In Vivo Quantification of Hsp90 in the Human Brain in Healthy Aging and Neurodegeneration Using the Novel PET Radioligand [11C]HSP990
This study tests the radiolabeled molecule (tracer), \[¹¹C\]HSP990, using positron emission tomography (PET) imaging to assess whether it can be used to measure levels of Heat Shock Protein 90 (Hsp90). The protein Hsp90 plays an important role in how proteins in the brain fold into their three-dimensional structure and how this protein helps maintain cellular homeostasis. Since neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by disrupted three-dimensional protein folding resulting in protein aggregation, we also aim to measure Hsp90 levels in patients with these conditions. \[¹¹C\]HSP990 is a promising tracer for this purpose and has already been extensively tested in animal models with safe and favorable results. The investigator now aims to evaluate this tracer in the human brain in healthy volunteers as well as in patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. The investigator expects that Hsp90 protein levels will be present at reduced concentrations in patients, possibly in different brain regions depending on the distribution of the disease-causing proteins associated with these disorders. Since the discovery of the important role of Hsp90 in neurodegenerative diseases, several candidate drugs targeting Hsp90 have been developed in recent years. The imaging method used in this study may support the development of Hsp90-targeting medications by enabling measurement of Hsp90 levels in the brain and assessment of the effects of these drugs.
⁃ Healthy controls
• Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
• Use of highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner.
• Male or female subjects, age between 18-55 (Part 1, n = 3), 18-40 (Part II, n = 5) or 40-70 (Part III, 40-55 n = 5, 55-70 n = 5) years old.
• Subject is judged to be in good health by the investigator on the basis of medical history, physical examination including vital signs, clinical laboratory test and urinalysis.
• No history or evidence of current major neurological, internal or psychiatric disorder, based on the medical assessment as described hereabove and neuropsychological assessment (SCL-90).
• (Part II and III only: ) In subjects \< 60 years of age, a normal structural MRI scan as assessed by expert radiologist. In subjects \>= 60 years of age white matter hyperintensities corresponding to a white matter lesion (WML) Fazekas score \< 2 on the Age-Related White Matter changes scale are acceptable
⁃ Parkinson's disease
• Age 45-85 years.
• Patient has clinically established PD based on the Movement Disorder Society (MDS) diagnostic criteria and is in Hoehn-Yahr stage I-III in the on medication state
• Patient has had a previous abnormal DaT-scan confirming the clinical diagnosis.
• Patient is able to understand the patient information brochure and give written informed consent
⁃ Alzheimer's disease
• Age 45-85 years.
• MoCA score \< 26
• Patient has a diagnosis of probable AD with evidence of the AD pathophysiological process (amyloid PET scan or CSF determination) according to the consensus criteria \[McKahn et al 2011, Alzh Dement\].
• Patient is able to understand the patient information brochure and give written informed consent.
⁃ Amyotrophic lateral sclerosis
• Age 20-85 years.
• Subjects will be recruited at the Neurology department of University Hospitals Leuven and must meet revised El Escorial Criteria and Awaji-Shima criteria for at least possible ALS.
• Patient is able to understand the patient information brochure and give written informed consent.