Antioxidant and Hepatoprotective Effect of Rosa davurica Pall Seed Oil on CCl4-Induced Acute Liver Injury in Mice.

The liver, being the most metabolically active organ, is highly vulnerable to damage caused by oxidative stress. Rosa davurica Pall. seed oil (RDPO), a novel vegetable oil, and its bioactive components have been extensively researched in the field of antioxidants. In this research, the antioxidant properties and hepatoprotection by RDPO were evaluated. A series of antioxidant evaluation systems and a CCl4-induced acute liver injury model in mice were used to investigate the antioxidant activity and hepatoprotective efficacy of RDPO. The results showed that the extraction rate of RDPO was 11.12% using the optimal extraction process. Three major unsaturated fatty acids of the oil were α-linolenic acid (11.89 ± 0.017%), linoleic acid (18.52 ± 0.072%), and oleic acid (11.54 ± 0.425%). Furthermore, its antioxidant small-molecule compounds were ß-sitosterol (1.429 ± 0.002 µg/g), α-tocopherol (1.273 ± 0.079 µg/g), ß-carotene (0.012 ± 0.001 µg/g), lycopene (0.108 ± 0.002 µg/g), squalene (178.950 ± 0.794 µg/g), total polyphenols (1.114 ± 0.032 µg GAE/mg), and total flavonoids (0.504 ± 0.009 mg RU/g), respectively. In vitro, RDPO significantly inhibited the production of ABTS+•, DPPH•, O2•-, and hydroxyl radicals, as well as Fe3+. In vivo, RDPO significantly reversed the activity of total superoxide-dismutase, catalase, L-glutathione, and the level of malondialdehyde (MDA) in liver tissue. It also obviously inhibited the activity of aspartate transaminase (AST) and the level of MDA in the serum. Therefore, RDPO has demonstrated excellent antioxidant activity and a potential liver protective effect. This effect may be ascribed to its capacity for decreasing AST activity, inhibiting lipid peroxidation, and boosting endogenous antioxidant enzyme activity. Therefore, RDPO has significant application value in the biopharmaceutical industry and as a dietary supplement.

GRN mutation spectrum and genotype-phenotype correlation in Chinese dementia patients: data from PUMCH dementia cohort.

BACKGROUND: METHODS: The GRN mutations, especially of the loss of function type, are causative of frontotemporal dementia (FTD). However, several GRN variants can be found in other neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease. So far, there have been over 300 GRN mutations reported globally. However, the genetic spectrum and phenotypic characteristics have not been fully elucidated in Chinese population.The participants were from the dementia cohort of Peking Union Medical College Hospital (n=1945). They received history inquiry, cognitive evaluation, brain imaging and exome sequencing. The dementia subjects carrying the rare variants of the GRN were included in this study. Those with the pathogenic or likely pathogenic variants of other dementia-related genes were excluded. RESULTS: 14 subjects carried the rare variants of GRN. They were clinically diagnosed with behavioural variant of FTD (n=2), non-fluent/agrammatic variant primary progressive aphasia (PPA, n=3), semantic variant PPA (n=1), AD (n=6) and mixed dementia (n=2). 13 rare variants of GRN were found, including 6 novel variants (W49X, S226G, M152I, A91E, G79E and A303S). The most prevalent symptom was amnesia (85.7%, 12/14), followed by psychiatric and behavioural disorder (78.6%, 11/14). In terms of lobar atrophy, temporal atrophy/hypometabolism was the most common (85.7%, 12/14), followed by parietal atrophy/hypometabolism (78.6%, 11/14). CONCLUSION: The novel GRN variants identified in this study contribute to enrich the GRN mutation repertoire. There is phenotypic similarity and diversity among Chinese patients with the GRN mutations.

Association between high-resolution magnetic resonance vessel wall imaging characteristics and recurrent stroke in patients with intracranial atherosclerotic steno-occlusive disease: A prospective multicenter study.

BACKGROUND: High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) is a promising technique for identifying intracranial vulnerable plaques beyond lumen narrowing. However, the association between HRMR-VWI characteristics and recurrent stroke remains uncertain. AIMS: This study aimed to investigate the association between HRMR-VWI characteristics and recurrent ipsilateral stroke in patients with symptomatic intracranial atherosclerotic steno-occlusive disease (ICAS). METHODS: This multicenter, observational study recruited first-ever acute ischemic stroke patients attributed to ICAS (>50% stenosis or occlusion) within 7 days after onset. Participants were assessed by multiparametric magnetic resonance imaging (MRI) including diffusion-weighted imaging, three-dimension time-of-flight magnetic resonance angiography, and three-dimensional T1-weighted HRMR-VWI. The patients were recommended to receive best medical therapy and were systematically followed up for 12 months. The association between HRMR-VWI characteristics and the time to recurrent ipsilateral stroke was investigated by univariable and multivariable analysis. RESULTS: Two hundred and fifty-five consecutive patients were enrolled from 15 centers. The cumulative 12 month ipsilateral recurrence incidence was 4.1% (95% confidence interval (CI): 1.6-6.6%). Patients with recurrent ipsilateral stroke exhibited higher rates of intraplaque hemorrhage (IPH) (30.0% vs 6.5%) and eccentric plaque (90.0% vs 48.2%), and lower occurrence of occlusive thrombus (10.0% vs 23.7%). Plaque length (5.69 ± 2.21 mm vs 6.67 ± 4.16 mm), plaque burden (78.40 ± 7.37% vs 78.22 ± 8.32%), degree of stenosis (60.25 ± 18.95% vs 67.50% ± 22.09%) and remodeling index (1.07 ± 0.27 vs 1.03 ± 0.35) on HRMR-VWI did not differ between patients with and without recurrent ipsilateral stroke. In the multivariable Cox regression analysis, IPH (hazard ratio: 6.64, 95% CI: 1.23-35.8, p = 0.028) was significantly associated with recurrent ipsilateral stroke after adjustment.Conclusions:Our results suggest intraplaque hemorrhage (IPH) is significantly associated with recurrent ipsilateral stroke and has potential value in the selection of patients for aggressive treatment strategies. DATA ACCESS STATEMENT: Data from this study are available and can be accessed upon request.

Assessment of cheese sign and its association with vascular risk factors: Data from PUMCH dementia cohort.

BACKGROUND: In the clinic, practitioners encounter many patients with an abnormal pattern of dense punctate magnetic resonance imaging (MRI) signal in the basal ganglia, a phenomenon known as "cheese sign". This sign is reported as common in cerebrovascular diseases, dementia, and old age. Recently, cheese sign has been speculated to consist of dense perivascular space (PVS). This study aimed to assess the lesion types of cheese sign and analyze the correlation between this sign and vascular disease risk factors. METHODS: A total of 812 patients from Peking Union Medical College Hospital (PUMCH) dementia cohort were enrolled. We analyzed the relationship between cheese sign and vascular risk. For assessing cheese sign and defining its degree, the abnormal punctate signals were classified into basal ganglia hyperintensity (BGH), PVS, lacunae/infarctions and microbleeds, and counted separately. Each type of lesion was rated on a four-level scale, and then the sum was calculated; this total was defined as the cheese sign score. Fazekas and Age-Related White Matter Changes (ARWMC) scores were used to evaluate the paraventricular, deep, and subcortical gray/white matter hyperintensities. RESULTS: A total of 118 patients (14.5%) in this dementia cohort were found to have cheese sign. Age (odds ratio [OR]: 1.090, 95% confidence interval [CI]: 1.064-1.120, P <0.001), hypertension (OR: 1.828, 95% CI: 1.123-2.983, P = 0.014), and stroke (OR: 1.901, 95% CI: 1.092-3.259, P = 0.025) were risk factors for cheese sign. There was no significant relationship between diabetes, hyperlipidemia, and cheese sign. The main components of cheese sign were BGH, PVS, and lacunae/infarction. The proportion of PVS increased with cheese sign severity. CONCLUSIONS: The risk factors for cheese sign were hypertension, age, and stroke. Cheese sign consists of BGH, PVS, and lacunae/infarction.

Association Between Wnt Target Genes and Cortical Volumes in Alzheimer's Disease.

The disproportionate cortical atrophy is an established biomarker for the pathophysiological process of Alzheimer's disease (AD). However, the genetic basis underlying the cortical atrophy remains poorly defined. Herein, we aim to illustrate the effect of the Wnt target genes on the cortical volumes of AD patients. 82 sporadic AD patients were recruited. All the subjects had history survey, blood biochemical examination, cognitive assessment, MRI morphometry and whole exome sequencing. This report focused on 84 common variants (minor allele frequency > 0.01) of 32 Wnt target genes, including the APC, DAAM1, DACT1, DISC1, LATS2, TLR2, WDR61, and the AXIN, DVL, FZD, LRP, TCF/LEF, WNT family genes. The Wnt target genes showed asymmetric effects on the cortical volumes of AD patients. The right temporal/parietal/occipital cortices were more affected than left temporal/parietal/occipital cortices. Nevertheless, the reverse applied to the frontal cortex. The DACT1 affected the cortical thickness most, followed by the TCF3 and APC. The DACT1 rs698025-GG genotype displayed greater right temporal pole and left medial orbito-frontal gyrus than rs698025-GA genotype (2.4 ± 0.4 vs. 2.0 ± 0.6, P = 0.005; 5.2 ± 0.6 vs. 5.0 ± 0.6, P = 0.001). The brain region most influenced by the Wnt target genes was the right calcarine cortex. In conclusion, the common variants of the Wnt target genes exert asymmetric effects on the cortical volumes of AD patients. The Wnt signaling pathway may play a role in the cortical atrophy of AD patients.

Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.

BACKGROUND: The pediatric genetic white matter disorders are characterized by a broad disease spectrum. Genetic testing is valuable in the diagnosis. However, there are few studies on the clinical and genetic spectrum of Chinese pediatric genetic white matter disorders. METHODS: The participants were enrolled from the cohort of Peking Union Medical College Hospital. They all received history collection, brain MRI and gene sequencing. Their neurologic complaints which were related to white matter disorders occurred before 18. Brain MRI indicated periventricular and/or deep white matter lesions, fazekas grade 2-3. RESULTS: Among the 13 subjects, there were 11 males and two females. The average age of onset was 10.0 ± 5.5 years old. The potential genetic variants were found in 84.6% (11/13) subjects. The ABCD1 showed the greatest mutation frequency (30.8%, 4/13). The EIF2B3 A151fs, EIF2B4 c.885 + 2T > G, EIF2B5 R129X and MPV17 Q142X were novel pathogenic/likely pathogenic variants. 100% (4/4) ABCD1 carriers were accompanied by visual impairment, whereas 100% (3/3) EIF2B carriers developed dysuria. 100% (4/4) ABCD1 carriers exhibited diffuse white matter hyperintensities mainly in the posterior cortical regions, while the EIF2B4 and EIF2B5 carriers were accompanied by cystic degeneration. CONCLUSION: There is genotypic and phenotypic heterogeneity among Chinese subjects with pediatric genetic white matter disorders. The knowledge of these clinical and genetic characteristics facilitates an accurate diagnosis of these diseases.

Toward a stable and low-resource PLM-based medical diagnostic system via prompt tuning and MoE structure.

Machine learning (ML) has been extensively involved in assistant disease diagnosis and prediction systems to emancipate the serious dependence on medical resources and improve healthcare quality. Moreover, with the booming of pre-training language models (PLMs), the application prospect and promotion potential of machine learning methods in the relevant field have been further inspired. PLMs have recently achieved tremendous success in diverse text processing tasks, whereas limited by the significant semantic gap between the pre-training corpus and the structured electronic health records (EHRs), PLMs cannot converge to anticipated disease diagnosis and prediction results. Unfortunately, establishing connections between PLMs and EHRs typically requires the extraction of curated predictor variables from structured EHR resources, which is tedious and labor-intensive, and even discards vast implicit information.In this work, we propose an Input Prompting and Discriminative language model with the Mixture-of-experts framework (IPDM) by promoting the model's capabilities to learn knowledge from heterogeneous information and facilitating the feature-aware ability of the model. Furthermore, leveraging the prompt-tuning mechanism, IPDM can inherit the impacts of the pre-training in downstream tasks exclusively through minor modifications. IPDM remarkably outperforms existing models, proved by experiments on one disease diagnosis task and two disease prediction tasks. Finally, experiments with few-feature and few-sample demonstrate that IPDM achieves significant stability and impressive performance in predicting chronic diseases with unclear early-onset characteristics or sudden diseases with insufficient data, which verifies the superiority of IPDM over existing mainstream methods, and reveals the IPDM can powerfully address the aforementioned challenges via establishing a stable and low-resource medical diagnostic system for various clinical scenarios.

Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis.

BACKGROUND: Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. AIMS: To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. METHOD: We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 59 trials (15,781 participants; mean age, 76.6 years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] -0.20, 95% credible interval [CrI] -0.40 to -0.10) and galantamine (-0.20, -0.39 to -0.02) were more effective than placebo in short-term treatment (median duration: 12 weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38-2.94) and rivastigmine (1.87, 1.24-2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. CONCLUSIONS: Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk-benefit profile of drugs.

Effects of exercise therapy on patients with poststroke cognitive impairment: A systematic review and meta-analysis.

Objective: To evaluate the effects of exercise therapy on patients with poststroke cognitive impairment and compare the differences in the effect of this method when compared with conventional measures, providing evidence for a more standardized and effective clinical application of exercise therapy. Methods: A search was conducted using 7 electronic databases, including PubMed, CINAHL, Web of Science, CENTRAL, CNKI, Wanfang, SinoMed, and clinical trials registry platforms for randomized controlled trials concerning exercise therapy on patients with poststroke cognitive impairment. Two researchers independently screened the literature, evaluated the quality, and extracted information. Meta-analysis was carried out using Review Manager 5.4 software. Results: There were 11 studies with 1,382 patients. Meta-analysis showed that exercise therapy could improve cognitive function [SMD = 0.67, 95% CI (0.31, 1.04), P = 0.0003], motor function [SMD = 1.81, 95% CI (0.41, 3.20), P = 0.01], and the activities of daily living [MD = 8.11, 95% CI (3.07, 13.16), P = 0.002] in patients with poststroke cognitive impairment. Conclusion: Exercise therapy can not only improve cognitive function in patients with poststroke cognitive impairment but also improve motor function and the activities of daily living. Medical staff should prioritize the management of patients with poststroke cognitive impairment and carry out exercise therapy actively to improve the cognitive function of patients with stroke. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023397553.

Association of APOE ε4/ε4 with fluid biomarkers in patients from the PUMCH dementia cohort.

Background: Apolipoprotein-E (APOE) ε4 is a major genetic risk factor for Alzheimer's disease (AD). Current studies, which were mainly based on the clinical diagnosis rather than biomarkers, come to inconsistent conclusions regarding the associations of APOE ε4 homozygotes (APOE ε4/ε4) and cerebrospinal fluid (CSF) biomarkers of AD. In addition, few studies have explored the associations of APOE ε4/ε4 with plasma biomarkers. Therefore, we aimed to investigate the associations of APOE ε4/ε4 with fluid biomarkers in dementia and biomarker-diagnosed AD. Methods: A total of 297 patients were enrolled. They were classified into Alzheimer's continuum, AD, and non-AD, according to CSF biomarkers and/or ß amyloid PET results. AD was a subgroup of the AD continuum. Plasma Amyloid ß (Aß) 40, Aß42, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and phosphorylated tau (P-tau)181 were quantified in 144 of the total population using an ultra-sensitive Simoa technology. We analyzed the associations of APOE ε4/ε4 on CSF and plasma biomarkers in dementia and biomarker diagnosed AD. Results: Based on the biomarker diagnostic criteria, 169 participants were diagnosed with Alzheimer's continuum and 128 individuals with non-AD, and among the former, 120 patients with AD. The APOE ε4/ε4 frequencies were 11.8% (20/169), 14.2% (17/120), and 0.8% (1/128) in Alzheimer's continuum, AD and non-AD, respectively. Only CSF Aß42 was shown to be decreased in APOE ε4/ε4 carriers than in non-carriers for patients with AD (p = 0.024). Furthermore, we did not find any associations of APOE ε4 with plasma biomarkers of AD and non-AD. Interestingly, we found that in non-AD patients, APOE ε4 carriers had lower CSF Aß42 (p = 0.018) and higher T-tau/Aß42 ratios (p < 0.001) and P-tau181/Aß42 ratios (p = 0.002) than non-carriers. Conclusion: Our data confirmed that of the three groups (AD continuum, AD, and non-AD), those with AD had the highest frequency of APOE ɛ4/ɛ4 genotypes. The APOE ɛ4/ɛ4 was associated with CSF levels of Aß42 but not tau for AD and non-AD, suggesting that APOE ɛ4/ɛ4 affected the Aß metabolism of both. No associations between APOE ε4/ɛ4 and plasma biomarkers of AD and non-AD were found.

Clinical Significance of Lymphatic Infiltration Detected by Immunohistochemical Double Staining in Patients with Endometrial Cancer.

Background: The presence of lymph-vascular space invasion is a powerful predictor of lymph node metastasis. However, most studies do not distinguish lymph vessel invasion (LVI) and blood vessel invasion (BVI). The aim of this study was to distinguish the role of LVI and BVI in lymphatic metastasis and recurrence in patients with endometrial cancer. Methods: We examined 171 patients with endometrial cancer. Immunohistochemical double staining was used to distinguish lymphatic invasion and vascular invasion. First, the relationship between lymphatic/vascular invasion and clinicopathological features and lymphatic metastasis was studied. Then, the expression of D2-40/LVI and CD31/BVI in patients with recurrence was analyzed. Results: Pathological grading (G3) and D2-40/LVI were independent high-risk factors for lymph node metastasis of endometrial cancer. The area under the receiver operating characteristic curve values for predicting lymphatic metastasis using pathological grading (G3) or D2-40/LVI alone were .642 and .680, respectively, and the area under the curve value for the combined detection of pathological grading (G3) and D2-40/LVI was .726, which was greater than the values obtained for the abovementioned independent variables. Among the 15 recurrent patients, 5 (33.3%) were D2-40/LVI positive, 2 (13.3%) were CD31/BVI positive, and 8 (53.3%) were both D2-40/LVI and CD31/BVI positive. Conclusion: D2-40/LVI combined with G3 can effectively predict lymph node metastasis of endometrial carcinoma.

Treatment of primary progressive aphasia by repetitive transcranial magnetic stimulation: a randomized, double-blind, placebo-controlled study.

To evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) in patients with primary progressive aphasia (PPA). In this randomized, double-blind trial in a single center, patients who were diagnosed with PPA were randomly assigned to receive either real rTMS or sham rTMS treatment. High-frequency rTMS was delivered to the dorsolateral prefrontal cortex (DLPFC). The primary outcome was the change in Boston Naming Test (BNT) score at each follow-up compared to the baseline. The secondary outcomes included change in CAL (Communicative Activity Log) and WAB (Western Aphasia Battery) compared to baseline and neuropsychological assessments. Forty patients (16 with nonfluent, 12 with semantic and 12 with logopenic variant PPA) were enrolled and randomly assigned to the rTMS or sham rTMS group, with 20 patients in each group. Thirty-five patients (87.5%) completed a 6-month follow-up. Compared to the sham rTMS group, the BNT improvement and WAB improvement in the real rTMS group were significantly higher. These significant improvements could be observed throughout the entire 6-month follow-up. At 1 month and 3 months after treatment, CAL improvements of real rTMS were significantly higher than sham rTMS. The improvements in BNT, CAL and WAB did not significantly differ among PPA variants. No significant improvement in neuropsychological assessments was observed. High-frequency rTMS delivered to DLPFC improved language functions in patients with different PPA variants. The efficacy was still observed after 6 months of treatment. Trial registration: NCT04431401 ( https://clinicaltrials.gov/ct2/show/NCT04431401 ).

The PUMCH Evaluation System of Idiopathic Normal Pressure Hydrocephalus and Clinical Practice.

OBJECTIVE: Differentiating idiopathic normal pressure hydrocephalus (iNPH) from other neurodegenerative diseases is challenging. Only a portion of the patients clinically suspected of iNPH would respond to surgical intervention. A cerebrospinal fluid (CSF) tap test is usually used to predict surgery outcomes and hence aid clinical decision-making, but the workup varies. We introduce the CSF tap test conducted at our center and examine its power by analyzing data from a series of iNPH cases that underwent shunt placement. We analyze common features in the past medical history of our patients and investigate whether they are related to the etiology of iNPH. METHODS: Data from 20 patients who were positive in the tap tests preoperatively and received ventriculoperitoneal shunting (VPS) were retrospectively analyzed. Preoperative and postoperative performance data were analyzed. History of any underlying medical conditions was taken into consideration. Patients with negative tap test results of the same period were also followed up. RESULTS: We performed VPS placement in 20 NPH patients from October 2019 to February 2022. Of these, 90% exhibited improvement in at least 1 of the clinical triad, proving the predictive power of the Peking Union Medical College Hospital test workflow. The underlying conditions like hypertension, diabetes and insufficiency in cerebral blood supply were also found to be associated with the onset of NPH. CONCLUSION: Our evaluation system is a valid tool for NPH assessment and can guide clinical decision-making. Comorbidities should be taken into consideration as they contribute to the pathogenesis and progression of NPH. Better identification of potential iNPH patients will lower the burden exerted on the family and the aging society.

Clinical-neuroimaging-pathological relationship analysis of adult onset Neuronal Intranuclear Inclusion Disease (NIID).

BACKGROUND: Neuronal Intranuclear Inclusion Disease (NIID) is a degenerative disease with heterogeneous clinical manifestations. We aim to analysis the relationship between clinical manifestations, neuroimaging and skin pathology in a Chinese NIID cohort. METHODS: Patients were recruited from a Chinese cohort. Detail clinical information were collected. Visual rating scale was used for evaluation of neuroimaging. The relationship between clinical presentations and neuroimaging, as well as skin pathology was statistically analyzed. RESULTS: Thirty-two patients were recruited. The average onset age was 54.3 y/o. 28.1% had positive family history. Dementia, autonomic nervous system dysfunction, episodic attacks were three main presentations. CSF analysis including Aß42 and tau level was almost normal. The most frequently involved on MRI was periventricular white matter (100%), frontal subcortical and deep white matter (96.6%), corpus callosum (93.1%) and external capsule (72.4%). Corticomedullary junction DWI high intensity was found in 87.1% patients. Frontal and external capsule DWI high intensity connected to form a "kite-like" specific image. Severity of dementia was significantly related to leukoencephalopathy (r = 0.465, p = 0.0254), but not cortical atrophy and ventricular enlargement. Grey matter lesions were significantly associated with encephalopathy like attacks (p = 0.00077) but not stroke like attacks. The density of intranuclear inclusions in skin biopsy was not associated with disease duration, severity of leukoencephalopathy and dementia. CONCLUSIONS: Specific distribution of leukoencephalopathy and DWI high intensity were indicative. Leukoencephalopathy and subcortical mechanism were critical in pathogenesis of NIID. Irrelevant of inclusion density and clinical map suggested the direct pathogenic factor need further investigation.

Distribution of Cortical Atrophy Associated with Cognitive Decline in Alzheimer's Disease: A Cross-Sectional Quantitative Structural MRI Study from PUMCH Dementia Cohort.

BACKGROUND: Quantitative measures of atrophy on structural MRI are sensitive to the neurodegeneration that occurs in AD, and the topographical pattern of atrophy could serve as a sensitive and specific biomarker. OBJECTIVE: We aimed to examine the distribution of cortical atrophy associated with cognitive decline and disease stage based on quantitative structural MRI analysis in a Chinese cohort to inform clinical diagnosis and follow-up of AD patients. METHODS: One hundred and eleven patients who were clinically diagnosed with probable AD were enrolled. All patients completed a systemic cognitive evaluation and domain-specific batteries. The severity of cognitive decline was defined by MMSE score: 1-10 severe, 11-20 moderate, and 21-30 mild. Cortical volume and thickness determined using 3D-T1 MRI data were analyzed using voxelbased morphometry and surface-based analysis supported by the DR. Brain Platform. RESULTS: The male:female ratio was 38:73. The average age was 70.8 ± 10.6 years. The mild: moderate: severe ratio was 48:38:25. Total grey matter volume was significantly related to cognition while the relationship between white matter volume and cognition did not reach statistical significance. The volume of the temporal-parietal-occipital cortex was most strongly associated with cognitive decline in group analysis, while the hippocampus and entorhinal area had a less significant association with cognitive decline. Volume of subcortical grey matter was also associated with cognition. Volume and thickness of temporoparietal cortexes were significantly correlated with the cognitive decline, with a left predominance observed. CONCLUSION: Cognitive deterioration was associated with cortical atrophy. Volume and thickness of the left temporal-parietal-occipital cortex were most important in early diagnosis and longitudinal evaluation of AD in clinical practice. Cognitively relevant cortices were left predominant.

Stroke incidence and cognitive outcomes of intracranial atherosclerotic stenosis: study protocol for a multicenter, prospective, observational cohort study.

Background: Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of stroke worldwide. Current diagnostic evaluations and treatments remain insufficient to assess the vulnerability of intracranial plaques and reduce the recurrence of stroke in symptomatic ICAS. On the other hand, asymptomatic ICAS is associated with an increased risk of cognitive impairment. The pathogenesis of ICAS related cognitive decline is largely unknown. The aim of SICO-ICAS study (stroke incidence and cognitive outcomes of ICAS) is to elucidate the pathophysiology of stroke and cognitive impairment in ICAS population, comprehensively evaluating the complex interactions among life-course exposure, genomic variation, vascular risk factors, cerebrovascular burden and coexisting neurodegeneration. Methods: SICO-ICAS is a multicenter, prospective, observational cohort study. We aim to recruit 3,000 patients with symptomatic or asymptomatic ICAS (>50% or occlusion) who will be followed up for ≥12 months. All participants will undergo pre-designed magnetic resonance imaging packages, blood biomarkers testing, as well as detailed cognitive domains assessment. All participants will undergo clinical visits every 6 months and telephone interviews every 3 months. The primary outcome measurement is ischemic stroke or cognitive impairment within 12 months after enrollment. Discussion: This study will establish a large prospective ICAS cohort, hopefully discover new biomarkers associated with vulnerable intracranial plaques, identify subjects at high risk for incident ischemic stroke or cognitive impairment, and eventually propose a precise diagnostic and treatment strategy for ICAS population. Trial Registration: Chinese Clinical Trials Register ChiCTR2200061938.

Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China. METHODS: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy. RESULTS: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission. CONCLUSIONS: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Learning Cognitive-Test-Based Interpretable Rules for Prediction and Early Diagnosis of Dementia Using Neural Networks.

BACKGROUND: Accurate, cheap, and easy to promote methods for dementia prediction and early diagnosis are urgently needed in low- and middle-income countries. Integrating various cognitive tests using machine learning provides promising solutions. However, most effective machine learning models are black-box models that are hard to understand for doctors and could hide potential biases and risks. OBJECTIVE: To apply cognitive-test-based machine learning models in practical dementia prediction and diagnosis by ensuring both interpretability and accuracy. METHODS: We design a framework adopting Rule-based Representation Learner (RRL) to build interpretable diagnostic rules based on the cognitive tests selected by doctors. According to the visualization and test results, doctors can easily select the final rules after analysis and trade-off. Our framework is verified on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 606) and Peking Union Medical College Hospital (PUMCH) dataset (n = 375). RESULTS: The predictive or diagnostic rules learned by RRL offer a better trade-off between accuracy and model interpretability than other representative machine learning models. For mild cognitive impairment (MCI) conversion prediction, the cognitive-test-based rules achieve an average area under the curve (AUC) of 0.904 on ADNI. For dementia diagnosis on subjects with a normal Mini-Mental State Exam (MMSE) score, the learned rules achieve an AUC of 0.863 on PUMCH. The visualization analyses also verify the good interpretability of the learned rules. CONCLUSION: With the help of doctors and RRL, we can obtain predictive and diagnostic rules for dementia with high accuracy and good interpretability even if only cognitive tests are used.

Genetic Spectrum and Clinical Heterogeneity of Chinese Frontotemporal Dementia Patients: Data from PUMCH Dementia Cohort.

BACKGROUND: There are relatively few data on the genetic spectrum of Chinese frontotemporal dementia (FTD) population. OBJECTIVE: With the dementia cohort of Peking Union Medical College Hospital, we aim to illustrate the genetic spectrum of FTD patients, as well as the phenotypic heterogeneity of FTD-gene variant carriers. METHODS: 204 unrelated, clinically diagnosed FTD patients of Chinese ancestry were enrolled. All the participants received demographic survey, history inquiry, physical examination, cognitive assessment, blood biochemical test, brain CT/MRI, and gene sequencing. RESULTS: 56.4% (115/204) participants were clinically diagnosed with behavioral variant of FTD, 20.6% (42/204) with nonfluent/agrammatic variant primary progressive aphasia (PPA), 20.1% (41/204) with semantic variant PPA, and 2.9% (6/204) with mixed variant PPA. 11.8% (24/204) subjects harbored the potential causative variants in FTD-related genes, including the MAPT (n = 7), TBK1 (n = 7), GRN (n = 2), TBK1+GRN (n = 1), VCP (n = 1), TARDBP (n = 1), UBQLN2 (n = 1), SQSTM1 (n = 1), DCTN1 (n = 1), HNRNPA1 (n = 1), and C9orf72 GGGGCC repeats (n = 1). The TBK1 T31fs, T457fs, K622fs, c.359-1G>A, the VCP P188T, and the GRN P50fs, P439fs were novel pathogenic/likely pathogenic variants. The TBK1 carriers showed a later disease onset and a higher incidence of parietal atrophy relative to the MAPTcarriers. CONCLUSION: There is genetic and clinical heterogeneity among Chinese FTD population. The TBK1 has a high mutation frequency in Chinese FTD patients.