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.

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.

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.

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.

Echolalia in patients with primary progressive aphasia.

OBJECTIVE: This study aimed to examine echolalia and its related symptoms and brain lesions in primary progressive aphasia (PPA). METHODS: Forty-five patients with PPA were included: 19 nonfluent/agrammatic variant PPA (nfvPPA), 5 semantic variant PPA, 7 logopenic variant PPA, and 14 unclassified PPA patients. We detected echolalia in unstructured conversations. An evaluation of language function and the presence of parkinsonism, grasp reflex, imitation behaviour, and disinhibition were assessed. We also measured regional cerebral blood flow (rCBF) using single-photon emission computed tomography. RESULTS: Echolalia was observed in 12 nfvPPA and 2 unclassified PPA patients. All patients showed mitigated echolalia. We compared nfvPPA patients with echolalia (echolalia group) to those without echolalia (non-echolalia group). The median age of the echolalia group was significantly lower than that of the non-echolalia group, and the echolalia group showed a significantly worse auditory comprehension performance than the non-echolalia group. In contrast, the performance of repetition tasks was not different between the two groups. The prevalence of imitation behaviour in the echolalia group was significantly higher than that in the non-echolalia group. The rCBFs in the bilateral pre-supplementary motor area and bilateral middle cingulate cortex in the echolalia group were significantly lower than those in the non-echolalia group. CONCLUSIONS: These findings suggest that echolalia is characteristic of nfvPPA patients with impaired comprehension. Reduced inhibition of the medial frontal cortex with release activity of the anterior perisylvian area account for the emergence of echolalia.

ASPECTS-Region-Dependent Functional Outcomes after Endovascular Therapy in Patients with Cardioembolic Stroke.

OBJECTIVES: Cardioembolic stroke has a poor prognosis. We evaluated the region-dependent efficacy of endovascular therapy (EVT) based on diffusion-weighted imaging-Alberta Stroke Program Early CT Score (DWI-ASPECTS). METHODS: This post-hoc analysis of the RELAXED study, which investigated the optimal timing of rivaroxaban to prevent nonvalvular atrial fibrillation (NVAF) recurrence in patients with acute ischemic stroke (AIS), included NVAF patients admitted with AIS or transient ischemic attack in the middle cerebral artery (MCA), with internal carotid artery (ICA), M1, or M2-MCA occlusion. Relationships between DWI-ASPECTS region and functional outcome (modified Rankin Scale [mRS]), mortality, recurrence, and hemorrhagic stroke were compared between patients with and without EVT, and adjusted odds ratios for age, pre-stroke mRS, National Institutes of Health Stroke Scale (NIHSS), ICA occlusion, infarct size, recombinant tissue plasminogen activator (rt-PA) use, and onset-to-hospitalization time were estimated. RESULTS: EVT patients had significantly lower hemoglobin levels, higher median NIHSS scores, more lentiform nucleus infarcts, ICA or M1-MCA occlusions, treatment with rt-PA, and fewer M3, M5, or M6 infarcts and M2-MCA occlusions than no-EVT patients. EVT patients had shorter onset-to-hospitalization times and more frequent favorable functional outcomes (p=0.007). Mortality, recurrent ischemic stroke, and hemorrhagic infarction were similar in both groups. EVT was associated with significantly better functional outcomes among patients with insular ribbon (p=0.043) and M3 (p=0.0008) infarcts. M3 patients had significantly fewer rt-PA and EVT, and longer onset-to-hospitalization times. CONCLUSIONS: An occlusion in the insular ribbon or M3 region was associated with favorable functional outcomes in patients treated with EVT after cardioembolic stroke.

Sex Differences in Management and Outcomes of Cardioembolic Stroke: Post HOC Analyses of the RELAXED Study.

INTRODUCTION: Experimental models have clearly demonstrated sex differences in the pathophysiology of stroke and prognosis, however clinical evidence remains elusive. In this study, we examined sex differences as a post hoc analysis of RELAXED (Recurrent Embolism Lessened by rivaroxaban, an anti-X agent, of Early Dosing for acute IS and TIA with atrial fibrillation) Study. METHODS: We stratified study participants by sex and compared baseline and clinical characteristics as well as clinical outcomes. The primary outcome measure was a good outcome defined as a modified Rankin Scale score of 0-2 at 90 days after stroke. Secondary outcomes were mortality at 90 days, intracranial hemorrhage within 90 days, and recurrence of stroke or transient ischemic attack within 90 days. We constructed a logistic regression model to estimate the adjusted odds ratio of female patients compared with male patients for the primary and secondary outcomes. RESULTS: Of 1303 patients, most were male (57.7%) with a mean age of 74.5 years. Female patients were older with a mean age of 80.6 ± 8.9 years and had significantly less frequent anticoagulation therapy before onset of stroke and more severe NIHSS scores. Good outcome was observed in 51.2% and 63.3% of the females and males (p < 0.0001). The adjusted odds ratio of a good outcome in females was 1.12 (95% confidence interval, 0.44-2.87) (p = 0.81). There were no sex differences in secondary outcomes. CONCLUSION: Adjusted regression analysis found no sex difference in the treatment outcomes at 90 days after stroke with non-valvular atrial fibrillation.

Clinical and Cerebral Metabolic Changes in Parkinson's Disease With Basal Forebrain Atrophy.

BACKGROUND: Cholinergic dysfunction plays a key role in cognitive dysfunction in Parkinson's disease (PD). Recent studies revealed that atrophy in the nucleus basalis of Meynert (NBM), the largest cholinergic nucleus in the basal forebrain, heralds cognitive decline in PD. Despite clinical importance of NBM atrophy in PD, clinical and radiological correlates of NBM atrophy remains to be elucidated. OBJECTIVE: We investigated the longitudinal changes in clinical and cerebral glucose metabolic characteristics in PD with atrophy in the NBM. METHODS: We analyzed the 3-year longitudinal data of 56 PD patients who underwent motor, nonmotor, and imaging evaluations at baseline. The patients were classified into PD with and without NBM atrophy based on the results of magnetic resonance imaging volumetry. We compared clinical characteristics and cerebral glucose metabolic changes between PD with and without NBM atrophy. RESULTS: At baseline, 20 patients and 36 patients were classified into PD with and without NBM atrophy groups, respectively. At follow-up, the data of the 14 PD patients in the NBM atrophy group and the 18 patients in the group without NBM atrophy completed full assessments and were available for the analysis. The PD with NBM atrophy group showed severe cognitive dysfunction and psychiatric symptoms both at baseline and follow-up. The NBM volume significantly correlated with motor and nonmotor functions. The PD with NBM atrophy showed significantly reduced metabolism in the parietal and occipital cortices both at baseline and follow-up. CONCLUSIONS: Basal forebrain atrophy is a simple and sensible marker of faster disease progression and cortical hypometabolism in PD. © 2020 International Parkinson and Movement Disorder Society.

Logopenic progressive aphasia with neologisms: a case report.

BACKGROUND: Neologisms are commonly encountered in patients with acute cerebrovascular diseases, particularly in those with Wernicke's aphasia. However, few studies have investigated primary progressive aphasia with neologisms in neurodegenerative disease. CASE PRESENTATION: We describe the case of a 74-year-old, right-handed man who developed logopenic progressive aphasia (LPA) with neologisms. He was assessed with neuropsychological tests, magnetic resonance imaging, and single-photon emission computed tomography. Neologisms accounted for a relatively large portion of the paraphasic errors in the naming tests performed during the neuropsychological assessment. He had all the diagnostic features of LPA. Notably, the unique feature of this patient was the presentation of neologisms, which are seldom observed in typical LPA. CONCLUSIONS: Neologisms are considered rare symptoms in patients with early-stage LPA. Our findings in this case report provide new insights into the spectrum of clinical features in LPA.

123I-MIBG myocardial scintigraphy for the diagnosis of DLB: a multicentre 3-year follow-up study.

BACKGROUND AND PURPOSE: We previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD. METHODS: We undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline. RESULTS: Sixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline. CONCLUSIONS: Our follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested. TRIAL REGISTRATION NUMBER: UMIN00003419.

Sentence composition ability in two patients with non-fluent/agrammatic variant primary progressive aphasia.

Agrammatism is one of the core clinical features of non-fluent/agrammatic variant primary progressive aphasia, and it has traditionally been considered the hallmark of non-fluent aphasia in Western countries. However, agrammatic speech may remain undetected in Japanese patients because of the agglutinative structure of the language and high flexibility in word order. In the present study, we aimed to analyze agrammatism in the speech production of Japanese patients with aphasia due to neurodegenerative disease using an anagram test generated by our laboratory. Four patients were recruited from the dementia clinic at Tohoku University Hospital between December 2014 and August 2015: two patients with non-fluent/agrammatic variant primary progressive aphasia, one with semantic variant primary progressive aphasia, and one with probable Alzheimer's disease experiencing episodic memory impairment accompanied by transcortical sensory aphasia. All patients underwent thorough neurological and neuropsychological testing before performing a Japanese anagram task based on the Northwestern Anagram Test. Our findings indicated that the two patients with non-fluent/agrammatic variant primary progressive aphasia exhibited poorer performance on the anagram task than the remaining two patients. Therefore, the anagram test used in the present study may aid in detecting output aspects of agrammatism in Japanese patients with aphasia, although future studies are required to develop a standardized version of test.

Deconstructing psychosis and misperception symptoms in Parkinson's disease.

OBJECTIVE: Patients with Lewy body disease develop a variety of psychotic and misperception symptoms, including visual hallucinations and delusions, as well as 'minor hallucinations', that is, a sense of presence, passage hallucinations and visual illusions. Although these symptoms have been suggested to have common underlying mechanisms, the commonalities and differences among them have not been systematically investigated at the neural level. METHODS: Sixty-seven patients with Parkinson's disease underwent neuropsychological and behavioural assessments, volumetric MRI and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). A factor analysis was performed to discover correlations among psychotic and misperception symptoms, other behavioural symptoms and neuropsychological performances. Partial least-squares correlation analysis was used to investigate the relationship between these symptoms and the joint features of MRI and FDG-PET. RESULTS: A sense of presence, passage hallucinations and visual illusions constituted a single behavioural factor (minor hallucinations/illusions). Visual hallucinations formed another behavioural factor along with delusions, depression and fluctuating cognition (psychosis/dysphoria). Three distinct brain-behaviour correlation patterns were identified: (1) posterior cortical atrophy/hypometabolism associated with minor hallucinations/illusions and visuospatial impairment; (2) upper brainstem and thalamic atrophy/hypometabolism associated with psychosis/dysphoria and (3) frontal cortical atrophy/hypometabolism associated with non-visual cognition. No significant differences in neuroimaging findings were identified between patients who had minor hallucinations/illusions alone and patients who also had visual hallucinations. CONCLUSIONS: Our findings suggest that combined damage to the upper brainstem/thalamus and the posterior neocortex underlies both minor hallucinations/illusions and visual hallucinations and that the former pathology is more associated with visual hallucinations/frank psychosis and the latter is more associated with minor hallucinations/illusions.

Sleep disturbances are key symptoms of very early stage Alzheimer disease with behavioral and psychological symptoms: a Japan multi-center cross-sectional study (J-BIRD).

BACKGROUND: Sleep disturbances in Alzheimer disease (AD) may affect behavioral and psychological symptoms of dementia (BPSD). Our aim was to elucidate the associations between sleep disturbances and other BPSD at different stages of AD. METHODS: This investigation was part of a multicenter-retrospective study in Japan (J-BIRD). Eligible for final analyses were 684 AD patients. Global severity of dementia was estimated using the Clinical Dementia Rating (CDR) scale. BPSD were assessed using the Neuropsychiatric Inventory (NPI). We analyzed the relationships between sleep disturbances and BPSD at different stages of AD according to the CDR score. RESULTS: Among the 684 AD patients, 146 (21.3%) had sleep disturbances. Patients with very early AD (CDR 0.5) and sleep disturbances had significantly more BPSD than those without sleep disturbances, as indicated by the higher prevalence of the following four NPI items: anxiety, euphoria, disinhibition, and aberrant motor behavior. In AD at CDR 2, (moderate AD) only one NPI item (irritability) was affected, while none was affected at CDR 1 (mild AD) and 3 (severe AD). Multiple regression analyses were performed in those with AD having various CDR scores. At CDR 0.5, the presence of sleep disturbances was associated with a high total NPI score (ß = 0.32, p < 0.001). However, other factors, including cognitive decline, age, gender, and years of education, were not significantly associated with the NPI score. At CDR 1 and 2, no factor was significantly related to BPSD. CONCLUSION: Sleep disturbances were strongly associated with other BPSD in the very early stage of AD. Copyright © 2016 John Wiley & Sons, Ltd.

Cost-effectiveness analysis of shunt surgery for idiopathic normal pressure hydrocephalus based on the SINPHONI and SINPHONI-2 trials.

BACKGROUND: We showed that ventriculoperitoneal (VP) shunt and lumboperitoneal (LP) shunt surgeries are beneficial for patients with idiopathic normal pressure hydrocephalus (iNPH) in the Study of Idiopathic Normal Pressure Hydrocephalus on Neurological Improvement (SINPHONI; a multicenter prospective cohort study) and in SINPHONI-2 (a multicenter randomized trial). Although therapeutic efficacy is important, cost-effectiveness analysis is equally valuable. METHODS: Using both a set of assumptions and using the data from SINPHONI and SINPHONI-2, we estimated the total cost of treatment for iNPH, which consists of medical expenses (e.g., operation fees) and costs to the long-term care insurance system (LCIS) in Japan. Regarding the natural course of iNPH patients, 10% or 20% of patients on each modified Rankin Scale (mRS) show aggravation (aggravation rate: 10% or 20%) every 3 months if the patients do not undergo shunt surgery, as described in a previous report. We performed cost-effectiveness analyses for the various scenarios, calculating the quality-adjusted life year (QALY) and the incremental cost-effective ratio (ICER). Then, based on the definition provided by a previous report, we assessed the cost-effectiveness of shunt surgery for iNPH. RESULTS: In the first year after shunt surgery, the ICER of VP shunt varies from 29,934 to 40,742 USD (aggravation rate 10% and 20%, respectively) and the ICER of LP shunt varies from 58,346 to 80,392 USD (aggravation rate 10% and 20%, respectively), which indicates that the shunt surgery for iNPH is a cost-effective treatment. In the 2nd postoperative year, the cost to the LCIS will continue to decrease because of the lasting improvement of the symptoms due to the surgery. The total cost for iNPH patients will show a positive return on investment in as soon as 18 months (VP) and 21 months (LP), indicating that shunt surgery for iNPH is a cost-effective treatment. CONCLUSIONS: Because the total cost for iNPH patients will show a positive return on investment within 2 years, shunt surgery for iNPH is a cost-effective treatment and therefore recommended. The SINPHONI-2 study was registered with the University Hospital Medical Information Network Clinical Trials registry: UMIN000002730) SINPHONI was registered with ClinicalTrials.gov, no. NCT00221091.

Damage to the Left Precentral Gyrus Is Associated With Apraxia of Speech in Acute Stroke.

BACKGROUND AND PURPOSE: Apraxia of speech (AOS) is a motor speech disorder, which is clinically characterized by the combination of phonemic segmental changes and articulatory distortions. AOS has been believed to arise from impairment in motor speech planning/programming and differentiated from both aphasia and dysarthria. The brain regions associated with AOS are still a matter of debate. The aim of this study was to address this issue in a large number of consecutive acute ischemic stroke patients. METHODS: We retrospectively studied 136 patients with isolated nonlacunar infarcts in the left middle cerebral artery territory (70.5±12.9 years old, 79 males). In accordance with speech and language assessments, the patients were classified into the following groups: pure form of AOS (pure AOS), AOS with aphasia (AOS-aphasia), and without AOS (non-AOS). Voxel-based lesion-symptom mapping analysis was performed on T2-weighted images or fluid-attenuated inversion recovery images. Using the Liebermeister method, group-wise comparisons were made between the all AOS (pure AOS plus AOS-aphasia) and non-AOS, pure AOS and non-AOS, AOS-aphasia and non-AOS, and pure AOS and AOS-aphasia groups. RESULTS: Of the 136 patients, 22 patients were diagnosed with AOS (7 patients with pure AOS and 15 patients with AOS-aphasia). The voxel-based lesion-symptom mapping analysis demonstrated that the brain regions associated with AOS were centered on the left precentral gyrus. CONCLUSIONS: Damage to the left precentral gyrus is associated with AOS in acute to subacute stroke patients, suggesting a role of this brain region in motor speech production.

Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. METHODS: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 µg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms. CONCLUSIONS: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Pretreatment Cognitive Profile Likely to Benefit from Donepezil Treatment in Dementia with Lewy Bodies: Pooled Analyses of Two Randomized Controlled Trials.

BACKGROUND/AIMS: Based on Mini-Mental State Examination (MMSE) subitem scores, in dementia with Lewy bodies (DLB), we aimed to delineate features of cognitive impairment, identify cognitive domains improved by donepezil, and define a pretreatment cognitive profile likely to benefit from donepezil. METHODS: Pooled data were used from two randomized controlled trials of donepezil in DLB (n = 235). Baseline MMSE subitem scores were calculated for all patients. Mean changes in subitem scores at week 12 were compared between the placebo and the active group. Finally, the subgroup identification based on differential effect search (SIDES) method was applied. RESULTS: Baseline subitem scores were relatively low for serial 7's, delayed recall, and copying. Significant improvement by donepezil was found for orientation, serial 7's, repetition, 3-step command, and copying. The subgroup with pretreatment scores of serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 were the best responders. MMSE change in subgroups increased as more of these three conditions were fulfilled. CONCLUSION: Cognitive domains characteristically impaired in DLB are particularly improved by donepezil. The number of fulfilled conditions for serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 (likely to benefit score) may predict the response to donepezil in DLB patients.

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development.

BACKGROUND/AIMS: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision. METHODS: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres. RESULTS: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed. CONCLUSION: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.