Trial document




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  DRKS00000780

Trial Description

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Title

Memory, Ageing, and the Cholinergic System a combined fMRI and PET study

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Trial Acronym

MACS

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URL of the Trial

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Brief Summary in Lay Language

Memory declines with increasing age. Differentiating normal, age-related memory decline from pathological memory deficits in Alzheimer's dementia is not always easy and is a challenge to modern medicine. An early diagnosis of Alzheimer's disease is important in order to start early treatment. Evidence converges that one reason for the memory decline in alzheimer's disease is the lack of the neutrotransmitter acetylcholine. There is evidence that such a lack is also present in normal ageing. In the first part of the study we want to investigate this relationship and want to test differences between healthy persons and patients with memory deficits. We will use several methods:
- positron emission tomography (PET) will show brain regions producing acetylcholine.
- functional magnet resonance imaging (fMRI) will show brain activity during memory and attention tasks.
- neuropsychological testing will show differences in behavioural memory measures.
In the first part of the study we will investigate whether brain activity during memory tasks depends upon the local production of acetylcholine.
In the sevcond part of the study we want to investigate whether the administration of rivastigmine, which elevates acetylcholine levels in the brain enhances memory and whether this effect differs between healthy subjects and patients with memory deficits.

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Brief Summary in Scientific Language

Using a combination of functional magnetic resonance imaging showing brain activity, positron emission tomography showing acetylcholine esterase (AChE) distribution and pharmacological modulation we want to test whether there is a direct relationship between the integrity of the cholinergic system and memory- and attention performance on a neural and behavioural level. The primary goal is to show group differences between healthy older subjects and patients with mild cognitive impairment (MCI) in the effect of regional AChE-Activity on memory- and attention specific brain activity.
In a second step, using a double blind, crossover, placebo-controlled, randomised design, we want to show that these two groups differ in the response to pharmacological stimulation of the cholinergic system using rivastigmine (3 mg single dose, 1 week washout phase). We expect that cholinergic stimulation will enhance memory- and attention-related brain activity in patients with a deficient cholinergic system more than in subjects with an intact cholinergic system.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00000780
  •   2011/03/30
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  •   yes
  •   Approved
  •   09-035, Ethik-Kommission der Medizinischen Fakultät der Universität zu Köln
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Secondary IDs

  •   2008-008896-32 
  •   4036400 
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Health Condition or Problem studied

  •   F06.7 -  Mild cognitive disorder
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Interventions/Observational Groups

  •   healthy subjects, oral application of rivastigmine 3 mg
  •   patients with mild cognitive impairment (MCI), oral application of rivastigmine 3 mg
  •   healthy subjects, oral application of placebo capsule
  •   patients with MCI, oral application of placebo capsule
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Placebo
  •   Basic research/physiological study
  •   Crossover
  •   II
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Primary Outcome

Experiment 1:
- group difference in the effect of AChE-activity on brain activity underlying episodic memory and attention
= Interaction effect of group on regional correlation of the equilibrium constant k3, measured using positron emission tomography (PET) with the blood oxygen level dependent (BOLD) signal, measured using functional magnetic resonance imaging (fMRI)



Experiment 2:
- group difference in the effect of cholinergic stimulation on brain activity (BOLD signal) underlying episodic memory and attention

- dependence of the effect of cholinergic stimulation on regional AChE-activity

= correlation of the difference Verum-Placebo in the BOLD-signal (fMRI) with k3 (PET)

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Secondary Outcome

Experiment 1:
– group difference in acetylcholine esterase (AChE)-activity (k3, see above)
– group difference in brain activity (BOLD signal) underlying episodic memory and attention
– group difference in the effect of regional AChE-activity on behavioural memory and attention measures = interaction effect of group on correlation between k3 and behavioural test measures in memory and attention tests
– adverse events (AEs) and group differences in AEs

Experiment 2:
– group difference in the effect of cholinergic stimulation on behavioural memory and attention measures = group difference in the difference between VErum and Placebo in behavioural test measures in memory and attention tests
– adverse events (AEs) and group differences in AEs

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2012/05/21
  •   40
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   50   Years
  •   80   Years
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Additional Inclusion Criteria

group 1:
• healthy older subjects (age 50-80 years)

group 2:
• patients with mild cognitive impairment (< 2 SD in Verbal learning and memory test, 50-80 years)

both groups:
• informed consent
• normal neurological examination
• normal physical examination of the body including auscultation of the lungs and heart as well as abdominal palpation
• normal ECG
• Systolic blood pressure 100-160 mmHg
• Diastolic blood pressure 50-100 mmHg
• heart frequency 50-100

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Exclusion Criteria

instable cardiovascular diseases, neurologic or psychiatric diseases (except for mild cognitive impairment in the MCI group), insable diseases of the lungs, instable gastrointestinal diseases, instable diseases of the kidneys and the urinary tract, thyreotoxicosis, cancer, pregnancy, breast feeding, persons standing in dependency on the sponsor or investigator, placement into an institution due to governmental or judicial order, participation in other interventional studies potentially interfering with the currrent study, existing therapy with acetylcholinesterase inhibitors, missing secure measure to prevent pregnancy

additionally for experiments with Rivastigmin:
– hypersensitivity to rivastigmin or other carbamate derivetives
– Asthma bronchiale
– liver insufficiency
– renal insufficiency
– gangrene
– coronary heart disease
– cardiac rhythm disturbances like bradycardia, tachycardia, Sick Sinus Syndrome
– gastric or duodenal ulces
– mechanic constipation or mechanic urinary retention
– intestinal obstruction
– concomitant application of cholinesterase inhibitor
– application of anticholinergic agents
– Hypotension

for the fMRI experiments
– pacemaker or other implanted stimulation devices
– Infusion device / medication pump
– metal parts in or at the body
– tattoos
– claustrophobia
– grinding of metallic objects up to 1 week before fMRI measures

healthy subjects:
– prior application of radioactive substances or ionising radiation during nuclear medicine investigations, hypersensitivity to MP4A.

Patients with mild cognitive impairment:
– participation in other nuclear medicine investigations if exceeding limits named in § 88 Abs. 2 Strahlenschutzverordnung
– prior application of radioactive substances or ionising radiation during nuclear medicine investigations in a radiation therapy
– hypersensitivity to MP4A.

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Addresses

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    • Universitätsklinikum Köln
    • Kerpener Str. 62
    • 50924  Köln
    • Germany
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    • Max-Planck-Institut für neurologische Forschung
    • Mr.  Univ.-Prof. Dr. med.  Jens  Brüning 
    • Gleueler Str. 50
    • 50931  Köln
    • Germany
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    • Klinik und Poliklinik für Neurologie Uniklinik Köln
    • Mr.  Dr. med.  Juraj  Kukolja 
    • Kerpener Str. 62
    • 50924  Köln
    • Germany
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    • Klinik und Poliklinik für Neurologie Uniklinik Köln
    • Mr.  Dr. med.  Juraj  Kukolja 
    • Kerpener Str. 62
    • 50924  Köln
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Köln
    • Kerpener Str. 62
    • 50924  Köln
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2014/05/07
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Trial Publications, Results and other Documents

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