Original Research Article
Intracerebroventricular Infusion of Nerve Growth Factor in Three Patients with Alzheimer’s DiseaseEriksdotter Jönhagen M.a · Nordberg A.a · Amberla K.a · Bäckman L.a · Ebendal T.b · Meyerson B.c · Olson L.d · Seiger Å.a · Shigeta M.f · Theodorsson E.e · Viitanen M.a · Winblad B.a · Wahlund L-O.a
a Department of Clinical Neuroscience and Family Medicine, Division of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, b Department of Developmental Neuroscience, Uppsala University, Biomedical Center, Uppsala, c Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institute, Karolinska Hospital, Stockholm, d Department of Neuroscience, Karolinska Institute, Stockholm, and e Department of Clinical Chemistry, University Hospital, Linköping, Sweden; f Department of Psychiatry, Jikei University School of Medicine, Tokyo, Japan
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Nerve growth factor (NGF) is important for the survival and maintenance of central cholinergic neurons, a signalling system impaired in Alzheimer’s disease. We have treated 3 patients with Alzheimer’s disease with a total of 6.6 mg NGF administered continuously into the lateral cerebral ventricle for 3 months in the first 2 patients and a total of 0.55 mg for 3 shorter periods in the third patient. The patients were extensively evaluated with clinical, neuropsychological, neurophysiological and neuroradiological techniques. Three months after the NGF treatment ended, a significant increase in nicotine binding was found in several brain areas in the first 2 patients and in the hippocampus in the third patient as studied by positron emission tomography. A clear cognitive amelioration could not be demonstrated, although a few neuropsychology tests showed slight improvements. The amount of slow-wave cortical activity as studied by electroencephalography was reduced in the first 2 patients. Two negative side effects occurred with NGF treatment: first, a dull, constant back pain was observed in all 3 patients, which in 1 patient was aggravated by axial loading resulting in sharp, shooting pain of short duration. When stopping the NGF infusion, the pain disappeared within a couple of days. Reducing the dose of NGF lessened the pain. Secondly, a marked weight reduction during the infusion with a clear weight gain after ending the infusion was seen in the first 2 patients. We conclude from this limited trial that, while long-term intracerebroventricular NGF administration may cause certain potentially beneficial effects, the intraventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects of the present protocol. Alternative routes of administration, and/or lower doses of NGF, perhaps combined with low doses of other neurotrophic factors, may shift this balance in favor of positive effects.
- Levi-Montalcini R: The nerve growth factor 35 years later. Science 1987;237:1154–1162.
- Olson L, Backlund EO, Ebendal T, Freedman R, Hamberger B, Hansson P, Hoffer B, Lindblom U, Meyerson B, Strömberg I, Sydow O, Seiger Å: Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson’s disease: One-year follow-up of first clinical trial. Arch Neurol 1991;48:373–381.
- Sydow O, Hansson P, Young D, Meyerson B, Backlund E-O, Ebendal T, Farnebo L-O, Freedman R, Hamberger B, Hoffer B, Seiger Å, Strömberg I, Olson L: Long-term beneficial effects of adrenal medullary autografts supported by nerve growth factor in Parkinson’s disease. Eur J Neurol 1995;2:445–454.
- Ebendal T: NGF in CNS: Experimental data and clinical implications. Prog Growth Factor Res 1989;1:143–159.
- Kordower J, Gash D, Bothwell M, Hersh L, Mufson E: Nerve growth factor receptor and choline acetyltransferase remain colocalized in the nucleus basalis (Ch4) of Alzheimer patients. Neurobiol Aging 1989;10:67–74.
- Fischer W, Wiktorin K, Björklund A, Williams LR, Varon S, Gage FH: Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 1987;329:65–68.
- Hefti F, Hartikka J, Knusel B: Function of neurotrophic factors in the adult and aging brain and their possible uses in the treatment of neurodegenerative diseases. Neurobiol Aging 1989;10:515–533.
- Olson L: NGF and the treatment of Alzheimer’s disease. Exp Neurol 1993;124:5–15.
- Chen KS, Nishimura MC, Armanini MP, Crowley C, Spencer SD, Phillips HS: Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J Neurosci 1997;17:7288–7296.
- Greitz D, Hannerz J: A proposed model for the CSF-circulation, based on observations with radionuclide cisternography and previous MRI studies. Am J Neuroradiol 1996;17:431–438.
Olson L, Nordberg A, von Holst H, Bäckman L, Ebendal T, Alafuzoff I, Amberla K, Hartvig P, Herlitz A, Lilja A, Lundqvist H, Långström B, Meyerson B, Persson A, Viitanen M, Winblad B, Seiger Å: Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report). J Neural Transm 1992;4:79–95.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3, rev. Washington, American Psychiatric Association, 1987.
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939–944.
- Folstein MF, Folstein SE, McHugh PR: Minimental state: A practical method for grading the cognitive state of the patient for the clinician. J Psychiatr Res 1975;12:189–198.
Ebendal T, Olson L, Seiger Å, Belew M: Nerve growth factor in chick and rat tissues; in Black IB (ed): Cellular and Molecular Biology of Neuronal Development. New York, Plenum Press, 1984, pp 231–242.
- Söderström S, Hallböök F, Ibanez CF, Persson H, Ebendal T: Recombinant human β-nerve growth factor (NGF): Biological activity and properties in an enzyme immunoassay. J Neurosci Res 1990;27:665–667.
- Theodorsson-Norheim E, Hemsén A, Brodin E, Lundberg JM: Sample handling techniques when analyzing regulatory peptides. Life Sci 1987;41:845–848.
- Brodin E, Lindefors N, Theodorsson-Norheim E, Rosell S: Tachykinin multiplicity in rat central nervous system as studied using antisera raised against substance P and neurokinin A. Regul Peptides 1986;13:253–272.
- Bäckman L: Adult age differences in cross-modal recoding and mental tempo and older adults utilization of compensatory task conditions. Exp Aging Res 1986;12:135–140.
Buschke H: Selective reminding for analysis of memory and learning. J Verb Learn Verb Behav 1973;12:543–550.
- Bäckman L: Recognition memory across the adult life span: The role of prior knowledge. Mem Cogn 1991;19:63–71.
- Sharps MJ, Gollin ES: Memory for object locations in young and elderly adults. J Gerontol 1987;42:336–341.
Wechsler D: WAIS-R manual. New York, Psych Corp, 1981.
Lezak MD: Neuropsychological assessment. New York, Oxford University Press, 1983.
Armitage SG: An analysis of certain psychological tests used for the evaluation of brain injury. Psychol Monogr 1946;60:277.
Kausler DH: Experimental Psychology and Human Aging. New York, Wiley, 1982.
- Herscovitch P, Markham J, Raichle ME: Brain blood flow measured with intravenous H215O. J Nucl Med 1983;24:782–789.
Nordberg A, Hartvig P, Lilja A, Viitanen M, Amberla K, Lundqvist H, Andersson Y, Ulin J, Winblad B, Långström B: Decreased uptake and binding of 11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography. J Neural Transm 1990;2:215–224.
Nordberg A, Lundqvist H, Hartvig P, Lilja A, Långström B: Kinetic analysis of regional (S)(–)11C-nicotine binding in normal and Alzheimer brains – In vivo assessment using positron emission tomography. Alzheimer Dis Assoc Disord 1995;1:21–27.
- Patlak CS, Blasberg JD, Fenstermacher JD: Graphical evaluation of blood to brain transfer constants from multiple tissue uptake data. J Cereb Blood Flow Metab 1983;3:1–7.
- Nordberg A, Winblad B: Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci Lett 1986;72:115–119.
- Nordberg A, Lilja A, Lundqvist H, Hartvig P, Amberla K, Viitanen M, Warpman U, Johanson M, Hellström-Lindahl E, Bjurling P, Fasth KJ, Långström B, Winblad B: Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography. Neurobiol Aging 1992;13:747–758.
- Nordberg A, Lundqvist H, Hartvig P, Andersson J, Johansson M, Hellström-Lindahl E, Långström B: Imaging of nicotinic and muscarinic receptors in Alzheimer’s disease: Effect of tacrine treatment. Dement Geriatr Cogn Disord 1997;8:78–84.
- Nilsson L, Nordberg A, Hardy J, Wester P, Winblad B: Physostigmine restores 3H-acetylcholine efflux from Alzheimer brain slices to normal level. J Neural Transm 1986;67:275–285.
- Svensson AL, Nordberg A: Tacrine interacts with an allosteric activator site on a4b2 nAChRs in M10 cells. Neuroreport 1996;7:2201–2205.
- Madhok TG, Sharp BM: Nerve growth factor enhances 1H-nicotine binding to a nicotinic cholinergic receptor on PC12 cells. Endocrinology 1992;130:825–830.
- Rogers SW, Mandelzys A, Deneris ES, Cooper E, Heinemann S: The expression of nicotinic receptors by PC12 cells treated with NGF. J Neurosci 1992;12:4611–4623.
Cuello CA: Toward the repair of cortical synapses in Alzheimer’s disease; in Giacobini E, Becker R (eds): Alzheimer Disease: Therapeutic Strategies. Boston, Birkhäuser, 1996, pp 277–283.
Obrist W, Busse E, Eisdorfer R, Kleemeier R: Relation of the electroencephalogram to intellectual function in senescence. J Gerontol 1962;17:192–206.
- Hartikainen P, Soininen H, Partanen J, Helkala E, Riekkinen P: Aging and spectral analysis of EEG in normal subjects: A link to memory and CSF AChE. Acta Neurol Scand 1992;86:148–155.
- Gordon E, Sim M: The EEG in presenile dementia. J Neurol Neurosurg Psychiatry 1967;30:285–291.
- Johannesson G, Brun A, Gustafson L, Ingvar D: EEG in presenile dementia related to blood flow and autopsy findings. Acta Neurol Scand 1982;65:59–70.
- Coben L, Danziger W, Storandt M: A longitudinal EEG study of mild senile dementia of Alzheimer type: Changes at 1 year and at 2.5 years. Electroencephalogr Clin Neurophysiol 1985;61:101–112.
- Palmer M, Eriksdotter-Nilsson M, Henschen A, Ebendal T, Olson L: Nerve growth factor-induced excitation of selected neurons in the brain which is blocked by a low-affinity receptor antibody. Exp Brain Res 1993;93:226–230.
- Kobayashi S, Ögren SO, Ebendal T, Olson L: Intraventricular injection of NGF, but not BDNF, induces rapid motor activation that is inhibited by nicotinic receptor antagonists. Exp Brain Res 1997;116:315–325.
Kobayashi S, Ögren SO, Ebendal T, Olson L: Dopamine receptor antagonists block nerve growth factor-induced hyperactivity. Eur J Pharmacol 1997;12:1–5.
- Lauterborn JC, Tran TM, Isackson PJ, Gall CM: Nerve growth factor mRNA is expressed by GABAergic neurons in rat hippocampus. Neuroreport 1993;5:273–276.
- Petty BG, Cornblath DR, Adornato BT, Chaudry V, Flexner C, Wachsman M, Sinicropi D, Burton LE, Peroutka SJ: The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994;36:244–246.
- Lewin GR: Neurotrophic factors and pain. Semin Neurosci 1995;7:227–232.
- Lewin GR, Mendell LM: Nerve growth factor and nociception. Trends Neurosci 1993;16:353–358.
- Shen KF, Crain SM: Nerve growth factor rapidly prolongs the action potential of mature sensory ganglion neurons in culture, and this effect requires activation of Gs-couples excitatory kappa-opioid receptors on these cells. J Neurosci 1994;14:5570–5579.
- Williams LR, Oostveen JA: Sensitivity of Fisher 344 × brown Norway hybrid rats to exogenous NGF: Weight loss correlates with stimulation of striatal choline acetyltransferase. Neurosci Lett 1992;147:136–138.
- White H, Pieper C, Schmader K, Fillenbaum G: Weight change in Alzheimer’s disease. J Am Geriatr Soc 1996;44:265–272.
- Venero JL, Hefti F, Knusel B: Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: Comparison between intraparenchymal and intraventricular administration. Mol Pharmacol 1996;49:303–310.
- Chao MV, Hempstead BL: p75 and Trk: A two-receptor system. Trends Neurosci 1995;18:321–326.
- Snyder SH, Sabatini DM: Immunophilins and the nervous system. Nat Med 1995;1:32–37.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.