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Fine particulate matter (PM

Background: In Alzheimer’s disease (AD), cognitive impairment begins 10–15 years later than neurodegeneration in the brain. Plasma biomarkers are promising candidates for assessing neurodegeneration in people with normal cognition. It has been reported that subjects with the concentration of plasma amyloid-β 1-42×total tau protein higher than 455 pg2/ml2 are assessed as having a high risk of amnesic mild impairment or AD, denoted as high risk of AD (HRAD). Objective: The prevalence of high-risk for dementia in cognitively normal controls is explored by assaying plasma biomarkers. Methods: 422 subjects with normal cognition were enrolled around Taiwan. Plasma Aβ1-40, Aβ1-42, and T-Tau levels were assayed using immunomagnetic reduction to assess the risk of dementia. Results: The results showed that 4.6% of young adults (age: 20–44 years), 8.5% of middle-aged adults (age: 45–64 years), and 7.3% of elderly adults (age: 65–90 years) had HRAD. The percentage of individuals with HRAD dramatically increased in middle-aged and elderly adults compared to young adults. Conclusion: The percentage of HRAD in cognitively normal subjects are approximately 10%, which reveals that the potentially public-health problem of AD in normal population. Although the subject having abnormal levels of Aβ or tau is not definitely going on to develop cognitive declines or AD, the risk of suffering cognitive impairment in future is relatively high. Suitable managements are suggested for these high-risk cognitively normal population. Worth noting, attention should be paid to preventing cognitive impairment due to AD, not only in elderly adults but also middle-aged adults.

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.

Introduction Concentrations of plasma biomarkers associated with Alzheimer’s disease have been reported to be as low as several tens of picograms/milliliter (pg/ml). However, in assays measuring these biomarkers, it is likely that repeated measurements are necessary to obtain reliable values. Methods We performed assays as a single test or as duplicate, quadruplicate, fivefold and tenfold repeated tests, on samples spiked with different concentrations of amyloid β 1–40 (Aβ1–40; 1–1000 pg/ml), Aβ1–42 (1–30,000 pg/ml) and total Tau protein (T-Tau; 0.1–1000 pg/ml), with the aim to to calculate the coefficients of variation (CVs). Results The results demonstrated common changes in the CVs with changes in the number of tests for a given sample: the CVs decreased with increases in the number of tests from one to ten. All CV values were distributed within the range of 0.35 to 15.5%; as such, the CV values were all lower than the acceptable value of 20%. Conclusion Based on this study, a single assay of Aβ1–40, Aβ1–42 and T-Tau, respectively, provides reliable results in terms of the measurement of that plasma biomarker.

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 by computerized random sampling from all administrative districts in Taiwan and were assessed by an in-person interview. We calculated the prevalence of MCI and dementia with their risk factors examined by 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. Conclusions 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 between urbanization statuses. Focus on the rural-urban inequality and the modification of associated factors specifically for different urbanization levels are needed.

Beta-amyloid (Aβ

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.

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.

Easily accessible biomarkers for Alzheimer&rsquo, s disease (AD), Parkinson&rsquo, s disease (PD), frontotemporal dementia (FTD), and related neurodegenerative disorders are urgently needed in an aging society to assist early-stage diagnoses. In this study, we aimed to develop machine learning algorithms using the multiplex blood-based biomarkers to identify patients with different neurodegenerative diseases. Plasma samples (n = 377) were obtained from healthy controls, patients with AD spectrum (including mild cognitive impairment (MCI)), PD spectrum with variable cognitive severity (including PD with dementia (PDD)), and FTD. We measured plasma levels of amyloid-beta 42 (A&beta, 42), A&beta, 40, total Tau, p-Tau181, and &alpha, synuclein using an immunomagnetic reduction-based immunoassay. We observed increased levels of all biomarkers except A&beta, 40 in the AD group when compared to the MCI and controls. The plasma &alpha, synuclein levels increased in PDD when compared to PD with normal cognition. We applied machine learning-based frameworks, including a linear discriminant analysis (LDA), for feature extraction and several classifiers, using features from these blood-based biomarkers to classify these neurodegenerative disorders. We found that the random forest (RF) was the best classifier to separate different dementia syndromes. Using RF, the established LDA model had an average accuracy of 76% when classifying AD, PD spectrum, and FTD. Moreover, we found 83% and 63% accuracies when differentiating the individual disease severity of subgroups in the AD and PD spectrum, respectively. The developed LDA model with the RF classifier can assist clinicians in distinguishing variable neurodegenerative disorders.

Objectives Recent neuropathological research suggests that recognition memory supported by familiarity rather than recollection may be the earliest cognitive change in course of Alzheimer's disease (AD). Nonetheless, the findings on the issue of familiarity capacity in the prodromal AD remain inconsistent. Boundary extension (BE), in which the view recollected by the subject covers a wider angle than was actually observed, is a form of false memory. Given that BE occurs implicitly and automatically, it may be a candidate for assessing familiarity functioning in cases of AD. This was the issue explored in the current study. Methods : One-hundred and six participants comprising a younger adult group (YA, n = 40), a healthy older adult group (OA, n = 40), and a group of patients with mild cognitive impairment (MCI, n = 26) underwent testing for BE and neuropsychological functions. Parts of OA and MCI underwent analysis for plasma tau levels. Receiver-operating characteristic analysis was used to assess memory associated with familiarity and recollection among participants. Results : The OA and MCI groups could be differentiated by the degree of familiarity associated with BE, wherein the latter group displayed minimal familiarity. Among OAs, familiarity was positively associated with education level. We observed a correlation between plasma tau levels and various neuropsychological functions. Most of the associations between plasma tau levels and neuropsychological functions were mediated by education level. Conclusions : Our findings indicate that BE could detect early decline in familiarity and assess preserved cognitive functions in aging

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.

To fill the gap in knowledge about associations of health-related quality of life (HRQoL) with comorbid diabetes mellitus (DM), hypertension (HTN), and/or mild cognitive impairment (MCI) in the elderly, we explored associations of comorbid DM, HTN, and/or MCI with HRQoL. Data for this study were from a population-based cross-sectional survey of elderly Taiwanese (≥ 65 years old). Participants (N = 4,634; 47.9% male) were categorized into eight chronic-illness groups: DM only (n = 224); HTN only (n = 1226); DM and HTN (n = 365); MCI only (n = 497); DM and MCI (n = 58); HTN and MCI (n = 303); DM, HTN, and MCI (n = 101); and none (healthy; n = 1860). Associations were examined between the eight chronic-illness groups and HRQoL (measured by EQ-5D scores) using binary logistic regression analyses and generalized linear models adjusted for covariates. Index scores were calculated from EQ-5D scores using Taiwan’s general population-preference weights. Compared to the healthy group, after adjusting covariates, MCI alone or with other comorbidities was significantly, negatively associated with HRQoL. Among all chronic-illness groups, comorbid DM, HTN, and MCI exhibited the lowest HRQoL. After adjusting covariates, between-group odds ratios for index scores were significant when comparing comorbid DM and MCI to DM only, comparing comorbid HTN and MCI to HTN only and comorbid DM, comparing HTN and MCI to comorbid DM and HTN, suggesting that MCI additively affects HRQoL. HRQoL of older Taiwanese adults was negatively associated with having MCI. Thus, clinicians managing older persons with chronic illnesses should assess their cognitive function to identify high-risk groups needing HRQoL assistance.

Recent study has suggested semantic memory deterioration may be the earliest cognitive changes in Alzheimer's disease (AD). Few previous researchers have investigated specific changes in the semantic structures in the memory of patients with amnestic mild cognitive impairment (aMCI). This study examined the clustering performance in semantic fluency among 160 participants in various MCI subgroups (aMCI single domain, aMCI-sd, n = 30; aMCI multiple domain, aMCI-md, n = 30; non-aMCI multiple domain, naMCI-md, n = 10) as well as a group of mildly impaired individuals with dementia of AD type (DAT, n = 20), and a group of healthy controls (HC, n = 70). Compared with HC group, DAT patients presented deficient clustering in each semantic category related to living things. aMCI-sd group presented defective clustering when dealing with the clustering of items that may be more strongly associated with praxis and perceptual information in the categories that included inanimate living things. aMCI-md group displayed defective patterns similar to those in the aMCI-sd group; however, they displayed more profound deficits in clustering that may require perceptual information. Patients with naMCI-md preserved their ability to perform clustering on all of the categories. The poor clustering of items that may be more strongly associated with praxis could be used as a means of predicting conversion from aMCI-sd to DAT, whereas performance on items that may require perceptual information could be used to predict conversion among aMCI-md patients. These findings demonstrate the degree to which the semantic structures in memory can be used for the assessment of aMCI patients and prediction of conversion to DAT.

Background many people living with dementia remain underdiagnosed and unrecognised. Screening strategies are important for early detection. Objective to examine whether the Lawton's Instrumental Activities of Daily Living (IADL) scale, compared with other cognitive screening tools-the Mini-Mental State Examination (MMSE), and the Ascertain Dementia 8-item Informant Questionnaire (AD8)-can identify older (≥ 65 years) adults with dementia. Design population-based cross-sectional observational study. Setting all 19 counties in Taiwan. Participants community-dwelling older adults (n = 10,340; mean age 74.87 ± 6.03). Methods all participants underwent a structured in-person interview. Dementia was identified using National Institute on Aging-Alzheimer's Association core clinical criteria for all-cause dementia. Receiver operator characteristic curves were used to determine the discriminant abilities of the IADL scale, MMSE and AD8 to differentiate participants with and without dementia. Results we identified 917 (8.9%) participants with dementia, and 9,423 (91.1%) participants without. The discriminant abilities of the MMSE, AD8 and IADL scale (cutoff score: 6/7; area under curve = 0.925; sensitivity = 89%; specificity = 81%; positive likelihood ratio = 4.75; accuracy = 0.82) were comparable. Combining IADL with AD8 scores significantly improved overall accuracy: specificity = 93%; positive likelihood ratio = 11.74; accuracy = 0.92. Conclusions our findings support using IADL scale to screen older community-dwelling residents for dementia: it has discriminant power comparable to that of the AD8 and MMSE. Combining the IADL and the AD8 improves specificity.

Long-term electroencephalogram (EEG) monitoring is effective for epilepsy diagnosis. However, it also takes a lot of time for clinicians to correctly interpret the long-time recordings. Real-time computer-based EEG monitoring and classification systems have attracted recently the attention of researchers to help clinicians locate online possible epileptic-form EEG signals. In this paper, we first present an accurate and fast EEG classification algorithm that can recognize three types of EEG signals: normal, spike, and seizure. 16-channel bipolar EEG recordings of epilepsy patients are preprocessed, segmented, and ensemble empirical mode decomposed (EEMD) into intrinsic mode functions (IMFs). Features are extracted and linear discriminant analysis (LDA) is applied to train two classifiers: one is for seizure and non-seizure discrimination, and the other is for normal and spike discrimination. In order to furthermore help the clinicians, the results of LDA are visualized and sonified. The changes of the discriminant in the LDA on continuous EEG segments are backtracked to each feature, and thus to each EEG channel. Accordingly, contours of the changes in EEG channels are depicted. At the same time, sinusoidal waves in 440 or 880 Hz are played when EEG segments are classified into spike or seizure respectively. In the experiment, EEG recordings of six subjects (two normal and four seizure patients) are examined. The experiment result shows that the accuracy of the proposed epileptic EEG classification algorithm is relatively high. In addition, the visualization and sonification algorithms of epileptic-form EEG may greatly help clinicians localize the focus of seizure and nurses take care of seizure patients, immediately.

This study investigated the associations of cognitive status with specific/overall health-related quality of life (HRQoL) in older stroke survivors in Taiwan.A subsample of 592 older stroke survivors in a nationwide population-based survey of cognitive-dysfunction prevalencewas analyzed. HRQoL was assessed using the EuroQol five-dimension questionnaire (EQ-5D).Stroke survivors with dementia were 5.60 times more likely to have mobility problems, 12.20 times to have self-care problems, 16.61 times to have problems in usual activities, 4.31 times to have pain/discomfort, and 3.28 times to have anxiety/depression than stroke survivors with normal cognitive function. Stroke survivors with mild cognitive dysfunction (MCD) were 2.57 times more likely to have mobility problems, 3.17 times to have self-care problems, 3.31 times to have problems in usual activities, 2.11 times to have pain/discomfort, and 2.35 times to have anxiety/depression than those with normal cognitive function. Both dementia (b = -15.13, p.001) and MCD (b = -6.24, p.001) significantly contributed to lower EQ-5D VAS; both dementia (b = -.15, p.001) and MCD (b = -.10, p.001) significantly contributed to lower EQ-5D index.Dementia and MCD strongly predicted worse overall and specific HRQoL dimensions, especially self-care and usual activities for older stroke survivors.

Introduction A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial. Methods UB-311 is constructed with two synthetic Aβ1–14–targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Mini–Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study–Clinician's Global Impression of Change (ADCS-CGIC). Results UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1–42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1–10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia. Discussion The UBITh® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).

Label-free high-resolution visualization of Alzheimer’s disease (AD) neuropathological hallmark, amyloid β (Aβ) plaques, is one of the prime goals of neuroscience. Till today, traditional histological procedures, which rely on fixation and tedious staining of tissues, can only provide definitive confirmation of AD. However, recent studies have shown that label-free third harmonic generation (THG) microscopy, a virtual transition based technology, can provide structural information of biological tissues with subcellular 3D resolution. In this study, using a 1263 nm Cr: Forsterite laser source, we performed THG studies on 3xTg AD mice brain tissues in vitro, with a focus on contrast origin evaluation for plaques. Our THG study can clearly differentiate, with very high resolution, neuropathological hallmark of AD: Aβ plaques. Moreover, THG can also distinguish white and gray matter along with axons, and soma of brain. The origin of THG contrasts for various structures of brain including AD pathological hallmarks were verified through standard immunohistochemical staining procedures. Our preliminary study has successfully demonstrated the capability of THG in revealing AD histopathological features with sub-femtoliter resolution without the need of any exogenous staining of the tissues.

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.

Additional file 1.

Dementia frequently occurs in Down syndrome (DS) patients, and early intervention is important in its management. We have previously demonstrated a positive correlation of plasma β-amyloid Aβ42 levels and negative correlations of Aβ40 and tau levels with dementia in DS. In this study, we examined more cases and constructed composite scores with both tau and amyloids to correlate with dementia in DS. Plasma Aβ42, Aβ40, and tau proteins were measured by an immunomagnetic reduction assay in DS patients. Data were randomly and repeatedly split into training and validating sets, and logistic regression was applied to calculate the area under the curve (AUC) for each biomarker. A total of 73 DS patients (among them, 23 had neurodegeneration) and 77 controls were recruited. In DS patients without dementia, plasma Aβ40 and tau levels were highly elevated, but Aβ42 levels were lower than those of the healthy controls. DS patients with dementia, compared with DS patients with no dementia, had a large decline in Aβ40 and tau but a rise in Aβ42. For biomarker scores correlating with dementia, Aβ40 revealed an AUC of 0.912; the composite score of Aβ40 × tau revealed an AUC of 0.953; and a combined composite score of 0.1 for Aβ40 × Tau +0.9 Tau × Aβ40/Aβ42 achieved the highest AUC of 0.965. Therefore, composite biomarker scores including both plasma tau and β-amyloid levels correlate with dementia in DS better than using individual biomarker scores. The pattern of tau decline and Aβ42 rise in DS patients with dementia are also different from previous findings in Alzheimer's disease.

Multicolor fluorescence imaging has been widely used by neuroscientists to simultaneously observe different neuropathological features of the brain. However, these optical modalities rely on exogenous labeling. Here, we demonstrate, for the first time, a label-free additive-color multi-harmonic generation microscopy to elucidate, concurrently with different hues, Alzheimer’s disease (AD) neuropathological hallmarks: amyloid β (Aβ) plaques and neurofibrillary tangles (NFT). By treating third harmonic generation (THG) and second harmonic generation (SHG) as two primary colors, our study can simultaneously label-free differentiate AD hallmarks by providing different additive colors between Aβ plaques, NFT, and neuronal axons, with weaker THG presentation from NFT in most places of the brain. Interestingly our pixel-based quantification and Pearson’s correlation results further corroborated these findings. Our proposed label-free technique fulfills the unmet challenge in the clinical histopathology for stain-free slide-free differential visualization of neurodegenerative disease pathologies, with a sub-femtoliter resolution in a single image field-of-view.

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., A 66‐year‐old man presented with progressive executive dysfunction, personality and behavioral changes, memory decline, and asymmetric motor symptoms. Brain molecular imaging revealed amyloid and tau retention, which suggest the diagnosis of frontal variant of Alzheimer's disease.

Identification of subjects at the early stages of Alzheimer's disease (AD) is fundamental for drug development and possible intervention or prevention of cognitive decline. The concept of mild cognitive impairment (MCI) evolved during the past two decades to define subjects at the transitional stage between normal aging and dementia. Evidence from cross-sectional and longitudinal studies has shown that MCI is associated with an increased risk of positive AD biomarkers and an increased annual conversion rate of 5%-17% to AD. The presence of AD biomarkers in subjects with MCI was associated with an even higher risk of progression to dementia. However, earlier clinical trials for pharmacotherapy in subjects with MCI were disappointing. To extend the spectrum of AD to an earlier stage before MCI, subjective cognitive decline (SCD) was introduced and was defined as self-reported cognitive decline before the deficits could be detected by cognitive tests. Subjects with SCD have an increased risk of underlying AD pathology. However, SCD can also develop secondary to other heterogeneous etiologies, including other neurodegenerative and psychiatric diseases, personality traits, physical conditions, and medication use. Several clinical and biomarker features were proposed to predict risk of conversion to AD in subjects with SCD. Further longitudinal studies are needed to support the validity of these high-risk features.

This study sought to determine predictors for successful endovascular treatment in patients with chronic carotid artery occlusion (CAO).Endovascular recanalization in patients with chronic CAO has been reported to be feasible, but technically challenging.Endovascular attempts in 138 consecutive chronic CAO patients with impaired ipsilateral hemisphere perfusion were reviewed. We analyzed potential variables including epidemiology, symptomatology, angiographic morphology, and interventional techniques in relation to the technical success.The technical success rate was 61.6%. Multivariate analysis showed absence of prior neurologic event (odds ratio [OR]: 0.27; 95% confidence interval [CI]: 0.10 to 0.76), nontapered stump (OR: 0.18; 95% CI: 0.05 to 0.67), distal internal carotid artery (ICA) reconstitution via contralateral injection (OR: 0.19; 95% CI: 0.05 to 0.75), and distal ICA reconstitution at communicating or ophthalmic segments (OR:0.12; 95% CI: 0.04 to 0.36) to be independent factors associated with lower technical success. Point scores were assigned proportional to model coefficients, and technical success rates were80% and 40% in patients with scores of ≤1 and ≥4, respectively. The c-indexes for this score system in predicting technical success was 0.820 (95% CI: 0.748 to 0.892; p 0.001) with a sensitivity of 84.7% and a specificity of 67.9%.Absence of prior neurologic event, nontapered stump, distal ICA reconstitution via contralateral injection, and distal ICA reconstitution at communicating or ophthalmic segments were identified as independent negative predictors for technical success in endovascular recanalization for CAO.

We thank Rumund et al. for interest in and comment on our article.1 Rumund et al. described the blood NfL levels' increase in patients with multiple system atrophy (MSA) in their study,2 which is consistent with our findings. By contrast, they found no significant difference between patients with Parkinson disease (PD) and controls. One of the reasons may come from the number and severity of recruited patients with PD. Our findings revealed that the blood NfL levels were comparable between patients with Hoehn-Yahr stage I–II and controls. However, it was significantly increased in patients with Hoehn-Yahr stage IV–V.2 A recent study assaying the longitudinal dynamics of blood NfL levels found that NfL levels were similar between subjects at the prodromal phase and controls; however, subjects—who later converted to motor PD—had a significant increase of age-dependent acceleration of NfL levels.3 Furthermore, another recent study revealed that the blood NfL levels were increased in de novo patients with PD and were associated with poor cognitive performance.4 This emerging evidence suggests that the blood NfL level is a promising marker for PD progression, albeit the diagnostic cutoff values remain to be determined by well-designed large-scale longitudinal studies.

Blood-based biomarker assays of plasma β-amyloid (Aβ) and tau have the advantages of cost-effective and less invasive for the diagnosis of Alzheimer's disease (AD). We used two independent cohorts to cross-validate the clinical use of the nanoparticle-based immunomagnetic assay of plasma biomarkers to assist in the differential diagnosis of early AD. There were in total 160 subjects in the derivation cohort, and 242 in the validation cohort both containing controls, mild cognitive impairment due to AD and AD dementia diagnosed according to the 2011 NIA-AA guidelines. The cutoff value for plasma Aβ1–42 (16.4 pg/ml) performed the best in differentiating between controls and patients with prodromal or clinical AD, with 92.5% for positive percent agreement (PPA), negative percent agreement (NPA), and overall rate of agreement (ORA). Aβ1–42 × tau (642.58) was useful for separating patients with dementia and prodromal states of AD, with 84.9% PPA, 78.8% NPA and 83% ORA.

[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.

Background: To examine the relationships between cognitive dysfunction status and quality of life. Methods: Secondary analysis of a nationwide population-based survey (≥65 years) in Taiwan. The 5-dimension EuroQoL questionnaire (EQ-5D) was completed by 10 013 participants. Results: Participants with mild cognitive impairment (MCI; odds ratio = 4.88), very mild dementia (VMD; 7.96), or dementia (32.85) were more likely than those with normal cognition to report self-care problems. Participants with MCI (3.86), VMD (9.26), or dementia (31.61) were more likely to have usual-activity problems, and those with MCI (3.04), VMD (3.82), or dementia (9.23) were more likely to have mobility problems. Participants with MCI (2.10 and 2.14), VMD (2.77 and 2.18), or dementia (3.04 and 3.02) were more likely to report pain/discomfort and anxiety/depression. Conclusion: Dementia was negatively associated with EQ-5D, especially self-care, usual activities, and mobility. Mild cognitive impairment or VMD was also negatively associated, with VMD more negatively associated. Developing interventions for patients with specific cognitive dysfunctions is critical.

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%.

Increases in plasma of β-amyloids (Aβ) and tau proteins have been noted in patients with Alzheimer’s dementia (AD). Our study investigated the associations of plasma Aβ and tau proteins with dementia in stroke patients. This cross-sectional study recruited 24 controls (mean age: 67.4 ± 7.5 years, 33.3% male), 27 stroke patients without dementia (mean age: 70.7 ± 6.9 years, 60.7% male), 34 stroke patients with dementia (mean age: 78.3 ± 5.3 years, 45.5% male, Clinical Dementia Ranking (CDR): 1.46 ± 0.63), and 21 AD patients (mean age: 77.1 ± 9.1 years, 42.9% male, CDR: 1.43 ± 0.60) from a medical center. Dementia was defined as a CDR scale score of ≥ 1. The plasma levels of Aβ-40, Aβ-42, and tau were analyzed using immunomagnetic reduction. One-way analysis of variance was used to compare the differences in measured protein levels between the groups. The results indicated that plasma levels of tau and Aβ-42, but not Aβ-40, in stroke patients were significantly higher than in the controls. After adjustment for age, sex, diabetes mellitus, hypertension, and hyperlipidemia, only plasma level of Aβ-42 remained significantly higher in stroke patients with dementia than in those without dementia (OR 1.85, 1.25–2.75, p = 0.002). In summary, our results suggest that plasma Aβ-42 is a potential biomarker for dementia in stroke patients.

ObjectiveTo examine whether plasma neurofilament light chain (NfL) levels were associated with motor and cognitive progression in Parkinson disease (PD).MethodsThis prospective follow-up study enrolled 178 participants, including 116 with PD, 22 with multiple system atrophy (MSA), and 40 healthy controls. We measured plasma NfL levels with electrochemiluminescence immunoassay. Patients with PD received evaluations of motor and cognition at baseline and at a mean follow-up interval of 3 years. Changes in the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score and Mini-Mental State Examination score were used to assess motor and cognition progression.ResultsPlasma NfL levels were significantly higher in the MSA group than in the PD and healthy groups (35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/mL, respectively, p < 0.001). In the PD group, NfL levels were significantly elevated in patients with advanced Hoehn-Yahr stage and patients with dementia (p < 0.001). NfL levels were modestly correlated with UPDRS part III scores (r = 0.42, 95% confidence interval 0.46–0.56, p < 0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox regression analysis adjusted for age, sex, disease duration, and baseline motor or cognitive status showed that higher baseline NfL levels were associated with higher risks for either motor or cognition progression (p = 0.029 and p = 0.015, respectively).ConclusionsPlasma NfL levels correlated with disease severity and progression in terms of both motor and cognitive functions in PD.Classification of evidenceThis study provides Class III evidence that plasma NfL level distinguishes PD from MSA and is a surrogate biomarker for PD progression.

The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.

The feasibility of assaying plasma phosphorylated tau protein (threonine 181), denoted p-tau181, using immunomagnetic reduction (IMR) is explored. The reagent for assaying p-tau181 with IMR was synthesized, and its analytic performances were characterized. Seventy-three subjects were recruited. Each participant was examined with neuropsychological tests, magnetic resonance imaging, and IMR assay for plasma p-tau181. Using commercially available IMR kits, the plasma total tau protein (T-tau) of each subject was assayed. The dynamic range for assaying p-tau181 using IMR was 1.96×10-2 pg/ml to 104 pg/ml. There was no significant interference from total tau protein in the assay of p-tau181. The measured concentrations of plasma p-tau181 were 2.46±1.09 pg/ml for healthy controls, 4.41±1.85 pg/ml for MCI due to AD, and 6.14±1.59 pg/ml for very mild AD. Meanwhile, the measured concentrations of plasma T-tau were 18.85±10.16 pg/ml for healthy controls, 32.98±10.18 pg/ml for MCI due to AD, and 37.54±12.29 pg/ml for very mild AD. A significant difference in plasma p-tau181 was observed between healthy controls and MCI due to AD (p < 0.001) and between MCI due to AD and very mild AD (p < 0.001). However, for the plasma T-tau concentration, a significant difference existed only between healthy controls and MCI due to AD (p < 0.001). This implies that the plasma p-tau181 level is correlated more to AD severity than plasma T-tau is. Additionally, p-tau181 was observed as approximately 14% of T-tau in human plasma.

Background: Evidence of the associations of dietary habits and body mass index with dementia is inconsistent and limited in East Asian countries. Objective: We aim to explore the associations of dietary habits and body mass index with the odds of dementia. Design: Cross-sectional observational study. Setting: A nationwide, population-based, door-to-door, in-person survey. Participants: Selected by computerized random sampling from all 19 counties in Taiwan. Measurement: Diagnosis of dementia using the criteria recommended by the National Institute on Aging-Alzheimer’s Association. Lifestyle factors, dietary habits and demographic data were compared between normal subjects and participants with dementia. Results: A total of 10432 residents were assessed, among whom 2049 were classified as having a mild cognitive impairment (MCI), 929 were diagnosed with dementia, and 7035 were without dementia or MCI. After adjustment for age, gender, education, body mass index (BMI), dietary habits, habitual exercises and co-morbidities, including hypertension, diabetes and cerebrovascular diseases, we found inverse associations of dementia with the consumption of fish (OR 0.62, 95% CI 0.41-0.94), vegetables (OR 0.35, 95% CI 0.13-0.95), coffee (OR 0.59, 95% CI 0.35-0.97), green tea (OR 0.51, 95% CI 0.34-0.75) and other types of tea (OR 0.41, 95% CI 0.28-0.60). There was no association between dementia and fruit consumption. Compared with people who had a normal BMI (18 < BMI

BACKGROUND Polypharmacy, defined as the concomitant use of 5 or more medications, has a documented negative association with cognitive impairment such as delirium and is associated, potentially, with a higher risk of dementia. However, whether polypharmacy contributes to increased risk of mild cognitive impairment (MCI) or decreased cognitive capacity requires further investigation. This nationwide population survey investigated the association among polypharmacy, MCI, and dementia. METHODS Through random sampling based on the proportion of all Taiwan counties, subjects were recruited and received in-person interviews between December 2011 and March 2013. Demographic data and clinical information included medical histories, medication use, and mental status measured by the Taiwanese Mini-Mental State Examination (TMSE) and Clinical Dementia Rating (CDR). Data on lifestyle and habits were collected, and subjects were distributed to cognitively normal, MCI, or all-cause dementia groups based on criteria by the National Institute on Aging and the Alzheimer's Association. RESULTS A total of 7,422 people aged 65 years or older were recruited. After adjustment for age, sex, body mass index, education, medical comorbidities, and lifestyle and habits, polypharmacy was associated with a 1.75-fold increased odds of MCI and 2.33-fold increased odds of dementia. Polypharmacy was associated with a 0.51-point decrease in TMSE scores (P = .001) and a 0.10-point increase in CDR score (P < .001). Additionally, for those without specific vascular comorbidities, polypharmacy had a greatly more negative impact on cognitive capacity. CONCLUSIONS Polypharmacy is common in the elderly and is associated with significantly lower cognitive capacity and higher risks of MCI and dementia, especially for persons without diabetes, hypertension, hyperlipidemia, or cerebrovascular diseases.

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.

Objective Evaluating social-functioning impairments in patients with Alzheimer's disease (AD) objectively is essential for clinical service. However, the existing instruments lack representative content, consensus on purposes of use, and adequate scoring systems and samples. This study was thus to develop a social functioning scale for patients: the Social Functioning Scale for Alzheimer's Disease (SFSAD). Method Questionnaires were analyzed from 142 AD patients, 30 patients with amnestic mild cognitive impairment (aMCI), and 50 normal controls. Results Based on the literature review and experts' opinions, the final scale includes 20 items in four subscales. The SFSAD showed high internal consistency coefficients (Cronbach's α = .97) and test-retest reliability (r = .99) coefficients. The content validity was desirable, and the criterion-related validity was demonstrated by a significant association with the MMSE, the IADL, and the Barthel ADL. The discriminant validity of the scale was also demonstrated as the level of social-functioning impairment was significantly related to the degree of dementia, and for construct validity, our findings supported the structure of the four-factor hypothesized model. Conclusions The SFSAD is thus a practical, psychometrically sound, and easy-to-administer measure to evaluate social functioning of AD and aMCI in brisk clinical settings.