Serotonin 1A receptors in the living brain of Alzheimer's disease patients.

4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

[1]  P. Van Bogaert,et al.  Comparative study of hippocampal neuronal loss and in vivo binding of 5-HT1a receptors in the KA model of limbic epilepsy in the rat , 2001, Epilepsy Research.

[2]  H. Wikström,et al.  Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635 , 1997, Brain Research.

[3]  A. Hirano,et al.  Nucleus raphe dorsalis in Alzheimer's disease: Neurofibrillary tangles and loss of large neurons , 1985, Annals of neurology.

[4]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[5]  E. Hoffman,et al.  Quantitation in Positron Emission Computed Tomography: 1. Effect of Object Size , 1979, Journal of computer assisted tomography.

[6]  Richard Hollister,et al.  Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease , 1997, Annals of neurology.

[7]  J. Palacios,et al.  Distribution of Serotonin Receptors , 1990, Annals of the New York Academy of Sciences.

[8]  Victoria Arango,et al.  Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635 , 2002, Brain Research.

[9]  J. Wegiel,et al.  Neurofibrillary pathology — correlation with hippocampal formation atrophy in Alzheimer disease , 1996, Neurobiology of Aging.

[10]  P. Grasby,et al.  Occupancy of Agonist Drugs at the 5-HT1A Receptor , 2004, Neuropsychopharmacology.

[11]  Kiralee M. Hayashi,et al.  Dynamics of Gray Matter Loss in Alzheimer's Disease , 2003, The Journal of Neuroscience.

[12]  M. J. Wade,et al.  Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. , 2001, Archives of neurology.

[13]  Chester A. Mathis,et al.  Gender-specific aging effects on the serotonin 1A receptor , 2001, Brain Research.

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

[15]  N. Foster,et al.  Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease , 1997, Annals of neurology.

[16]  G. Alexander,et al.  Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease , 1998, Neurology.

[17]  H. Stähelin,et al.  Morphometric investigation of nerve cells, neuropil and senile plaques in senile dementia of the Alzheimer type. , 1985, Archives of gerontology and geriatrics.

[18]  J. Wegiel,et al.  Duration of neurofibrillary changes in the hippocampal pyramidal neurons , 1998, Brain Research.

[19]  G. V. Van Hoesen,et al.  Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. , 1984, Science.

[20]  J. Bohl,et al.  Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer's disease , 2002, Acta Neuropathologica.

[21]  HERMAN BUSCHKE,et al.  Evaluating storage, retention, and retrieval in disordered memory and learning , 1974, Neurology.

[22]  D Comar,et al.  High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635. , 1998, Nuclear medicine and biology.

[23]  Sung-Cheng Huang,et al.  A general technique for interstudy registration of multifunction and multimodality images , 1994 .

[24]  F Kruggel,et al.  Hippocampal volume discriminates between normal cognition; questionable and mild dementia in the elderly , 2001, Neurobiology of Aging.

[25]  André Luxen,et al.  Modeling [18F]MPPF Positron Emission Tomography Kinetics for the Determination of 5-Hydroxytryptamine(1A) Receptor Concentration with Multiinjection , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  J. Morrison,et al.  Life and death of neurons in the aging brain. , 1997, Science.

[27]  M. Bobinski,et al.  The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease , 1999, Neuroscience.

[28]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[29]  H. Soininen,et al.  Hippocampus and entorhinal cortex in mild cognitive impairment and early AD , 2004, Neurobiology of Aging.

[30]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  M. Torrens.  Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[32]  Javier DeFelipe,et al.  Pyramidal cell axons show a local specialization for GABA and 5‐HT inputs in monkey and human cerebral cortex , 2001, The Journal of comparative neurology.

[33]  M. Pangalos,et al.  5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin. , 1992, The Journal of pharmacology and experimental therapeutics.

[34]  J. Baron,et al.  Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer's disease. , 1999, Brain : a journal of neurology.

[35]  M. Riad,et al.  Effect of the selective lesion of serotoninergic neurons on the regional distribution of 5-HT1A receptor mRNA in the rat brain. , 1992, Brain research. Molecular brain research.

[36]  V. Kepe,et al.  In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile , 2003, Neuroscience.

[37]  J. Talairach,et al.  Co-Planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System: An Approach to Cerebral Imaging , 1988 .

[38]  K. Jellinger.  A conventional approach to dorsal raphe nucleus staining , 2000, Neuropathology and Applied Neurobiology.

[39]  J. Morris,et al.  Current concepts in mild cognitive impairment. , 2001, Archives of neurology.

[40]  C. Jack,et al.  Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment , 2004, Journal of internal medicine.

[41]  G. Small,et al.  Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.