Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Voxel-based clustered imaging by multiparameter diffusion tensor images for predicting the grade and proliferative activity of meningioma.

INTRODUCTION: Meningiomas are the most common primary central nervous system tumors. Predicting the grade and proliferative activity of meningiomas would influence therapeutic strategies. We aimed to apply the multiple parameters from preoperative diffusion tensor images for predicting meningioma grade and proliferative activity. METHODS: Nineteen patients with low-grade meningiomas and eight with high-grade meningiomas were included. For the prediction of proliferative activity, the patients were divided into two groups: Ki-67 monoclonal antibody labeling index (MIB-1 LI) < 5% (lower MIB-1 LI group; n = 18) and MIB-1 LI ≥ 5% (higher MIB-1 LI group; n = 9). Six features, diffusion-weighted imaging, fractional anisotropy, mean, axial, and radial diffusivities, and raw T2 signal with no diffusion weighting, were extracted as multiple parameters from diffusion tensor imaging. The two-level clustering approach for a self-organizing map followed by the K-means algorithm was applied to cluster a large number of input vectors with the six features. We also validated whether the diffusion tensor-based clustered image (DTcI) was helpful for predicting preoperative meningioma grade or proliferative activity. RESULTS: The sensitivity, specificity, accuracy, and area under the curve of receiver operating characteristic curves from the 16-class DTcIs for differentiating high- and low-grade meningiomas were 0.870, 0.901, 0.891, and 0.959, and those from the 10-class DTcIs for differentiating higher and lower MIB-1 LIs were 0.508, 0.770, 0.683, and 0.694, respectively. The log-ratio values of class numbers 13, 14, 15, and 16 were significantly higher in high-grade meningiomas than in low-grade meningiomas (p < .001). With regard to MIB-1 LIs, the log-ratio values of class numbers 8, 9, and 10 were higher in meningiomas with higher MIB-1 groups (p < .05). CONCLUSION: The multiple diffusion tensor imaging-based parameters from the voxel-based DTcIs can help differentiate between low- and high-grade meningiomas and between lower and higher proliferative activities.

People with high empathy show increased cortical activity around the left medial parieto-occipital sulcus after watching social interaction of on-screen characters.

People with high empathy interpret others' mental states in daily social interactions. To investigate their characteristics of social cognitive processing, we compared neuromagnetic activities between 20 males with high empathy and 23 males with low empathy while watching social interactions between two characters. Twenty stories of four-panel comic strips were presented; the first three panels described social interactions, and the last panel described empathic/nonempathic behaviors. People with high empathy exhibited increased cortical activity in the right occipital region, medial part of the bilateral superior frontal gyri, and right posterior insula while watching social interaction scenes, which suggests that they paid attention to others' faces and bodies, and inferred others' mental states. They also exhibited increased cortical activity in the left superior frontal gyrus while watching empathic behaviors. Moreover, they exhibited increased cortical activity in the region around the left medial parieto-occipital sulcus, which is related to self-projection, while passively watching both empathic and nonempathic endings. Taken together, these results suggest that people with high empathy pay attention to others and actively infer others' mental states while watching social interactions and that they reconstruct others' mental states and intentions through self-projection after watching a sequence of others' behaviors.

Salient Properties in Bimanual Haptic Volume Perception: Influence of Object Shape, Finger Pair, and Schizotypal Personality Traits.

Bimanual haptic volume perception refers to somatosensory access to volume information through both hands, and the characteristics that influence this perception remain unclear. This article investigated the influence of target object shapes and finger pairs on bimanual haptic perception; in addition, associations of bimanual haptic impairment and schizotypal features in nonpsychotic individuals were investigated. Twenty blindfolded participants bimanually discriminated volume variations in regular solid objects under different shape (tetrahedron, cube, or sphere) and finger pair (high- or low-sensitivity pairs) conditions using a newly developed bimanual haptic volume presentation device. Discrimination thresholds were then associated with schizotypal traits using the Chinese version of the Schizotypal Personality Questionnaire. Target object shape and finger pairs significantly influenced bimanual haptic volume perception. Volume discrimination thresholds were significantly higher with the tetrahedron stimuli than the cubic or spherical stimuli in high-sensitivity pair conditions, but no significant differences among shapes were found in low-sensitivity pair conditions. Moreover, volume discrimination thresholds with high-sensitivity pairs were correlated with the paranoid score of the schizotypal personality questionnaire. The findings provide initial evidence toward understanding the nature of bimanual haptic volume perception, including the properties of objects, individuals, and object-individual interfaces.

Optimal Model Mapping for Intravoxel Incoherent Motion MRI.

In general, only one diffusion model would be applied to whole field-of-view voxels in the intravoxel incoherent motion-magnetic resonance imaging (IVIM-MRI) study. However, the choice of the applied diffusion model can significantly influence the estimated diffusion parameters. The quality of the diffusion analysis can influence the reliability of the perfusion analysis. This study proposed an optimal model mapping method to improve the reliability of the perfusion parameter estimation in the IVIM study. Six healthy volunteers (five males and one female; average age of 38.3 ± 7.5 years). Volunteers were examined using a 3.0 Tesla scanner. IVIM-MRI of the brain was applied at 17 b-values ranging from 0 to 2,500 s/mm2. The Gaussian model, the Kurtosis model, and the Gamma model were found to be optimal for the CSF, white matter (WM), and gray matter (GM), respectively. In the mean perfusion fraction (fp) analysis, the GM/WM ratios were 1.16 (Gaussian model), 1.80 (Kurtosis model), 1.94 (Gamma model), and 1.54 (Optimal model mapping); in the mean pseudo diffusion coefficient (D*) analysis, the GM/WM ratios were 1.18 (Gaussian model), 1.19 (Kurtosis model), 1.56 (Gamma model), and 1.24 (Optimal model mapping). With the optimal model mapping method, the estimated fp and D* were reliable compared with the conventional methods. In addition, the optimal model maps, the associated products of this method, may provide additional information for clinical diagnosis.

Intact in vivo visualization of telencephalic microvasculature in medaka using optical coherence tomography.

To date, various human disease models in small fish-such as medaka (Oryzias lapties)-have been developed for medical and pharmacological studies. Although genetic and environmental homogeneities exist, disease progressions can show large individual differences in animal models. In this study, we established an intact in vivo angiographic approach and explored vascular networks in the telencephalon of wild-type adult medaka using the spectral-domain optical coherence tomography. Our approach, which required neither surgical operations nor labeling agents, allowed to visualize blood vessels in medaka telencephala as small as about 8 µm, that is, almost the size of the blood cells of medaka. Besides, we could show the three-dimensional microvascular distribution in the medaka telencephalon. Therefore, the intact in vivo imaging via optical coherence tomography can be used to perform follow-up studies on cerebrovascular alterations in metabolic syndrome and their associations with neurodegenerative disease models in medaka.

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

OBJECTIVES: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. METHODS: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. RESULTS: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. CONCLUSION: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

Dynamic reconfiguration of functional brain networks supporting response inhibition in a stop-signal task.

Response inhibition is the ability to suppress automatic actions or behaviors that are not appropriate or are no longer adaptive to the situation. Although many studies have suggested regional brain activation, the nature of the reconfiguration of functional brain networks involved in response inhibition remains unknown. Here, we assessed brain changes associated with response inhibition using graph theoretical analysis applied to functional connectivity data acquired while subjects performed a simple stop-signal task. We identified several ways in which global network organization shifted to meet the demand for response inhibition. Increased demand for response inhibition was associated with a global network configuration with more efficient communication across the network (functional integration) and more specialized processing (functional segregation). Regions distributed in the frontoparietal network and attention networks were found to be highly efficient in the stop condition. Nodal efficiency was significantly associated with reaction time and showed a different pattern between the go and stop conditions. In addition, the conditional differences (stop vs. go) in nodal efficiency and regional task activation were common in the postcentral gyrus (PoCG) and superior temporal lobe gyrus (STG), and a negative correlation between these differences was found in the frontal and parietal lobes. These results provide compelling evidence that response inhibition is associated with truly global changes in brain functional connectivity and additional insights into how defects in response inhibition are associated with neurological or psychiatric difficulties.

Comparison of Phase Synchronization Measures for Identifying Stimulus-Induced Functional Connectivity in Human Magnetoencephalographic and Simulated Data.

Phase synchronization measures are widely used for investigating inter-regional functional connectivity (FC) of brain oscillations, but which phase synchronization measure should be chosen for a given experiment remains unclear. Using neuromagnetic brain signals recorded from healthy participants during somatosensory stimuli, we compared the performance of four phase synchronization measures, imaginary part of phase-locking value, imaginary part of coherency (ImCoh), phase lag index and weighted phase lag index (wPLI), for detecting stimulus-induced FCs between the contralateral primary and ipsilateral secondary somatosensory cortices. The analyses revealed that ImCoh exhibited the best performance for detecting stimulus-induced FCs, followed by the wPLI. We found that amplitude weighting, which is related to computing both ImCoh and wPLI, effectively attenuated the influence of noise contamination. A simulation study modeling noise-contaminated periodograms replicated these findings. The present results suggest that the amplitude-dependent measures, ImCoh followed by wPLI, may have the advantage in detecting stimulus-induced FCs.

A venous mechanism of ventriculomegaly shared between traumatic brain injury and normal ageing.

Recently, age-related timing dissociation between the superficial and deep venous systems has been observed; this was particularly pronounced in patients with normal pressure hydrocephalus, suggesting a common mechanism of ventriculomegaly. Establishing the relationship between venous drainage and ventricular enlargement would be clinically relevant and could provide insight into the mechanisms underlying brain ageing. To investigate a possible link between venous drainage and ventriculomegaly in both normal ageing and pathological conditions, we compared 225 healthy subjects (137 males and 88 females) and 71 traumatic brain injury patients of varying ages (53 males and 18 females) using MRI-based volumetry and a novel perfusion-timing analysis. Volumetry, focusing on the CSF space, revealed that the sulcal space and ventricular size presented different lifespan profiles with age; the latter presented a quadratic, rather than linear, pattern of increase. The venous timing shift slightly preceded this change, supporting a role for venous drainage in ventriculomegaly. In traumatic brain injury, a small but significant disease effect, similar to idiopathic normal pressure hydrocephalus, was found in venous timing, but it tended to decrease with age at injury, suggesting an overlapping mechanism with normal ageing. Structural bias due to, or a direct causative role of ventriculomegaly was unlikely to play a dominant role, because of the low correlation between venous timing and ventricular size after adjustment for age in both patients and controls. Since post-traumatic hydrocephalus can be asymptomatic and occasionally overlooked, the observation suggested a link between venous drainage and CSF accumulation. Thus, hydrocephalus, involving venous insufficiency, may be a part of normal ageing, can be detected non-invasively, and is potentially treatable. Further investigation into the clinical application of this new marker of venous function is therefore warranted.

Tactile Angle Discrimination Decreases due to Subjective Cognitive Decline in Alzheimer's Disease.

BACKGROUND: Subjective Cognitive Decline (SCD) is the early preclinical stage of Alzheimer's Disease (AD). Previous study provided an invaluable contribution by showing that a tactile angle discrimination system can be used to distinguish between healthy older individuals and patients with mild cognitive impairment and AD. However, that study paid little attention to the relationship between tactile angle discrimination and SCD. Therefore, a means of differentiating Normal Controls (NCs), elderly subjects with SCD, patients with amnestic Mild Cognitive Impairment (aMCI), and AD is urgently needed. METHODS: In the present study, we developed a novel tactile discrimination device that uses angle stimulation applied to the index finger pad to identify very small differences in angle discrimination between the NC (n = 30), SCD (n = 30), aMCI (n = 30), and AD (n = 30) groups. Using a three-alternative forced-choice and staircase method, we analyzed the average accuracy and threshold of angle discrimination. RESULTS: We found that accuracy significantly decreased while thresholds of angle discrimination increased in the groups in the following order: NC, SCD, aMCI, and AD. The area under the receiver operating characteristic curve also indicated that the tactile angle discrimination threshold was better than Mini-Mental State Examination scores in distinguishing NC individuals and SCD patients. CONCLUSION: These findings emphasize the importance of tactile working memory dysfunction in explaining the cognitive decline in angle discrimination that occurs in SCD to AD patients and offer further insight into the very early detection of subjects with AD.

Correction: Axial variation of deoxyhemoglobin density as a source of the low-frequency time lag structure in blood oxygenation level-dependent signals.

[This corrects the article DOI: 10.1371/journal.pone.0222787.].

Axial variation of deoxyhemoglobin density as a source of the low-frequency time lag structure in blood oxygenation level-dependent signals.

Perfusion-related information is reportedly embedded in the low-frequency component of a blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal. The blood-propagation pattern through the cerebral vascular tree is detected as an interregional lag variation of spontaneous low-frequency oscillations (sLFOs). Mapping of this lag, or phase, has been implicitly treated as a projection of the vascular tree structure onto real space. While accumulating evidence supports the biological significance of this signal component, the physiological basis of the "perfusion lag structure," a requirement for an integrative resting-state fMRI-signal model, is lacking. In this study, we conducted analyses furthering the hypothesis that the sLFO is not only largely of systemic origin, but also essentially intrinsic to blood, and hence behaves as a virtual tracer. By summing the small fluctuations of instantaneous phase differences between adjacent vascular regions, a velocity response to respiratory challenges was detected. Regarding the relationship to neurovascular coupling, the removal of the whole lag structure, which can be considered as an optimized global-signal regression, resulted in a reduction of inter-individual variance while preserving the fMRI response. Examination of the T2* and S0, or non-BOLD, components of the fMRI signal revealed that the lag structure is deoxyhemoglobin dependent, while paradoxically presenting a signal-magnitude reduction in the venous side of the cerebral vasculature. These findings provide insight into the origin of BOLD sLFOs, suggesting that they are highly intrinsic to the circulating blood.

[Overcoming Fear of Death in Home Caregiving].

This study aimed to clarify the factors for reducing the burden of caregivers caring for terminal patients. We conducted semi-structured interviews with bereaved caregivers, seeking those who had felt neither fear nor anxiety during caregiving; their responses were analyzed using the Steps for Coding and Theorization. The one caregiver who showed neither fear nor anxiety(1)believed in an afterlife,(2)sought a physician who would respect her belief,(3)sought respect for her medical decisions, and(4)found distance to the clinic to be a critical factor. Our findings suggest that doctors' respect for caregivers' beliefs may be an important factor in reducing caregiver burden at the end of life.

Do theta oscillations explain the somatosensory change detection mechanism?

Recent research has indicated that the mismatch negativity (MMN) is elicited in response to a discernible small change of a somatosensory stimulus applied on the hand. However, the neural mechanism for detecting small change of somatosensory stimulus remains unknown. In the present study, we developed a novel pressure stimulation device using air jet applied on the index finger pad, and determined the just noticeable differences (JNDs) of pressure discrimination for each subject. Using the deviant-standard-reversed oddball paradigm, we analyzed the average dynamic changes in MMN amplitude and changes of evoked spectral power. We found a clear MMN component at the frontal and central regions at 100-300 msec after deviant stimulus presentation. Statistical tests showed that theta band activity played pivotal roles in the generation of the MMN elicited by a change in somatosensory pressure stimulation. Our results indicate that the somatosensory discriminatory process reflected on MMN is accompanied by phase-locked oscillation at the theta frequency.

Resting-state Functional Magnetic Resonance Imaging Identifies Cerebrovascular Reactivity Impairment in Patients With Arterial Occlusive Diseases: A Pilot Study.

BACKGROUND: The development of noninvasive approaches for identifying hypoperfused brain tissue at risk is of major interest. Recently, the temporal-shift (TS) maps estimated from resting-state blood oxygenation level-dependent (BOLD) signals have been proposed for determining hemodynamic state. OBJECTIVE: To examine the equivalency of the TS map and the cerebrovascular reactivity (CVR) map derived from acetazolamide-challenged single-photon emission computed tomography (SPECT) in identifying hemodynamic impairment in patients with arterial occlusive diseases. METHODS: Twenty-three patients with arterial occlusive diseases who underwent SPECT were studied. With a recursive TS analysis of low-frequency fluctuation of the BOLD signal, a TS map relative to the global signal was created for each patient. The voxel-by-voxel correlation coefficient was calculated to examine the image similarity between TS and SPECT-based cerebral blood flow (CBF) or CVR maps in each patient. Furthermore, simple linear regression analyses were performed to examine the quantitative relationship between the TS of BOLD signals and CVR in each cerebrovascular territory. RESULTS: The within-patient, voxel-by-voxel comparison revealed that the TS map was more closely correlated with SPECT-CVR map ([Z(r)] = 0.42 ± 0.18) than SPECT-CBF map ([Z(r)] = 0.058 ± 0.11; P < .001, paired t-test). The regression analysis showed a significant linear association between the TS of BOLD signals and CVR in the anterior circulation where the reduction of CVR was evident in the patient group. CONCLUSION: BOLD TS analysis has potential as a noninvasive alternative to current methods based on CVR for identification of tissue at risk of ischemic stroke.

Transcallosal Fiber Disruption and its Relationship with Corresponding Gray Matter Alteration in Patients with Diffuse Axonal Injury.

Diffuse axonal injury (DAI) is characterized by diffuse white matter (WM) disruption caused by shearing forces acting on the brain. Cortical atrophy can be accompanied by WM disruption, which is assumed to reflect the loss of neuron cell bodies in gray matter (GM) regions adjacent to disrupted WM. It remains unclear whether WM disruption leads to regional GM alteration in DAI. The aim of the present study was to assess WM disruption and corresponding GM alterations in patients with DAI using a connectome-based approach. Twenty-four patients and 24 healthy controls underwent magnetic resonance imaging with diffusion tensor imaging (DTI). Deterministic fiber tracking was conducted to investigate structural connectivity between the corpus callosum (CC) and each pre-defined regional cortical area. We calculated 85 × 85 connectivity matrices for fractional anisotropy (FA). Group comparisons were conducted to identify abnormal connectivity in patients. Further, the regional cortical volume of each connectivity matrix was compared between patients and controls. Finally, correlation analyses between the matrices and regional cortical volumes were performed within the patient group. Connectome analyses revealed that, compared with controls, patients exhibited a FA reduction in connectivity via CC to 32 cortical regions including the frontal, parietal, and occipital cortices. Among these regions, GM volume was reduced in 19 of 32 regions. There were no significant correlations between WM disruption in which abnormal connectivity was identified and the corresponding GM alterations. These results suggest that GM pathology is, at least in part, independent of the corresponding WM damage in DAI.

Simultaneous infrared thermal imaging and laser speckle imaging of brain temperature and cerebral blood flow in rats.

Infrared thermal imaging of brain temperature changes is useful for evaluating cortical activity and disease states, such as stroke. However, the changes depend on a balance between changes in heat generation from metabolism and in heat convection related to blood flow. To discriminate between these effects and gain a clearer understanding of neurovascular metabolic coupling, brain temperature imaging must be improved to measure temperature and blood flow simultaneously. We develop an imaging technique that shows a two-dimensional (2-D) distribution of absolute brain temperature and relative cerebral blood flow changes in anesthetized rats by combining infrared thermal imaging with laser speckle imaging. The changes in brain metabolism and cerebral blood flow are achieved using two different anesthetics (isoflurane and α-chloralose) to evaluate our system. Isoflurane increased cerebral blood flow but decreased metabolism, whereas α-chloralose decreased both parameters. This technique enables simultaneous visualization of brain surface changes in temperature and cerebral blood flow in the same regions. This imaging system will permit further study of neurovascular metabolic coupling in normal and diseased brains.