Bone marrow transplantation improves outcome in a mouse model of congenital muscular dystrophy

AbstractWe examined whether pathogenesis in dystrophin-deficient (mdx) mice and laminin-α2-deficient (dy) mice is ameliorated by bone marrow transplantation (BMT). Green fluorescent protein (GFP) mice were used as donors. In mdx mice, BMT failed to produce any significant differences in muscle pathology, although some GFP-positive fibers with restored dystrophin expression were observed. In contrast, in the dy mice, BMT led to a significant increase in lifespan and an increase in growth rate, muscle strength, and respiratory function. We conclude that BMT improved outcome in dy mice but not mdx mice

Social problems in daily life of patients with dementia

AIM: Most patients with dementia frequently encounter various problems in their daily lives. Those troubles embarrass both the patients and their families, and cause problems for society. However, there have been few scientific reports on the difficulties in the daily life of patients with dementia. Therefore, we tried to clarify the frequency and characteristics of troubles experienced by patients with dementia. METHODS: Seven medical centers treating dementia patients in Okayama Prefecture, Japan, participated in this survey. A total of 737 patients were placed in one of the three groups: a dementia group (n = 478), a mild cognitive impairment group (n = 199) and a control group (n = 60). The frequency of 13 difficulties was scored for each patient. RESULTS: Among normal participants, no person caused these problems once a year or more frequently. "Massive, recurrent buying" and "acts that risk causing a fire" were reported once a year or more for >10% of mild cognitive impairment patients. "Troubles with wealth management" and "troubles with money management" were the most frequent problems of dementia patients. CONCLUSIONS: Several problems are already sometimes encountered in patients with mild cognitive impairment. It would be useful to know which social difficulties are often seen in dementia patients in order to protect the safety of the patients. It is always difficult to balance respecting the autonomy of dementia patients and ensuring their safely

Development of sensory neuropathy in streptozotocin-induced diabetic mice.

Diabetic polyneuropathy is a major complication of diabetes and the most common cause of peripheral neuropathy. Sensory-dominant neuropathy is the most common type. We previously used streptozotocin (STZ)-induced diabetic ddY mice with sensory neuropathy to evaluate the therapeutic effects of vascular endothelial growth factor and placental growth factor isoforms. In this study, to characterize the development of diabetic sensory neuropathy, electrophysiological, behavioral, and histopathological studies were performed in these diabetic mice. A significant difference in sensory conduction velocity in the tail nerve was observed between healthy and diabetic mice at 1 week after STZ injection. Diabetic mice developed hypoalgesia at 5 weeks after STZ injection. Axon area and myelin thickness of the myelinated fibers were increased in 17-week-old healthy mice compared with those in 8-week-old healthy mice. However, these increases were retarded in 17-week-old diabetic mice. In unmyelinated fibers, axon area was significantly reduced in 17-week-old diabetic mice compared with 8- and 17-week-old healthy mice. These findings suggest that both impaired maturation of myelinated fibers and atrophy of unmyelinated fibers simultaneously occur in the early stage of diabetes in these mice. Our mouse model may be useful for studying the pathogenesis of and therapies for diabetic sensory neuropathy.Diabetic polyneuropathy is a major complication of diabetes and the most common cause of peripheral neuropathy. Sensory-dominant neuropathy is the most common type. We previously used streptozotocin (STZ)-induced diabetic ddY mice with sensory neuropathy to evaluate the therapeutic effects of vascular endothelial growth factor and placental growth factor isoforms. In this study, to characterize the development of diabetic sensory neuropathy, electrophysiological, behavioral, and histopathological studies were performed in these diabetic mice. A significant difference in sensory conduction velocity in the tail nerve was observed between healthy and diabetic mice at 1 week after STZ injection. Diabetic mice developed hypoalgesia at 5 weeks after STZ injection. Axon area and myelin thickness of the myelinated fibers were increased in 17-week-old healthy mice compared with those in 8-week-old healthy mice. However, these increases were retarded in 17-week-old diabetic mice. In unmyelinated fibers, axon area was significantly reduced in 17-week-old diabetic mice compared with 8- and 17-week-old healthy mice. These findings suggest that both impaired maturation of myelinated fibers and atrophy of unmyelinated fibers simultaneously occur in the early stage of diabetes in these mice. Our mouse model may be useful for studying the pathogenesis of and therapies for diabetic sensory neuropathy

Placental growth factor-2 gene transfer by electroporation restores diabetic sensory neuropathy in mice.

Placental growth factor-2 (PlGF-2) exhibits neurotrophic activity in dorsal root ganglion (DRG) neurons through the neuropilin-1 (NP-1) receptor in vitro. To examine the potential utility of PlGF-2 therapy for treating diabetic neuropathy, we performed intramuscular PlGF-2 gene transfer by electroporation, and examined its effects on sensory neuropathy in diabetic mice. PlGF-2 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia using a PlGF-2 plasmid injection with electroporation. The nociceptive threshold was measured using a paw-pressure test. In addition, we overexpressed PlGF-1, an isoform of PlGF that does not bind NP-1. The sciatic nerve and skin were examined 3weeks after PlGF-2 electro-gene transfer. The overexpression and secretion of PlGF-2 in TA muscles were confirmed by an increase in PlGF levels in TA muscles and plasma, and strongly PlGF positive myofibers in TA muscles. Two weeks after electro-gene transfer into the bilateral TA muscles, the previously elevated nociceptive threshold was found to be significantly decreased in all treated mice. PlGF-1 gene transfer by electroporation did not significantly decrease the nociceptive threshold in diabetic mice. No increase in the number of endoneurial vessels in the sciatic nerve was found in the PlGF-2 plasmid-electroporated mice. A reduction of area of immunoreactivity in epidermal nerves in diabetic mice was restored by PlGF-2 gene transfer. These findings suggest that PlGF-2 electro-gene therapy can significantly ameliorate sensory deficits (i.e. hypoalgesia) in diabetic mice through NP-1 in DRG and peripheral nerves.Placental growth factor-2 (PlGF-2) exhibits neurotrophic activity in dorsal root ganglion (DRG) neurons through the neuropilin-1 (NP-1) receptor in vitro. To examine the potential utility of PlGF-2 therapy for treating diabetic neuropathy, we performed intramuscular PlGF-2 gene transfer by electroporation, and examined its effects on sensory neuropathy in diabetic mice. PlGF-2 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia using a PlGF-2 plasmid injection with electroporation. The nociceptive threshold was measured using a paw-pressure test. In addition, we overexpressed PlGF-1, an isoform of PlGF that does not bind NP-1. The sciatic nerve and skin were examined 3weeks after PlGF-2 electro-gene transfer. The overexpression and secretion of PlGF-2 in TA muscles were confirmed by an increase in PlGF levels in TA muscles and plasma, and strongly PlGF positive myofibers in TA muscles. Two weeks after electro-gene transfer into the bilateral TA muscles, the previously elevated nociceptive threshold was found to be significantly decreased in all treated mice. PlGF-1 gene transfer by electroporation did not significantly decrease the nociceptive threshold in diabetic mice. No increase in the number of endoneurial vessels in the sciatic nerve was found in the PlGF-2 plasmid-electroporated mice. A reduction of area of immunoreactivity in epidermal nerves in diabetic mice was restored by PlGF-2 gene transfer. These findings suggest that PlGF-2 electro-gene therapy can significantly ameliorate sensory deficits (i.e. hypoalgesia) in diabetic mice through NP-1 in DRG and peripheral nerves

Relationship between BPSD and regional cortical volume in dementia

　認知症の症状，特に BPSD は罹患した本人のみならずその家族や周りの人の生活，QOL にも影響を与える．BPSD は中核症状と環境要因，身体要因，心理要因などの相互作用によって起こることが多く症状の軽重には個人差もあることからその発症予測は難しい．BPSD 発症に関わる神経基盤の理解とその発症リスク予測につながる客観的な指標の確立のための探索的検討として， BPSD の発症と脳の構造的変化との関連を検討する目的で，MRI データにおける大脳皮質の局所容積変化を BPSD 発症の有無で比較し，BPSD 発症に関連する脳領域の検討を行った．川崎医科大学附属病院脳神経内科ものわすれ外来を受診した患者20名（平均74.8歳，男性５名）を対象に年齢，性別，認知機能（MMSE-J，FAB），うつ（GDS-15-J），BPSD の程度（阿倍式 BPSD スコア： ABS）を用い，BPSD の有無（ABS：０vs１以上）によって患者を２群に分け患者背景，臨床指標評価を比較した．また同時期に測定した MRI 3DT1画像データを使用し，SPM12ソフトウェアを用いて患者の灰白質，白質，脳脊髄液領域を分離し，解剖学的標準化を行って灰白質容積の群間差を検討した．結果，年齢，性別，MMSE，FAB，GDS は両群間で有意差を認めなかった．灰白質容積の群間差の検討では，BPSD あり群では右中前頭回（BA6），右下前頭回三角部（BA45）の灰白質容積が有意に低下していた．BA6と BA45における ABS と灰白質容積にはそれぞれ負の相関があった．認知症患者の BPSD 発症が右前頭葉皮質の灰白質容積低下が関連している可能性が示唆された．先行研究により BA6は他者の意図を推察する心の理論課題に関与し，BA45の灰白質容積の低下は統合失調症患者における妄想や陽性症状との相関が示唆されている．今後 BPSD の発症予測や個別治療の可能性につながる重要な知見と考えられ，今後の研究の進展が期待される．　Symptoms of dementia, especially Behavioral and Psychological Symptom of Dementia (BPSD), affect the quality of life of not only patients but also family members and caregivers. Underlying mechanisms of BPSD is still unknown but multiple factors including cognitive impairments as well as environmental, physical, and psychological factors may cause BPSD and the severity of symptoms varies individually. In this study, we aimed to investigate the underlying neural mechanisms for emerging BPSD by comparing the regional volume change of the cerebral cortex in patients with or without BPSD to identify the cortical region critical for emerging BPSD. We evaluated 20 patients (average age 74.8, M5) who visited our memory clinic for their age, gender, cognitive function (MMSE-J, FAB), depression (GDS-15-J), and BPSD (ABS) degree. We divided patients into two groups according to the presence of BPSD (ABS: 0 vs 1 or higher) and background characteristics and clinical indicators were compared. Using 3DT1 image data acquired by 3-Tesla MRI apparatus, we segmented the patient’s brain into gray matter, white matter, and cerebrospinal fluid. After anatomical normalization, we conducted group-wise comparison between patients with and without BPSD to investigate cortical area associated with emerging BPSD. Patients’characteristics and baseline cognitive factiors including Age, sex, MMSE-J, FAB, and GDS-15-J showed no significant difference between the two groups. The gray matter volume of the right middle frontal gyrus (BA6) and the right lower frontal gyrus triangle (BA45) were significantly reduced in the patients with BPSD. Furthermore, in BA6 and BA45, there were negative correlation between severity of BPSD and gray matter volumes suggesting possible association between gray matter volume in the right frontal cortex and BPSD. Previous studies have shown that BA6 is associated with the Theory of Mind, and that a decrease in the gray matter volume of BA45 is correlated with delusions and positive symptoms in patients with schizophrenia. This is an important finding that leads to the prediction of the onset of BPSD and the possibility of individual treatment

Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study : randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process

Temporal dispersion in vasculitic neuropathy: its microscopic ultrastructural findings

　症例は35歳男性．32歳のときに右腓腹神経・足底神経支配領域の異常感覚で発症し，その後，左腓腹神経・足底神経領域，両側尺骨神経領域に感覚障害が拡大した．神経伝導検査では，左脛骨神経複合筋活電位において，時間的分散の所見が認められた．腓腹神経生検では，神経上膜にフィブリノイド壊死を伴う壊死性血管炎を認めた．エポン包埋トルイジン青染色では、有髄神経線維の脱落が著明であり，髄鞘の薄い再生軸索が認められた．電子顕微鏡による観察では，脱髄は認められず，軸索の再生が認められたが，髄鞘再生に乏しい thin myelin が特徴的であった．神経伝導検査で，伝導ブロックや時間的分散といった脱髄を疑う所見を呈する血管炎性ニューロパチーについて24例の報告があるが，これまで電子顕微鏡による観察はされていない．血管炎性ニューロパチーによって惹起される時間的分散の出現機序について，微細構造所見を基に考察する．　A previously healthy 35-year-old man developed abnormal sensation in the right sural and medial plantar nerve territory 2 years ago. The sensory impairment gradually spread to the left sural and medial plantar nerve regions, then bilateral ulnar nerve regions. Nerve conduction study showed temporal dispersion in the left tibial nerve. Sural nerve biopsy revealed necrotizing vasculitis with fibrinoid necrosis in the epineurium. Toluidine blue staining of Epon-embedded tissue showed significant loss of myelinated nerve fibers without demyelination, even in the teased nerve fiber preparations. Electron microscopy showed immature regenerated nerve fibers with thin myelin sheaths. Even including 24 reported cases of vasculitic neuropathy with either conduction block, pseudo-conduction block, or temporal dispersion, this is the first case examined by electron microscopy. Herein, we discuss the ultrastructural background of“temporal dispersion”in vasculitic neuropathy

Activin signaling as an emerging target for therapeutic interventions

After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-β, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-β ligands, and control the signaling and availability of ligands