In vivo imaging markers for the characterization of molecular changes in Parkinson and Huntington's disease

Parkinson’s disease (PD) and Huntington’s disease (HD) are neurodegenerative disorders characterized by a progressive multi-systemic accumulation of misfolded proteins associated with neuronal dysfunction and neuronal loss. The rationale of this thesis is to examine, by means ofthe state of the art Positron emission tomography (PET) methodology combined with the use of high resolution MRI image molecular changes associated to the early stages of PD and HD. PET is a molecular imaging technique that, due to recent advancements in terms ofradioligand development and PET instrumentation, such as the high-resolution research tomograph (HRRT) and PET quantification, may contribute to examine in vivo the distribution and availability of different biochemical targets. The work included in the thesis can be subdivided into two projects. The first project is dedicated to PD and to the study of two relevant molecular targets (dopamine and serotonin transporters), examined respectively with the radioligands [18F]FEPE2I and [11C]MADAM. In paper I, it is shown that [18F]FE-PE2I represents a reliable imaging biomarker to study the dopamine transporter (DAT) in the striatum and in the substantia nigra in PD. In paper II, a validation of a new approach to examine the serotonin transporter protein in small brainstem structures is presented. In paper III, [18F]FE-PE2I was used to study the entire nigro-striatal dopaminergic system, including dopamine projections, in a larger group of PD patients. The study was able to show a prominent involvement of the dopamine transporter in the striatum, a relatively milder reduction of DAT in the substantia nigra and a relative preservation of the protein along the nigro-striatal projections. The second project is dedicated to the evaluation of Phosphodiesterase 10A as new molecular target for HD. This project includes two studies in which the radioligand [18F]MNI-659 has been used as radioligand for PDE10A and the D2/3 receptors radioligand [11C]raclopride that has been used as internal reference. In paper IV, it is shown that aging is associated with a considerable reduction of PDE10A. In Paper V, the same targets are examined in selected cohorts of HD subjects in pre-manifest and manifest stages. The study shows that PDE10A was preserved in early pre-manifest HD subjects and progressively decreased in late premanifest and manifest HD stages. In conclusion the presented applications of new PET molecular imaging probes provided relevant information that contributes to measure early changes of molecular targets associated with the onset and progression of neuronal loss occurring in PD and HD

Simultaneous EEG-fMRI in Patients with Unverricht-Lundborg Disease: Event-Related Desynchronization/Synchronization and Hemodynamic Response Analysis

We performed simultaneous acquisition of EEG-fMRI in seven patients with Unverricht-Lundborg disease (ULD) and in six healthy controls using self-paced finger extension as a motor task. The event-related desynchronization/synchronization (ERD/ERS) analysis showed a greater and more diffuse alpha desynchronization in central regions and a strongly reduced post-movement beta-ERS in patients compared with controls, suggesting a significant dysfunction of the mechanisms regulating active movement and movement end. The event-related hemodynamic response obtained from fMRI showed delayed BOLD peak latency in the contralateral primary motor area suggesting a less efficient activity of the neuronal populations driving fine movements, which are specifically impaired in ULD

Superconductor coupled to two Luttinger liquids as an entangler for electron spins

We consider an s-wave superconductor (SC) which is tunnel-coupled to two spatially separated Luttinger liquid (LL) leads. We demonstrate that such a setup acts as an entangler, i.e. it creates spin-singlets of two electrons which are spatially separated, thereby providing a source of electronic Einstein-Podolsky-Rosen pairs. We show that in the presence of a bias voltage, which is smaller than the energy gap in the SC, a stationary current of spin-entangled electrons can flow from the SC to the LL leads due to Andreev tunneling events. We discuss two competing transport channels for Cooper pairs to tunnel from the SC into the LL leads. On the one hand, the coherent tunneling of two electrons into the same LL lead is shown to be suppressed by strong LL correlations compared to single-electron tunneling into a LL. On the other hand, the tunneling of two spin-entangled electrons into different leads is suppressed by the initial spatial separation of the two electrons coming from the same Cooper pair. We show that the latter suppression depends crucially on the effective dimensionality of the SC. We identify a regime of experimental interest in which the separation of two spin-entangled electrons is favored. We determine the decay of the singlet state of two electrons injected into different leads caused by the LL correlations. Although the electron is not a proper quasiparticle of the LL, the spin information can still be transported via the spin density fluctuations produced by the injected spin-entangled electrons.Comment: 15 pages, 2 figure

Intraputamenal cerebral dopamine neurotrophic factor in Parkinson's disease: a randomized, double‐blind, multicenter phase 1 trial

Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone‐anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo‐controlled, double‐blind, 6‐month main study followed by an active‐treatment 6‐month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE‐PE2I. Results: Drug‐related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

П. Первое в мире документальное описание рассеянного склероза (случай Августа д’Эсте) [The case of Augustus d’Este: the first documented account of multiple sclerosis]

(Граниери Э)(Фацио П): с таким напутстви- ем Джордж Эберс, профессор неврологии Оксфорд- ского университета, широко известный эксперт в области рассеянного склероза, некоторое время на- зад подарил нам небольшую книгу Д. Фирта «Слу- чай Августа д’Эсте», изданную в 1948 г.[7, 8], кото- рая затем была переведена на итальянский язык [9] (рис. 1). В ней приведены выдержки из заметок, сде- ланных потомком семьи д’Эсте, которая правила в Ферраре (Италия) с XIII по XVI век. В дневнике Ав- густ д’Эсте описывает симптомы своего заболева- ния, которые сейчас рассматривают как рассеянный склероз и который ранее называли склерозом в бляшках

From hand actions to speech: evidence and speculations

This chapter reviews experimental evidence and presents new data supporting the idea that human language may have evolved from hand/mouth action representation. Some of the findings include the discovery that the listener's motor system becomes active as if pronouncing the listened words during speech listening and that hand gestures where the hand is not explicitly visible activate the hand-related mirror neuron system, including Broca's region. This chapter concludes that the property of recursion, considered peculiar to human language, may have been introduced to hand actions by the fabrication of tools

The first case history of Multiple Sclerosis – Augustus d`Este (1794-1848)

none4The first case history of Multiple Sclerosis – Augustus d`Este (1794-1848). The personal diary of Sir Augustus d'Esté, born 1794 grandson of King George III of England, reveals a medical history strongly suggesting that Augustus suffered from multiple sclerosis (MS). It could well be the first record of a person having this disease. Charcot coined the term sclérose en plaques 20 years after the death of this patient in 1848. The onset of this man's MS seems to have been in 1822 with bilateral optic neuritis, the disease gradually developing in the classic manner with bouts derived from different loci in the central nervous system and eventually a secondary progressive form with paraparesis, sphincter incontinence, urinary problems and impotence. In 1941, Firth highlighted the case of Augustus d'Esté and later wrote a description of the pathology including a discussion on the aetiology of MS. No previous medical records have given such a characteristic picture of MS as this.impact factor: 1.435noneLandtblom A.M.; Fazio P.; Fredrikson S.; Granieri ELandtblom, A. M.; Fazio, Patrik; Fredrikson, S.; Granieri, Enrico Gavino Giusepp

Storia del Tic Doloureux Autopatografia di un ferrarese con nevralgia del trigemino (1803-1824)

Storia del Tic Doloureux Autopatografia di un ferrarese con nevralgia del trigemino (1803-1824

Development of Parkinsonism in a Patient with Central Pontine Myelinolysis

Osmotic demyelination syndrome (ODS) is caused by damage to the pons myelin sheath and nerve cells. Although the pathophysiological mechanism responsible for the damage is not yet fully understood, it is currently believed that osmotic-type changes (especially if they are massive and too rapid) cause oedema that leads to compression and, subsequently, demyelination of white matter fibres. It generally manifests with acute paraparesis/tetraparesis, dysphagia, dysarthria, diplopia, and loss of consciousness, as well as hallucinations, spasms, and other neurological symptoms related to brainstem damage. In extreme cases, the locked-in syndrome may also appear. Of note, in some cases an association between osmotic demyelinating damage and the onset of movement disorders has been documented and, although the pathophysiology is still unknown, a correlation has been postulated between ODS and movement disorders. Here, we present a patient with ODS who developed parkinsonism, thus supporting the hypothesis of a correlation between these pathological events