Age and APOE-epsilon4 genotype influence the effect of physostigmine infusion on the in-vivo distribution volume of the muscarinic-2-receptor dependent tracer [18F]FP-TZTP.

Geriatric Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Synapse (Impact Factor: 2.43). 07/2006; 60(1):86-92. DOI: 10.1002/syn.20276
Source: PubMed

ABSTRACT The apolipoprotein E-epsilon4 allele (APOE-epsilon4) confers greater susceptibility to age-related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE-epsilon4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F-18 labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), in aging healthy subjects with an APOE-epsilon4 allele. To examine the effects of aging and the APOE-epsilon4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [18F]FP-TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline (n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE-epsilon4 allele and 7 without an APOE-epsilon4 allele). Using a multiple regression analysis, both AGE (beta = 0.621 +/- 0.135, B = 0.353 +/- 0.077, t(10) = 4.61, P < 0.001) and APOE-epsilon4 genotype (beta = 0.742, B = 14.8 +/- 2.69, t(10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R2 for the model as a whole was 0.786 (F(2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE-epsilon4 allele modifying the response to physostigmine in the direction of larger decreases in [18F]FP-TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE-epsilon4 genotype, contribute to the growing body of evidence that suggests that the APOE-epsilon4 genotype is likely to contribute to brain structure and function prior to aging.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Single photon emission tomography (SPECT) and positron emission tomography (PET) are techniques to study in vivo neurotransmitter systems, neuroinflammation and amyloid deposits in normal human brain and in dementia. These methods used to explore the integrity of dopaminergic, cholinergic and serotonergic systems in Alzheimer's disease and in other dementias allowed to understand how the neurotransmission was modified in these disorders. Progress in the understanding of pathophysiological and clinical signs of dementia requires an evolution of the radioligands used to carry out an increasingly early and differential diagnosis in addition to monitoring the progression of disease and the effects of therapies. New emerging radiotracers for neuroinflammation or amyloid deposits are essential. In this article, new SPECT and PET tracers are presented.
    Medecine Nucleaire 03/2009; 33(3):137-141. DOI:10.1016/j.mednuc.2009.01.005 · 0.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The epsilon4 allele of the apolipoprotein E gene (ApoE), as well as aging increase the risk of Alzheimer's and vascular diseases. Electroencephalogram (EEG) reactivity to hyperventilation (HV) depends on hypocapnia-induced cerebral vasoconstriction, which may be impaired in subjects with subclinical cerebrovascular disease. Quantitative EEG at rest and under 3-minute HV was examined in 125 healthy subjects divided into younger (age range 28-50) and older (age range 51-82) cohorts and stratified by ApoE genotype. The younger ApoE-epsilon4 carriers had excessive EEG reactivity to HV characterized by the manifestation of high-voltage delta, theta activity and sharp waves, and larger HV-induced changes in EEG relative powers than in the younger ApoE-epsilon4 noncarriers. EEG reactivity to HV decreased with aging, and in the ApoE-epsilon4 carriers the decrease was more pronounced than in the ApoE-epsilon4 noncarriers. The older ApoE-epsilon4 carriers had smaller HV-induced changes in EEG relative powers than the older ApoE-epsilon4 noncarriers. A marked decline of EEG reactivity to HV in the older ApoE-epsilon4 carriers suggests the possible impact of vascular factors on the pathogenesis of ApoE-induced Alzheimer disease.
    Neurobiology of aging 12/2011; 33(4):839.e11-21. DOI:10.1016/j.neurobiolaging.2011.11.013 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Muscarinic receptors have been implicated in neurological disorders including Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Nineteen derivatives of thiadiazolyltetrahydropyridine (TZTP), a core that has previously shown high affinities towards muscarinic receptor subtypes, were synthesized and evaluated via in vitro binding assays. The title compound, a fluoro-polyethyleneglycol analog of TZTP (4c), was subsequently labelled with fluorine-18. Fluorine-18-labelled 4c was produced, via an automated synthesis, in an average radiochemical yield of 36% (uncorrected for decay), with high radiochemical purity (>99%) and high specific activity (326 GBq/µmol; end-of-bombardment), within 40 min (n = 3). Ex vivo biodistribution studies following tail-vein injection of [18F]4c in conscious rats displayed sufficient brain uptake (0.4%–0.7% injected dose / gram of wet tissue in all brain regions at 5 min post injection); however, there were substantial polar metabolites present in the brain, thereby precluding future use of [18F]4c for imaging in the central nervous system.
    Canadian Journal of Chemistry 11/2010; 88(12):1222-1232. DOI:10.1139/V10-149 · 1.01 Impact Factor