[The expected role of Dementia Support Doctors in dealing with complex cases of older people with dementia].

AIM: The present studyinvestigated the roles expected of Dementia Support Doctors (DSDs) in dealing with complex cases. METHODS: The participants were attendees of the education programs organised by the Center for Promoting Dementia Support and the Medical Center for Dementia at the Tokyo Metropolitan Geriatric Hospital from April 2021 to March 2022. A self-administered postal questionnaire survey was conducted. The questionnaire included items on the basic attributes of the participants, their experiences with the issues associated with complex cases, and role expectations of consulting/collaboration partners when dealing with complex cases. RESULTS: The valid response rate was 49.3%. DSDs were expected by primary physicians, Community General Support Center staff and administrative staff to diagnose dementia and give advice on support strategies for complex cases. Primary physicians further expected them to initiate pharmacotherapy with anti-dementia drugs and address the pharmacotherapy needs for managing Behavioral and Psychological Symptoms of Dementia. It was also found that DSDs' experience with complex cases was comparable to that of the staff at the Medical Centers for Dementia. Of note, DSDs were mentioned less frequently as consulting/collaboration partners than Medical Centers for Dementia and primary physicians. CONCLUSIONS: The study showed that DSDs play an important role in dealing with complex cases. The roles of DSDs and ways to collaborate with them need to be communicated through interprofessional education.

Exploratory study on the factors related with the early detection of missing older persons with dementia living alone in Japan.

AIM: To clarify the factors related to the early detection of missing older persons with dementia (PwD) who lived alone in Japan. METHODS: We carried out a multiple regression analysis with data from 88 missing PwD. RESULTS: The location of the discovery was within the municipality where the missing PwD lived. Furthermore, the use of long-term care insurance services was significantly associated with early detection. CONCLUSION: Missing PwD were located within the municipality in which they lived, which meant that the individual was found before they went far. In addition, with the long-term care insurance services, professionals should regularly visit the home of PwD according to a care plan. Planned regular visits might trigger the early recognition of a missing person with dementia and enable early search activities. Therefore, use of long-term care insurance services might lead to the early detection of missing PwD living alone. Geriatr Gerontol Int 2023; 23: 362-365.

Suppression of amyloid-ß secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid.

Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-ß (Aß) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aß in mouse neurons. CLA treatment did not affect the level of ß-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment, or Aß protein precursor (APP) in cultured neurons. BACE1 and γ-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aß generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic Aß in neurons.

GPR120 signaling controls amyloid-ß degrading activity of matrix metalloproteinases.

Alzheimer disease (AD) is characterized by the extensive deposition of amyloid-ß peptide (Aß) in the brain. Brain Aß level is regulated by a balance between Aß production and clearance. The clearance rate of Aß is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Aß clearance mechanisms affects the pathological process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Aß via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including ω3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Aß-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Aß-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120 specific antagonist substantially decreased the levels of Tris-buffered saline-soluble Aß in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Aß degrading activity of MMPs.SIGNIFICANT STATEMENTThe level of amyloid ß (Aß) in the brain is a crucial determinant of the development of Alzheimer disease. Here we found that astrocytes, which are the most abundant cell type in the central nervous system, harbors degrading activity against amyloid ß, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Aß-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Aß therapeutics.

Dietary cis-9, trans-11-conjugated linoleic acid reduces amyloid ß-protein accumulation and upregulates anti-inflammatory cytokines in an Alzheimer's disease mouse model.

Conjugated linoleic acid (CLA) is an isomer of linoleic acid (LA). The predominant dietary CLA is cis-9, trans-11-CLA (c-9, t-11-CLA), which constitutes up to ~ 90% of total CLA and is thought to be responsible for the positive health benefits associated with CLA. However, the effects of c-9, t-11-CLA on Alzheimer's disease (AD) remain to be elucidated. In this study, we investigated the effect of dietary intake of c-9, t-11-CLA on the pathogenesis of an AD mouse model. We found that c-9, t-11-CLA diet-fed AD model mice significantly exhibited (1) a decrease in amyloid-ß protein (Aß) levels in the hippocampus, (2) an increase in the number of microglia, and (3) an increase in the number of astrocytes expressing the anti-inflammatory cytokines, interleukin-10 and 19 (IL-10, IL-19), with no change in the total number of astrocytes. In addition, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatographic analysis revealed that the levels of lysophosphatidylcholine (LPC) containing c-9, t-11-CLA (CLA-LPC) and free c-9, t-11-CLA were significantly increased in the brain of c-9, t-11-CLA diet-fed mice. Thus, dietary c-9, t-11-CLA entered the brain and appeared to exhibit beneficial effects on AD, including a decrease in Aß levels and suppression of inflammation.

Relationship between pedestrian detection specifications of parking sensor and potential safety benefits.

Measures to protect vulnerable road users during low-speed maneuvers are required. For example, systems that use cameras to display the vehicle's rearview are popular. However, some vehicles are difficult to equip with a rear view camera system. To avoid a crash when driving in reverse, it is also effective to identify the presence of pedestrians via an audible warning using a device (e.g., clearance sonar). It may be cheaper to install than a rearview camera system. Installation cost is also important for the spread of equipment that reduces a crash. It is necessary to clarify the minimum specifications that balance cost and reduce crashes. Device specifications (e.g., detection distance and response delay) may affect the crash reduction rate. There should be a detection distance required for the sonar to have the same crash reduction effect as the rear view camera system. Thus, in this study, we conducted experiments and obtained data about how a vehicle moves and driver reactions to audible warnings when driving in reverse. Based on the acquired data, a numerical simulation was performed to determine whether a driver could avoid a crash under various circumstances. As a result, it was shown that the clearance sonar must have a detection distance of 0.8 m or more to expect the same effect as a rearview camera system. In other words, to expect sonar to have the same performance as a rearview camera, a detection distance of at least 0.8 m should be set as a specification.

Incidence and distribution of subtypes of early-onset dementia in Japan: A nationwide analysis based on annual performance reports of the Medical Centers for Dementia.

AIM: Investigating the incidence rate of early-onset dementia is challenging. We explored the incidence rate of early-onset dementia in Japan using annual performance reports from the Medical Centers for Dementia. METHODS: Medical Centers for Dementia are specialized health services for dementia established as part of Japan's national health program. There are 440 such centers nationwide as of 2018. Using the annual performance reports of these centers, we calculated the number of newly diagnosed cases of early-onset dementia or late-onset dementia from April 1, 2018 to March 31, 2019, and the composition ratio by diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The annual incidence rate of early-onset dementia was estimated using the number of cases as the numerator and the national population aged 18-64 years as the denominator. RESULTS: In total, 1733 of cases were diagnosed with early-onset dementia, of which 52.1% were diagnosed as major neurocognitive disorder due to Alzheimer's disease, 8.9% major frontotemporal neurocognitive disorder, 8.8% major vascular neurocognitive disorder, 7.1% substance/medication-induced major neurocognitive disorder, 6.5% major neurocognitive disorder with Lewy bodies and 3.9% major neurocognitive disorder due to another medical condition. The annual incidence rate of early-onset dementia was estimated to be 2.47/100 000 person-years. CONCLUSIONS: This study provides the first nationwide estimate of the incidence rate of early-onset dementia in Japan and suggests that Medical Centers for Dementia are important resources for the epidemiological monitoring of early-onset dementia nationwide. Geriatr Gerontol Int 2020; 20: 1050-1055..

Neuromuscular Activation Differences During Gait in Patients With Ehlers-Danlos Syndrome and Healthy Adults.

OBJECTIVE: Ehlers-Danlos syndrome (EDS) is a group of genetic disorders affecting connective tissue. Symptoms include joint and ligament laxity. The objectives of this study were to compare muscle activation, joint angles, and spatiotemporal parameters during gait, and to compare isometric strength between participants with EDS (hypermobility and classical subtypes) and healthy adults. METHODS: Participants with EDS (n = 14) and healthy adults (n = 14) were recruited for this cross-sectional study. Lower extremity muscle activation, sagittal joint angles, and spatiotemporal parameters during gait were measured using surface electromyography (EMG), motion capture, and force plates. Isometric strength of the lower extremity joints was measured with an isokinetic dynamometer. Important characteristics (principal components [PCs]) were determined from EMG and angle waveforms using PC analysis; relationships between PC scores and groups were examined using multilevel linear models after accounting for gait speed. Spatiotemporal parameters and strength were compared using independent t-tests and effect sizes (Cohen's d coefficient). RESULTS: The EDS group was associated with delayed vastus lateralis (b = 16.69) and medialis activation (b = 11.33), higher rectus femoris (b = 28.34) and tensor fascia latae activation (b = -11.06), prolonged gluteus medius activation (b = -32.78), and lower medial gastrocnemius activation (b = -27.18). Joint angles were similar between the EDS and healthy groups. The EDS group had slower gait speeds, shorter stride lengths, and a greater percentage of time in stance (d = -1.05 to 0.96). The EDS group had weaker hip and ankle muscles (d = -0.83 to -0.97). CONCLUSION: Alterations in muscle activation and spatiotemporal parameters during gait in patients with EDS may be a result of impaired proprioception and balance and muscle weakness. Interventions should target these deficits.

Pathological complete response after preoperative chemotherapy including FOLFOX plus bevacizumab for locally advanced rectal cancer: A case report and literature review.

BACKGROUND: In Japan, the significance and efficacy of preoperative chemotherapy alone for locally advanced rectal cancer remain controversial. This case report presents the apparent effectiveness of preoperative FOLFOX plus bevacizumab as shown by pathological complete response (pCR). Additionally, we review the relevant literature and discuss the clinical management of locally advanced rectal cancer with preoperative chemotherapy. CASE PRESENTATION: A 59-year-old male presented with severe constipation, bloody stool and a loss of 10% of his body weight over 3 months. Preoperative examination revealed locally advanced rectal cancer with extensive invasion of the bladder wall and enlarged regional lymph nodes. Thus, this lesion was assigned a preoperative classification of T4bN2bM0 stage IIIC according to the 8th Union for International Cancer Control (UICC) guidelines. Therefore, the patient initially underwent an external loop colostomy of the transverse colon. Next, the patient received chemotherapy including FOLFOX plus bevacizumab. After 12 cycles of chemotherapy, the tumor size was markedly decreased, and all lymph node metastases had disappeared. Therefore, the patient underwent conventional resection of the rectum with D3 lymph node dissection and closure of the colostomy. Histopathological analysis of the resected specimen revealed that all lesions were fibrotic and devoid of any viable cancer cells. Thus, this lesion was assigned a final classification of ypT0N0M0 stage 0. CONCLUSIONS: We present the rare case of a patient with surgically resected locally advanced rectal cancer who demonstrated an impressive pCR with preoperative chemotherapy, which included FOLFOX plus bevacizumab.

Exploratory research on outcomes for individuals missing through dementia wandering in Japan.

AIM: To clarify the factors related to outcomes of individuals missing through dementia wandering. METHODS: We carried out binary logistic regression analysis with 160 family members of missing persons (88 survivors, 72 decedents). RESULTS: Living alone at the point of going missing (OR 13.45, 95% CI 1.12-161.56), being found within the local area (OR 6.36, 95% CI 2.26-17.88), and a long period between going missing and being found (OR 6.14, 95% CI 3.14-12.00) were significantly related with death. CONCLUSIONS: Early detection of missing persons is essential in preventing dementia wandering-related deaths. The time taken to locate missing dementia patients who lived alone was longer, relative to that of those who lived with others, and this increased the risk of death. Furthermore, the locations where the deceased were located tended to be local, rather than distant areas. Geriatr Gerontol Int 2019; 19: 902-906.

Gastric adenocarcinoma of fundic gland mucosa type localized in the submucosa: A case report.

RATIONALE: Gastric adenocarcinoma of fundic gland type (GA-FG) is a new histological type of gastric cancer manifesting with differentiation into a fundic gland. Furthermore, gastric adenocarcinoma of fundic gland mucosa type (GA-FGM) is a tumor that shows differentiation into not only a fundic gland but also foveolar epithelium and a mucous gland. These tumors tend to invade the submucosal layer. However, no cases of these tumors being localized only in the submucosa have been reported. Here, we present a case of GA-FGM localized in the submucosa and describe the cytological features of this tumor. To our knowledge, this is the first reported case of GA-FGM localized in the submucosa. PATIENT CONCERNS: A man in his early 70s was referred to our institution because of the detection of a gastric submucosal tumor during a health checkup. DIAGNOSES: Gastric adenocarcinoma of fundic gland mucosa type. INTERVENTIONS: Endoscopic ultrasound-guided fine-needle aspiration (FNA), endoscopic submucosal dissection (ESD), and total gastrectomy with lymph node dissection were performed. OUTCOMES: The FNA specimen showed epithelial cells with low-grade atypia. In the ESD specimen, adenocarcinoma showing a gastric fundic gland mucosa-like morphology was observed. Immunohistochemical analysis showed positive staining for pepsinogen I, H+/K+-adenosine triphosphatase, MUC6, and MUC5AC and negative staining for MUC2 and CD10, indicating tumor differentiation into fundic gland mucosa. Therefore, the tumor was diagnosed as GA-FGM, with localization in the submucosal layer. Total gastrectomy and lymph node dissection were performed because of the positive margins of the ESD specimen. Neither residual tumor nor lymph node metastasis was detected; however, many foci of heterotopic gastric glands (HGGs) were observed in the gastric wall, suggesting that GA-FGM arose from an HGG. After treatment, no recurrence was observed during a 1-year follow-up period. LESSONS: Various tumors may arise from HGGs. Furthermore, when an FNA specimen shows gastric fundic gland mucosa-like epithelial cells with weak atypia, the possibility of GA-FG and GA-FGM should be considered.

Collision tumor consisting of a colorectal adenocarcinoma and dissemination of a gastric adenocarcinoma.

BACKGROUND: Collision tumors, composed of histologically distinct tumor types, are rare entities, especially in the colorectum, and corresponding evidence-based clinical management or treatment strategies are poorly defined. This is the first report of a collision tumor composed of two histologically distinct adenocarcinomas. CASE PRESENTATION: A 78-year-old male showed severe anemia and a 10% body weight loss over 1 month. Preoperative examination revealed T3N1M0 stage IIIA gastric cancer and T3N0M0 stage IIA rectal cancer. Distal gastrectomy and rectectomy with regional lymph node dissection were performed. Immunohistochemistry revealed two distinct adenocarcinomas with gland duct structures - a colorectal adenocarcinoma and a disseminated gastric adenocarcinoma - that had collided to form an invasive tumor on the serosal surface of the anterior rectum wall. CONCLUSION: This extremely rare case of a collision tumor supports that precise immunohistochemical identification of all tumor components is needed for guiding decisions affecting overall prognosis, adjuvant treatment and survival.

Assessing competence at a higher level among older adults: development of the Japan Science and Technology Agency Index of Competence (JST-IC).

BACKGROUND AND AIMS: Older adults' ever-improving health and changing lifestyles necessitate the development of a scale that can better measure their competence at a higher level. We developed the Japan Science and Technology Agency Index of Competence (JST-IC) via item analysis and assessed its psychometric properties. METHODS: Participants were 1306 community-dwelling older adults (623 men and 683 women, 74.0 ± 2.8 years old) who completed the 54-item draft JST-IC to determine their level of independence. Three procedures (including item selection, factor analyses, and reliability and validity analyses) were conducted to finalize the JST-IC and evaluate its psychometric properties. RESULTS: The item selection resulted in exclusion of 26 items for the following reasons: (a) 15 because of very high ratios (80% or more) of responders who answered "yes", (b) one because of gender differences (phi coefficient = 0.34), (c) five because of their weak association with the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) (Pearson correlation coefficient of 0.30 or smaller), and (d) five because of redundancy of meaning with other items. Through factor analyses, we selected 16 items with a four-factor solution for the final version. JST-IC score exhibited a near-normal distribution and significant gender and age differences, and had moderate correlations with size of social network and level of subjective well-being and strong correlations with TMIG-IC score, physical fitness, and health literacy. CONCLUSIONS: The JST-IC is useful for assessing competence at a higher level in community-dwelling older adults.

Dysregulated Metabolism of the Amyloid-ß Protein and Therapeutic Approaches in Alzheimer Disease.

Amyloid-ß protein (Aß) is the main component of senile plaques in the brains of Alzheimer disease (AD) patients. Aß is proteolytically derived from amyloid-ß precursor protein by ß- and γ-secretases. Secreted Aß is then eliminated from the central nervous system by multiple clearance mechanisms, including phagocytosis, immune responses, and proteolytic degradation. These dynamic metabolic processes, which are referred to as Aß economy, regulate steady-state brain Aß levels. Familial AD-linked genetic mutations augment the production and aggregation of Aß. In contrast, rare genetic variants that reduce Aß production were protective against AD. Moreover, decreased Aß clearance has been demonstrated in sporadic AD patients, suggesting that dysregulation of Aß economy contributes to the development of AD. Thus, several approaches to inhibit the production as well as to enhance the clearance of Aß have been investigated as potential therapeutics against AD. In this manuscript, we introduce the molecules and cellular mechanisms involved in the regulation of Aß economy and discuss the current understanding of these processes in the development of therapeutics against AD. J. Cell. Biochem. 118: 4183-4190, 2017. © 2017 Wiley Periodicals, Inc.

Enlarged mediastinal air cyst in a patient with bronchial diverticula localized in the left main bronchus: a case report with surgical and bronchoscopic findings.

BACKGROUND: A mediastinal air cyst is a rare computed tomography (CT) finding. Once the lesion is identified, it is difficult to diagnose and treat. Meanwhile, bronchial diverticula have been reported as a CT finding observed in certain pulmonary pathologic conditions. We encountered the case of an enlarged mediastinal air cyst accompanied with bronchial diverticula and upper lobe-dominant fibrous changes of the lung. CASE PRESENTATION: A 69-year-old man with a chronic cough who had regularly visited a chest physician for upper lobe-dominant pulmonary fibrosis was referred to our hospital for the examination of an enlarged mediastinal air cyst. Chest CT exhibited an air cyst (size, 30 mm) connected to the lumen of the left main bronchus (LMB) and multiple tiny outpouches only on the LMB. Flexible bronchoscopy showed bubbling from slits or indentations of the bronchial mucosa only in the LMB but not in the right main bronchus or lobar bronchus. For therapeutic diagnosis, we removed the air cyst. Based on clinical, surgical, and pathological findings, we diagnosed the air cyst as an enlarged bronchial diverticulum. CONCLUSIONS: This is the first case wherein bronchoscopic and surgical findings of bronchial diverticula and an enlarged bronchial diverticulum are reported. There are possible pathogenic mechanisms in cases of pulmonary disease that are attributable to enlargement of the bronchial diverticula.

Age-Related Renal Microvascular Changes: Evaluation by Three-Dimensional Digital Imaging of the Human Renal Microcirculation Using Virtual Microscopy.

The renal microvasculature is targeted during aging, sometimes producing chronic kidney disease (CKD). Overdiagnosis of CKD in older persons is concerning. To prevent it, a new concept of "healthy aging" is arising from a healthy renal donor study. We investigated the renal microcirculatory changes of three older persons and compared them with that of one patient with nephrosclerosis using a three-dimensional (3D) reconstruction technique that we previously developed. This method uses a virtual slide system and paraffin-embedded serial sections of surgical material that was double-immunostained by anti-CD34 and anti-α smooth muscle actin (SMA) antibodies for detecting endothelial cells and medial smooth muscle cells, respectively. In all cases, the 3D images proved that arteriosclerotic changes in large proximal interlobular arteries did not directly induce distal arterial change or glomerulosclerosis. The nephrosclerotic patient showed severe hyalinosis with luminal narrowing of small arteries directly inducing glomerulosclerosis. We also visualized an atubular glomerulus and intraglomerular dilatation of an afferent arteriole during healthy aging on the 3D image and showed that microcirculatory changes were responsible for them. Thus, we successfully visualized healthy aged kidneys on 3D images and confirmed the underlying pathology. This method has the ability to investigate renal microcirculatory damage during healthy aging.

A study on the mortality patterns of missing and deceased persons with dementia who died due to wandering.

AIM: To clarify the mortality patterns derived from differences in the causes of death and to subsequently promote search activity and prevent the death of missing persons. METHODS: The Ministry of Health, Labour and Welfare (MHLW) performed a mail survey using a self-administered questionnaire. The families of all 388 deceased dementia patients from among all of the missing persons reports involving dementia patients that were submitted to the police in 2013, and the 10,322 missing persons with dementia (or suspected cases) were the subjects of this survey. The survey was conducted from January 5 to February 2 in 2015. We analyzed the data provided by the MHLW on 61 cases in which the cause of death was recorded; the factors that were related to the differences in the causes of death were examined using a chi-squared test (Fisher's direct method) and a residual analysis. Based on previous studies, we classified the causes of death into three categories: "drowning," "hypothermia," and "others (e.g., traumatic injury, disease progression)." RESULTS: When the cause of death was hypothermia, death often occurred between three to four days from the time that the deceased individual went missing. A significantly higher number of patients who died of other causes were found to have died on the day that they went missing. More than 40% of the drowning cases occurred on the day that the deceased individual went missing. CONCLUSION: We identified 3 patterns of mortality: (1) death on the day that the deceased individual went missing due to traumatic injury, disease progression, drowning, and other causes; (2) death due to hypothermia within a few days after the deceased individual went missing; and (3) patterns other than (1) and (2).