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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    334—Aging: Physiology and Molecular Correlates

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    334.16: Relationships between cerebral acetycholinesterase activity and verbal memory

    Location: Halls B-H

    ">*N. RICHTER1,3, I. ALLENDORF1, ÷. ONUR1,3, L. KRACHT4, M. TITTGEMEYER4, B. NEUMAIER4, M. DIETLEIN2, M. SCHMIDT2, G. FINK1,3, J. KUKOLJA1,3;
    1Dept. of Neurol., 2Nuclear Med., Univ. Hosp. of Cologne, Cologne, Germany; 3Inst. of Neurosci. and Med. (INM-3), Res. Ctr. Juelich, Juelich, Germany; 4Max-Planck-Institute for Neurolog. Res., Cologne, Germany

    Abstract Body: Background: The cerebral cholinergic system plays a central role in memory and attention-related processes. Disorders resulting in mnestic deficits such as Alzheimer’s disease (AD) lead to an extensive neuronal loss, especially affecting cholinergic populations. The cerebral acetycholinesterase activity as a measure for the integrity of the cholinergic system can be assessed in vivo using positron emission tomography (PET) and the tracer [11C]N-methyl-4-piperidyl acetate (MP4A). A positive correlation between the local kinetic constant k3 of MP4A and neuropsychological measures of mnestic function has been demonstrated for patients suffering from amnestic mild cognitive impairment and AD, but not for healthy individuals. Under the hypothesis that local acetylcholinesterase activity and mnestic function are also correlated in healthy human subjects, we conducted the present study in healthy elderly individuals.
    Methods: Elderly subjects with no history of neurological or psychiatric disease and normal scores on a series of neuropsychological tests (MMST, LPS4, BDI, B-ADL, BTA, VLMT, Rey-Osterrieth Complex-Figure Test) were included after giving informed consent. MP4A-PET and high-resolution T1-weighted magnetic resonance (MR) images were obtained from each subject. The MR images were automatically segmented and parcellated into regions of interest (ROI). PET data were analyzed by computing k3 values for each ROI and entering them into a principal component analysis (PCA). Correlations were computed between neuropsychological test results and PCA factor scores.
    Results: Fourteen healthy adults (53-77y, 9m) were included in this study. No correlations between neuropsychological scores and age or gender were observed. The PCA yielded two components associated with neuropsychological test results. The first component included inferior frontal and medial temporal structures and was highly correlated with verbal memory delayed recall (VLMT; R = 0.716, p < 0.01). The second component consisted of a more extensive network of cortical structures, including parietal and frontal areas, and was correlated with the visual memory delayed recall (Rey-Osterrieth Complex Figure Test; R = 0.525, p < 0.05).Conclusion: Kinetic analysis of MP4A-PET data is sufficiently sensitive to detect subtle alterations in the local activity of cerebral acetylcholinesterase. Even in human subjects without cognitive impairment, acetylcholinesterase activity in memory relevant brain regions is correlated with mnestic function. Hence, MP4A-PET might be useful to detect prodromal stages of neurological or psychiatric illnesses, prior to manifest disease.

    Lay Language Summary: Using non-invasive brain imaging, we have detected a relationship between memory function in healthy human individuals and the integrity of a specific neurotransmitter system.
    Neurodegenerative disorders associated with memory loss such as Alzheimer’s disease play an increasing role in today’s ageing society. The present understanding is that the underlying progressive loss of nerve cells (neurons) is largely irreversible and that, in order to avoid or mitigate the resulting cognitive impairment, a potential neuroprotective treatment would have to be initiated as early as possible. For this reason, diagnostic methods are required to identify individuals at risk for such neurodegeneration prior to manifest disease.
    Brain imaging is a diagnostic tool that allows the non-invasive study of various aspects of brain function. The neurotransmitter acetylcholine plays a central role in learning and in recalling information. An impairment of neurons that communicate via acetylcholine, i.e. the cholinergic network, has been demonstrated in patients with memory problems and with manifest Alzheimer’s disease. To date, a similar relationship between measures of cholinergic function and performance on memory tests has not been reported in healthy individuals. We hypothesizedthat, since acetylcholine plays a central role in memory processes, imaging measures of cholinergic function should also be correlated with the performance in memory tasks in healthy individuals.
    To investigate this, thirteen healthy individuals, ages fifty-three to seventy, were recruited. They underwent a series of behavioral tests to measure cognitive and mnestic function and were then injected with a substance that temporarily accumulates in structures with cholinergic activity. This substance was labeled with a low dose of radioactivity, allowing subsequent measurement of its uptake and distribution. Brain areas were then grouped according to their cholinergic activity and analyzed regarding a potential relationship with the memory scores.
    Interestingly, such a relationship was observed in the frontal lobe and the medial temporal lobe, both brain areas known to play a central role in memory. In fact, structures in the medial temporal lobe are among the first to be affected in the course of Alzheimer’s disease. These data suggest that a cholinergic deficit might precede even subtle memory problems, possibly years before Alzheimer’s dementia would be manifest. This imaging method could thus be used to identify individuals that would benefit from a potential neuroprotective treatment.

    Red indicates areas where cholinergic acitivity is correlated with memory performance.
    Moreover, in the stages of neurodegeneration when memory deficits become relevant, but are not yet severe enough to constitute dementia, the response to cholinergic drugs is quite heterogeneous. While some individuals with mere memory problems have been shown to benefit from these drugs, others only report side-effects, which is why these substances are currently only approved for the treatment of manifest dementia. Our findings suggest that the brain imaging technique presented here might be useful to identify patients who will benefit from cholinergic drugs at earlier stages of the disease.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    334—Aging: Physiology and Molecular Correlates

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    334.16: Relationships between cerebral acetycholinesterase activity and verbal memory

    Location: Halls B-H

    ">*N. RICHTER1,3, I. ALLENDORF1, ÷. ONUR1,3, L. KRACHT4, M. TITTGEMEYER4, B. NEUMAIER4, M. DIETLEIN2, M. SCHMIDT2, G. FINK1,3, J. KUKOLJA1,3;
    1Dept. of Neurol., 2Nuclear Med., Univ. Hosp. of Cologne, Cologne, Germany; 3Inst. of Neurosci. and Med. (INM-3), Res. Ctr. Juelich, Juelich, Germany; 4Max-Planck-Institute for Neurolog. Res., Cologne, Germany

    Abstract Body: Background: The cerebral cholinergic system plays a central role in memory and attention-related processes. Disorders resulting in mnestic deficits such as Alzheimer’s disease (AD) lead to an extensive neuronal loss, especially affecting cholinergic populations. The cerebral acetycholinesterase activity as a measure for the integrity of the cholinergic system can be assessed in vivo using positron emission tomography (PET) and the tracer [11C]N-methyl-4-piperidyl acetate (MP4A). A positive correlation between the local kinetic constant k3 of MP4A and neuropsychological measures of mnestic function has been demonstrated for patients suffering from amnestic mild cognitive impairment and AD, but not for healthy individuals. Under the hypothesis that local acetylcholinesterase activity and mnestic function are also correlated in healthy human subjects, we conducted the present study in healthy elderly individuals.
    Methods: Elderly subjects with no history of neurological or psychiatric disease and normal scores on a series of neuropsychological tests (MMST, LPS4, BDI, B-ADL, BTA, VLMT, Rey-Osterrieth Complex-Figure Test) were included after giving informed consent. MP4A-PET and high-resolution T1-weighted magnetic resonance (MR) images were obtained from each subject. The MR images were automatically segmented and parcellated into regions of interest (ROI). PET data were analyzed by computing k3 values for each ROI and entering them into a principal component analysis (PCA). Correlations were computed between neuropsychological test results and PCA factor scores.
    Results: Fourteen healthy adults (53-77y, 9m) were included in this study. No correlations between neuropsychological scores and age or gender were observed. The PCA yielded two components associated with neuropsychological test results. The first component included inferior frontal and medial temporal structures and was highly correlated with verbal memory delayed recall (VLMT; R = 0.716, p < 0.01). The second component consisted of a more extensive network of cortical structures, including parietal and frontal areas, and was correlated with the visual memory delayed recall (Rey-Osterrieth Complex Figure Test; R = 0.525, p < 0.05).Conclusion: Kinetic analysis of MP4A-PET data is sufficiently sensitive to detect subtle alterations in the local activity of cerebral acetylcholinesterase. Even in human subjects without cognitive impairment, acetylcholinesterase activity in memory relevant brain regions is correlated with mnestic function. Hence, MP4A-PET might be useful to detect prodromal stages of neurological or psychiatric illnesses, prior to manifest disease.

    Lay Language Summary: Using non-invasive brain imaging, we have detected a relationship between memory function in healthy human individuals and the integrity of a specific neurotransmitter system.
    Neurodegenerative disorders associated with memory loss such as Alzheimer’s disease play an increasing role in today’s ageing society. The present understanding is that the underlying progressive loss of nerve cells (neurons) is largely irreversible and that, in order to avoid or mitigate the resulting cognitive impairment, a potential neuroprotective treatment would have to be initiated as early as possible. For this reason, diagnostic methods are required to identify individuals at risk for such neurodegeneration prior to manifest disease.
    Brain imaging is a diagnostic tool that allows the non-invasive study of various aspects of brain function. The neurotransmitter acetylcholine plays a central role in learning and in recalling information. An impairment of neurons that communicate via acetylcholine, i.e. the cholinergic network, has been demonstrated in patients with memory problems and with manifest Alzheimer’s disease. To date, a similar relationship between measures of cholinergic function and performance on memory tests has not been reported in healthy individuals. We hypothesizedthat, since acetylcholine plays a central role in memory processes, imaging measures of cholinergic function should also be correlated with the performance in memory tasks in healthy individuals.
    To investigate this, thirteen healthy individuals, ages fifty-three to seventy, were recruited. They underwent a series of behavioral tests to measure cognitive and mnestic function and were then injected with a substance that temporarily accumulates in structures with cholinergic activity. This substance was labeled with a low dose of radioactivity, allowing subsequent measurement of its uptake and distribution. Brain areas were then grouped according to their cholinergic activity and analyzed regarding a potential relationship with the memory scores.
    Interestingly, such a relationship was observed in the frontal lobe and the medial temporal lobe, both brain areas known to play a central role in memory. In fact, structures in the medial temporal lobe are among the first to be affected in the course of Alzheimer’s disease. These data suggest that a cholinergic deficit might precede even subtle memory problems, possibly years before Alzheimer’s dementia would be manifest. This imaging method could thus be used to identify individuals that would benefit from a potential neuroprotective treatment.

    Red indicates areas where cholinergic acitivity is correlated with memory performance.
    Moreover, in the stages of neurodegeneration when memory deficits become relevant, but are not yet severe enough to constitute dementia, the response to cholinergic drugs is quite heterogeneous. While some individuals with mere memory problems have been shown to benefit from these drugs, others only report side-effects, which is why these substances are currently only approved for the treatment of manifest dementia. Our findings suggest that the brain imaging technique presented here might be useful to identify patients who will benefit from cholinergic drugs at earlier stages of the disease.