Assessment of Neuroinflammation and Microglial Activation in Alzheimer’s Disease with Radiolabelled PK11195 and Single Photon Emission Computed Tomography

Objectives: Inflammation contributes to degeneration in Alzheimer’s disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [123I]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, the latter being expressed on microglia (brain resident macrophages) and upregulated under inflammatory circumstances. The objectives were to assess AD inflammation by detecting [123I]iodo-PK11195 uptake changes and investigate how uptake values relate with perfusion SPECT and neuropsychological findings. Methods: Ten AD and 9 control subjects were included. [123I]iodo-PK11195 SPECT images were realigned into stereotactic space where binding indices, normalized on cerebellar uptake, were calculated. Results: The mean [123I]iodo-PK11195 uptake was increased in AD patients compared with controls in nearly all neocortical regions; however, statistical significance was only reached in the frontal and right mesotemporal regions. Significant correlations were found between regional increased [123I]iodo-PK11195 uptake and cognitive deficits. Conclusions: [123I]iodo-PK11195 is a cellular disease activity marker and allows in vivo assessment of microglial inflammation in AD.

[1]  Jeffrey L. Cummings,et al.  Cognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis , 2000, Neurobiology of Aging.

[2]  C. Braestrup,et al.  Benzodiazepine receptors. , 1985, Clinical neuropharmacology.

[3]  N L Foster,et al.  PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer's disease. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[4]  R. Butterworth,et al.  Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex , 1991, Neurobiology of Aging.

[5]  D. Selkoe,et al.  Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease. , 1989, The American journal of pathology.

[6]  E. Mohr,et al.  Heterogeneity in Alzheimer's disease: progression rate segregated by distinct neuropsychological and cerebral metabolic profiles. , 1992, Journal of neurology, neurosurgery, and psychiatry.

[7]  Federico E. Turkheimer,et al.  Imaging Activated Microglia in the Aging Human Brain , 2001 .

[8]  P. Mcgeer,et al.  Polymorphisms in inflammatory genes and the risk of Alzheimer disease. , 2001, Archives of neurology.

[9]  A. Hofman,et al.  Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. , 2001, The New England journal of medicine.

[10]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[11]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[12]  Roger N Gunn,et al.  In-vivo measurement of activated microglia in dementia , 2001, The Lancet.

[13]  R B Banati,et al.  PK (‘peripheral benzodiazepine’) – binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK 11195 binding to activated microglia , 1997, Journal of neurocytology.

[14]  G. Waldemar.  Functional brain imaging with SPECT in normal aging and dementia. Methodological, pathophysiological, and diagnostic aspects. , 1995, Cerebrovascular and brain metabolism reviews.

[15]  L Bouwens,et al.  Nonuniform transmission in brain SPECT using 201Tl, 153Gd, and 99mTc static line sources: anthropomorphic dosimetry studies and influence on brain quantification. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  Šimon Scharf,et al.  A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease , 1999, Neurology.

[17]  P. Ferrara,et al.  Anti-inflammatory effects of peripheral benzodiazepine receptor ligands in two mouse models of inflammation. , 2000, European journal of pharmacology.

[18]  P. Mcgeer,et al.  The peripheral benzodiazepine receptor ligand PK 11195 inhibits arthritis in the MRL-lpr mouse model. , 1999, Rheumatology.

[19]  N. Robakis,et al.  Alzheimer's disease: a re-examination of the amyloid hypothesis , 1998, Trends in Neurosciences.

[20]  K Van Laere,et al.  Automated stereotactic standardization of brain SPECT receptor data using single-photon transmission images. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[21]  H. Soininen,et al.  Comparative MR analysis of the entorhinal cortex and hippocampus in diagnosing Alzheimer disease. , 1999, AJNR. American journal of neuroradiology.

[22]  J. Lindeboom,et al.  [Differentiation between dementia and functional psychiatric disorders in a geriatric ward of a general psychiatric hospital using the 'Amsterdam Dementia-Screening Test']. , 1994, Nederlands tijdschrift voor geneeskunde.

[23]  A. Kaszniak,et al.  Clinical trial of indomethacin in Alzheimer's disease , 1993, Neurology.

[24]  P. Aisen,et al.  Randomized pilot study of nimesulide treatment in Alzheimer’s disease , 2002, Neurology.

[25]  P. Eikelenboom,et al.  Acute phase proteins are present in amorphous plaques in the cerebral but not in the cerebellar cortex of patients with Alzheimer's disease , 1990, Neuroscience Letters.

[26]  H. Thierens,et al.  Biodistribution and dosimetry of [123I]iodo-PK 11195: a potential agent for SPET imaging of the peripheral benzodiazepine receptor , 2000, European Journal of Nuclear Medicine.

[27]  R B Banati,et al.  The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. , 2000, Brain : a journal of neurology.

[28]  J. Hardy,et al.  Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease , 2000, Nature.

[29]  R B Banati,et al.  In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion. , 2001, Brain : a journal of neurology.

[30]  D. Middleton,et al.  Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimer's disease and vascular dementia: a case-control study , 2001, The Lancet.

[31]  A. Young,et al.  Synthesis of a high specific activity 125I-labeled analog of PK 11195, potential agent for SPECT imaging of the peripheral benzodiazepine binding site. , 1989, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.

[32]  Patrick L. McGeer,et al.  Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease , 1996, Neurology.

[33]  P J Whitehouse,et al.  Evaluation of dementia. , 1996, The New England journal of medicine.

[34]  Koen Van Laere,et al.  Validation of the cerebellum as a reference region for SPECT quantification in patients suffering from dementia of the Alzheimer type , 1999, Psychiatry Research: Neuroimaging.

[35]  C. D. Morgan,et al.  Neuropsychological testing and assessment scales for dementia of the Alzheimer's type. , 1997, The Psychiatric clinics of North America.

[36]  R B Banati,et al.  Imaging cerebral vasculitis in refractory epilepsy using [(11)C](R)-PK11195 positron emission tomography. , 2001, AJR. American journal of roentgenology.

[37]  R. V. Van Heertum,et al.  SPECT perfusion imaging in the diagnosis of Alzheimer’s disease , 2001, Neurology.

[38]  G. Baltuch,et al.  Microglia as mediators of inflammatory and degenerative diseases. , 1999, Annual review of neuroscience.

[39]  M. Schlumpf,et al.  Receptors for psychoactive drugs: autoradiographic visualization of benzodiazepine binding sites. , 1984, Acta histochemica. Supplementband.

[40]  P. Scheltens,et al.  Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study , 2001, The Lancet.

[41]  R. Frackowiak,et al.  Monitoring by PET of macrophage accumulation in brain after ischaemic stroke , 1992, The Lancet.

[42]  T. Guilarte,et al.  Cellular and Subcellular Localization of Peripheral Benzodiazepine Receptors After Trimethyltin Neurotoxicity , 2000, Journal of neurochemistry.

[43]  N. Calingasan,et al.  Identification of CD40 ligand in Alzheimer’s disease and in animal models of Alzheimer’s disease and brain injury , 2002, Neurobiology of Aging.

[44]  Jean-Claude Baron,et al.  In Vivo Mapping of Brain Benzodiazepine Receptor Changes by Positron Emission Tomography After Focal Ischemia in the Anesthetized Baboon , 1993, Stroke.

[45]  P. Zandi,et al.  Do NSAIDs prevent Alzheimer’s disease? And, if so, why? The epidemiological evidence , 2001, Neurobiology of Aging.

[46]  J. Korf,et al.  In vivo evaluation in mice and metabolism in blood of human volunteers of [123I]iodo-PK11195: a possible single-photon emission tomography tracer for visualization of inflammation , 1999, European Journal of Nuclear Medicine.

[47]  S. Eagger,et al.  Quantification of regional cerebral blood flow (rCBF) using 99Tcm-HMPAO and SPECT: choice of the reference region. , 1992, Nuclear medicine communications.

[48]  A. Lbert,et al.  Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease , 2022 .

[49]  N. Delanty,et al.  Risk of Alzheimer's disease and duration of NSAID use , 1998, Neurology.

[50]  P. Mcgeer,et al.  Inhibitory action of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK 11195) on some mononuclear phagocyte functions. , 2000, Biochemical pharmacology.

[51]  W F Stewart,et al.  Risk of Alzheimer's disease and duration of NSAID use , 1997, Neurology.

[52]  C. Pert,et al.  Benzodiazepine receptor-mediated chemotaxis of human monocytes. , 1985, Science.

[53]  D. Perl,et al.  Alzheimer's disease and parkinson's disease: Distinct entities or extremes of a spectrum of neurodegeneration? , 1998, Annals of neurology.

[54]  Julie S. Snowden,et al.  Choice of reference region in the quantification of single-photon emission tomography in primary degenerative dementia , 1994, European Journal of Nuclear Medicine.

[55]  Michel Koole,et al.  99mTc-ECD brain perfusion SPET: variability, asymmetry and effects of age and gender in healthy adults , 2001, European Journal of Nuclear Medicine.

[56]  F E Turkheimer,et al.  [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis , 1999, Neurology.

[57]  J. Cummings,et al.  Progression of clinical deterioration and pathological changes in patients with Alzheimer disease evaluated at biopsy and autopsy. , 1999, Archives of neurology.

[58]  M. Mesulam.  Neuroplasticity Failure in Alzheimer's Disease Bridging the Gap between Plaques and Tangles , 1999, Neuron.

[59]  L. Wilkins.  Assessment of brain SPECT , 1996, Neurology.