Donepezil for dementia with Lewy bodies: meta-analysis of multicentre, randomised, double-blind, placebo-controlled phase II, III, and, IV studies.

BACKGROUND: Current evidence for the management of symptoms associated with dementia with Lewy bodies (DLB) using donepezil is limited. We conducted a meta-analysis of three randomised controlled trials of donepezil in patients with DLB to investigate the overall efficacy of donepezil on Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). METHODS: A meta-analysis was performed using the data of 312 patients administered placebo or 10 mg donepezil. Overall mean score differences for MMSE, NPI-2, and NPI-10 from baseline to week 12 and their 95% confidence intervals (CI) were estimated. For CIBIC-plus, which was transformed from a seven-point grade to a dichotomous outcome (improvements/no improvements), odds ratio (OR) and its 95% CI were estimated. Random-effects models were used, and heterogeneity was evaluated using the Cochrane's Q test and I2 statistic. RESULTS: Heterogeneity was suspected for NPI-2 (P < 0.05; I2 = 87.2%) and NPI-10 (P < 0.05; I2 = 67.7%) while it was not suspected for MMSE (P = 0.23; I2 = 32.4%) and CIBIC-plus (P = 0.26; I2 = 19.8%). The overall mean MMSE score difference (mean difference: 1.50; 95% CI, 0.67-2.34) and the overall odds of improving CIBIC-plus (OR: 2.20; 95% CI, 1.13-4.26) from baseline to week 12 were higher in the donepezil group than in the placebo group. CONCLUSION: Results of our meta-analysis indicated overall efficacy of donepezil on cognitive impairment and global clinical status in patients with DLB.

Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

[Symptomatology of Idiopathic Normal Pressure Hydrocephalus].

Idiopathic normal pressure hydrocephalus causes a triad of gait disturbance, dementia, and urinary incontinence in the elderly. All these symptoms may manifest as age-related functional decline or from neurological and non-neurological diseases common in the elderly. In idiopathic normal pressure hydrocephalus, characterized by ataxic-ataxic gait, subcortical dementia, and urge urinary incontinence, it is clinically important to consider these characteristic features. This overview describes the symptomatology of idiopathic normal pressure hydrocephalus.

Utility of the Japanese version of the Clinical Dementia Rating® plus National Alzheimer's Coordinating Centre Behaviour and Language Domains for sporadic cases of frontotemporal dementia in Japan.

BACKGROUND: We aimed to validate the Clinical Dementia Rating (CDR®) dementia staging instrument plus the National Alzheimer's Coordinating Centre Behaviour and Language Domains (CDR® plus NACC FTLD) for use in clinical settings in Japan and in the Japanese language. METHODS: This prospective observational study enrolled 29 patients with frontotemporal dementia (FTD) and 21 patients with Alzheimer's disease (AD) dementia from the Departments of Psychiatry at Osaka University Hospital and Asakayama General Hospital and the Brain Function Centre at Nippon Life Hospital. CDR® plus NACC FTLD, CDR®, Mini-Mental State Examination (MMSE), Western Aphasia Battery (WAB), Neuropsychiatric Inventory-plus (NPI-plus), Stereotypy Rating Inventory (SRI), and frontal behavioural symptom scores obtained from items of NPI-plus and SRI, were conducted to assess inter- and intra-rater reliability, validity, and responsiveness. We performed receiver operating characteristic (ROC) curve analysis to evaluate the discriminating power of the Behaviour/Comportment/Personality (BEHAV) and Language (LANG) domains of the CDR® plus NACC FTLD and the MEMORY domain of the CDR® in patients AD dementia and FTD. RESULTS: The CDR® plus NACC FTLD showed good inter- and intra-rater reliabilities. In patients with FTD, the BEHAV domain of the CDR® plus NACC FTLD was significantly correlated with all clinical measures except for the SRI total score, while the LANG domain of the CDR® plus NACC FTLD was significantly correlated with the MMSE and the WAB-Aphasia quotient. In addition, the CDR® plus NACC FTLD sum of boxes significantly changed after 6 months and after 1 year. ROC curve analysis showed that the BEHAV and LANG domains of the CDR® plus NACC FTLD distinguished between patients with AD dementia and FTD better than the MEMORY domain of the CDR®. CONCLUSIONS: This study validated the Japanese version of the CDR® plus NACC FTLD with good reliability, validity, and responsiveness.

Association of gait and cognition after surgery in patients with idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a treatable disease in older adults. The association between gait and cognition has recently become a topic of interest. Sequential changes in this association were investigated in patients with iNPH using a newly developed statistical method. Data were extracted from the SINPHONI-2 multicenter study on iNPH. Fifty patients who underwent shunt surgery were included in this study. Gait and cognition were assessed using the Timed Up and Go (TUG) and Mini-Mental State Examination (MMSE) tests. In addition to the MMSE total score, changes in the sub-item scores were examined. The ordinal sub-items of the MMSE are usually treated as continuous or categorical; however, both are unsuitable. An ordinal smoothing penalty with a generalized additive model enables precise statistical inference of ordinal and binary predictors. The TUG time improved significantly at 3, 6, and 12 months after surgery. The MMSE total scores increased without statistical significance. Preoperatively, there was no association between TUG time and MMSE sub-items. At 3 months, the "Registration," "3-step command," "Read," and "Copy" sub-items were statistically significant. The number of significant sub-items increased after 12 months. Thus, the association between gait and cognition gradually increased after surgery in patients with iNPH.

Behavioral and neural correlates of pareidolic illusions in dementia with Lewy bodies.

INTRODUCTION: Pareidolia, a form of visual illusions phenomenologically similar to complex visual hallucinations, is a phenomenon that is associated with visual hallucinations in dementia with Lewy bodies (DLB). This study aimed to identify commonalities and differences in behavioral and neural correlates between pareidolic illusions and visual hallucinations in DLB. METHODS: Forty-three patients with DLB underwent the scene pareidolia test, which evokes and measures pareidolic illusions, and standardized neuropsychological and behavioral assessments. Regional cerebral blood flow (rCBF) was measured by single-photon emission computed tomography. Factor analysis was performed to assess the relationships among pareidolic illusions, cognitive functions, and behavioral symptoms. Partial least squares correlation analysis was used to investigate the relationship between these symptoms and rCBF. RESULTS: Factor analysis yielded three behavior factors: the first factor (hallucinations/fluctuations) consisted of pareidolic illusions, visual hallucinations, and fluctuating cognition; the second factor (general cognitive function) consisted of general cognitive function and working memory; and the third factor (visual processing) consisted of visual processing and pareidolic illusions. Partial least squares correlation analysis identified two brain-behavior correlation patterns: (1) rCBF reduction in the frontal and perisylvian/periventricular regions was associated with lower general cognitive function and lower visual processing; and (2) rCBF reduction in the bilateral occipitotemporal cortex was associated with more severe hallucinations/fluctuations and lower visual processing. CONCLUSIONS: At the behavioral level, pareidolic illusions are associated with visual hallucinations, fluctuating cognition, and visual processing in DLB. At the neural level, pareidolic illusions may arise from the synergistic effects of global neuropathological changes and occipitotemporal cortical dysfunctions.

Efficacy of Adjunctive Therapy with Zonisamide Versus Increased Dose of Levodopa for Motor Symptoms in Patients with Dementia with Lewy Bodies: The Randomized, Controlled, Non-Inferiority DUEL Study.

BACKGROUND: In patients with dementia with Lewy bodies (DLB), it is unknown whether adjunct zonisamide is as effective and safe as increasing levodopa dose when levodopa has inadequate efficacy on parkinsonism. OBJECTIVE: To compare adjunct zonisamide 25 mg/day versus an increased levodopa dose (increased by 100 mg/day) in patients with DLB treated with levodopa ≤300 mg/day for parkinsonism. METHODS: The DUEL study was a multicenter, randomized, controlled, open-label, parallel-group, interventional, non-inferiority trial. During the observation period, levodopa was administered at ≤300 mg/day for 4 weeks. Subsequently, patients were randomized to receive adjunct zonisamide 25 mg/day or levodopa increased by 100 mg/day. RESULTS: Respective adjusted mean changes in MDS-UPDRS Part III total score at 16 and 24 weeks (primary endpoint) were -6.3 and -4.4 in the zonisamide add-on and -0.8 and 2.0 in the levodopa increase groups. The adjusted mean difference at 24 weeks was -6.4 (95% confidence interval [CI] -13.5, 0.7); the upper limit of the 95% CI (0.7) was lower than the non-inferiority margin (3.0). No significant between-group differences were observed in total scores of the MDS-UPDRS Part II, Eating Questionnaire, EuroQol-5 dimension-5 level, Zarit Caregiver Burden Interview, or other secondary endpoints. No notable between-group differences were observed in adverse event incidences. CONCLUSION: Adjunct zonisamide 25 mg/day may yield moderate improvement in motor symptoms in patients with DLB when the levodopa effect is insufficient, but it could not be verified that the zonisamide 25 mg/day was as effective as levodopa 100 mg/day because levodopa showed no sufficient efficacy as assumed.

Aphasic mild cognitive impairment in prodromal dementia with Lewy bodies.

Introduction: This study aimed to determine the characteristics of aphasic mild cognitive impairment (aphasic MCI), which is characterized by a progressive and relatively prominent language impairment compared with other cognitive impairments, in the prodromal phase of dementia with Lewy bodies (DLB). Methods: Of the 26 consecutive patients with aphasic MCI who had been prospectively recruited at our hospital, 8 patients were diagnosed with prodromal DLB and underwent language, neurological, neuropsychological, and neuroimaging (N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography; IMP-SPECT) testing. Three of these patients also underwent cholinesterase inhibitor therapy with donepezil. Results: In our aphasic MCI cohort, the clinical diagnosis of probable prodromal DLB accounted for more than 30% of cases; therefore, the presence of language impairment in prodromal DLB was not very uncommon. Five patients were diagnosed with progressive anomic aphasia and three with logopenic progressive aphasia. Anomic aphasia was characterized by apparent anomia but relatively preserved repetition and comprehension ability and logopenic progressive aphasia by anomia, phonemic paraphasia, and impaired repetition. IMP-SPECT revealed hypoperfusion of the temporal and parietal lobes in the left hemisphere in all but one patient. All patients who underwent cholinesterase inhibitor therapy with donepezil showed improvement in general cognitive function, including language function. Discussion: The clinical and imaging features of aphasic MCI in prodromal DLB are similar to those observed in Alzheimer's disease. Progressive fluent aphasia, such as progressive anomic aphasia and logopenic progressive aphasia, is one of the clinical presentations in prodromal state of DLB. Our findings provide further insight into the clinical spectrum of prodromal DLB and may contribute to the development of medication for progressive aphasia caused by cholinergic insufficiency.

EEG resting-state networks in Alzheimer's disease associated with clinical symptoms.

Alzheimer's disease (AD) is a progressive neuropsychiatric disease affecting many elderly people and is characterized by progressive cognitive impairment of memory, visuospatial, and executive functions. As the elderly population is growing, the number of AD patients is increasing considerably. There is currently growing interest in determining AD's cognitive dysfunction markers. We used exact low-resolution-brain-electromagnetic-tomography independent-component-analysis (eLORETA-ICA) to assess activities of five electroencephalography resting-state-networks (EEG-RSNs) in 90 drug-free AD patients and 11 drug-free patients with mild-cognitive-impairment due to AD (ADMCI). Compared to 147 healthy subjects, the AD/ADMCI patients showed significantly decreased activities in the memory network and occipital alpha activity, where the age difference between the AD/ADMCI and healthy groups was corrected by linear regression analysis. Furthermore, the age-corrected EEG-RSN activities showed correlations with cognitive function test scores in AD/ADMCI. In particular, decreased memory network activity showed correlations with worse total cognitive scores for both Mini-Mental-State-Examination (MMSE) and Alzheimer's Disease-Assessment-Scale-cognitive-component-Japanese version (ADAS-J cog) including worse sub-scores for orientation, registration, repetition, word recognition and ideational praxis. Our results indicate that AD affects specific EEG-RSNs and deteriorated network activity causes symptoms. Overall, eLORETA-ICA is a useful, non-invasive tool for assessing EEG-functional-network activities and provides better understanding of the neurophysiological mechanisms underlying the disease.

Cerebrospinal fluid amyloid beta and response of cognition to a tap test in idiopathic normal pressure hydrocephalus: a case-control study.

OBJECTIVES: To examine the relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and tap test response to elucidate the effects of comorbidity of AD in idiopathic normal-pressure hydrocephalus (iNPH). DESIGN: Case-control study. SETTING: Osaka University Hospital. PARTICIPANTS: Patients with possible iNPH underwent a CSF tap test. MEASUREMENTS: Concentrations of amyloid beta (Aß) 1-40, 1-42, and total tau in CSF were measured. The response of tap test was judged using Timed Up and Go test (TUG), 10-m reciprocation walking test (10MWT), Mini-Mental State Examination (MMSE), and iNPH grading scale. The ratio of Aß1-42 to Aß1-40 (Aß42/40 ratio) and total tau concentration was compared between tap test-negative (iNPH-nTT) and -positive (iNPH-pTT) patients. RESULTS: We identified 27 patients as iNPH-nTT and 81 as iNPH-pTT. Aß42/40 ratio was significantly lower (mean [SD] = 0.063 [0.026] vs. 0.083 [0.036], p = 0.008), and total tau in CSF was significantly higher (mean [SD] = 385.6 [237.2] vs. 293.6 [165.0], p = 0.028) in iNPH-nTT than in iNPH-pTT. Stepwise logistic regression analysis revealed that low Aß42/40 ratio was significantly associated with the negativity of the tap test. The response of cognition was significantly related to Aß42/40 ratio. The association between Aß42/40 ratio and tap test response, especially in cognition, remained after adjusting for disease duration and severity at baseline. CONCLUSIONS: A low CSF Aß42/40 ratio is associated with a poorer cognitive response, but not gait and urinary response, to a tap test in iNPH. Even if CSF biomarkers suggest AD comorbidity, treatment with iNPH may be effective for gait and urinary dysfunction.

Mirror writing and cortical hypometabolism in Parkinson's disease.

Mirror writing (MW) is the production of individual letters, words, or word strings in the reverse direction. Parkinson's disease (PD) is a progressive neurodegenerative disorder, and high MW rates have been reported in patients with PD. Thus, the present study sought to identify the factors that cause MW in patients with PD. We examined the frequency of MW in patients with PD and investigated the area of the brain where such frequency inversely correlates with reduced regional cerebral metabolic rates of glucose (rCMRglc). We also examined whether this area satisfied the motor and visual monitoring hypotheses of MW that have been presented in previous studies. Thirty-six subjects with idiopathic PD and 23 healthy controls were included in the study. We asked the participants to write down words, numerals, and sentences from left to right using their dominant and non-dominant hands. Patients with PD underwent an 18F-fluorodeoxyglucose positron emission tomography scan to measure the rCMRglc. Neither the patients with PD nor the healthy subjects exhibited MW in the use of the right hand. In the use of the left hand, MW occurred in 15 of the 36 patients with PD, but in none of the healthy controls. The right intraparietal sulcus was identified as the area where rCMRglc was inversely correlated with the number of left-right reversed characters. Previous functional imaging studies have suggested that the right superior parietal cortex and intraparietal sulcus play an important role in recognizing left-right reversed letters. Therefore, dysfunction in the intraparietal sulcus may hinder the recognition of left-right reversed characters, resulting in MW. Consequently, our findings in patients with PD are consistent with the visual-monitoring hypothesis of MW.

Risk factors for unfavourable outcomes after shunt surgery in patients with idiopathic normal-pressure hydrocephalus.

A number of vascular risk factors (VRFs) have been reported to be associated with idiopathic normal-pressure hydrocephalus (iNPH), but it remains unclear whether these VRFs are related to patient outcomes after shunt surgery. Therefore, we investigated the risk factors for unfavourable outcomes after shunt surgery in iNPH patients using two samples from Tohoku University Hospital and from a multicentre prospective trial of lumboperitoneal (LP) shunt surgery for patients with iNPH (SINPHONI-2). We enrolled 158 iNPH patients. We compared the prevalence of VRFs and clinical measures between patients with favourable and unfavourable outcomes and identified predictors of unfavourable outcomes using multivariate logistic regression analyses. The presence of hypertension, longer disease duration, more severe urinary dysfunction, and a lower Evans' index were predictors of unfavourable outcomes after shunt surgery. In addition, hypertension and longer disease duration were also predictors in patients with independent walking, and a lower Evans' index was the only predictor in patients who needed assistance to walk or could not walk. Our findings indicate that hypertension is the only VRF related to unfavourable outcomes after shunt surgery in iNPH patients. Larger-scale studies are needed to elucidate the reason why hypertension can affect the irreversibility of symptoms after shunt placement.

Effect of donepezil for dementia prevention in Parkinson's disease with severe hyposmia (The DASH-PD study): A randomized long-term placebo-controlled trial.

Background: Dementia greatly contributes to poor prognosis in patients with Parkinson's disease (PD). We previously reported that severe olfactory dysfunction may be a good predictor of Parkinson's disease dementia (PDD). In this trial, we investigated whether early administration of donepezil to patients with severe hyposmia can reduce the development of PDD. Methods: This was a multi-centre, randomized, double-blind, parallel group, placebo-controlled trial in patients with non-demented PD with severe hyposmia (The Donepezil Application for Severe Hyposmic Parkinson's Disease [DASH-PD] study). A total of 201 patients were randomly allocated to receive donepezil or placebo in addition to standard therapy for PD. Patients were followed up every 6 months until the onset of PDD or for a maximum of 4 years. The primary endpoint was the onset of dementia. The secondary endpoint was cognitive impairment measured by Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Clinical Dementia Rating (CDR).(UMIN000009958: February 2013 to May 2019). Findings: A total of 201 hyposmic patients with PD were randomly assigned to a treatment: 103 to donepezil and 98 to placebo. Overall, 141 (70%) patients completed the 4-year intervention. During follow-up, 7 of 103 (6.8%) patients in the donepezil group and 12 of 98 (12.2%) patients in the placebo group developed PDD; however, the hazard ratio of PDD incidence was not statistically significant (hazard ratio (HR), 0.609; 95% confidence interval, 0.240 to 1.547; p = 0.2969). At week 208, the patients in the donepezil group had better scores on the ACE-R (p < 0.005) and the CDR (p < 0.005) than those taking placebo. Interpretation: Administration of donepezil to PD patients with severe olfactory dysfunction for 4 years did not change the incidence of dementia but had a beneficial effect on neuropsychological function, with good tolerability. Funding: The Ministry of Health Labour and Welfare and the Japan Agency for Medical Research and Development provided funding for this study.

Impaired neuronal integrity in traumatic brain injury detected by 123I-iomazenil single photon emission computed tomography and MRI.

This study was aiming at investigating the extent of neuronal damage in cases of traumatic brain injury (TBI) with diffuse axonal injury (DAI) using 123I-iomazenil(IMZ) SPECT and MRI. We compared the findings in 31 patients with TBI without any major focal brain lesions and 25 age-matched normal controls. Subjects underwent 123I-IMZ SPECT and MRI, and also assessment by cognitive function tests. The partial volume effect of 123I-IMZ SPECT was corrected using MRI. In the patients with TBI, decreased spatial concentration of 123I-IMZ binding was detected in the medial frontal/orbitofrontal cortex, posterior cingulate gyrus, cuneus, precuneus, and superior region of the cerebellum. ROC analysis of 123I-IMZ SPECT for the detection of neuronal injury showed a high diagnostic ability of 123I-IMZ binding density for TBI in these areas. The decreased 123I-IMZ uptake density in the cuneus and precuneus was associated with cognitive decline after the injury. In the patients with TBI, brain atrophy was detected in the frontal lobe, anterior temporal and parietal cortex, corpus callosum, and posterior part of the cerebellum. Evaluation of the neuronal integrity by 123I-IMZ SPECT and MRI provides important information for the diagnosis and pathological interpretation in cases of TBI with DAI.

Unclassified fluent variants of primary progressive aphasia: distinction from semantic and logopenic variants.

Primary progressive aphasia, a neurodegenerative syndrome, presents mainly with language impairment. Both semantic and logopenic variants are fluent variants of primary progressive aphasia. Before the research criteria of primary progressive aphasia were proposed, progressive fluent aphasias, such as progressive anomic aphasia, transcortical sensory aphasia and Wernicke's aphasia, were reported as classical progressive fluent aphasias seen in Alzheimer's disease. However, since the research criteria of primary progressive aphasia were established, classical fluent variants (other than semantic and logopenic variants) have been neglected and have not been included in the current classification of primary progressive aphasia. This study aimed to determine whether unclassified fluent variants (other than semantic and logopenic variants) can be manifestations of primary progressive aphasia. This study also reconfirmed the characteristics of classical progressive fluent aphasia, such as progressive anomic aphasia, progressive transcortical sensory aphasia and progressive Wernicke's aphasia as unclassified fluent variants of primary progressive aphasia, using comparison with the current model of primary progressive aphasia. Twelve consecutive patients with an unclassified fluent variant other than semantic or logopenic variant underwent language, neurological, neuropsychological and neuroimaging (MRI and single-photon emission computed tomography) testing. Based on comprehensive language tests, we redefined the diagnoses as primary progressive anomic aphasia (n = 8), primary progressive transcortical sensory aphasia (n = 3) and primary progressive Wernicke's aphasia (n = 1). Anomic aphasia was characterized by anomia but preserved repetition and comprehension; transcortical sensory aphasia by relatively preserved repetition but poor word comprehension; and Wernicke's aphasia by poor repetition and word comprehension. In patients with anomic aphasia, voxel-based morphometry of MRI data revealed cortical atrophy, which was most prominent in the temporoparietal lobes, with no obvious lateralization; in two-thirds of patients with transcortical sensory aphasia and in one patient with Wernicke's aphasia, it revealed atrophy, predominantly in the left temporoparietal lobe. Statistical analysis of single-photon emission computed tomography using three-dimensional stereotactic surface projections revealed patterns of left-sided hypoperfusion in the majority of patients. The temporal and parietal lobes were involved in all cases; the degree of hypoperfusion was higher in patients with transcortical sensory aphasia or Wernicke's aphasia than in patients with anomic aphasia. The present study demonstrated the clinical and imaging features of 12 patients with an unclassified fluent variant of primary progressive aphasia, which we redefined as primary progressive anomic aphasia, primary progressive transcortical sensory aphasia and primary progressive Wernicke's aphasia. Classical fluent variants other than semantic and logopenic variants can be found in primary progressive aphasia.

The Role of the Ventromedial Prefrontal Cortex in Preferential Decisions for Own- and Other-Age Faces.

Own-age bias is a well-known bias reflecting the effects of age, and its role has been demonstrated, particularly, in face recognition. However, it remains unclear whether an own-age bias exists in facial impression formation. In the present study, we used three datasets from two published and one unpublished functional magnetic resonance imaging (fMRI) study that employed the same pleasantness rating task with fMRI scanning and preferential choice task after the fMRI to investigate whether healthy young and older participants showed own-age effects in face preference. Specifically, we employed a drift-diffusion model to elaborate the existence of own-age bias in the processes of preferential choice. The behavioral results showed higher rating scores and higher drift rate for young faces than for older faces, regardless of the ages of participants. We identified a young-age effect, but not an own-age effect. Neuroimaging results from aggregation analysis of the three datasets suggest a possibility that the ventromedial prefrontal cortex (vmPFC) was associated with evidence accumulation of own-age faces; however, no clear evidence was provided. Importantly, we found no age-related decline in the responsiveness of the vmPFC to subjective pleasantness of faces, and both young and older participants showed a contribution of the vmPFC to the parametric representation of the subjective value of face and functional coupling between the vmPFC and ventral visual area, which reflects face preference. These results suggest that the preferential choice of face is less susceptible to the own-age bias across the lifespan of individuals.

Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation.

BACKGROUND: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. METHODS: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. RESULTS: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). CONCLUSIONS: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

A prospective multicenter validation study of a machine learning algorithm classifier on quantitative electroencephalogram for differentiating between dementia with Lewy bodies and Alzheimer's dementia.

BACKGROUND AND PURPOSE: An early and accurate diagnosis of Dementia with Lewy bodies (DLB) is critical because treatments and prognosis of DLB are different from Alzheimer's disease (AD). This study was carried out in Japan to validate an Electroencephalography (EEG)-derived machine learning algorithm for discriminating DLB from AD which developed based on a database of EEG records from two different European countries. METHODS: In a prospective multicenter study, patients with probable DLB or with probable AD were enrolled in a 1:1 ratio. A continuous EEG segment of 150 seconds was recorded, and the EEG data was processed using MC-004, the EEG-based machine learning algorithm, with all clinical information blinded except for age and gender. RESULTS: Eighteen patients with probable DLB and 21 patients with probable AD were the included for the analysis. The performance of MC-004 differentiating probable DLB from probable AD was 72.2% (95% CI 46.5-90.3%) for sensitivity, 85.7% (63.7-97.0%) for specificity, and 79.5% (63.5-90.7%) for accuracy. When limiting to subjects taking ≤5 mg donepezil, the sensitivity was 83.3% (95% CI 51.6-97.9), the specificity 89.5% (66.9-98.7), and the accuracy 87.1% (70.2-96.4). CONCLUSIONS: MC-004, the EEG-based machine learning algorithm, was able to discriminate between DLB and AD with fairly high accuracy. MC-004 is a promising biomarker for DLB, and has the potential to improve the detection of DLB in a diagnostic process.

Bridging Therapy With Heparin Before Starting Rivaroxaban in Ischemic Stroke or Transient Ischemic Attack With Non-Valvular Atrial Fibrillation.

BACKGROUND: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant. CONCLUSIONS: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.