Peripheral neuropathy and altered cobalamin metabolism in Parkinson's disease and other movement disorders

Peripheral neuropathy is a disorder of the peripheral nervous system (PNS) that may carry different underlying aetiologies. Studies have suggested PNS involvement may be prevalent in neurological diseases that traditionally have been regarded primarily as disorders of the central nervous system (CNS), including the neurodegenerative disorder Parkinson’s disease (PD). In PD, an increased prevalence of large and/or small fiber neuropathy has been reported. Underlying associations with biochemical signs of disturbed vitamin B12 (cobalamin) metabolism have been suggested, and proposed to be driven by chronic exposure to treatment with levodopa. However, peripheral neuropathy as an intrinsic disease feature has also been suggested, possibly driven by peripheral neurodegeneration associated with PD. We investigated the prevalence of clinical signs of peripheral neuropathy in a levodopa treated population followed at Karolinska University Hospital. Assessments included biochemical, genetic, and clinical evaluations. We observed a significantly higher prevalence of clinical signs indicative of a peripheral neuropathy, as assessed by the Utah Early Neuropathy Scale (UENS), in PD patients relative to controls. Furthermore, an association between UENS scores and plasma levels of homocysteine, an amino acid involved in the cobalamin dependent methionine cycle, was demonstrated.(Study I) In Study II we explored if Restless legs syndrome (RLS) may constitute a clinical expression of peripheral neuropathy in patients with PD and co-existent RLS. PNS assessments included both functional and structural evaluations of large and small fibers. More specifically, we employed the UENS, nerve conduction studies, quantitative sensory testing, and a novel method visualising the small fibers of the corneal subbasal nerve plexus, in vivo corneal confocal microscopy. An association between PNS assessments and the clinical expression of RLS, in the setting of PD, could not be demonstrated. This finding argues against a peripheral degenerative aetiology of RLS in this context. However, associations between PNS assessments and direct or indirect measures of disease burden in PD were demonstrated. This may possibly support the notion that PNS pathology, to some extent, could reflect ongoing CNS pathology in PD. Previous studies have highlighted a possible role of altered cobalamin metabolism also in the setting of CNS manifestations in PD. In Study IV we characterized an adult patient with PD demonstrating a rare biochemical alteration, related to the cobalamin dependent metabolic pathway that takes place in the mitochondrial compartment. We present the underlying genetic variants, including a novel variant, presumed to drive this alteration, and discuss possible clinical implications. Gaucher disease (GD) is a hereditary lysosomal storage disorder that, to some extent, shares genetic background with PD. An increased prevalence of both small and large fiber neuropathy has been associated with GD. We examined patients with GD type 1 followed at Karolinska University Hospital and patients with the Norrbottnian GD type 3 followed at Sunderby Region Hospital. We assessed symptoms and clinical signs compatible with a peripheral neuropathy, followed by electrodiagnostic testing in selected cases. Acknowledging small sample size, we believe our study may support the notion that small fiber neuropathy could represent an inherent disease feature in GD type 1, but argues against this being a prevalent finding in Norrbottnian GD type 3. We suggest that the recognition of an ongoing small fiber neuropathy in this disease may harbour treatment implications with regard to pain management.(Study III) Hereditary spastic paraparesis (HSP) constitutes a group of genetic movement disorders with vast phenotypic and genotypic hetereogeneity. We characterized the clinical phenotype, PNS involvement, and cerebrospinal fluid findings in two families with HSP-KIF5A. We confirm previous reports of inter- and intrafamilial variability of the clinical phenotype. Furthermore, we argue that elevated cerebrospinal fluid neurofilament light chain is not a mandatory finding in this upper motor neuron disease.(Study V) In conclusion, I suggest monitoring and treatment of biochemical signs of altered cobalamin metabolism in PD may serve a protective role with regard to the PNS. I speculate that PNS pathology in PD may reflect both levodopa mediated effects and manifestations inherent to the disease itself, possibly with a predilection for large and small fibers respectively. Thus, I believe future studies addressing the potential biomarker role of PNS assessments, as a surrogate marker of general disease progression in PD, are warranted. Such studies must account for the possibility of clouding effects related to altered cobalamin metabolism mediated by levodopa

Wide-field mosaics of the corneal subbasal nerve plexus in Parkinson’s disease using in vivo confocal microscopy

In vivo confocal microscopy (IVCM) is a non-invasive imaging technique facilitating real-time acquisition of images from the live cornea and its layers with high resolution (1-2 mu m) and high magnification (600 to 800-fold). IVCM is extensively used to examine the cornea at a cellular level, including the subbasal nerve plexus (SBNP). IVCM of the cornea has thus gained intense interest for probing ophthalmic and systemic diseases affecting peripheral nerves. One of the main drawbacks, however, is the small field of view of IVCM, preventing an overview of SBNP architecture and necessitating subjective image sampling of small areas of the SBNP for analysis. Here, we provide a high-quality dataset of the corneal SBNP reconstructed by automated mosaicking, with an average mosaic image size corresponding to 48 individual IVCM fields of view. The mosaic dataset represents a group of 42 individuals with Parkinsons disease (PD) with and without concurrent restless leg syndrome. Additionally, mosaics from a control group (n = 13) without PD are also provided, along with clinical data for all included participants.Funding Agencies|Hofgrens fond, NEURO Sweden; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)German Research Foundation (DFG) [273371152]</p

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

KOMPETENSUTVECKLING OCH PRINCIPER FÖR DESIGN AV IT-STÖD EN FALLSTUDIE AV SPECIALISTERS KUNSKAPSSPRIDNING OCH LÄRANDE

Anställdas kompetens är idag avgörande för organisationens konkurrenskraft och framgång. Magisteruppsatsen syftar till att studera hur specialister i ett kunskapsföretag inom applikationsutveckling kompetensutvecklas och blir bättre i sin yrkesroll. Vi vill även förstå och belysa vilka implikationer detta får vid design av IT-stöd för kompetensutveckling. Vår forskning har sin utgångspunkt i teorier vilka hävdar att lärande och kunskapsspridning är sociala processer som är djupt integrerat i den dagliga praktiken. För att finna svaret på forskningsfrågan valde vi en interpretativ fallstudie och insamlandet av empirin skedde med hjälp av ostrukturerade intervjuer. Resultatet påvisar att den mest effektiva formen av kompetensutveckling är informell och social och sker i den dagliga praktiken. Vi fann tre huvudkategorier som utgör kärnan för informell kompetensutveckling: iterativ problemlösning, social interaktion och historieberättande. Dessa tre kategorier anser vi är centrala vid design av IT-stöd för kompetensutveckling

MCEE Mutations in an Adult Patient with Parkinson’s Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid

Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding MCEE gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson&rsquo;s disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the MCEE gene, c.139C&gt;T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with MCEE mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient&rsquo;s ongoing neurodegeneration attributed to Parkinson&rsquo;s disease

Does Information from the Parkinson KinetiGraph™ (PKG) Influence the Neurologist’s Treatment Decisions?—An Observational Study in Routine Clinical Care of People with Parkinson’s Disease

Management of Parkinson’s disease traditionally relies solely on clinical assessment. The PKG objectively measures affected persons’ movements in daily life. The present study evaluated how often PKG data changed treatment decisions in routine clinical care and to what extent the clinical assessment and the PKG interpretation differed. PKG recordings were performed before routine visits. The neurologist first made a clinical assessment without reviewing the PKG. Signs and symptoms were recorded, and a treatment plan was documented. Afterward, the PKG was evaluated. Then, the neurologist decided whether to change the initial treatment plan or not. PKG review resulted in a change in the initial treatment plan in 21 of 66 participants (31.8%). The clinical assessment and the PKG review differed frequently, mainly regarding individual overall presence of motor problems (67%), profile of bradykinesia/wearing off (79%), dyskinesia (35%) and sleep (55%). PKG improved the dialogue with the participant in 88% of cases. PKG and clinical variables were stable when they were repeated after 3–6 months. In conclusion, PKG information changes treatment decisions in nearly a third of people with Parkinson’s disease in routine care. Standard clinical assessment and PKG evaluation are often non-identical. Objective measurements in people living with Parkinson’s disease can add therapeutically relevant information

Triplet photophysics of gold(III) porphyrins

Gold porphyrins are often used as electron-accepting chromophores in donor-acceptor complexes for the study of photoinduced electron transfer, and they can also be involved in triplet-triplet energy-transfer interactions with other chromophores. Since the lowest excited singlet state is very short-lived (240 fs), the triplet state is usually the starting point for the transfer reactions, and it is therefore crucial to understand its photophysics. The triplet state of various gold porphyrins has been reported to have a lifetime of around 1.5 ns at room temperature and to have a biexponential decay both in emission and in transient absorption with decay times of around 10 and 100,us at 80 K. In this paper, the triplet photophysics of two gold porphyrins (Au-III 5,15-bis(3,5-di-tert-butylphenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetrame thylporphyrin and Au-III 5,10,15,20-tetra(3,5-di-tert-butylphenyl)porphyrin) are studied by steady-state and time-resolved absorption and emission spectroscopy over a wide temperature range (4-300 K). The study reveals the existence of a dark state with an approximate lifetime of 50 ns, which was not previously observed. This state acts as an intermediate between the short-lived singlet and the triplet state manifold. In addition, we present DFT calculations, in which the core electrons of the central metal were replaced by a pseudopotential to account for the relativistic effects, which suggest that the lowest excited singlet state is an optically forbidden ligand-to-metal charge-transfer (LMCT) state. This LMCT state is an obvious candidate for the experimentally observed dark state, and it is shown to dictate the photophysical properties of gold porphyrins by acting as a gate for triplet state formation versus direct return to the ground state

<i>MCEE</i> Mutations in an Adult Patient with Parkinson’s Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid

Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding MCEE gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson&#8217;s disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the MCEE gene, c.139C&gt;T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with MCEE mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient&#8217;s ongoing neurodegeneration attributed to Parkinson&#8217;s disease