Early ReportIn-vivo measurement of activated microglia in dementia
Introduction
The process of neurodegeneration in Alzheimer's disease is associated with a local glial response within the brain parenchyma1 that involves activation of microglial cells—a normally dormant population of brain-tissue macrophages.2 Although Alois Alzheimer3 described a close association between brain phagocytes and amyloid plaques in 1911, recent studies have implied an active role for microglia in the mediation of amyloid toxicity and subsequent secondary tissue damage via release of cytokines and cytotoxic molecules.4, 5 Suppression of the brain's inflammatory and immune reaction to neuronal degeneration—eg, by use of non-steroidal anti-inflammatory therapy—has been suggested as a means to reduce the risk of developing Alzheimer's disease and to slow its progression.1, 6
PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) is a specific ligand for a receptor known as the peripheral benzodiazepine binding site, which is abundant on cells of mononuclear phagocyte lineage,7, 8, 9 but expressed only in small numbers in normal brain parenchyma. Labelled with carbon-11, PK11195 can be used as a ligand in positron emission tomography (PET).9, 10 PK11195 binding is present in cultured astrocytes.11 However, results of high-resolution autoradiography and double immune-labelling of animal and human postmortem brain tissue confirm those of previous studies: in vivo and in the absence of infiltrating haematogenous macrophages, (R)-PK11195—the enantiomer used in this study—binds to activated microglia or brain macrophages.7, 8, 10 Likewise, tissue pathology characterised mainly by reactive astrocytes, such as hippocampal sclerosis in clinically stable epilepsy patients with low seizure frequency, is not associated with significantly increased binding of [11C](R)-PK11195.10 This relative cellular selectivity in the central nervous system supports the use of [11C](R)-PK11195 as an in-vivo marker of activated microglia.9, 10
To examine whether microglial activation is present in the early stages of Alzheimer's disease, we compared findings on [11C](R)-PK11195 PET and volumetric magnetic resonance imaging (MRI) in patients with mild to moderate dementia—ie, a group of patients representative of those most likely to benefit from potential neuroprotective therapy—with those in healthy individuals.
Section snippets
Participants
We studied 15 healthy volunteers (seven women, eight men) between 32 and 80 years (median 57, IQR 21) and eight patients between 58 and 68 years (median 63·5, IQR 8) with probable Alzheimer's disease (table 1). In all individuals, general medical or neurological disease was ruled out by extensive general medical screening, formal neurological assessment, and brain MRI. The diagnosis of probable Alzheimer's disease was made in accordance with criteria defined by the Diagnostic and Statistical
Results
In normal individuals, low levels of constitutive [11C](R)-PK11195 binding were seen in the midbrain and pons, particularly near the floor of the fourth ventricle and the central canal. The only other region with [11C](R)-PK11195 binding significantly higher than background was the thalamus, where the level of binding increased linearly with age (mean binding potential 0·39, SD 0·07, range 0·26–0·56; correlation with age r=0·72, p=0·0024; figure 1). There was no correlation of size of thalamus
Discussion
In normal individuals, the thalamus and brainstem showed increased [11C](R)-PK11195 binding above backgound levels. The constitutive binding in the latter could be related to areas, such as near the floor of the fourth ventricle and the central canal, where the blood-brain barrier is absent and microglia even under normal conditions show some upregulation of activation markers, including the expression of peripheral benzodiazepine binding sites.7
The amount of [11C](R)-PK11195 binding in the
References (30)
- et al.
The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases
Brain Res Rev
(1995) Microglia: a sensor for pathological events in the CNS
Trends Neurosci
(1996)NSAIDs and incident Alzheimer's disease: the Rotterdam Study
Neurobiol Aging
(1998)- et al.
Simplified reference tissue model for PET receptor studies
Neuroimage
(1996) - et al.
Parametric imaging of ligand-receptor interactions using a reference tissue model and cluster analysis
- et al.
Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects
Psychiatry Res Neuroimaging
(2000) - et al.
(3H) PK 11195 and the localisation of secondary thalamic lesions following focal ischemia in rat motor cortex
Neurosci Lett
(1991) - et al.
Synthesis of the enantiomer of [N-methyl-11C]PK11195 and comparison of their behaviours as PK (peripheral benzodiazepine) binding site radioligands in rats
Nucl Med Biol
(1994) Über eigenartige Krankheitsfälle des späteren Alters. Z. ges
Neurol Psych
(1911)- et al.
Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E
Nature
(1997)
Microglial activation resulting from CD40-CD40L interaction after beta-amyloid
Science
PK (‘peripheral benzodiazepine’)-binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia
J Neurocytol
Temporal changes in glial fibrillary acidic protein messenger RNA and [3H]PK11195 binding in relation to imidazoline-I2-receptor and alpha 2-adrenoreceptor binding in the hippocampus following transient global forebrain ischaemia in the rat
Neuroscience
In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in the anaesthetised baboon
Stroke
The peripheral benzodiazepine binding sites in the brain in multiple sclerosis: quantitative in vivo-imaging of microglia as a measure of disease activity
Brain
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