発話障害が緩徐に進行する63歳女性の臨床経過・画像所見の検討

今回われわれは,発症4年目から6年間の経過を観察しえた原発性進行性失語(PPA)の1例を経験した.症例は63歳女性.55歳頃から言葉が出にくい,詰まる,速くしゃべれないことを自覚し,徐々に進行するため58歳時に当科を受診した.60歳時よりたどたどしい会話となり,電話では「外国の方ですか」と問われた.塩酸ドネペジルを処方されたが,その後も症状は進行し,電話番号を暗記できなくなったため,62歳時に当科へ入院した.発話は非流暢で,音韻性錯語が目立った.また,プロソディー障害,失文法,Foreign accent syndrome,アナルトリー障害を認めた.本例の発話障害の特徴と123I-IMP SPECT所見の検討から,縁上回病変による音韻障害と概念の音韻系列の実現障害が主体で,そこに中前頭回病変によるプロソディー障害,下前頭回病変による失文法とForeign accent syndrome,中心前回病変のアナルトリー障害が徐々に加わって進行していると考えた.本例では発症9年目の現時点でも意味システムが比較的保たれており,今後の経過が注目される.We report the case of a 62-year-old woman with primary progressive aphasia (PPA). We performed a 6-year follow-up assessment corresponding changes in magnetic resonance imaging (MRI) and ^I-IMP SPECT findings. Linguistic examination showed a severe impairment in repetition, as well as fluent spontaneous speech with phonemic paraphasia, anarthria, foreign accent syndrome and agraphia. Brain MRI showed very mild atrophy of the left frontal lobe, parietal lobe, and temporal lobes. ^I-IMP SPECT showed that the temporoparietal lobe was the most severely affected region. Key neuropsychological features in this case were impairments of the phonological system. We speculate that the characteristic feature of aphasia may result from dysfunction of the left supramarginal gyrus in this patient

大学病院もの忘れ外来に長期通院継続している軽度認知障害患者の特徴

　軽度認知機能障害（MCI）は認知症の前段階として注目されてきた．今回，認知機能低下のため当院もの忘れ外来を長期通院継続しているMCI 患者の特徴を把握し，MCI 患者の認知症への進展を予測する要因について検討した．対象は2003年４月～2017年４月に当科もの忘れ外来を受診した患者1,646人のうち，初診時Mini-Mental State Examination（MMSE）20/30以上ある40歳以上のMCI 患者125人．患者背景，神経心理検査，画像所見，薬物治療の有無を検討し，さらに，これらを認知機能維持群（MMSE の変化<5）と悪化群（MMSE の変化≧5）の2群に分けてその特徴を比較した．初診時平均年齢72.8±10.5歳，教育歴は平均11.1±2.1年，基礎疾患は高血圧症48.8%，糖尿病 23.2%，脂質異常症 47.2% と生活習慣病を併存している例が多かった．初診時の主訴が記憶障害であった例が92.8％と高かった．神経心理検査ではMMSE 24.2±2.8，長谷川式簡易知能評価スケール改訂版（HDS-R）22.5±3.8，Test Your Memory 日本語版一部改変（TYM-J川崎医大ヴァージョン；TYM-J）37.4±6.4であった．画像検査では，アルツハイマー病（AD）に特徴的な側頭頭頂連合野や後部帯状回の集積低下を認めた患者は41.6% に留まった．2017年４月の時点での臨床診断は，AD 69%，MCI 12% であった．認知機能維持群と悪化群での比較では，悪化群は初診後１年でMMSE, HDS-R ともに有意に低下した．MMSE，TYM-J 下位項目での比較では，１年後にMMSE で注意と計算，遅延再生で，TYM-J では知識と想起で減点が多かった．以上から，初診時にMCI と診断しても，受診１年間の認知機能の変化で，ある程度，認知症への進展を予想できるかもしれない．　Mild Cognitive Impairment (MCI) has drawn attention as the pre-stage of dementia. In the present study, we characterized the clinical features of MCI patients who were continuing long-term visits to our memory clinic and examine the factors predicting progression　to dementia. Among 1,646 patients who visited our memory clinic from April 2003 to April 2017, 125 MCI patients over the age of 40 years with a Mini-Mental State Examination (MMSE) score of 20 or more at the first visit were characterized by disease backgrounds, neuropsychological test data, and brain imaging findings. In addition, we examined factors that predict the prognosis between two groups categorized by whether cognitive function was maintained (decline in MMSE score <5) or deteriorated (decline in MMSE score ≥5) through observation for more than 5 years.　Many patients had lifestyle-related diseases including hypertension (48.8%), diabetes mellitus (23.2%), and dyslipidemia (47.2%) as underlying diseases. The average scores of the neuropsychological tests were 24.2±2.8 for MMSE, 22.5±3.8 for Hasegawa’s Dementia　Scale-Revised (HDS-R), and 37.4±6.4 for the Japanese version of Test Your Memory (TYM-J), respectively. A total of 41.6% of patients showed hypoperfusion in the temporoparietal or posterior cingulate areas, which is characteristic for Alzheimer’s disease. In comparison,　between the maintaining group and the deteriorating group, the cognitive function evaluated by MMSE and HDS-R significantly declined within 1 year after the first visit in the deteriorating group. Among subitems, the scores of attention, calculation, and delayed recall in MMSE, and knowledge and recall in TYM-J decreased.These results suggest that the risk of progression to dementia can be predicted by changes in the cognitive function at 1 year after the first visit to a memory clinic

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

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

頭部MRI上両側錐体路にT2高信号域を認めた脾静脈－腎静脈シャントによるAcquired hepatocerebral degeneration

患者は68歳女性．５か月前より徐々に動作緩慢や歩行障害が出現し当科を受診した．神経学的所見では，軽度の意識障害とasterixis を認め，左右差のない無動，痙固縮，下肢腱反射亢進，足クローヌスおよびバビンスキー徴候があった．頭部MRI 検査では，半卵円中心から内包後脚，および大脳脚にかけて拡散強調画像，T2強調画像，FLAIR 画像で高信号，T1強調画像で低信号の病変を認めた．採血ではアンモニア値が155 μg/dL と高値で，血清銅やセルロプラスミンは正常範囲内であった．脳波検査で基礎律動はθ波であったが，三相波は認められなかった．腹部造影CT 検査では，巨大な脾静脈－左腎静脈シャントを認め，Acquired hepatocerebral degenerationと診断した．蛋白制限食とラクツロース製剤内服を開始し，意識障害やパーキンソニズムなどの神経症状は改善し，アンモニア値は34 μg/dL と正常化したが，頭部MRI 病変の改善は認められなかった．本例は巨大脾腎シャントによるAcquired hepatocerebral degeneration（AHD）と考えられた．頭部MRIT2強調画像で両側錐体路に高信号病変を認めるAHD が散見され，文献的考察を含めて報告する．68-year-old woman was admitted to our hospital for five months’ episode of progressive gait disturbance and bradykinesia. Neurological examination showed a mild unconsciousness, asterixis, symmetrical akinesia, rigospasticity, hyperreflexia, foot clonus, and extensor toes. Brain MRI disclosed symmetrical hyperintense lesion on T2-weighted images in the centrum semiovale, posterior limb of internal capsule, and cerebral peduncle. The serum ammonia level was increased to 155 μg/dL, whereas the levels of serum copper and caeruloplasmin were normal. The electroencephalogram did not show triphasic wave. Abdominal contrast CT examination revealed a large splenorenal shunt between splenic vein and left renal vein. The patient was diagnosed as acquired hepatocerebral degeneration (AHD) caused by splenorenal shunt. A protein-restricted diet and lactulose preparations ameliorated neurological symptoms and normalized serum ammonia level to 34 μg/dL. However, the abnormalities in the brain MRI were unchanged after the treatment. We report the case an AHD patient who had an unique hyperintense pyramidal tract lesion on T2-weighted magnetic resonance images. Future studies are required to clarify underlying pathophysiological mechanisms causing pyramidal tract lesion

完全房室ブロックを合併した抗 signal recognition particle（SRP）抗体陽性ミオパチー

患者は70歳代前半女性．心不全で発症し，当院循環器内科で治療を受けた．心不全は利尿薬投与などで改善したが，CK 高値があり，その後に，首下がりや四肢近位筋筋力低下が出現進行したため，当科に入院した．右上腕二頭筋筋生検では，筋線維の大小不同，内部核の増加があり，壊死筋線維が多数みられたが，再生筋，myophagia や炎症細胞浸潤は軽度であった．抗体検査の結果と合わせ，抗signal recognition particle（SRP）抗体陽性ミオパチーと診断した．治療として，経口ステロイド療法を開始したが，治療開始17日目に失神発作を来たすようになった．心電図検査では完全房室ブロックであり，発作後３日目に永久ペースメーカー植え込み術を行った．経口ステロイド療法に加え，免疫グロブリン大量療法（IVIg 療法）を行ったところ，高CK 血症や頸部四肢筋力低下は徐々に改善した．抗SRP 抗体陽性ミオパチーの心合併症については，心伝導障害を含め，様々な議論があるが，これまでに完全房室ブロックを来たした報告はなく，貴重な症例と考えられた．A 70-year-old woman was admitted to our hospital owing to heart failure. She was treated and improved with diuretics. However, her serum CK values were persistently elevated throughout her hospitalization. She quickly developed head drop and showed muscle weakness, predominantly in the shoulders and pelvic girdles. A muscle biopsy from the right biceps brachialis revealed large variability in the myofiber size with many necrotic myofibers and few regenerative myofibers, as well as inflammatory cell infiltration. These findings combined with the immunological blood test led to a diagnosis of anti-SRP-positive myopathy, and she was treated with oral glucosteroids. However, she had frequent syncope attack 17 days after the beginning of treatment. Her ECG revealed complete atrioventral block, and she received a pacemaker implantation 3 days after the attack occurred. Her muscle weakness and hyperCKemia gradually improved by additional intravenous immunoglobulin treatment. The existence of cardiac complications of anti-SRP-positive inflammatory myopathy has been a matter of debate. Further extensive clinical observations will be required to clarify the clinical existence and the significance of anti-SRP antibodies on the pathogenesis of cardiac complications, including conduction block

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

Current status and problems of elderly drivers in our outpatient clinic

　当院では平成29年３月12日の道路交通法改正を踏まえて平成29年４月より，もの忘れ外来とは別に「運転免許外来」を新設し，時間をかけた丁寧な診療と告知，指導，運転免許返納後の生活確保・支援ができるよう，多職種で受診者に対応している．平成31年４月までの運転免許外来受診者は31人で，平均年齢80.07±3.91歳．第一分類該当者19人，交通違反での紹介３人で，その他は自発的な受診であった．10例は既に事故を起こし，６例は既に抗認知症薬を内服していた . 受診者のほとんどが，通院，買い物，農作業など運転中止後の生活が困るとの理由から，運転継続を希望した．神経心理検査では，MMSE-J 22.32/30±3.87, Kohs IQ 66.42±11.87, DASC-21 29.53±7.07, CDR 0.58±0.19と比較的認知機能低下が軽度な者が多かった．頭部 MRI では20例に陳旧性脳梗塞や脳挫傷，12例に脳萎縮を認め，123I-IMP 脳血流 SPECT では14例にアルツハイマー病を示唆する脳血流低下を認めた．診断後，全例に運転免許返納を推奨したが，自発的に運転中止に至った例は９例のみであった．かかりつけ医による診断書作成が普及し自主返納事例も増加したためか，当院の受診者数ならびに運転免許取り消し処分となる事例は外来開設当初の予想より少なかった．認知機能低下は認めるものの明らかな認知症に至っていない MCI 症例については，診断書提出後も運転継続している事例が多かった．運転継続希望者に丁寧に現制度の意義を説明し，移動手段の確保や生活支援について地域で相談できる体制作りが必要である．　Following the revision of the Road Traffic Act, which obligates elderly drivers to undergo cognitive screening tests at license renewal, we established a new outpatient memory clinic specializing in issues surrounding elderly drivers’ driver licenses. In this new outpatient clinic, we provide guidance and information about supporting resources for life after returning their driver’s licenses and the usual medical care and education. In the past two years, 31 patients, with an average age of 80.1±3.9 years, visited this clinic. Among these, 19 were referred to our clinic because of impaired cognition by screening test (the first classification), three were referred us for traffic violations and the others visited voluntarily. Among these 31 patients, ten had already experienced car accidents and six had already been prescribed cholinesterase inhibitors. Neuropsychological examination revealed mildly impaired cognitive function including MMSE-J 22.3±3.9, Kohs IQ 66.4±11.9, DASC-21 29.5±7.1 and CDR 0.58 ±0.19. Brain MRI revealed significant brain atrophy in 20 patients and brain contusions in 12. 123I-IMP SPECT showed decreased cerebral blood flow in 14 patients. Although driving is necessary for most patients to maintain activities of daily living and quality of life, we recommended all to stop driving based on the revised Road Traffic Act, which restricts driving by people with dementia. However, only nine patients suspended their driving and returned their licenses voluntarily; most MCI patients continued driving even after diagnosis. More effort is necessary to persuade patients of the significance of the current system, as is a social system that offers alternative means of transportation and supports patients in their lives in their local community

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