Coffee and tea consumption and dementia risk: The role of sex and vascular comorbidities.

BACKGROUND: Coffee and tea consumption has been linked to dementia. However, it remained unknown how sex and vascular risk factors modify the association. We aimed to investigate the association of coffee and tea consumption with dementia and whether sex and vascular comorbidities modified the association. METHODS: We included 278 elderly patients with Alzheimer's disease (AD) and 102 patients with vascular dementia (VaD) from three hospitals; controls (N = 468) were recruited during the same period. We collected the frequency and amount of coffee and tea consumption and the presence of vascular comorbidities. The multinomial logistic regression model was utilized to evaluate the association of coffee and tea consumption with dementia, stratified by sex and vascular comorbidities. RESULTS: Different combinations and quantities of coffee and tea consumption protected against AD and VaD. Consumption of ≥3 cups of coffee or tea per day was protective against AD [adjusted odds ratio (aOR) = 0.42; 95% confidence interval (CI) = 0.22-0.78)] and VaD (aOR = 0.42; 95% CI = 0.19-0.94). Stratified analyses showed that the protective effects of a higher quantity of coffee and tea against AD were more pronounced among females and individuals with hypertension. Consumption of either coffee or tea was associated with a decreased risk of VaD among diabetic participants (aOR = 0.23; 95% CI = 0.06-0.98). Hyperlipidemia modified the association of coffee or tea consumption on the risk of AD and VaD (both Pinteraction < 0.01). CONCLUSION: The risk of AD and VaD was lower with increased consumption of coffee and tea; the impact differed by sex and vascular comorbidities including hypertension, hyperlipidemia, and diabetes.

More than a piece of cake: Noun classifier processing in primary progressive aphasia.

INTRODUCTION: Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. METHODS: We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. RESULTS: Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. DISCUSSION: This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. HIGHLIGHTS: Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.

Substantia nigra nigrosome-1 imaging correlates with the severity of motor symptoms in Parkinson's disease.

BACKGROUND: Nigrosome-1 imaging has been used for assisting the diagnosis of Parkinson's disease (PD). We aimed to examine the diagnostic performance of loss of nigrosome-1 in PD and the correlation between the size of the nigrosome-1 and motor severity of PD. METHODS: We included 237 patients with PD and 165 controls. The motor severity of PD was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III score and Hoehn-Yahr staging. The 3 or 1.5 Tesla susceptibility-weighted imaging combined with a deep-learning algorithm was applied for detecting the loss and the size of nigrosome-1. Clinical correlations and diagnostic performance of size of nigrosome-1 were also investigated. RESULTS: The mean nigrosome-1 size was significantly smaller in PD patients than in controls (0.06 ± 0.07 cm2 vs. 0.20 ± 0.05 cm2, P < 0.001). The area under the receiver operating characteristic curve (AUC) of the established model showed 0.94 accuracy (95% confidence interval [CI]: 0.87, 1.01, P < 0.01) in differentiating between the PD and control groups. Moreover, the partial loss of nigrosome-1 detected with SWI had an AUC of 0.96 in discriminating early-stage PD from controls (95% CI: 0.88, 1.02, P < 0.001). After adjusting for age, sex, disease duration, and levodopa equivalent daily dose, the estimated size of nigrosome-1 was negatively associated with the UPDRS part III motor score (ρ = -0.433, P < 0.001), but not with Mini-Mental State Examination scores (ρ = 0.006, P = 0.894). CONCLUSIONS: The extent of loss and the size of nigrosome-1 may potentially assist in the diagnosis of PD. Nigrosome-1 size reflects the motor severity of PD.

Brain imaging signatures in amyotrophic lateral sclerosis: Correlation with peripheral motor degeneration.

OBJECTIVE: This study aimed to explore the clinical significance of brain imaging signatures in the context of clinical neurological deficits in association with upper and lower motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: We performed brain MRI examinations to quantitatively evaluate (1) gray matter volume and (2) white matter tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Image-derived indices were correlated with (1) global neurological deficits of MRC muscle strength sum score, revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R), and forced vital capacity (FVC), and (2) focal scores of University of Pennsylvania Upper motor neuron score (Penn score) and the summation of compound muscle action potential Z scores (CMAP Z sum score). RESULTS: There were 39 ALS patients and 32 control subjects matched for age and gender. Compared to controls, ALS patients had a lower gray matter volume in the precentral gyrus of the primary motor cortex, which was correlated with FA of corticofugal tracts. The gray matter volume of the precentral gyrus was correlated with FVC, MRC sum score, and CMAP Z sum score, while the FA of the corticospinal tract was linearly associated with CMAP Z sum score and Penn score on multivariate linear regression model. INTERPRETATION: This study indicated that clinical assessment of muscle strength and routine measurements on nerve conduction studies provided surrogate markers of brain structural changes for ALS. Furthermore, these findings suggested parallel involvement of both upper and lower motor neurons in ALS.

Multimorbid Patterns and Cognitive Performance in the Presence of Informative Dropout Among Community-Dwelling Taiwanese Older Adults.

Background and Objectives: Longitudinal studies among older adults often feature elevated dropout rates and multiple chronic conditions. How Taiwanese multimorbid patterns relate to different cognitive domains remains unclear. This study aims to identify sex-specific multimorbid patterns and associate them with cognitive performance while modeling the risk for dropout. Research Design and Methods: A prospective cohort study (2011-19) in Taiwan recruited 449 Taiwanese older adults without dementia. Global and domain-specific cognition were assessed biennially. We used exploratory factor analysis to identify baseline sex-specific multimorbid patterns of 19 self-reported chronic conditions. We utilized a joint model incorporating longitudinal and time-to-dropout data to examine the association between multimorbid patterns and cognitive performance accounting for the informative dropout via the shared random effect. Results: At the end of the study, 324 participants (72.1%) remained in the cohort, with an average annual attrition rate of 5.5%. We found that advanced age, low levels of physical activities, and poor cognition at baseline were associated with increased dropout risks. Besides, 6 multimorbid patterns were identified, labeled Mental, Renal-vascular, and Cancer-urinary patterns in men, and Mental, Cardiometabolic, and Cancer-endocrine patterns in women. For men, as the follow-up time increased, the Mental pattern was associated with poor global cognition and attention; the Renal-vascular pattern was associated with poor executive function. For women, the Mental pattern was associated with poor memory; as follow-up time increased, and Cardiometabolic patterns were related to poor memory. Discussion and Implications: Sex-specific multimorbid patterns identified in the Taiwanese older population showed differences (notably Renal-vascular pattern in men) from patterns found in Western countries and were differentially associated with cognitive impairment over time. When informative dropout is suspected, appropriate statistical methods should be applied.

The association between retinal vascular fractal dimension and cognitive function in the community-dwelling older adults cohort TIGER.

BACKGROUND/PURPOSE: The small retinal vessels reflect cerebral microcirculation and its fractal dimension (Df), representing the complexity of the retinal microcirculation. However, the connection between retinal circulation and cognitive function lacked consistent and longitudinal evidence. This study aimed to explore the association between retinal vascular complexity and cognitive impairment over time in non-demented community-dwelling older adults. METHODS: This four-year prospective cohort study (2015-2019) is part of the ongoing Taiwan Initiative for Geriatric Epidemiological Research (TIGER, 2011 to present). Of the 434 older adults (age >65) recruited, 207 participants were included for analysis. The retinal vascular Df was assessed by baseline images from fundus photography (2015-2017). Global (Montreal Cognitive Assessment-Taiwanese version, MoCA-T) and domain-specific cognition were assessed at the baseline and 2-year follow-up (2017-2019). The multivariable linear regression models and generalized linear mixed models were used to evaluate the association of Df with cognitive decline/impairment over time. RESULTS: Decreased left retinal vascular complexity was associated with poor attention performance (ß = -0.40). As follow-up time increased, decreased vascular complexity was associated with poor memory performance (right: ß = -0.25; left: ß = -0.19), and decreased right vascular complexity was associated with poor attention performance (ß = -0.18). CONCLUSION: Low retinal vascular complexity of the right or left eye may be differentially associated with cognitive domains in community-dwelling older adults over two years. The retinal vascular Df of either eye may be served as a screening tool for detecting cognitive impairment in the preclinical phase of dementia.

Association of subclinical depressive symptoms and sleep with cognition in the community-dwelling older adults.

BACKGROUND: /Purpose: This study aimed to explore the association of subclinical depressive symptoms and sleep with cognition in community-dwelling Taiwanese older adults. METHODS: This four-year prospective cohort study (2015-2019) included 379 participants aged 65 years or older from the annual senior health checkup program at National Taiwan University Hospital who were followed up two years later. Global and domain cognitive functions were assessed using validated neuropsychological tests. Depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression (CES-D) Scale. Sleep quality was evaluated using the Pittsburg Sleep Quality Index (PSQI). Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Generalized linear mixed models were used to explore the associations of subclinical depressive symptoms and sleep variables with cognition, adjusting for important covariates. Stratification analyses were performed using the sleep variables. RESULTS: Over time, depressive symptoms were associated with poor performance of memory (߈ = 0.24, P = 0.04) and executive function (߈ = -0.24, P = 0.03). Poor sleep quality (elevated PSQI score) was associated with poor memory performance (߈ = -0.04 to -0.03, P < 0.05). Excessive daytime sleepiness (elevated ESS score) was associated with poor performance of memory (߈ = -0.02, P < 0.05) and executive function (߈ = -0.02, P = 0.001). At baseline, better sleep quality and no excessive daytime sleepiness were associated with better memory performance over time. CONCLUSION: Subclinical depressive symptoms, worse sleep quality, and excessive daytime sleepiness were differentially associated with impairment of cognitive domains (mainly memory and executive function).

Grip Strength and Sarcopenia Predict 2-Year Cognitive Impairment in Community-Dwelling Older Adults.

OBJECTIVES: Using the Asian Working Group for Sarcopenia (AWGS2019) and the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria, this study examined associations of sarcopenia and its components with specific domains of cognitive impairment over time. DESIGN: A prospective cohort study with a 2-year follow-up. SETTING AND PARTICIPANTS: This study is part of the Taiwan Initiatives for Geriatric Epidemiological Research (TIGER), which recruited participants aged 65 years old who attended the senior health checkup program at National Taiwan University Hospital (NTUH). METHODS: Grip strength was measured using a handgrip dynamometer. Walking speed (m/s) was measured as the time required to walk 8 feet. Muscle mass was measured by performing a bioelectrical impedance analysis. Global cognition (assessed using the Taiwanese version of the Montreal Cognitive Assessment) and 4 cognitive domains (memory, executive function, verbal fluency, and attention) were assessed over time. Associations of sarcopenia and its components with cognitive impairment were evaluated after stratification by sex using generalized linear mixed models adjusted for essential covariates for cognitive impairment. RESULTS: Compared with robust women, those with severe sarcopenia were more likely to have a global cognitive impairment over time (ß = -0.87, P = .03 based on AWGS2019 criteria and ß = -1.07, P = .02 based on the EWGSOP2 criteria). Among men, low grip strength was associated with poor scores on measures of global cognition (ß = -0.80, P = .03), executive function (ß = -0.35, P = .001), verbal fluency (ß = -0.31, P = .02), and attention (ß = -0.34, P = .008) over time. CONCLUSIONS AND IMPLICATIONS: Severe sarcopenia predicted global and specific domains of cognitive impairment in older adults. Poor grip strength predicted cognitive impairment in men but not in women. A screen for sarcopenia severity and low muscle strength may be used to identify the risk of cognitive impairment.

Machine Learning-Based Classification of Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Dementia Using Neuroimage and Plasma Biomarkers.

Alzheimer's disease (AD) progresses relentlessly from the preclinical to the dementia stage. The process begins decades before the diagnosis of dementia. Therefore, it is crucial to detect early manifestations to prevent cognitive decline. Recent advances in artificial intelligence help tackle the complex high-dimensional data encountered in clinical decision-making. In total, we recruited 206 subjects, including 69 cognitively unimpaired, 40 subjective cognitive decline (SCD), 34 mild cognitive impairment (MCI), and 63 AD dementia (ADD). We included 3 demographic, 1 clinical, 18 brain-image, and 3 plasma biomarker (Aß1-42, Aß1-40, and tau protein) features. We employed the linear discriminant analysis method for feature extraction to make data more distinguishable after dimension reduction. The sequential forward selection method was used for feature selection to identify the 12 best features for machine learning classifiers. We used both random forest and support vector machine as classifiers. The area under the receiver operative curve (AUROC) was close to 0.9 between diseased (combining ADD and MCI) and the controls. AUROC was higher than 0.85 between SCD and controls, 0.90 between MCI and SCD, and above 0.85 between ADD and MCI. We can differentiate between adjacent phases of the AD spectrum with blood biomarkers and brain MR images with the help of machine learning algorithms.

A task-specific cognitive domain decline is correlated with plasma and neuroimaging markers in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a disabling non-motor symptom of Parkinson's disease (PD). It remains uncertain whether declines in specific cognitive domains relate to imaging or plasma biomarkers across the disease continuum. OBJECTIVE: We investigated whether neuroimaging and plasma biomarkers correlate with individual task-specific cognitive domain declines evidenced by computerized neuropsychological tests in PD patients. METHODS: A total of 107 participants, including 87 PD patients (30 with normal cognition [PD-NC], 30 with mild cognitive impairment [PD-MCI], 27 with dementia [PDD]), and 20 healthy controls, were recruited. All received the Cambridge Neuropsychological Test Automatic Battery (CANTAB) test, brain MRI, and assays of plasma biomarkers, including α-synuclein, tau, Aß42, and Aß40. RESULTS: PD patients had generally poorer cognitive performance than controls. Patients with PD-MCI and PDD had worse performance in visual, verbal, and working memory and executive function than those with PD-NC. After adjusting for covariates, PDD patients had global cortical thinning, especially in the temporal and parietal lobes, and higher plasma α-synuclein levels and tau:Aß42 ratios than PD-NC group. Plasma α-synuclein level was associated with frontal lobe-mediated tasks, while the tau:Aß42 ratio was associated with posterior cortical-mediated tasks. Facial emotion recognition tasks and visual pattern recognition associated with frontotemporal cortical thinning. The accuracy of predicting PDD using age alone (area under the curve [AUC] 0.756) increased by incorporating plasma biomarkers (AUC = 0.851, p = 0.025). CONCLUSIONS: Cognitive decline in PD patients has a task-specific correlation with neuroimaging and plasma biomarkers, which may implicate the underlying neuropathological process of PDD.

White matter pathology in alzheimer's transgenic mice with chronic exposure to low-level ambient fine particulate matter.

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.

Distinct brain lipid signatures in response to low-level PM2.5 exposure in a 3xTg-Alzheimer's disease mouse inhalation model.

Fine particulate matter (PM2.5) poses a significant risk to human health. The molecular mechanisms underlying low-level PM2.5-induced neurotoxicity in the central nervous system remain unclear. In addition, changes in lipids in response to PM2.5 exposure have not yet been fully elucidated. In this study, 3xTg-Alzheimer's disease (AD) mice experienced continuous whole-body exposure to non-concentrated PM2.5 for three consecutive months, while control mice inhaled particulate matter-filtered air over the same time span. A liquid chromatography-mass spectrometry-based lipidomic platform was used to determine the distinct lipid profiles of various brain regions. The average PM2.5 concentration during the exposure was 11.38 µg/m3, which was close to the regulation limits of USA and Taiwan. The partial least squares discriminant analysis model showed distinct lipid profiles in the cortex, hippocampus, and olfactory bulb, but not the cerebellum, of mice in the exposure group. Increased levels of fatty acyls, glycerolipids, and sterol lipids, as well as the decreased levels of glycerophospholipids and sphingolipids in PM2.5-exposed mouse brains may be responsible for the increased energy demand, membrane conformation, neuronal loss, antioxidation, myelin function, and cellular signaling pathways associated with AD development. Our research suggests that subchronic exposure to low levels of PM2.5 may cause neurotoxicity by changing the lipid profiles in a susceptible model. Lipidomics is a powerful tool to study the early effects of PM2.5-induced AD toxicity.

Dysgraphia Phenotypes in Native Chinese Speakers With Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: Most primary progressive aphasia (PPA) literature is based on English language users. Linguistic features that vary from English, such as logographic writing systems, are underinvestigated. The current study characterized the dysgraphia phenotypes of patients with PPA who write in Chinese and investigated their diagnostic utility in classifying PPA variants. METHODS: This study recruited 40 participants with PPA and 20 cognitively normal participants from San Francisco, Hong Kong, and Taiwan. We measured dictation accuracy using the Chinese Language Assessment for PPA (CLAP) 60-character orthographic dictation test and examined the occurrence of various writing errors across the study groups. We also performed voxel-based morphometry analysis to identify the gray matter regions correlated with dictation accuracy and prevalence of writing errors. RESULTS: All PPA groups produced significantly less accurate writing responses than the control group and no significant differences in dictation accuracy were noted among the PPA variants. With a cut score of 36 out of 60 in the CLAP orthographic dictation task, the test achieved sensitivity and specificity of 90% and 95% in identifying Chinese participants with PPA vs controls. In addition to a character frequency effect, dictation accuracy was affected by homophone density and the number of strokes in semantic variant PPA and logopenic variant PPA groups. Dictation accuracy was correlated with volumetric changes over left ventral temporal cortices, regions known to be critical for orthographic long-term memory. Individuals with semantic variant PPA frequently presented with phonologically plausible errors at lexical level, patients with logopenic variant PPA showed higher preponderance towards visual and stroke errors, and patients with nonfluent/agrammatic variant PPA commonly exhibited compound word and radical errors. The prevalence of phonologically plausible, visual, and compound word errors was negatively correlated with cortical volume over the bilateral temporal regions, left temporo-occipital area, and bilateral orbitofrontal gyri, respectively. DISCUSSION: The findings demonstrate the potential role of the orthographic dictation task as a screening tool and PPA classification indicator in Chinese language users. Each PPA variant had specific Chinese dysgraphia phenotypes that vary from those previously reported in English-speaking patients with PPA, highlighting the importance of language diversity in PPA.

A Digital Screening System for Alzheimer Disease Based on a Neuropsychological Test and a Convolutional Neural Network: System Development and Validation.

BACKGROUND: Alzheimer disease (AD) and other types of dementia are now considered one of the world's most pressing health problems for aging people worldwide. It was the seventh-leading cause of death, globally, in 2019. With a growing number of patients with dementia and increasing costs for treatment and care, early detection of the disease at the stage of mild cognitive impairment (MCI) will prevent the rapid progression of dementia. In addition to reducing the physical and psychological stress of patients' caregivers in the long term, it will also improve the everyday quality of life of patients. OBJECTIVE: The aim of this study was to design a digital screening system to discriminate between patients with MCI and AD and healthy controls (HCs), based on the Rey-Osterrieth Complex Figure (ROCF) neuropsychological test. METHODS: The study took place at National Taiwan University between 2018 and 2019. In order to develop the system, pretraining was performed using, and features were extracted from, an open sketch data set using a data-driven deep learning approach through a convolutional neural network. Later, the learned features were transferred to our collected data set to further train the classifier. The first data set was collected using pen and paper for the traditional method. The second data set used a tablet and smart pen for data collection. The system's performance was then evaluated using the data sets. RESULTS: The performance of the designed system when using the data set that was collected using the traditional pen and paper method resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.913 (SD 0.004) when distinguishing between patients with MCI and HCs. On the other hand, when discriminating between patients with AD and HCs, the mean AUROC was 0.950 (SD 0.003) when using the data set that was collected using the digitalized method. CONCLUSIONS: The automatic ROCF test scoring system that we designed showed satisfying results for differentiating between patients with AD and MCI and HCs. Comparatively, our proposed network architecture provided better performance than our previous work, which did not include data augmentation and dropout techniques. In addition, it also performed better than other existing network architectures, such as AlexNet and Sketch-a-Net, with transfer learning techniques. The proposed system can be incorporated with other tests to assist clinicians in the early diagnosis of AD and to reduce the physical and mental burden on patients' family and friends.

Evidence of plasma biomarkers indicating high risk of dementia in cognitively normal subjects.

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 Aß1-42 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 Aß1-42 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 Aß1-42 and T-Tau in were significantly higher in the PS, ADFH, diabetes, ESRD and OSA groups than controls (Aß1-42 in PS: 15.43 ± 1.76 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.005; T-Tau in PS: 19.29 ± 8.01 vs. 15.13 ± 3.62 pg/mL, p < 0.005, Aß1-42 in ADFH: 15.52 ± 1.60 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in ADFH: 17.93 ± 6.26 vs. 15.13 ± 3.62 pg/mL, p < 0.005, Aß1-42 in diabetes: 16.15 ± 1.05 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in diabetes: 19.74 ± 2.92 vs. 15.13 ± 3.62 pg/mL, p < 0.001, Aß1-42 in ESRD: 16.52 ± 0.59 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in ESRD: 21.54 ± 2.72 vs. 15.13 ± 3.62 pg/mL, p < 0.001, Aß1-42 in OSA: 15.97 ± 0.54 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in OSA: 20.17 ± 2.77 vs. 15.13 ± 3.62 pg/mL, p < 0.001). This evidence indicates the high risk for dementia in these groups from the perspective of plasma biomarkers.

Prognostic Features of Sporadic Creutzfeldt-Jakob Disease: An Analysis of Taiwan's Nationwide Surveillance.

OBJECTIVES: To study the prognostic features of Creutzfeldt-Jakob disease (CJD) and shed light on its future therapy. DESIGN: Retrospective cohort study of a longitudinal national cohort of the Taiwan Centers for Disease Control. SETTING AND PARTICIPANTS: All patients with suspected CJD are reported to the CJD surveillance unit of the Taiwan Centers for Disease Control. An expert committee discussed the reported cases and designated a consensus-based diagnosis. From 1996 to 2020, a total of 809 cases were referred to the CJD surveillance unit for confirmation; of these, 441 cases (women, n = 230) were determined to be sporadic CJD. METHODS: We investigated the clinical manifestations and laboratory findings for 400 patients diagnosed with definite or probable sporadic CJD. We used Kaplan-Meier analyses and Cox proportional hazards model to identify prognostic factors. RESULTS: The mean age of onset was 67 ± 9.9 years. The mean survival duration was 13.3 ± 14.2 (median 10) months. The leading clinical symptoms were myoclonus (73%) and akinetic mutism (54%). For PRNP polymorphism, 99% of patients (195/197) showed a methionine homozygous genotype at codon 129 (M129M). The sensitivity of periodic sharp wave complexes (PSWCs) on electroencephalograms (EEGs) was 59.7%. The sensitivity of cerebrospinal fluid 14-3-3 protein and total tau protein (>1200 pg/mL) were 69.7% and 75.6%, respectively. Younger patients lived longer than those aged ≥65 years [hazard ratio (HR) 0.466, P < .001]. Women had a better survival probability in the first 3 years than their male counterparts (HR 0.712, P = .005). PSWCs had a persistent negative effect on survival (HR 0.788, P < .05). Although uncommon, epileptic seizures were the only clinical prognostic factor for survival time (HR 0.768, P < .05). PSWCs can be used as an EEG biomarker for prognosis. Epileptic seizures, though not common, are the only clinical prognostic factor for a short survival. CONCLUSIONS AND IMPLICATIONS: We found that a lower age of onset and female gender favor the survival of patients with sCJD. PSWCs are EEG biomarkers unfavorable for survival, and so are epileptic seizures.

Assessment of High Risk for Alzheimer's Disease Using Plasma Biomarkers in Subjects with Normal Cognition in Taiwan: A Preliminary Study.

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-ß 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 Aß1-40, Aß1-42, 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 Aß 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.

The association between metabolic syndrome and successful aging- using an extended definition of successful aging.

OBJECTIVES: To examine the association between metabolic syndrome (MetS) and successful aging among community-dwelling older adults. METHODS: Adults aged ≥ 65 years who participated in the senior health checkup program at National Taiwan University Hospital during 2011-2013 were recruited (N = 467 at baseline). The participants were followed after 4 years and 6 years. MetS was assessed at baseline. Successful aging was evaluated at baseline, 4-year follow-up, and 6-year follow-up. We adopted an extended definition of successful aging, which was defined as three major domains: physiological, psychological, and sociological and economic domains. Generalized linear mixed models were used to assess the association between MetS and successful aging adjusting for time (follow-up years), age, sex, years of education, alcohol consumption and MetS×time interaction term. RESULTS: The mean age of the study population was 72.9 (SD 5.5) years. The absence of baseline MetS had a positive effect on the probability of successful aging over six years. The absences of abdominal obesity, hyperglycemia, reduced high-density lipoprotein cholesterol, and hypertension were associated with the physiological successful aging. The absence of hypertension was the most significant predictor of physiological successful aging [aOR (95% CI) = 2.76 (1.67-4.58), p<0.001]. Significant increased trend was found in the overall and physiological successful aging across MetS status (No MetS, pre MetS, MetS; Ptrend <0.001). CONCLUSIONS: We found that MetS is a risk factor of successful aging among community-dwelling older adults. Public health policy should aim at avoidance of MetS in order to facilitate successful aging in older population.

A Longitudinal Study on the Association of Interrelated Factors Among Frailty Dimensions, Cognitive Domains, Cognitive Frailty, and All-Cause Mortality.

BACKGROUND: Cognitive frailty integrating impaired cognitive domains and frailty dimensions has not been explored. OBJECTIVE: This study aimed to explore 1) associations among frailty dimensions and cognitive domains over time and 2) the extended definitions of cognitive frailty for predicting all-cause mortality. METHODS: This four-year cohort study recruited 521 older adults at baseline (2011-2013). We utilized 1) generalized linear mixed models exploring associations of frailty dimensions (physical dimension: modified from Fried et al.; psychosocial dimension: integrating self-rated health, mood, and social relationship and support; global frailty: combining physical and psychosocial frailty) with cognition (global and domain-specific) over time and 2) time-dependent Cox proportional hazard models assessing associations between extended definitions of cognitive frailty (cognitive domains-frailty dimensions) and all-cause mortality. RESULTS: At baseline, the prevalence was 3.0% for physical frailty and 37.6% for psychosocial frailty. Greater physical frailty was associated with poor global cognition (adjusted odds ratio = 1.43-3.29, ß: -1.07), logical memory (ß: -0.14 to -0.10), and executive function (ß: -0.51 to -0.12). Greater psychosocial frailty was associated with poor global cognition (ß: -0.44) and attention (ß: -0.15 to -0.13). Three newly proposed definitions of cognitive frailty, "mild cognitive impairment (MCI)-psychosocial frailty," "MCI-global frailty," and "impaired verbal fluency-global frailty," outperformed traditional cognitive frailty for predicting all-cause mortality (adjusted hazard ratio = 3.49, 6.83, 3.29 versus 4.87; AIC = 224.3, 221.8, 226.1 versus 228.1). CONCLUSION: Notably, extended definitions of cognitive frailty proposed by this study better predict all-cause mortality in older adults than the traditional definition of cognitive frailty, highlighting the importance of psychosocial frailty to reduce mortality in older adults.

Effectiveness of the 10 cm2 Rivastigmine Patch in Taiwanese Patients with Mild-to-Moderate Alzheimer's Dementia: A 48-Week Real-World Observational Study.

INTRODUCTION: The current study aimed to provide data on the effectiveness of the 10 cm2 rivastigmine patch in patients with Alzheimer's disease (AD) in a real-world setting in Taiwan. METHODS: This was a 48-week, single-arm, open-label, observational, and post-marketing study conducted across seven centers in Taiwan between May 5, 2016 and July 10, 2017. Eligible patients (aged 55-95 years) treated with the 10 cm2rivastigmine patch were enrolled based on physicians' judgment and according to the Taiwan reimbursement criteria of the drug. Data were prospectively collected at Week 0 (baseline), Week 24, and Week 48. The primary endpoint was the change in the cognitive assessment screening instrument (CASI) scores at Week 48 versus baseline. The changes from baseline in clinical dementia rating (CDR), mini-mental state examination (MMSE), and neuropsychiatric inventory (NPI) scores were evaluated, as were treatment persistence and the safety profile. RESULTS: Of the 285 eligible patients [full analysis set (FAS)], 216 (75.8%) completed the study protocol while 180 (63.2%) persisted on the 10 cm2 rivastigmine patch for the full 48 weeks. At baseline, 89.8% of patients had a CDR score of 0.5 or 1, while the change in CDR score at Week 48 was not significant. In the FAS, both the CASI and MMSE scores had numerical improvement at Week 24 but declined by 2.1 and 0.4 points, respectively, at Week 48 (p = 0.005 and p = 0.022). The increment in NPI scores was not significant. The most common drug-related adverse events (AEs) were pruritus (11.2%), nausea (3.5%), rash (3.2%), and vomiting (2.8%). CONCLUSIONS: The use of the 10 cm2 rivastigmine patch in the mild stage of AD maintained cognitive function at Week 24 and neuropsychiatric function at Week 48. The treatment persistency and safety profile support the clinical tolerability of the rivastigmine patch in the management of mild-to-moderate AD in Taiwan.