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Thesis for doctoral degree (Ph.D.) 2007 Thesis for doctoral degree (Ph.D.) 2007 Functional Brain Activity In Alzheimer Patients as Studied by Multi-tracer Positron Emission Tomography – Effects of Treatment with Cholinesterase Inhibitors Functional Brain Activity In AD Patients as Studied by Multi-tracer PET – Effects of Treatment with ChEIs Treatment of – Effects AD Patients as Studied by Multi-tracer PET Activity In Functional Brain Ahmadul Kadir MD Ahmadul Kadir Division of Alzheimer Neurobiology Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden FUNCTIONAL BRAIN ACTIVITY IN ALZHEIMER PATIENTS AS STUDIED BY MULTI-TRACER POSITRON EMISSION TOMOGRAPHY – EFFECTS OF TREATMENT WITH CHOLINESTERASE INHIBITORS AHMADUL KADIR, MD Stockholm 2007 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Larserics Digital Print AB © Ahmadul Kadir, 2007 ISBN 978-91-7357-357-3 To My parents for their support and caring & My wife for love and affection ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease accompanied by cognitive impairment and disturbances in several neurotransmitter systems, especially the cholinergic system. Studies have correlated the cognitive impairment observed in AD patients with a deficit in central cholinergic neurotransmission. The most successful therapeutic agents for symptomatic treatment of AD patients are cholinesterase inhibitors (ChEIs), e.g. donepezil, rivastigmine and galantamine, which are targeted towards enhancing cholinergic neurotransmission. One of the most valuable tools for evaluating cholinergic neurotransmission in AD patients is positron emission tomography (PET). PET with high spatial resolution, has successfully been used in the early diagnosis, differential diagnosis and evaluation of drug treatment in patients suffering from AD. The overall aim of this thesis was to utilize the multi-tracer PET technique to measure brain glucose metabolism, nicotinic acetylcholine receptor (nAChR) density, acetylcholinesterase (AChE) activity and amyloid load of patients with mild AD. These brain functional aspects were measured during the natural course of the disease or during treatment with ChEIs and/or anti-amyloid therapy in conjunction with assessment of changes in CSF biomarkers, ChE activity as well as with cognitive performance of the patients. In this thesis, it was demonstrated that cortical nAChRs as assessed by a dual tracer PET model with administration of 15O-water and (S)(-)11C-nicotine in mild AD patients (n = 27) are associated with the cognitive function of attention rather than with episodic memory. The effect of different ChEIs on cortical nAChRs was also evaluated in this thesis. Rivastigmine treated mild AD patients (n = 10) showed a significant increase of nAChRs in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of treatment. In a randomized double-blind placebo-controlled study, mild AD patients (n = 18) treated with galantamine demonstrated no change in cortical nAChRs after both short- (3 months) and long-term (12 months) treatment. However, it should be noted that individual subjects with higher plasma galantamine levels also demonstrated an increase in cortical nAChR binding. Additionally, patients treated with galantamine for 12 months demonstrated a 30–40% decrease in cortical AChE activity (as assessed by 11 C-PMP-PET) and a 30-36% decrease in CSF AChEsynaptic activity. In addition to rivastigmine and galantamine, the effects of (-)-phenserine, a new ChEI, were evaluated in mild AD patients (n = 20) in a randomized double-blind placebo-controlled study. Phenserine is a tentative AD drug that demonstrates an additional mechanism of action as an inhibitor of the formation of β-amyloid precursor protein (β-APP). Mild AD patients treated with (-)-phenserine demonstrated an increase in cerebral glucose metabolism as evaluated by 18F-FDG-PET after 3 months compared with baseline. We also observed that cortical amyloid load, measured by 11C-PIB-PET, inversely correlated with CSF β-amyloid (Aβ) levels, suggesting that (-)-phenserine treatment influenced both brain and CSF amyloid. After treatment with galantamine and (-)-phenserine we observed the highest level of improvement of cognitive performance up to 3 to 6 months, and maintenance of cognitive performance was observed after 12 months’ treatment, indicating stabilization of the disease. Attention was shown to be the main cognitive domain improved by the treatment. Positive correlations were also observed between the changes in number of cortical nicotinic receptors, AChE inhibition and changes in cognitive measures of attention. In conclusion, the present findings demonstrate that utilizing the multi-tracer PET method is important in the investigation of functional activity, neurotransmitters and pathology in the brains of patients with AD, in conjunction with measures of cognitive function, to evaluate the efficacy of the currently available ChEI treatments and future treatment strategies. Keywords: Alzheimer’s disease, cholinesterase inhibitors, positron emission tomography, nicotinic acetylcholine receptor, acetylcholinesterase, multi-tracer, 11C- Nicotine, 11C-PMP, 18F-FDG, 11C-PIB, donepezil, rivastigmine, galantamine, phenserine. ISBN 978-91-7357-357-3 LIST OF PUBLICATIONS I. Ahmadul Kadir, Ove Almkvist, Anders Wall, Bengt Långström, Agneta Nordberg: PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer's disease. Psychopharmacology 2006 188:509-520. II. Ahmadul Kadir, Taher Darreh-Shori, Ove Almkvist, Anders Wall, Bengt Långström, Agneta Nordberg: Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer’s disease following rivastigmine treatment as assessed by PET. Psychopharmacology (2007) 191:1005–1014 III. A. Kadir, T. Darreh-Shori, O. Almkvist, A. Wall, M. Grut, B. Strandberg, A. Ringheim, B. Eriksson, G. Blomquist, B. Långström, A Nordberg: PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiology of Aging (2007), Article in press IV. T. Darreh-Shori, A. Kadir, O. Almkvist, M. Grut, A. Wall, G. Blomquist, B. Eriksson, B. Långström, A. Nordberg: Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine. Neurobiology of Aging (2006), Article in press V. Ahmadul Kadir, Niels Andreasen, Ove Almkvist, Anders Wall, Anton Forsberg, Henry Engler, Göran Hagman, Marie Lärksäter, Bengt Winblad, Henrik Zetterberg, Kaj Blennow, Bengt Långström, and Agneta Nordberg: Effect of phenserine treatment on brain functional activity and amyloid in AD (Submitted manuscript, 2007) CONTENTS 1 Introduction.......................................................................................................1 1.1 Dementia ............................................................................................. 1 1.2 Alzheimer's disease............................................................................. 1 1.3 Neuropathology in Alzheimer's disease.............................................. 3 1.4 The Cholinergic nervous system......................................................... 5 1.4.1 Nicotinic acetylcholine receptors................................................. 6 1.4.2 Muscarinic acetylcholine receptors.............................................. 8 1.4.3 Cholinesterase .............................................................................. 8 1.5 Tools for diagnosis.............................................................................. 9 1.5.1 Neuropsychological investigation.............................................. 10 1.5.2 Cerebrospinal fluid biomarkers.................................................. 12 1.5.3 Neuroimaging............................................................................. 13 1.5.3.1 Structural neuroimaging........................................................ 13 1.5.3.2 Functional neuroimaging ...................................................... 14 1.5.3.2.1 Single photon emission computed tomography..................14 1.5.3.2.2 Positron emission tomography ............................................14 1.5.3.2.2.1 Functional activity....................................................... 15 1.5.3.2.2.1.1 Glucose metabolism............................................. 15 1.5.3.2.2.2 Neurotransmitter system ............................................. 16 1.5.3.2.2.2.1 Acetylcholinesterase ...............................................16 1.5.3.2.2.2.2 Nicotinic receptors ............................................... 17 1.5.3.2.2.3 Pathology .................................................................... 19 1.5.3.2.2.3.1 Amyloid .............................................................. 19 1.5.3.2.2.3.2 Microglia ............................................................. 20 1.6 Treatment strategies in Alzheimer's disease ..................................... 20 1.6.1 Symptomatic/Neurotransmitter treatment.................................. 21 1.6.2 Anti-amyloid disease-modifying treatment................................ 22 1.6.2.1 Amyloid precursor protein processing .....................................22 1.6.2.2 Beta-amyloid clearance by immunization............................. 23 1.6.2.3 Decreased beta-amyloid production.....................................
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  • Time-Dependent Cytokine and Chemokine Changes in Mouse

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    RESEARCH ARTICLE Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury David Tweedie1†*, Hanuma Kumar Karnati1†, Roger Mullins2, Chaim G Pick3, Barry J Hoffer4, Edward J Goetzl5, Dimitrios Kapogiannis2, Nigel H Greig1 1Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, United States; 2Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, Baltimore, United States; 3Department of Anatomy and Anthropology, Sackler School of Medicine, Sylvan Adams Sports Institute, and Dr. Miriam and SheldonG. Adelson Chair and Center for the Biology of Addictive Diseases, Tel Aviv University, Tel Aviv, Israel; 4Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, United States; 5Department of Medicine, University of California Medical Center, San Francisco, San Francisco, United States Abstract Traumatic brain injury (TBI) is a serious global health problem, many individuals live with TBI-related neurological dysfunction. A lack of biomarkers of TBI has impeded medication development. To identify new potential biomarkers, we time-dependently evaluated mouse brain tissue and neuronally derived plasma extracellular vesicle proteins in a mild model of TBI with parallels to concussive head injury. Mice (CD-1, 30–40 g) received a sham procedure or 30 g weight-drop and were euthanized 8, 24, 48, 72, 96 hr, 7, 14 and 30 days later. We quantified ipsilateral cortical proteins, many of which differed from sham by 8 hours post-mTBI, particularly *For correspondence: GAS-1 and VEGF-B were increased while CXCL16 reduced, 23 proteins changed in 4 or more of the [email protected] time points.