What are the psychological symptoms following disclosure of a positive amyloid–positron emission tomography (PET) imaging result on patients with subjective cognitive decline?This study of 105 patients found that the disclosure of a positive amyloid-PET result was associated with a greater psychological changes, yet such changes did not reach the threshold for clinical concern.These findings suggest that the disclosure of a positive amyloid-PET result in patients with subjective cognitive decline was not associated with clinically meaningful psychological risk. This study investigates the psychological outcome of the amyloid-positron emission tomography (PET) result disclosure in patients with subjective cognitive decline and explores which variables are associated with a safer disclosure in individuals who are amyloid positive. Individuals who are amyloid-positive with subjective cognitive decline and clinical features increasing the likelihood of preclinical Alzheimer disease (SCD+) are at higher risk of developing dementia. Some individuals with SCD+ undergo amyloid-positron emission tomography (PET) as part of research studies and frequently wish to know their amyloid status; however, the disclosure of a positive amyloid-PET result might have psychological risks.To assess the psychological outcomes of the amyloid-PET result disclosure in individuals with SCD+ and explore which variables are associated with a safer disclosure in individuals who are amyloid positive.This prospective, multicenter study was conducted as part of The Amyloid Imaging to Prevent Alzheimer Disease Diagnostic and Patient Management Study (AMYPAD-DPMS) (recruitment period: from April 2018 to October 2020). The setting was 5 European memory clinics, and participants included patients with SCD+ who underwent amyloid-PET. Statistical analysis was performed from July to October 2022.Disclosure of amyloid-PET result.Psychological outcomes were defined as (1) disclosure related distress, assessed using the Impact of Event Scale–Revised ; and (2) anxiety and depression, assessed using the Hospital Anxiety and Depression scale .P < .001), IES-R avoidance , IES-R intrusions , and IES-R hyperarousal  scores than the 78 patients who were amyloid-negative . There were no observed differences between amyloid-positive and amyloid-negative patients in the median (IQR) HADS Anxiety  and Depression  deltas (score after disclosure – scores at baseline). In patients with amyloid-positive SCD+, despite the small sample size, higher education was associated with lower disclosure-related distress  whereas the presence of study partner was associated with higher disclosure-related distress . No participants with amyloid-positive SCD+ showed probable presence of PTSD or severe anxiety or depression symptoms at follow-up.After disclosure, 27 patients with amyloid-positive SCD+  had higher median (IQR) IES-R total score (10 [2 to 14] vs 0 [0 to 2]; The disclosure of a positive amyloid-PET result to patients with SCD+ was associated with a bigger psychological change, yet such change did not reach the threshold for clinical concern. The use of amyloid-PET in clinical practice is recommended only for some categories of patients with objective cognitive impairment, although it is discouraged in cognitively unimpaired older individuals.5 However, consistent evidence suggests that individuals with subjective cognitive decline (SCD), a category of patients representing 21% to 29% of a general memory clinic population,7 are at higher risk of developing dementia in the upcoming years (incidence of dementia: 20.1/1000 person-years in SCD population vs 14.2/1000 person-years in controls8). Moreover, some additional clinical features further increase the likelihood of preclinical AD, defining the so-called subjective cognitive decline plus (SCD+) construct.9 Furthermore, the risk of progression to dementia is substantially increased in case of the presence of amyloid deposition . For these reasons, individuals with SCD are increasingly targeted in research and prevention initiatives,11 and are frequently included in research studies involving amyloid-PET . Previous studies have shown that amyloid-PET has substantial clinical consequences in terms of diagnostic change and improvement of diagnostic confidence in SCD,20 and many of these individuals are proactively seeking medical advice and information about their amyloid status.11Amyloid deposition in the brain is considered as the strongest risk factor for Alzheimer disease (AD),21 Moreover, individuals without cognitive impairment who are amyloid-positive reported to contemplate and make more changes to health behaviors and future plans after disclosure than individuals who are amyloid negative.22 Nevertheless, it has been reported that the prognostic uncertainty of amyloid-PET is correctly understood by two-thirds of patients.23 The psychological outcomes of the amyloid-PET result disclosure in cognitively unimpaired individuals has been assessed by some previous studies. For example, one of these studies showed no association with depression and minor increases in disclosure-related distress and anxiety that are mild and well-tolerated over 6 months.24 Another study found that individuals who were cognitively unimpaired and receiving a positive amyloid-PET result disclosure were no more likely to experience short-term increases in anxiety, depression, or suicidality than those receiving a negative amyloid-PET result disclosure.25 Taken together, these results suggest that, in a research setting, the disclosure of the amyloid status in cognitively unimpaired individuals is associated with a low risk of psychological harm.28 As these studies mostly took place in research settings, evidence on the impact of the amyloid-PET result disclosure in clinical settings is currently missing. Moreover, to the best of our knowledge, no studies have empirically assessed which variables may facilitate a safer disclosure of a positive amyloid-PET result. The aims of this study were to assess (1) the psychological outcomes of the amyloid-PET result disclosure in a memory clinic population of individuals with SCD+ and (2) which variables may facilitate a safer disclosure in individuals with amyloid-positive SCD+.Although cognitively unimpaired individuals receiving a negative amyloid-PET result are relieved as they can reinterpret their subjective memory impairment as normal aging, individuals who are amyloid-positive perceive the result as more serious and sensitive than other examinations given its implications for identity, self-determination, and stigma.13 A total of 840 memory clinic patients with variable disease stage  were recruited in 8 European memory clinics from April 16, 2018 to October 30, 2020,14 and allocated into 3 study groups: (1) ARM1, amyloid-PET was performed early in the diagnostic workup ; (2) ARM2, amyloid-PET was performed late in the diagnostic workup ; and (3) ARM3, amyloid-PET was performed if and when the managing physician chooses to request it (free-choice group). According to the study design, the AMYPAD-DPMS participants underwent up to 5 clinical visits: screening (baseline), 3-month, 6-month, 13-month, and 18-month  visits.14 In the present observational study, we assessed the study outcomes irrespective of participants’ randomization into the study groups .This study was carried out in the context of AMYPAD-DPMS. AMYPAD-DPMS is a European, multicenter, prospective, and randomized clinical study implementing amyloid-PET in clinical practice.14 and who were asked to take part in an add-on study on the disclosure of the amyloid-PET result. These participants were enrolled from the 5 AMYPAD-DPMS recruiting memory clinics that accepted to participate in this study: (1) University and University Hospital of Geneva , (2) Amsterdam University Medical Center, location VUmc , (3) Barcelonaßeta Brain Research Center , (4) University College London , and (5) Centre Hospitalier Universitaire Vaudois . Criteria to define SCD+ were based on a modified version of the SCD-I Working group criteria,9 of which the most relevant features are age between 60 and 85 years, perceived decline in memory over time, SCD onset within the previous 5 years and duration greater than 6 months, Mini-Mental State Examination (MMSE) score between 27 to 30, exclusion of MCI, explicit concerns (worries) about the cognitive symptoms, and active seeking of consultation. More information on inclusion and exclusion criteria was reported in previous papers.14In the present study, participants were memory clinic patients with SCD+ who underwent amyloid-PET as part of AMYPAD-DPMS2017-002527-21). This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.The Ethics Committees of all recruiting memory clinics approved the study. All participants gave written informed consent. The trial was registered  or [18F]florbetaben  as amyloid-PET tracers, and visually assessed by trained local nuclear medicine physicians using reading methods approved by the US Food and Drug Administration and the European Medicines Agency for the 2 tracers. The AMYPAD consortium recommended the disclosure of the amyloid-PET result in participants with SCD+. Before the beginning of participants’ recruitment, we developed ad hoc nonprescriptive disclosure guidelines (eTable 1 in In the present study we assessed: (1) the psychological outcomes after the amyloid-PET result disclosure in a memory clinic population of SCD+ individuals, and (2) which variables were associated with a safer disclosure in patients with amyloid-positive SCD+. The psychological outcomes after the amyloid-PET result disclosure were defined as disclosure-related distress, assessed using the Impact of Event Scale–Revised (IES-R); and anxiety and depression, assessed using the Hospital Anxiety and Depression scale (HADS).30 In previous studies, the IES-R total score has been used to assess the presence of PTSD-like symptoms in the context of medical bad news delivery , and also to assess the disclosure-related distress in patients undergoing amyloid-PET.28 The IES-R was administered to all participants included in this study 1 to 3 days after the amyloid-PET result disclosure.IES-R a 22-item self-report measure assessing subjective distress caused by traumatic events  that occurred in the past 7 days, and consists of 1 total score (0 to 88) and 3 average subscores (0 to 4): avoidance , intrusions , and hyperarousal , with higher scores meaning more symptoms. The IES-R total score is normally used to support a clinical diagnosis of posttraumatic stress disorder .32 Items referring to symptoms that may have a physical cause  are not included in the scale, so the HADS is considered to be unbiased by coexisting general medical conditions.33 HADS has 2 distinct subscales (HADS Anxiety and HADS Depression) and scores of at least 15 indicate the probable presence of severe mood disorder symptoms, and scores of at least 8 indicate mild symptoms.34 HADS was administered to all participants at different times during the study. For the present study, we used HADS scores collected at baseline and after the amyloid-PET result disclosure . Deltas (follow-up HADS score minus the baseline HADS score) were used to assess changes in anxiety and depression after amyloid-PET. For participants who underwent amyloid-PET before the 3-month visit, we also assessed anxiety and depression after 13 months .HADS is a 14-item self-report screening scale containing two 7-item scales: one for anxiety and one for depression, both with a score range of 0 to 21, with higher scores meaning higher levels of anxiety or depression.In order to assess which variables were associated with a safer amyloid-PET result disclosure in individuals with amyloid-positive SCD+, we assessed the association of age, sex, education (years), global cognition (MMSE score), communication that SCD+ is a risk condition, disclosure type (face-to-face vs phone), disclosure duration, and presence of study partner (independent variables) with IES-R total and subscale scores, and HADS Anxiety and Depression (dependent variables).P < .05, and post hoc pairwise comparisons  were adjusted using Bonferroni correction. Associations between continuous variables were assessed using Spearman correlations (ρ). All statistical analyses were performed with R, version 4.1.2  from July to October 2022.Continuous variables are described as median and IQR, and categorical variables as percentages (raw numbers). Between-group differences were assessed using Wilcoxon rank sum test for continuous variables, or test for equality of proportions for categorical variables. Significance was set at 2-tailed W = 1269.5; P = .11; gender: 52% men [14 of 27] vs 58% men [45 of 78]; χ2 = 0.09, P = .76; median [IQR] years of education: 15 [13 to 17] years vs 15 [12 to 17] years; W = 1076.5; P = .87; median [IQR] MMSE score: 29 [28 to 30] vs 29 [28 to 30]; W = 1090.0; P = .78).A total of 105 participants with SCD+ of AMYPAD-DPMS, who received their amyloid-PET results, participated in this study  and lasted longer  than in participants who were amyloid negative. It is important to note that at a certain point (approximatively corresponding to March 2020) the number of disclosures done over the phone increased due to the COVID-19 pandemic . Disclosure was done face to face in 87% (13 of 15) of participants who were amyloid-positive SCD+ and 95% (39 of 41) of participants who were amyloid negative  before March, 2020; and in 75% (9 of 12) of amyloid-positive participants and 16% (6 of 37) of amyloid-negative participants  after March 1, 2020.In participants who were amyloid positive, disclosure was more frequently done face to face rather than over the phone , IES-R avoidance , IES-R intrusions , and IES-R hyperarousal  compared with patients who were amyloid negative  and median (IQR) Depression  deltas (scores after disclosure minus scores at baseline)  and median (IQR) Depression  deltas (scores after 13 months minus scores at baseline).After disclosure, patients with amyloid-positive SCD+ had significantly higher median (IQR) IES-R total score  . A total2 = 2.9; P = .09) or depression  symptoms at follow-up  , or seveollow-up .W = 7.5; P = .03). Higher education was associated with lower IES-R hyperarousal  (In participants with amyloid-positive SCD+ (n = 27), the presence of study partner was associated with higher IES-R total score (P = .02) .Our results found that the disclosure of a positive amyloid-PET result to individuals with SCD+ was associated with a greater change in psychological well-being than a negative amyloid-PET result, but this change did not reach the threshold for clinical concern. Specifically, patients with amyloid-positive SCD+ experienced higher levels of avoidance, intrusion, and hyperarousal than amyloid-negative patients directly after disclosure. In contrast, the disclosure of the amyloid-PET result had no statistically significant differences for anxiety and depression in individuals with amyloid-positive and amyloid-negative SCD+ . Finally, in individuals with SCD+ receiving a positive amyloid-PET result, we observed that higher education was associated with lower hyperarousal symptoms , and that disclosure-related distress was higher when a study partner was present.35Our results are in line with previous studies demonstrating that the disclosure of a positive amyloid-PET result does not cause significant psychological risk. Moreover, to the best of our knowledge, this is the first study exploring which variables may facilitate a safer disclosure of a positive amyloid-PET result. In particular, higher education might help participants elaborate and interpret the meaning of a positive biomarker result, and cope with its psychological consequences. Thus, special attention should be paid to individuals with lower education levels during the disclosure. In addition, although the number of participants with SCD+ who were accompanied by a study partner was very small, we can speculate that these individuals were more sensitive to the disclosure of positive biomarker results or might have been more distressed by the worry of how this information may change their families’ and friends’ perceptions of them than participants with SCD+ without study partners. Concerning risk communication, a recent study found that the use of some communication strategies might maximize the information uptake in mild cognitive impairment patients, thus resulting in higher trust and satisfaction.31 consistently with the nature and meaning of the disclosed result .Delivering bad news to cognitively unimpaired patients could be one of the most challenging tasks physicians have to face in their clinical practice. Therefore, it is crucial to highlight that disclosing a positive amyloid-PET result was not associated with a clinically relevant psychological change. Comparing the psychological changes associated with the disclosure of a positive amyloid-PET result with the psychological changes associated with a cancer diagnosis, we qualitatively observed higher distress, anxiety, and depression levels in oncological patients,14 and we believe that our results are generalizable to the clinical practice of memory clinics where individuals who are cognitively unimpaired proactively seek medical help and therefore expect to undergo medical examination and receive their results. This is supported by previous studies reporting that cognitively unimpaired individuals support the amyloid-PET result disclosure,37 and by a survey showing that patients and caregivers placed greater value on testing in asymptomatic individuals than clinicians.38The AMYPAD consortium recommended the disclosure of the amyloid-PET result in participants with SCD+. One could argue that, as AMYPAD-DPMS is a research project, this propensity to disclose (physicians’ perspective) and receive (patients’ perspective) the amyloid-PET result might be different in a clinical setting. However, our sample is representative of a wider memory clinic population,The main limitations of the present study are the lack of long-term assessment of health-related outcomes  and the lack of follow-up on the psychological outcomes of amyloid-PET disclosure. Indeed, the absence of follow-up data prevents us from alleging that the disclosure of a positive amyloid-PET does not cause significant psychological risk in the long term. Another issue is the relatively small sample size, possibly resulting in insufficient power to detect small associations and preventing us from drawing strong conclusions. Moreover, only some of the multiple aspects of psychological risk have been assessed , possibly neglecting relevant issues such as suicidal ideation, which is a potential negative outcome reported in previous studies of risk disclosure.This study found that the disclosure of a positive amyloid-PET result to participants with SCD+ was associated with greater psychological changes, yet such changes did not reach the threshold for clinical concern. This study adds evidence to previous studies showing that the disclosure of the amyloid-PET result is associated with a low risk of psychological harm.


Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous disease entity with diverse etiologies and no uniform treatment protocols. Patients with MINOCA can be clinically classified into two groups based on whether they have an ST-segment elevation (STE) or non-ST segment elevation (NSTE), based on electrocardiogram (ECG) results, whose clinical prognosis is unclear. This study aimed to compare the outcomes and predictors of patients with STE and NSTE in the MINOCA population.We collected the data for 196 patients with MINOCA (115 with STE and 81 with NSTE) in China. Clinical characteristics, prognoses, and predictors of major adverse cardiovascular events (MACE) were analyzed during the follow-up of all patients.P = 0.73) and those without MACE. The multivariable predictors of MACE in the NSTE groups were Killip grades ≥ 2 , reduced use of β-blockers during hospitalization , and higher levels of low-density lipoprotein cholesterol (LDL-C) ; the reduced use of β-blockers during hospitalization was the only independent risk factor of MACE in the STE group.The proportion of patients with STE was greater than that with NSTE in the MINOCA population. Patients with NSTE were older and had a higher incidence of hypertension. No differences were observed in the outcomes between the STE and NSTE groups during a median follow-up period of 49  months. No significant differences were observed in those with MACE (24.35% vs 22.22%, There were differences between the clinical characteristics of patients with STE and NSTE in the MINOCA population, even though outcomes during follow-up were similar. Independent risk factors for major adverse cardiac events were not identical in the STE and NSTE groups, which could be attributable to the differences in disease pathogenesis. Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous group of diseases with different pathogeneses. It is characterized by acute myocardial infarction with normal coronary arteries or mild coronary artery stenosis (stenosis <50%), and occurs commonly in young women . The prePrevious studies have reported that patients with MINOCA had lower rates of major adverse cardiovascular events (MACE) and mortality during follow-up than patients with MI-CAD . AlthougHowever, the differences in clinical features and prognosis between patients with ST-segment elevated myocardial infarction (STEMI) and non-ST segment elevated myocardial infarction (NSTEMI) remain controversial. The occurrence of NSTEMI is more common than STEMI in the MINOCA population . PreviouSome studies have shown that the history of atrial fibrillation, Killip grade, age, and treatment strategy were significant independent risk factors for prognosis in MINOCA patients , while te.g., non-ischemic causes such as sepsis, acute renal failure, pulmonary embolism, and myocarditis); and (4) age >18 years. Patients were excluded if: (1) thrombolytic therapy had been performed prior to coronary angiography; (2) they had a previous myocardial infarction or coronary revascularization; (3) previously underwent cardiac surgery; (4) had malignant tumors.We conducted a retrospective study of patients who had been admitted to the First Hospital at Jilin University due to AMI from January 2015 to July 2018 and had undergone coronary angiography during hospitalization. Patients were included in the study if: (1) they met the diagnostic criteria specified in the AMI guidelines ; (2) no This study has been conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review Board of the hospital . Patient informed consent was waived, as this study was retrospective.e.g., age, sex) and past medical history  were recorded in detail. The history of arrhythmias including previous atrial arrhythmias or ventricular arrhythmias or heart block. We collected information regarding biochemical markers, including blood cardiac troponin-T(cTnT), creatine kinase-MB(CK-MB), brain natriuretic peptide (BNP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and indicators of echocardiography, including LV (left ventricle) and LVEF (left ventricular ejection fraction) in 24 h after hospitalization. We classified the patients into the STE and NSTE groups based on their ECG results. STE and NSTE were defined in accordance with the Fourth Universal Definition of Myocardial Infarction  images, coronary angiography, and medications provided during hospitalization. Basic patient information , including rehospitalization for increased chest pain that did not meet the criteria of AMI, based on ECG results and myocardial injury marker levels, and occurrence of non-fatal MI, heart failure, stroke, heart valve replacement, and all-cause deaths, which included cardiovascular and non-cardiovascular deaths. A diagnosis of MI was made if patients exhibited the dynamic development of cardiac troponin in conjunction with symptoms suggestive of myocardial ischemia. Cardiovascular death was defined as death because of acute coronary syndrome (ACS), cardiac rupture, severe arrhythmias, or refractory severe heart failure. A stroke was defined as an ischemic cerebral infarction caused by thrombotic or embolic occlusions in any major intracranial artery. A diagnosis of heart failure (HF) was established according to the current guidelines of the European Society of Cardiology (ESC) .t-test and the Mann–Whitney U test were used to perform a comparison of continuous variables between groups. Categorical variables were compared using the Chi-square and Fisher’s exact tests. We used logistic regression analysis to evaluate the independent risk factors of outcomes in the STE and NSTE groups, while the adjusted OR for MACE was calculated via logistic regression analysis. All the tests performed were two-sided tests and values were identified to be statistically significant at a P-value <0.05.Statistical analysis was performed using SPSS 25.0 software. Normally distributed continuous variables were presented as mean ± standard deviation (SD) values. Non-normally distributed continuous variables were presented in terms of the median and inter-quartile range (IQR). Categorical variables were presented as counts and percentages. An independent sample In our study, the median follow-up period was 49  months. A total of 9696 patients were diagnosed with MI; among these, 196 patients (2.02%) satisfied the diagnostic criteria for MINOCA. Based on the ECG results, 115 patients (58.7%) were included in the STE group, while 81 patients (41.3%) were included in the NSTE group . A compae.g., diabetes, hyperlipidemia, previous arrhythmia, smoking history). The medications administered at discharge have been shown in In comparison to NSTE patients, patients with STE were younger. Patients with NSTE had a higher incidence of hypertension, whereas no significant differences were observed in the incidence of other coronary risk factors (During a median follow-up period of 49 months (interquartile range [IQR] 37-61), MACE occurred in 46 (23.47%) out of a total of 51 patients. In the STE and NSTE groups, we observed the occurrence of MACE in 28 (24.35%) and 18 (22.22%) patients, respectively. The data are shown in P = 0.73). In this study, five patients died of cardiogenic diseases. During the follow-up period, there was no significant difference in the incidence of chest pain, non-fatal MI, heart failure, stroke, heart valve replacement, and all-cause death between the STE and NSTE groups among the MINOCA population (P > 0.05).There were no statistical differences in the prevalence of MACE between the NSTE and STE groups , lowered use of β-blockers during hospitalization  and higher LDL-C levels  were independent risk factors for MACE in patients with STE . The results showed that Killip grades ≥ 2 . Thus, the use of β-blockers could improve the prognosis of MINOCA patients with NSTE.The age and extent of use of β-blockers and aspirin during hospitalization were adjusted The objective of this study was to compare the prognosis and predictors of MACE among MINOCA patients with STE and NSTE. Our major findings were as follows: (1) There were differences in clinical features between the STE and NSTE groups among MINOCA patients; (2) there was no statistical difference in the incidence of MACE between the STE and NSTE groups during follow-up; (3) the independent risk predictors of MACE in MINOCA patients with STE include a higher level of LDL-C, Killip grades ≥2, and lowered use of β-blockers during hospitalization, whereas the lowered use of β-blockers during hospitalization was the only multivariable predictor of MACE in MINOCA patients with NSTE.e.g., hypertension, diabetes) between the two groups  in the follow-up period between the STEMI and NSTEMI groups, which may be related to the similar drug therapies administered to patients from different sub-groups.The prognostic differences between STEMI and NSTEMI patients in the MINOCA population remain controversial. Previous studies have reported higher short-term mortality in STEMI patients and higher long-term mortality in NSTEMI patients , which wThere are several inconsistencies regarding the predictors of MACE in STEMI and NSTEMI patients in previous studies. One study reported that STEMI and NSTEMI patients differed significantly with regard to predictors of early and late-term mortality . In addiCurrently, there is no uniform treatment for the MINOCA population. We found that β-blocker medication was a protective factor for MACE during the follow-up period in the MINOCA population with NSTEMI and STEMI, which is consistent with the findings of There are several limitations to our study. One of the major limitations is that our study was a single-center retrospective study with a small sample size and a short follow-up period, because of which our findings might lead to biased findings. Second, cardiac magnetic resonance (CMR) cloud not be performed for all patients due to medical insurance-related issues and the lack of CMR may influence the accuracy of our findings in MINOCA patients. Finally, information regarding medications to be administered in the follow-up period could not be obtained for all patients. Hence, we could not further analyze whether the long-term use of secondary preventative medications was beneficial for patients with MINOCA. A larger multi-center randomized controlled study is necessary to clarify the results of this study.In conclusion, the clinical characteristics of the STE and NSTE groups differed in patients with MINOCA, whereas the outcomes during the 49-month follow-up were similar. The predictors for MACE in patients between the STE group and NSTE group were not thoroughly identical.10.7717/peerj.14958/supp-1Supplemental Information 1Click here for additional data file.


More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.The dual-hit hypothesis of Parkinson’s disease (PD) originally postulated that a neurotropic pathogen leads to formation of α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in  Overall, this theory seems to be in general agreement with the known observations that hyposmia and autonomic symptoms appear before parkinsonism in some cases of PD3. The dual-hit hypothesis has been much debated and has inspired a large number of clinical and preclinical studies investigating possible spreading routes of pathogenic α-synuclein and trigger factors, which could initiate or aggravate the initial formation of Lewy pathology in these two origin sites11.The dual-hit hypothesis of Parkinson’s disease (PD) originally suggested by Braak, Del Tredici, and Hawkes postulated that a neurotropic pathogen enters the brain simultaneously in the olfactory bulb (OB) and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage.Nevertheless, very little work has been carried out to study and validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology in fact does arise 15.To this end, we conducted a focused re-analysis of two recently published postmortem datasets from Vantaa, Finland, and Tokyo, Japan. Both datasets included a large number of patients with mild incidental Lewy body disease (ILBD). Of note, we assume that mild ILBD is the asymptomatic preclinical stage seen years before more widespread Lewy body disease characteristic of clinical PD and dementia with Lewy bodies. This temporal relationship is also an underlying assumption in all major neuropathological staging systems of Lewy body disordersThe two datasets contained 302 Lewy pathology-positive cases. In the main analysis, we included only ILBD cases with very mild pathology, defined as cases with pathology in 0 to 3 CNS regions (not including the OB itself). There were 80 such cases with mild ILBD and 71 (89%) of these could be divided unambiguously into two categories, those with amygdala-predominant Lewy pathology, and those with pathology restricted to the peripheral autonomic nervous system (PNS) and/or spinal cord and lower brainstem  had OB pathology . The three OB-negative cases had mild global pathology (GBS < 9) mainly in the brainstem and PNS, and thus also conformed to brainstem-/PNS-predominant cases.p < 10−10). The four brainstem-/PNS-predominant cases with OB pathology also showed pathology in the LC, SN, or amygdala, respectively (Tables Combining the early cases from the Vantaa and Tokyo datasets yielded 39 brainstem-/PNS-predominant cases of whom only 4 10%) showed OB pathology. In contrast, 29 of 32 (91%) amygdala-predominant cases had OB pathology. This difference was statistically highly significant (0% showedp = 0.0003), but not different from that of the amygdala-predominant group (p = 0.30).Finally, nine cases had pathology only in the LC and/or SN of which 7 (78%) had OB pathology. This frequency of OB pathology was significantly higher when compared to the brainstem-/PNS-predominant group  had CERAD stage B-C. In the brainstem/PNS-predominant groups, the mild (1–10) and moderate (11–20) GBS subgroups contained 50% and 38% CERAD stage B-C cases, respectively. The severe (21–30) and very severe (31+) subgroups contained 65% and 75% CERAD stage B-C cases, respectively.In the Tokyo data, consisting of slightly younger cases, 50–54% of mild-to-severe  amygdala-predominant cases had CERAD stage B-C, and 65% of the very severe GBS cases had CERAD B-C. In the brainstem/PNS-predominant groups, the mild and moderate GBS group included 17–23% cases with CERAD stage B-C, and the severe GBS group included 33% cases with CERAD stage B-C. The very severe GBS group contained only 1 case. The declining number of brainstem/PNS-predominant cases at high GBS levels in the Tokyo dataset is caused by the neuropathological scoring system in this dataset, which tends to rate the amygdala higher than brainstem structures—as explained above in the methods section and discussed more below.When studying each GBS category as a whole , in the Vantaa data, the frequency of CERAD B-C climbed from 65% (17/26) at the mild GBS level to 82% (27/33) at the very severe GBS level. In the Tokyo data, the frequency of CERAD B-C increased from 33% (18/54) at the mild GBS level to 66% (25/38) at the very severe GBS level.2. In the original postmortem study by Braak et al., serving as the basis for the dual-hit hypothesis, cases were included based on mandatory presence of Lewy pathology in the DMV16. Thus, all early-stage cases by design conformed to a brainstem-predominant distribution of Lewy pathology. Nevertheless, only 40% (8/20) of the Braak stage 1 cases in that study harbored Lewy-type pathology in the OB.The dual-hit hypothesis originally proposed that formation of pathogenic α-synuclein species starts simultaneously in both the OB and ENS plexuses and encroaches on the CNS in a two-pronged attacksimultaneous OB and DMV” scenario proposed by the original dual-hit hypothesis, the present data seem to instead support a “single-hit OB or autonomic” scenario.In the two newer datasets presented here, only 10% of early cases with mild brainstem/PNS-predominant pathology had Lewy pathology in the OB. These data do not support a dual-hit etiology. Thus, rather than the “2. However, less than half of PD patients develop constipation during the prodromal phase17, only approximately 1/3 of PD patients develop RBD prodromally19, and about 70% develop hyposmia before diagnosis22. These frequencies of prodromal symptoms also suggest that not all patients conform to the dual-hit hypothesis, but that there is more than one prodromal subtype of LBD, including a clinical brain-first subtype, which tend to develop parkinsonism before RBD and constipation emerges.It has often been argued that the dual-hit hypothesis receives support from the fact that PD patients develop constipation, REM sleep behavior disorder (RBD), and hyposmia prior to diagnosisone single location in most patients  model23. The SOC model assumes that clinical brain-first and body-first LBD subtypes reflect underlying amygdala- vs. brainstem/PNS-predominant distribution of Lewy pathology at early disease stages. Early amygdala-predominant (=brain-first) cases have little or no pathology in the lower brainstem and autonomic/enteric nervous system at early time points. Most of these brain-first patients do not develop RBD and autonomic symptoms until after parkinsonism has appeared. The prodromal phase is short due to early  involvement of the SN via mono-synaptic connections between the central amygdala nucleus and SN pars compacta24.A revised hypothesis might therefore postulate that external trigger factors  initiate the first α-synuclein misfolding and aggregation in only nts Fig. . Initial26. Body-first LBD is characterized by a long prodromal phase, which means that Lewy pathology is disseminated more widely at the time of diagnosis. Furthermore, bilateral PNS-to-CNS invasion of pathology, due to overlapping bilateral vagal and sympathetic innervation of the gastro-intestinal (GI) tract, causes a more bilateral disease progression in the brain of these patients. This wider disseminated pathology, including more bilateral involvement of cerebral structures, could explain the well-documented faster symptomatic progression and accelerated dementia in clinical body-first Lewy body disease34. Note that the majority of patients with Dementia with Lewy bodies are probably body-first, whereas only approximately 1/3 of PD patients show the body-first clinical phenotype37.In contrast, early brainstem/PNS-predominant distribution of Lewy pathology is caused by initial α-synuclein pathology in the ENS plexuses, which propagates to the DMV and, importantly, also via the sympathetic ganglia and trunk to the IML. Such body-first cases generally have no pathology in the OB or limbic system at the earliest preclinical time points, and they often develop autonomic symptoms and RBD years before diagnosis29.It is important to consider that there could be many different pathogenic trigger factors, and not just a single “smoking gun”. Some common factors may, in susceptible or just unlucky individuals, trigger α-synuclein pathology primarily or exclusively in either a nasal or in an ENS location, but rarely in both at the same time. Thus, some upper respiratory infections or inhaled toxins might trigger Lewy pathology primarily in the OB. In contrast, GI infections, GI inflammatory conditions, and some ingested toxins might trigger Lewy pathology primarily in the ENS. For instance, it has been shown that pesticide exposure is more common in PD cases with RBD and symmetric parkinsonism, i.e., a body-first subtype. This suggests that ingested pesticides may have a stronger propensity to trigger enteric pathology rather than OB pathologyIn a minority of cases, the triggering event could initiate pathology in both the OB and enteric nervous plexuses, leading to a true dual-hit initiation of the disease. However, the present data suggest that such cases are relatively rare. Finally, in another minority of cases the first pathology may arise in the LC or SN before detectable pathology in the OB or autonomic structures appears, but such cases also seem to be relatively rare. These cases are not shown in the theoretical framework depicted in Fig. deterministic process, i.e., that a pathogenic factor triggers formation of α-synuclein inclusions with high probability. In that hypothetical scenario, a pathogenic factor would commonly lead to simultaneous pathology in both the left and right OB and in the ENS. If this were true, one would expect that the OB, ENS, and DMV would show more or less simultaneous involvement in most ILBD cases at the earliest stages of Lewy pathology. But as reviewed here, this does not seem to be the case.It may be helpful to consider α-synuclein pathobiology in the context of a cancer analogy. Implicitly, the original dual-hit hypothesis can be construed as postulating an almost stochastic process. Thus, the formation of seeding-competent prion-like α-synuclein species by an external trigger may be a very low probability event. This means that a trigger factor, e.g., a common virus infection, in most people may not lead to any sustained prion-like α-synuclein pathology at all, but in the rare cases when it does, it will most likely lead to only a single locus of pathology—perhaps in a single neuron (neuron zero). This locus could be in one OB (both OBs at the same time would be improbable) or in a small patch of the ENS plexuses—perhaps in a single parasympathetic motor neuron. The initial low-probability formation of prion-like species is then followed by a high probability secondary spreading from the originator locus. In most ILBD cases with minimal Lewy pathology, the distribution of pathology shows relatively stereotypical patterns and gradients, where the pathology is concentrated in one or a few heavily interconnected neurons. This distribution of pathology is more in line with an originally uni-focal disease with spreading to closely connected structures, more so than with a multi-focal disease, where pathology starts simultaneously in distant, unconnected structures, such as in the OB and enteric plexuses.The revised single-hit hypothesis presented here suggests that the formation of the first pathogenic α-synuclein inclusions may be more of a 38. Thus, the formation of the first cancer cell is stochastic, highly improbable, and therefore happens only in a single locus in most patients. In contrast, the subsequent metastatic propagation via available lymphogenic and hematogenic spreading routes is a high probability event, which in many cancers is inevitable given enough time. Since α-synuclein is a natively unfolded protein with countless different possible conformations, it seems plausible that the formation of a seeding-competent, prion-like conformation inside a single neuron could likewise be a rare, stochastic event39.Thinking about α-synuclein pathobiology as a stochastic, low-probability process would make it analogous to cancer. Approximately 90% of all cancers have only one primary tumor, but most cancers metastasize sooner or later from this primary tumor40. In addition, another study reported that 71% of de novo PD patients with abnormal MIBG heart scintigraphy were hyposmic, while only 48% of de novo PD with normal MIBG were hyposmic—also suggesting that hyposmia is significantly more common in body-first LBD with pathological MIBG20.Olfactory dysfunction is important to the present discussion, since it develops in the majority of LBD patients, and frequently before diagnosis. Although counterintuitive, prodromal hyposmia seems to be more closely linked to the body-first subtype of LBD, which we assume has an underlying brainstem-/PNS-predominant profile of Lewy pathology. The majority of isolated RBD patients are hyposmic, and nearly all have lost the cardiac sympathetic innervation on [123I]MIBG scintigraphies, while their nigrostriatal dopaminergic innervation is still fairly intacttotal burden of CNS Lewy pathology, but show little or no correlation with the burden of Lewy pathology in the OB itself42. This means that hyposmia is a symptom of widespread CNS Lewy pathology, but not so much of pathology in the OB per se. This observation is in line with the idea that body-first LBD have more widespread Lewy pathology at diagnosis, including early involvement of both hemispheres. This equates to a higher total burden of CNS Lewy pathology, which could promote earlier development of hyposmia. Importantly, it must be remembered that the vast majority of olfaction tests is carried out with an identification test, where the subject must correctly name an odor. Such a test relies not only on OB function but also higher order information processing in olfactory cortex and memory. Thus, it may not be surprising that hyposmia, as measured with an identification test, correlates better with total burden of Lewy pathology than with pathology in the OB itself.The apparently closer association between hyposmia and body-first LBD can be explained in two ways. Recent postmortem studies have reported that hyposmia, measured before death, correlates with the 43.The second possible explanation, which may work in concert with the first explanation outlined above, relates to asymmetry. Briefly, in an OB- or brain-first case, the pathology would be triggered in one OB unilaterally, leaving the other OB initially intact. The neural connections in the mammalian CNS are highly lateralized and only ~1% of projections are commissural innervating the contralateral hemisphere. Thus, if the initial Lewy pathology locus is unilateral, the initial propagating pathology would remain mostly in the same hemisphere, causing quite asymmetric Lewy pathology in the CNS during early disease stages. Olfaction tests are nearly always performed on both nostrils at the same time, so even if one OB is dysfunctional, the patient will not appear hyposmic on such tests. This idea is supported by animal studies, where α-synuclein seeds are injected unilaterally into one OB, which leads to quite lateralized, asymmetric α-synuclein propagation in the hemisphere ipsilateral to injectionbilaterally to the CNS, since both the vagus and sympathetic nerves show a great deal of left-right overlap in their innervation fields of the ENS23. Thus, the initial Lewy pathology in the brainstem is already more bilateral from the onset, and therefore spreads more symmetrically. Approximately one-quarter of LC neurons directly innervate the OB, so once the LC is involved, the left and right OB may be directly seeded from the bilaterally affected LC44.In contrast, body-first Lewy pathology spreads within the CNS—probably from lower brainstem structures such as the LC. This is corroborated by animal studies, where α-synuclein seeds injected into the gut or into the striatum propagates throughout the CNS and leads to marked OB pathology via centrifugal α-synuclein propagation46.As also shown here, once Lewy pathology is widespread in the CNS (GBS > 9), all cases show OB pathology. The most parsimonious explanation seems to be that in brainstem/PNS-predominant cases, the OB is seeded as a secondary phenomenon from not lateralized in early PD48, whereas another study did find unilateral hyposmia in early PD, which correlated with the most affected brain hemisphere49. Thus, it remains unclear whether unilateral hyposmia can occur in early PD.Of note, the second explanation implies that olfaction tests performed on each nostril separately might disclose unilateral hyposmia. However, two studies reported that hyposmia is Put together, hyposmia may arise earlier in body-first LBD, since (1) these patients may have a higher total burden of Lewy pathology at diagnosis, which has been shown to correlate with hyposmia, and (2) both OBs may be sufficiently involved earlier during the prodromal stage of body-first LBD compared to brain-first LBD. The first of these two explanations may be the most important.51. These observations lend support to the fundamental idea that body-first LBD has greater involvement of both hemispheres at diagnosis compared to the more lateralized brain-first subtype.Finally, we note that brain-first PD patients  generally show more asymmetrical parkinsonism and asymmetrical dopaminergic loss on imaging, compared to RBD-positive body-first PD and DLB patients, who display on average much more symmetric dopaminergic loss on imaging44. A direct SN-to-OB tract has also been demonstrated in rats, which could account for the two remaining cases with OB + SN pathology52. Nevertheless, the high frequency of OB pathology in LC/SN-only cases remains to be explained.Approximately 10% (9/80) of cases presented here showed very early pathology limited to the LC and/or SN Tables . Of thes55. It has been suggested that amygdala-predominant Lewy pathology is a special type of pathology seen mainly in association with AD co-pathology16.Cases with amygdala-predominant profiles of Lewy pathology had higher frequencies of neuritic plaque co-pathology. This is in accordance with previous findingsHowever, the Tokyo dataset suggests that although an amygdala-predominant profile is more commonly seen in association with neuritic plaques, approximately 50% of early amygdala-predominant cases showed little or no such AD co-pathology (CERAD 0-A). This frequency is in general agreement with previous studies investigating the amount of AD co-pathology in amygdala-predominant Lewy pathology. In the Vantaa data, nearly all amygdala-predominant cases showed CERAD B-C stages, which could be related to the extreme age (92 ± 4 years) of this population-based cohort of cases.56.Regarding the brainstem/PNS-predominant cases, in the Vantaa data, the frequency of CERAD B-C stages increased from 40–50% at mild and moderate GBS levels to 65–75% at severe and very severe GBS levels Table . In the Importantly, when the cases were not divided into amygdala- and brainstem/PNS-predominant cases, but instead the CERAD B-C frequencies simply calculated in each GBS category, we find that the frequency of CERAD B-C increases significantly in association with increasing global Lewy pathology burden—from 65% to 82% in the Vantaa data, and from 35% to 59% in the Tokyo data , the amount of neuritic plaque pathology also increases. This may be particularly true for cases with brainstem/PNS-predominant Lewy pathology, since these cases started at the background level of AD co-pathology. This suggests that accumulating Lewy pathology generally predisposes to secondary formation of amyloid-β (Aβ) pathology, perhaps via cross seeding mechanisms or simply because proteostatic mechanisms are overwhelmed and therefore unable to prevent accumulation of other types of protein pathologies34, assumed to correspond to the brainstem/PNS-predominant profile of Lewy pathology. On the other hand, it is well known that higher levels of AD co-pathology are seen in demented Lewy body patients at postmortem and also in vivo on amyloid PET scans60. However, the early-stage brainstem/PNS ILBD cases (=body-first) have less AD pathology than early-stage amygdala-predominant (=brain-first) ILBD cases, which constitutes the paradox. But as shown here, AD co-pathology seems to accumulate progressively in association with an increasing global burden of Lewy pathology, and this may be especially true in brainstem/PNS-predominant cases, which provides a solution to the apparent paradox.The third tentative conclusion mentioned above is important, since it potentially solves a paradox within LBD research: on the one hand, it is known that patients with a body-first subtype of LBD are at an increased risk of accelerated dementia. Prodromal RBD, constipation, symmetric dopamine loss, and pathological MIBG scintigraphies are all risk factors of dementia, and these symptoms and signs constitute the clinical body-first subtype23. This more aggressively propagating pathology may in turn predispose to more rapid induction of AD co-pathology. Therefore, end-stage body-first cases with severe levels of global Lewy pathology will on average also display high levels of AD co-pathology, even though they did not have particularly high levels of AD pathology when their brainstem/PNS-predominant Lewy pathology originally started.In short, brainstem/PNS-predominant cases seems to start out with normal, background levels of AD co-pathology, but this particular subtype of Lewy pathology may be more aggressive, perhaps due to the more symmetrical, ascending CNS pathology as proposed by the SOC modelThis study has several limitations. The study was carried out on postmortem cases with very limited Lewy pathology. The assumption of this study was that such early-stage ILBD patients are representative of early preclinical stages of PD and DLB, but this has never been formally proved due to the cross-sectional nature of postmortem data.12. Thus, it is possible that not all of the 40% OB-positive Braak stage 1 cases represent true α-synuclein pathology, but instead a kind of non-specific α-synuclein species. On the other hand, Braak et al. used thick microsections (100 µm). This may be a more efficient way to screen for even minimal amounts of OB pathology, which could easily be missed in thin (5–6 µm) sections typically used by other groups, potentially causing false-negative results in the OB. Importantly, the two datasets interrogated in the present study was based on more modern immunostaining techniques directed toward pathological species of α-synuclein61. Thus, these datasets may more accurately reflect the presence of true α-synuclein pathology in the OB.Lewy-type pathology is studied with variable methodologies. Braak and colleagues used immunostaining against total α-synuclein9.For the moment, it cannot be concluded, whether the findings of very rare OB pathology in brainstem/PNS-predominant cases of the two recent datasets, or alternatively Braak’s finding of 40% OB pathology in stage 1 patients more accurately reflects the truth. Of note, animal studies investigating Braak’s gut-first hypothesis often observe that the OB is one of the first affected brain areas (soon after lower brainstem involvement) upon gut-initiation of disease by injection of artificial pathology into the gut plexuses62. It has also been shown that α-synuclein and Aβ42 inclusions can be seen in the OB of children and young adults, potentially due to air pollution63. This suggests that formation of aggregated protein pathologies may be a common response to various insults, but it remains unknown whether such pathologies are unspecific and self-limiting or, alternatively, whether they always constitute true precursors of neurodegenerative disease.Future studies or re-analyses of other existing postmortem datasets are needed to resolve this issue. In general, more work is also needed to define criteria for what constitutes pathological α-synuclein—especially in non-brain structures. For instance, it has been shown that norovirus infection in children triggers an apparent α-synuclein accumulation in the ENS, which disappears after a few monthssingle-hit hypothesis of PD pathogenesis may be more appropriate, and at the very least, is worthy of more investigation. We found that cases with Lewy pathology restricted to the peripheral autonomic nervous system and/or lower brainstem, very rarely shows olfactory bulb pathology during the earliest disease stages. This suggests that Lewy pathology is triggered in the GI tract or autonomic nervous system without concomitant involvement of the olfactory bulb. In contrast, cases with mild, early-stage amygdala-predominant pathology nearly always show olfactory bulb pathology. This could be compatible with an external pathogenic factor triggering initial pathology restricted to the OB, which then spreads rapidly to amygdala and connected structures, but without initial involvement of the ENS.In summary, the data reviewed suggests that a This revised single-hit hypothesis is also in better agreement with the recently proposed brain-first vs. body-first model of Lewy body disorders, which is itself based on well-documented differences in symptoms and signs in prodromal subtypes of LBD patients.61. All subjects provided written informed consent before enrolling into the two studies.Data from two postmortem datasets were reviewed in this study. Full details on these cohorts and immunohistochemical methods including antibodies and protocols were previously published64. Immunostainings were conducted with the disease-associated α-synuclein antibody 5G4 on 5 µm thick tissue sections 65. Lewy pathology severity was assessed with a semi-quantitative system in all anatomical regions 61, which is very similar to the DLB consortium staging system13. This study included 10 CNS and 2 spinal cord anatomical regions, including the DMV, LC, SN, amygdala (AMY), transentorhinal cortex (TOX), OB, thoracic spinal cord (spTh) and sacral spinal cord (spSa). The remaining anatomical regions are not listed here, since these regions did not show Lewy pathology in any of the early-stage cases primarily interrogated in the present study. Fifteen cases in the Vantaa dataset had olfactory bulb-only α-synuclein pathology, and were not included in this study.The Vantaa85+ population-based cohort consists of 304 postmortem cases (age at death 92 ± 4 years), of which 124 were Lewy-body positive in at least one of the screened regions of the CNS56. Immunostainings were conducted with the anti-phosphorylated-α-synuclein antibody pSyn#64 on 6 µm thick tissue sections 15. Lewy pathology severity was assessed semi-quantitatively following the DLB consortium guidelines 13. This study included 10 CNS and 6 PNS anatomical regions, including the DMV, LC, SN, nucleus basalis of Meynert (NBM), AMY, TOX, anterior cingulum (CING), temporal cortex (TEMP), OB, sympathetic trunk ganglia (SYMP), adrenal gland (ADR), the myocardium (HE), and esophagus. The remaining regions are not mentioned, as they did not show pathology in any of the early-stage cases primarily interrogated in this study.The dataset from the Tokyo Brain Bank for Ageing Research consists of 518 postmortem cases (mean age at death 83 ± 9 years), of which 178 were Lewy-body positive in at least one of the screened regions of the CNS or PNSOB-positive, if one or both of these two structures contained any Lewy pathology. Also, in both datasets the presence of Alzheimer’s disease (AD) co-pathology was assessed. Neuritic plaques were assessed according to the CERAD protocol66 and neurofibrillary tangles according to the protocol by Braak and Braak67.Of note, in the Vantaa and Tokyo datasets, the peripheral OB and the anterior olfactory nucleus were assessed individually. In the present paper, a case is designated From the Vantaa and Tokyo datasets, we identified cases with minimal Lewy pathology. In the Vantaa data, cases with pathology restricted to 1, 2, or 3 CNS locations  were considered early and included. In the Tokyo dataset, cases with pathology in 0, 1, 2, or 3 CNS locations were included. The Tokyo dataset contained 9 cases with Lewy pathology restricted to the sympathetic ganglia and/or heart without any concomitant CNS pathology, i.e., cases with “PNS-only pathology”.Brainstem/PNS-predominant, when the average pathology in the sympathetic ganglia (Tokyo) or thoracic spinal cord (Vantaa) plus DMV was higher than the averaged pathology of the amygdala and transentorhinal cortex. Conversely, a case was defined as amygdala-predominant when the average pathology in the amygdala and transentorhinal cortex was higher than in the sympathetic ganglia or thoracic spinal cord and DMV. We have previously shown that this simple dichotomization algorithm is able to categorize the majority of cases with early-stage Lewy pathology into these two groups and we have shown that a blinded K-means cluster algorithm identifies nearly the same subjects61. A minority of cases were not classifiable, since they had isolated pathology in the LC and/or SN (termed other cases). The anatomical regions and brainstem/PNS- vs. amygdala-predominant categories are illustrated in Fig. For each case, we calculated a simple metric to determine whether the magnitude of pathology was greatest in autonomic structures or in the limbic system. A case was categorized as The presence or absence of OB pathology in each of these early cases was recorded. All individual cases are listed in tables under the three main categories . The Vantaa and Tokyo data were then fused into one dataset, and simple statistical group-comparisons were carried out on the fused dataset with GraphPad PRISM (ver. 8) using Fisher’s exact test.We also recorded the frequency of OB pathology in all remaining cases, i.e., advanced cases with more widespread pathology corresponding to 4 or more CNS regions. Finally, we calculated a global burden score (GBS) of Lewy pathology for each case by summing the Lewy pathology severity score of all examined regions. Four GBS categories were defined: mild global pathology (GBS 1–10), moderate global pathology (GBS 11–20), severe global pathology (GBS 21–30), very severe global pathology (GBS > 30).Importantly, the semi-quantitative assessment of pathology used in these studies is not normalized to the maximal pathology value of each individual brain region. For example, pathology in brainstem regions incl. the DMV is very rarely scored as 4 (very severe), even in cases with severe, widespread Lewy pathology. In contrast, the amygdala is commonly assigned a score 3 (severe) or 4 (very severe), even in cases with limited global pathology. Thus, the semi-quantitative scoring introduces a bias and limits differentiation of brainstem/PNS- vs. amygdala-cases at mid-to-late disease stages. At late stages, most cases will be categorized as amygdala-predominant by the simple categorization algorithm we used. However, at early and moderate levels of global Lewy pathology , most cases can be unequivocally categorized into brainstem/PNS- or amygdala-predominant groups. Since most cases with such limited Lewy pathology fall distinctly into these two categories, we assume that the majority of later stage cases developed from these two original starting profiles, even though brainstem/PNS- and amygdala-predominant profiles are less clear at later stages.


COVID-19 has been affecting the world unprecedentedly and will remain widely prevalent due to its elusive pathophysiological mechanism and the continuous emergence of new variants. Critically ill patients with COVID-19 are commonly associated with cytokine storm, multiple organ dysfunction, and high mortality. To date, growing evidence has shown that extracorporeal hemoadsorption can exert its adjuvant effect to standard of care by regulating immune homeostasis, reducing viremia, and decreasing endotoxin activity in critically ill COVID-19 cases. However, the selection of various hemofilters, timing of initiation and termination of hemoadsorption therapy, anticoagulation management of extracorporeal circuits, identification of target subgroups, and ultimate survival benefit remain controversial. The purpose of this narrative review is to comprehensively summarize the rationale for the use of hemoadsorption in critically ill patients with COVID-19 and to gather the latest clinical evidence in this field. A recent systematic analysis found that the number of people who died from COVID-19 from Jan 1, 2020, to Dec 31, 2021 globally reached 18.2 million  employs a unique polyethyleneimine coating to modify the conventional AN69 membrane, with significant endotoxin and cytokine adsorption properties by the polyethyleneimine layer and the bulk negatively charged hydrogel structures, respectively , 65. In Most small-size case series –71 colleAlthough current evidence collectively suggests that the use of the oXiris membrane in COVID-19 patients is well tolerated in most cases, adequate anticoagulation to maintain the patency of the extracorporeal circuit remains a challenge in COVID-19 patients with a hypercoagulable state. Compared to non-COVID-19 patients, a significantly higher incidence of metabolic alkalosis and hypercalcemia consistent with reduced filter patency was observed in COVID-19 patients undergoing CRRT with regional citrate anticoagulation . HoweverCurrently, there is an ongoing open-label randomized controlled trial (RCT) (oXAKI-COV study) comparing CRRT with the oXiris membrane vs. standard AN69 membrane during a 72-h treatment period in critically ill COVID-19 patients with AKI (NCT04597034) . The pri3.2®  has long been approved for the removal of cytokines, bilirubin, and myoglobin by hemoadsorption  circuits , inspired fraction of oxygen (FiO2)] ratio remained <150 after the prone position) and hyperinflammatory state , cytokine hemoadsorption with the CytoSorb adsorber was used as an effective and safe rescue therapy. After the CytoSorb treatment, the extra high median baseline IL-6 concentration  had a significant reduction to 2.403 pg/ml [917–3.724], p = 0.043. Oxygenation also improved significantly from 103 (18.4) mm Hg to 222 (20.9) mm Hg, p = 0.029  circuit, and 26 patients received standard CVVHD therapy  compared with the control group . Importantly, the ICU mortality rate was 78% in the CytoSorb® group and 73% in the control group . Meanwhile, the effects on the kinetics of inflammatory parameters  and catecholamine requirements were similar between the groups. The negative results may be attributed to the late intervention given the severity of disease, and the results of the statistical analysis were limited by the total number of cases. In addition, it was unclear to what extent vasoparalytic shock can be attributed to COVID-19-driven hyperinflammation or sepsis due to secondary recurrent infections, so there might be potential confounding factors. In the latest prospective, randomized controlled pilot study to date, 24 COVID-19 patients with refractory shock, hypercytokinemia (defined as IL-6 ≥500 ng/L), and indication for RRT or ECMO were enrolled. Compared with standard of care, hemoadsorption with the CytoSorb® adsorber for up to 5 days was not associated with an significant improvement in shock resolution  and survival , possibly because critically ill patients with high sequential organ failure assessment (SOFA) and simplified acute physiology score II scores in this cohort were more likely to have a high in-hospital mortality  is an extracorporeal heparin-immobilized sorbent hemofilter that can remove pathogens from the bloodstream. On April 17th, 2020, the FDA granted COVID-19 emergency use authorizations for the Seraph 100 filter because it can utilize the structural similarity between heparin and pathogen receptors  to bind certain pathogens , 93. Hep® 100 treatment after ICU admission (>60 h) was associated with increased mortality  evaluating the safety and effectiveness of Seraph 100 in COVID-19 patients with organ dysfunction is ongoing in Germany and Spain, which takes the change in organ failure from baseline to 48 hours as a primary outcome . All-cau3.4®, Toray Medical, Tokyo, Japan) is composed of polymyxin B-immobilized polypropylene-polystyrene fiber fabrics. Polymyxin B hemoperfusion (PMX) is characterized by removing endotoxin for the treatment of sepsis caused by gram-negative bacteria  during the course of treatment, causing the need for reconfiguration of the circuit. It is still difficult to determine whether longer (>12 hours) treatment with PMX is effective in improving oxygenation   have been widely used to remove a wide spectrum of endogenous and exogenous toxins . The car2 were significantly higher in the hemoperfusion group than in the matched group. Likewise, Ruslan et al. demonstrated that cytokine adsorption with HA330 or Mediasorb cartridges significantly decreased CRP and fibrinogen at postfiltration in COVID-19 patients admitted to the ICU  integrates plasma exchange, hemoperfusion, continuous hemofiltration, hemodialysis and bilirubin adsorption . It has 3.72/FiO2 ratios of the two enrolled patients also increased from 55 and 58 to 200 and 192, respectively, within hours of SCD initiation. Another recent prospective, single-arm treatment clinical trial at two academic medical centers enrolled 22 COVID-10 patients with ARDS to further evaluate the safety and clinical outcomes of extracorporeal immunomodulation treatment with SCD (The selective cytopheretic device (SCD) is an immunomodulatory extracorporeal device that can promote a lower proinflammatory phenotype in circulating neutrophils and monocytes, thereby modulating the immune response and moderating tissue damage , 124. Thwith SCD . The reswith SCD . More imwith SCD . These e4Although the management of critically ill COVID-19 patients is still challenging, hemoadsorption therapy may be life-saving by regulating immune homeostasis, alleviating viraemia, and reducing endotoxin activity in critically ill COVID-19 patients. Inspiringly, data from low-quality case series and observational studies show that hemoadsorption therapy effectively reduces the levels of inflammatory mediators and improves hemodynamics and organ function. However, it is worth noting that there are still several open problems to tackle: 1) knowledge of unintended removal during hemoadsorption is still scant, and the determination of an individualized anticoagulation regime remains a puzzle that is much more complicated due to the hypercoagulable state in COVID-19 patients; 2) the optimal timing of initiation and duration of hemoadsorption and hemofilter replacement intervals are unknown; 3) the identification of specific patient subgroup who will benefit from hemoadsorption therapy is urgently required; 4) the effect of hemoadsorption therapy in patient-centered outcomes remains to be investigated. Therefore, for the moment these techniques should be considered experimental, high-quality of clinical studies with standardized study design and implementation, rigorous quality control, individualized consideration of risks and benefits, and even evidence-based advice on health economics in such resource-constrained settings are still needed.KC, YL, and BS conceived the idea, KC and YL performed the literature search and drafted the manuscript. The article was critically reviewed and revised by all authors. All authors contributed to the article and approved the submitted version.


IVW-random effects 1.49 [1.23–1.80]) and negative causal effects of serum calcium (ORIVW-random effects 0.69 [0.57–0.83]) and LDL levels (ORIVW-random effects 0.93 [0.90–0.96]) on OA. Despite the heterogeneous designs and estimates of causal effects provided by various MR studies, our meta-analysis suggests that lifestyle-related risk factors in the form of BMI, serum calcium, and LDL have true biological effects on the development of OA.Risk factors for osteoarthritis (OA) often exert effects over protracted time-courses. Mendelian randomization (MR) studies therefore have an advantage over conventional observational studies when studying the causal effect of long-term lifestyle-related risk factors on OA. However, given the heterogeneous design of existing MR studies on OA, the reported causal estimates of these effects remain inconsistent, thus obscuring the true extent of the biological effects of OA lifestyle-risk factors. We conducted a PRISMA systematic review and specifically included MR studies that investigated the causal effect between lifestyle-related risk factors and OA, where causal estimates for various lifestyle factors were pooled for meta-analysis. Quality of studies was assessed according to STROBE-MR guidelines. A total of 1576 studies were evaluated and 23 were included. Overall, the studies included were of high quality and had a low risk of bias. Our meta-analysis demonstrates the positive causal effect of BMI (OR Osteoarthritis (OA) is a degenerative joint disease that ranks fifth amongst all causes of disability globally . It is cWhilst cartilage loss and injury are an inevitable result of ageing, not all individuals develop osteoarthritis, therefore research into modifiable lifestyle factors that predispose to the condition may provide ways of improving primary prevention and insight into putative biological pathways that may be targeted by new treatments . The timMendelian randomization (MR) studies are becoming increasingly prevalent and use genetic variants associated with a risk factor as instrumental variables to assess whether there is a causal effect, or if there are spurious associations due to retro-causality on a disease outcome in an observational setting ,6. WhileSystematic reviews for MR studies have indeed been previously conducted, such as for abdominal aortic aneurysms ,8 but toThis systematic review was performed in accordance with the 2020 updated Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines ,10. The Any studies that used MR to investigate the causal effect between any risk factor with osteoarthritis or related phenotypes;Any studies that used genetic variation as a proxy (Lawlor definition) for an exposure to make causal inferences  regarding the effect of the instrumental variable on the outcome of osteoarthritis ;Any studies with genome-wide or phenome-wide association studies (GWAS/PheWAS) that included MR as part of their analysis;Studies of all sex, age, cohorts, and ethnicities;The following were used as exclusion criteria:Any studies that were unrelated to risk factors on osteoarthritis outcome ;Any studies not conducted on humans;Any case reports, narrative reviews, letters, editorials, opinions, incomplete manuscripts, and conference abstracts;Any studies in which a full English manuscript was not accessible.The following were used as inclusion criteria for all studies screened:Data from included studies were extracted  A qualitp-value of <0.05 was considered statistically significant. Meta-analyses were performed using the ‘meta’ package from RStudio . The inverse variance method with both fixed and random effects models was used alongside the DerSimonian–Laird estimator for tau2 in random effects analysis and the Jackson method for confidence interval of tau2 and tau. All ten studies were included for developing funnel plots to analyze publication bias.Data were pooled in a meta-analysis when at least 3 separate studies assessing whether there was a causal effect between the causal factor/genetic instrument with OA were identified. Meta-analyses were performed on data utilizing both the same risk factor and MR technique. Primary outcomes were defined as the association of genetic risk with osteoarthritis diagnosis or risk and were reported as OR with 95% confidence intervals. A two-sided The database searches returned a total of 1576 results, of which 560 duplicates were removed to yield 1016 unique records .The 1576 studies were screened, and 23 studies were included  16,17,1,36,37,38The OA phenotype investigated as the outcome variable showed heterogeneity across the included studies . A totalA total of 7 studies for BMI ,24,27,28We assessed the causal effect between BMI on all OA outcomes using values obtained only by the inverse variance-weighted method ,24,27,28We then meta-analyzed studies that used the MR-Egger methods to include all OA outcomes ,24,27 toSamples were then stratified and analyzed by the ethnicity of the population investigated. In the meta-analysis of studies involving European individuals ,23,24, t2 statistic reported a value of 83%.We assessed the causal effect between serum calcium on all OA outcomes using values obtained only by the inverse variance-weighted method ,29,30. TThe analysis of LDL cholesterol values obtained by the IVW method ,18,23 ilp-values for fixed and mixed effects (restricted maximum likelihood) were 0.159 and 0.822, respectively. We also constructed funnel plots when the sampling variance, inverse standard error and inverse sampling variance were used as predictor  is a significant public health issue affecting 303 million people. It is therefore critical that recommendations for management and primary prevention focused on modifiable risk factors are informed by robust research that establishes a causal effect with osteoarthritis, beyond the delimited information of non-causal associations reported by conventional observational studies .Despite the heterogeneous designs and findings of independent MR studies studying the causal effect of various lifestyle-related risk factors on OA, our systematic review and meta-analyses of these MR studies have conclusively demonstrated the extent of the positive causal effect of BMI and that of the negative causal effects of serum calcium and LDL levels on osteoarthritis.Given the established biological causality between lifestyle-related risk factors and the development of OA, future studies should aim to study how precisely modulating these risk factors with pharmacological and non-pharmacological strategies could modify the incidence and progression of osteoarthritis in various joints as per a dose–response relationship ,62.


Due to the lack of evidence and inconsistency of sex differences in Heart failure (HF) in the Chinese population, this study aimed to compare sex differences in functional capacity and quality of life (QoL) between women and men after standard HF medications therapies, and analyze whether sex differences were associated with the composite endpoints of all-cause mortality or HF-related hospitalization and cardiac event-free survival rate in Chinese patients with HF.This was a 1-year longitudinal study. Participants included patients with HF from March 2017 to December 2018. At baseline and followed up at 1, 6, and 12 months later, functional capacity was assessed by 6-minute walk testing (6MWT), QoL was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQoL five dimensions (EQ-5D). The Cox proportional hazards model and Kaplan-Meier curves were used to determine sex differences in subsequent outcomes. The Cox proportional hazards model was used to identify the risk factors for composite endpoints. Kaplan-Meier curves were used to compare survival.P < 0.001); however, women reported a lower level of all parameters at the 1, 6, and 12 months follow-ups . In addition, women had a higher risk of all-cause mortality or HF-related hospitalization and a lower cardiac event-free survival rate than men .All patients were assigned to either men group (n = 94) or women group (n = 60). Longitudinal follow-ups showed a continuously increasing in 6MWT, Kansas City Cardiomyopathy Questionnaire overall score, EQ-5D visual analogue scale, and EQ-5D Index score in both groups (all Women reported worse functional capacity, QoL, and prognosis than men in a sample of Chinese patients with HF. Our findings highlight the importance of paying attention to sex differences in HF. Lower QoL in HF is associated with increased hospitalizations and mortality.,8 Thus, it appears to be particularly true for women, who experience higher rates of death and HF hospitalizations than men.,9 However, Previous studies have reported either men had higher hospitalization rates for HF and in-hospital mortality across virtually all ages, or similar in-hospital mortality rates between the sexes.,12 The inconsistency of these findings makes it difficult for us to understand sex differences of HF and implies the need for more clinical trials from different regions and races to verify this point of view. An in-depth understanding of these sex differences may help choose treatment strategies and achieve precise treatment in clinical work. Only a recent retrospective study has reported sex-related differences in the quality of life and short-term mortality rates in Chinese patients with HF, and the clinical trials evidence on sex differences in HF is insufficient due to the limitations of selection bias and information bias in retrospective studies.Although recent studies have demonstrated women with HF experienced poorer QoL as compared to men.Therefore, we conducted a single-center prospective cohort study to compare differences in the functional capacity and QoL between women and men after standard HF medications therapies at different follow-up points. Moreover, we analyzed whether sex differences were associated with the composite endpoints of all-cause mortality or HF-related hospitalization and cardiac event-free survival rate in patients with HF. The main inclusion criteria were aged ≥18 years with signs and/or symptoms of new-onset or worsening heart failure and had objective evidence of cardiac dysfunction.From March 2017 to December 2018, a total of 164 hospitalized patients who were diagnosed with HF at the First Affiliated Hospital of Kunming Medical University were enrolled in this study, regardless of EF and etiology. The study protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Kunming Medical University and conforms to the Declaration of Helsinki and its subsequent revisions. All patients involved provided informed consent before enrolling in the study. HF was diagnosed based on standard guideline criteria.The exclusion criteria were: heart transplant recipient or admitted for cardiac transplantation; implantable cardioverter defibrillator and/or cardiac resynchronization therapy; acute myocarditis or hypertrophic obstructive; restrictive, or constrictive cardiomyopathy; acute coronary syndrome or stroke; septicemia; usage of tricyclic antidepressants, anxiolytics, or other central nervous system medications.,15After having obtained written informed consent, the following assessments were performed: demographics (including medication), a medical history and physical examination, and blood draw of plasma and serum, a 12-lead resting ECG and echocardiogram. All patients were treated with maximum targeted doses with beta-blockers, ACEI (angiotensin-converting enzyme inhibitor)/ARB (angiotensin receptor blocker), and/or diuretics according to the European Society of Cardiology guidelines except for patients with related drug contraindications.–18 It also has been used as a predictor of mortality in patients with HF. The 6MWT should be conducted on a flat, straight indoor corridor usually at least 300 cm long. The patients were told to be calm, to walk continuously if possible, and to cover as much ground as possible in 6 minutes, but they were allowed to stop or slow down if necessary. The total distance achieved was recorded at the end of the test. (2) The 12-item abbreviated version of the KCCQ is specifically designed and validated for health-related QoL assessment in patients with HF, including 4 domains .,22 The EQ-5D questionnaire is a widely used for measuring generic health status consisting of 2 parts: the Index score and the Visual Analogue Scale (VAS). The Index score covers 5 domains of health , where the patients are asked to rate the severity of each domain in 5 levels. The VAS is a vertical type of measure from 0 (worst QoL) to 100 (best QoL). The higher KCCQ and EQ-5D score indicate the better the health status of subjects.We used 6MWT, Kansas City Cardiomyopathy Questionnaire (KCCQ) and EQ-5D to compare functional capacity and quality of life at 1, 6, and 12 months with baseline in men and women: (1) the 6MWT is a simple, safe, inexpensive, widely available and well-tolerated test for assessing the functional capacity of patients with HF in daily clinical practice.In addition, the composite endpoints including all-cause mortality and HF-related hospitalization were recorded during 1-year follow-up. All clinical outcomes were collected by standard clinic follow-up or telephone contact until the end of the study , followed by post hoc Dunnett’s multiple comparison test. Multivariable analyses with the Cox proportional-hazards model were used to estimate the simultaneous effects of prognostic factors on composite endpoints. The cumulative survival was plotted and compared using Kaplan–Meier curves and log-rank test. Significance level was set at P<0.05. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 26.Normally distributed continuous variables are presented as means ± standard deviation and nonnormally distributed variables as median , and categorical data are presented as frequencies (percentages). The baseline group comparisons were made using P < 0.001), had slightly higher left ventricular EF , and had less atrial fibrillation or flutter aetiology (P = 0.036). Notably, there was no significant sex difference in New York Heart Association (NYHA) class (P = 0.563), and B-type natriuretic peptide (BNP) (P = 0.058). Also, there was no significant sex difference in the fraction of target dose of ACEIs/ARBs, beta-blockers or diuretics.Of the 164 patients included in the study, 10 patients were lost to follow-up. Complete data were obtained for 154 patients, 94 of whom were men and the remaining 60 patients were women. Baseline characteristics of men and women are displayed in Table P < 0.001). A comparison of 6MWT between the men and women groups showed no significant difference walking distance at baseline. . However, women had a shorter walking distance than men at 1, 6, and 12 months  . Although women reported similar QoL score with men at baseline as assessed with KCCQ overall score , EQ-5D VAS score , and EQ-5D Index score , women had a lower KCCQ and EQ-5D score than men during subsequent 1-year follow-up period Distributions of overall QoL measures at baseline and their change after 1, 6, 12 months followed a similar trend and are showed in Table P = 0.028) (Table P = 0.006), after adjusting for age, BMI, NYHA class, blood pressure, and LVEF. Among the covariates age was a risk factor . In Figure P=0.027).At the end of the follow-up period, 19 patients died and 100 patients were first hospitalized for HF-related reasons. In the univariate Cox regression model, the sex differences were associated with the composite endpoints of all-cause mortality or first HF-related hospitalization  Table . In the 8) Table . Women hDue to the lack of evidence of sex differences in the Chinese population with HF, this study aimed to compare the differences in functional capacity and QoL between women and men, and analyze whether sex differences were associated with the composite endpoints in patients with HF. We found women reported worse functional capacity and QoL than men from 1 to 12 months compared with baseline in Chinese HF patients, although all these parameters have a significant improvement during subsequent 1-year follow-up period. In addition, women had higher risk of composite endpoints of all-cause mortality or HF-related hospitalization and lower cardiac event-free survival rate than men. ACEI/ARB and beta-blockers are widely known to improve QoL,–28 ejection fraction (EF),,30 and functional capacity.,27 Thirdly, patients enrolled in this study might have benefited from the close follow-up and clinical management even if there had no improvement in medication adherence. Hence, the findings from this study highlight the importance of regular follow-up and optimal management of patients after discharge, as QoL and functional capacity benefit is equally present in both men and women when managed according to guidelines.At 1-year follow-up, both men and women showed a similar improvement in functional capacity and QoL. Several potential contributions to the phenomenon include: Firstly, the improvement presented maximum opportunity at follow-up owing to patients were enrolled either with new-onset or worsening HF symptoms. Secondly, the majority of patients accepted standard HF drugs included ACEI/ARB and beta-blockers according to recent ESC guidelines. Although compelling evidence and guidelines emphasized that the benefit of using maximum targeted doses with HF medications such as beta-blockers and ACEI/ARB strengthened over time, target doses are usually not achieved in clinical practice. A study published in the journal of JACC showed HF medications doses is lower than what is recommended by trials, and a proportion of patients receiving maximum target doses were low at 10.8% for ACEI/ARB, 18.7% for beta-blockers. A lower use of guideline recommended drugs in female with HF has been reported in series of studies which could lead a negative influence on the HF treatment.,34 In our study, all patients involved were treated with maximum targeted doses with beta-blockers and ACEI/ARB except for patients with related drug contraindications. Also, baseline characteristics showed there was similar fraction of targeted dose of these HF drugs; however, our findings reported that women had a lower improvement of 6MWT, KCCQ overall score, EQ-5D VAS and EQ-5D Index score, and indicated women had a worse functional capacity and QoL although after standard HF therapy. Recently, health-related QoL has been shown to have prognostic relevance in patients with HF.,8 Therefore, it is also important for us to recognize the sex differences in HF for prognostic assessment and personalized therapeutic strategies. When it comes to worse prognosis in women, our study showed women was associated with a higher risk composite endpoints of all-cause mortality or HF-related hospitalization than men, after controlling for demographic and clinical confoundings. Kaplan Meier survival curves indicated that women had lower cardiac event-free survival rate. The reason may be owing to the fact that women with HF are more likely to be older, have more comorbidities, and underrepresented in clinical trials, which makes physician worried about less effective and adverse drug reactions in female patients. It is noteworthy to mention that women are more likely to have HF with preserved EF, for which therapies are aimed only at alleviating symptoms. The difference of demographics and clinical characteristics may contribute to the outcome.Delaying the progress of HF, preventing cardiovascular events, and prolonging survival are recommended in current guidelines.,39 To our best knowledge, menopause is related to fat mass, hypertension, endothelial function and cardiomyocyte fibrosis.,41 Moreover, coronary microvascular dysfunction and endothelial inflammation plays a key role in female HF syndromes. Compared with men, women have smaller vessels and appear to be predisposed to poorer diastolic reserve and arterial compliance. This may further contribute to the impact of hypertension on diastolic function and exercise capacity. In addition, women with HF not only have greater physical limitations, but also much higher rates of anxiety and depression than men. Taken together, these findings suggest that women living with HF experience impairment in functional status, poorer QoL, and worse prognosis. Hence, our findings highlight the importance of sex-specific strategies to improve the prognosis of patients with HF. More HF clinical trials performed sex disaggregated analyses should be encouraged to show the sex-specific outcomes and efficacy. A national registry study of 167 US outpatient cardiology practices has showed women received less HF education and less device therapy in the outpatient cardiology setting than their male counterparts with HF; so more education is needed to improve rates of provision of guideline-recommended therapies in women. The patient-centered transitional care model improved discharge preparedness and quality of care transition in both men and women, particularly effective in women, implying more care for women could improve women’s poor HF prognosis. Therapeutic strategies should consider patient characteristics, including sex, rather than same approach. For example, women may benefit from an emphasis on caloric restriction, exercise training, and/or SGLT2 inhibitors. Further research is needed to identify sex differences in medical therapy and patient care to improve outcomes in women.Interestingly, these sex differences in functional capacity, QoL and prognosis were observed during subsequent 1-year follow-up period in this study even though slightly higher left ventricular ejection in women and similar age, NYHA class, BNP, comorbidities, medication and 6MWT and QoL score at baseline between men and women. Additional attention should be paid to the role of hormones in modulating heart function and anatomy.Our study has several potential limitations. First, our sample size was small, which may have also resulted in the inability to detect significant interactions between sex and treatment over serial time points. Future studies with a larger population and longer follow-up are required to validate the long-term consequences of sex difference in HF. Second, lack of effective therapies in preserved EF HF may confound outcomes, the influence of heart failure phenotype must be taken into account. Third, we are unable to comment on important changes in the characteristics or outcomes of patients during the study period owing to the short period of observation. Fourth, the single-center nature of our study potentially limits the heterogeneity of sample considered, which may cannot be extrapolated to other population elsewhere.Women reported worse functional capacity and QoL than men compared with baseline in Chinese HF patients, although all these parameters have a significant improvement in both men and women during longitudinal 1-year follow-up period. In addition, women had higher risk of composite endpoints of all-cause mortality or HF-related hospitalization and lower cardiac event-free survival rate than men. These sex differences in functional capacity, QoL, and prognosis were observed in this study even though similar demographics and clinical characteristics. Our findings highlight the importance of paying attention to sex differences in HF, which may result in the improvement of outcomes in HF.Conceptualization: Hongyan Cai, Yong DuanData curation: Hongyan Cai, Xingyu CaoFunding acquisition: Hongyan Cai, Zhao HuInvestigation: Yiming Ma, Dan Yang, Mingqiang Wang, Shulin He, Xiang LuoMethodology: Yiming Ma, Yunke Shi, Min Zhang, Chaoyue ZhangFormal analysis: Wenfang Ma, Shulin He, Min ZhangSupervision: Hongyan Cai, Yong DuanWriting-original draft: Yiming Ma, Yunke ShiWriting-review and editing: Zhao Hu, Min Zhang