Autonomic and cognitive functions in Parkinson's disease (PD)

We performed this study to evaluate the relationship between the stages of PD and autonomic dysfunction, and to find an association between the autonomic dysfunction and cognitive impairment in PD. Sixty-three patients who met the criteria of the United Kingdom PD Society Brain Bank were enrolled prospectively. Clinical stages were using the Hoehn and Yahr (H&Y) staging and unified PD rating scale motor scores. Cognitive functions were evaluated using the mini-mental state examination (MMSE) and the modified MMSE (3MS) test. The scale for outcome in PD-autonomic (SCOPA-AUT) was used to evaluate autonomic symptoms. Severities of autonomic dysfunction were classified using the composite autonomic scoring scale (CASS). Fifty-four of the 63 patients (86%) had shown abnormalities on CASS. H&Y stages correlated with SCOPA-AUT (p < 0.05) and 3MS and MMSE scores (p < 0.05). H&Y stages were positively related with autonomic dysfunction, heart rate ratios during deep breathing and the quantitative sudomotor axon reflex test (QSART) scores. Autonomic dysfunction may be present from disease onset, whereas the rate of cognitive decline increases with disease progression. We recommend that both qualitative and quantitative autonomic evaluation from the early stage of disease and regular cognitive screening with disease progression might be useful to facilitate optimal management in PD.     

快速眼动期睡眠行为障碍与帕金森病的关联及其早期生物学标志物的研究

目的 探讨帕金森病（PD）潜在的早期生物学标志物在快速眼动期睡眠行为障碍（RBD）患者与PD患者之间的关联与差异.方法 采用统一帕金森病评定量表（UPDRS）、简易智能精神状态检查量表（MMSE）、汉密尔顿抑郁量表（HAMD-17）、帕金森病自主神经功能量表（SCOPA-AUT）、RBD筛查问卷（RBDSQ）对10例特发性RBD患者、15例PD伴RBD患者、15例PD不伴RBD患者和10例健康对照者进行运动症状及非运动症状的评定,并将上述指标在4组间进行组间比较及相关分析.结果 SCOPA-AUT评定结果显示,特发性RBD患者的非运动症状评分介于正常对照与PD患者之间（P＜0.05）,且所有被试者SCOPA-AUT评分与RBDSQ评分呈显著正相关（R=0.561,P＜0.05）.HAMD-17、MMSE评分在4组间比较差异无统计学意义（P＞0.05）,且与RBDSQ评分相关性无统计学意义（P＞0.05）.结论 RBD与PD密切相关,特发性RBD患者自主神经功能症状的严重程度介于正常对照与PD患者之间,提示自主神经功能症状有可能成为预测RBD患者发展成为PD风险的潜在生物学标记物.     

帕金森病疲劳的相关因素研究

目的探讨帕金森病（Parkinson disease,PD）患者疲劳的相关因素及其存在的可能机制。方法人组PD患者73例,采用疲劳量表（Fatigue Severity Scale,FSS）评定患者是否存在疲劳,详细记录患者的年龄、病程、用药情况,并进行UPDRS、Hoehn—Yahr分期、汉密顿抑郁量表（HMDS）、PD自主神经症状量表（thescale for outcomes in PD for autonomic symptoms,SCOPA—AUT）等评定,比较疲劳组（FSS分值／9〉4）和非疲劳组（FSS分值／9≤4）在各方面是否存在差别。结果73例参与疲劳评价的PD患者中,56例（76．7％）存在疲劳。日常生活能力、运动障碍、治疗的并发症、自主神经功能及HMDS与疲劳相关。Logistic回归分析显示,UPDRS第二部分评分及HMDS是疲劳的独立危险因素。结论疲劳是PD患者的常见非运动症状,日常生活能力、运动障碍、自主神经功能及抑郁对疲劳存在一定影响。     

From the Cover: PNAS Plus: Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP^Sc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83^+/− mice expressing α-synuclein (A53T). The TgM83^+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83^+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83^+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83^+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.Looking back almost 50 y ago, kuru was the first human prion disease to be transmitted to an experimental animal (1). Subsequently, Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia were transmitted to nonhuman primates or transgenic (Tg) mice; all of these disorders were eventually found to be caused by PrP^Sc prions that were initially discovered in hamsters with experimental scrapie. Attempts to transmit other neurodegenerative diseases, including Alzheimer’s and Parkinson’s, to monkeys were disappointing; none of the animals developed signs of neurological dysfunction, and none showed recognizable neuropathological changes at autopsy (2).In 1960, Milton Shy and Glenn Drager described two male patients suffering from orthostatic hypotension, additional forms of autonomic insufficiency, and a movement disorder resembling Parkinson’s disease (PD). They also found an additional 40 cases of idiopathic hypotension in the literature, which shared many features with their patients. Nine years later, Graham and Oppenheimer suggested that Shy–Drager syndrome should be combined with striatonigral degeneration and olivopontocerebellar atrophy and that these three entities should be called multiple system atrophy (MSA) (3). They presciently argued that all three disorders were likely caused by a similar neurodegenerative process. Two decades passed before support for this hypothesis began to emerge when the brains of 11 MSA patients were reported to contain silver-positive accumulations or glial cytoplasmic inclusions (GCIs) primarily in oligodendrocytes (4). The nature of these GCIs remained elusive for another decade until three groups reported that GCIs exhibited positive immunostaining for α-synuclein (5–7). The discovery that MSA is a synucleinopathy followed a study reported 1 y earlier showing that Lewy bodies in PD contain α-synuclein by immunostaining (8). Such investigations were prompted by molecular genetic studies showing genetic linkage between the A53T point mutation in α-synuclein and inherited PD (9).MSA is a sporadic, adult-onset, progressive neurodegenerative disorder with an annual incidence of ∼3 per 100,000 individuals over the age of 50 (10, 11). The duration of MSA is generally 5–10 y and is substantially shorter than most cases of PD, which leads to death in 10–20 y. MSA has been subdivided based on the predominance of Parkinson’s symptoms (MSA-P) or cerebellar dysfunction (MSA-C) (12).The unanticipated results of an earlier study in 2013 showed that two cases of MSA transmitted CNS dysfunction to transgenic (TgM83^+/−) mice expressing mutant human α-synuclein*A53T protein (13). In that initial report, brain homogenates prepared from two cases of MSA were intracerebrally (IC) injected into TgM83^+/− mice, which resulted in progressive CNS dysfunction after ∼120 d. The brains of the Tg mice exhibited extensive phosphorylated α-synuclein deposits in the cytoplasm and axons of neurons.To determine whether the transmissions of two MSA cases were anomalous, we inoculated TgM83^+/− mice with another dozen cases from three different countries: the United Kingdom, Australia, and the United States. We report here that homogenates prepared from each of the additional 12 cases produced an experimental synucleinopathy in all of the IC inoculated TgM83^+/− mice with incubation times of ∼120 d. The mice developed intraneuronal deposits of aggregated, phosphorylated α-synuclein in their brainstems and some other CNS regions. Using multiple brain regions from some of the MSA cases, a total of 19 homogenates from 14 MSA cases produced CNS dysfunction in TgM83^+/− mice and infected human embryonic kidney (HEK) cells expressing α-syn140*A53T–YFP, resulting in cytoplasmic aggregates of the fusion protein that were measured by fluorescence microscopy (14). From these transmission studies in both TgM83^+/− mice and cultured cells, we conclude that MSA is a transmissible human neurodegenerative disease caused by α-synuclein prions.     

Opioid Use is Associated with Decreased Quality of Life in Patients with Crohn's Disease

Background/Aims:

Quality of life is an important consideration in the management of patients with Crohn''s disease. Previous studies suggest that Crohn''s disease patients using opioids may have decreased quality of life and increased risk of mortality. Our aim was to determine the association between health-related quality of life (HRQoL) and opioid use in patients with Crohn''s disease while controlling for disease severity.

Patients and Methods:

We conducted a cross-sectional study recruiting Crohn''s disease patients at our center. Disease activity was measured using the Harvey-Bradshaw Index (HBI), and HRQoL was measured using the Inflammatory Bowel Disease Questionnaire (IBDQ).

Results:

We enrolled 38 Crohn''s disease patients using opioids and 62 patients not using opioids. Patients using opioids had an increased duration of disease (median 18.5 vs. 9 years, P = 0.005), increased surgeries related to Crohn''s disease (median 3 vs. 0, P < 0.001), and increased prednisone use (29% vs. 11.3%, P = 0.03). Patients using opioids had increased disease activity (median HBI score 9.0 vs. 3.0, P < 0.001). Quality of life was lower in patients using opioids (mean IBDQ score 109.3 vs. 162.9, P < 0.001). This finding was significant when controlling for HBI scores, number of previous surgeries, and prednisone use (P = 0.003).

Conclusions:

Opioid use in Crohn''s disease patients appears to be associated with disease activity and severity. HRQoL is markedly decreased in patients using opioids and this association is significant even when controlling for variables reflecting disease severity. Our findings suggest that Crohn''s disease patients using opioids are likely to be significantly impacted by their disease.     

Acute cardiovascular hospitalizations and illness severity before and during the COVID‐19 pandemic

BackgroundCardiovascular disease (CVD) hospitalizations declined worldwide during the COVID‐19 pandemic. It is unclear how shelter‐in‐place orders affected acute CVD hospitalizations, illness severity, and outcomes.HypothesisCOVID‐19 pandemic was associated with reduced acute CVD hospitalizations (heart failure [HF], acute coronary syndrome [ACS], and stroke [CVA]), and worse HF illness severity.MethodsWe compared acute CVD hospitalizations at Duke University Health System before and after North Carolina''s shelter‐in‐place order (January 1–March 29 vs. March 30–August 31), and used parallel comparison cohorts from 2019. We explored illness severity among admitted HF patients using ADHERE (“high risk”: >2 points) and GWTG‐HF (“>10%”: >57 points) in‐hospital mortality risk scores, as well as echocardiography‐derived parameters.ResultsComparing hospitalizations during January 1–March 29 (N = 1618) vs. March 30–August 31 (N = 2501) in 2020, mean daily CVD hospitalizations decreased (18.2 vs. 16.1 per day, p = .0036), with decreased length of stay (8.4 vs. 7.5 days, p = .0081) and no change in in‐hospital mortality (4.7 vs. 5.3%, p = .41). HF hospitalizations decreased (9.0 vs. 7.7 per day, p = .0019), with higher ADHERE (“high risk”: 2.5 vs. 4.5%; p = .030), but unchanged GWTG‐HF (“>10%”: 5.3 vs. 4.6%; p = .45), risk groups. Mean LVEF was lower (39.0 vs. 37.2%, p = .034), with higher mean LV mass (262.4 vs. 276.6 g, p = .014).ConclusionsCVD hospitalizations, HF illness severity, and echocardiography measures did not change between admission periods in 2019. Evaluating short‐term data, the COVID‐19 shelter‐in‐place order was associated with reductions in acute CVD hospitalizations, particularly HF, with no significant increase in in‐hospital mortality and only minor differences in HF illness severity.     

The role of working memory and attentional disengagement on inhibitory control: effects of aging and Alzheimer's disease

Patients with Alzheimer''s disease have an impairment of inhibitory control for reasons that are currently unclear. Using an eye-tracking task (the gap-overlap paradigm), we examined whether the uncorrected errors relate to the task of attentional disengagement in preparation for action. Alternatively, the difficulty in correcting for errors may be caused by the working memory representation of the task. A major aim of this study was to distinguish between the effects of healthy aging and neurodegenerative disease on the voluntary control of saccadic eye movements. Using the antisaccade task (AST) and pro-saccade task (PST) with the ‘gap’ and ‘overlap’ procedures, we obtained detailed eye-tracking measures in patients, with 18 patients with probable Alzheimer''s disease, 25 patients with Parkinson''s disease and 17 healthy young and 18 old participants. Uncorrected errors in the AST were selectively increased in Alzheimer''s disease, but not in Parkinson''s disease compared to the control groups. These uncorrected errors were strongly correlated with spatial working memory. There was an increase in the saccade reaction times to targets that were presented simultaneously with the fixation stimulus, compared to the removal of fixation. This ‘gap’ effect (i.e. overlap–gap) saccade reaction time was elevated in the older groups compared to young group, which yielded a strong effect of aging and no specific effect of neurodegenerative disease. Healthy aging, rather than neurodegenerative disease, accounted for the increase in the saccade reaction times to the target that are presented simultaneously with a fixation stimulus. These results suggest that the impairment of inhibitory control in the AST may provide a convenient and putative mark of working memory dysfunction in Alzheimer''s disease.     

RETRACTED: Association between erectile dysfunction and coronary artery disease and it's severity

Background/aims

To investigate the prevalence of erectile dysfunction (ED) in patients with coronary artery disease (CAD), its relationship between the severity of ED and the extent of coronary vessel involvement and to register the mean time interval between them.

Methods

240 patients with CAD divided into three age-matched groups: Group 1 (n = 60), ACS with one-vessel disease (1VD); group 2 (n = 60), ACS with 2,3VD; group 3 (n = 60), CSA. Control group (C, n = 60) was composed of patients with suspected CAD who were found to have entirely normal coronary arteries by angiography. ED as any value <26 according to the Gensini''s scores and according to the International Index of Erectile Function (IIEF).

Results

ED prevalence was 76%. ED prevalence was lower in G1 vs. G3 (22 vs.65%). G2 ED rate [55%, P < 0.0001] IIEF = 24 (17–29) & Gensini''s scores-21 (12.5–32) were significantly different from G1 and similar to G3, ED in ACS differs according to the extent of CAD. G3 patients who had ED symptoms prior to CAD symptoms and time interval between ED and CAD symptom onset in CCS according to number of vessels. Onset of sexual dysfunction occurred before CAD onset with a mean time interval of 24 m [12–36].

Conclusion

Early diagnosis of ED, cardiovascular assessment and aggressive treatment of cardiovascular risk factors might have contributed to prevent the acute events of this patient. Patients should be systematically screened for ED as a part of periodic examination programs. This would lead to early detection of modifiable vascular risk factors, or already existing vascular disease and to prevent ED and vascular disease progression through pharmacological and life style modifications.     

Endothelial Dysfunction Is Associated With Major Adverse Cardiovascular Events in Peritoneal Dialysis Patients

Endothelial dysfunction is implicated in increased cardiovascular risk in nondialyzed population. However, the prognostic impact of endothelial dysfunction on cardiovascular outcome has not been investigated in peritoneal dialysis (PD) patients.We prospectively determined endothelial function by brachial artery endothelium-dependent vasodilation (flow-mediated dilation [FMD]) in 143 nondiabetic PD patients and 32 controls. Primary outcome was a major adverse cardiac and cerebrovascular event (MACCE).Brachial FMD was significantly lower in PD patients than in controls (2.9% [1.3–4.7] vs 6.2% [5.4–8.3], P < 0.001). During a mean follow-up of 42 months, primary outcome was observed in 25 patients (17.5%). When patients were dichotomized by the median value of FMD (2.9%), incidence rates of MACCEs were significantly higher in the group with lower FMD compared with higher FMD (7.2 vs 3.0/100 person-years, P = 0.03). In multivariate Cox analysis, low FMD (≤2.9%) was a significant independent predictor of MACCEs (hazard ratio = 2.73, 95% confidence interval = 1.03–7.22, P = 0.04). Furthermore, multivariate fractional polynomial analysis showed that the risk of MACCE decreased steadily with higher FMD values.Impaired brachial FMD was a significant independent predictor of MACCEs in PD patients. Estimating endothelial dysfunction by brachial FMD could be useful for stratifying cardiovascular risk in these patients.     

α-Synuclein–induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi–tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.Parkinson’s disease (PD) is an age-dependent neurodegenerative disorder characterized by the accumulation of a synaptic protein, α-synuclein (α-syn), within Lewy bodies and neurites of the nervous system in the form of amyloid fibrils (1). Although the factors that convert α-syn from a normal soluble protein into insoluble amyloid aggregates are not known, recent studies have indicated that perturbations in cellular pathways that mediate the synthesis or degradation of α-syn may play a role. The formation of toxic aggregates in vitro is dramatically accelerated by increased α-syn concentration (2), a notion that is supported in vivo through PD patients that overproduce α-syn through SNCA gene triplication (trp) (3). In addition to aberrant synthesis, disruptions in protein clearance pathways have been linked to PD. For example, recent clinical, genetic, and pathological data demonstrate a linkage between the lysosomal storage disorder (LSD), Gaucher disease (GD), and synucleinopathies (4–6), suggesting that lysosomal dysfunction contributes to α-syn aggregation and PD pathogenesis (7).Over 50 LSDs exist, and nearly all are characterized by neurodegeneration, emphasizing the importance of lysosomal function for neuronal health. Although biochemical identification of the storage material(s) has advanced our understanding of cellular dysfunction in these diseases, the mechanisms that lead to neurodegeneration are unknown. Previously, we demonstrated that the primary storage material of GD, glucosylceramide (GluCer), directly interacted with α-syn and promoted conformational conversion into pathogenic oligomeric species and amyloidogenic fibrils (8). We also showed that accumulated α-syn interfered with trafficking and activity of mutant or wild-type GCase (8).In addition to lysosomal dysfunction, genetic analysis has indicated that defects in vesicular trafficking can lead to PD (9, 10). Interestingly, functional studies of trafficking proteins implicate their role in α-syn–mediated cell death (11–13). Whereas these studies imply that vesicle trafficking deficits may lead to α-syn accumulation, no studies have demonstrated a mechanistic linkage between these processes.Here we show that α-syn impairs key vesicular trafficking components at the early secretory pathway, resulting in disrupted hydrolase trafficking and reduced lysosomal function. Expression of the small GTPase rab1a restored trafficking machinery and elevated lysosomal function, further suggesting that decreased trafficking of hydrolases represents the main mechanism of altered lysosomal function in synucleinopathies. Importantly, we confirmed our findings in induced pluripotent stem cell (iPSC)-derived midbrain neurons that naturally form amyloidogenic α-syn inclusions after culturing for hundreds of days. Our results suggest that improved trafficking of lysosomal hydrolases may be a viable target for the treatment of synucleinopathies.     

Repression of α-synuclein expression and toxicity by microRNA-7

α-Synuclein is a key protein in Parkinson''s disease (PD) because it accumulates as fibrillar aggregates in pathologic hallmark features in affected brain regions, most notably in nigral dopaminergic neurons. Intraneuronal levels of this protein appear critical in mediating its toxicity, because multiplication of its gene locus leads to autosomal dominant PD, and transgenic animal models overexpressing human α-synuclein manifest impaired function or decreased survival of dopaminergic neurons. Here, we show that microRNA-7 (miR-7), which is expressed mainly in neurons, represses α-synuclein protein levels through the 3′-untranslated region (UTR) of α-synuclein mRNA. Importantly, miR-7-induced down-regulation of α-synuclein protects cells against oxidative stress. Further, in the MPTP-induced neurotoxin model of PD in cultured cells and in mice, miR-7 expression decreases, possibly contributing to increased α-synuclein expression. These findings provide a mechanism by which α-synuclein levels are regulated in neurons, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for PD and other α-synucleinopathies.     

From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease

CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human genetic polymorphisms in the CD39 gene might influence susceptibility to Crohn''s disease. We induced colitis in mice using Dextran Sodium Sulfate (DSS). Readouts included disease activity scores, histological evidence of injury, and markers of inflammatory activity. We used HapMap cell lines to find SNPs that tag for CD39 expression, and then compared the frequency of subjects with high vs. low CD39-expression genotypes in a case-control cohort for Crohn''s disease. Mice null for CD39 were highly susceptible to DSS injury, with heterozygote mice showing an intermediate phenotype compared to wild type (WT). We identified a common SNP that tags CD39 mRNA expression levels in man. The SNP tagging low levels of CD39 expression was associated with increased susceptibility to Crohn''s disease in a case-control cohort comprised of 1,748 Crohn''s patients and 2,936 controls (P = 0.005–0.0006). Our data indicate that CD39 deficiency exacerbates murine colitis and suggest that CD39 polymorphisms are associated with inflammatory bowel disease in humans.     

Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers–Danlos syndrome

Objectives

Many non-musculoskeletal complaints in EDS-HT may be related to dysautonomia. This study therefore aims to investigate whether dysautonomia is present and to explore the underlying mechanisms.

Methods

A total of 39 females with EDS-HT and 35 age-matched controls underwent autonomic function testing. Resting autonomic tone was assessed using heart rate variability (frequency domain) and baroreflex sensitivity analysis (cross correlation). Autonomic reactivity was assessed using the Autonomic Reflex Screen test battery. Factors suspected to contribute to dysautonomia, e.g., neuropathy, medication use, decreased physical activity, depression, pain-induced sympathetic arousal, and connective tissue laxity, were quantified using validated questionnaires, the Beighton score, and measurement of skin extensibility.

Results

The EDS-HT group showed autonomic deregulation with increased sympathetic activity at rest and reduced sympathetic reactivity to stimuli. Increased resting activity was indicated by a higher LF/HF ratio compared to controls (1.7 ± 1.23 vs 0.9 ± 0.75, p = 0.002); decreased reactivity by a greater BP fall during valsalva (−19 ± 12 vs −8 ± 10, p < 0.001), and a smaller initial diastolic BP increase during tilt (7% vs 14%, p = 0.032). Orthostatic intolerance was significantly more prevalent in EDS-HT than controls (74% vs 34%) and was most frequently expressed as postural orthostatic tachycardia. Lowered QSART responses suggest that sympathetic neurogenic dysfunction is common in patients (p < 0.013), which may explain the dysautonomia in EDS-HT. Further, connective tissue laxity and vasoactive medication use were identified as important factors in aggravating dysautonomia (p < 0.035).

Conclusion

Dysautonomia consisting of cardiovascular and sudomotor dysfunction is present in EDS-HT. Neuropathy, connective tissue laxity, and vasoactive medication probably play a role in its development.     

The cognitive dysfunction related to Alzheimer disease or cerebral small vessel disease: What's the differences

Alzheimer disease (AD) and sporadic cerebral small vessel disease (CSVD) are common cognitive disorders. Both AD and CSVD have mental symptoms including chronic progressive cognitive impairment, dysfunction, and behavioral abnormalities. However, the differences on the cognitive dysfunction of AD and CSVD remain unclear. It is necessary to elucidate the cognitive dysfunction differences of AD and CSVD, and to identify the potential risk factors.AD or sporadic CSVD patients treated in our hospital from December 1, 2018 to May 31, 2019 were included. And we selected healthy participants as controls. The mini-mental state examination and Montreal Cognitive Assessment Scale were used for neuropsychological assessment, and related medical information were collected and compared.A total of 190 patients were included. The total mini-mental state examination scores in AD, CSVD group were significantly less than that of control group, there were significant differences in the domains of directional ability, attention and computing ability, delayed recall, and visual perception (all P < .05); the total Montreal Cognitive Assessment Scale scores in AD, CSVD group were significantly less than that of control group. There were significant differences in the domains of visual space and execution, immediate remember, attention and computing ability, language, delayed recall, and directional ability (all P < .05); diabetes was a risk factor both for AD (hazard ratio = 1.63, 95% confidence interval: 1.35–1.97) and CSVD (hazard ratio = 1.15, 95% confidence interval: 1.08–1.27).The cognitive dysfunctions of AD are difference to that of CSVD patients, and diabetes is the risk factor both for AD and CSVD, future studies are needed to further identify the prevention and treatment of AD and CSVD.     

Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients

Background and study aimsCirrhosis is a multisystem disorder characterized by hyperdynamic circulation which can progress to multiple organ dysfunctions. Recent studies have demonstrated autonomic dysfunction and cirrhotic cardiomyopathy including diastolic dysfunction, systolic dysfunction with electrophysiologic abnormalities in patients with cirrhosis. Due to the long and complicated course of the disease, health related quality of life is affected. We aimed to evaluate the frequency of diastolic dysfunction and autonomic dysfunction in cirrhosis, and the effects on health-related quality of life.Patients and methodsHundred cirrhotic patients were enrolled in the study. According to the Child-Pugh classification 35 patients were of Child A, 36 of Child B and 29 of Child C. The proportion of autonomic dysfunction was 52%, and diastolic dysfunction 51%. Autonomic dysfunction was diagnosed using bedside maneuvers and tests; diastolic dysfunction was diagnosed using the E/A ratio in echocardiographic findings. Health-related quality of life measurements was obtained from an SF-36 questionnaire.ResultsPatients with advanced Child-Pugh classifications were found to have significantly lower health-related quality of life values (p < 0.05). Likewise, health-related quality of life values were observed to be significantly lower in patients with autonomic dysfunction (p < 0.05). No significant difference was found in health related quality of life measurements between patients with and without diastolic dysfunction.ConclusionOur study showed that autonomic dysfunction and diastolic dysfunction are found in patients with cirrhosis. Further studies are needed to assess the effects of autonomic dysfunction and diastolic dysfunction on health-related quality of life.     

Impairment of autonomic reactivity is a feature of heart failure whether or not the left ventricular ejection fraction is normal

Background

Autonomic dysfunction (AD) is associated with morbidity and mortality in patients with systolic heart failure (SHF). The extent of AD when LV ejection fraction is preserved (HF-NEF), is unclear. Our objectives were: 1) quantitative assessment of autonomic function in SHF and HF-NEF; and 2) exploration of relationships among AD, symptoms and cardiac function.

Methods

This was an observational study of patients newly referred from primary care with a heart failure diagnosis; 21 SHF, 20 HF-NEF patients and 21 normal subjects were recruited. All subjects underwent clinical evaluation, 6-minute walk test (6MWT), Minnesota Questionnaire (MLWHFQ) and echocardiography. Autonomic assessment included haemodynamic responses to standing, deep breathing and handgrip. Concomitant blood pressure variability (BPV) and heart rate variability (HRV) parameters were also derived.

Results

There were significant differences in all haemodynamic responses between SHF, HF-NEF and normal. Log transformed (ln) low frequency spectral component of BPV was lower in SHF (4.1 ± 0.3) than HF-NEF (4.2 ± 0.4) and normal (4.4 ± 0.1; p = 0.001 SHF vs HF-NEF and vs normal). Ln LF/HF was greater in normal than HF-NEF and SHF (1.5 ± 0.7 vs 0.9 ± 1.0 vs 0.6 ± 0.6; p = 0.003). Autonomic modulations correlated negatively with severity of heart failure.

Conclusions

Autonomic responses in heart failure were blunted and the attenuation of responses correlated strongly with symptomatic and functional markers of disease severity. Autonomic dysfunction is a feature of the heart failure syndrome but is not dependent on ejection fraction.     

Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-β peptide and neuronal cell interactions

By using a highly sensitive technique of atomic force microscopy-based single-cell compression, the rigidity of cultured N2a and HT22 neuronal cells was measured as a function of amyloid-β42 (Aβ42) protein treatment. Aβ42 oligomers led to significant cellular stiffening; for example, 90–360% higher force was required to reach 80% deformation for N2a cells. Disaggregated or fibrillar forms of Aβ42 showed much less change. These observations were explained by a combination of two factors: (i) incorporation of oligomer into cellular membrane, which resulted in an increase in the Young''s modulus of the membrane from 0.9 ± 0.4 to 1.85 ± 0.75 MPa for N2a cells and from 1.73 ± 0.90 to 5.5 ± 1.4 MPa for HT22 cells, and (ii) an increase in intracellular osmotic pressure (e.g., from 7 to 40 Pa for N2a cells) through unregulated ion influx. These findings and measurements provide a deeper, more characteristic, and quantitative insight into interactions between cells and Aβ42 oligomers, which have been considered the prime suspect for initiating neuronal dysfunction in Alzheimer''s disease.     

Autonomic dysfunction in primary biliary cirrhosis correlates with fatigue severity

BACKGROUND AND AIMS: Autonomic dysfunction has previously been described in primary biliary cirrhosis patients. In nonhepatic diseases, fatigue is associated with autonomic dysfunction and impaired baroreflex sensitivity. Here, we investigate the prevalence of autonomic dysfunction using highly sensitive detection modalities and its relationship with fatigue in both noncirrhotic and cirrhotic primary biliary cirrhosis patients. METHODS: Autonomic reflex tests were performed, using continuous blood pressure and electrocardiograph measurement in 47 primary biliary cirrhosis patients and age and sex-matched controls. Fatigue was measured using the primary biliary cirrhosis-40. RESULTS: In all, 100% of precirrhotic and 81% of cirrhotic primary biliary cirrhosis patients exhibited autonomic dysfunction. Valsalva ratio and 30 : 15 ratio (measures of parasympathetic autonomic dysfunction) were significantly lower in primary biliary cirrhosis patients than in controls (valsalva ratio: 1.42 vs. 1.57; P=0.01, 30 : 15: 1.1 vs. 1.2; P=0.01). Blood pressure drop on standing (sympathetic autonomic dysfunction) was greater in the primary biliary cirrhosis group (31+/-22 vs. 23+/-15 mmHg; P=0.03). Valsalva phase IV size was similar between primary biliary cirrhosis patients and controls, however, time to phase IV was significantly longer (P=0.01), suggesting adrenergic failure. Increasing fatigue was associated with impaired baroreflex sensitivity and an earlier, bigger phase IV (sympathetic overactivity). No significant differences were seen, between cirrhotic and noncirrhotic patients. CONCLUSION: The prevalence of autonomic dysfunction in primary biliary cirrhosis patients is significantly higher than has previously been thought to be the case. Indeed, when sensitive detection modalities are used, it is found to be almost universal at all stages of the disease process. Fatigue in primary biliary cirrhosis is associated with abnormalities of autonomic function.     

Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure

Studies by solid-state nuclear magnetic resonance (NMR) of amyloid fibrils prepared in vitro from synthetic 40-residue β-amyloid (Aβ_1–40) peptides have shown that the molecular structure of Aβ_1–40 fibrils is not uniquely determined by amino acid sequence. Instead, the fibril structure depends on the precise details of growth conditions. The molecular structures of β-amyloid fibrils that develop in Alzheimer''s disease (AD) are therefore uncertain. We demonstrate through thioflavin T fluorescence and electron microscopy that fibrils extracted from brain tissue of deceased AD patients can be used to seed the growth of synthetic Aβ_1–40 fibrils, allowing preparation of fibrils with isotopic labeling and in sufficient quantities for solid-state NMR and other measurements. Because amyloid structures propagate themselves in seeded growth, as shown in previous studies, the molecular structures of brain-seeded synthetic Aβ_1–40 fibrils most likely reflect structures that are present in AD brain. Solid-state ¹³C NMR spectra of fibril samples seeded with brain material from two AD patients were found to be nearly identical, indicating the same molecular structures. Spectra of an unseeded control sample indicate greater structural heterogeneity. ¹³C chemical shifts and other NMR data indicate that the predominant molecular structure in brain-seeded fibrils differs from the structures of purely synthetic Aβ_1–40 fibrils that have been characterized in detail previously. These results demonstrate a new approach to detailed structural characterization of amyloid fibrils that develop in human tissue, and to investigations of possible correlations between fibril structure and the degree of cognitive impairment and neurodegeneration in AD.     

C-terminal peptides coassemble into Abeta42 oligomers and protect neurons against Abeta42-induced neurotoxicity

Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of Aβ42 are believed to be the main cause of AD; therefore, disruption of Aβ oligomerization is a promising approach for developing therapeutics for AD. Formation of Aβ42 oligomers is mediated by intermolecular interactions in which the C terminus plays a central role. We hypothesized that peptides derived from the C terminus of Aβ42 may get incorporated into oligomers of Aβ42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using Aβ fragments with the general formula Aβ(x−42) (x = 28–39). A cell viability screen identified Aβ(31–42) as the most potent inhibitor. In addition, the shortest peptide, Aβ(39–42), also had high activity. Both Aβ(31–42) and Aβ(39–42) inhibited Aβ-induced cell death and rescued disruption of synaptic activity by Aβ42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of Aβ42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with Aβ42 to form heterooligomers. Thus, Aβ(31–42) and Aβ(39–42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure–activity approach.