Visualising Cerebral and Peripheral Cholinergic Nerves in Patients With Dementia Lewy Bodies.
Condition: Dementia With Lewy Bodies; Degeneration Nerves; Positron-Emission Tomography; Acetylcholine
MeSH terms: Dementia; Lewy Body Disease
Study type: Observational

Summary: 
      Lewy Body Dementia (DLB) is the second most common type of neurodegenerative dementia and
      characterized by loss of cholinergic neurons in the cerebrum and possibly also internal
      organs. A novel tracer, 18F-fluoroethoxybenzovesamicol (18F-FEOBV), binds to the cholinergic
      vesicle transporter, a protein expressed uniquely in the vesicles of cholinergic
      pre-synapses. Our aim is to investigate the cholinergic denervation in patients with DLB
      using 18F-FEOBV. The investigators plan to recruit 30 patients with DLB and 20 healthy
      controls to extensive cognitive assessment, computed and positron emission topography,
      magnetic resonance imaging, and samples of blood. The investigators hypothesize that patients
      with DLB, compared to controls, have decreased cholinergic innervation in cortical and
      subcortical areas of the brain, intestines and heart, and that the denervation corresponds to
      symptoms of autonomic and cognitive dysfunction.
    

Detailed description: 
      Dementia with Lewy Bodies (DLB) is the second most common type of neurodegenerative dementia
      after Alzheimer's disease. It is characterized by cognitive decline, cognitive fluctuations,
      visual hallucinations, parkinsonism, and sleep disturbances. There is evidence of cholinergic
      neuron loss in the cerebrum of DLB patients, and Lewy body pathology in the cholinergic
      parasympathetic nerves of internal organs. A novel tracer, 18F-fluoroethoxybenzovesamicol
      (18F-FEOBV), binds to the cholinergic vesicle transporter, a protein expressed uniquely in
      the vesicles of cholinergic pre-synapses, and therefore a very specific marker for
      cholinergic innervation. There is only one previous FEOBV publication in DLB (4 patients).
      That study showed impressive imaging quality, far better than earlier cholinergic
      PET-ligands, such as 11C-donepezil. Per Borghammer has pioneered the use of 11C-donepezil PET
      to visualize cholinergic loss, and 18F-FEOBV PET represents the next generation of
      high-resolution cholinergic imaging. The aim is to investigate the cholinergic denervation in
      patients with DLB using 18F-FEOBV. The investigators hypothesize that, compared to healthy
      elderly controls, patients with DLB show: (i) Cholinergic denervation in cortical and
      subcortical structures of the brain, and in peripheral organs, specifically the gut,
      pancreas, and heart. (ii) Correlations between cerebral cholinergic denervation and cognitive
      decline, assessed with neuropsychometric measures. (iii) Correlations between cholinergic
      denervation of internal organs and relevant symptoms of autonomic dysfunction, e.g.
      orthostatic hypotension and constipation, and with objective measures of autonomic
      malfunction, e.g. increased colonic transit time, increased intestinal volume, and reduced
      heart rate variability. (iv) Thinning of the vagal nerve detected by ultra sound. (v)
      Correlations between cerebral cholinergic denervation and perturbed neural networks measured
      by functional MRI. Secondary aims are to compare the cerebral uptake of 18F-FEOBV in DLB
      patients with/without markers of Alzheimer's Disease in the cerebrospinal fluid, relate the
      pattern of glucose uptake (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose, 18F-FDG PET) to
      that of 18F-FEOBV uptake in the cerebrum, and contribute to development of a diagnostic
      alpha-synuclein assay.

      The investigators plan to include 25-30 DLB patients and 20 matched healthy elderly controls.
      Patients are recruited from the dementia clinic, Aarhus University. Inclusion criteria are
      mild to moderate DLB, ability to give informed consent, and typical signs of DLB on an
      18F-FDG-PET scan. Exclusion criteria are major psychiatric, neurologic and medical
      comorbidities. The investigators will do a clinical assessment including full somatic and
      neurological examinations, an extensive neuropsychological cognitive assessment, assess
      autonomic symptoms and evaluate for sleep disorders, test for orthostatic hypotension and
      heart rate variability and colonic transit time. The investigators will inject 300
      megabecquerel (MBq) of 18F-FEOBV in a peripheral vein and scan the internal organs from 0-70
      minutes. The patient then rests, and from 180-210 minutes post-injection, the brain is
      imaged. This two-step method has been validated to give a robust estimate of the cholinergic
      innervation of the brain. The investigators will also do magnetic resonance imaging of the
      brain, ultrasound of vagal nerve, cerebrospinal fluid analysis and blood work. The
      investigators plan to write a manuscript describing the cerebral uptake of 18F-FEOBV as
      measure of cholinergic denervation of patients with DLB. A second manuscript will describe
      the uptake of 18F-FEOBV in the internal organs. A third manuscript will compare the
      cholinergic denervation of brain and organs to cognitive and autonomic symptoms. NO will
      participate in recruitment of patients, drafting of protocol and manuscripts, organizing
      logistics, analysis of data, and collecting clinical and paraclinical data. The investigators
      will pay particular attention the ethical issues of obtaining informed consent from demented
      persons and emphasize an evaluation of competence. The investigators expect that this method
      is better than the currently used 11C-donepezil, in which case it will replace its use for
      studies of cholinergic denervation in the future. Developing non-invasive PET imaging of
      short duration is particularly important in a demented patient population that often struggle
      to lie still during prolonged scanning sessions. Development of strong objective measures to
      aid diagnosis of DLB is important because DLB is a common disease projected to increase even
      further in prevalence in the years to come. Also, our side project of contributing to the
      development of a prion-assay to detect alpha-synuclein in the cerebrospinal fluid has
      promising clinical potential.
    

Intervention name(s): PET-CT using FEOBV; MRI-scan; Cognitive assessment; Clinical assessment
Intervention type(s): Radiation; Radiation; Diagnostic Test; Diagnostic Test
Intervention description(s): We will inject 300 MBq of 18F-FEOBV in a peripheral vein and scan the internal organs from (0-70 minutes). The patient then rests, and from 180-210min after injection, we will scan the brain on our Siemens High Resolution Research Tomograph.; All patients will have an MRI scan of the brain. T1-weighted images will be used to assess general anatomy and identify white matter. T2-weighted sequences will be performed to quantify competing brain pathology. Also, we will collect functional MRI data.; Full neuropsychometric examination including tests in 5 cognitive domains.; Age, sex, duration of disease, patient history and full somatic and neurological examinations. Constipation assessed with Rome-III criteria. Evaluation of Rapid Eye Movement (REM) sleep Behaviour Disorder (RBDSQ) questionnaire. Test for orthostatic hypotension, heart rate variability, and deep breathing.
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Patients with DLB will be recruited from neurological and psychiatric departments in
        Denmark. Healthy controls will be recruited by advertising in local news papers.