Plasma-based diagnostic and screening platform using a combination of biosensing signals in Alzheimer's disease.

Using biosensor to screen for Alzheimer's disease (AD) facilitates early detection of AD with high sensitivity and accuracy. This approach overcomes the limitations of conventional AD diagnostic methods, such as neuropsychological assessment and neuroimaging analysis. Here, we propose a simultaneous analysis of signal combinations generated by four crucial AD biomarkers (Amyloid beta 1-40 (Aß40), Aß42, total tau 441 (tTau441), and phosphorylated tau 181 (pTau181)) by inducing a dielectrophoretic (DEP) force on fabricated interdigitated microelectrode (IME) sensor. By applying an optimal DEP force, our biosensor selectively concentrates and filters the plasma-based AD biomarkers, exhibiting high sensitivity (limit of detection <100 fM) and selectivity in the plasma-based AD biomarkers detection (p < 0.0001). Consequently, it is demonstrated that a complex combined signal comprising four AD-specific biomarker signals (Aß40- Aß42+ tTau441- pTau181) can differentiate between patients with AD and healthy subjects with high accuracy (78.85%) and precision (80.95%) (p < 0.0001).

Clinical application of serological Alzheimer's disease diagnosis using a highly sensitive biosensor with hydrogel-enhanced dielectrophoretic force.

Analysis of a ratio between amyloid beta 1-40 and 1-42 (Aß1-40 and Aß1-42) presented in plasm enables a highly accurate diagnosis of Alzheimer's disease (AD). However, the analysis of plasma Aßs is not routinely conducted because of the lack of Aß detection techniques sensitive enough to specifically detect Aß from thousands of biomaterials present in the plasma. We developed a hydrogel-patterned spiral microelectrode sensor combined with a hopping dielectrophoretic (DEP) force, combining the negative DEP and positive DEP forces, for Aß detection. The hydrogel effectively increased the number of immobilized fragmented antibodies in the reaction region of the sensor and enabled size-exclusive passive filtration of non-specific plasma proteins from that region. The hopping DEP force further concentrated the Aßs and removed the non-specific plasma proteins. Consequently, our sensor achieved a limit of detection (LOD) of approximately âˆ¼ 0.15 pg/mL for both Aß1-40 and Aß1-42 in the standard plasma. Finally, comparing the ratio between Aß1-40 and Aß1-42 signals, we distinguished AD patients from cognitively normal subjects with 95.83% accuracy and 92.31% precision (n = 24, p < 0.0001, One-way ANOVA).

Development and evaluation of a T1 standard brain template for Alzheimer disease.

BACKGROUND: Patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) have high variability in brain tissue loss, making it difficult to use a disease-specific standard brain template. The objective of this study was to develop an AD-specific three-dimensional (3D) T1 brain tissue template and to evaluate the characteristics of the populations used to form the template. METHODS: We obtained 3D T1-weighted images from 294 individuals, including 101 AD, 96 amnestic MCI, and 97 cognitively normal (CN) elderly individuals, and segmented them into different brain tissues to generate AD-specific brain tissue templates. Demographic data and clinical outcome scores were compared between the three groups. Voxel-based analyses and regions-of-interest-based analyses were performed to compare gray matter volume (GMV) and white matter volume (WMV) between the three participant groups and to evaluate the relationship of GMV and WMV loss with age, years of education, and Mini-Mental State Examination (MMSE) scores. RESULTS: We created high-resolution AD-specific tissue probability maps (TPMs). In the AD and MCI groups, losses of both GMV and WMV were found with respect to the CN group in the hippocampus (F >44.60, P<0.001). GMV was lower with increasing age in all individuals in the left (r=-0.621, P<0.001) and right (r=-0.632, P<0.001) hippocampi. In the left hippocampus, GMV was positively correlated with years of education in the CN groups (r=0.345, P<0.001) but not in the MCI (r=0.223, P=0.0293) or AD (r=-0.021, P=0.835) groups. WMV of the corpus callosum was not significantly correlated with years of education in any of the three subject groups (r=0.035 and P=0.549 for left, r=0.013 and P=0.821 for right). In all individuals, GMV of the hippocampus was significantly correlated with MMSE scores (left, r=0.710 and P<0.001; right, r=0.680 and P<0.001), while WMV of the corpus callosum showed a weak correlation (left, r=0.142 and P=0.015; right, r=0.123 and P=0.035). CONCLUSIONS: A 3D, T1 brain tissue template was created using imaging data from CN, MCI, and AD participants considering the participants' age, sex, and years of education. Our disease-specific template can help evaluate brains to promote early diagnosis of MCI individuals and aid treatment of MCI and AD individuals.

Long-term Non-Anesthetic Preclinical Study Available Extra-Cranial Brain Activator (ECBA) System for the Future Minimally-Invasive Human Neuro-Modulation.

Long-term preclinical study available extracranial brain activator (ECBA) system, ECBAv2, is proposed for the non-anesthetic canine models. The titanium-packaged module shows enhanced durability, even after a year of implantation in the scalp. In addition, the wearable helmet type base station provides a stable experimental environment without anesthesia. In this work, HFS stimulation is induced to six canine models for 30 minutes every day over 4 weeks (10Hz, 40Hz and no stimulation for each pair of subjects). Pre- and post-HFS stimulation PET-CT image shows remarkable increases of glucose metabolism in the temporal and parietal lobes. Moreover, both the 40-Hz and 10-Hz groups shows noticeable increase and the former group has more increments than the latter. Our results establish that HFS stimulation definitely worked as facilitating brain activity which may affect memory and sensory skills, respectively.

Differences in neuroimaging features of early- versus late-onset nonfluent/agrammatic primary progressive aphasia.

This study investigated distinct neuroimaging features measured by cortical thickness and subcortical structural shape abnormality in early-onset (EO, onset age <65 years) and late-onset (LO, onset age ≥65 years) nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) patients. Cortical thickness and subcortical structural shape analyses were performed using a surface-based method from 38 patients with nfvPPA and 76 cognitively normal individuals. To minimize the effects of physiological aging, we used W-scores in comparisons between the groups. The EO-nfvPPA group exhibited more extensive cortical thickness reductions predominantly in the left perisylvian, lateral and medial prefrontal, temporal, posterior cingulate, and precuneus regions than the LO-nfvPPA group. The EO-nfvPPA group also exhibited significantly greater subcortical structural shape abnormality than the LO-nfvPPA group, mainly in the left striatum, hippocampus, and amygdala. Our findings suggested that there were differences in neuroimaging features between these groups by the age of symptom onset, which might be explained by underlying heterogeneous neuropathological differences or the age-related brain reserve hypothesis.

Isolated Trochlear Nerve Palsy in a Patient with Superior Cerebellar Rete Mirabile.

BACKGROUND: Rete mirabile is a very rare vascular malformation and superior cerebellar artery (SCA) rete mirabile is not reported previously. We report a new case of rete mirabile of SCA initially detected by magnetic resonance imaging and transfemoral cerebral angiography. CASE DESCRIPTION: This report illustrates the case of a 58-year-old man who presented with vertical diplopia. Brain magnetic resonance angiography and transfemoral cerebral angiography revealed a rete mirabile of SCA and 3-dimensional volume isotropic turbo spin echo acquisition, brain magnetic resonance imaging sequence, demonstrated that the cisternal segment of the ipsilateral trochlear nerve was compressed by this vascular malformation. We assumed that his cranial nerve palsy was caused by the rete mirabile of the right SCA. During the 8 weeks presence of diplopia, the patient was observed and the symptom was relieved spontaneously. CONCLUSIONS: We provide a first report in the literature of rete mirabile involving the SCA and suggest a descriptive knowledge of rete mirabile for clinicians during decision-making of treatment.

Long-Term Outcome After Carotid Endarterectomy in Patients with Ischemic Heart Disease.

BACKGROUND: The long-term outcome after carotid endarterectomy (CEA) is determined by many confounding factors. Ischemic heart disease (IHD) is linked to atherosclerotic stroke, and it is an important cause of death during the perioperative and follow-up periods after CEA. We aimed to investigate mortality and long-term major adverse cardiovascular events (MACEs) in patients with IHD compared with patients who do not have IHD. METHODS: We consecutively enrolled 229 patients who underwent CEA procedures from 2000 to 2011. Of these patients, 45 had known or probable IHD defined by history or medical record of myocardial infarction, stable/unstable angina, previous coronary revascularization such as percutaneous coronary intervention or coronary artery bypass graft, or positive stress test. Long-term outcome was identified by using death certificates from the Korean National Statistical Office and telephone interviews by June 2013. We investigated predictors of early (≤30 days) and long-term mortality and MACEs (stroke, myocardial infarction, and death). RESULTS: Mean follow-up period was 49 months. Cox proportional analysis adjusted for potent predictors revealed symptomatic stenosis (hazard ratio, 1.72; 95% confidence interval, 1.02-2.88; P = 0.042) and presence of IHD (hazard ratio, 1.93; 95% confidence interval, 1.09-3.42; P = 0.025) as significant predictors of long-term MACEs. Kaplan-Meier analysis showed a significantly lower rate of survival (P = 0.030) and MACE-free survival (P = 0.003) in the IHD group. CONCLUSIONS: In this study, a poor long-term outcome was observed in patients with IHD and symptomatic stenosis but not in patients with conventional high-risk factors for surgery. Therefore, appropriate evaluation and treatment of IHD before and after CEA might be helpful for better outcome.

Assessment of Extent and Role of Tau in Subcortical Vascular Cognitive Impairment Using 18F-AV1451 Positron Emission Tomography Imaging.

Importance: Amyloid-ß (Aß), tau, and cerebral small vessel disease (CSVD), which occasionally coexist, are the most common causes of cognitive impairments in older people. However, whether tau is observed in patients with subcortical vascular cognitive impairment (SVCI), as well as its associations with Aß and CSVD, are not yet established. More importantly, the role of tau underlying cognitive impairments in SVCI is unknown. Objective: To investigate the extent and the role of tau in patients with SVCI using 18F-AV1451, which is a new ligand to detect neurofibrillary tangles in vivo. Design, Setting, and Participants: This cross-sectional study recruited 64 patients with SVCI from June 2015 to December 2016 at Samsung Medical Center, Seoul, Korea. The patients had significant ischemia on brain magnetic resonance imaging, defined as periventricular white matter hyperintensity at least 10 mm and deep white matter hyperintensity at least 25 mm. We excluded 3 patients with SVCI owing to segmentation error during AV1451 positron emission tomography analysis. Main Outcomes and Measures: We calculated CSVD scores based on the volumes of white matter hyperintensities, numbers of lacunes, and microbleeds using magnetic resonance imaging data. The presence of Aß was assessed using fluorine 18-labeled (18F) florbetaben positron emission tomography. Tau was measured using 18F-AV1451 positron emission tomography. We determined the spreading order of tau by sorting the regional frequencies of cortical involvement. We evaluated the complex associations between Aß, CSVD, AV1451 uptake, and cognition in patients with SVCI. Results: Of the 61 patients with SVCI, 44 (72.1%) were women and the mean (SD) age was 78.7 (6.3) years. Patients with SVCI, especially patients with Aß-negative SVCI, showed higher AV1451 uptake in the inferior temporal areas compared with normal control individuals. In patients with SVCI, Aß positivity and CSVD score were each independently associated with increased AV1451 uptake in the medial temporal and inferior temporal regions, respectively. Involvement frequency of AV1451 uptake in the fusiform gyrus, inferior temporal, and precuneus regions were higher than that in the parahippocampal region. In patients with SVCI, higher AV1451 uptake in the inferior temporal and medial temporal regions correlated with worse language and general cognitive function. In patients with SVCI, Aß positivity and CSVD score each correlated with worse general cognitive function, which was completely mediated by AV1451 uptake in the entorhinal cortex and inferior temporal gyrus, respectively. Conclusions and Relevance: Our findings suggest that in SVCI, both Aß and CSVD were independently associated with increased tau accumulation. Furthermore, tau burden played a pivotal role because it was the final common pathway for the cognitive impairment in patients with SVCI.

Gray and white matter changes linking cerebral small vessel disease to gait disturbances.

OBJECTIVE: To investigate the topographic changes of white matter (WM) integrity and cortical thickness related to gait disturbances and determine whether these neural correlates mediate the association between cerebral small vessel disease (CSVD) and gait disturbances. METHODS: A total of 129 patients with subcortical vascular cognitive impairment were included. CSVD severity was quantified as global and regional WM hyperintensities (WMH) volume and lacune and microbleed numbers. Amyloid burdens were assessed using Pittsburgh compound B (PiB)-PET scanning. Gait score was measured using a standardized scale. WM integrity was assessed by applying tract-based spatial statistics. Cortical thickness was measured using surface-based methods. Path analysis for gait score was performed using regional CSVD markers as predictors and fractional anisotropy (FA) and cortical thickness as mediators. RESULTS: Periventricular WMH (PWMH) volume was associated with gait score, regardless of other CSVD. PiB retention ratio was not associated with gait score. Gait score was correlated with FA in the frontal and parietal WM and bilateral corpus callosum and with cortical thinning in the bilateral frontal and lateral temporo-parieto-occipital regions. Path analysis for gait score showed that PWMH contributed to gait disturbances with the mediation of mean FA or cortical thickness. CONCLUSIONS: Our findings suggest that WMH-related cortical thinning as well as disrupted integrity of periventricular WM is linked to gait disturbances.