Motoki Fujimaki

Decreased long-chain acylcarnitines from insufficient β-oxidation as potential early diagnostic markers for Parkinson’s disease

Increasing evidence shows that metabolic abnormalities in body fluids are distinguishing features of the pathophysiology of Parkinson’s disease. However, a non-invasive approach has not been established in the earliest or pre-symptomatic phases. Here, we report comprehensive double-cohort analyses of the metabolome using capillary electrophoresis/liquid chromatography mass-spectrometry. The plasma analyses identified 18 Parkinson’s disease-specific metabolites and revealed decreased levels of seven long-chain acylcarnitines in two Parkinson’s disease cohorts (n = 109, 145) compared with controls (n = 32, 45), respectively. Furthermore, statistically significant decreases in five long-chain acylcarnitines were detected in Hoehn and Yahr stage I. Likewise, decreased levels of acylcarnitine(16:0), a decreased ratio of acylcarnitine(16:0) to fatty acid(16:0), and an increased index of carnitine palmitoyltransferase 1 were identified in Hoehn and Yahr stage I of both cohorts, suggesting of initial β-oxidation suppression. Receiver operating characteristic curves produced using 12–14 long-chain acylcarnitines provided a large area of under the curve, high specificity and moderate sensitivity for diagnosing Parkinson’s disease. Our data demonstrate that a primary decrement of mitochondrial β-oxidation and that 12–14 long-chain acylcarnitines decreases would be promising diagnostic biomarkers for Parkinson’s disease.

Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease

Objective To investigate the kinetics and metabolism of caffeine in serum from patients with Parkinson disease (PD) and controls using liquid chromatography–mass spectrometry. Methods Levels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age-matched healthy controls were examined by liquid chromatography–mass spectrometry. Mutations in caffeine-associated genes were screened by direct sequencing. Results Serum levels of caffeine and 9 of its downstream metabolites were significantly decreased even in patients with early PD, unrelated to total caffeine intake or disease severity. No significant genetic variations in CYP1A2 or CYP2E1, encoding cytochrome P450 enzymes primarily involved in metabolizing caffeine in humans, were detected compared with controls. Likewise, caffeine concentrations in patients with PD with motor complications were significantly decreased compared with those without motor complications. No associations between disease severity and single nucleotide variants of the ADORA2A gene encoding adenosine 2A receptor were detected, implying a dissociation of receptor sensitivity changes and phenotype. The profile of serum caffeine and metabolite levels was identified as a potential diagnostic biomarker by receiver operating characteristic curve analysis. Conclusion Absolute lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine previously revealed by epidemiologic and experimental studies. Classification of evidence This study provides Class III evidence that decreased serum levels of caffeine and its metabolites identify patients with PD.

Demyelinating Peripheral Neuropathy Due to Renal Cell Carcinoma

Renal cell carcinoma (RCC) patients who develop a paraneoplastic syndrome may present with neuromuscular disorders. We herein report the case of a 50-year-old man who suffered from progressive gait disturbance and muscle weakness. The results of a nerve conduction study fulfilled the criteria of chronic inflammatory demyelinating polyneuropathy. An abdominal CT scan detected RCC, the pathological diagnosis of which was clear cell type. After tumor resection and a single course of intravenous immunoglobulin therapy, the patients symptoms drastically improved over the course of one year. The patients neurological symptoms preceded the detection of cancer. A proper diagnosis and the initiation of suitable therapies resulted in a favorable outcome.

Lymphomatoid Granulomatosis with Central Nervous System Involvement Successfully Treated with Cyclophosphamide, High-dose Cytarabine, Dexamethasone, Etoposide, and Rituximab (CHASER therapy) Followed by Brain Irradiation: A Case Study

Lymphomatoid granulomatosis (LYG) is a rare subtype of diffuse large B-cell lymphoma. It is an extranodal angiocentric and angiodestructive lymphoproliferative disease involving the lungs, skin, and central nervous system (CNS), including abundant reactive T cells with varying numbers of atypical clonal Epstein–Barr virus (EBV)-infected B cells [1]. Clinical diagnosis of LYG is difficult because of a lack of characteristic manifestations, suitable laboratory tests, and imaging findings. No optimal treatment for LYG has yet been established, especially in cases involving the CNS. Several previous reports of rituximab monotherapy, rituximab-containing chemotherapy, interferon alpha-2b, or hematopoietic stem cell transplantation have been published [2], as well as a report of cyclophosphamide (CPM), high-dose cytarabine, dexamethasone, etoposide, and rituximab (CHASER therapy) for lung lesions of LYG [3]. Spontaneous remission has also been reported in patients with LYG involving the CNS and lungs [4]. Here, we describe a case of LYG with lung onset responsive to corticosteroid treatment, but with subsequent CNS involvement resistant to corticosteroid and rituximab monotherapy, which was successfully treated with CHASER therapy followed by brain irradiation. We also propose the value of repetitive evaluation of specimens and gradient-echo T2*-weighted magnetic resonance imaging (T2*-MRI) for diagnosis of CNS involvement in LYG (CNS–LYG). A healthy 40-year-old woman presented with persistent fever, cough, and dyspnea 2 years before admission to our hospital. Thoracic computed tomography (CT) performed at a local hospital revealed diffuse ground-glass opacity with nodular lesions in both lungs (Figure 1A). Blood examination showed highly elevated soluble interleukin-2 receptor (11,726 U/ml), and slightly elevated aspartate aminotransferase (86 IU/L) and alanine transaminase (131 IU/L). EBV antiviral capsid antigen (VCA) IgG and Epstein–Barr nuclear antigen (EBNA) were positive, and EBV anti-VCA IgM was negative, indicating past EBV infection. Pathological diagnosis was performed using videoassisted thoracic surgery (VATS), revealing atypical large lymphoid cells infiltrating the regions around the blood vessels (Figure 2A). These infiltrating lymphocytes comprised a large number of CD3-positive T cells and a few large CD20-positive B cells (Figure 2B). However, the lymphocytes were negative for EBV-encoded small RNA (EBER) according to in situ hybridization. Although LYG was suspected from the results, a definitive diagnosis was not made at the time. Prednisolone (50 mg/day; 1 mg/kg/day) was administered orally. The patient’s fever and respiratory symptoms disappeared and thoracic CT revealed disappearance of the bilateral nodular lesions (Figure 1B). However, 1 month after initiation of steroid therapy, prednisolone was tapered to 30 mg/day and she developed neurological deficits, including left facial dysesthesia, dysarthria, and gait disturbance due to left dominant spastic paraplegia, limb ataxia, and sensory disturbance. CPM (100 mg/day) was added and prednisolone was repeatedly increased or decreased from 50 to 2.5 mg/day, with no improvement. The patient was therefore

Progressive multifocal leukoencephalopathy with immune reconstitution inflammatory syndrome following treatment for granulomatosis with polyangiitis

A 56‐year‐old man with granulomatosis with polyangiitis (GPA) developed progressive multifocal leukoencephalopathy (PML) after a combined immune therapy with methotrexate and prednisolone. Despite negative conversion of JC virus after cessation of methotrexate treatment and tapering of prednisone, he developed amnestic aphasia, left hemispatial neglect, and left hemiplegia, which was confirmed as immune reconstitution inflammatory syndrome (IRIS) based on a rapid expansion of the lesions bilaterally with marginal gadolinium enhancement on brain magnetic resonance imaging. This case suggests that it may be important to be aware of possibility of IRIS, in cases of worsening neurological symptoms despite discontinuation of immunosuppressive treatments for GPA with PML.

Immunocytochemical Monitoring of PINK1/Parkin-Mediated Mitophagy in Cultured Cells

Both PINK1 and parkin are the responsible genes (PARK6 and PARK2, respectively) for familial early-onset Parkinsons disease (PD). Several lines of evidences have suggested that mitochondrial dysfunction would be associated with PD pathogenesis. Lewy body, one of PD pathological hallmarks, contains alpha-synuclein, a familial PD (PARK1/4)-gene product, which is eliminated by macroautophagy, while PINK1 and parkin coordinately mediate mitophagy (hereafter called as PINK1/parkin-mediated mitophagy) reported firstly by Youles group. The mitochondrial quality control system is specific for elimination of damaged mitochondria especially in the loss of mitochondrial membrane potential induced by treatment with mitochondrial uncoupler like CCCP or FCCP. In this chapter, we summarized immunocytochemical methods to monitor the PINK1/parkin-mediated mitophagy using cultured cells.

Parkinsonism in a patient with valosin-containing protein gene mutation showing: a case report

The valosin-containing protein (VCP) gene has been identified as being responsible for hereditary inclusion body myopathy (IBM) with Paget’s disease of the bones and frontotemporal dementia (IBMPFD) [1] as well as familial amyotrophic lateral sclerosis [2]. Pathologically, phosphorylated TDP-43 accumulates in various tissues, such as motor neurons in the anterior horn, cerebral cortex, bone, muscle, and substantia nigra [2–4]. Recently, a family with a VCP mutation showed diverse clinical manifestations, including parkinsonism; thus, the concept of multisystem proteinopathy was proposed [3]. Here we report a case of a patient with a VCP mutation who presented with limb-girdle muscle weakness/atrophy and Ldopa-unresponsive parkinsonism related to a progressive supranuclear palsy (PSP)-like symptoms. A 51-year-old woman visited our hospital because of postural abnormality and gait instability that had developed 7 years previously and had progressed gradually. Neurological examination revealed proximal weakness in her upper limbs, as indicated by aMedical ResearchCouncil scale grade of 4/5 for the deltoid and biceps brachii muscles, and in her trunk, as evidenced by a waddling gait. She had muscle atrophy of the upper-limb girdle, bilateral scapular winging (Fig. 1a), and lumbar hyperlordosis. However, facial, distal upper-limb, and lower-limb weakness were not observed. In addition, mild but significant parkinsonism (e.g., slight limitation of vertical eye movement compensated by doll’s eye phenomenon, loss of postural reflexes, cervical dystonic features, difficulty rising from a chair, mild bilateral rigidity, limited facial expression, and mild bradykinesia; Suppl Video) was observed. Generalized hyperreflexia without sensory loss, ataxia, and autonomic disturbances was not observed. No obvious dementia was noted, and her MiniMental State Examination scores were 29/30. A detailed past history suggested that she had gradually developed emotional blunting and showed a decline in personal grooming. She had a family history of muscle and neurological diseases: her father and uncle had similar symptoms of waddling gait and muscle weakness, and her uncle’s muscle biopsy revealed rimmed vacuolarmyopathy. In addition, her grandmother had been diagnosed with Parkinson’s disease. Brain magnetic resonance (MR) imaging revealed frontoparietal cortical atrophy (Fig. 2a), but the midbrain/ pons ratio (M/P ratio) [5] and MR parkinsonism index (MRPI) [6] were 0.257 and 10.55, respectively; this indicated that significant atrophies of the midbrain, pons, and superior/middle cerebellar peduncle were absent (Fig. 2b– d). Brain single-photon emission computed tomography (SPECT) showed significantly decreased blood flow in the frontotemporal cortex (Fig. 2e). Biopsy of the right biceps brachii muscle revealed IBM with rimmed vacuoles (Fig. 1b), and nuclear and cytoplasmic aggregates showed abnormal phosphorylated TDP-43 staining (data not shown). Genetic analysis revealed a p.R191Q mutation (c.572G[A) in VCP (Fig. 1c); thus, IBMPFD was diagnosed. She was started on levodopa/carbidopa therapy (300 mg/day), but her parkinsonism did not improve. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8467-2) contains supplementary material, which is available to authorized users.

3-2-01. Decreased motor axonal potassium currents in peripheral nerve hyperexcitability syndrome with negativity for anti-VGKC antibody and positivity for anti-CRMP5 antibody

Peripheral nerve hyperexcitability (PNH) syndromes are caused by spontaneous discharges originating from motor axons. Antibodies against voltage-gated potassium channels (VGKC) are detected in some patients with PNH syndrome, but the cause in the remaining patients has not yet been clarified. The index patient was a 46-year-old female with recurred thymoma and myasthenia gravis. Six month after the start of chemotherapy, she developed myokymia, fasciculations and muscle cramps in both her lower limbs. A nerve conduction studies revealed mild axonal polyneuropathy and a motor F-wave examination showed marked after-discharges. Needle electromyography showed fasciculation potentials and myokymic discharges. From these results, the patient was diagnosed with PNH syndrome. Nerve excitability study showed extremely greater supernormality in the recovery cycle and greater changes in depolarizing threshold electrotonus than control, suggesting decreased slow potassium currents in the motor axons. Serological tests revealed the absence of anti-VGKC antibody and the presence of anti-collapsin response mediator protein 5 (CRMP5) antibody. A recent study reported that CRMP5 plays an important role in axon–Schwann cell cooperation during development and nerve regeneration. The coexistence of nerve regeneration and anti-CRMP5 antibody may cause abnormal axon–Schwann cell interaction, which would result in slow potassium channel dysfunction and associated symptoms such as myokymia.