Hypertensive intracerebral hemorrhage (ICH) is caused by fibrinoid necrosis and vascular failure as a result of hypertension–associated pathological changes in small arteries, accounting for about 80% of all ICH. In the developed countries, as a result of the enlightenment for the general public through education, the prevalence of low–salt diet and increase in the use of antihypertensive drugs have reduced frequency of ICH, but the incidence of ICH in Japan is still higher than in Western countries. In many epidemiological studies, the relationship of stroke with oral diseases such as dental caries and periodontal disease, so–called “brain-oral association”, has been reported. In both basic and cross–sectional epidemiological studies, Streptococcus mutans harboring cnm gene encoding the collagen–binding protein Cnm has been linked with hypertensive ICH. The Cnm–positive Streptococcus mutans is presumed to attach to exposed collagen in areas of disrupted blood–brain barrier, induce inflammation, block platelet accumulation, and subsequently induce microbleeds and ICH. Endothelial damage due to shear stress, oxidative injury, or other causes may be a prerequisite for the collagen exposure and attachment of Cnm–positive S. mutans to collagen. To prospectively determine the link between the Cnm–expressing Streptococcus mutans and ICH, a longitudinal study named RAMESSES (Risk Assessment of cnM–positivE Streptococcus mutans in StrokE Survivors) study was started. Further elucidation of the clinical and pathological condition in which specific oral bacteria contribute to the development of vascular diseases including ICH is important for the establishment of new prevention and treatment strategies against cardiovascular diseases.

Stem cell therapy for central nervous system disorders have launched from basic research to the clinical trial phase. Many clinical trials are currently executed in Japan including ischemic stroke, traumatic brain injury, Parkingson's disease, and spinal cord injury. The preliminary data from these trials are promising and there is a strong expectation both from the medical and patient point of view. However, there are still so many unsolved questions which require further experimental procedures. The questions include cell types, transplantation route, transplantation timing and cell dosages. This article will highlight the basic knowledge of stem cell and the preliminary result of clinical trials launched in Japan.

Idiopathic basal ganglia calcification (IBGC), which is also called Fahr's disease or recently referred to as primary familial brain calcification (PFBC), is an idiopathic and intractable disease that is characterized by abnormal deposits of minerals including calcium in the basal ganglia and other brain regions such as the thalamus and cerebellum. Variants in SLC20A2, PDGFRB, PDGFB, XPR1 and MYORG have been reported in the past several years. The pathophysiological basis presumed by the genetic studies is the impairment of transport of inorganic phosphate (Pi) inside and outside the cells in the brain. The flow between cerebrospinal fluid and interstitial fluid in the brain and the drainage flow through the perivascular space in the concept of perivascular drainage system can well explain the distribution and pathology of mineralization in IBGC. Here we discuss the pathophysiology of IBGC and present our therapeutic strategies for IBGC.

Protein misfolding underlies the molecular basis of amyotrophic lateral sclerosis (ALS) of either sporadic or familial cases. TAR DNA–binding protein 43kDa (TDP–43) is a pathogenic protein in most sporadic ALS, in which aberrantly mislocalized species disrupt the homeostasis of RNA metabolism and protein quality control. In Japan, the mutation in superoxide dismutase 1 (SOD1) is the most prevalent genetic cause in familial ALS, in which the gain of toxic function is implicated in the pathogenesis. We have successfully generated monoclonal antibodies against misfolded forms of TDP–43 or mutant SOD1 proteins exclusively as a tool for molecular targeting of these pathogenic proteins. For TDP–43 in ALS, we constructed short–chain variable fragments (scFv) for intrabody with proteolytic signals, to eliminate the immunocomplex in the proteasome or autophagosome. Autolytic intrabody eliminated TDP–43 aggregates and prevented cell death caused by TDP aggregates in vitro and in the utero–transporated pup brain.

On the other hand, a misfolded–specific monoclonal antibody against SOD1 was introduced intrathecally to capture extracellular species to prevent cell to cell propagation or inhibit microglial activation, resulting in the significant prolongation of the longevity of the mutant SOD1 transgenic rat. Immunotherapy is a promising strategy for protein misfolding diseases such as ALS. However, the immunization approaches should be cautiously considered depending on the site of pathogenic proteins inside or outside motor neurons.

Amyotrophic lateral sclerosis (ALS) is an adult–onset, devastating neurodegenerative disease characterized by systemic loss of motor neurons in the central nervous system. Using a transgenic rat model overexpressing ALS–linked mutant Cu/Zn superoxide dismutase gene, which is the most frequent causative gene in Japanese ALS, we reported a dose–dependent neuroprotective effect of recombinant human hepatocyte growth factor (rhHGF) by intrathecal infusion, even with administration from onset of the motor neuron disease (Ishigaki A et al., J Neuropathol Exp Neurol 2007). Based on the pharmacokinetic and safety data in our phase I/first–in–human trial (Warita H et al., J Clin Pharmacol, 2018), we are going to accomplish the novel phase II proof–of–concept (POC) study of intrathecal rhHGF administration on ALS in the present study. In other CNS degenerative diseases, possible application of the intrathecal rhHGF delivery might be warranted.

Molecular targeted therapy including monoclonal antibody therapy is a new treatment strategy for demyelinating diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In Japan, only fingolimod and natalizumab are currently approved for treatment in MS. A novel S1P receptor modulator and a monoclonal antibody targeting CD20 are willing to be approved soon. In NMO, several monoclonal antibodies are waiting for the approval in Japan. Although either drug has a strong effect to prevent relapses in NMO, the indication should be considered by their high costs. In this review, I summarize the characteristics of each molecular targeted therapy.

Guillain–Barré syndrome (GBS), which is an acute immune–mediated polyneuropathy, rapidly causes limb weakness. Although the clinical course is monophasic, 10–20% of GBS patients can't walk without aid at one year from onset. The prognostic tools, such as Erasmus GBS Respiratory Insufficiency Score (EGRIS), modified Erasmus GBS Outcome Score (mEGOS), and ΔIgG are useful for prediction of prognosis at early phase. Recent Japanese retrospective study indicated that intensive therapies may improve the prognosis in GBS patients prospected to be poor prognosis using mEGOS. In addition, a recent study has shown that eculizumab, the inhibitor of C5 complement, improved the long–term prognosis in GBS. In future, more accurate prognostic tool and intensive therapies including a novel therapy possibly improve the prognosis in GBS.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy caused by heterogeneous immununological processes. In addition to the typical form of CIDP, several atypical forms, such as distal acquired demyelinating symmetric (DADS), multifocal acquired demyelinating sensory and motor, focal, pure motor, and pure sensory types, have also been included as subtypes of CIDP. Demyelination caused by macrophages has been reported in CIDP and is considered to play an important role in the pathogenesis of this disease irrespective of subtypes. By contrast, recent studies have suggested the association of IgG4 antibodies directed against paranodal junction proteins, such as anti–neurofascin 155 and anti–contactin 1 antibodies, to subpopulations of typical CIDP and DADS patients. Paranodal dissection resulting from the attachment of IgG4 at paranodal junctions and the absence of macrophage–induced demyelination are the characteristic pathological features in patients with these antibodies. Therefore, two distinct mechanisms that lead to nerve conduction abnormalities exist from a pathological viewpoint in CIDP. Regarding the treatment of CIDP, maintenance therapy using intravenous or subcutaneous administration of immunoglobulin has become available. Advances in the search for autoantibodies and development of new therapeutic options may make it necessary to reconsider the classification of CIDP and establish a long–term therapeutic strategy based on the mechanisms of this disease.

Myasthenia gravis (MG) has been classified into six subgroups : ocular MG (OMG), early–onset MG (EOMG), late–onset MG (LOMG), thymoma–associated MG (TAMG), muscle–specific receptor tyrosine kinase antibody–positive MG (MuSK–MG), and seronegative MG (SNMG). The treatment strategies differ among these subgroups. Based on the Japanese Clinical Guidelines for MG published in 2014, treatment strategies for each subgroup are described and illustrated in the figure. This paper should be a help for physicians taking care of MG patients.

薬剤抵抗性の日内変動とジスキネジアを呈するParkinson病（Parkinson disease：PD）の3例（59～78歳，全例女性）に対して，経頭蓋MRIガイド下集束超音波（MRI–guided focused ultrasound：MRgFUS）による片側淡蒼球内節破壊術を施行した．治療から1年後の時点で，運動障害の改善（2例）とジスキネジアの改善（3例）とを認めた．有害事象は軽微かつ一過性だった．多数例をより長期に検討する必要があるが，MRgFUSによる片側淡蒼球破壊術は進行期PDの治療選択肢の1つになる可能性がある．

誤嚥性肺炎はParkinson病（PD）の生命予後にかかわる重要な合併症の一つであるが，その発症に関連する因子についての報告は少ない．本研究では，嚥下造影検査を施行したPD患者の誤嚥性肺炎に関連する因子について検討した．対象は当院脳神経内科へ入院したPD患者24名．平均年齢は75.3歳，平均罹病期間は9.2年．方法：入院から嚥下造影検査までの期間に誤嚥性肺炎を発症したか否かによって，肺炎あり群と肺炎なし群の2群に分け，両群間で年齢，PDの罹病期間，入院期間，Hoehn & Yahr（HY）重症度，血清アルブミン値，body mass index，mini mental state examination（MMSE），歩行能力，咳嗽時の最大呼気流量（peak cough flow：PCF）値，反復唾液のみテスト，自己喀痰排出，声量，嚥下機能，不顕性誤嚥を比較した．結果：HY，MMSE，歩行能力，PCF値，自己喀痰排出，声量，嚥下機能，反復唾液のみテスト，不顕性誤嚥の項目で有意差を認めた（各々p＜0.05）．ロジスティック回帰分析の結果から，肺炎発症の有無に関連する因子としてPCF値（p＜0.01）と，不顕性誤嚥（p＜0.01），および嚥下機能（p＜0.01）が抽出された．結論：PD患者の誤嚥性肺炎発症に関連する因子としてはPCFが有用であることが示唆された．