Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, caused by unstable genomic expansions of CTG repeats. The mutant RNA transcripts containing expanded repeats cause a toxic gain–of–function by perturbing splicing factors in the nucleus, resulting in misregulation of alternative pre–mRNA splicing. Recent advances in basic and translational research and pharmacological approaches provide clues for therapeutic intervention in DM. Here, we review the therapeutic approaches for targeting the toxic RNA with antisense oligonucleotides and small molecules.

In the acute treatment of cerebral ischemic stroke, intravenous alteplase infusion therapy and mechanical thrombectomy should be carried out rapidly. The treatment algorithm named “stroke scramble” was started from 2015 at Kochi Health Sciences Center to perform consistent team medical care completed in the shortest time.

The emergency physician declared the start of the scramble. By the patient arrival, the patient condition including each item of GAI₂AA scale was evaluated and intravenous alteplase therapy and mechanical thrombectomy were carried out as soon as possible. To keep the acute medical system, the patients were transferred to the other hospitals soon after the acute treatment.

As the result, door–to–needle time was reduced from 84 to 42 minutes. After the introduction of GAI₂AA scale in March 2017, door–to–puncture time was reduced from 91 to 52 minutes. The average length of hospital stay decreased by about 3 days from 21.4 in 2014 to 18.4 in 2019. The stroke scramble and its resemblant algorithm was activated in the whole Kochi Prefecture due to the open information to the other hospitals.

Since the medical care system is limited in local cities, it is important to establish high–efficient and stereotyped team medical care. Close cooperation under comprehensible slogans such as the stroke scramble could be useful.

Since 2009, the city of Yokohama has been operating the Yokohama Emergency Medical System for Cerebrovascular Diseases, which consists of 31 medical institutions and is integrated with the administrative agencies responsible for emergency transport. The system is designed to transport emergency patients suspected of having cerebrovascular disease to facilities capable of administering intravenous rt–PA or thrombus retrieval therapy as soon as possible. Since its inception, the number of eligible patients has been increasing. A liaison meeting with each participating medical institution, with the administrative body as the secretariat, consolidates and reviews clinical data on the number of patients, treatment details, time required for intravenous rt–PA and thrombectomy, and prognosis after 3 months, and publishes the results on the Yokohama City website.

We believe that the establishment of a system for collecting medical information on acute stroke patients, sharing it among related institutions, and verifying it will contribute to the development of acute stroke care in the future.

Kanagawa Prefecture is the second most populous prefecture after Tokyo. There are four universities that have medical schools : Yokohama City University, St. Marianna Medical University, Kitasato University, and Tokai University.

April 2008, the regional cooperation medical care plan management fee and discharge guidance fee were posted. By April 2008, there were already nine stroke regional networks active, and some had their own critical path.

In March 2008, at the request of Dr. Kuroiwa (Professor of Neurology, Yokohama City University at that time, affiliation and position at that time), the “Pan Yokohama Stroke Rehabilitation Strategy Conference” was held with Dr. Takagi (Professor of Neurology, Tokai University), Dr. Hasegawa (Professor of Neurology, St. Marianna University School of Medicine) and Dr. Hayashi (Director of Shintotsuka Hospital). On the other hand, the “Yokohama City Convalescent Rehabilitation Conference” was held by gathering convalescent hospitals with Dr. Yamamoto (Director of Yokohama Stroke and Brain Medical Center) as the founder. Both conferences shared the recognition that a meeting to unite each network is necessary to realize seamless medical care. Therefore, the “Yokohama-Kawasaki (later Kanagawa) Wide-area Seamless Stroke Care Association (YKWSSCA)” manager meeting was held and aimed to make a unified path (later common path).

In November 2008, the unified path creation executive committee including Dr. Kuroiwa, Dr. Hayashi, and the five directors of the regional core hospitals, including myself, created an overview path for patients. The path for medical professionals was created in collaboration with the Nanasawa Rehabilitation Hospital Cerebral Vascular Center and Tokai University in December 2007.

In February 2009, the “1st YKWSSCA” was held, and a unified path for both medical professionals and patients was announced. The name was changed to “Kanagawa Prefecture Stroke Regional Cooperation Path” by the medical section chief in September.

We introduced the medical cooperation of rehabilitation in acute treatment of stroke practiced at our hospital by dividing it into the multidisciplinary team medical care in Stroke Care Unit in our hospital and the medical cooperation in the production and use of Knee–Ankle–Foot–Orthosis and botulinum therapy in the community.

Eculizumab, a terminal complement inhibitor, is licensed for treatments of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and Neuromyelitis Optica Spectrum Disorders, which were life–threatening hematologic and neurological diseases. The Food and Drug Administration in US approved prescribing information includes a warning regarding increased risk for meningococcal disease in eculizumab recipients.

Taking of eculizumab is associated with a 1,000 to 2,000 fold increased incidence of meningococcal disease. Administration of meningococcal vaccines is recommended for patients receiving eculizumab before the treatment. 16 patients of meningococcal disease were identified in eculizumab recipients in the US during 2008 to 2016, and 4 patients also identified in Japan. In Japan, two patients were died, rest two patients were completely recovered by the appropriate antibiotics treatment. Eculizumab recipients remain at risk for meningococcal disease even after receipt of meningococcal vaccines. Initial symptoms of meningococ­cemia are nonspecific, and might include fever, chills, vomiting, and headaches. However, these symptoms can progress to severe illness and death within hours. Health care workers should be careful of suspicion for meningococcal disease in patients taking eculizumab who develop any symptoms consistent with either meningitis or meningococcemia.

Prion diseases are characterized by spongiform changes and scrapie form of prion protein (PrP^Sc) in the brain, and can transmit among individuals. PrP^Sc is infectious agent of prion diseases, which is difficult to decontaminate with general sterilization methods for bacteria or viruses. Furthermore, because PrP^Sc shows some resistance against treatments with proteolytic enzymes and protein denaturants, it is difficult to completely prevent transmissions of prion diseases among individuals in the clinical situation. So it is important to diagnose the patients as having prion diseases in the early phase of the disease correctly, and we should use single use devices in the high risk medical procedures, such as neurosurgeries, for the patients with prion diseases. In addition, if re–use instruments are used in the high–risk medical procedures for the patients with prion diseases, it is strongly recommended that sterilization methods of the instruments should follow the ‘Guideline for prevention of transmission in prion diseases 2020’. So far, several clinical trials using quinacrine or doxycycline have been conducted, but all of them resulted in failure. Some drugs have been reported to be able to modify the pathogenesis of prion diseases under experimental settings, and we are now preparing for future clinical trials for prion diseases.

Nearly 200 years after James Parkinson wrote ‘An essay on the shaking palsy’, advances in understanding of the pathogenesis of Parkinson's disease have led to the development of various therapies. In the early stages of Parkinson's disease, pharmacotherapy such as L–dopa, dopamine agonists, and MAO–B inhibitors play a central role in the treatment of motor symptoms. In the advanced stages, when movement complications such as wearing–off and dyskinesia appear, adjunct therapeutics such as COMT inhibitors, zonisamide, and adenosine A2A receptor antagonist are used. In addition to motor symptoms, Parkinson's disease is also associated with a wide variety of non–motor symptoms such as constipation, olfactory disturbance, REM sleep behavior disorder, and depression, which are observed from the prodromal phase, and orthostatic hypotension, cognitive dysfunction, and psychiatric symptoms, especially in the advanced stages. Recently, the importance of exercise and rehabilitation as non–pharmacological treatments has been reaffirmed, and they have become indispensable in the entire course of Parkinson's disease from the early stage to the advanced stage. In this article, I introduced the latest trends and prospects of Parkinson's disease treatment.

In Parkinson's disease (PD), accumulation and aggregation of α–synuclein (SNCA) trigger cytotoxicity and neurodegeneration. When treating PD, a therapy to exogenously compensate for dopamine deficiency in the brain due to the degeneration of dopaminergic neurons, has become most common. However, the treatment is not immune to decreased drug efficacy with disease progression. In contrast, if a therapy targeting SNCA, which constitutes the essential disease condition for PD, became available, it could be a fundamental treatment that suppresses the progression of neuronal degeneration. In line with the rapid progress in nucleic acid modification techniques, a therapeutic approach that prevents the production of target proteins using nucleic acids medicine has become available. Our group is attempting to treat PD using nucleic acid medicine targeting SNCA. We use Gamper–type antisense oligonucleotides (ASOs) that incorporate a novel nucleic acid modification, amino–bridged nucleic acids (AmNA). These AmNA–ASOs have the advantages of enhanced binding capacity and stability, as well as reduced toxicity. In our recent studies, we optimized the sequence and structure of ASOs that most effectively suppresses SNCA mRNA. By administration into lateral ventricles in mouse models of PD, the ASO was efficiently delivered into mouse brains. Furthermore, the ASO suppressed the levels of SNCA in the striatum of mouse models and improved their motor symptoms. We are currently testing the efficacy and safety of the ASO in non–human primate to proceed this therapeutic approach to clinic, especially for familial PD (PARK4) that is caused by SNCA overexpression. If we can establish an SNCA suppression treatment for PARK4 using ASO, this therapy might eventually be applied to all kinds of PD and serve as a groundbreaking disease–modifying therapy.

Precision medicine is a medical model that provides each patient with more customized medical decision, treatments and practices based on detailed information including individual genetic information using the latest technology, instead of a one–drug–fits–all model. We report the current status and prospects of precision medicine for monogenic form of Parkinson's disease (PD).

The outcome of deep brain stimulation (DBS) is generally favorable, with improved motor function and decreased levodopa equivalent daily dose in PD patients with PRKN, LRRK2 mutations. Around 30% of PD patients with GBA mutations had poor outcomes in motor function and progressive cognitive decline was reported after DBS.

A clinical trial (MOVES–PD) using Venglustat, a small–molecule glucosylceramide synthase inhibitor, has begun in PD patients with GBA mutations. The Phase II trial of venglustat failed to meet its primary endpoint and this study was discontinued.

In PLA2G6 (PARK14) deficient Drosophila, lipid replacement therapy corrected the brain lipid composition suppressed dopaminergic neurodegeneration and α–synuclein aggregation, and improved motor function in Drosophila. The dietary manipulation of fatty acids over a long time period could change brain lipid components to prevent α–synuclein aggregation in PD patients with PLA2G6 mutations.

In CHCHD2 (PARK22) deficient Drosophila, the light–dependent activation of mitochondrial proton–motive force using Delta–rhodopsin to recover the function of mitochondria, improved α–synuclein aggregation, DA neuronal loss, and motor behaviors, suggesting that maintaining the mitochondrial proton–motive force may serve as a therapeutic strategy for PD.

Finally, we introduce “PD Registry” in our department. We are planning to recruit hundreds of PD patients, and register a clinical information with many clinical scales, advanced MRI information and genetic information, and started to create a database. Using network science and artificial intelligence, we aim to elucidate the objective evaluation method of clinical subtypes of PD, and to develop precision medicine.

The number of dementia patients is rapidly increasing worldwide, however, in some cohorts in western countries the number shows a decreasing trend oppositely. The initial trial for disease modifying drug has started in 1999 by Schenk et al., but in vail for a long duration. The obstacles to be overcome appear to be an accurate diagnosis of dementia other than Alzheimer's disease, as well as autoimmune encephalitis and a similar but milder condition named amyloid–related imaging abnormalities (ARIA). When the diagnosis of Alzheimer's disease is delayed, accumulated fibrillary amyloid may be degraded and result in ARIA as a perivascular edema and microhemorrhages after administration of anti–amyloid β (Aβ) antibodies. Therefore, an early diagnosis of Alzheimer's disease is pivotal for safe and efficient strategies for disease modifying drugs.

At present, amyloid PET study and cerebrospinal fluid (CSF) Aβ42 levels are an established biomarker for early diagnosis of Alzheimer's disease. These biomarkers still have drawbacks because of high cost and invasiveness, respectively. However, more recently, peripheral blood biomarkers have been introduced. Moreover, novel findings on aggregation mechanism of anti Aβ has been revealed, thereby accelerating development of disease modifying drug for Alzheimer's disease.

At present, the direction of research and therapy of Alzheimer's disease (AD) is shifting from conventional neurotransmitter approach to pathological and biochemical approach aimed at disease–modifying therapy (DMT). Basic and clinical researches aiming at anti–amyloid effects based on the amyloid hypothesis have been mainly carried out at the present. Although it was previously thought that insoluble fibrils of amyloid β–protein (Aβ), which accumulates as amyloid in the brain, exert toxicity, recently attention has been focused on the study of oligomers and protofibrils, which are more toxic aggregates of Aβ. The developments of anti–Aβ antibodies targeting these Aβ aggregates are ongoing. In addition, it is considered that administration of DMT from the early stage or preclinical stage of AD patients will progress.

By utilizing a new marker of necrosis pSer46–MARCKS, which was identified by comprehensive phosphoproteome analysis as a phosphoprotein changed before appearance of extracellular amyloid aggregation, we discovered that neuronal necrosis occurs much earlier in Alzheimer's disaese pathology than expected. The necrosis is induced by intracellular amyloid accumulation that deprives a critical effector molecule, YAP in Hippo signaling pathway essential for cell survival, similarly to TRIAD necrosis observed in transcriptional repression and in other neurodegenerative disease such as Huntington's disease. The initial TRIAD necrosis due to intracellular amyloid releases HMGB1 to extracellular space and induces a cluster of secondary necrosis around the primary necrotic neurons, and finally the cluster grows to an extracellular amyloid plaque. Inhibition of HMGB1 by anti–HMGB1 antibody prevents expansion of neurodegeneration and administration even after the onset significantly ameliorates the cognitive decline of Alzheimer's disease model mice. Our results present a new scheme of Alzheimer's disease pathology, which can be named as “intracellular amyloid hypothesis”.

In the trials of more versus less statin, the RR per 1.0mmol/L further reduction in LDL cholesterol did not depend on the baseline LDL cholesterol concentration, with significant reductions of 23% in participants who had LDL cholesterol of 2.0–2.5mmol/L reduced further and of 29% in those who had LDL cholesterol lower than 2.0mmol/L (mean 1.71mmol/L) reduced further. “The lower, the better” relation was further confirmed with ezetimibe and PCSK9 inhibitors down to the range of 30mg/dL as the level of LDL–C after treatment. Based on the recent TST trial, target LDL–C level for the prevention of recurrent cardiovascular event may be set below 70mg/dL though Aisan, low body–weight patient, age older than 75 years old may not benefit from the strict control.

Antithrombotic agents for ischemic stroke or transient ischemic attack (TIA) should be considered based on three points : acute or chronic, antiplatelets or anticoagulants, and risk of ischemic event and hemorrhagic risk. The baseline treatment on the acute settings is aspirin 160–300mg within 48 hours of onset. In addition, the efficacy of dual antiplatelet therapy (DAPT) with aspirin and loading dose of clopidogrel for non–cardioembolic stroke or high–risk TIA within 24 hours of onset has been established. On the other hand, there is not enough evidence for intravenous anticoagulants for acute ischemic stroke. In the chronic settings, DAPT including cilostazol might be reasonable with decrease of recurrent stroke without increasing bleeding risk, whereas continuous DAPT with aspirin and clopidogrel is not recommended due to the increased risk of bleeding that outweighs the reduction of ischemic events. In patients complicated with both cardioembolic stroke and atherosclerosis, randomised controlled trial, which is called ATIS–NVAF, is on going to elucidate the effect of additional antiplatelets to oral anticoagulants.

Around 30% of cases of spontaneous intracerebral hemorrhage (ICH) occur in patients taking antithrombotic drugs (i.e., oral antiplatelet drugs and oral anticoagulants). However, antithrombotic drugs themselves are not a direct cause of vascular structure disruption, and only promote and/or prolong bleeding from vulnerable arterioles with pathology such as microaneurysms or fibrinoid necrosis, which are characteristics of cerebral small vessel diseases (SVDs). Thus, to a substantial degree, SVD, which is caused by aging, hypertension, or cerebral amyloid angiopathy (CAA), is the true cause of spontaneous ICH. Cerebral microbleeds (CMBs) are prone to bleeding and cause most spontaneous ICH. CMBs may thus be a specific and promising neuroimaging biomarker of SVDs and a clinically useful predictor of antithrombotic drug–related ICH. Such a relationship raises concerns about the increased ICH risk due to administration of antithrombotic drugs in patients with CMBs. Since 2017, several studies suggested some answers to this issue, and at this time, no evidence shows that the presence or number of CMBs on MRI can determine the pros and cons of antithrombotic therapy. A remaining major issue is validation of the risks and benefits of antithrombotic therapies for patients with CAA–related ICH. As a local issue, determining whether antithrombotic therapy for patients with a large number of CMBs is beneficial in East Asians will be necessary. East Asians are considered to be prone to hypertensive SVDs. Some of these issues will be clarified by an ongoing Japanese prospective, multicenter, observational study called “The Bleeding with Antithrombotic Therapy Study 2”, which enrolled patients with cerebrovascular or cardiovascular diseases who were taking oral antithrombotic agents.

Variant forms of transthyretin (TTR) cause hereditary transthyretin (ATTRv) amyloidosis. To date, more than 150 variants in the TTR gene have been reported. Genotype–phenotype correlations are seen in ATTRv amyloidosis. Diagnosis is sometimes delayed, especially in patients without a clear family history and typical clinical manifestations. Several therapeutic strategies, such as liver transplantation, stabilizers of TTR tetramers, and TTR gene silencing therapies, have been developed.

Ascorbic acid, curcumin, neurotrophin 3, and neuregulin 1 have been investigated for the treatment of Charcot–Marie–Tooth disease (CMT), but none have shown efficacy. Recently, PXT3003, a fixed–dose combination of baclofen, naltrexone, and D–sorbitol, has been attracting attention. The drug is believed to reduce the expression of overexpressed PMP22 mRNA. Phase III studies have been conducted mainly in Europe, and the Overall Neuropathy Limitations Scale (ONLS) evaluation has shown efficacy as well as safety, and future reports are expected. Finally, we will discuss HDAC6 inhibitors as potential therapeutic agents for axonal CMT.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27–hydroxylase.

Decreased sterol 27–hydroxylase activity results in impaired bile acid synthesis, leading to a reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol. Clinical presentation is characterized by neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and progressive neuropsychiatric disturbances. Although replacement treatment with CDCA in the early stage of the disease has been reported to improve or even prevent clinical symptoms of CTX, after significant neurological pathology is established, the effect of the treatment is limited. Therefore, early diagnosis and subsequent treatment initiation are essential in CTX.

Adrenoleukodystrophy (ALD) is an X–linked neurodegenerative disorder sometimes accompanied with adrenal insufficiency. The causative gene is ABCD1. Wide variety of phenotypes is the characteristic of ALD even in the same family. For childhood–onset cerebral ALD (CCALD) at early stages, hematopoietic stem cell transplantation (HSCT) is effective to stop the progression of inflammatory demyelination of the cerebral white matter. For adult–onset cerebral ALD (ACALD), there were little experience of HSCT. We performed HSCT for adult–onset cerebral/cerebellobrainstem form ALD patients at early stages (8 ACALD patients and 4 cerebellobrainstem form patients). The survival probability was significantly better in patients who underwent HSCT compared with patients who did not undergo HSCT (P＝0.0089). For all the patients who underwent HSCT, symptoms caused by cerebral/cerebellobrainstem white matter lesions became stable or partially improved after HSCT. Gadolinium–enhancement on brain MRI was disappeared/obscured in all the patients after HSCT. Enlarging white matter lesions became stable within one year after HSCT in all the patients. In 7 patients, white matter lesions reduced in size after HSCT. For ACALD and cerebellobrainstem form ALD patients at early stages, HSCT is effective to stop the progression of inflammatory demyelination of white matter lesions.

Spinal Muscular Atrophy (SMA) is an autosomal recessive lower motor neuron degenerative disease. About 90% of patients do not produce normal SMN protein due to deletion of the SMN1 gene. Instead, SMN2 gene produces SMN protein, but when transcribed into mRNA, exon 7 is slipped by about 90%, and full–length functional SMN protein is produced by only about 10%. In July 2017, nusinersen became available as a therapeutic agent for SMA. Expected to strengthen muscle strength and maintain function. Nusinersen treatment for adult SMA patients is performed by the Department of Neurology, but there is still insufficient information regarding nusinersen for adult SMA patients. In pediatric case such as SMA type 1 or 2, a visible muscle strengthening effect such as acquisition of standing walking can be expected, but the therapeutic effect in adult SMA patients is unknown. The Department of Neurology, Kagoshima University provides this treatment to 16 adult SMA patients. HFMSE (Hammersmith functional motor scale–expanded), RULM (Revised upper limb module), respiratory function, and 6–minute walking for walkable patients are evaluated as therapeutic effect. Normal lumbar puncture is difficult for patients who have severe scoliosis or surgery for scoliosis. In such case, cooperation with other departments such as orthopedics and anesthesiology is required. There is little information on long–term effects, but patients have high expectations.

In this case series, we described two patients of spinocerebellar ataxia type 3 (SCA 3) administered intrathecal baclofen (ITB). Patient 1 was 46–year–old man presented lower limbs with pain during walking. ITB improved spasticity and pain, which led to an extension of walking distance. Patient 2 was 36–year–old woman presented severe spasticity in upper and lower limbs, which made it difficult to care for her. ITB improved spasticity and care burden. We observed no adverse events in both patients. ITB is an effective therapeutic option for spasticity and might be useful for pain and caregiving.

A 73–year–old man began treatment with bilateral subthalamic deep brain stimulation (STN–DBS) 14 years after the onset of Parkinson's disease. After DBS, motor fluctuation and dyskinesia improved, and the dosage of anti–parkinson drugs was successfully decreased. However, eight months later, his wife complained of his hypersexuality that had not been present preoperatively. The symptom did not improve even after reduction of the dopamine agonist dose. The STN–DBS stimulation site was then changed from the ventral to the dorsal region, and his pathological hypersexuality resolved completely. In the context of our experience, this finding suggested that pathological hypersexuality may result from unnecessary stimulation to the limbic division by STN–DBS. Because it is a controllable symptom, hypersexuality should be evaluated in routine follow–up of patients treated with STN–DBS.