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Figure 1.
Box-and-whiskers plots of choline acetyltransferase (ChAT) (A) and acetylcholinesterase (AChE) (B) activities and nerve growth factor (NGF) protein levels (C) in the primary visual cortex from the no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer disease (AD) groups. The ChAT activity is decreased in the AD group.

Box-and-whiskers plots of choline acetyltransferase (ChAT) (A) and acetylcholinesterase (AChE) (B) activities and nerve growth factor (NGF) protein levels (C) in the primary visual cortex from the no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer disease (AD) groups. The ChAT activity is decreased in the AD group.

Figure 2.
Scatter plots showing significant correlations of primary visual cortex choline acetyltransferase (ChAT) activity with Mini-Mental State Examination (MMSE) (A) and Global Cognitive Score (GCS) (B) but not with a composite z score of visuospatial function (C). AD indicates Alzheimer disease; MCI, mild cognitive impairment; and NCI, no cognitive impairment.

Scatter plots showing significant correlations of primary visual cortex choline acetyltransferase (ChAT) activity with Mini-Mental State Examination (MMSE) (A) and Global Cognitive Score (GCS) (B) but not with a composite z score of visuospatial function (C). AD indicates Alzheimer disease; MCI, mild cognitive impairment; and NCI, no cognitive impairment.

Table 1. 
Demographic and Pathological Characteristics by Clinical Diagnosis Category
Demographic and Pathological Characteristics by Clinical Diagnosis Category
Table 2. 
Cognitive Function by Clinical Diagnosis Category
Cognitive Function by Clinical Diagnosis Category
Table 3. 
Summary of ChAT and AChE Activities and NGF Protein, Levels (After Natural Logarithm Transformation) in the Primary Visual Cortex
Summary of ChAT and AChE Activities and NGF Protein, Levels (After Natural Logarithm Transformation) in the Primary Visual Cortex
1.
Mendez  MFMendez  MAMartin  RSmyth  KAWhitehouse  PJ Complex visual disturbances in Alzheimer’s disease. Neurology 1990;40439- 443
PubMedArticle
2.
Cronin-Golomb  ACorkin  SGrowdon  JH Visual dysfunction predicts cognitive deficits in Alzheimer’s disease. Optom Vis Sci 1995;72168- 176
PubMedArticle
3.
Kaskie  BStorandt  M Visuospatial deficit in dementia of the Alzheimer type. Arch Neurol 1995;52422- 425
PubMedArticle
4.
Rizzo  MAnderson  SWDawson  JNawrot  M Vision and cognition in Alzheimer’s disease. Neuropsychologia 2000;381157- 1169
PubMedArticle
5.
Cronin-Golomb  ARizzom  JFCorkin  SGrowdon  JH Visual function in Alzheimer’s disease and normal aging. Ann N Y Acad Sci 1991;64028- 35
PubMed
6.
Lewis  DACampbell  MJTerry  RDMorrison  JH Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: a quantitative study of visual and auditory cortices. J Neurosci 1987;71799- 1808
PubMed
7.
Morrison  JHHof  PRBouras  C An anatomic substrate for visual disconnection in Alzheimer’s disease. Ann N Y Acad Sci 1991;64036- 43
PubMed
8.
Beach  TGMcGeer  EG Cholinergic fiber loss occurs in the absence of synaptophysin depletion in Alzheimer’s disease primary visual cortex. Neurosci Lett 1992;142253- 256
PubMedArticle
9.
Davis  KLMohs  RCMarin  D  et al.  Cholinergic markers in elderly patients with early signs of Alzheimer’s disease. JAMA 1999;2811401- 1406
PubMedArticle
10.
Beelke  MSannita  WG Cholinergic function and dysfunction in the visual system. Methods Find Exp Clin Pharmacol 2002;24113- 117
PubMed
11.
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
PubMedArticle
12.
DeKosky  STIkonomovic  MDStyren  S  et al.  Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002;51145- 155
PubMedArticle
13.
Mufson  EJIkonomovic  MDStyren  SD  et al.  Preservation of brain nerve growth factor in mild cognitive impairment and Alzheimer’s disease. Arch Neurol 2003;601143- 1148
PubMedArticle
14.
Bennett  DAWilson  RSSchneider  JA  et al.  Natural history of mild cognitive impairment in older persons. Neurology 2002;59198- 205
PubMedArticle
15.
Wilson  RSBeckett  LABarnes  LL  et al.  Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging 2002;17179- 193
PubMedArticle
16.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer’s disease: Report of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939- 944
PubMedArticle
17.
Petersen  RCSmith  GEWaring  SC Mild cognitive impairment. Arch Neurol 1999;56303- 308
PubMedArticle
18.
Albert  MSmith  LASteer  PATaylor  JOEvans  DAFunkenstein  HH Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer’s disease. Int J Neurosci 1991;57167- 178
PubMedArticle
19.
Devanand  DPFolz  MGorlyn  MMoeller  JRStern  Y Questionable dementia: clinical course and predictors of outcome. J Am Geriatr Soc 1997;45321- 328
PubMed
20.
Morris  JCStorandt  MMiller  JP  et al.  Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58397- 405
PubMed
21.
Braak  HBraak  E Neuropathological staging of Alzheimer’s disease. Acta Neuropathol (Berl) 1991;82239- 259
PubMedArticle
22.
National Institute on Aging and Reagan Institute Working Group on Diagnosis Criteria for the Neuropathological Assessment of Alzheimer’s disease, Consensus recommendations for the postmortem diagnosis of AD. Neurobiol Aging 1997;18S1- S3
PubMedArticle
23.
DeKosky  STScheff  SWMarkesbery  WR Laminar organization of cholinergic circuits in human frontal cortex in Alzheimer’s disease and aging. Neurology 1985;351425- 1431
PubMedArticle
24.
Rosen  WGMohs  RCDavis  KL A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;1411356- 1364
PubMed
Original Contribution
March 2005

Reduction of Choline Acetyltransferase Activity in Primary Visual Cortex in Mild to Moderate Alzheimer's Disease

Author Affiliations

Author Affiliations: Departments of Neurology and Psychiatry and the Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, Pa (Drs Ikonomovic and DeKosky); and the Department of Neurological Sciences (Drs Mufson and Bennett and Ms Wuu), Rush University Medical Center and Rush Alzheimer’s Disease Center (Dr Bennett), Chicago, Ill.

Arch Neurol. 2005;62(3):425-430. doi:10.1001/archneur.62.3.425
Abstract

Background  Cholinergic deficits in the primary visual cortex (PVC) may underlie some of the abnormalities in visual processing and global cognitive performance in Alzheimer’s disease (AD).

Objective  To correlate measures of general cognition (Mini-Mental State Examination and Global Cognitive Score) and visuospatial function with choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities, and nerve growth factor protein levels in the PVC.

Design  The ChAT and AChE enzyme assays and a nerve growth factor protein enzyme-linked immunoabsorbent assay were performed on PVC tissue samples from subjects clinically diagnosed as having mild cognitive impairment (MCI), AD, or no cognitive impairment (NCI).

Setting and Patients  Nuns, priests and brothers enrolled in the Religious Order Study, with annual premortem records of neuropsychological testing.

Results  Significant differences in ChAT activity, but not in AChE activity or nerve growth factor protein levels, were found among diagnostic groups (P = .049). The ChAT activity was lower in AD than in MCI or NCI (P<.01); MCI was not different from NCI. The PVC ChAT activity correlated with measures of overall cognitive function (Mini-Mental State Examination and Global Cognitive Score), but less so with a composite measure of visuospatial function.

Conclusions  The reduction in ChAT activity in the PVC of mild to moderate AD, but not in MCI, might serve to distinguish between clinical and preclinical forms of the disease. It appears that this change relates to generalized cognitive abnormalities but not specifically to visuospatial function.

Abnormalities in higher-order visual processing are frequently seen in patients with Alzheimer’s disease (AD). Clinical studies support a link between impaired cognitive performance and visual dysfunction,14 even in the absence of neuro-ophthalmological changes.5 Although the primary visual cortex (PVC) has traditionally been regarded as spared in AD, significant pathology including neurofibrillary tangles (NFTs) and amyloid plaques occurs in this region.6,7 Similar to other cortical areas, the PVC has significant reductions in cholinergic fibers8 and enzyme activity in end-stage AD,9 suggesting that cholinergic deficits in the PVC may play a role in the cognitive impairment observed in these patients.10

Recent studies suggest the stability of cortical cholinergic markers, including choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and nerve growth factor (NGF), during the early stages of AD.9,1113 The status of these markers in the PVC of subjects with early and preclinical disease is unknown. We evaluated subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD to assess the status of ChAT and AChE enzyme activities and NGF protein levels in the PVC, and to correlate them with measures of visuospatial and overall cognitive functions.

METHODS
SUBJECTS

Subjects were 54 individuals (Table 1) from a longitudinal clinicopathological study of aging and AD of older Catholic clergy (Religious Orders Study) categorized as having NCI, MCI, or AD.14 The investigators were blinded to the selection process. The PVC samples were obtained from the same Religious Orders Study cases previously showing stable association cortex ChAT activity and NGF protein levels in MCI and mild to moderate AD.12,13 No PVC tissue samples were available from 1 AD and 3 NCI subjects studied in these earlier reports. The AD group included 1 severe case (Mini-Mental State Examination [MMSE] score = 7) in the analysis of ChAT and AChE activities, and 1 severe case (MMSE score = 5) in NGF protein level analysis); excluding these cases constrained the AD group to the mild to moderate AD category (MMSE score range, 12-25). The Rush University Medical Center (Chicago, Ill) and University of Pittsburgh (Pittsburgh, Pa) Human Investigations Committees approved the study.

CLINICAL EVALUATION

Descriptions of the clinical evaluation have been published.14 The score on each neuropsychological test was standardized to that of a reference population (the first 82 deceased Religious Orders Study cases), then averaged across 20 tests to derive a Global Cognitive Score (GCS), a composite z score.14 A GCS of 0 indicated overall cognitive function similar to the reference population average. A GCS of +1 (or –1) indicated that one’s overall cognitive function was 1 SD above (or below) the reference population average. Subjects were classified as having NCI (mean GCS = 0.5 ± 0.3) (Table 2), MCI (GCS = 0.2 ± 0.3), or AD (GCS = −1.0 ± 0.6). A composite z score specific to visuospatial ability included the Standard Progressive Matrices (SCPMAT) and Standard Line Orientation (SCLOPAIR) tests.15 Diagnosis of AD dementia was made using standard criteria.16 Mild cognitive impairment was defined as impairment on neuropsychological testing but without a diagnosis of dementia by the examining neurologist,14 criteria similar to those describing patients who were not cognitively intact but nonetheless did not meet the criteria for dementia.1720 A postmortem interview with family or caregivers determined that no other medical conditions occurred after the last clinical evaluation (within 12 months prior to death). A consensus conference of neurologists and neuropsychologists reviewed all the clinical data, the postmortem interview, medical records, and neuroimaging studies and assigned final clinical diagnoses.

PATHOLOGICAL EVALUATION AND TISSUE PREPARATION

Brains were processed as described previously.12,13 Blocks of tissue containing the PVC (Brodmann area 17) were dissected from one hemisphere and fresh frozen. Cases were excluded if they showed non-AD pathology. A board-certified neuropathologist blinded to the clinical diagnosis determined the Braak neuropathological staging score of the NFT pathology21 and the National Institute of Aging–Reagan Institute diagnosis criteria.22 Cases were coded, and all assays were performed in triplicate by a technician blinded to the diagnosis.

ChAT AND AChE ACTIVITY ASSAYS

Frozen PVC gray matter samples were processed as described previously.12,23 The ChAT activity assay used radioactive carbon 14–labeled acetyl coenzyme A (New England Nuclear, Boston, Mass). Protein assay kits (Pierce, Rockford, Ill) were used to determine the protein content of the samples. The ChAT activity was expressed as micromoles per hour per gram of protein, and the AChE activity as millimoles per hour per gram of protein.

NGF PROTEIN ASSAY

The NGF protein assay was performed on frozen tissue samples.13 A sandwich enzyme immunoassay used mouse anti-β (2.5S,7S) NGF as the capture antibody and mouse anti-β (2.5S,7S) NGF β-galactosidase as the detection antibody (Roche Diagnostics, Mannheim, Germany). Protein determination was done using a BCA Protein Assay Kit (Pierce). Results were expressed as picograms of NGF per milligram of protein.

STATISTICAL ANALYSES

Summary statistics were presented as mean ± SD, range, frequency, or percentage. The PVC ChAT and AChE activities and the NGF protein level data were log-transformed to approximate a normal distribution. For the comparison of clinical, demographic, and neuropathological characteristics among diagnostic groups, 1-way analysis of variance, Fisher exact test, and the nonparametric Kruskal-Wallis test were used, as appropriate. Cognitive functions and biomarker activity were compared among diagnostic groups with the use of analysis of variance. Post hoc pair-wise comparisons were performed, adjusting for multiple comparisons by Tukey studentized range test. Spearman rank correlation and the Kruskal-Wallis test determined the relationship between clinical, demographic, and neuropathological variables vs and ChAT and AChE activities and NGF protein levels. The age- and education-adjusted analyses were performed by regression models. Statistical significance was set at .01 (2-sided).

RESULTS

The 3 Religious Orders Study diagnostic groups (NCI, MCI, and AD) were similar in age, sex, years of education, presence of APOE ε4 allele, and postmortem interval (Table 1). Significant NFT pathology was observed in all of the groups. Sixty-five percent of NCI, 89% of MCI, and 92% of AD cases were diagnosed as having Braak stage III or higher. The AD cohort performed worse than the NCI or MCI cohort on the MMSE and GCS (P<.0001 in both); the NCI and MCI were not significantly different (Table 2). The clinical groups were also different on the composite measure of visuospatial function (P<.0001) and on the individual SCPMAT and SCLOPAIR tests (Table 2).

The PVC ChAT activity was reduced significantly in those with AD compared with those with NCI and MCI (P = .0049, Table 3, Figure 1); the latter 2 groups were not different. When ChAT activity analysis excluded the only severe case (MMSE score = 7), a significant difference was achieved among the 3 groups (P = .015), with reduced PVC ChAT activity in the mild to moderate AD group (mean MMSE score = 19.4 ± 4.7) compared with the NCI group, but not when compared with the MCI group. The PVC AChE activity and NGF protein levels were not significantly different among the 3 groups (Table 3, Figure 1). Across the entire cohort, there were no correlations between PVC ChAT and AChE activities and the NGF protein level. Small sample size precluded analyses within the diagnostic groups.

Associations between PVC ChAT, AChE activity, or NGF protein levels and clinical variables were assessed on all subjects combined. Only PVC ChAT activity, but not AChE activity or NGF protein level, showed consistent association with MMSE scores (Spearman rank correlation, r = 0.35, P = .017) and GCS (r = 0.39, P = .0081; Figure 2). The data were suggestive of a possible correlation between the PVC ChAT activity and the composite z score for visuospatial ability (r = 0.26, P = .083) and the SCPMAT test score (r = 0.25, P = .099). In addition, there was a correlation between PVC AChE activity and SCPMAT test scores (r = 0.35, P = .023). Results remained unchanged after adjusting for age and education, except for a notably stronger association between PVC ChAT activity and the MMSE score (P = .0027). Despite a slightly weaker level of statistical significance, the above findings were maintained when the AD group was restricted to mild to moderate cases.

The ChAT activity was lower in Braak neuropathological stages V/VI (mean ± SD = −1.45 ± 1.62, log-transformed) compared with stages III/IV (−0.37 ± 1.36) and I/II (−0.35 ± 0.65), although statistical significance was not determined owing to sample size limitation.

COMMENT

The ChAT activity in the PVC was significantly reduced in AD, even when the analysis was restricted to mild to moderate AD (MMSE score range, 12-25), while remaining stable in MCI. This deficit could relate to some of the cognitive problems seen early in the course of AD, including difficulties in recognizing persons and objects. Furthermore, they may predispose to or precipitate more complex problems in higher visual cortex processing including visuospatial or naming deficits in patients with AD. Interestingly, the sensory visual input is mainly intact in AD, suggesting that changes in the PVC and association areas are more likely responsible for resulting cognitive abnormalities.5 The present study found only a trend for PVC ChAT activity to correlate with the measure of integrative visuospatial abilities while there were significant relationships with global cognitive abilities. Thus, a reduction in PVC ChAT activity may not only affect visuospatial functions but might interfere with the integration of higher visual processing into global cognitive performance. This finding provides a structural basis for the involvement of visual processing pathways during the clinical course of AD.1,2,4

The reduction in ChAT activity appears to be specific for PVC, the only cortical area examined in which ChAT activity was reduced in patients with mild to moderate AD.12 Davis and colleagues9 reported a significant loss of PVC ChAT and AChE activities only in severe dementia (Clinical Dementia Rating scale score = 5). This discordance could be due to differences in education, age, or neuropsychological testing information available. While our subjects were evaluated cognitively on the MMSE and GCS scales, Davis and colleagues used the Clinical Dementia Rating scale24 to define disease severity. Contrary to the synchronous loss of ChAT and AChE activity in severe AD,9 we found a selective ChAT activity deficit in the PVC in individuals with mild to moderate AD, suggesting that a reduction in ChAT activity precedes AChE loss. Thus, in early stages of the disease, there could be a deficit in the capacity of cholinergic neurons to produce and/or transport ChAT to PVC, thereby reducing the ability to synthesize acetylcholine in the PVC, while stable AChE activity could augment neurotransmitter deficit.

CONCLUSIONS

A reduction in PVC ChAT activity was found in mild to moderate AD but not in MCI. Such change might serve to distinguish between clinical and preclinical forms of the disease. A selective loss of the acetylcholine-synthesizing enzyme in PVC implies worsened cholinergic neurotransmission in this region of the brain, which could affect both higher visual processing and overall cognitive performance during the initial stages of the disease. A trend for a reduction in PVC ChAT activity in cases with Braak neuropathological stage V/VI suggests that cholinergic changes are not marked until the last (neocortical) stages of NFT pathology progression have occurred. Future studies should determine the extent of the visual cortex NFT and amyloid pathology and possible correlations with changes in the cholinergic projections and cholinergic enzyme activity in individuals with MCI and AD.

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Article Information

Correspondence: Steven T. DeKosky, MD, Department of Neurology, Alzheimer’s Disease Research Center, University of Pittsburgh, 3471 Fifth Ave, Suite, 811, Pittsburgh, PA 25213 (dekoskyst@upmc.edu).

Accepted for Publication: May 10, 2004.

Author Contributions:Study concept and design: Ikonomovic, Mufson, and DeKosky. Acquisition of data: Ikonomovic, Bennett, and DeKosky. Analysis and interpretation of data: Ikonomovic, Mufson, Wuu, Bennett, and DeKosky. Drafting of the manuscript: Ikonomovic, Mufson, Wuu, and DeKosky. Critical revision of the manuscript for important intellectual content: Ikonomovic, Mufson, Bennett, and DeKosky. Statistical analysis: Wuu and DeKosky. Obtained funding: Mufson, Bennett, and DeKosky. Administrative, technical, and material support: Ikonomovic and DeKosky. Study supervision: Ikonomovic, Mufson, Bennett, and DeKosky.

Funding/Support: This study was supported by grants AG05133, AG14449, AG10161, AG10688, and AG09466 from the National Institute on Aging, Bethesda, Md.

Acknowledgment: We are indebted to the nuns, priests, and brothers participating in the Religious Orders Study. A complete list of the groups is found at www.archneurol.com. We thank Elizabeth J. Cochran, MD, for neuropathological evaluations and William R. Paljug, BS, for technical support.

References
1.
Mendez  MFMendez  MAMartin  RSmyth  KAWhitehouse  PJ Complex visual disturbances in Alzheimer’s disease. Neurology 1990;40439- 443
PubMedArticle
2.
Cronin-Golomb  ACorkin  SGrowdon  JH Visual dysfunction predicts cognitive deficits in Alzheimer’s disease. Optom Vis Sci 1995;72168- 176
PubMedArticle
3.
Kaskie  BStorandt  M Visuospatial deficit in dementia of the Alzheimer type. Arch Neurol 1995;52422- 425
PubMedArticle
4.
Rizzo  MAnderson  SWDawson  JNawrot  M Vision and cognition in Alzheimer’s disease. Neuropsychologia 2000;381157- 1169
PubMedArticle
5.
Cronin-Golomb  ARizzom  JFCorkin  SGrowdon  JH Visual function in Alzheimer’s disease and normal aging. Ann N Y Acad Sci 1991;64028- 35
PubMed
6.
Lewis  DACampbell  MJTerry  RDMorrison  JH Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: a quantitative study of visual and auditory cortices. J Neurosci 1987;71799- 1808
PubMed
7.
Morrison  JHHof  PRBouras  C An anatomic substrate for visual disconnection in Alzheimer’s disease. Ann N Y Acad Sci 1991;64036- 43
PubMed
8.
Beach  TGMcGeer  EG Cholinergic fiber loss occurs in the absence of synaptophysin depletion in Alzheimer’s disease primary visual cortex. Neurosci Lett 1992;142253- 256
PubMedArticle
9.
Davis  KLMohs  RCMarin  D  et al.  Cholinergic markers in elderly patients with early signs of Alzheimer’s disease. JAMA 1999;2811401- 1406
PubMedArticle
10.
Beelke  MSannita  WG Cholinergic function and dysfunction in the visual system. Methods Find Exp Clin Pharmacol 2002;24113- 117
PubMed
11.
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
PubMedArticle
12.
DeKosky  STIkonomovic  MDStyren  S  et al.  Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002;51145- 155
PubMedArticle
13.
Mufson  EJIkonomovic  MDStyren  SD  et al.  Preservation of brain nerve growth factor in mild cognitive impairment and Alzheimer’s disease. Arch Neurol 2003;601143- 1148
PubMedArticle
14.
Bennett  DAWilson  RSSchneider  JA  et al.  Natural history of mild cognitive impairment in older persons. Neurology 2002;59198- 205
PubMedArticle
15.
Wilson  RSBeckett  LABarnes  LL  et al.  Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging 2002;17179- 193
PubMedArticle
16.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer’s disease: Report of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939- 944
PubMedArticle
17.
Petersen  RCSmith  GEWaring  SC Mild cognitive impairment. Arch Neurol 1999;56303- 308
PubMedArticle
18.
Albert  MSmith  LASteer  PATaylor  JOEvans  DAFunkenstein  HH Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer’s disease. Int J Neurosci 1991;57167- 178
PubMedArticle
19.
Devanand  DPFolz  MGorlyn  MMoeller  JRStern  Y Questionable dementia: clinical course and predictors of outcome. J Am Geriatr Soc 1997;45321- 328
PubMed
20.
Morris  JCStorandt  MMiller  JP  et al.  Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58397- 405
PubMed
21.
Braak  HBraak  E Neuropathological staging of Alzheimer’s disease. Acta Neuropathol (Berl) 1991;82239- 259
PubMedArticle
22.
National Institute on Aging and Reagan Institute Working Group on Diagnosis Criteria for the Neuropathological Assessment of Alzheimer’s disease, Consensus recommendations for the postmortem diagnosis of AD. Neurobiol Aging 1997;18S1- S3
PubMedArticle
23.
DeKosky  STScheff  SWMarkesbery  WR Laminar organization of cholinergic circuits in human frontal cortex in Alzheimer’s disease and aging. Neurology 1985;351425- 1431
PubMedArticle
24.
Rosen  WGMohs  RCDavis  KL A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;1411356- 1364
PubMed
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