Taiki Kambe

Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3-positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long-term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice.

Posterior cortical atrophy with [11C] Pittsburgh compound B accumulation in the primary visual cortex

Sirs, Posterior cortical atrophy (PCA) is a presenile dementia that presents primarily with signs and symptoms of cortical visual dysfunction [1]. The most common associated pathologic findings of PCA are amyloid plaques and neurofibrillary tangles predominantly affecting the visual association areas [8]. Although [C] Pittsburgh compound B (PIB) PET studies of amnestic Alzheimer’s disease (AD) have been conducted [2, 3, 5], the link between amyloid-b (Ab) and regional brain dysfunction remains controversial. However, two PIB studies of PCA supported the possible link between Ab deposition and clinical features [7, 10]. Here, we describe a patient with PCA who showed left homonymous hemianopsia and uncoupling between PIB uptake and glucose metabolism in the right occipital lobe. A 63-year-old woman consulted our hospital with a 5-year history of poor vision. She first noticed that characters on posters appeared to be shaking. One year later, she found difficulty in reading subtitles in movies and then she became unable to read books. On neurological examination, she showed left homonymous hemianopsia. A Goldmann dynamic visual field examination demonstrated macular-sparing left homonymous hemianopsia. Visual acuity was normal and bilateral light reflexes were prompt. Other neurological examinations were normal. On neuropsychological evaluations, she showed visuospatial dysfunction and dyscalculia. MMSE score was 26 of 30. Memory function was preserved. She demonstrated disturbed recognition of superimposed figures. Face and color recognition were normal. Cerebrospinal fluid (CSF) Ab42 was decreased (297 pg/ ml) and in normal controls, the levels are 874 ± 293 pg/ml (mean ± SD, INNOTEST b-AMYLOID(1-42), Innogenetics, Ghent, Belgium). CSF tau protein phosphorylated at serine 199 was increased (1.36 pM). In normal controls, these levels are 0.6 ± 0.4 pM [4]. [F] fluorodeoxyglucose (FDG) PET image was acquired for 6 min starting 45 min after the injection of 150 MBq of tracer. The accumulation of [C] PIB was evaluated by a standardized uptake value ratio (SUVR) on a summing image obtained 40–60 min after injection of 500 MBq of tracer taking the cerebellar cortex as a reference region. [F] FDG PET showed hypometabolism in the temporo-parieto-occipital lobe predominantly on the right (Fig. 1d–f). [C] PIB PET demonstrated increased uptake in the bilateral frontal lobes and parietal and occipital cortices with more intense uptake on the right (Fig. 1g–i). In the right occipital lobe, FDG uptake showed lower metabolism in the lateral occipital cortex (Fig. 1d, e, arrow) than in the calcarine cortex (Fig. 1d, e, arrowhead). In contrast, amyloid imaging demonstrated high PIB uptake in the right calcarine cortex (Fig. 1g, h, arrowhhead) while the adjacent lateral occipital cortex showed normal PIB uptake (Fig. 1g, h, arrow). It was shown that macular sparing occurred when the posterior part of the calcarine cortex was spared in patients with striate cortical disease such as infarction, neoplasm and cerebromalacia, while macular splitting occurred when the occipital pole and operculum were involved [6]. Neuroimaging studies of our patient demonstrated that in the occipital lobe, there were two regions showing different T. Kambe Y. Motoi (&) N. Hattori Department of Neurology, Juntendo University School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo 113-8421, Japan e-mail: motoi@juntendo.ac.jp

Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice

Tauopathies differ in terms of the brain regions that are affected. In Alzheimers disease, basal forebrain and hippocampus are mainly involved, while frontotemporal lobar degeneration affects the frontal and temporal lobes and subcortical nuclei including striatum. Over 90% of human cases of tauopathies are sporadic, although the majority of established tau-transgenic mice have had mutations. This prompted us to establish transgenic mice expressing wild-type human tau (Tg601). Old (>14 months old) Tg601 mice displayed decreased anxiety in the elevated plus maze test and impaired place learning in the Morris water maze test. Immunoblotting of brain tissue identified that soluble tau multimer was increased with aging even though insoluble tau was not observed. In the striatum of old Tg601, the level of AT8- or AT180-positive tau was decreased compared with that of other regions, while PHF-1-positive tau levels remained equal. Phosphorylated tau-positive axonal dilations were present mainly in layers V and VI of the prefrontal cortex. Loss of synaptic dendritic spine and decreased immunohistochemical level of synaptic markers were observed in the nucleus accumbens. In vivo 2-[(18)F]fluoro-2-deoxy-d-glucose positron emission tomography analysis also showed decreased activity exclusively in the nucleus accumbens of living Tg601 mice. In Tg601 mice, the axonal transport defect in the prefrontal cortex-nucleus accumbens pathway may lead to decreased anxiety behavior. Differential distribution of hyperphosphorylated tau may cause region-specific neurodegeneration.

Vivid visual hallucinations manifested as the initial symptom in a patient with neurosyphilis.

Late neurosyphilis tends to affect the brain and spinal cord parenchyma, typically presenting as dementia, tabes dorsalis, general paresis, sensory ataxia, or bowel/ bladder dysfunction. We present a case of neurosyphilis with manifestations of vivid visual hallucinations as the initial symptom. Only later did the patient develop agitation, auditory hallucinations, and monopolizing conversation. In patients with neurosyphilis, auditory hallucinations are common, but visual hallucinations have rarely been reported.

Acute transient freezing of gait in a patient with posterior reversible encephalopathy syndrome

BackgroundPosterior reversible encephalopathy syndrome (PRES) is a transient clinical and neuroradiologic syndrome caused by cerebral vasogenic edema. Various reversible neurologic symptoms were shown in patients with PRES. Freezing of gait (FOG) is mainly observed in neurodegenerative diseases.Case presentationWe report a 43-year-old man, with undergoing hemodialysis therapy for chronic renal failure, had mild elevation of blood pressure. His consciousness level suddenly deteriorated, and brain MRI demonstrated hyperintense lesions in the bilateral basal ganglia on fluid-attenuated inversion recovery images, diffusion-weighted images, and apparent diffusion coefficient maps. After improvement of disturbance of consciousness, he showed FOG accompanied by bradykinesia and postural instability. His FOG spontaneously improved concurrently with alleviation of basal ganglionic lesions on follow-up MRI.ConclusionsIt is suggested that vasogenic edema on bilateral basal ganglia associated with PRES can cause acute transient FOG.

Recurrent Embolic Strokes Associated with Vertical Atlantoaxial Subluxation in a Patient with Rheumatoid Arthritis: A Case Report and Review of Literature

We report a 78-year-old woman with rheumatoid arthritis who developed recurrent embolic cerebellar strokes associated with vertical atlantoaxial subluxation (AAS). On contrast angiography, the bilateral vertebral arteries (VAs) were occluded between the C1 and C2 levels, and the distal parts of bilateral VA were supplied by the collateral circulations. Dynamic cerebral angiography and carotid duplex ultrasonography showed that blood flow was substantially decreased in the left VA and left posterior inferior cerebellar artery on cervical anteflexion. It is suggested that vertical AAS reduced the blood flow of collateral circulation in the left VA with cervical anteflexion and might be a cause of recurrent ischemic stroke.

Truncated tau causes microtubule disassembly with aging in tauopathy model mice

P4-045 TRUNCATED TAU CAUSES MICROTUBULE DISASSEMBLY WITH AGING IN TAUOPATHY MODEL MICE Shin-ei Matsumoto, Taiki Kambe, Yumiko Motoi, Koichi Ishiguro, Yukako Hasegawa, Takeshi Tabira, Fuyuki Kametani, Masato Hasegawa, Nobutaka Hattori, Juntendo University School of Medicine, Tokyo, Japan; Juntendo University School of Medicine, Tokyo, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Contact e-mail: shimatsu@juntendo.ac.jp

Tau and neurodegenerative disorders.

Abstract The mechanisms that render tau a toxic agent are still unclear, although increasing evidence supports the assertion that alterations of tau can directly cause neuronal degeneration. In addition, it is unclear whether neurodegeneration in various tauopathies occurs via a common mechanism or that specific differences exist. The aim of this review is to provide an overview of tauopathies from bench to bedside. The review begins with clinicopathological findings of familial and sporadic tauopathies. It includes a discussion of the similarities and differences between these two conditions. The second part concentrates on biochemical alterations of tau such as phosphorylation, truncation and acetylation. Although pathological phosphorylation of tau has been studied for many years, recently researchers have focused on the physiological role of tau during development. Finally, the review contains a summary of the significance of tauopathy model mice for research on neurofibrillary tangles, axonopathies, and synaptic alteration.