“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.

We report a female whose gait characteristics was analyzed using a three–dimensional motion analysis device in the exacerbation (three months after onset) and recovery (eight months after onset) periods. In the exacerbation period, she showed an increased dorsiflexion angle in the terminal stance and decreased dorsiflexion angle in the terminal swing in the ankle joints, increased extension angle in the stance phase in the knee joints, and increased extension angle in the terminal swing in the hip joints in association with muscle weakness. She also showed increased ankle plantar flexion moment, increased hip extension moment, and decreased knee extension moment. In the recovery period, she showed increases of all joint angles excluding the ankle dorsiflexion angle in the terminal swing, accompanied by an increase in the muscle strength. On the other hand, joint moments in the recovery period were similar to those in the exacerbation period.

Over a course of 4 years, the 74–year–old patient presented here experienced progressive loss of balance and of sensory function in the limbs. He was diagnosed with lymphoplasmacytic lymphoma and neuropathy caused by the presence of anti–myelin–associated glycoprotein (anti–MAG) antibody. He received a one dose of R–CHOP and four treatments of rituximab given once weekly. Two weeks after the initiation of chemotherapy, he developed weakness in all four extremities and difficulty in walking. Rituximab was discontinued, and intravenous immunoglobulin and methylprednisolone pulse therapies were initiated. His weakness improved gradually, and he regained his ability to walk without assistance 7 months after the discontinuation of rituximab. Although the mechanism of deterioration in this patient remains unknown, caution should be exercised when using rituximab in cases of anti–MAG neuropathy.

A 38–year–old man with a family history of spinal and bulbar muscular atrophy and Parkinson's disease (PD) in his father and grandfather respectively, developed tremor and clumsiness of his left hand. His diagnosis was given as young–onset PD with resting and postural tremor, clumsiness and muscular rigidity of his left side. The patient developed neck extension (retrocollis) with pain when he had been treated with rotigotine and zonisamide, after 4 years from onset of parkinsonism. An analgesic patch was used for reducing the pain. There are various postural abnormalities known to be disabling complications of PD. Dystonia of foot is a common feature among patients with young–onset PD however, retrocollis is extremely rare. Consequently, attention should be paid to the presentation of retrocollis since both the pain and progession of postural abnormalities could influence the patient's quality of life.