Glyceraldehyde metabolism in mouse brain and the entry of blood-borne glyceraldehyde into the brain.

D-Glyceraldehyde, a reactive aldehyde metabolite of fructose and glucose, is neurotoxic in vitro by forming advanced glycation end products (AGEs) with neuronal proteins. In Alzheimer's disease brains, glyceraldehyde-containing AGEs have been detected intracellularly and in extracellular plaques. However, little information exists on how the brain handles D-glyceraldehyde metabolically or if glyceraldehyde crosses the blood-brain barrier from the circulation into the brain. We injected [U-13C]-D-glyceraldehyde intravenously into awake mice and analyzed extracts of serum and brain by 13C nuclear magnetic resonance spectroscopy. 13C-Labeling of brain lactate and glutamate indicated passage of D-glyceraldehyde from blood to brain and glycolytic and oxidative D-glyceraldehyde metabolism in brain cells. 13C-Labeling of serum glucose and lactate through hepatic metabolism of [U-13C]-D-glyceraldehyde could not explain the formation of 13C-labeled lactate and glutamate in the brain. Cerebral glyceraldehyde dehydrogenase and reductase activities, leading to the formation of D-glycerate and glycerol, respectively, were 0.27-0.28 nmol/mg/min; triokinase, which phosphorylates D-glyceraldehyde to D-glyceraldehyde-3-phosphate, has been demonstrated previously at low levels. Thus, D-glyceraldehyde metabolism toward glycolysis could proceed both through D-glycerate, glycerol, and D-glyceraldehyde-3-phosphate. The aldehyde group of D-glyceraldehyde was overwhelmingly hydrated into a diol in aqueous solution, but the diol dehydration rate greatly exceeded glyceraldehyde metabolism and did not restrict it. We conclude that (1) D-glyceraldehyde crosses the blood-brain barrier, and so blood-borne glyceraldehyde could contribute to AGE formation in the brain, (2) glyceraldehyde is taken up and metabolized by brain cells. Metabolism thus constitutes a detoxification mechanism for this reactive aldehyde, a mechanism that may be compromised in disease states.

A man in his fifties with variable weakness and difficulty in walking. / En mann i 50-årene med varierende kraftsvikt og gangvansker.

BACKGROUND: An active man in his fifties was treated for atrial fibrillation with ablation. One week later he noticed variable weakness in his lower extremities. In the days that followed, his symptoms improved but could vary from day to day. CASE PRESENTATION: On admission 3 months after the initial symptoms, he had spasticity and weakness in both lower extremities, with hyperreflexia and positive Babinski. Spinal fluid contained slightly elevated protein levels. Spinal MRI showed cord oedema and gadolinium enhancement over multiple spinal levels. Autoimmune myelitis was suspected, and he was treated with high dose steroids and rituximab. Due to lack of effect, repeated examinations were initiated. Information from his patient history regarding symptom exacerbation by walking or bending forward was emphasised. Repeated MRI showed unchanged spinal oedema and dilated peri- and intramedullary vessels. MRA and spinal digital DSA revealed a dural fistula at third lumbar level, with the left L3 radiculomedullary artery as the feed artery. The fistula was successfully ligated by the neurosurgeon. INTERPRETATION: Spinal vascular lesions are rare and the diagnosis may be challenging due to atypical presentation. The case shows that detailed information from the patient history and thorough clinical investigation is of paramount importance to disclose this probably underreported condition.

Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro.

Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose-labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of hexokinase 1, which channels fructose into glycolysis, and whose activity was similar with fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. We asked how the brain handles fructose, which may react spontaneously with proteins to form 'advanced glycation end products' and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was expressed too. Neocortical cells also took up and metabolized glyceraldehyde oxidatively.

Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.

OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis.

Fatigue in myasthenia gravis: is it more than muscular weakness?

BACKGROUND: Few studies have focused on fatigue in myasthenia gravis (MG), and fatigue in relation to the autonomic system has never been systematically explored in these patients. The study aimed to document the prevalence of MG-related fatigue in ethnic Norwegians and to examine whether MG severity is associated with symptoms of autonomic disturbance, which in turn is associated with fatigue and functional disability. METHODS: Eighty two of the 97 who fulfilled the study inclusion criteria participated in the study. Controls were 410 age- and sex-matched subjects drawn from a normative sample (n = 2136) representative of the Norwegian population. Bivariate analyses and multivariate linear regression analyses were used to assess associations between questionnaire-reported MG severity, symptoms of autonomic disturbance, fatigue (mental and physical) and functional disability. RESULTS: Forty-four per cent (36/82) of patients fulfilled the criteria for fatigue compared with 22% (90/410) of controls (odds ratio 2.0; p = 0.003). Twenty-one per cent of patients (17/82) met the criteria for chronic fatigue versus 12% (48/410) of controls (odds ratio 1.96; p = 0.03). MG patients had higher total fatigue scores than controls (p < 0.001) and a high prevalence of autonomic symptoms, especially poor thermoregulation and sleep disturbance. According to multivariate analyses controlled for MG score, symptoms of autonomic disturbances were independently positively associated with fatigue (p < 0.001), and fatigue was independently negatively associated with functional level (p < 0.001). CONCLUSION: Norwegian ethnic patients with MG have higher levels of fatigue and a higher prevalence of chronic fatigue than controls, even in patients in full remission. MG severity is highly suggestive to be associated with symptoms of autonomic disturbance, which in turn is associated with fatigue and the level of functional disability.

[Drugs that may trigger or exacerbate myasthenia gravis]. / Medikamenter som kan utløse og forverre myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease causing muscle weakness due to impaired transmission at the neuromuscular junction. MG or a MG-like condition may be triggered or exacerbated by several drugs used for treatment of other diseases. Drugs may interfere with the neuromuscular transmission through several mechanisms, either by affecting pre- or postsynaptic ion channels or by affecting acetylcholinesterase. Based on a literature search in PubMed and the authors' own clinical experiences, we provide an overview focusing on the most frequently used drugs that may exacerbate weakness in patients with MG. In our experience, symptomatic MG-patients who have a generalised disease are especially vulnerable to drug-induced exacerbations, while stable MG patients with few symptoms more seldom are. Nevertheless, patients with MG must receive treatment for co-existing conditions. It is important to be aware of a possible increase in muscle weakness when introducing a new drug. If the patient deteriorates, the new treatment must be withdrawn or the dose reduced.

Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease. Patients without detectable antibodies against the nicotinic acetylcholine receptor or the muscle-specific tyrosine kinase are referred to as seronegative MG (SNMG). Because late-onset congenital myasthenic syndromes (CMSs) due to RAPSN or DOK7 mutations may be mistaken for SNMG, we investigated their frequency in a nationwide SNMG cohort. METHODS: We performed sequencing of RAPSN and DOK7 in all Norwegian SNMG patients (n = 74) and 37 healthy controls, examining for the N88K and c.1124_1127dupTGCC mutations, respectively. RESULTS: We found 1 patient homozygous for N88K and 2 carriers of the N88K mutation. Sequencing of DOK7 revealed no mutations. CONCLUSIONS: This study confirms that rapsn CMS can be mistaken for SNMG. In addition, the frequency of rapsn CMS in our nationwide SNMG cohort was found to be low. SNMG patients with an atypical clinical presentation and pediatric cases should be tested for the N88K mutation before initiation of immunosuppressive drug treatment or thymectomy.

A Middle-Aged Man Presenting With Progressive Heart Failure, Myopathy, and Monoclonal Gammopathy of Uncertain Significance.

A 48-year-old man presented with rapidly progressive heart failure and monoclonal gammopathy of uncertain significance. No specific cause was detected on endomyocardial biopsy. As the heart failure worsened, he also developed progressive skeletal myopathy. This provided the clue to the diagnosis, and cardiac function recovered rapidly with cause-directed therapy. (Level of Difficulty: Intermediate.).

Imaging in Lyme neuroborreliosis.

Lyme neuroborreliosis (LNB) is a tick-borne spirochetal infection with a broad spectrum of imaging pathology. For individuals who live in or have travelled to areas where ticks reside, LNB should be considered among differential diagnoses when clinical manifestations from the nervous system occur. Radiculitis, meningitis and facial palsy are commonly encountered, while peripheral neuropathy, myelitis, meningoencephalitis and cerebral vasculitis are rarer manifestations of LNB. Cerebrospinal fluid (CSF) analysis and serology are key investigations in patient workup. The primary role of imaging is to rule out other reasons for the neurological symptoms. It is therefore important to know the diversity of possible imaging findings from the infection itself. There may be no imaging abnormality, or findings suggestive of neuritis, meningitis, myelitis, encephalitis or vasculitis. White matter lesions are not a prominent feature of LNB. Insight into LNB clinical presentation, laboratory test methods and spectrum of imaging pathology will aid in the multidisciplinary interaction that often is imperative to achieve an efficient patient workup and arrive at a correct diagnosis. This article can educate those engaged in imaging of the nervous system and serve as a comprehensive tool in clinical cases. KEY POINTS: • Diagnostic criteria for LNB emphasise exclusion of an alternative cause to the clinical symptoms. • MRI makes a crucial contribution in the diagnosis and follow-up of LNB. • MRI may have normal findings, or show neuritis, meningitis, myelitis, encephalitis or vasculitis. • White matter lesions are not a prominent feature of LNB.

Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population.

BACKGROUND: Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. METHODOLOGY/PRINCIPAL FINDINGS: This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. CONCLUSION: The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.