The goal of this study is to use ultra-high-resolution (UHR) PET imaging to better understand how the brain and spinal cord change in healthy aging and in neurological and psychiatric disorders such as Alzheimer's disease (AD), Parkinson's disease and related movement disorders, amyotrophic lateral sclerosis (ALS), and psychotic disorders. Researchers will use the NeuroExplorer PET/CT system, a new scanner that can show very small structures in the brain and spinal cord in much more detail than regular PET.

The main questions this study aims to answer are:

• How do small but important brain regions (like the locus coeruleus, substantia nigra, and thalamic nuclei) change in healthy aging?
• What early brain changes occur in neurodegenerative and psychotic disorders, and can they help improve early diagnosis?

Participants will:

• Undergo PET and MRI brain scans using different tracers that measure brain metabolism (18F-FDG), synaptic density (¹⁸F-SynVesT-1), dopamine transporters (¹⁸F-PE2I), and tau protein buildup (¹⁸F-MK6240).
• Complete cognitive and clinical assessments related to memory, mood, and motor or psychiatric symptoms, depending on their group.

This study will include healthy volunteers and patients with mild cognitive impairment due to Alzheimer´s disease, ALS, Parkinson's disease and related disorders, or psychotic disorders.

The results will help create detailed brain imaging maps for healthy aging and identify early biomarkers for different diseases to support better diagnosis and treatment in the future.

Inclusion Criteria:

• WP1: Healthy controls
• Age between 18 and 90 years old (15 aged 18-50 years and 25 aged 50 90 years);
• Subject is judged to be in good health by the investigator on the basis of medical history, physical examination including vital signs and clinical laboratory tests;
• No history or evidence of current major neurological, internal or psychiatric disorder, based on the medical assessment as described hereabove and neuropsychological assessment;
• No evidence of cognitive impairment as assessed by a Montreal Cognitive Assessment (MoCA) score of 26 or higher at baseline;
• 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 WML (white matter lesion) score <= 2 (of 3) on the Age-Related White Matter changes scale are acceptable;
• When older than 50 years of age, the volunteer is willing to undergo a p- tau217 blood sample.
• WP2: Dementia
• Patient has a clinical diagnosis of biomarker-proven prodromal AD
• WP3: ALS spectrum
• Subject must meet El Escorial Criteria (30) and Awaji-Shima criteria (31) for at least possible ALS;
• WP4: Movement disorders
• (all): Patient (or legal representative, when applicable) is able to understand the patient information form and give written informed consent.
• Parkinson´s disease (PD):
• Patient has clinically established PD based on the Movement Disorder Society (MDS) diagnostic criteria (32);
• Patient has an abnormal 18F-PE2I PET;
• No evidence of cognitive impairment as assessed by a Montreal Cognitive Assessment (MoCA) score of 26 or higher at baseline.
• Multiple system atrophy (MSA)
• Patient has clinically established or clinically probable MSA-P based on the
• Movement Disorder Society (MDS) diagnostic criteria (33);
• Patient has an abnormal 18F-PE2I PET.
• Progressive supranuclear palsy (PSP)
• Patient has an abnormal 18F-PE2I PET;
• Patient has clinically established probable PSP according to the latest MDS criteria
• Dementia with Lewy bodies (DLB)
• Patient has probable DLB by consensus criteria (cognitive impairment MoCA < 26 + visual hallucinations and/or fluctuating alertness);
• Patient has an abnormal 18F-PE2I PET.
• Idiopathic REM sleep behavior disorder (iRBD)
• Patient has Polysomnography-confirmed iRBD;
• No evidence of cognitive impairment as assessed by a Montreal Cognitive Assessment (MoCA) score of 26 or higher at baseline;
• No clinical evidence of parkinsonism at baseline.
• WP5: Psychosis
• DSM 5 criteria for a non-affective schizophrenia spectrum psychotic disorder;
• Age between 18 and 55 years old for adult-onset psychosis, onset of psychosis (and age) above 60 years old for very late onset psychosis.

Exclusion Criteria:

• Subject has a history of any major (other) internal, psychiatric or neurological disease that may interfere with the investigations (especially liver and kidney disease, uncontrolled diabetes, cancer, severe depression, stroke, severe TBI);
• Subject is currently a user (including recreational use) of any illicit drugs, including cannabis, or has a history of drug or alcohol abuse;
• Subject chronically uses medication that has central nervous system effects (e.g. strong painkillers such as opioids, neuroleptics,..; ) (other than prescribed for the illness in case of patients);
• Subject has had exposure to ionizing radiation (> 1 mSv) in other research studies within the last 12 months;
• Subject has a contra-indication for MRI scanning;
• Subject suffers from claustrophobia or cannot tolerate confinement during PET-MRI scanning procedures; subject cannot lie still for (at least) 60 minutes inside the scanner;
• (For subjects with arterial sampling): The subject is hypersensitive to lidocaine (used for local anaesthesia during the placement of the arterial catheter), has an abnormal Allen test (a test to check blood flow in the arteries of the forearm) or is on anti-coagulant therapy;
• Subject (or his/her legal representative) does not understand the study procedures;
• Subject is unwilling or unable to perform all of the study procedures, or is considered unsuitable in any way by the principal investigator;
• Subject is potentially pregnant (hCG test can be done if doubt exists).