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Blood-based biomarkers (BBM) are potentially powerful tools that assist in the biological diagnosis of Alzheimer's disease (AD) in vivo with minimal invasiveness, relatively low cost, and good accessibility. This review summarizes current evidence for using BBMs in AD, focusing on amyloid, tau, and biomarkers for neurodegeneration. Blood-based phosphorylated tau and the Aβ42/Aβ40 ratio showed consistent concordance with brain pathology measured by CSF or PET in the research setting. In addition, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are neurodegenerative biomarkers that show the potential to assist in the differential diagnosis of AD. Other pathology-specific biomarkers, such as α-synuclein and TAR DNA-binding protein 43 (TDP-43), can potentially detect AD concurrent pathology. Based on current evidence, the working group from the Taiwan Dementia Society (TDS) achieved consensus recommendations on the appropriate use of BBMs for AD in clinical practice. BBMs may assist clinical diagnosis and prognosis in AD subjects with cognitive symptoms; however, the results should be interpreted by dementia specialists and combining biochemical, neuropsychological, and neuroimaging information. Further studies are needed to evaluate BBMs' real-world performance and potential impact on clinical decision-making.

Background: Screening or diagnosis for the elderly with dementia in rural regions might be delayed and underestimated due to limited utilization of healthcare resources. This study aimed to evaluate the disparities of prevalence and risk factors of mild cognitive impairment (MCI) and dementia between urban and rural residence. Methods: In this nationwide door-to-door survey, 10,432 participants aged 65 years and more were selected through computerized random sampling from all administrative districts in Taiwan and were assessed using an in-person interview. We calculated the prevalence of MCI and dementia, with their risk factors examined using multivariable logistic regression. Results: The prevalence of dementia in rural, suburban, and urban areas among the elderly was 8.69% (95% CI, 8.68–8.69), 6.63% (95% CI, 6.62–6.63), and 4.46% (95% CI, 4.46–4.47), respectively. A similar rural-suburban-urban gradient relationship on the dementia prevalence was observed in any age and sex group. The rural:urban ratio was higher in women than in men for both MCI and dementia. Urbanization remained to be an independent factor for both MCI and dementia after adjustment for age, gender, education, lifestyle, and health status. The beneficial effects of exercise on dementia were more evident in rural areas than in urban ones. Conclusion: Significantly higher prevalence of MCI and dementia were found in rural areas than in urban ones, especially for women. The odds of risk factors for MCI and dementia varied by urbanization status. Focus on the rural-urban inequality and the modification of associated factors specifically for different urbanization levels are needed.

Abstract Amyloid plaques and tau tangles are pathological hallmarks of Alzheimer’s disease (AD). Parkinson’s disease (PD) results from the accumulation of α-synuclein. TAR DNA-binding protein (TDP-43) and total tau protein (T-Tau) play roles in FTD pathology. All of the pathological evidence was found in the biopsy. However, it is impossible to perform stein examinations in clinical practice. Assays of biomarkers in plasma would be convenient. It would be better to investigate the combinations of various biomarkers in AD, PD and FTD. Ninety-one subjects without neurodegenerative diseases, 76 patients with amnesic mild cognitive impairment (aMCI) or AD dementia, combined as AD family, were enrolled. One hundred and nine PD patients with normal cognition (PD-NC) or dementia (PDD), combined as PD family, were enrolled. Twenty-five FTD patients were enrolled for assays of plasma amyloid β 1–40 (Aβ1–40), Aβ1–42, T-Tau, α-synuclein and TDP-43 using immunomagnetic reduction (IMR). The results show that Aβs and T-Tau are major domains in AD family. α-synuclein is highly dominant in PD family. FTD is closely associated with TDP-43 and T-Tau. The dominant plasma biomarkers in AD family, PD family and FTD are consistent with pathology. This implies that plasma biomarkers are promising for precise and differential assessments of AD, PD and FTD in clinical practice.

Summary: Background: Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti–amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease. Methods: A 78-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2a study was conducted in Taiwan. Participants were randomised in a 1:1:1 ratio to receive seven intramuscular injections of UB-311 (Q3M arm), or five doses of U311 with two doses of placebo (Q6M arm), or seven doses of placebo (placebo arm). The primary endpoints were safety, tolerability, and immunogenicity of UB-311. Safety was assessed in all participants who received at least one dose of investigational product. This study was registered at ClinicalTrials.gov (NCT02551809). Findings: Between 7 December 2015 and 28 August 2018, 43 participants were randomised. UB-311 was safe, well-tolerated, and generated a robust immune response. The three treatment-emergent adverse events (TEAEs) with the highest incidence were injection-site pain (14 TEAEs in seven [16%] participants), amyloid-related imaging abnormality with microhaemorrhages and haemosiderin deposits (12 TEAEs in six [14%] participants), and diarrhoea (five TEAEs in five [12%] participants). A 97% antibody response rate was observed and maintained at 93% by the end of the study across both UB-311 arms. Interpretation: These results support the continued development of UB-311. Funding: Vaxxinity, Inc. (Formerly United Neuroscience Ltd.)

Abstract Background Air pollution, especially fine particulate matter (PM), can cause brain damage, cognitive decline, and an increased risk of neurodegenerative disease, especially alzheimer’s disease (AD). Typical pathological findings of amyloid and tau protein accumulation have been detected in the brain after exposure in animal studies. However, these observations were based on high levels of PM exposure, which were far from the WHO guidelines and those present in our environment. In addition, white matter involvement by air pollution has been less reported. Thus, this experiment was designed to simulate the true human world and to discuss the possible white matter pathology caused by air pollution. Results 6 month-old female 3xTg-AD mice were divided into exposure and control groups and housed in the Taipei Air Pollutant Exposure System (TAPES) for 5 months. The mice were subjected to the Morris water maze test after exposure and were then sacrificed with brain dissection for further analyses. The mean mass concentration of PM2.5 during the exposure period was 13.85 μg/m3. After exposure, there was no difference in spatial learning function between the two groups, but there was significant decay of memory in the exposure group. Significantly decreased total brain volume and more neuronal death in the cerebral and entorhinal cortex and demyelination of the corpus callosum were noted by histopathological staining after exposure. However, there was no difference in the accumulation of amyloid or tau on immunohistochemistry staining. For the protein analysis, amyloid was detected at significantly higher levels in the cerebral cortex, with lower expression of myelin basic protein in the white matter. A diffuse tensor image study also revealed insults in multiple white matter tracts, including the optic tract. Conclusions In conclusion, this pilot study showed that even chronic exposure to low PM2.5 concentrations still caused brain damage, such as gross brain atrophy, cortical neuron damage, and multiple white matter tract damage. Typical amyloid cascade pathology did not appear prominently in the vulnerable brain region after exposure. These findings imply that multiple pathogenic pathways induce brain injury by air pollution, and the optic nerve may be another direct invasion route in addition to olfactory nerve.

Abstract Subjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration. In this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ1–42 and total tau protein (T-Tau) levels in poststroke (PS, n = 27), family history of Alzheimer’s disease (ADFH, n = 35), diabetes (n = 21), end-stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer’s disease (AD, n = 65). Thirty-seven healthy controls (HCs) were enrolled. The measured concentrations of plasma Aβ1–42 were 14.26 ± 1.42, 15.43 ± 1.76, 15.52 ± 1.60, 16.15 ± 1.05, 16.52 ± 0.59, 15.97 ± 0.54 and 20.06 ± 3.09 pg/mL in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T-Tau were 15.13 ± 3.62, 19.29 ± 8.01, 17.93 ± 6.26, 19.74 ± 2.92, 21.54 ± 2.72, 20.17 ± 2.77 and 41.24 ± 14.64 pg/mL. The plasma levels of Aβ1–42 and T-Tau in were significantly higher in the PS, ADFH, diabetes, ESRD and OSA groups than controls (Aβ1–42 in PS: 15.43 ± 1.76 pg/mL vs. 14.26 ± 1.42 pg/mL, p

Background/Purpose: Post-stroke dysphagia is a frequent complication. Although most patients with dysphagia recover after the acute phase, some patients require long-term enteral feeding, either through a nasogastric (NG) or gastrostomy tube; the effectiveness of using either tube is still under debate. This study elucidated the natural course of NG tube installation and removal and examined the predictors and associating factors based on clinical and brain imaging data. Methods: This retrospective cohort study with medical record reviews recruited patients received NG tube installation after their acute stroke events between January 1, 2016, and December 31, 2016. Inclusion criteria were subjects above 20 years of age and with a diagnosis of a newly onset stroke except SAH whose comprehensive clinical and imaging data were available. Survival analysis was performed for the right-censored data because some patients were lost to follow-up after discharge or transferal. Results: In total we recruited 135 patients. Among these patients, the timing of their NG tube removal reached a plateau at 12–16 weeks after stroke. The modified Rankin score on discharge, representing the overall subacute disease status, was the most significant factor. Other clinical variables could be divided into 2 categories: baseline patient characteristics and stroke event severity. Moreover, semi-quantitative brain imaging scores corresponding to the aforementioned 3 categories were correlated significantly. Conclusion: In Taiwan, the NG tube removal rate reached a plateau at around 12–16 weeks after stroke onset. Variables related to long-term NG tube use were divided into baseline characteristics of patient and stroke event severity.

Abstract Background Optimization of vascular risk factor control is emerging as an alternative approach to improve cognitive outcomes in Alzheimer’s disease, although its efficacy is still under debate. We aimed to investigate the contribution of vascular risk factors on Alzheimer’s biomarkers and conversion rate to dementia in subjects with mild cognitive impairment (MCI) with low cerebral small vessel disease burden. Methods Two hundred ninety-five newly diagnosed MCI subjects were enrolled from March 2005 to May 2017 for a cross-sectional assessment of vascular risk factors and Alzheimer’s plasma and imaging biomarkers, followed by a cognitive outcome assessment 24 months after enrollment. The association between vascular risk factors and Alzheimer’s biomarkers were tested using multivariable linear regression models adjusted with age, gender, education, and APOE ε4 allele. The association between vascular risk factors and conversion to dementia was tested using multivariable logistic regression models adjusted with age, gender, education, and baseline Mini-Mental State Examination (MMSE) score. Results At baseline, higher low-density lipoprotein (LDL) cholesterol level was associated with more advanced plasma biomarkers, including Aβ42/Aβ40 ratio (P = 0.012) and tau level (P = 0.001). A history of hypertension was associated with more advanced white matter hyperintensity (P = 0.011), while statin therapy for dyslipidemia was associated with less advanced white matter hyperintensity (P = 0.002). At 24 months, individual vascular risk factor was not significantly associated with cognitive outcome. By contrast, statin therapy for dyslipidemia was associated with reduced conversion to dementia (adjusted OR = 0.191, 95% CI = 0.062~0.586, P = 0.004). Conclusions For MCI subjects, dyslipidemia may contribute to AD-related neurodegeneration while hypertension may contribute to vascular pathology. The association between statin therapy for dyslipidemia and reduced conversion to dementia supports further interventional study to evaluate the potential beneficial effect of statin in MCI subjects.

Introduction: Blood biomarkers of Alzheimer’s disease (AD) have attracted much attention of researchers in recent years. In clinical studies, repeated freeze/thaw cycles often occur and may influence the stability of biomarkers. This study aims to investigate the stability of amyloid-β 1–40 (Aβ1–40), amyloid-β 1–42 (Aβ1–42), and total tau protein (T-tau) in plasma over freeze/thaw cycles. Methods: Plasma samples from healthy controls (n = 2), AD patients (AD, n =3) and Parkinson’s disease patients (PD, n = 3) were collected by standardized procedure and immediately frozen at –80°C. Samples underwent 5 freeze/thaw (–80°C/room temperature) cycles. The concentrations of Aβ1–40, Aβ1–42, and T-tau were monitored during the freeze/thaw tests using an immunomagnetic reduction (IMR) assay. The relative percentage of concentrations after every freeze/thaw cycle was calculated for each biomarker. Results: A tendency of decrease in the averaged relative percentages over samples through the freeze and thaw cycles for Aβ1–40 (100 to 97.11%), Aβ1–42 (100 to 94.99%), and T-tau (100 to 95.65%) was found. However, the decreases were less than 6%. For all three biomarkers, no statistical significance was found between the levels of fresh plasma and those of the plasma experiencing 5 freeze/thaw cycles (p > 0.1). Conclusions: Plasma Aβ1–40, Aβ1–42, and T-tau are stable through 5 freeze/thaw cycles measured with IMR.

Background: The stability of Alzheimer’s disease (AD) biomarkers in plasma, measured by immunomagnetic reduction (IMR) after long-term storage at –80°C, has not been established before. Method: Ninety-nine human plasma samples from 53 normal controls (NCs), 5 patients with amnestic mild cognitive impairment (aMCI), and 41 AD patients were collected. Each plasma sample was aliquoted and stored as single-use aliquots at –80°C. The baseline measurements for Aβ1–40, Aβ1–42, and total Tau protein (T-Tau) concentrations for each sample were done within 3 months of blood draw by IMR. They are referred to as baseline concentrations. A separate aliquot from each sample was assayed with IMR to assess the stability of the measured analytes during storage at –80°C between 1.1 and 5.4 years. This is referred to as a repeated result. Results: IMR shows that plasma levels of Aβ1–40 and Aβ1–42 exhibit stability over 5-year storage at –80°C and that plasma levels of T-Tau are less stable (approximately 1.5 years). Conclusion: Although the measured concentrations of T-Tau in human plasma may alter during storage, the diagnostic utility of the results are only slightly affected when the product of Aβ1–42 and T-Tau concentrations are used. The results show that the overall agreement between baseline and repeated measurements in the ability of discriminating NCs from aMCI/AD patients is higher than 80%.

Background and Objective: Tau-specific positron emission topography (PET) imaging enables in vivo assessment of Alzheimer's disease (AD). We aimed to investigate its performance in combination with plasma tau levels in patients with non-AD tauopathy.Methods: A total of 47 participants were enrolled, including 10 healthy controls, 16 with tauopathy parkinsonism syndromes (9 with corticobasal syndrome [CBS], 7 with progressive supranuclear palsy [PSP]), 9 with frontotemporal dementia (FTD), 4 with AD, and 8 with Parkinson's disease (PD). All participants underwent clinical assessments, 18F-T807 tau PET, brain MRI, and plasma tau assay.Results: The global cortical standard uptake value ratio (SUVR) of 18F-T807 PET was comparable between PD and control (p = 0.088). The cortical SUVR was significantly higher in AD group (p = 0.002) but was modestly increased in PSP group compared to the PD group (p = 0.044), especially in parietal and pallidal regions. Asymmetric 18F-T807 uptake at the pallidum was noted in patients with CBS and FTD. Cortical tau tracer uptake was associated with increased plasma total tau level (p = 0.016), especially in frontal and parietal regions. Regional tracer uptake was correlated with cortical thinning in patients with CBS and PSP (CBS: r = −0.092, p = 0.025; PSP: r = −0.114, p = 0.015).Conclusions: The 18F-T807 tau tracer uptake was only modestly increased in patients with PSP. Although the cortical tau tracer uptake correlated with regional cortical atrophy and plasma tau levels, a four-repeated tau-specific tracer is needed for future classifying tauopathy parkinsonism syndromes.

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer's disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

Abstract Introduction Frontal variant of Alzheimer's disease (fvAD) is a rare nonamnestic syndrome of Alzheimer's disease (AD). Differentiating it from behavior variant of frontotemporal dementia (bvFTD), which has implications for treatment responses and prognosis, remains a clinical challenge. Methods Molecular neuroimaging and biofluid markers were performed for the index patient for accurate premortem diagnosis of fvAD. The clinical, neuroimaging, and biofluid characteristics of the patient were compared to those reported in previous studies of fvAD from 1999 to 2019. Results A 66‐year‐old man presented with progressive executive dysfunction, personality and behavioral changes, and memory decline since age 59. He had no family history of neurodegenerative disorders. A stimulus‐sensitive myoclonus was noted over his left upper extremity. Neuropsychological assessment revealed moderate dementia with a Mini‐Mental State Exam score of 10/30 and compromised executive and memory performance. Brain imaging showed asymmetrical atrophy and hypometabolism over the right frontal and temporal areas, mimicking bvFTD. However, we observed increased tau depositions based on 18F‐labeled T807 Tau PET in these areas and diffusely increased amyloid deposition based on 11C‐labeled Pittsburgh compound B positron emission tomography (PET). Plasma biomarker measures indicated an AD profile with increased Aβ1‐42 (18.66 pg/ml; cutoff: 16.42 pg/ml), Aβ1‐42/Aβ1‐40 ratio (0.45; cutoff: 0.30), total tau (29.78 pg/ml; cutoff: 23.89 pg/ml), and phosphorylated tau (4.11 pg/ml; cutoff: 3.08 pg/ml). These results supported a diagnosis of fvAD. Conclusions Our results with asymmetrical presentations extend current knowledge about this rare AD variant. Application of biofluid and molecular imaging markers could assist in early, accurate diagnosis.

Axonal damage leads to the release of neurofilament light chain (NFL), which enters the CSF or blood. In this work, an assay kit for plasma NFL utilizing immunomagnetic reduction (IMR) was developed. Antibodies against NFL were immobilized on magnetic nanoparticles to develop an IMR NFL kit. The preclinical properties, such as the standard curve, limit of detection (LoD), and dynamic range, were characterized. Thirty-one normal controls (NC), fifty-two patients with Parkinson's disease (PD) or PD dementia (PDD) and thirty-one patients with Alzheimer's disease (AD) were enrolled in the study evaluating the plasma NFL assay using an IMR kit. T-tests and receiver operating characteristic (ROC) curve analysis were performed to investigate the capability for discrimination among the clinical groups according to plasma NFL levels. The LoD of the NFL assay using the IMR kit was found to be 0.18 fg/ml. The dynamic range of the NFL assay reached 1000 pg/ml. The NC group showed a plasma NFL level of 7.70 ± 4.00 pg/ml, which is significantly lower than that of the PD/PDD (15.85 ± 7.82 pg/ml, p < 0.001) and AD (19.24 ± 8.99 pg/ml, p < 0.001) groups. A significant difference in plasma NFL levels was determined between the PD and AD groups (p < 0.01). Through ROC curve analysis, the cut-off value of the plasma NFL concentration for differentiating NCs from dementia patients (AD and PD/PDD) was found to be 12.71 pg/ml, with a clinical sensitivity and specificity of 73.5% and 90.3%, respectively. The AUC was 0.868. Furthermore, the cut-off value of the plasma NFL concentration for discriminating AD from PD/PDD was found to be 18.02 pg/ml, with a clinical sensitivity and specificity of 61.3% and 65.4%, respectively. The AUC was 0.630. An ultrasensitive assay for measuring plasma NFL utilizing IMR technology was developed. Clear differences in plasma NFL concentrations were observed among NCs and PD and AD patients. These results imply that the determination of plasma NFL is promising not only for screening dementia but also for differential diagnosis.

Background/purpose: Helicobacter pylori (H. pylori) infection has been positively associated with cognitive impairment. However, previous studies have shown inconsistent findings. Methods: This cross-sectional study included 587 elderly participants (age ≧ 65) from the annual elderly health checkup program at the National Taiwan University Hospital from 2011 to 2013. Both global and domain-specific cognition were assessed using various neuropsychiatric tests. Multivariable linear regression and logistic regression models were utilized to assess the association between the serum H. pylori IgG level and cognitive impairment. Results: Compared with the lowest quartile of H. pylori IgG (Q1), the highest quartile (Q4) was associated with lower scores on verbal fluency-vegetables (β = −0.24), domain-specific attention [digit span-forward: β = −0.19; odds ratio (OR) = 1.83, 95% confidence interval (CI) = 1.03–3.24], and attention factors (β = −0.20; OR= 2.67, 95% CI = 1.51–4.73). No significant association was observed for global cognition. Stratified analyses revealed that, among men, the highest quartile of serum H. pylori IgG (Q4) was associated with impaired scores on verbal fluency-vegetables (β = −0.38; OR = 3.01, 95% CI = 1.42–6.38). Conclusion: Our findings disclosed a positive association between serum H. pylori level and cognitive impairment, which provides important information for the primary prevention of cognitive impairment through the eradication of H. pylori. Keywords: Helicobacter pylori, Infection, Cognitive impairment, Elders

Abstract Chronic kidney disease has been linked to cognitive impairment and morphological brain change. However, less is known about the impact of kidney functions on cerebral cortical thickness. This study investigated the relationship between kidney functions and global or lobar cerebral cortical thickness (CTh) in 259 non-demented elderly persons. Forty-three participants (16.7%) had kidney dysfunction, which was defined as either a glomerular filtration rate (GFR) of

Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer’s disease (AD). However, the constituents of these hallmarks, amyloid beta (Aβ) 40, Aβ42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23–91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of Aβ40, Aβ42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aβ42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = −0.126, p = 0.0128 for Aβ42), ranging from ages 23 to 91. Significant positive correlations were detected between Aβ42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aβ40 and t-Tau from age 40 to 91 (r ranged from −0.293 to −0.582) and between Aβ40 and Aβ42 in the age groups of 30–39 (r = −0.562, p = 0.0235), 50–59 (r = −0.261, p = 0.0142), 60–69 (r = −0.303, p = 0.0004), and 80–91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aβ42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aβ40, Aβ42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/μmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 μSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) μSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.

Studies have shown that Tai Chi Chuan (TCC) training has benefits on task-switching ability. However, the neural correlates underlying the effects of TCC training on task-switching ability remain unclear. Using task-related functional magnetic resonance imaging (fMRI) with a numerical Stroop paradigm, we investigated changes of prefrontal brain activation and behavioral performance during task-switching before and after TCC training and examined the relationships between changes in brain activation and task-switching behavioral performance. Cognitively normal older adults were randomly assigned to either the TCC or control (CON) group. Over a 12-week period, the TCC group received three 60-min sessions of Yang-style TCC training weekly, whereas the CON group only received one telephone consultation biweekly and did not alter their life style. All participants underwent assessments of physical functions and neuropsychological functions of task-switching, and fMRI scans, before and after the intervention. Twenty-six (TCC, N = 16; CON, N = 10) participants completed the entire experimental procedure. We found significant group by time interaction effects on behavioral and brain activation measures. Specifically, the TCC group showed improved physical function, decreased errors on task-switching performance, and increased left superior frontal activation for Switch > Non-switch contrast from pre- to post-intervention, that were not seen in the CON group. Intriguingly, TCC participants with greater prefrontal activation increases in the switch condition from pre- to post-intervention presented greater reductions in task-switching errors. These findings suggest that TCC training could potentially provide benefits to some, although not all, older adults to enhance the function of their prefrontal activations during task-switching.

Background: Neuritic plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer’s disease (AD), while the role of brain amyloid deposition in the clinical manifestation or brain atrophy remains unresolved. We aimed to explore the relation between brain amyloid deposition, cortical thickness, and plasma biomarkers.Methods: We used 11C-Pittsburgh compound B-positron emission tomography to assay brain amyloid deposition, magnetic resonance imaging to estimate cortical thickness, and an immunomagnetic reduction assay to measure plasma biomarkers. We recruited 39 controls, 25 subjects with amnesic mild cognitive impairment (aMCI), and 16 subjects with AD. PiB positivity (PiB+) was defined by the upper limit of the 95% confidence interval of the mean cortical SUVR from six predefined regions (1.0511 in this study).Results: All plasma biomarkers showed significant between-group differences. The plasma Aβ40 level was positively correlated with the mean cortical thickness of both the PiB+ and PiB- subjects. The plasma Aβ40 level of the subjects who were PiB+ was negatively correlated with brain amyloid deposition. In addition, the plasma tau level was negatively correlated with cortical thickness in both the PiB+ and PiB- subjects. Moreover, cortical thickness was negatively correlated with brain amyloid deposition in the PiB+ subjects. In addition, the cut-off point of plasma tau for differentiating between controls and AD was higher in the PiB- group than in the PiB+ group (37.5 versus 25.6 pg/ml, respectively). Lastly, ApoE4 increased the PiB+ rate in the aMCI and control groups.Conclusion: The contributions of brain amyloid deposition to cortical atrophy are spatially distinct. Plasma Aβ40 might be a protective indicator of less brain amyloid deposition and cortical atrophy. It takes more tau pathology to reach the same level of cognitive decline in subjects without brain amyloid deposition, and ApoE4 plays an early role in amyloid pathogenesis.

Objective: Parkinson’s disease (PD) has significant clinical overlaps with atypical parkinsonism syndromes (APS), which have a poorer treatment response and a more aggressive course than PD. We aimed to identify plasma biomarkers to differentiate PD from APS.Methods: Plasma samples (n = 204) were obtained from healthy controls and from patients with PD, dementia with Lewy bodies (DLB), multiple system atrophy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or frontotemporal dementia (FTD) with parkinsonism (FTD-P) or without parkinsonism. We measured plasma levels of α-synuclein, total tau, p-Tau181, and amyloid beta 42 (Aβ42) by immunomagnetic reduction-based immunoassay.Results: Plasma α-synuclein level was significantly increased in patients with PD and APS when compared with controls and FTD without parkinsonism (p < 0.01). Total tau and p-Tau181 were significantly increased in all disease groups compared to controls, especially in patients with FTD (p < 0.01). A multivariate and receiver operating characteristic curve analysis revealed that a cut-off value for Aβ42 multiplied by p-Tau181 for discriminating patients with FTD from patients with PD and APS was 92.66 (pg/ml)2, with an area under the curve (AUC) of 0.932. An α-synuclein cut-off of 0.1977 pg/ml could separate FTD-P from FTD without parkinsonism (AUC 0.947). In patients with predominant parkinsonism, an α-synuclein cut-off of 1.388 pg/ml differentiated patients with PD from those with APS (AUC 0.87).Conclusion: Our results suggest that integrated plasma biomarkers improve the differential diagnosis of PD from APS (PSP, CBD, DLB, and FTD-P).

Objectives. To investigate the effects of practice variability combined with task-oriented electromyographic biofeedback (EMGBFB) on strength and balance in people with chronic stroke. Methods. Thirty-three participants were randomly assigned into the constant force EMGBFB tibialis anterior (TA) exercise (constant) group, the variable force EMGBFB tibialis anterior exercise (variable) group, or the upper extremity exercise without EMGBFB (control) group. Subjects in each group received 6 weekly sessions of exercise training (18 sessions, 40 minutes each). Motor outcomes were TA strength, balance (anteroposterior sway amplitude defined by limits of stability test in dynamic posturography), walking speed, Timed Up and Go test (TUGT), and six-minute walk test (6MWT). Data were measured at baseline, 1 day, 2 weeks, and 6 weeks posttraining. Results. TA strength increased significantly in both the constant and variable groups after training. Balance significantly improved only in the variable group. All participants showed improvements in walking speed, TUGT, and 6MWT. Conclusions. Task-oriented EMGBFB-assisted TA exercise training improved muscle strength in people with chronic stroke. Practicing to reach varying force levels during EMGBFB-assisted tibialis anterior exercises facilitated improvements in the ability to sway in the anteroposterior direction while standing. Our findings highlight the importance of task-oriented and motor learning principles while using the EMGBFB as an adjunct therapy in stroke rehabilitation. This trial was registered with trial registration number NCT01962662.

This study aimed to identify lifestyle factors associated with cognitive change and to explore whether the effect of lifestyle varies by socioeconomic status (SES). Participants aged 65 years and older were recruited from elderly health checkup programs from 2011 to 2013 in Taiwan. Neuropsychological tests, including tests of global cognition, logical memory, executive function, verbal fluency and attention, were administered at baseline (N = 603) and 2 years later (N = 509). After literature review, 9 lifestyle factors and 3 SES indicators were chosen and their effects on cognitive change were evaluated using linear regression adjusting for age, sex, education, APOE ε4 status, and baseline cognitive score. Five lifestyle factors (high vegetable and fish intake, regular exercise, not smoking, and light to moderate alcohol consumption) and 3 SES indicators [annual household income (> 33,333 USD vs. less), occupational complexity (high vs. low mental demanding job), and years of education (> 12 years vs. less)] were found to be protective against cognitive decline (P < 0.1 in any cognitive domains, ß ranging from 0.06 to 0.38). After further adjusting for all the lifestyle and SES factors, fish intake, higher income and occupational complexity remained protective. Significant interactions were found between a healthful lifestyle (defined as having ≥ 3 healthful lifestyle factors) and income on changes of global cognition and verbal fluency (Pinteraction = 0.02 and 0.04). The protective effect of a healthful lifestyle was observed only among participants with lower income in global cognition and logical memory [ß = 0.17, 95% confidence interval (CI) = 0.07-0.26; ß = 0.30, 95% CI = 0.14-0.46]. To the best of our knowledge, this study for the first time explored how the interactions of lifestyle and SES affect cognitive change. Our findings will aid in developing dementia prevention programs and reduce health inequalities.

The utility of plasma amyloid beta (Aβ) and tau levels for the clinical diagnosis of Alzheimer’s disease (AD) dementia has been controversial. The main objective of this study was to compare Aβ42 and tau levels measured by the ultra-sensitive immunomagnetic reduction (IMR) assays in plasma samples collected at the Banner Sun Health Institute (BSHRI) (United States) with those from the National Taiwan University Hospital (NTUH) (Taiwan). Significant increase in tau levels were detected in AD subjects from both cohorts, while Aβ42 levels were increased only in the NTUH cohort. A regression model incorporating age showed that tau levels identified probable ADs with 81 and 96% accuracy in the BSHRI and NTUH cohorts, respectively, while computed products of Aβ42 and tau increased the accuracy to 84% in the BSHRI cohorts. Using 382.68 (pg/ml)2 as the cut-off value, the product achieved 92% accuracy in identifying AD in the combined cohorts. Overall findings support that plasma Aβ42 and tau assayed by IMR technology can be used to assist in the clinical diagnosis of AD.

BACKGROUND:Comorbid medical diseases are highly prevalent in the geriatric population, imposing hardship on healthcare services for demented individuals. Dementia also complicates clinical care for other co-existing medical conditions. This study investigated the comorbidities associated with dementia in the elderly population aged 65 years and over in Taiwan. METHODS:We conducted a nationwide, population-based, cross-sectional survey; participants were selected by computerized random sampling from all 19 Taiwan counties between December 2011 and March 2013. After exclusion of incomplete or erroneous data, 8,456 subjects were enrolled. Of them, 6,183 were cognitively normal (control group), 1,576 had mild cognitive impairment (MCI), and 697 had dementia. We collected information about types of comorbidities (i.e., vascular risk factors, lung diseases, liver diseases, gastrointestinal diseases, and cancers), Charlson comorbidity index score, and demographic variables to compare subjects with normal cognition, MCI, and dementia. RESULTS:Regardless of the cognitive condition, over 60% of the individuals in each group had at least one comorbid disease. The proportion of subjects possessing at least three comorbidities was higher in those with cognitive impairment (MCI 20.9%, dementia 27.3%) than in control group (15%). Hypertension and diabetes mellitus were the most common comorbidities. The mean number of comorbidities and Charlson comorbidity index score were greater in MCI and dementia groups than in control group. Logistic regression demonstrated that the comorbidities significantly associated with MCI and dementia were cerebrovascular disease (OR 3.35, CI 2.62-4.28), cirrhosis (OR 3.29, CI 1.29-8.41), asthma (OR 1.56, CI 1.07-2.27), and diabetes mellitus (OR 1.24, CI 1.07-1.44). CONCLUSION:Multiple medical comorbid diseases are common in older adults, especially in those with cognitive impairment. Cerebrovascular disease, cirrhosis, asthma, and diabetes mellitus are important contributors to cognitive deterioration in the elderly. Efforts to lower cumulative medical burden in the geriatric population may benefit cognitive function.

An alternating-current magnetosusceptometer of antibody-functionalized magnetic nanoparticles (MNPs) was developed for immunomagnetic reduction (IMR). A high-sensitivity, high-critical-temperature superconducting quantum interference device was used in the magnetosusceptometer. Minute levels of biomarkers of early-stage neurodegeneration diseases were detectable in serum, but measuring each biomarker required approximately 4 h. Hence, an eight-channel platform was developed in this study to fit minimal screening requirements for Alzheimer’s disease. Two consistent results were measured for three biomarkers, namely Aβ40, Aβ42, and tau protein, per human specimen. This paper presents the instrument configuration as well as critical characteristics, such as the low noise level variations among channels, a high signal-to-noise ratio, and the coefficient of variation for the biomarkers’ IMR values. The instrument’s ultrahigh sensitivity levels for the three biomarkers and the substantially shorter total measurement time in comparison with the previous single- and four-channels platforms were also demonstrated in this study. Thus, the eight-channel instrument may serve as a powerful tool for clinical high-throughput screening of Alzheimer’s disease.

Evidence of an association between lifestyle and marital status and risk of dementia is limited in Asia.In this nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 counties in Taiwan. A total of 10432 residents were assessed by a door-to-door in-person survey, among whom 7035 were normal and 929 were diagnosed with dementia using the criteria recommended by National Institute on Aging-Alzheimer's Association. Premorbid lifestyle habits and demographic data including marital status were compared between normal subjects and participants with dementia.After adjustment for age, gender, education, body mass index, smoking, drinking, marital status, sleep habits, exercise, social engagement and co-morbidities including hypertension, diabetes and cerebrovascular diseases, an increased risk for dementia was found in people with widow or widower status (OR 1.42, 95% CI 1.15-1.77) and people who used to take a nap in the afternoon (OR 1.33, 95% CI 1.02-1.72). Decreased risk was found in people with the habit of regular exercise (OR 0.12, 95% CI 0.09-0.16), adequate night sleep (OR 0.55, 95% CI 0.39-0.76) and regular social engagement (OR 0.53, 95% CI 0.36-0.77).Our results provide preliminary evidence of possible risk-reduction effects for dementia, including regular exercise even in modest amounts, social engagement and adequate night sleep, whereas people with the widow/widower status or who used to take an afternoon nap might have increased risk of dementia.

Behavioral and psychologic symptoms of dementia (BPSD) are major sources of a caregiver's burden and also the most important factor when considering the need for institutionalization of dementia patients. BPSD occur in about 90% of patients with dementia. Studies comparing the BPSD in the major types of dementia using unitary behavioral rating scales are limited. We studied BPSD in patients with four major types of dementias from a memory clinic. Methods: We recruited patients with dementia from our memory clinic from January 2003 to February 2004. The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) was used to measure BPSD severity. Clinical Dementia Rating and Mini Mental State Examination were used to determine dementia severity. Results: A total of 137 patients with four major types of dementia were recruited from 155 patients with dementia who attended the clinic during the study period. The main dementia types identified were Alzheimer's dementia (AD) in 54.8%, vascular dementia (VaD) in 20.6%, frontotemporal dementia (FTD) in 8.4%, dementia with Lewy bodies (DLB) in 4.5%, and other dementias in 11.6%. BPSD were found in 92.0% of the patients but only 43.1% received psychotropic treatment. The relative risk of receiving psychotropic treatment for BPSD subscales paralleled the extent of caregivers' burden as assessed by the BEHAVE-AD global rating. Type-specific BPSD, e.g. hallucination was identified for DLB, activity disturbances for FTD, anxiety and phobias for AD and affective disturbance for VaD. Conclusion: A strategy of targeting type-specific BPSD may be beneficial, such as environmental stimulus control for DLB patients who are prone to have hallucinations, design of a pacing path for patients with FTD who need support for symptoms of wandering and emotional support for patients with VaD who are susceptible to depression.

Although a deficit of semantic memory is evident in the dementia of the Alzheimer's type (DAT), the underlying neuropsychologic mechanism remains controversial. Breakdown of the semantic network during the course of DAT and an inability to access semantic information have been postulated as possible explanations, but supporting data are limited, particularly in low-educated patients. This study examined semantic memory in low-educated patients with different degrees of dementia severity. Methods: In total, 197 adult subjects were recruited, including 165 DAT patients and 32 normal controls. Subjects were divided into four subgroups according to their dementia severity. All subjects completed an episodic memory task, the Six-Object Memory Test, and semantic memory tasks including the Object Naming Test, the Remote Memory Test and the Semantic Association of Verbal Fluency Test. One-way ANOVA and ANCOVA with a post hoc Scheffe's procedure were used to evaluate differences between groups. Results: All patients, irrespective of the degree of dementia, showed impaired performance on the Six-Object Memory Test [F(4, 163) = 69.95, p< 0.0001 for immediate recall; F(4, 163) = 41.34, p< 0.0001 for delayed recall]. On the semantic memory tasks, patients with moderate to severe dementia showed impaired performances on the Object Naming Test [F(4, 180) =28.25, p

An increasing population of dementia patients produces substantial societal impacts. We assessed the prevalence of mild cognitive impairment (MCI) and all-cause dementia, including very mild dementia (VMD), in Taiwan. In a nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 Taiwan counties and were enrolled between December 2011 and March 2013. Cases were identified through in-person interviews based on the National Institute on Aging-Alzheimer's Association clinical criteria. Demographic data and histories involving mental status and function in daily living were collected. The principal objective assessments were the Taiwanese Mental Status Examination and Clinical Dementia Rating. In all, 10,432 people aged 65 years or older (mean age 76.2 ± 6.7, 52.3% women) were interviewed. The age-adjusted prevalence of all-cause dementia was 8.04% (95% CI 7.47-8.61), including a 3.25% (95% CI 2.89-3.61) prevalence of VMD; that of MCI was 18.76% (95% CI 17.91-19.61). Women had a higher prevalence than men of both all-cause dementia (9.71% vs. 6.36%) and MCI (21.63% vs. 15.57%). MCI affects a considerable portion of the population aged 65 and above in Taiwan. The inclusion of VMD yields dementia prevalence rates higher than those previously reported from Taiwan. Old age, female gender, and a low educational level are significant associated factors.

BACKGROUND: Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. Electroencephalogram (EEG) signals play a critical role in the diagnosis of epilepsy. Multichannel EEGs contain more information than do single-channel EEGs. Automatic detection algorithms for spikes or seizures have traditionally been implemented on single-channel EEG, and algorithms for multichannel EEG are unavailable. METHODOLOGY: This study proposes a physiology-based detection system for epileptic seizures that uses multichannel EEG signals. The proposed technique was tested on two EEG data sets acquired from 18 patients. Both unipolar and bipolar EEG signals were analyzed. We employed sample entropy (SampEn), statistical values, and concepts used in clinical neurophysiology (e.g., phase reversals and potential fields of a bipolar EEG) to extract the features. We further tested the performance of a genetic algorithm cascaded with a support vector machine and post-classification spike matching. PRINCIPAL FINDINGS: We obtained 86.69% spike detection and 99.77% seizure detection for Data Set I. The detection system was further validated using the model trained by Data Set I on Data Set II. The system again showed high performance, with 91.18% detection of spikes and 99.22% seizure detection. CONCLUSION: We report a de novo EEG classification system for seizure and spike detection on multichannel EEG that includes physiology-based knowledge to enhance the performance of this type of system.

OBJECTIVES: Endophenotypes in schizophrenia research is a contemporary approach to studying this heterogeneous mental illness, and several candidate neurophysiological markers (e.g. P50 sensory gating) and neuropsychological tests (e.g. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST)) have been proposed. However, the clinical utility of a single marker appears to be limited. In the present study, we aimed to construct a diagnostic model incorporating P50 sensory gating with other neuropsychological tests in order to improve the clinical utility. METHODS: We recruited clinically stable outpatients meeting DSM-IV criteria of schizophrenia and age- and gender-matched healthy controls. Participants underwent P50 sensory gating experimental sessions and batteries of neuropsychological tests, including CPT, WCST and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). RESULTS: A total of 106 schizophrenia patients and 74 healthy controls were enrolled. Compared with healthy controls, the patient group had significantly a larger S2 amplitude, and thus poorer P50 gating ratio (gating ratio = S2/S1). In addition, schizophrenia patients had a poorer performance on neuropsychological tests. We then developed a diagnostic model by using multivariable logistic regression analysis to differentiate patients from healthy controls. The final model included the following covariates: abnormal P50 gating (defined as P50 gating ratio >0.4), three subscales derived from the WAIS-III (Arithmetic, Block Design, and Performance IQ), sensitivity index from CPT and smoking status. This model had an adequate accuracy (concordant percentage = 90.4%; c-statistic = 0.904; Hosmer-Lemeshow Goodness-of-Fit Test, p = 0.64>0.05). CONCLUSION: To the best of our knowledge, this is the largest study to date using P50 sensory gating in subjects of Chinese ethnicity and the first to use P50 sensory gating along with other neuropsychological tests to develop a diagnostic model for schizophrenia. Further research to validate the predictive accuracy of this model by applying it on other samples is warranted.

BACKGROUND: Schizophrenia is a heterogeneous disorder with diverse presentations. The current and the proposed DSM-V diagnostic system remains phenomenologically based, despite the fact that several neurobiological and neuropsychological markers have been identified. A multivariate approach has better diagnostic utility than a single marker method. In this study, the mismatch negativity (MMN) deficit of schizophrenia was first replicated in a Han Chinese population, and then the MMN was combined with several neuropsychological measurements to differentiate schizophrenia patients from healthy subjects. METHODOLOGY/PRINCIPAL FINDINGS: 120 schizophrenia patients and 76 healthy controls were recruited. Each subject received examinations for duration MMN, Continuous Performance Test, Wisconsin Card Sorting Test, and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). The MMN was compared between cases and controls, and important covariates were investigated. Schizophrenia patients had significantly reduced MMN amplitudes, and MMN decreased with increasing age in both patient and control groups. None of the neuropsychological indices correlated with MMN. Predictive multivariate logistic regression models using the MMN and neuropsychological measurements as predictors were developed. Four predictors, including MMN at electrode FCz and three scores from the WAIS-III (Arithmetic, Block Design, and Performance IQ) were retained in the final predictive model. The model performed well in differentiating patients from healthy subjects (percentage of concordant pairs: 90.5%). CONCLUSIONS/SIGNIFICANCE: MMN deficits were found in Han Chinese schizophrenia patients. The multivariate approach combining biomarkers from different modalities such as electrophysiology and neuropsychology had a better diagnostic utility.

The status of cerebral autoregulation (CA) is an important prognostic factor for acute head trauma, but the role of CA in patients with acute encephalitis has not been previously discussed. We present the case of a 30-year-old woman with severe acute encephalitis who underwent craniectomy for intractable increased intracranial pressure (ICP). Preoperatively, adjustments of blood pressure (BP) with simultaneous recording of changes in cerebral blood flow velocity with transcranial Doppler indicated increased ICP and impaired CA. Postoperatively, ICP declined remarkably but CA remained impaired when the relationship between spontaneous fluctuation of mean BP and ICP was analyzed. Increased ICP recurred again within 24 hours of the decompression surgery and caused death of the patient. We propose that evaluating the status of CA could be of prognostic importance in patients with severe encephalitis. [J Formos Med Assoc 2007;106(2 Suppl):S7-S12]