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Alzheimer’s disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient’s cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a destructive disease of wheat that seriously threatens production safety in wheat-producing areas worldwide. In China, the disease has been largely controlled with the fungicide triadimefon. Although high levels of fungicide resistance in other fungal pathogens have been reported, failure to control Pst with any fungicides has seldomly been reported, and fungicide sensitivity of Pst has not been evaluated in China. The distribution of triadimefon-resistant Pst isolates was investigated in the present study. The baseline sensitivity of 446 Pst isolates across the country to triadimefon was determined, and the concentration for 50% of maximal effect showed a unimodal distribution curve, with a mean value of 0.19 μg ml−1. The results indicated a wide range of sensitivity to triadimefon, with more insensitive isolates collected from Pst winter-increasing areas and northwest oversummering areas, whereas more sensitive isolates were collected from southwest oversummering areas and epidemic areas of Xinjiang and Tibet. The majority of the tested Pst isolates were sensitive to triadimefon; only 6.79% had developed varying degrees of resistance. Characterization of parasitic fitness revealed that the triadimefon-resistant isolates exhibited strong adaptive traits in the urediniospore germination rate, latent period, sporulation intensity, and lesion expansion rate. Positive cross-resistance was observed between triadimefon and tebuconazole or hexaconazole, but not between pyraclostrobin or flubeneteram. The point mutation Y134F in the 14α-demethylase enzyme (CYP51) was detected in triadimefon-resistant isolates. A molecular method (kompetitive allele-specific PCR) was established for the rapid detection of Y134F mutants in the Pst population. Two genotypes with one point mutation Y134F conferred resistance to triadimefon in Pst. The risk of resistance to triadimefon in Pst may be low to moderate. This study provided important data for establishment of high throughput molecular detection methods, fungicide resistance risk management, and the development of new target fungicides.

Treatment of depression with antidepressants is partly effective. Transcranial alternating current stimulation can provide a non-pharmacological alternative for adult patients with major depressive disorder. However, no study has used the stimulation to treat first-episode and drug-naïve patients with major depressive disorder. We used a randomized, double-blind, sham-controlled design to examine the clinical efficacy and safety of the stimulation in treating first-episode drug-naïve patients in a Chinese Han population. From 4 June 2018 to 30 December 2019, 100 patients were recruited and randomly assigned to receive 20 daily 40-min, 77.5 Hz, 15 mA, one forehead and two mastoid sessions of active or sham stimulation (n = 50 for each group) in four consecutive weeks (Week 4), and were followed for additional 4-week efficacy/safety assessment without stimulation (Week 8). The primary outcome was a remission rate defined as the 17-item Hamilton Depression Rating Scale (HDRS-17) score ≤ 7 at Week 8. Secondary analyses were response rates (defined as a reduction of ≥ 50% in the HDRS-17), changes in depressive symptoms and severity from baseline to Week 4 and Week 8, and rates of adverse events. Data were analysed in an intention-to-treat sample. Forty-nine in the active and 46 in the sham completed the study. Twenty-seven of 50 (54%) in the active treatment group and 9 of 50 (18%) in the sham group achieved remission at the end of Week 8. The remission rate was significantly higher in the active group compared to that in the sham group with a risk ratio of 1.78 (95% confidence interval, 1.29, 2.47). Compared with the sham, the active group had a significantly higher remission rate at Week 4, response rates at Weeks 4 and 8, and a larger reduction in depressive symptoms from baseline to Weeks 4 and 8. Adverse events were similar between the groups. In conclusion, the stimulation on the frontal cortex and two mastoids significantly improved symptoms in first-episode drug-naïve patients with major depressive disorder and may be considered as a non-pharmacological intervention for them in an outpatient setting.

This review aimed to explore the concept, etiology, classification, classical cortical mapping, assessment, diagnosis and differential diagnosis, treatment, rehabilitation, mechanism, recovery, prognosis, and influencing factors for Chinese post‐stroke aphasia (PSA). The review emphasized the necessity and significance of neuroimaging assessment of brain and blood vessels and neuropsychological assessment in diagnosis and differential diagnosis of Chinese PSA. In addition, it suggested and recommended to use “dichotomies of internal and external, and anterior and posterior” as a starting point, based on the anatomic location of brain and blood vessels and their relationship with language area and language disorder. As a result, the formulated Chinese PSA classification was more suitable to guide the clinical treatment of cerebral stroke. Diagnosis, classification, and differential diagnosis of Chinese PSA types were performed according to the “dichotomy” and “four elements.” The formulated “flow diagram” enabled to determine the classification of Chinese PSA types. It was beneficial for patients to establish targeted and individualized rehabilitation training plans. This review introduced the use of memantine, piracetam, donepezil, etc. in PSA treatment, evaluated clinical studies conducted in China and abroad, investigated the mechanism of action related to the use of drugs in PSA treatment, and explored the therapeutic mechanism of rehabilitation training. It suggested the use drugs of memantine, piracetam, donepezil, etc. combine with non‐pharmacotherapy and rehabilitation training in clinical studies on PSA treatment and also in practical settings., This review aimed to explore the concept, etiology, classification, classical cortical mapping, assessment, diagnosis and differential diagnosis, treatment, rehabilitation, mechanism, recovery, prognosis, and influencing factors for Chinese post‐stroke aphasia (PSA).

Alzheimer's disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient's cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.

White matter hyperintensities (WMHs) on magnetic resonance imaging are commonly found in older adults. The mechanisms underpinning the dose-dependent association between WMH severity and cognition are not well understood. This study aimed to investigate how brain activity changes with WMH severity, and if altered brain activity mediates the relationship between WMH and cognitive function. A total of 35 participants with moderate to severe WMHs (Fazekas grade 2 or 3) and 34 participants with mild WMHs (Fazekas grade 1), who were cognitively normal, were included. Resting-state brain function was analyzed using the amplitude of low-frequency fluctuation (ALFF). A mean fractional anisotropy (FA) value of 20 tract-specific regions of interest was calculated. Mediation analysis was used to assess whether ALFF values mediated the relationship between WMH and cognition. The results showed that compared to those with mild WMHs, participants with confluent WMHs had worse memory and naming ability and also had increased ALFF in the right middle frontal gyrus and decreased ALFF in the left middle occipital gyrus. After controlling for age, gender, education and apolipoprotein E (ApoE) e4 status, increased ALFF in the right prefrontal cortex was associated with worse immediate recall and recognition, and ALFF values mediated the relationships between both Fazekas scores and FA values and memory. In conclusion, our study suggests that cognitively normal adults with high WMH load exhibit subclinical cognitive dysfunction and altered spontaneous brain activity. The mediating effects of brain activity help to shed light on our understanding of the relationship between WMHs and cognition.

Introduction Leptomeningeal amyloidosis (LA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges. Of >120 TTR mutations identified, few have been associated with LA. Case report A 27-year-old male presented with a 2-year history of progressive symptoms including cognitive decline and right-sided weakness and numbness. Cerebrospinal fluid (CSF) analyses demonstrated high protein level. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed extensive leptomeningeal enhancement over the surface of the brain and spinal cord. Pathologic analyses revealed a TTR mutation c.113A>G (p.D38G). Review summary Fifteen mutations and genotype-phenotype correlation of 72 LA patients have been summarized to provide an overview of LA associated with transthyretin mutations. The mean age of clinical onset was 44.9 years and the neurological symptoms primarily included cognitive impairment, headache, ataxia seizures and hearing, visual loss. CSF analysis showed elevated high CSF protein level and MRI revealed extensive leptomeningeal enhancement. Conclusion Clinicians should be aware of this rare form of familial transthyretin amyloidosis as well as its typical MRI enhancement and high CSF protein. The important role of biopsy, genetic testing and the potential early diagnosis value of contrast MRI were suggested. Early recognition of these characteristics is important to provide misdiagnosis and shorten the time before correct diagnosis. These findings expand the phenotypic spectrum of TTR gene and have implications for the diagnosis, treatment, and systematic study of LA.

Preferential flow is a non-equilibrium flow in unsaturated soil through which water infiltrates deep into the ground quickly. It has been studied in many fields, such as environment, agriculture, and hydrology. However, researchers from different disciplines have a different understanding of preferential flow, and it is difficult to grasp its development trends and research frontiers through qualitative analysis in a single field, while they can be quantitatively and objectively analyzed through bibliometrics with scientific knowledge map tools. This paper collects 3315 research studies on preferential flow in soil from the Web of Science (WoS) core collection database within 30 years, conducts a statistical analysis on keywords, countries, and research institutions of these studies based on CiteSpace, draws visualized scientific knowledge maps, and presents the development trends and research frontiers of preferential flow. Results showed that preferential flow is a multi-scale coexistence phenomenon, and researchers from different disciplines study preferential water flow movement and pollution at different research scales. New techniques and ideas are research hotspots and directions. Moreover, the difference between bibliometrics methods and review methods is analyzed. This paper is presented to provide a referable knowledge structure and new ideas for research in related fields and to help promote cross-integration between disciplines.

Objective To evaluate the association of MALAT-1 and the prognosis of patients with systemic lupus erythematosus (SLE). Materials and Methods A total of 87 SLE patients and 50 healthy controls were recruited. The expression levels of MALAT-1 were measured by quantitative PCR at baseline. Multivariate Cox regression analysis was performed to assess the association of MALAT-1 levels with survival after adjusting for potential confounding factors. Results The MALAT-1 levels in patients with SLE were significantly higher compared with healthy controls (p Conclusion The expression levels of MALAT-1 may be a promising biomarker for evaluating the prognosis of SLE patients.

To identify novel risk genes and better understand the molecular pathway underlying Alzheimer’s disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

Summary Background China has a large population of older people, but has not yet undertaken a comprehensive study on the prevalence, risk factors, and management of both dementia and mild cognitive impairment (MCI). Methods For this national cross-sectional study, 46 011 adults aged 60 years or older were recruited between March 10, 2015, and Dec 26, 2018, using a multistage, stratified, cluster-sampling method, which considered geographical region, degree of urbanisation, economic development status, and sex and age distribution. 96 sites were randomly selected in 12 provinces and municipalities representative of all socioeconomic and geographical regions in China. Participants were interviewed to obtain data on sociodemographic characteristics, lifestyle, medical history, current medications, and family history, and then completed a neuropsychological testing battery administered by a psychological evaluator. The prevalence of dementia (Alzheimer's disease, vascular dementia, and other dementias) and MCI were calculated and the risk factors for different groups were examined using multivariable-adjusted analyses. Findings Overall age-adjusted and sex-adjusted prevalence was estimated to be 6·0% (95% CI 5·8–6·3) for dementia, 3·9% (3·8–4·1) for Alzheimer's disease, 1·6% (1·5–1·7) for vascular dementia, and 0·5% (0·5–0·6) for other dementias. We estimated that 15·07 million (95% CI 14·53–15·62) people aged 60 years or older in China have dementia: 9·83 million (9·39–10·29) with Alzheimer's disease, 3·92 million (3·64–4·22) with vascular dementia, and 1·32 million (1·16–1·50) with other dementias. Overall MCI prevalence was estimated to be 15·5% (15·2–15·9), representing 38·77 million (37·95–39·62) people in China. Dementia and MCI shared similar risk factors including old age (dementia: odds ratios ranging from 2·69 [95% CI 2·43–2·98] to 6·60 [5·24–8·32]; MCI: from 1·89 [1·77–2·00] to 4·70 [3·77–5·87]); female sex (dementia: 1·43 [1·31–1·56]; MCI: 1·51 [1·43–1·59]); parental history of dementia (dementia: 7·20 [5·68–9·12]; MCI: 1·91 [1·48–2·46]); rural residence (dementia: 1·16 [1·06–1·27]; MCI: 1·45 [1·38–1·54]); fewer years of education (dementia: from 1·17 [1·06–1·29] to 1·55 [1·38–1·73]; MCI: from 1·48 [1·39–1·58] to 3·48 [3·25–3·73]); being widowed, divorced, or living alone (dementia: from 2·59 [2·30–2·90] to 2·66 [2·29–3·10]; MCI: from 1·58 [1·44–1·73] to 1·74 [1·56–1·95]); smoking (dementia: 1·85 [1·67–2·04]; MCI: 1·27 [1·19–1·36]), hypertension (dementia: 1·86 [1·70–2·03]; MCI: 1·62 [1·54–1·71] for MCI), hyperlipidaemia (dementia: 1·87 [1·71–2·05]; MCI: 1·29 [1·21–1·37]), diabetes (dementia: 2·14 [1·96–2·34]; MCI: 1·44 [1·35–1·53]), heart disease (dementia: 1·98 [1·73–2·26]; MCI: 1·17 [1·06–1·30]), and cerebrovascular disease (dementia: 5·44 [4·95–5·97]; MCI: 1·49 [1·36–1·62]). Nine of these risk factors are modifiable. Interpretation Dementia and MCI are highly prevalent in China and share similar risk factors. A prevention strategy should be developed to target the identified risk factors in the MCI population to thwart or slow down disease progression. It is also crucial to optimise the management of dementia and MCI as an important part of China's public health system. Funding Key Project of the National Natural Science Foundation of China, National Key Scientific Instrument and Equipment Development Project, Mission Program of Beijing Municipal Administration of Hospitals, Beijing Scholars Program, Beijing Brain Initiative from Beijing Municipal Science & Technology Commission, Project for Outstanding Doctor with Combined Ability of Western and Chinese Medicine, and Beijing Municipal Commission of Health and Family Planning.

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10−19, 2.49 × 10−23, 1.35 × 10−67, and 4.81 × 10−9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P, Jia et al. identify novel Alzheimer’s disease-related variants in a two-stage genome-wide association study in a Chinese population, and use the variants to build 11 predictive models. Validation of the models in a separate longitudinal cohort confirms that they can predict Alzheimer's disease risk.

Introduction The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. Methods In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE ε4 were analyzed across groups. Results The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE ε4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57–5.45, P < .001). Discussion APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention.

Background Efficacy and dose-effect relationship of donepezil for treating patients with Alzheimer's disease (AD) have been proven. However, few studies focused on the safety of donepezil, particularly in Chinese patients. Objective To assess the safety of donepezil 10 mg/day in Chinese patients with mild-to-moderate AD. Methods In this single-arm, prospective, multicenter trial, 241 patients with mild to moderate AD who had been treated with donepezil 5 mg/day for at least 4 weeks were enrolled. All patients received donepezil 10 mg/day for 20 weeks. Primary outcome was the incidence of adverse events (AEs). Safety profile was evaluated by physical examinations including vital signs and weight, clinical laboratory tests and electrocardiograms, and also correlation analysis between AEs and APOE genotypes. Results 241 patients were enrolled. Of which, 38.59% patients experienced at least one AE and 17.43% discontinued due to AEs. Most AEs were mild to moderate, with diarrhea, vomiting, and nausea the most frequently reported. Risk of AEs was significantly increased by concomitant use of drugs for cardiovascular and cerebrovascular diseases. Mean changes in heart rate and corrected QT relative to baseline were -1.08±6.02 beat/min (p = 0.009) and -3.91±18.68 ms (p = 0.0062) at week 4 and -1.48 beat/min±7.18 (p = 0.0028) and -0.66 ms±19.66 (p = 0.6561) at week 20, respectively. There were no significant changes in other vital sign parameters. Patients' MMSE scores improved significantly after treatment (p = 0.0038), especially for non-APOEɛ4 allele carriers and patients ≤75 years. Conclusion Donepezil 10 mg/day can be tolerated and is effective in Chinese patients with mild-to-moderate AD.

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White matter hyperintensities (WMHs) on magnetic resonance imaging are commonly found in older adults. The mechanisms underpinning the dose-dependent association between WMH severity and cognition are not well understood. This study aimed to investigate how brain activity changes with WMH severity, and if altered brain activity mediates the relationship between WMH and cognitive function. A total of 35 participants with moderate to severe WMHs (Fazekas grade 2 or 3) and 34 participants with mild WMHs (Fazekas grade 1), who were cognitively normal, were included. Resting-state brain function was analyzed using the amplitude of low-frequency fluctuation (ALFF). A mean fractional anisotropy (FA) value of 20 tract-specific regions of interest was calculated. Mediation analysis was used to assess whether ALFF values mediated the relationship between WMH and cognition. The results showed that compared to those with mild WMHs, participants with confluent WMHs had worse memory and naming ability and also had increased ALFF in the right middle frontal gyrus and decreased ALFF in the left middle occipital gyrus. After controlling for age, gender, education and apolipoprotein E (ApoE) ε4 status, increased ALFF in the right prefrontal cortex was associated with worse immediate recall and recognition, and ALFF values mediated the relationships between both Fazekas scores and FA values and memory. In conclusion, our study suggests that cognitively normal adults with high WMH load exhibit subclinical cognitive dysfunction and altered spontaneous brain activity. The mediating effects of brain activity help to shed light on our understanding of the relationship between WMHs and cognition.

Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem-commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.

Background: Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and has become a major health issue. However, a large number of genetic risk factors remain undiscovered. Methods: To identify novel risk genes and better understand the molecular pathway underlying AD, whole-exome sequencing (WES) was performed in 215 early-onset AD (EOAD) patients and 55 unrelated healthy controls of Han Chinese ethnicity. Subsequent direct sequencing was performed in 4962 individuals to validate the selected rare mutations. Computational annotation and in vitro functional studies were performed to evaluate the role of candidate mutations in EOAD and the underlying mechanisms.Results: We identified two rare missense mutations in the phosphodiesterase 11A (PDE11A) gene, resulting in p.Arg202His, and p.Leu756Gln, in individuals with EOAD. Both mutations are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at T181, S404, S202, S416, S214, S396 and AT8 epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A mutation-induced p-Tau formation.Conclusions: Our results demonstrate that both PDE11A mutations and PDE11A knockdown increase Tau phosphorylation through the cAMP/PKA pathway, suggesting that PDE11A is a novel risk gene for AD. This study provides insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

The current status of the diagnosis and management of poststroke aphasia (PSA) in China is unknown. To analyze the physicians’ strategy and knowledge about the management of PSA in clinical practice and the needs for standardization of diagnosis and treatment. This survey was conducted in March-August 2019 at 32 tertiary hospitals in 16 provinces/municipalities in China. The attending physicians from the Neurology and Neuro-rehabilitation/Rehabilitation Departments were included. The online questionnaire inquired about patient information, physicians’ diagnosis and treatment behavior for PSA, and physicians’ understanding of PSA. A total of 236 physicians completed the survey. Regarding PSA assessment, 99.2% of the physicians reported using medical history and physical examination, 93.2% reported using neuroimaging, and 76.3% reported using dedicated scales. Most physicians used a combination of drug and non-drug treatment. Neuro-regenerators/cerebral activators and anti-dementia drugs were the most common pharmacotherapies; butylphthalide, edaravone, and memantine were most frequently prescribed. Six months poststroke was rendered as a spontaneous language recovery period, and a ≥6-month treatment for PSA was suggested by many physicians. The lack of standardized treatment regimen/clinical guidelines and the limited number of approved drugs for PSA were the primary challenges encountered by physicians during practice. The majority of the physicians agreed with the necessity of guidelines or consensus for the diagnosis and treatment of PSA. The knowledge gaps exist among physicians in China regarding the assessment and management of PSA. The improved awareness of the available guidelines/consensus could improve the performance of the physicians.

Background: Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and has become a major health issue. However, a large number of genetic risk factors remain undiscovered. Methods: To identify novel risk genes and better understand the molecular pathway underlying AD, whole-exome sequencing (WES) was performed in 215 early-onset AD (EOAD) patients and 55 unrelated healthy controls of Han Chinese ethnicity. Subsequent direct sequencing was performed in 620 individuals to validate the selected rare mutations. Computational annotation and in vitro functional studies were performed to evaluate the role of candidate mutations in EOAD and the underlying mechanisms.Results: We identified two rare missense mutations in the phosphodiesterase 11A (PDE11A) gene, resulting in p.Arg202His, and p.Leu756Gln, in 4 individuals with EOAD. Both mutations are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at T181, S404, S202, S416, S214, S396 and AT8 epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A mutation-induced p-Tau formation.Conclusions: Our results demonstrate that both PDE11A mutations and PDE11A knockdown increase Tau phosphorylation through the cAMP/PKA pathway, suggesting that PDE11A is a novel risk gene for AD. This study provides insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

Background: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation. Methods: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models. Discussion: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism. Trial registration number: NCT03903068, pre-results.

Neurosarcoidosis is relatively rare and has diverse manifestations. The clinical characteristics, diagnosis, treatment, and outcome for neurosarcoidosis in China are poorly understood. We retrospectively analyzed the clinical features, laboratory and imaging results, treatment, and outcomes in patients who met the criteria for definite or probable neurosarcoidosis in Xuan Wu Hospital of Capital Medical University from 2000 to 2015. Eight patients were included in this study, accounting for 5.84% of all cases with sarcoidosis. The mean age at onset was 50.25 years, and 75% of the patients were female. Five cases had a prior diagnosis of extraneurologic sarcoidosis, leading to a shorter lag time between onset of symptoms and diagnosis (3.4 vs. 16.2 months). Neurological symptoms were the first clinical feature of sarcoidosis in three cases, and no patients presented isolated nervous system manifestation. The most common symptom was sensory disturbance, and the most common site of nervous system involvement was brain parenchyma and meninges. Disturbance of consciousness, seizures, hydrocephalus, and abnormal CSF assays were associated with poor prognosis. All patients were treated with corticosteroids and one was also given azathioprine. Five patients had complete or partial improvement, one remained stabilized, and two deteriorated and died. Neurosarcoidosis is difficult to diagnose early and might be associated with a poor prognosis. Tissue biopsy for a definitive diagnosis and aggressive therapy with corticosteroids plus other alternative immunosuppressive treatment should be recommended in China.

Introduction The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. Methods We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. Results The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. Discussion China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

BACKGROUND Delayed Matching-to-Sample Task 48 (DMS48), a brief tool measuring visual recognition memory, is valid to identify the early stage of Alzheimer's disease (AD) in Caucasians. However, little data is available in Chinese. OBJECTIVE To develop norms and optimal cutoff points for the DMS48 in Chinese elders. METHODS A cross-sectional study was conducted in seven memory clinics from five cities across China. DMS48 was applied to 369 Chinese aged 50 or older (138 cognitively normal [CN], 112 mild cognitive impairment due to AD (MCI-A), and 119 mild AD dementia). The demographic factors which influence DMS48 scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff points. RESULTS Age was shown to influence DMS48 scores (r = -0.36, p

Introduction No licensed medications are available to treat vascular dementia (VaD). Methods Patients were randomly assigned to experimental groups (SaiLuoTong [SLT] 360 or 240 mg for groups A and B for 52 weeks, respectively) or placebo group (SLT 360 mg and 240 mg for group C only from weeks 27 to 52, respectively). Results Three hundred twenty-five patients were included in final analysis. At week 26, the difference in VaD Assessment Scale–cognitive subscale scores was 2.67 (95% confidence interval, 1.54 to 3.81) for groups A versus C, and 2.48 (1.34 to 3.62) for groups B versus C (both P

Introduction The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. Methods In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. Results In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEe4 allele, and 14.85% two APOEe4 alleles. Discussion The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEe4 might be a major gene for some FAD without PSENs/APP mutations.

Clinical case study and functional characterization of the disease-associated presenilin-1 (PSEN1) mutations may help reveal the roles of PSEN1 in the pathogenesis of Alzheimer's disease (AD). By mutation screening of PSEN1, presenilin-2, and amyloid precursor protein genes in two Chinese Alzheimer's pedigrees, we identified two novel PSEN1 mutations, I249L and P433S. The two probands presented with progressive memory decline and subsequent psychiatric symptoms, with the age of onset at 54 and 34 years old, respectively. The effects of these two mutations on presenilin-1 endoproteolysis and β-amyloid (Aβ) production were examined in SH-SY5Y neuroblastoma cells infected with lentiviruses expressing presenilin-1 wild type (WT), I249L and P433S mutants. Both mutants showed increased Aβ42 levels and Aβ42/Aβ40 ratios. However, the I249L did not affect presenilin-1 endoproteolysis or Aβ43 production, whereas the P433S mutant inhibited presenilin-1 endoproteolysis and enhanced Aβ43 production. Our findings suggest that both I249L and P433S are pathogenic for early onset of AD by increasing Aβ42 production and Aβ42/Aβ40 ratios. Furthermore, P433S may contribute to the very early onset of AD by inhibiting PS1 endoproteolysis and enhancing the production of longer Aβ peptide Aβ43.

Background CSF1R-related encephalopathy refers to adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (ALSP) due to CSF1R mutations, which is a rare autosomal dominant white matter disease including two pathological entities, hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). The aim of this study was to identify additional causative mutations in the CSF1R gene and clarify their pathogenic effects. Methods Whole-exome sequencing was conducted for nine Chinese patients diagnosed with possible ALSP based on clinical and neuroimaging findings from March 2014 to June 2020 at Xuanwu Hospital (Beijing, China). Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) Standards and Guidelines. Results Mean ± standard deviation (range) age of disease onset in the nine patients was 39.22±9.63 [25-54] years. Four of the nine patients were male, and four out of nine had a remarkable family history. Seven CSF1R mutations were identified in the nine patients; four (p.G17C, p.R579Q, p.I794T and c.2909_2910insATCA) have been previously reported, while three (p.V613L, p.W821R and c.2442+2_2442+3dupT) were novel. Of the latter, two (p.V613L and p.W821R) were likely pathogenic and 1 (c.2442+2_2442+3dupT) was of uncertain significance according to ACMG/AMP criteria. Conclusions These findings expand the mutational spectrum of ALSP and provide a basis for future investigations on etiologic factors and potential management strategies for this disease.

Table S1. Genes detected relate to hereditary leukoencephalopathies disease. (DOCX 18 kb)

Background: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. This study was conducted to examine whether the association of a proliferation-inducing ligand (APRIL), spermatogenesis associated 8 (SPATA8), platelet-derived growth factor receptor-alpha (PDGFRA), and DNA polymerase beta (POLB) with SLE can be replicated in a Chinese Han population. Methods: Chinese SLE patients ( n = 1247) and ethnically and geographically matched healthy controls ( n = 1440) were genotyped for the APRIL, SPATA8, PDGFRA, and POLB single-nucleotide polymorphisms (SNPs), rs3803800, rs8023715, rs1364989, and rs12678588 using the Sequenom MassARRAY System. Results: The Chinese Han SLE patients and controls had statistically similar frequencies of alleles and genotypes of four gene polymorphisms. Moreover, no association signal was detected on different genetic models (additive, dominant, and recessive, all, P > 0.05) or in SLE subgroups stratified by various clinical manifestations (all, P > 0.05). Conclusions: Different genetic backgrounds from different ancestries and various populations may result in different genetic risk factors for SLE. We did not detect any significant association with SNPs of APRIL, SPATA8, PDGFRA, and POLB.