Elsevier

The Lancet

Volume 358, Issue 9280, 11 August 2001, Pages 461-467
The Lancet

Early Report
In-vivo measurement of activated microglia in dementia

https://doi.org/10.1016/S0140-6736(01)05625-2Get rights and content

Summary

Background

Background Activated microglia have a key role in the brain's immune response to neuronal degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of receptors known as peripheral benzodiazepine binding sites, which are abundant on cells of mononuclear phagocyte lineage. We used brain imaging to study expression of these sites in healthy individuals and patients with Alzheimer's disease.

Methods

We studied 15 normal individuals (age 32–80 years), eight patients with Alzheimer's disease, and one patient with minimal cognitive impairment. Quantitative in-vivo measurements of glial activation were obtained with positron emission tomography (PET) and carbon-11-labelled (R)-PK11195, a specific ligand for the peripheral benzodiazepine binding site.

Findings

In normal individuals, regional [11C](R)-PK11195 binding did not significantly change with age, except in the thalamus, where an age-dependent increase was found. By contrast, patients with Alzheimer's disease showed significantly increased regional [11C](R)-PK11195 binding in the entorhinal, temporoparietal, and cingulate cortex.

Interpretation

In-vivo detection of increased [11C](R)-PK11195 binding in Alzheimer-type dementia, including mild and early forms, suggests that microglial activation is an early event in the pathogenesis of the disease.

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

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