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Table 1. 
Clinical and Pathological Features of 41 Patients With LBV*
Clinical and Pathological Features of 41 Patients With LBV*
Table 2. 
Correlation of Clinical Indexes With Presynaptic Cholinergic Markers in Patients With LBV*
Correlation of Clinical Indexes With Presynaptic Cholinergic Markers in Patients With LBV*
1.
Liebson  EAlbert  ML Cognitive changes in dementia of the Alzheimer type. Calne  DBedNeurodegenerative Diseases. Philadelphia, Pa WB Saunders Co1994;615- 629
2.
Blessed  GTomlinson  BERoth  M The associations between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114797- 811Article
3.
Wilcock  GKEsiri  MM Plaques, tangles and dementia: a quantitative study. J Neurol Sci. 1982;56343- 356Article
4.
Neary  DSnowden  JSMann  DM  et al.  Alzheimer's disease: a correlative study. J Neurol Neurosurg Psychiatry. 1986;49229- 237Article
5.
Martin  EMWilson  RSPenn  RDFox  MDClasen  RASavoy  SM Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits. Neurology. 1987;371201- 1204Article
6.
Terry  RDMasliah  ESalmon  DP  et al.  Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30572- 580Article
7.
Berg  LMcKeel  DWMiller  PBaty  JMorris  JC Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older. Arch Neurol. 1993;50349- 358Article
8.
Samuel  WTerry  RDDeTeresa  RButters  NMasliah  E Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch Neurol. 1994;51772- 778Article
9.
Cummings  BJCotman  CW Image analysis of β-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet. 1995;3461524- 1528Article
10.
Davies  PMaloney  AJF Selective loss of cholinergic neurons in Alzheimer's disease [letter]. Lancet. 1976;21403Article
11.
Perry  EKPerry  RHGibson  PHBlessed  GTomlinson  BE A cholinergic connection between normal aging and senile dementia in the human hippocampus. Neurosci Lett. 1977;685- 89Article
12.
Perry  EKTomlinson  BEBlessed  GBergmann  KGibson  PHPerry  RH Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J. 1978;21457- 1459Article
13.
Wilcock  GKEsiri  MMBowen  DMSmith  CC Alzheimer's disease: correlation of cortical choline acetyltranferase activity with the severity of dementia and histological abnormalities. J Neurol Sci. 1982;57407- 417Article
14.
Francis  PTPalmer  AMSims  NR  et al.  Neurochemical studies of early-onset Alzheimer's disease: possible influence on treatment. N Engl J Med. 1985;3137- 11Article
15.
Bierer  LMHaroutanian  VGabriel  S  et al.  Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64749- 760Article
16.
James  JRNordberg  A Genetic and environmental aspects of the role of nicotinic receptors in neurodegenerative disorders: emphasis on Alzheimer's disease and Parkinson's disease. Behav Genet. 1995;25149- 159Article
17.
Nordberg  AWinblad  B Brain nicotinic and muscarinic receptors in normal aging and dementia. Fisher  AHanin  ILachman  CedsAlzheimer's and Parkinson's Disease Strategies for Research and Development. New York, NY Plenum Press1986;95- 108
18.
DeKosky  STScheff  SW Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27457- 464Article
19.
Hansen  LSalmon  DGalasko  D  et al.  The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990;401- 8Article
20.
McKeith  IGGalasko  DKosaka  K  et al.  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- 1124Article
21.
Connor  DJSalmon  DPSandy  TJGalasko  DHansen  LAThal  LJ Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer disease. Arch Neurol. 1998;55994- 1000Article
22.
Olichney  JMGalasko  DSalmon  DP  et al.  Cognitive decline is faster in the Lewy body variant of Alzheimer's disease. Neurology. 1998;51351- 357Article
23.
Langlais  PJThal  LHansen  LGalasko  DAlford  MMasliah  E Neurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies. Neurology. 1993;431927- 1934Article
24.
Hansen  LADaniel  SEWilcock  GKLove  S Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia. J Neurol Neurosurg Psychiatry. 1998;64653- 656Article
25.
Samuel  WAlford  MHoffstetter  CRHansen  L Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol. 1997;56499- 508Article
26.
Perry  EKMarshall  EPerry  RH  et al.  Cholinergic and dopaminergic activities in senile dementia of the Lewy body type. Alzheimer Dis Assoc Disord. 1990;487- 95Article
27.
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105Article
28.
Mirra  SSHeyman  AMcKeel  D  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991;41479- 486Article
29.
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
30.
McKhann  GDrachmann  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease. Neurology. 1984;34939- 944Article
31.
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- 198Article
32.
Terry  RPeck  ADeTeresa  RSchecter  RHoroupian  DS Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol. 1981;10184- 192Article
33.
Kuzuhara  SMori  HIzumiyama  NYoshimura  MIhara  Y Lewy bodies are ubiquinated: a light and electron microscopic immunocytochemical study. Acta Neuropathol (Berl). 1988;75345- 353Article
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Lennox  GLowe  JMorrell  KLandon  MMayer  RJ Antiubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. J Neurol Neurosurg Psychiatry. 1989;5267- 71Article
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Fonnum  F Radiochemical micro assays for the determination of choline acetyltransferase and acetylcholinesterase and acetylcholinesterase activities. Biochem J. 1969;115465- 472
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Hansen  LADeTeresa  RTobias  HAlford  MTerry  RD Neocortical morphometry and cholinergic neurochemistry in Pick's disease. Am J Pathol. 1988;131507- 518
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Hansen  LADeTeresa  RDavies  PTerry  RD Neocortical morphometry, lesion counts, and choline acetyltransferase levels in the age spectrum of Alzheimer's disease. Neurology. 1988;3848- 54Article
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Alford  MFMasliah  EHansen  LATerry  RD A simple dot-immunobinding assay for quantification of synaptophysin-like immunoreactivity in human brain. J Histochem Cytochem. 1994;42283- 287Article
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Neary  DSnowden  JSBowen  DM  et al.  Neuropsychological syndromes in presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry. 1986;49163- 174Article
40.
Carroll  PT Membrane-bound choline-O-acetyltransferase in rat hippocampal tissue is associated with synaptic vesicles. Brain Res. 1994;633112- 118Article
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de la Torre  JCGoldsmith  HS Supraspinal fiber outgrowth and apparent synaptic remodelling across transected-reconstructed feline spinal cord. Acta Neurochir (Wien). 1992;114118- 127Article
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Torack  RMMiller  JW Denervation induced abnormal phosphorylation in hippocampal neurons. Brain Res. 1995;669135- 139Article
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Romijn  HJvan Marle  JJanszen  AW Permanent increase of the GAD67/synaptophysin ratio in rat cerebral cortex nerve endings as a result of hypoxic ischemic encephalopathy sustained in early postnatal life: a confocal laser scanning microscopic study. Brain Res. 1993;630315- 329Article
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Gomez-Isla  TGrowdon  WMcNamara  MGrowdon  JHHyman  BT Diffuse Lewy body dementia: quantitative neuropathological studies and APOE genotyping [abstract]. Neurology. 1997;48A140- A141
Original Contribution
December 1999

Neurochemical Markers Do Not Correlate With Cognitive Decline in the Lewy Body Variant of Alzheimer Disease

Author Affiliations

From the Department of Neurosciences, University of California, San Diego, La Jolla (Drs Sabbagh, Corey-Bloom, Thomas, and Masliah); the Neurology Service, San Diego Veterans Affairs Medical Center, San Diego (Drs Sabbagh, Corey-Bloom, and Thal); and Neurologia Prima, Ospedali Riuniti di Bergamo, Bergamo, Italy (Dr Tiraboschi).

Arch Neurol. 1999;56(12):1458-1461. doi:10.1001/archneur.56.12.1458
Abstract

Background  Reductions in neocortical synapses and cholinergic function occur in patients with Alzheimer disease (AD) and in patients with the Lewy body variant of AD (LBV). The relation between these losses and cognitive decline has been reported frequently in patients with AD but remains unclear for patients with LBV.

Objectives  To investigate the relation between clinical markers of disease progression and choline acetyltransferase activity or synaptic density, measured by synaptophysin (Syn) level, in patients with LBV, and to investigate the relation of these neurochemical markers with one another.

Methods  Brain specimens of 41 patients with autopsy-confirmed (National Institute on Aging criteria for AD) LBV were examined. The last Mini-Mental State Examination and Blessed Information-Memory-Concentration test scores before death were reviewed. Midfrontal synapse counts were quantified by a dot-immunobinding assay for Syn. Choline acetyltransferase activity of the midfrontal cortex was assayed by established protocols.

Results  The last Mini-Mental State Examination score before death did not correlate significantly with Syn level (n=25, r=0.25, P=.24); however, there was a trend toward significance for the relation between last Mini-Mental State Examination score and choline acetyltransferase activity (n=39, r=0.31, P=.05). The last Blessed Information-Memory-Concentration test score did not correlate with either Syn level (n=24, r=−0.17, P=.44) or choline acetyltransferase activity (n=39, r=−0.16, P=.33). Finally, there was only a modest correlation between Syn level and choline acetyltransferase activity (n=25 , r=0.38, P=.06), which did not reach statistical significance.

Conclusion  Unlike AD, neurochemical markers do not appear to correlate well with cognitive decline in LBV.

ALZHEIMER disease (AD) is a progressive disorder of cognitive function, characterized by gradually worsening memory in association with aphasia, apraxias, agnosias, and disturbances of perception.1 Several studies29 have correlated neuropathologic markers of AD with global measures of dementia and deficits in specific cognitive domains. Following the demonstration that the cholinergic system was particularly vulnerable in this disorder,10,11 a great deal of research has focused on investigating the functional role of this system in patients with AD. Loss of 1 presynaptic marker of the cholinergic system, choline acetyltransferase (ChAT), has been correlated with several clinical indexes of dementia severity.1215 Changes in other cholinergic markers have also been reported, including a decline in high-affinity nicotinic receptors16 and a reduction in presynaptic muscarinic activity.17 Furthermore, loss of synapses has also been shown to correlate highly with dementia severity using global dementia rating scales in patients with AD.6,18

Dementia with Lewy bodies (DLB) has become recognized as another common form of dementia. Much attention has been focused on identifying criteria that allow discrimination of DLB from AD.19,20 In addition to dementia, the core clinical features of patients with DLB that may aid in distinguishing them from patients with AD include visual hallucinations, fluctuating attention, and parkinsonism.20 Neuropsychologically, patients with DLB have a different pattern of cognitive decline, with worse performance on initiation and perseveration tests,21 and they may undergo dementia more rapidly.22 As in patients with AD, neurochemical decline in ChAT activity and loss of synapses have been observed in patients with DLB.23,24 Most studies25,26 of patients with DLB have included a mixture of those with AD changes (the Lewy body variant of AD [LBV]) and those without AD changes (diffuse Lewy body disease).

In the present study, we wanted to investigate whether cognitive decline in patients with LBV would correlate with neurochemical markers in a fashion similar to that seen in patients with AD. To test this hypothesis, we examined the relations between synaptophysin (Syn), a marker of synaptic density, ChAT, and dementia severity based on the Mini-Mental State Examination (MMSE) and the Blessed Information-Memory-Concentration (BIMC) test in subjects with autopsy-proved LBV.

SUBJECTS AND METHODS
SUBJECTS

The subjects with LBV in the present study were followed up clinically at the University of California, San Diego, Alzheimer's Disease Research Center; the Senior's Only Care, a program sponsored by the University of California, San Diego; or the private practices of its senior clinicians.

Brain specimens of 41 patients with autopsy-confirmed LBV were examined. These specimens, with brainstem or neocortical Lewy bodies, met National Institute on Aging27 and Consortium to Establish a Registry for Alzheimer's Disease28 criteria for definite or probable AD and clinically fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition29 criteria for a diagnosis of dementia; most of them also fulfilled National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association30 criteria for a clinical diagnosis of probable or possible AD. The last MMSE31 and BIMC test scores2 were used to assess dementia severity. Patients were excluded if they had not undergone a clinical examination within 24 months of death.

NEUROPATHOLOGIC EXAMINATION

The postmortem interval varied from 2 to 24 hours. The autopsy was performed using a protocol described by Terry et al.6,32 The left hemibrain was fixed by immersion in 10% formaldehyde solution for 5 to 7 days, at which time blocks were taken for paraffin embedding from the midfrontal (MF), rostral superior temporal, and inferior parietal areas of the neocortex; hippocampus; basal ganglia or innominate substance; mesencephalon; and pons. The cortical areas correspond to Brodmann areas 46, 38, and 39. The paraffin blocks of the isocortex were cut at 7-mm thickness for hematoxylin-eosin staining. Sections (10 µm thick) were prepared for thioflavine S staining. Quantification of Lewy bodies was performed by methods previously described.19,33,34

ChAT MEASUREMENTS

Samples were taken from MF areas of frozen unfixed right hemibrain isocortex and homogenized in EDTA, pH 7.0, 1 mmol/L, containing 0.1% alkaryl polyether alcohol (Triton X-100). Analysis of ChAT activity was performed in triplicate by the modified Fonnum technique.3537 The coefficient of variation was 3%, with an intra-assay variability of 7.9%.

SYNAPSE DENSITY MEASUREMENTS

Synaptic density measurements from the right MF cortex were performed by the dot-immunobinding assay for Syn immunoreactivity described by Alford et al.38 Briefly, this is a technique that uses immunocytochemical labeling of the synapse-associated protein, Syn, coupled with quantification by optical density measurement. Particulate fractions were prepared, and the pellet was resuspended and sonicated. After total protein determination, samples were diluted to a uniform concentration of 40 µg of protein per milliliter. Samples were then blotted in a microsample filtration manifold (Schleicher & Schuell, Keene, NH) on a 0.45-mm pore size nitrocellulose membrane, drawn through by vacuum, and then dried. Mouse monoclonal Syn antibody was incubated with the samples overnight followed by consecutive incubations of rabbit anti–mouse IgG and iodine 125–protein A for 2 hours each. Autoradiography was then performed on these preparations. Each sample has 6 replications, with an intrasample coefficient of variation of 7.9%.

STATISTICAL ANALYSIS

Correlation analyses for patients with LBV were performed by Pearson product moment correlations.

RESULTS

The mean values for the demographics, clinical indexes, and biochemical results are summarized in Table 1. The correlations between presynaptic markers and global mental test scores for the subjects with LBV are summarized in Table 2. The correlation between last MMSE score before death and Syn level was not statistically significant; however, there was a trend toward significance for the correlation between last MMSE score and ChAT activity. The last BIMC test scores did not correlate with either Syn level or ChAT activity.

There was only a modest correlation between Syn level and ChAT activity, which approached but did not reach statistical significance.

COMMENT

The present study examines the relation between the presynaptic markers ChAT and Syn in a well-characterized cohort of subjects with LBV. Furthermore, it assesses the relation between these presynaptic markers and global measures of dementia severity in patients with LBV.

A relation between global measures of dementia severity and synapse loss has been established in patients with AD.6,18 Using electron microscopy of biopsy specimens, DeKosky and Scheff18 reported a correlation coefficient of 0.69 between scores on the MMSE and number of synapses in Brodmann area 9 in 8 patients with AD. Likewise, Terry and coworkers6 and Samuel and coworkers8 reported correlation coefficients of 0.73 for the MMSE and −0.76 for the BIMC test and neocortical synapse density in 15 patients with AD. However, in the present study using subjects with LBV, synapse loss did not correlate with level of cognitive decline, which was quite surprising since mean Syn counts were akin to those seen in patients with AD.24 In a smaller cohort of subjects with LBV (n=12), Samuel et al25 also found no correlation between synapse loss and cognitive decline.

Choline acetyltransferase activity has been shown to correlate with cognitive decline in patients with AD by several investigators. Perry et al12 first demonstrated a relation between ChAT activity and the BIMC test score in 1978. A correlation coefficient of 0.82 was reported by these researchers, but careful examination of their data reveals that this high correlation resulted from a mixture of patients with dementia and patients with depression. A significant correlation between ChAT activity and measures of dementia severity was also reported in a mixed population of patients with dementia and patients without dementia in another series.13 Using a clinical index of dementia severity that ranged from 0 to 9,39 Francis et al14 found a correlation of 0.63 between ChAT levels and cognitive impairment in 17 young patients with AD who underwent cortical biopsy. Their correlation may be somewhat influenced by selection bias and the younger age of their subjects. A recent report by Bierer et al15 examining the relation between ChAT activity in the temporal cortex and the Clinical Dementia Rating scale reported a correlation coefficient of 0.46.

For LBV, the relation between ChAT activity and dementia severity has not been clear. Using a large sample of well-characterized subjects with LBV, we did not find a correlation between ChAT activity and BIMC test score and observed only a weak correlation between ChAT activity and MMSE score. This is in contrast to the previous study by Samuel et al25 from our institution using a smaller cohort (n=17) of mixed subjects with diffuse Lewy body disease and subjects with LBV in which correlation coefficients of 0.62 (MMSE) and −0.33 (BIMC) were reported. When their analysis was limited to patients with LBV (n=9), MF ChAT activity continued to correlate with MMSE (r=0.67) and BIMC test (r=−0.60) scores. Likewise, the small study of 8 subjects with senile dementia of the Lewy body type by Perry et al26 reported a strong correlation (n=8, r=0.9, P<.01) between ChAT activity and BIMC test scores before death. Using a considerably larger, but possibly more demented, cohort of well-characterized subjects with LBV, we were unable to confirm these findings with either the BIMC test or the MMSE. Only 6 subjects overlapped with the previous report from our institution, and their test death interval was considerably longer. Hypothetically, the severity of dementia in our sample might have affected our ability to demonstrate correlations owing to the presence of floor or ceiling limitations on the MMSE and the BIMC test in many subjects (about one third). Nevertheless, when we excluded from analysis subjects who had achieved a floor score on the MMSE, the correlation did not change appreciably (ChAT vs MMSE, r=0.36; P=.07).

An additional finding of our study is that there is only a modest correlation between ChAT activity and neocortical synaptic density measurements in the MF cortices of subjects with LBV. For AD, this correlation in a small study of 12 subjects was somewhat stronger (r=0.54, P<.05), although hardly robust.25 Since studies40 of rat hippocampus had shown that ChAT is membrane bound to synaptic vesicles that contain Syn, we had expected that there might be a tight correlation between the 2. Our finding of only a modest correlation between ChAT and Syn may have several explanations. First, not all synapses labeled by Syn are cholinergic. Synaptophysin labels noradrenergic,41 dopaminergic,42 and γ-aminobutyric acid43 neuronal populations in the brain. Second, the Syn immunobinding assay used in our study may not be as accurate as evaluation of Syn staining by laser confocal microscopy. While clearly easier to perform, the dot blot assay does not have the anatomic accuracy of examining tissue sections; however, the dot blot Syn immunobinding assay has a correlation coefficient of 0.82 to the measurement of Syn by laser confocal microscopy.38

In the present study, we sought to examine the relations between neurochemical markers and several clinical indexes of dementia severity in a relatively large, well-characterized cohort of subjects with autopsy-proved LBV. The relations between these markers and cognitive decline have been reported frequently in patients with AD but remained unclear in patients with LBV. The lack of correlation between the presynaptic markers ChAT and Syn and global cognitive measures, the MMSE and BIMC test scores in the present study, suggests that other factors, which are not operative in patients with AD, may be operative in determining dementia in patients with LBV; these factors include greater neuronal loss44 and the presence and number of Lewy bodies.25

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Article Information

Accepted for publication March 22, 1999.

This study was supported by grant AG05131 from the National Institutes of Health, Bethesda, Md; and a geriatric neurology fellowship from San Diego Veterans Affairs Medical Center, San Diego, Calif (Dr Sabbagh).

We thank Kathy Foster, Michael Alford, and Barbara Reader for the technical assistance they provided in this study.

Reprints: Leon J. Thal, MD, Neurology Service (9127), San Diego Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161 (e-mail: msabbagh@vapop.ucsd.edu).

References
1.
Liebson  EAlbert  ML Cognitive changes in dementia of the Alzheimer type. Calne  DBedNeurodegenerative Diseases. Philadelphia, Pa WB Saunders Co1994;615- 629
2.
Blessed  GTomlinson  BERoth  M The associations between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114797- 811Article
3.
Wilcock  GKEsiri  MM Plaques, tangles and dementia: a quantitative study. J Neurol Sci. 1982;56343- 356Article
4.
Neary  DSnowden  JSMann  DM  et al.  Alzheimer's disease: a correlative study. J Neurol Neurosurg Psychiatry. 1986;49229- 237Article
5.
Martin  EMWilson  RSPenn  RDFox  MDClasen  RASavoy  SM Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits. Neurology. 1987;371201- 1204Article
6.
Terry  RDMasliah  ESalmon  DP  et al.  Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30572- 580Article
7.
Berg  LMcKeel  DWMiller  PBaty  JMorris  JC Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older. Arch Neurol. 1993;50349- 358Article
8.
Samuel  WTerry  RDDeTeresa  RButters  NMasliah  E Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch Neurol. 1994;51772- 778Article
9.
Cummings  BJCotman  CW Image analysis of β-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet. 1995;3461524- 1528Article
10.
Davies  PMaloney  AJF Selective loss of cholinergic neurons in Alzheimer's disease [letter]. Lancet. 1976;21403Article
11.
Perry  EKPerry  RHGibson  PHBlessed  GTomlinson  BE A cholinergic connection between normal aging and senile dementia in the human hippocampus. Neurosci Lett. 1977;685- 89Article
12.
Perry  EKTomlinson  BEBlessed  GBergmann  KGibson  PHPerry  RH Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J. 1978;21457- 1459Article
13.
Wilcock  GKEsiri  MMBowen  DMSmith  CC Alzheimer's disease: correlation of cortical choline acetyltranferase activity with the severity of dementia and histological abnormalities. J Neurol Sci. 1982;57407- 417Article
14.
Francis  PTPalmer  AMSims  NR  et al.  Neurochemical studies of early-onset Alzheimer's disease: possible influence on treatment. N Engl J Med. 1985;3137- 11Article
15.
Bierer  LMHaroutanian  VGabriel  S  et al.  Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64749- 760Article
16.
James  JRNordberg  A Genetic and environmental aspects of the role of nicotinic receptors in neurodegenerative disorders: emphasis on Alzheimer's disease and Parkinson's disease. Behav Genet. 1995;25149- 159Article
17.
Nordberg  AWinblad  B Brain nicotinic and muscarinic receptors in normal aging and dementia. Fisher  AHanin  ILachman  CedsAlzheimer's and Parkinson's Disease Strategies for Research and Development. New York, NY Plenum Press1986;95- 108
18.
DeKosky  STScheff  SW Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27457- 464Article
19.
Hansen  LSalmon  DGalasko  D  et al.  The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 1990;401- 8Article
20.
McKeith  IGGalasko  DKosaka  K  et al.  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- 1124Article
21.
Connor  DJSalmon  DPSandy  TJGalasko  DHansen  LAThal  LJ Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer disease. Arch Neurol. 1998;55994- 1000Article
22.
Olichney  JMGalasko  DSalmon  DP  et al.  Cognitive decline is faster in the Lewy body variant of Alzheimer's disease. Neurology. 1998;51351- 357Article
23.
Langlais  PJThal  LHansen  LGalasko  DAlford  MMasliah  E Neurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies. Neurology. 1993;431927- 1934Article
24.
Hansen  LADaniel  SEWilcock  GKLove  S Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia. J Neurol Neurosurg Psychiatry. 1998;64653- 656Article
25.
Samuel  WAlford  MHoffstetter  CRHansen  L Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol. 1997;56499- 508Article
26.
Perry  EKMarshall  EPerry  RH  et al.  Cholinergic and dopaminergic activities in senile dementia of the Lewy body type. Alzheimer Dis Assoc Disord. 1990;487- 95Article
27.
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105Article
28.
Mirra  SSHeyman  AMcKeel  D  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991;41479- 486Article
29.
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
30.
McKhann  GDrachmann  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease. Neurology. 1984;34939- 944Article
31.
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- 198Article
32.
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