Intravenous immunoglobulins containing antibodies against ?-amyloid for the treatment of Alzheimer’s disease
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《神经病学神经外科学杂志》
1 Department of Neurology, Friedrich-Wilhelms-University, Bonn, Germany
2 Department of Neurology, Indiana University Medical School, Indianapolis, USA
3 Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany
4 Department of Psychiatry, Johann Wolfgang Goethe University, Frankfurt, Germany
5 Department of Neurology, Philipps-University Marburg, Germany
6 Department of Psychiatry, Philipps-University Marburg, Germany
7 Department of Psychiatry, University of Giessen, Germany
Correspondence to:
R C Dodel
Department of Neurology, Friedrich-Wilhelms-University, Sigmund-Freudstr. 25, 53105 Bonn, Germany; richard.dodel@ukb.uni-bonn.de
ABSTRACT
Objective: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer’s disease (AD). Recently, it has been shown that antibodies against ?-amyloid (A?) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of A?. This study reports the results from a pilot study using IVIgG in patients with AD.
Methods: Five patients with AD were enrolled and
Results: Following IVIgG, total A? levels in the CSF decreased by 30.1% (17.3–43.5%) compared to baseline (p<0.05). Total A? increased in the serum by 233% (p<0.05). No significant change was found in A?1–42 levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7±2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline.
Conclusion: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.
Abbreviations: A?, ?-amyloid; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; IVlgG, human immunoglobulin preparations; MMSE, Mini-Mental State Examination
Keywords: alzheimer; immunoglobulin; beta amyloid; immunisation
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder with a devastating prognosis. Recently, active immunisation against ?-amyloid (A?) in preclinical studies using transgenic animal models resulted both in a reduction of A? in the cerebrospinal fluid (CSF) and plaque burden.1,2 The change in A? plaque burden was also associated with restored cognitive function in some of these transgenic animals.3,4 The pathophysiological mechanisms of A? removal from the brain after vaccination are still unclear, but may involve microglial-mediated phagocytosis or passage/transport of soluble A? into the plasma with a subsequent antibody-mediated degradation.5 Similar results were obtained in animal studies with passive immunisation using monoclonal antibodies against A?.6 Polyclonal antibodies against A? have been detected long before these animal studies in humans; however, their function in AD and non-diseased humans as well as their role in A?-degradation were unknown.7 The detection of antibodies against A? in human immunoglobulin preparations (IVIgG) has made them readily available for further investigations.8 Research into their function have shown that there is a narrow and specific epitopal recognition of A? peptides and that they are able to reduce A? toxicity and inhibit A? fibrillation.9 We investigated whether treatment using IVIgG, based on the findings above, may have an impact on A? levels in the CSF and serum of AD patients.
PATIENTS AND METHODS
Using a prospective, clinical trial design, the safety and preliminary efficacy of IVIgG treatment was evaluated. Each patient
Table 1 Clinical characterisation of included patients
All subjects were allowed to continue antidementia medications if stable for at least 6 months before study entry (table 1). No change was allowed during the trial.
Concomitant medications, vital signs, and adverse events were recorded at baseline and at every visit; laboratory tests, electrocardiograms, and physical examinations were performed at the screening and at every subsequent visit. Patients and their relatives were interviewed at each visit to evaluate side effects.
Efficacy measure for this study was the change in A? levels in the CSF and serum at 6 months compared to baseline levels. In addition, efficacy was measured by neuropsychological testing, which included the ADAS-cog and the CERAD neuropsychological test battery.
CSF samples were obtained at baseline and at 6 months. It was taken in the morning by lumbar puncture at the L3/L4 or L4/L5 interspace after obtaining appropriate informed consent. CSF white blood cell count and protein levels were determined by standard procedures. No contamination by erythrocytes was seen in any of the samples. Aliquots were then stored at –80°C until biochemical analysis. Albumin and IgG concentrations were determined in the serum and CSF by immunoprecipitation nephelometry. The CSF albumin/serum albumin quotient was used to evaluate the integrity of the CSF blood barrier. All CSF samples had standard laboratory values within normal ranges.
The A? antibody ELISA was performed as described previously.11 The measurement of total A? and A?1–42 was performed using a sandwich ELISA with commercially available antibodies against A?1–40 and A?1–42 (21F12).
Before screening, written informed consent was obtained from all individuals. The clinical trial protocol was approved by the local ethical committee of the Philipps-University, Marburg.
Statistical analysis
Median levels of anti-A? titres were compared at baseline and at 6 months in the CSF and serum by using a Wilcoxon non-parametric test with a p-value of 0.05 regarded as significant. All statistical analyses were performed using SPSS computer software for Windows (Version 11.0).
RESULTS
The demographic and baseline values of the patients enrolled in the study are presented in table 1.
The concentration of total A? in the CSF decreased in all patients following 6 months of treatment (mean: 327.5 pg/ml) compared to baseline (mean: 467.0 pg/ml). The decrease was between 17.3–43.5% (mean: 30.1%) of baseline values (p<0.05; table 2). No difference in the concentration of A?1–42 was detectable in the CSF after 6 months.
Table 2 Concentrations of total A? (A?tot), A?1–42 and antibodies against A? (A?-Ab) in the CSF and serum at baseline and 6 months following IVIgG
In the serum, concentration of total A? increased with a mean value of 558.2 pg/ml compared to 240.4 pg/ml at baseline (p<0.05). No difference in the concentration of A?1–42 was detectable in the serum after 6 months.
On the ADAS-cog a slight improvement was observed on neuropsychological testing at 6 months in all patients except one where the score did not change between baseline and at 6 months (table 3). A mean improvement of 3.7±2.9 points was calculated. Remarkably, no patient deteriorated. Similar findings were observed for the Mini-Mental State Examination (MMSE). Visual construction abilities, which often fail early in the course of AD, were improved in three of these patients and remained unchanged in two.
Table 3 Results of the neuropsychological testing
This study was completed by all patients. No serious adverse events associated with IVIgG were noted during the clinical trial (one patient was admitted to the hospital because of confusion 2 weeks following IVIgG but it was resolved within a few days). In three patients headaches were reported, which fulfilled the criteria for tension headache. The duration of the headaches were less than 1 day and without any further neurological signs. One patient experienced a tooth infection during the trial; however, this was not directly linked to the treatment as a similar tooth infection occurred twice before the initiation of the study. There were no clinically relevant changes in blood pressure, heart rate, and electrocardiogram findings. There were no clinically relevant differences in haematological or biochemical laboratory test values.
DISCUSSION
In this study we evaluated the effects of IVIgG in patients with AD. In earlier studies we have demonstrated the presence of antibodies directed against A? in human IVIgG preparations. These antibodies selectively target A? and are capable of antagonising the potential neurotoxic effects of A? as well as its fibrillisation — the prerequisite for plaque formation.8,9,11 The results from the current pilot study clearly show a reduction of total A? in the CSF following treatment with IVIgG. In the serum, total A? levels were increased similar to earlier findings from studies using transgenic mice expressing a V717F mutation in APP associated with AD.12 No significant change in the CSF or serum of A?1–42 were observed, although in some patients a change towards an increased efflux of A?1–42 may have taken place. In an earlier study using IVIgG in non-demented patients, we had detected an increase of peripheral A?1–42.8 The question of whether immunisation may have an effect on plaque burden or may result in a change of the dynamics of A? as described previously remains unsolved.13 Currently, no definite statement on the effects of IVIgG on A?1–42 is feasible.
In our study we found a reduction in the CSF of total A? of 17.3–43.5%. No data are available on the quantitative decrease of A? concentration necessary to reduce A? deposition. Therefore, one can only speculate whether the observed reduction may have an impact on plaque formation. Further studies, including careful dose studies in animals, are necessary. From earlier studies, however, some information can be obtained. First, a relatively modest A? clearance already reduced memory impairment in transgenic mice expressing AD mutations.3,4 Second, an increase in A? concentration of approximately 1.5 times in familial AD patients, because of mutations in the APP gene, shifts the disease onset earlier by several decades. It can be assumed that already small changes in A? concentrations in the CSF may have an impact on A? deposition and plaque development.14
In addition to the CSF markers used in this study, we evaluated the effects on cognitive deficits in AD patients using several established neuropsychological test b batteries. ADAS-cog, which is a commonly used cognitive measure test to evaluate AD patients in clinical studies, showed a modest improvement following 6 months of IVIgG. Evidence from longitudinal studies suggests that the mean level of decline in ADAS-cog over 1 year for untreated AD patients will be approximately 7–11 points and approximately 4–6 points in patients treated with cholinesterase inhibitors.15 In contrast, a mean improvement of 3.7 points above baseline was observed in this study after 6 months. In addition, other cognitive test scores also improved or were stable at 6 months. Whether these changes following IVIgG may represent a significant stabilisation of the disease or even an improvement in cognitive function cannot be derived from this study because of the small number of patients studied and the potential for considerable variance in cognitive test scores. In addition, the study was not blinded and was not tested against placebo and therefore a bias cannot be excluded. Studies including a larger number of patients, a placebo control, as well as a longer observation period, will be necessary.
In conclusion, the application of IVIgG in AD patients in this setting was well tolerated; however, much more exposure is necessary before a definitive statement about safety can be made. Furthermore, IVIgG caused a reduction of A? concentration in the CSF and may also have had a beneficial effect on cognitive functioning in these AD patients. Determining whether passive immunisation with IVIgG varies, stabilises, or significantly delays the cognitive decline in AD will depend upon more detailed clinical assessments over a larger period of time. The results of this pilot study provide further evidence suggesting a more detailed investigation of IVIgG and passive immunisation for the treatment of AD.5
ACKNOWLEDGEMENTS
We would like to thank Christine H?ft and Annette Hehenkamp for expert technical assistance. We would like to thank Dr Sybille Kremer and Octapharma (Langenfeld, Germany) for providing the intravenous immunoglobulins, and Kelly Bales and Eli Lilly and Company (Indianapolis, USA) for providing the A? antibodies for this study. Both companies had no impact on the design and the data analysis in this investigator driven study.
REFERENCES
Schenk D , Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400 (6740) :173–7.
DeMattos RB, Bales KR, Cummins DJ, et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2001;98 (15) :8850–5.
Morgan D , Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000;408 (6815) :982–5.
Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 2002;5 (5) :452–7.
Dodel RC, Hampel H, Du Y. Immunotherapy for Alzheimer’s disease. Lancet Neurol 2003;2 (4) :215–20.
Bard F , Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6 (8) :916–19.
Xu S , Gaskin F. Increased incidence of anti-beta-amyloid autoantibodies secreted by Epstein-Barr virus transformed B cell lines from patients with Alzheimer’s disease. Mech Ageing Dev 1997;94 (1–3) :213–22.
Dodel R , Hampel H, Depboylu C, et al. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 2002;52 (2) :253–6.
Du Y , Wei X, Gao F, et al. Human anti-Abeta antibodies block Abeta fibril formation and prevent Abeta-induced neurotoxicity. Brain 2003;126:1–5.
McKhann G , Drachman D, Folstein M, et al. 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 (7) :939–44.
Du Y , Dodel R, Hampel H, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology 2001;57 (5) :801–5.
DeMattos RB, Bales KR, Cummins DJ, et al. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002;295 (5563) :2264–7.
Nicoll JA, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003;9 (4) :448–52.
Hardy J , Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 1991;12 (10) :383–8.
Kramer-Ginsberg E , Mohs RC, Aryan M, et al. Clinical predictors of course for Alzheimer patients in a longitudinal study: a preliminary report. Psychopharmacol Bull 1988;24 (3) :458–62.(R C Dodel1, Y Du2, C Depb)
2 Department of Neurology, Indiana University Medical School, Indianapolis, USA
3 Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany
4 Department of Psychiatry, Johann Wolfgang Goethe University, Frankfurt, Germany
5 Department of Neurology, Philipps-University Marburg, Germany
6 Department of Psychiatry, Philipps-University Marburg, Germany
7 Department of Psychiatry, University of Giessen, Germany
Correspondence to:
R C Dodel
Department of Neurology, Friedrich-Wilhelms-University, Sigmund-Freudstr. 25, 53105 Bonn, Germany; richard.dodel@ukb.uni-bonn.de
ABSTRACT
Objective: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer’s disease (AD). Recently, it has been shown that antibodies against ?-amyloid (A?) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of A?. This study reports the results from a pilot study using IVIgG in patients with AD.
Methods: Five patients with AD were enrolled and
Results: Following IVIgG, total A? levels in the CSF decreased by 30.1% (17.3–43.5%) compared to baseline (p<0.05). Total A? increased in the serum by 233% (p<0.05). No significant change was found in A?1–42 levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7±2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline.
Conclusion: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.
Abbreviations: A?, ?-amyloid; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; IVlgG, human immunoglobulin preparations; MMSE, Mini-Mental State Examination
Keywords: alzheimer; immunoglobulin; beta amyloid; immunisation
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder with a devastating prognosis. Recently, active immunisation against ?-amyloid (A?) in preclinical studies using transgenic animal models resulted both in a reduction of A? in the cerebrospinal fluid (CSF) and plaque burden.1,2 The change in A? plaque burden was also associated with restored cognitive function in some of these transgenic animals.3,4 The pathophysiological mechanisms of A? removal from the brain after vaccination are still unclear, but may involve microglial-mediated phagocytosis or passage/transport of soluble A? into the plasma with a subsequent antibody-mediated degradation.5 Similar results were obtained in animal studies with passive immunisation using monoclonal antibodies against A?.6 Polyclonal antibodies against A? have been detected long before these animal studies in humans; however, their function in AD and non-diseased humans as well as their role in A?-degradation were unknown.7 The detection of antibodies against A? in human immunoglobulin preparations (IVIgG) has made them readily available for further investigations.8 Research into their function have shown that there is a narrow and specific epitopal recognition of A? peptides and that they are able to reduce A? toxicity and inhibit A? fibrillation.9 We investigated whether treatment using IVIgG, based on the findings above, may have an impact on A? levels in the CSF and serum of AD patients.
PATIENTS AND METHODS
Using a prospective, clinical trial design, the safety and preliminary efficacy of IVIgG treatment was evaluated. Each patient
Table 1 Clinical characterisation of included patients
All subjects were allowed to continue antidementia medications if stable for at least 6 months before study entry (table 1). No change was allowed during the trial.
Concomitant medications, vital signs, and adverse events were recorded at baseline and at every visit; laboratory tests, electrocardiograms, and physical examinations were performed at the screening and at every subsequent visit. Patients and their relatives were interviewed at each visit to evaluate side effects.
Efficacy measure for this study was the change in A? levels in the CSF and serum at 6 months compared to baseline levels. In addition, efficacy was measured by neuropsychological testing, which included the ADAS-cog and the CERAD neuropsychological test battery.
CSF samples were obtained at baseline and at 6 months. It was taken in the morning by lumbar puncture at the L3/L4 or L4/L5 interspace after obtaining appropriate informed consent. CSF white blood cell count and protein levels were determined by standard procedures. No contamination by erythrocytes was seen in any of the samples. Aliquots were then stored at –80°C until biochemical analysis. Albumin and IgG concentrations were determined in the serum and CSF by immunoprecipitation nephelometry. The CSF albumin/serum albumin quotient was used to evaluate the integrity of the CSF blood barrier. All CSF samples had standard laboratory values within normal ranges.
The A? antibody ELISA was performed as described previously.11 The measurement of total A? and A?1–42 was performed using a sandwich ELISA with commercially available antibodies against A?1–40 and A?1–42 (21F12).
Before screening, written informed consent was obtained from all individuals. The clinical trial protocol was approved by the local ethical committee of the Philipps-University, Marburg.
Statistical analysis
Median levels of anti-A? titres were compared at baseline and at 6 months in the CSF and serum by using a Wilcoxon non-parametric test with a p-value of 0.05 regarded as significant. All statistical analyses were performed using SPSS computer software for Windows (Version 11.0).
RESULTS
The demographic and baseline values of the patients enrolled in the study are presented in table 1.
The concentration of total A? in the CSF decreased in all patients following 6 months of treatment (mean: 327.5 pg/ml) compared to baseline (mean: 467.0 pg/ml). The decrease was between 17.3–43.5% (mean: 30.1%) of baseline values (p<0.05; table 2). No difference in the concentration of A?1–42 was detectable in the CSF after 6 months.
Table 2 Concentrations of total A? (A?tot), A?1–42 and antibodies against A? (A?-Ab) in the CSF and serum at baseline and 6 months following IVIgG
In the serum, concentration of total A? increased with a mean value of 558.2 pg/ml compared to 240.4 pg/ml at baseline (p<0.05). No difference in the concentration of A?1–42 was detectable in the serum after 6 months.
On the ADAS-cog a slight improvement was observed on neuropsychological testing at 6 months in all patients except one where the score did not change between baseline and at 6 months (table 3). A mean improvement of 3.7±2.9 points was calculated. Remarkably, no patient deteriorated. Similar findings were observed for the Mini-Mental State Examination (MMSE). Visual construction abilities, which often fail early in the course of AD, were improved in three of these patients and remained unchanged in two.
Table 3 Results of the neuropsychological testing
This study was completed by all patients. No serious adverse events associated with IVIgG were noted during the clinical trial (one patient was admitted to the hospital because of confusion 2 weeks following IVIgG but it was resolved within a few days). In three patients headaches were reported, which fulfilled the criteria for tension headache. The duration of the headaches were less than 1 day and without any further neurological signs. One patient experienced a tooth infection during the trial; however, this was not directly linked to the treatment as a similar tooth infection occurred twice before the initiation of the study. There were no clinically relevant changes in blood pressure, heart rate, and electrocardiogram findings. There were no clinically relevant differences in haematological or biochemical laboratory test values.
DISCUSSION
In this study we evaluated the effects of IVIgG in patients with AD. In earlier studies we have demonstrated the presence of antibodies directed against A? in human IVIgG preparations. These antibodies selectively target A? and are capable of antagonising the potential neurotoxic effects of A? as well as its fibrillisation — the prerequisite for plaque formation.8,9,11 The results from the current pilot study clearly show a reduction of total A? in the CSF following treatment with IVIgG. In the serum, total A? levels were increased similar to earlier findings from studies using transgenic mice expressing a V717F mutation in APP associated with AD.12 No significant change in the CSF or serum of A?1–42 were observed, although in some patients a change towards an increased efflux of A?1–42 may have taken place. In an earlier study using IVIgG in non-demented patients, we had detected an increase of peripheral A?1–42.8 The question of whether immunisation may have an effect on plaque burden or may result in a change of the dynamics of A? as described previously remains unsolved.13 Currently, no definite statement on the effects of IVIgG on A?1–42 is feasible.
In our study we found a reduction in the CSF of total A? of 17.3–43.5%. No data are available on the quantitative decrease of A? concentration necessary to reduce A? deposition. Therefore, one can only speculate whether the observed reduction may have an impact on plaque formation. Further studies, including careful dose studies in animals, are necessary. From earlier studies, however, some information can be obtained. First, a relatively modest A? clearance already reduced memory impairment in transgenic mice expressing AD mutations.3,4 Second, an increase in A? concentration of approximately 1.5 times in familial AD patients, because of mutations in the APP gene, shifts the disease onset earlier by several decades. It can be assumed that already small changes in A? concentrations in the CSF may have an impact on A? deposition and plaque development.14
In addition to the CSF markers used in this study, we evaluated the effects on cognitive deficits in AD patients using several established neuropsychological test b batteries. ADAS-cog, which is a commonly used cognitive measure test to evaluate AD patients in clinical studies, showed a modest improvement following 6 months of IVIgG. Evidence from longitudinal studies suggests that the mean level of decline in ADAS-cog over 1 year for untreated AD patients will be approximately 7–11 points and approximately 4–6 points in patients treated with cholinesterase inhibitors.15 In contrast, a mean improvement of 3.7 points above baseline was observed in this study after 6 months. In addition, other cognitive test scores also improved or were stable at 6 months. Whether these changes following IVIgG may represent a significant stabilisation of the disease or even an improvement in cognitive function cannot be derived from this study because of the small number of patients studied and the potential for considerable variance in cognitive test scores. In addition, the study was not blinded and was not tested against placebo and therefore a bias cannot be excluded. Studies including a larger number of patients, a placebo control, as well as a longer observation period, will be necessary.
In conclusion, the application of IVIgG in AD patients in this setting was well tolerated; however, much more exposure is necessary before a definitive statement about safety can be made. Furthermore, IVIgG caused a reduction of A? concentration in the CSF and may also have had a beneficial effect on cognitive functioning in these AD patients. Determining whether passive immunisation with IVIgG varies, stabilises, or significantly delays the cognitive decline in AD will depend upon more detailed clinical assessments over a larger period of time. The results of this pilot study provide further evidence suggesting a more detailed investigation of IVIgG and passive immunisation for the treatment of AD.5
ACKNOWLEDGEMENTS
We would like to thank Christine H?ft and Annette Hehenkamp for expert technical assistance. We would like to thank Dr Sybille Kremer and Octapharma (Langenfeld, Germany) for providing the intravenous immunoglobulins, and Kelly Bales and Eli Lilly and Company (Indianapolis, USA) for providing the A? antibodies for this study. Both companies had no impact on the design and the data analysis in this investigator driven study.
REFERENCES
Schenk D , Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400 (6740) :173–7.
DeMattos RB, Bales KR, Cummins DJ, et al. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2001;98 (15) :8850–5.
Morgan D , Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000;408 (6815) :982–5.
Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 2002;5 (5) :452–7.
Dodel RC, Hampel H, Du Y. Immunotherapy for Alzheimer’s disease. Lancet Neurol 2003;2 (4) :215–20.
Bard F , Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6 (8) :916–19.
Xu S , Gaskin F. Increased incidence of anti-beta-amyloid autoantibodies secreted by Epstein-Barr virus transformed B cell lines from patients with Alzheimer’s disease. Mech Ageing Dev 1997;94 (1–3) :213–22.
Dodel R , Hampel H, Depboylu C, et al. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 2002;52 (2) :253–6.
Du Y , Wei X, Gao F, et al. Human anti-Abeta antibodies block Abeta fibril formation and prevent Abeta-induced neurotoxicity. Brain 2003;126:1–5.
McKhann G , Drachman D, Folstein M, et al. 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 (7) :939–44.
Du Y , Dodel R, Hampel H, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology 2001;57 (5) :801–5.
DeMattos RB, Bales KR, Cummins DJ, et al. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002;295 (5563) :2264–7.
Nicoll JA, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003;9 (4) :448–52.
Hardy J , Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 1991;12 (10) :383–8.
Kramer-Ginsberg E , Mohs RC, Aryan M, et al. Clinical predictors of course for Alzheimer patients in a longitudinal study: a preliminary report. Psychopharmacol Bull 1988;24 (3) :458–62.(R C Dodel1, Y Du2, C Depb)