Comparison of caregiver burden between dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: Caring for patients with dementia with Lewy bodies (DLB) would be more stressful for their caregivers than those with Alzheimer's disease (AD). In this study, we compared levels of caregiver burden and the possible influential factors on the caregiver burden between DLB and AD. METHODS: Ninety-three DLB patients and 500 AD patients were selected from the Kumamoto University Dementia Registry. Caregiver burden, neuropsychiatric symptoms, basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were assessed by the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI), the Neuropsychiatric Inventory (NPI), the Physical Self-Maintenance Scale (PSMS), and the Lawton IADL scale, respectively. RESULTS: Despite the comparable Mini-Mental State Examination score, the J-ZBI score was significantly higher in the DLB group than the AD group (P = 0.012). A stepwise multiple regression analysis revealed that IADL score (ß = -0.23, P = 0.049), PSMS score (ß = -0.31, P = 0.010), disinhibition (ß = 0.22, P = 0.008), and anxiety (ß = 0.19, P = 0.027) were significantly associated with J-ZBI score in DLB. In AD, caregiver's relationship with patient (child) (ß = 0.104, P = 0.005), caregiver's gender (female) (ß = 0.106, P = 0.004), IADL score (ß = -0.237, P < 0.001), irritability (ß = 0.183, P < 0.001), apathy (ß = 0.132, P = 0.001), agitation (ß = 0.118, P = 0.007), and aberrant motor behaviour (ß = 0.107, P = 0.010) were associated with caregiver burden. CONCLUSIONS: Caring for DLB patients caused a higher degree of caregiver burden than AD patients in the same level of cognitive decline. The factors responsible for the caregiver's burden were different between DLB and AD. The caregiver burden for DLB patients was associated with the disability of basic ADL, IADL impairment, anxiety and disinhibition.

Preservation of pelvic floor muscles contributes to early continence recovery after robot-assisted radical prostatectomy.

PURPOSE: Postoperative recovery of urinary continence has a great impact on quality of life for patients undergoing robot-assisted radical prostatectomy (RARP). A variety of surgical techniques including reconstruction of the periurethral structure have been introduced, and yet there are no effective methods that promote early urinary continence recovery after surgery. We hypothesized that the preservation of pelvic floor muscle structure could be responsible for early recovery of urinary continence after surgery. METHODS: A total of 94 consecutive patients who underwent RARP at our hospital were enrolled in this study. Operative video records were reviewed and the severity of pelvic floor muscle injury was classified according to the scoring system that we devised in this study. Briefly, damage of pelvic floor muscles was classified into 4 categories; intact, fascial injury, unilateral muscle injury, and bilateral muscle injury. The volume of urinary incontinence was measured for 2 days after removal of the urethral catheter, and the incontinence ratio (amount of incontinence/total volume of urine per day) was calculated. Predictive factors for immediate incontinence after catheter removal were identified by multivariate regression analysis. RESULTS: The severity of puboperineal muscle injury was significantly associated with the early incontinence ratio after catheter removal (p < 0.001). Age at surgery and severity of puboperineal muscle injury were independent predictors for early incontinence after catheter removal. CONCLUSION: Preservation of the pelvic floor muscle, particularly the puboperineal muscle is an important factor for early continence recovery after RARP.

Impact of age on the cerebrospinal fluid spaces: high-convexity and medial subarachnoid spaces decrease with age.

BACKGROUND: Impaired cerebrospinal fluid (CSF) dynamics may contribute to the pathophysiology of neurodegenerative diseases, and play a crucial role in brain health in older people; nonetheless, such age-related changes have not been well elucidated. Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a neuroimaging phenotype of idiopathic normal-pressure hydrocephalus, originating from impaired CSF dynamics, and closely associated with aging. This study aimed to investigate the pathophysiology of DESH and determine age-related changes in CSF dynamics. METHODS: Using magnetic resonance imaging, we investigated the pathophysiology of DESH by quantitatively evaluating the volumes of DESH-related regions (ventricles [VS], Sylvian fissure [SF], and subarachnoid spaces at high convexity and midline [SHM]) and brain parenchyma in community-dwelling individuals aged ≥ 65 years. DESH-related regions were assessed using a visual rating scale, and volumes measured using voxel-based morphometry. Brain parenchyma volumes were measured using FreeSurfer software. RESULTS: Data from 1,356 individuals were analyzed, and 25 (1.8%) individuals had DESH. Regarding the relationships between the volume of each CSF space and age, VS and SF volumes increased with age, whereas SHM volume did not increase. VS and SF volumes increased as the whole brain volume decreased, whereas SHM volume did not increase even if the whole brain volume decreased; that is, SHM did not expand even if brain atrophy progressed. Moreover, lower Mini-Mental State Examination scores were significantly associated with lower SHM volume and higher VS volume. These associations remained significant even when individuals with DESH were excluded. CONCLUSIONS: This study showed that the volume of high-convexity and medial subarachnoid spaces did not expand and tended to decrease with age; the human brain continuously progresses toward a "DESH-like" morphology with aging in community-dwelling older persons (i.e., DESH might be an "accelerated aging stage" rather than an "age-related disorder"). Our results indicated that brain atrophy may be associated with the development of "DESH-like" morphology. In addition, this morphological change, as well as brain atrophy, is an important condition associated with cognitive decline in older adults. Our findings highlight the importance of investigating the aging process of CSF dynamics in the human brain to preserve brain health in older people.

Late-manifestation of attention-deficit/hyperactivity disorder in older adults: an observational study.

BACKGROUND: The age of attention-deficit/hyperactivity disorder onset is usually during the first 12 years of life; however, there have been recent reports of late-onset attention-deficit/hyperactivity disorder. These reports have been limited to that of young adults, and details in older adults remain unknown. As such, we had previously presented the first case report of "very" late-onset attention-deficit/hyperactivity disorder, wherein the symptoms presented in senile age. In this observational study, we aimed to investigate the prevalence and clinical features of such attention-deficit/hyperactivity disorders in older adults visiting our dementia clinic. METHODS: Four hundred forty-six consecutive patients visiting our specialty outpatient clinic for dementia during the 2-year period from April 1, 2015 to March 31, 2017 were included in this study. First, the patients were examined for the presence or absence of dementia in our specialty outpatient clinic for dementia. Those not diagnosed with dementia were examined for the presence or absence of attention-deficit/hyperactivity disorder in our specialty outpatient clinic for developmental disorders. Finally, these patients who were diagnosed with attention-deficit/hyperactivity disorder were investigated in detail to clarify their clinical characteristics. RESULTS: Of 446 patients (246 women and 200 men), 7 patients were finally diagnosed with attention-deficit/hyperactivity disorder. Although these 7 patients were initially suspected to have Alzheimer's disease (considering their age, 6 of these 7 patients were suspected to have early onset Alzheimer's disease), it was found that these symptoms were due to attention-deficit/hyperactivity disorder. These patients had four characteristics in common: (1) they were significantly younger than the complete study population; (2) they predominantly showed inattention-related symptoms; (3) they showed latent manifestation; and (4) they experienced a stressful life event before manifestation. CONCLUSIONS: Our previous case report suggested that very late-onset attention-deficit/hyperactivity disorder patients could be incorrectly diagnosed with dementia. In this observational study, 1.6% of patients who were initially suspected of having dementia were actually diagnosed with attention-deficit/hyperactivity disorder. This study also showed that the "late-onset" described in our previous report would be better described as "late-manifestation." A clinician should consider late-manifestation of attention-deficit/hyperactivity disorder in the differential diagnosis when encountering dementia patients, especially early onset Alzheimer's disease.

[AUTOTRANSPLANTATION FOR IATROGENIC URETERAL INJURY FOLLOWING GYNECOLOGICAL SURGERY].

A 48-year-old woman underwent total hysterectomy and oophorectomy for uterine fibroids and bilateral ovarian cysts. Postoperatively, her renal function worsened, and the histological specimen contained ureteral tissue. She was referred to our department for left ureteral injury repair. An anterograde pyelogram revealed a ureteral defect, 9.5 cm in size. We considered ureteral bladder anastomosis to be complicated. She underwent kidney autotransplantation into her right iliac fossa to repair the ureteral injury. Six months after the operation, renal function was preserved, no hydronephrosis was observed by ultrasonography, and renal blood flow was good. Based on the literature on the difficulty of reconstructing ureteral injury, we developed an algorithm based on the length of ureteral injury.

Genomic analysis of circulating tumor cells in adenosquamous carcinoma of the prostate: a case report.

BACKGROUND: Adenosquamous carcinoma of the prostate (ASCP) is an extremely rare and aggressive prostate cancer variant, whose genomic characteristics have not been elucidated. Although liquid biopsy of circulating tumor cells (CTCs) is an emerging topic in oncology, no study has assessed CTCs in patients with ASCP. CASE PRESENTATION: A 76-year-old man presented with discomfort in his urethra. His prostate-specific antigen (PSA) level was 13.37 ng/mL. A computed tomography (CT) scan indicated a prostate mass with multiple lymph node and lung metastases. The patient underwent transurethral resection of the prostate and prostatic needle biopsy; both specimens demonstrated Gleason grade group 5 acinar adenocarcinoma of the prostate. Bone scintigraphy indicated bone metastasis in the ischium. Combined androgen blockade was implemented, and his serum PSA level rapidly decreased to 0.01 ng/mL. However, a CT scan 6 months after the initial diagnosis revealed worsening of the disease. The patient therefore underwent repeated prostatic needle biopsy; its specimen demonstrated prostatic adenocarcinoma together with squamous carcinoma components. As immunohistochemical analyses showed the tumor cells to be negative for CD56, chromogranin A, synaptophysin, and PSA, the definitive diagnosis was ASCP. Although the patient underwent chemotherapy (docetaxel and cabazitaxel), he died of the disease 3 months after the diagnosis of ASCP, or 13 months after the initial diagnosis of prostatic adenocarcinoma. His PSA values remained ≤ 0.2 ng/mL. CTCs from the patient's blood (collected before starting docetaxel) were analyzed and genomically assessed. It showed 5 cytokeratin (CK)+ CTCs, 14 CK- CTCs, and 8 CTC clusters, per 10 mL. Next-generation sequencing identified a total of 14 mutations in 8 oncogenes or tumor suppressor genes: PIK3CB, APC, CDKN2A, PTEN, BRCA2, RB1, TP53, and CDK12. Of 14 mutations, 9 (64%) were detected on CK- CTCs and 5 (36%) were detected on CK+ CTCs. CONCLUSIONS: This is the first report of CTC analysis and genomic assessment in ASCP. Although the prognosis of ASCP is dismal due to lack of effective treatment, genomic analysis of CTCs might lead to effective treatment options and improved survival.

Pigmented median raphe cyst of the penis that developed after middle age without infection or trauma history.

INTRODUCTION: Median raphe cysts are rare benign lesions of the male genitalia that can develop anywhere along the midline from meatus to anus. They are believed to be caused by a defect in closure of median raphe during embryonic development. These cysts commonly appear in childhood or adolescence, although some are diagnosed after middle age, typically triggered by infection or trauma. Pigmented median raphe cysts, or those containing melanin pigment and/or melanocytes, are extremely rare. CASE PRESENTATION: A 78-year-old man visited our hospital with a complaint of a penile mass that he first noticed in his 50s which slowly grew, eventually causing voiding difficulty. He had no history of infection or trauma. The lesion was excised, and the pathological diagnosis was pigmented median raphe cyst. CONCLUSION: We successfully treated a rare case of pigmented median raphe cyst of the penis that developed after middle age without infection or trauma history.

Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice.

Narcolepsy is caused by the loss of hypocretin (Hcrt) neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif) receptor 3 (CCR3) as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO) mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT) littermates. Intraperitoneal injection of lipopolysaccharide (LPS) promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.

Anti-Tribbles Pseudokinase 2 (TRIB2)-Immunization Modulates Hypocretin/Orexin Neuronal Functions.

Study Objectives: Recent findings showed that 16%-26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti-TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice. Methods: Plasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons. Results: TRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons. Conclusions: Our results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti-TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction.

Classifying eating-related problems among institutionalized people with dementia.

AIMS: Various eating-related problems are commonly observed among people with dementia, and these problems place a huge burden on the caregivers. An appropriate classification of these problems is important in order to understand their underlying mechanisms and to develop a therapeutic approach for managing them. The aim of this study was to develop a possible classification of eating-related problems and to reveal the background factors affecting each of these problems across various conditions causing dementia. METHODS: The participants were 208 institutionalized patients with a diagnosis of dementia. Care staff were asked to report all kinds of eating-related problems that they observed. After the nurses' responses were analyzed, 24 items relating to eating-related problems were extracted. A factor analysis of these 24 items was conducted, followed by a logistic regression analysis to investigate the independent variables that most affected each of the eating-related factors. RESULTS: Four factors were obtained. Factor 1 was overeating, factor 2 was swallowing problems, factor 3 was decrease in appetite, and factor 4 was obsession with food. Each factor was associated with different background variables, including Mini-Mental State Examination scores, Clinical Dementia Ratings, and neuropsychiatric symptoms. CONCLUSIONS: This study suggests that eating-related problems are common across conditions causing dementia and should be separately considered in order to understand their underlying mechanisms.

Hypocretin/orexin prevents recovery from sickness.

Sickness behavior is defined as states of lethargy, depression, anxiety, loss of appetite, hypersomnia, hyperalgesia, reduction of grooming and failure to concentrate that can be induced by inflammatory diseases, such as infections and cancer. Recent findings revealed that the lipopolysaccharide (LPS) injection causes lethargy as a consequence of the inhibition of hypocretin signaling. The hypocretin system maintains the vigilance state in various physiological processes. In order to investigate the sleep arousal system against sickness behavior, LPS-induced sickness behavior was examined in hypocretin-ataxin-3 transgenic mice, whose hypocretin neurons were postnatally ablated. Sleep-wake activity was determined following the administration of LPS at Zeitgeber time (ZT) 8.0 in ataxin-3 transgenic mice, and the age-, gender-matched wild-type littermates. LPS injection induced increases in non-rapid eye movement (REM) sleep in the matched wild-type littermates. In addition, a further increase in periods of sleep according to the loss of hypocretin neurons was identified in the ataxin-3 transgenic mice. A marked reduction of awakening during ZT12-ZT18 was observed as expected following LPS injection in the mouse lines. The increase in the period of non-REM sleep was not observed on the next day following LPS administration in either of the mouse lines. Complete recovery of physical activity was not observed in the matched wild-type littermates. Ataxin-3 transgenic mice recovered their physical activity to the same level as that on the first day before LPS administration. These results suggest the possibility that a faster recovery is the result of deeper resting according to the absence of hypocretin neurons, as ataxin-3 transgenic mice demonstrated more non-REM sleep.

Relationship between Dementia Severity and Behavioral and Psychological Symptoms of Dementia in Dementia with Lewy Bodies and Alzheimer's Disease Patients.

BACKGROUND/AIMS: Behavioral and psychological symptoms of dementia (BPSD) are common in the clinical manifestation of dementia. Although most patients with dementia exhibit some BPSD during the course of the illness, the association of BPSD with the stage of dementia remains unclear. It was the aim of this study to evaluate the impact of severity of dementia on the expression of BPSD in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: Ninety-seven patients with DLB and 393 patients with AD were recruited from 8 dementia clinics across Japan. BPSD were assessed by the Neuropsychiatric Inventory (NPI). A relationship between BPSD and dementia stage classified by the Clinical Dementia Rating (CDR) in each type of dementia was assessed. RESULTS: No significant difference was seen in NPI total score across CDR staging in the DLB group. On the other hand, the NPI total score significantly increased with dementia stage in the AD group. CONCLUSION: The relationship of dementia stage with the expression of BPSD was different according to the type of dementia. BPSD and dementia stage were correlated in AD subjects, in whom psychiatric symptoms increase as the disease progresses, but not in DLB subjects.

Investigation of CuGaSe2/CuInSe2 double heterojunction interfaces grown by molecular beam epitaxy.

In-situ reflection high-energy electron diffraction (RHEED) observation and X-ray diffraction measurements were performed on heterojunction interfaces of CuGaSe2/CnInSe2/CuGaSe2 grown on GaAs (001) using migration-enhanced epitaxy. The streaky RHEED pattern and persistent RHEED intensity oscillations caused by the alternate deposition of migration-enhanced epitaxy sequence are observed and the growths of smooth surfaces are confirmed. RHEED observation results also confirmed constituent material interdiffusion at the heterointerface. Cross-sectional transmission electron microscopy showed a flat and abrupt heterointerface when the substrate temperature is as low as 400 °C. These have been confirmed even by X-ray diffraction and photoluminescence measurements.

Relationship between dementia severity and behavioural and psychological symptoms in early-onset Alzheimer's disease.

BACKGROUND: The features of behavioural and psychological symptoms of dementia (BPSD) are influenced by dementia stage. In early-onset Alzheimer's disease (EOAD), the association between BPSD and dementia stage remains unclear because of the difficulty of recruiting subjects with a wide range of disease severity. We used a combination of community-based and hospital-based approaches to investigate the relationship between dementia severity and BPSD in EOAD patients. METHODS: Sixty-three consecutive EOAD outpatients and 29 EOAD patients from a community-based survey were divided into three dementia severity groups according to the Clinical Dementia Rating scale (CDR): mild (CDR 0.5-1, n = 55), moderate (CDR 2, n = 17), and severe (CDR 3, n = 20). BPSD were rated using the Neuropsychiatric Inventory. RESULTS: Scores of the Neuropsychiatric Inventory subscales agitation, euphoria, apathy, disinhibition, irritability, and aberrant motor behaviour increased significantly with increased dementia severity. Hallucinations were greater in the moderate group than in the mild group. For delusions, depression, and anxiety, no significant differences were observed among the three severity groups. CONCLUSIONS: The pattern of apathy, agitation, disinhibition, irritability, and aberrant motor behaviour worsening with severity progression in EOAD is similar to the pattern in late-onset Alzheimer's disease. In contrast, hallucinations, depression, and anxiety showed different patterns in EOAD.

Patient-related factors associated with depressive state in caregivers of patients with dementia at home.

OBJECTVES: To identify patient-related factors associated with depressive state in caregivers of patients with dementia, we investigated the caregivers' and patients' characteristics in relation to the depressive state in their caregivers. DESIGN: Prospective hospital-based cohort study. SETTING: Two memory clinics in Japan. PARTICIPANTS: Outpatients with dementia (n = 135) and their caregivers at home. MEASUREMENTS: The outpatients and their caregivers were divided into 2 groups according to the Center for Epidemiologic Studies Depression Scale for caregivers. To identify the patient-related factors that cause depressive state in caregivers, Mini-Mental State Examination (MMSE), the Physical Self-Maintenance Scale for fundamental activities of daily living (ADL), and the instrumental ADL scale (IADL) scores for instrumental ADL and the neuropsychiatric inventory (NPI) subscale score for behavioral and psychological symptoms of dementia were compared between the 2 groups. We used logistic regression to determine the independent predictors of caregiver depressive state. RESULTS: There was no significant difference in MMSE score between the 2 groups. Logistic regression analysis revealed that the depressive state in caregivers was related with IADL score and delusion in NPI subscale of patients. CONCLUSIONS: Depressive state in caregivers was independent of the decline in cognitive function in patients with dementia but was associated with decline in instrumental ADL and severity of delusion.

Acute enhancement of non-rapid eye movement sleep in rats after drinking water contaminated with cadmium chloride.

Cadmium (Cd) is a heavy metal widely used or effused by industries. Serious environmental Cd pollution has been reported over the past two centuries, whereas the mechanisms underlying Cd-mediated diseases are not fully understood. Interestingly, an increase in reactive oxygen species (ROS) after Cd exposure has been shown. Our group has demonstrated that sleep is triggered via accumulation of ROS during neuronal activities, and we thus hypothesize the involvement of Cd poisoning in sleep-wake irregularities. In the present study, we analyzed the effects of Cd intake (1-100 ppm CdCl2 in drinking water) on rats by monitoring sleep encephalograms and locomotor activities. The results demonstrated that 100 ppm CdCl2 administration for 28 h was sufficient to increase non-rapid-eye-movement (non-REM) sleep and reduce locomotor activities during the night (the rat active phase). In contrast, free-running locomotor rhythms under constant dim red light and their re-entrainment to 12:12-h light/dark cycles were intact under chronic (1 month) 100 ppm CdCl2 administrations, suggesting a limited influence on circadian clock movements at this dosage. The relative amount of oxidized glutathione increased in the brain after the 28-h 100 ppm CdCl2 administrations similar to the levels in cultured astrocytes receiving H2O2 or CdCl2 in culture medium. Therefore, we propose Cd-induced sleep as a consequence of oxidative stress. As oxidized glutathione is an endogenous sleep substance, we suggest that Cd rapidly induces sleepiness and influences activity performance by occupying intrinsic sleep-inducing mechanisms. In conclusion, we propose increased non-REM sleep during the active phase as an index of acute Cd exposure.

Efficacy of increasing donepezil in mild to moderate Alzheimer's disease patients who show a diminished response to 5 mg donepezil: a preliminary study.

BACKGROUND: With the recent approval of several new drugs, pharmacological management of Alzheimer's disease has become more complicated in Japan. The efficacy and safety of increasing the dose of donepezil to 10 mg daily were assessed in an open-label study of patients with mild to moderate Alzheimer's disease who were showing a diminished response to 5 mg daily. METHODS: The subjects included 27 patients with mild to moderate probable Alzheimer's disease whose primary caregivers had confirmed progression of symptoms during treatment with donepezil 5 mg daily. The dose of donepezil was increased to 10 mg daily, and the Alzheimer's disease assessment scale-cognitive subscale (Japanese version), Neuropsychiatric Inventory, and Zarit caregiver burden interview scores were compared before and after dose escalation. Adverse events were also investigated. RESULTS: Efficacy was evaluated in 24 patients; three dropped out because of adverse reactions. The Alzheimer's disease assessment scale score showed significant improvement after dose escalation of donepezil (P = 0.006). The total score of the Neuropsychiatric Inventory and the Zarit score showed no significant changes. However, the anxiety score of the Neuropsychiatric Inventory showed a significant increase (P = 0.028). Safety assessment revealed that the dropout rate was 11.1% and adverse reactions occurred in 40.7%. Nausea (29.6%) and loss of appetite (22.2%) were common adverse reactions. CONCLUSIONS: Because cognitive function showed improvement after increasing the dose of donepezil, the dosage of this drug should probably be adjusted based on the overall severity of Alzheimer's disease as well as the progression of cognitive dysfunction.

The usefulness of monitoring sleep talking for the diagnosis of Dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia. It is frequently difficult to differentiate DLB from Alzheimer's disease (AD) and other types of dementia. This study examined the usefulness of monitoring sleep talking for the diagnosis of DLB. METHODS: A total of 317 patients with dementia were selected from a consecutive series at the Dementia Clinic of Kumamoto University Hospital. Diagnostic categories consisted of probable DLB (n = 55), probable AD (n = 191), frontotemporal lobar degeneration (FTLD) (n = 16), vascular dementia (VaD) (n = 18), and other/unspecified dementia (n = 37). We evaluated sleep talking in all dementia patients and normal elderly subjects (n = 32) using an originally designed sleep talking questionnaire. RESULTS: Sleep talking occurred most frequently in the DLB group (61.8%), followed by the VaD group (33.3%), other/unspecified dementia group (27.0%), AD group (18.8%), FTLD group (12.5%), and normal elderly subjects group (6.3%). The prevalence of sleep talking in the DLB group was significantly higher than in other groups, except in the VaD group. The sleep talking yielded high specificity (81.2%) and some sensitivity (61.8%) for the differential diagnosis of DLB from AD. Furthermore, loud sleep talking may improve the specificity (96.9%). For the differentiation of DLB from all other dementia types, the specificity of sleep talking and loud sleep talking was also high (79.4% and 95.8% respectively). CONCLUSIONS: Assessing sleep talking, especially the volume of sleep talking, may be useful in the clinical discrimination of DLB from not only AD but also from all other types of dementia.

Association of cerebral small vessel disease with delusions in patients with Alzheimer's disease.

BACKGROUND: Cerebral small vessel disease (SVD) is frequently observed in patients with Alzheimer's disease (AD). However, the association between SVD and clinical symptoms exhibited by patients with AD remains unclear. This study examined the association of SVD as observed on magnetic resonance imaging (MRI) with behavioural and psychological symptoms of dementia and cognitive function of patients with probable AD. METHODS: A total of 163 consecutive patients (55 men, 108 women) with probable AD were included in this cross-sectional study of a prospective cohort. Patients were divided into two groups based on the presence or absence of cerebral SVD [white matter hyperintensities (WMH) grade 0/1 (Fazekas scale) and no lacunes: SVD absent, WMH grade 2/3 (Fazekas scale) or the number of lacunes ≥1: SVD present]. Cognitive functions were assessed using the Mini mental state examination, word recall and recognition subtests in the Alzheimer's Disease Assessment Scale-Cognitive Subscale, as well as the letter fluency task and the category fluency task. Psychiatric symptoms were rated according to Neuropsychiatric Inventory. RESULTS: Patients with probable AD with cerebral SVD had significantly more delusions and depression than those without SVD. No significant differences were observed in other neuropsychiatric symptoms, MMSE or word recall and recognition tests between both groups. CONCLUSIONS: Our results suggest that cerebral SVD observed on MRI of patients with AD is associated with delusions and depression.

First and second generation H1 histamine receptor antagonists produce different sleep-inducing profiles in rats.

First generation H1 histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H1 histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H1 histamine receptor antagonist which is more permeable to the brain than newer H1 histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H1 histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H1 histamine receptor antagonists may be mediated by H1 histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention.