PSP - Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with a prevalence estimated at 6 per 100,000 in France and a rapidly progressive course. In its classic form (known as the Richardson type), it presents with a predominantly axial Parkinsonian syndrome, postural instability with early falls, oculomotor disorders, and cognitive and behavioral disturbances. Apart from levodopa, which may provide a modest improvement in Parkinsonian syndrome in some patients, the current therapeutic approach relies primarily on rehabilitation techniques, with no proven efficacy. Cognitive-behavioral symptoms are common in this disease and are primarily characterized by impaired executive functions, linked to dysfunction of the frontal cortex. They often have a devastating effect on quality of life, are associated with an increased risk of falls, and represent a considerable burden for caregivers. Among these symptoms, apathy is the most commonly described symptom. Impulsivity, associated with impaired inhibitory control, is present in 32-74% of cases and may coexist with apathy. Cognitive and behavioral inhibition depends on a complex brain network that includes, among others, the right inferior frontal gyrus (IFG), the dorsolateral prefrontal cortex, the supplementary motor area, the motor cortex, and the basal ganglia. It has recently been shown that patients with PSP have impaired functional connectivity between the right LFC and other brain structures in the network, and that neurotransmitter deficits in the right LFC correlate with their impulsivity Alongside pharmacological approaches, non-invasive brain stimulation techniques are rapidly expanding as a potential therapeutic tool. Transcranial direct current stimulation (tDCS), by modulating cortical excitability, is a promising technique. It is simple to administer and has demonstrated efficacy in several clinical settings. Furthermore, a recent meta-analysis of 45 clinical studies shows that single or repeated tDCS sessions could modestly but significantly improve the inhibitory response-measured by reaction time in the stop-signal paradigm-especially when active (anodal) stimulation was applied to the right GFI. These studies primarily involved healthy subjects. A few studies have examined the effects of tDCS in neurodegenerative diseases and in PSP. These studies are still preliminary, involving small sample sizes, but are encouraging. Among these, a randomized study comparing tDCS to sham tDCS demonstrated a beneficial effect of a single-session tDCS session targeting the dorsolateral prefrontal cortex on verbal fluency in patients with PSP. The hypothesis of our study is that applying tDCS stimulation over the right GFI will improve certain cognitive functions and reduce behavioral impulsivity in patients. Very little data on tDCS in PSP is available to date. Only three studies have been published. With very different designs-including only one randomized trial comparing tDCS to sham tDCS-these studies evaluated the effects of tDCS applied to the dorsolateral prefrontal cortex or to motor and premotor areas on language and motor symptoms, respectively. In this randomized, double-blind, controlled study, the investigators propose to explore the effects of tDCS on the right GFI on executive functions and, more specifically, on inhibitory control. Another strength of our study is that only patients with proven frontal cerebral hypometabolism on FDG-PET-MRI will be included, which will allow us to test the effect of tDCS on a clearly dysfunctional neural network. Furthermore, as a secondary objective, the investigators will be able to assess whether the effects of tDCS depend on the intensity and/or topography of cerebral hypometabolism. The neurophysiological effects of a single tDCS session appear to last up to 60 to 90 minutes. In this proof-of-concept study, the assessment tests were deliberately chosen for their short administration time and low test-retest effect. Finally, the Stop Signal Test, already used in this population, is widely used and well-standardized. This pilot study will provide initial data on the cognitive and motor effects of a tDCS session on the GFI, with a focus on inhibition. Given the limited effectiveness of symptomatic treatments-particularly pharmacological ones-having a new option capable of improving cognitive and/or behavioral performance would have a significant impact on the quality of life of patients and their families. tDCS has the advantage of being easily accessible and generally well-tolerated by patients and could eventually be administered in patients' homes. If our study demonstrates an improvement in certain cognitive/motor functions, it would lead to a larger-scale study with repeated sessions to assess its benefits over a longer period. Finally, if an improvement in executive functions is demonstrated in PSP, this could apply to other neurodegenerative diseases.

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.

This study is an observational, prospective genetic study. It aims to obtain DNA for research and testing from patients with PSP, CBS, MSA, and related neurological conditions and their families. Up to 1,000 adults who have been clinically diagnosed with PSP, CBS, MSA, or related neurological conditions will be enrolled. The study intervention involves sequencing of participant blood samples using non-CLIA-approved whole genome sequencing at the National Institutes of Health. Pathogenic variants that are deemed possibly related to these conditions will be confirmed using CLIA-approved testing. The study involves minimal risk to participants.