“Cortical cerebellar atrophy (CCA)” is a neuropathologically–defined disease entity, which is characterized by pure cerebello–olivary degeneration. Corresponding to the neuropathological findings, CCA patients are believed to show purely cerebellar ataxic syndrome, however, some cases with pathologically–proven CCA have been reported to show extracerebellar features such as involuntary movements, cognitive decline or decreased vibration sense. On the other hands, some cases with a clinical diagnosis of CCA have revealed affected lesions outside the cerebello–olivary system by postmortem examinations. These facts suggest the so–called “CCA” may have a clinical and neuropathological heterogeneity.

The heterogeneity is partly due to the uncertainty of the diagnosis of CCA. There is no specific biomarker for cerebello–olivary degeneration, therefore, the diagnosis of CCA is largely dependent on the exclusion of other diseases with cerebellar ataxia at present. Firstly, we should exclude olivopontocerebellar atrophy (OPCA, alternatively, multiple system atrophy with predominant cerebellar ataxia: MSA–C) because it accounts for approximately 60–70% of sporadic ataxias in Japan. It is sometimes quite difficult to distinguish OPCA (MSA–C) in the early stage of disease (less than 5 years from onset) from CCA. Secondly, hereditary ataxias need to be excluded. It is known that 10–20% of apparently sporadic cases are proven to have one of common autosomal dominant cerebellar ataxias (especially, SCA6, SCA31 in Japan) when genetic testing is conducted. Further, next generation sequencing has increasingly identified rare disease–causing variants in apparently sporadic cases. Lastly, secondary ataxias should be addressed by means of a detailed medical history and physical examination, as well as a focused diagnostic evaluation. Acquired causes for cerebellar ataxia include autoimmune–mediated, toxic (alcohol, drugs), demylinating, vascular, metabolic, infectious (parainfectious), others (PSP–C, prion disease, superficial siderosis, etc.). Approach to the acquired causes is very important because some of them are medically actionable.

Here we have replaced the neuropathologically–based nomenclature “CCA” with the clinical–based one “idiopathic cerebellar ataxia (IDCA)” to refine sporadic, degenerative cerebellar ataxia of adult–onset and proposed its diagnostic criteria.

A novel ALS (amyotrophic lateral sclerosis)/spinocerebellar ataxia (SCA) crossroad mutation Asidan shows characteristic clinical features was first reported by us in 2000 (Manabe et al.) and 2007 (Ohta et al.). Asidan is also called SCA36, and is caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene (Kobayashi H, Abe K et al., 2011). Clinical, genetic, neuropathologic, and neuroradiologic characteristics of 29 Asidan patients were examined. Histologic evaluation of a muscle biopsy specimen from 1 patient of Asidan, and neuropathologic evaluation of an autopsied brain from another patient of Asidan were also examined.

The mean age at onset was 53.1 years, with the most frequent symptoms of truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%). Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration. Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases. Most cases showed normal general cognitive function, but reduced frontal lobe functions, corresponding to frontal lobe atrophy on MRI. Lower motor involvement was confirmed by EMG and muscle biopsy. The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons. Although most patients did not show Parkinsonism, some showed decreases of DAT (dopamine transporter) image (DWEP=decreased DAT without evident Parkinsonism, Abe K 2016, Ohta et al., 2017).

Thus the novel ALS/SCA crossroad mutation Asidan (SCA36) showed unique clinical features, such as cerebellar ataxia, progressive motor neuron involvement, frontal cognitive decline, and a potential multi-system involvement.

Spinocerebellar degeneration (SCD) is a genetically heterogeneous disorder. To date, 41 genetic loci with autosomal dominant inheritance have been reported, and 30 causative genes have been elucidated. In order to identify a new causative gene, we analyzed a large family with dominant inherited SCD. We performed linkage analysis based on high–density SNP typing and exome sequencing. We used the whole cell patch–clamp technique to assess the electrophysiological change caused by mutation. In addition, differentiation into cerebellar Purkinje cells was conducted using iPS cells derived from the patients.

From the result of genetic analysis, we identified CACNA1G encoding Ca_V3.1 one of voltage–dependent calcium channels as a new causative gene, the phenotype termed SCA42. The same mutation was also observed in another SCD family. The patients exhibited pure cerebellar ataxia and some of them showed remarkable tremor. Ages at onset were varied from 18 to 70 years old. Ca_V3.1 is classified as low–voltage–activated (T–type) calcium channel and abundantly expressed in central nervous system including the cerebellum. The mutation we identified was located in the fourth segment (S4) of repeat IV. S4 of each repeat is a very important domain as a voltage sensor. From the result of electrophysiological study, the current change due to the prepulse was shifted toward positive membrane potential in the mutant compared with the wild–type. No morphological and immunocytochemical changes were observed in differentiation into Purkinje cells.

Many subtypes of SCD are caused by abnormal extension of repetitive sequences. In recent years, mutations in several channel–coding genes including calcium channels have been reported as the causes of SCDs. It is expected that investigation of SCD pathology as a channel disorder will contribute to further comprehension of the disease mechanism.

Alzheimer's disease (AD) represents the so–called “conformational disorders”. From a therapeutic view point, identification of targeting molecules which can trigger a complex downstream cascade (e.g., primary amyloid–relating process or secondary tau–related neuronal degeneration process) leading to AD dementia is a promising strategy. Evidence has shown that amyloid β (Aβ), particularly Aβ oligomers (AβOs), plays a causative role in Alzheimer's disease. If AβO cascade hypothesis is valid, therapeutic intervention targeting AβOs or for preventing the interaction between AβOs and tau is a promising treatment strategy for AD. We performed a hypothesis–driven, proof of concept study to prove the relevance of the in vivo Aβ oligomer cascade hypothesis using novel monoclonal antibodies specific to AβOs.

We herein review our AβO–immunotherapy with particular focus in the confirmation the relevance of our therapeutic strategy, which resulted in the phase I trial in prodromal and early AD.

Tau is well established as a microtubule–associated protein in neurons. However, under pathological conditions, aberrant post–translational modifications of tau such as phosphorylation cause tau protein to detach the microtubules. In recent years, clinical trials of tau targeting drugs such as immunotherapy, phosphorylation inhibitor and microtubule stabilizer have been conducted. Three phase II clinical trials on active and passive tau immunizations are being carried out. AADvac–1 is a vaccine using a KLH–conjugated peptide of second microtubule binding domain. This vaccine inhibits tau recombinant oligomerization and decreases tau phosphorylation in tau transgenic mice. C2N8E12 is a humanized monoclonal antibody which binds 4 microtubule–binding domains, consisting of 4 conserved sequence repeats. In vitro cell study showed that C2N8E12 was able to interrupt the cellular tau propagation. In tau transgenic mice, intraventricular injection of C2N8E12 inhibited cognitive dysfunction and decreased the number of phosphorylated tau–positive neurons. BMS–986168 is a humanized monoclonal antibody which was raised against extracellular tau, eTau. Previously, eTau had been affinity purified from Alzheimer's disease patient–derived cortical neuron conditioned media. Two Phase I studies on active and passive immunization are also being conducted. ACI–35 is a liposome–based vaccine which would recognize phosphor–serine–396 and –404. RO7105705 antibody against phosphor–serine–409 was modulated by mutations in the immunoglobulin G Fc region to reduce effector function. In terms of tau–aggregation inhibitor, the primary analysis of phase III clinical trial of TRx0327 did not suggest benefit as an add–on treatment for patients with mild to moderate Alzheimer's disease (AD). With regard to microtubule–stabilizing drug, TPI287 which crosses the blood–brain barrier is also being clinically developed at phase I. As for tau phosphorylation inhibitor, meta–analysis of 3 randomized placebo–controlled trials of lithium with AD and mild cognitive impairment revealed lithium may have beneficial effects on cognitive performance.

Microglia are macrophage–like resident immune cells in the central nervous system (CNS). When inflammation or neuronal damage occurs in the CNS, they are activated and change their form to ameboid microglia that phagocytose and remove the unnecessary substances in the brain. Accumulation of activated microglia in and around senile plaques has been demonstrated in autopsied brains from Alzheimer's disease (AD) patients. There are various opinions about the role of microglia in AD pathology ; some believe that activated microglia contribute to the progression of AD by producing both reactive oxidative species (ROS) and proinflammatory cytokines, while others believe that they inhibit the progression of AD through the phagocytosis of amyloid–β (Aβ) and microglial dysfunction in Aβ phagocytosis increase the risk of development and progression of AD. Those opinions may suggest the complexity and variety of microglial response in AD pathology. In this manuscript, we focus on microglia as the potential target for treatment of dementia, particularly AD.

Mutations in the gene MAPT encoding tau, a microtubules–associated protein, cause a subtype of familial neurodegenerative disease, known as frontotemporal lobar degeneration tauopathy (FTLD–Tau). We modeled FTLD–Tau using FTLD–Tau patient iPSCs. FTLD–Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death. FTLD–Tau neurons showed dysregulation of the augmentation of Ca²⁺ transients evoked by electrical stimulation. The introduction of designer receptors exclusively activated by designer drugs (DREADDs) or the treatment with glutamate receptor blockers attenuated misfolded tau–related neurodegeneration (Imamura et al., Sci Rep., 2016). These data suggest that neuronal hyperexcitability may regulate neurodegeneration in tauopathy. This FTLD–Tau model provides a useful tool for tauopathy treatments.

多巣性運動ニューロパチー1症例で歩容の特徴とその変化を筋力低下が進行した増悪期（発症3ヵ月後）と筋力が改善した改善期（発症8ヵ月後）に三次元動作解析装置を用いて解析した．増悪期では筋力低下に伴い立脚終期の過度な足関節背屈，遊脚終期の背屈減少，立脚期の膝関節過伸展，遊脚終期の股関節伸展を認め，足関節底屈モーメントの増大，膝関節伸展モーメントの不足，股関節伸展モーメントの増大を示した．改善期に筋力が改善したことで遊脚終期の足関節背屈減少以外の関節角度変化は改善を認めたが，関節モーメント変化は全般的に増悪期と同様であり改善は乏しかった．

症例は74歳の男性．4年の経過で四肢の感覚障害，歩行時のふらつきが徐々に進行していた．他院神経内科にて精査の結果，リンパ形質細胞性リンパ腫に伴う抗myelin–associated glycoprotein（MAG）抗体陽性ニューロパチーと診断され当院に紹介された．化学療法（R–CHOP療法）を1コース施行後，weekly rituximabを4コース施行された．R–CHOP開始2週間後から急激な四肢脱力が出現し，rituximab単独投与後も増悪し歩行不能となった．Rituximabを中止し，ステロイドパルス療法1コース，γグロブリン静注療法2コース施行し，代替治療開始から6か月後に再度独歩可能となるまで改善した．抗MAG抗体陽性ニューロパチーにおいてrituximabにより神経症状が悪化した症例の報告は散見されるが，本邦での報告は本症例が第1例である．神経症状悪化の病態の機序は明らかにされていないが，抗MAG抗体陽性ニューロパチーのrituximabによる治療を行う際に注意する必要がある．

症例は46歳男性．家族歴では，父が球脊髄性筋萎縮症，父方祖父がParkinson病（Parkinson disease；PD）である．38歳時に左手の震えを自覚し，その後左手が使いにくくなった．左上肢の安静・姿勢時振戦と運動緩慢，左上下肢の筋強剛があり，若年性PDと診断した．四肢のジストニアは認めなかった．ドパミンアゴニストとzonisamideを中心に投薬していたが，顕著な効果はみられなかった．rotigotineとzonisamideを投与中の発症4年後（43歳時）から，痛みを伴う頸部の後屈（retrocollis）が出現し，経皮鎮痛消炎薬を必要とした．44歳時のMIBG心筋シンチグラフィでは軽度の集積低下を認めた．PDでは様々な姿勢異常が知られており，特に若年発症PDでは足に出現するジストニアの報告が多い．頭頸部では首下がりが多くretrocollisの出現は極めて少ない．痛みを含め，quality of life（QOL）に影響をおよぼす場合もあり，積極的に注意を払う必要がある．