinn  NPEdwardson  JAInce  PGBergeron  CBurns  AMiller  BLLovestone  SCollerton  DJansen  ENBallard  Cde Vos  RAWilcock  GKJellinger  KAPerry  RH Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB International Workshop. Neurology. 1996;471113- 1124
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;53902- 905
Connor  DJSalmon  DSandy  TJGalasko  DHansen  LAThal  LJ Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer's disease. Arch Neurol. 1998;55994- 1000
Folstein  MFFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Mattis  S Mental status examination for organic mental syndrome in the elderly patient. Bellack  LKarasu  Teds.Geriatric Psychiatry New York, NY Grune & Stratton Inc1976;77- 121
Olichney  JMGalasko  DSalmon  DHofstetter  CRHansen  LAKatzman  RThal  LJ Cognitive decline is faster in the Lewy body variant of Alzheimer's disease. Neurology. 1998;51351- 357
Tiraboschi  PHansen  LAAlford  MSabbagh  MNSchoos  BMasliah  EThal  LJCorey-Bloom  J Cholinergic dysfunction in diseases with Lewy bodies. Neurology. 2000;54407- 411
Perry  EKMarshall  EPerry  RHIrving  DSmith  CJBlessed  GFairbairn  AF Cholinergic and dopaminergic activities in senile dementia of the Lewy body type. Alzheimer Dis Assoc Disord. 1990;487- 95
Samuel  WAlford  MHofstetter  CRHansen  LA Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol. 1997;56499- 508
Sabbagh  MNCorey-Bloom  JTiraboschi  PThomas  RMasliah  EThal  LJ Neurochemical markers do not correlate with cognitive decline in the Lewy body variant of Alzheimer's disease. Arch Neurol. 1999;561458- 1461
Bowen  DMBenton  JSSpillane  JASmith  CCTAllen  SJ Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci. 1982;57191- 202
Neary  DSnowden  JSMann  DMBowen  DMSims  NRNorthen  BYates  PODavison  AN Alzheimer's disease: a correlative study. J Neurol Neurosurg Psychiatry. 1986;49229- 237
DeKosky  STScheff  SW Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27457- 464
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