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Abstract. Four personality disorders (PD) have become “lost” throughout the various editions of the DSM: Depressive, Passive-Aggressive, Sadistic, and Self-Defeating. The Alternative Model of Personality Disorders (AMPD) is a novel approach to PD classification, containing two diagnostic criteria: personality functioning and pathological personality traits. This study identifies the personality functioning and pathological personality trait features of the Lost PDs among older adults ( N = 202; Mage = 67.47 years). Results indicate that the Lost PDs related more strongly with the self-functioning domains (versus the interpersonal domains). Some pathological traits emerged in expected directions, whereas others did not, which is consistent with research on the traditional PDs. The AMPD appears to have mixed validity in capturing the Lost PDs in older adults, though overall it performed comparably well and warrants further examination.

Older adults (Results suggested high correlational overlap between subjective cognitive problems with personality functioning and pathological personality, as measured by the AMPD. Hierarchical regressions revealed that subjective measures of executive functions, perceptual motor, and language difficulties were most strongly related to the AMPD's constructs. Results are discussed in the context of prior research on objective cognitive impairment among individuals with PDs.The degree of overlap found within the current older adult sample suggested an age-related problem or potential age-bias, with older adults being at-risk of (a) having their subjective cognitive problems being incorrectly interpreted as personality pathology under the AMPD or (b) having personality pathology being overlooked under the AMPD, with symptoms instead attributed to subjective cognitive issues. This study suggested that subjective cognitive dysfunction may be one mechanism that contributes to differential performance of the AMPD among older adults.

Introduction: This study examined relationships between personality disorder (PD) features, Big Five personality traits, and interpersonal problems with anxiety. Method: Older adults ( N = 130) completed the Geriatric Anxiety Scale, Coolidge Axis Two Inventory, Big Five Inventory-2, and Circumplex Scales of Interpersonal Problems. Pearson correlation analyses were used to assess simple relationships between anxiety with PD features (CATI scales), Big Five personality domains (BFI-2 scales), and interpersonal problems (CSIP scales). Multiple linear regression analyses were performed to determine the extent to which the PD scales of the CATI, the personality scales of the BFI-2, and the scales of the CSIP explained variance in anxiety. Results: Anxiety was positively correlated with 13 of 14 PD scales, ranging from .23 (Narcissistic) to .61 (Depressive). Regarding Big Five personality traits, anxiety was negatively associated with Agreeableness (−.23), Conscientiousness (−.30), and Extraversion (−.31) but was positively associated with Negative Emotionality (.56). Regarding interpersonal problems, anxiety was positively related to all eight CSIP scales, ranging from Self-sacrificing (.30) to Distant/Cold (.62). Regression analyses indicated that PD features accounted for the most variance in anxiety symptoms (53%), followed by interpersonal problems (46%), and Big Five personality traits (33%). Discussion: Anxiety appears to be meaningfully associated with PD features, several aspects of Big Five personality traits, and interpersonal problems, suggesting that these variables may play important roles in the development and maintenance of anxiety, or vice versa. Our findings especially speak to the growing awareness of the deleterious impact of PD features on clinical syndromes in later life, as evidenced by strong comorbidities with anxiety.

The Levels of Personality Functioning Scale-Brief Form 2.0 (LPFS-BF 2.0) is a new measure of personality functioning according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition's, alternative model of personality disorders, containing a total personality functioning score and two subscales (Self and Interpersonal). The LPFS-BF 2.0 has limited evidence of validity among older adults. Subsequently, this study examined relationships between the LPFS-BF 2.0 and anxiety, interpersonal functioning, and normative personality traits to establish convergent validity. In all, 130 community-dwelling older adults (Mage = 64.61) completed the LPFS-BF 2.0, Geriatric Anxiety Scale, Circumplex Scales of Interpersonal Problems (CSIP), and Big Five Inventory-2 (BFI-2). Internal consistency (Cronbach's α) was acceptable to good for each of the LPFS-BF 2.0 scale scores (Self, α = .74; Interpersonal, α = .85; Total Personality Functioning, α = .79). Correlations were computed between the LPFS-BF 2.0 scales and the Geriatric Anxiety Scale, CSIP, and BFI-2. Overall, significant correlations were detected in expected directions. Additionally, to further establish convergent validity, regression analyses were conducted with the CSIP and BFI-2 scales predicting each of the LPFS-BF 2.0 scales. The models accounted for significant variance, and significant predictors were found in anticipated and theoretically consistent directions. Results provide strong but initial psychometric support for the use of the LPFS-BF 2.0 as an assessment tool for measuring personality functioning among older adults. An implication is that this measure may be used to identify important personality features that are part of a full assessment of personality pathology. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The von Hippel-Lindau tumor suppressor protein (pVHL) is involved in maintaining cellular oxygen homeostasis through the regulated degradation of HIF-α. The intrinsically disordered nature of pVHL makes it prone to aggregation that impairs its function, and this is further aggravated in mutant versions of the protein, thus promoting tumor development. By using in silico analysis, we predicted six peptide fragments from pVHL to be amyloidogenic. This was verified for two of the peptides by biophysical approaches, which demonstrated self-assembly and formation of β-sheet-rich aggregates, which, under transmission electron microscopy, atomic force microscopy, and X-ray diffraction, displayed typical fibrillar amyloid characteristics. These motifs may serve as proxies for exploring the nature of pVHL aggregation.

We developed a new Italian short version of the Geriatric Anxiety Scale (GAS-12) and evaluated its psychometric properties. The GAS-12 specifically screens for anxiety symptoms in the Italian older adult population by identifying items that best discriminate anxiety in this population.In Study 1, we administered the full-length Italian translation of the GAS to 517 older adults and used item response theory to identify the most discriminating items and to develop the short form used in Study 2. In Study 2, we evaluated the functioning of the new short form of the questionnaire in a new sample of 427 older adults using Confirmatory factor analysis.Analyses indicated 12 items that discriminated well between anxious and non-anxious participants and distributed along the latent continuum of each trait. The GAS-12 fits a three-factor structure. There was also evidence for convergent and divergent validity.The Italian GAS-12 appears to be a useful instrument for the quantitative screening of anxiety in Italian older adults.Anxiety imposes significant impairment thus making imperative the screening and assessment of anxiety symptoms. The GAS-12 is particularly indicated with limited time and many scales in a clinical assessment or research protocols.

Assessment of personality disorders (PDs) in older adults is a nuanced trade of its own. The aim of this practice guide is to illustrate gerontological assessment challenges using 3 case vignettes. We argue that it is important to pay extra attention to the influence of cognitive and medical (somatic) disorders on personality functioning in older adults during personality assessment. We also note that information provided by informants contributes added value to personality assessment. Personality assessment should be sufficiently age-specific to prevent overdiagnosis or underdiagnosis in older adults. Furthermore, given the reduced psychological or somatic capacity of some older adults, phased or sequential personality assessment is recommended. This should be focused on the assessment questions to be answered, for example starting with short general screening of personality functioning, followed by more in-depth exploration. Personality assessment should be kept as brief and simple as possible in terms of formulation of the items.

The Severity Indices of Personality Problems (SIPP; Verheul et al., 2008) is a popular self-report questionnaire that measures severity of maladaptive personality functioning. Two studies demonstrated the utility of the short form (SIPP-SF) among older adults but validation in clinical settings is lacking. Therefore, we examined the psychometric properties of the SIPP-SF in a large sample of older adult Dutch outpatients (N = 124; age range = 60-85 years, M = 69.8, SD = 5.3). The SIPP-SF domains showed good to excellent internal reliability (Cronbach's α = .75-.91) and effectively discriminated between participants with and without a personality disorder, as assessed with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Convergent validity of the SIPP-SF was examined with instruments for measuring personality pathology among older adults (Informant Personality questionnaire [HAP]; Gerontological Personality Disorders Scale [GPS]). The GPS generally correlated with the SIPP-SF domains in expected directions, with small to large effect sizes. For the HAP, only 1 scale correlated with all SIPP-SF domains. No associations were found between the SIPP-SF and psychiatric symptomatology as measured by the Brief Symptom Inventory (BSI). The SIPP-SF appears to be a promising instrument for assessing maladaptive personality functioning among older adult outpatients.

The aims of this study were to examine age-differences regarding various worry components among younger and older adults and to characterize the relationships between worry domains and anxiety. A total of 311 younger adults (18 - 30 years) and 100 older adults (65+ years) completed seven worry and anxiety questionnaires, focusing on worry content, worry severity, and responses to worry. A series of 2 × 2 ANOVAs was computed to examine differences in worry and anxiety related to age and gender. Interaction effects indicated that gender differences among younger adults were significantly more pronounced than older adults with women reporting greater worry and anxiety than men. Main effects of age indicated that younger adults reported greater worry than older across all worry domains. Worry and anxiety measures were found to be highly correlated across all domains. Findings indicate that worry is fundamentally related to anxiety across age groups and that a variety of aspects of worry should be considered to understand the breadth of worry’s influence on anxiety. Additionally, age and gender have unique relationships with worry and anxiety and interact to complicate individuals’ symptom profiles. Thus, worry is a multifaceted construct that is crucial to understanding anxiety in general and warrants multifaceted assessment and intervention.

Personality disorders (PDs) in the Diagnostic and Statistical Manual of Mental Disorders ( DSM-5) are conceptualized as distinct clinical syndromes. However, debate persists about the clinical utility of this categorical model, with many researchers supporting a dimensional model that focuses on pathological personality traits and personality dysfunction. This model was published in Section III of DSM-5 and named the Alternative Model of Personality Disorders (AMPD). This study evaluated the AMPD by examining relationships between traits and dysfunction with traditional categorical PD constructs among older adults. Older adults ( N = 202) completed the Personality Inventory for DSM-5, Levels of Personality Functioning Scale-Self-Report, and Coolidge Axis II Inventory. Results indicated that pathological personality traits do not relate to categorical PDs in directions predicted by the AMPD. Personality functioning related to categorical PDs in expected theoretical patterns according to the AMPD but lacked incremental validity above pathological personality traits. An implication of these findings is that the AMPD does not fully resolve the age-related issues with the traditional categorical PD model.

The eye lens is rich in proteins called crystallins, whose native conformation is crucial for preserving its transparency. With aging, crystallins may be exposed to environmental changes, which could lead to their aggregation and eventually to cataract development. Human γD-crystallin, among the most abundantly expressed γ-crystallins in the lens, was shown to form amyloid aggregates under denaturing conditions in vitro. However, the exact mechanism of aggregation remains to be clearly defined. Here, using prediction algorithms and biophysical methods, we identified a hexapeptide 41GCWMLY46 as a most aggregative fragment in human γD-crystallin. Two aromatic naphthoquinone-tryptophan hybrid molecules (NQTrp and Cl-NQTrp), inhibited the in vitro aggregation of this hexapeptide as well as full-length γD-crystallin in a dose-dependent manner, plausibly facilitated by hydrogen bonding and aromatic contacts with the hydrophobic residues. The two compounds had no toxic effect toward retinal cell culture and reduced the cytotoxicity induced by aggregates of the hexapeptide. In addition, NQTrp and Cl-NQTrp were able to disassemble pre-formed aggregates of the hexapeptide and the full-length γD-crystallin. Our results indicate that the amyloidogenic hexapeptide is a useful model for screening inhibitors of γD-crystallin and that the NQTrp hybrid scaffolds may serve as leads for developing new drugs for treating cataract.

Objective To compare Emergency Department (ED) care of suicidal patients with and without documented acute alcohol use. Methods Retrospective chart review of randomly sampled patient visits (n = 800; January 2014 to December 2015) at an urban ED with universal screening for suicide risk. Eligible visits were by adults (18+ years) who screened positive for suicide risk at the ED visit (i.e., suicidal ideation in past two weeks or suicide attempt in past six months). Analyses compared those with and without documentation of acute alcohol use. Results Among these patients with suicide risk, 19% had documented acute alcohol use (versus 43% with no use and 38% without documentation); individuals with acute alcohol use were more often male and aged 35–59 years. Overall, 62% were evaluated by a mental health professional in the ED. Individuals with acute alcohol use were significantly less likely (vs those without use) to be evaluated by a mental health professional in the ED (odds ratio 0.49, 95%CI 0.28–0.87) after adjustment for age, recent suicide ideation, current suicide plan, self-harm as a chief complaint, contact with family, and ED disposition. Conclusions Although alcohol use can increase suicide risk, ED patients with acute use appear to receive less thorough suicide risk assessments.

Objectives: The Pathological Narcissism Inventory (PNI) is a measure of narcissism, with two domains of Vulnerability and Grandiosity, that has limited evidence of validity among older adults. Subsequently, the objective of the present study was to examine relationships between the PNI and measures of diverse pathological personality features.Method: Participants consisted of 125 community-dwelling older adults (M age = 71.8 years) who completed the PNI, the Personality Inventory for DSM-5 (PID-5), and the Coolidge Axis II Inventory (CATI).Results: Total Narcissism, Vulnerability, and Grandiosity were significantly correlated with every PD scale, with the exception of Grandiosity with Schizotypal PD. Regression analyses revealed that Narcissistic and Avoidant PDs had the strongest relationships with the PNI. Total Narcissism was also significantly correlated with all five PID-5 domains, with regression indicating Negative Affect and Antagonism as the strongest predictors.Conclusions: Findings generally support the convergent validity of the PNI for use among older adults and suggest that pathological narcissism may be related to general personality pathology in later life.

Objectives: Anxiety is a significant problem for many individuals in various long-term care (LTC) settings and is often undetected and under-treated. This study examined the psychometric properties...

Despite the fundamental clinical importance of amyloid fibril formation, its mechanism is still enigmatic. Crystallography of minimal amyloid models was a milestone in the understanding of the architecture and biological activities of amyloid fibers. However, the crystal structure of ultimate dipeptide-based amyloids is not yet reported. Herein, we present the crystal structure of a typical amyloid-forming minimal dipeptide, Ac-Phe-Phe-NH2 (Ac-FF-NH2 ), showing a canonical β-sheet structure at the atomic level. The simplicity of the structure helped in investigating amyloid-inhibition using crystallography, never previously reported for larger peptide models. Interestingly, in the presence of an inhibitor, the supramolecular packing of Ac-FF-NH2 molecules rearranged into a supramolecular 2-fold helix (21 helix). This study promotes our understanding of the mechanism of amyloid formation and of the structural transitions that occur during the inhibition process in a most fundamental model.

Objectives: The perception of being a burden is a well-known risk factor for dying by suicide. Research on factors that precede the state of perceived burdensomeness, such as fearing being a burden, is necessary. We investigated the extent to which health status, elevated depressive symptoms, and elevated anxiety symptoms are associated with fear of being a burden in late life.Method: Older adult participants (N = 155) completed the Geriatric Anxiety Scale (GAS), Patient Health Questionnaire (PHQ-8), and demographic and health questions. Fear of being a burden, assessed with a supplemental item on the GAS, was categorically grouped as 'no fear' or 'some fear'. Using logistic regression, we examined predictors of fear of being a burden.Results: In the first step, elevated depression was associated with fear of being a burden (OR = 2.30, 95% CI: 1.09, 4.89, p = .03), but health status was not significant. In the second step, elevated anxiety was significant (OR = 2.63, 95% CI: 1.15, 5.99, p = .02); depression was no longer significant.Conclusion: Contrary to expectations, anxiety more strongly predicted fear of being a burden than depression. Future research should further investigate the role of anxiety in fear of being a burden and ways of intervening.

Worry is a ubiquitous human experience and core symptom of anxiety. The present study examined the extent to which specific aspects of worry are related to perceived executive dysfunction in older adults. A total of 100 older adult participants ( M age = 68.82 years; range = 65–79 years) completed the Worry Behaviors Inventory, the Coolidge Axis II Inventory Executive Dysfunctions Scale, and the Constructive and Unconstructive Worry Questionnaire. Multiple regression analyses found that worry constructiveness and response behaviors were predictive of executive dysfunction. Specifically, greater avoidance behaviors and unconstructive worry were uniquely predictive of greater executive dysfunctions. Thus, findings indicate that worry constructiveness and approaches to worry management are significantly related to cognitive functioning in older adults. These findings imply a need to assess both worry and executive dysfunction to more accurately determine causal factors regarding anxiety and cognitive decline in older adults.

Objectives:Current guidelines recommend highly specialized care for patients with severe personality disorders (PDs). However, there is little knowledge about how to detect older patients with severe PDs. The aim of the current study was to develop an age-specific tool to detect older adults with severe PDs for highly specialized mental health care.Design:In a Delphi study, a tool to detect adults with severe PDs for highly specialized mental health care was adjusted for older adults based on expert opinion. Subsequently, the psychometric properties of the age-specific tool were evaluated.Setting:The psychometric part of the study was performed in two Dutch highly specialized centers for PDs in older adults.Participants:Patients (N = 90) from two highly specialized centers on PDs in older adults were enrolled.Measurements:The age-specific tool was evaluated using clinical judgment as the gold standard.Results:The Delphi study resulted in an age-specific tool, consisting of seven items to detect older adults with severe PDs for highly specialized mental health care. Psychometric properties of this tool were evaluated. Receiver operating curve analysis showed that the questionnaire was characterized by sufficient diagnostic accuracy. Internal consistency of the tool was sufficient and inter-rater reliability was moderate.Conclusions:An age-specific tool to detect older adults with severe PDs was developed based on expert opinion. Psychometric properties were evaluated showing sufficient diagnostic accuracy. The tool may preliminarily be used in mental health care to detect older adults with severe PDs to refer them to highly specialized care in an early phase.

Anxiety symptoms and anxiety disorders are highly prevalent among older adults, and are associated with considerable distress, functional impairment, and burden. Also, there is growing need for brief instruments to measure anxiety symptoms in primary care and geriatric medical settings. Therefore, the current study focuses on the development and psychometric evaluation of a short-form of the Geriatric Anxiety Scale (GAS-G), a well-established anxiety instrument for use with older adults. Study 1 draws on the original data from the GAS-G validation study (

International audience; Neurofibrillary tangles of the Tau protein and plaques of the amyloid β peptide are hallmarks of Alzheimer's disease (AD), which is characterized by the conversion of monomeric proteins/peptides into misfolded β-sheet rich fibrils. Halting the fibrillation process and disrupting the existing aggregates are key challenges for AD drug development. Previously, we performed in vitro high-throughput screening for the identification of potent inhibitors of Tau aggregation using a proxy model, a highly aggregation-prone hexapeptide fragment 306VQIVYK311 (termed PHF6) derived from Tau. Here we have characterized a hit molecule from that screen as a modulator of Tau aggregation using in vitro, in silico, and in vivo techniques. This molecule, an anthraquinone derivative named Purpurin, inhibited ~ 50% of PHF6 fibrillization in vitro at equimolar concentration and disassembled pre-formed PHF6 fibrils. In silico studies showed that Purpurin interacted with key residues of PHF6, which are responsible for maintaining its β-sheets conformation. Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau. Purpurin was non-toxic when fed to Drosophila and it significantly ameliorated the AD-related neurotoxic symptoms of transgenic flies expressing WT-FL human Tau (hTau) plausibly by inhibiting Tau accumulation and reducing Tau phosphorylation. Purpurin also reduced hTau accumulation in cell culture overexpressing hTau. Importantly, Purpurin efficiently crossed an in vitro human blood-brain barrier model. Our findings suggest that Purpurin could be a potential lead molecule for AD therapeutics.

Protein misfolding and amyloid formation are associated with various human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Type-2 Diabetes mellitus (T2DM). No disease-modifying therapeutics are available for them. Despite the lack of sequence homology between the corresponding proteins, aromatic residues are recognized as common key motifs in the formation and stabilization of amyloid structures via π-π stacking. Thus, targeting aromatic recognition interfaces could be a useful approach for inhibiting amyloid formation as well as disrupting the preformed amyloid fibrils. Combining experimental and computational approaches, we demonstrated the anti-amyloidogenic effect of naphthoquinone-tryptophan-based hybrid molecules toward PHF6 (τ-derived aggregative peptide), Amyloid β (Aβ42), and human islet amyloid polypeptide (hIAPP) implicated in AD and T2DM, respectively. These hybrid molecules significantly inhibited the aggregation and disrupted their preformed fibrillar aggregates in vitro, in a dose-dependent manner as evident from Thioflavin T/S binding assay, CD spectroscopy, and electron microscopy. Dye leakage assay from LUVs and cell-based experiments indicated that the hybrid molecules inhibit membrane disruption and cytotoxicity induced by these amyloids. Furthermore, in silico studies provided probable mechanistic insights into the interaction of these molecules with the amyloidogenic proteins in their monomeric or aggregated forms, including the role of hydrophobic interaction, hydrogen bond formation, and packing during inhibition of aggregation and fibril disassembly. Our findings may help in designing novel therapeutics toward AD, T2DM, and other proteinopathies based on the naphthoquinone derived hybrid molecules.

As the proportion and sheer number of older adults in the United States continues to increase, we need to plan for their behavioral health care. Access to accurate data about current workforce characteristics in psychology can provide essential information to inform workforce planning. In this paper, we present results of the American Psychological Association’s Center for Workforce Studies survey of psychologists, with a focus on older adults. Participants (N = 4,109) were doctoral psychologists identified through state licensing boards. Only 1.2% of those surveyed described geropsychology as their specialty area, although 37.2% reported seeing older adults frequently or very frequently, most often from the specialties of rehabilitation psychology, clinical neuropsychology, and clinical health psychology. Frequent providers of aging services were more likely to be older, nonethnic minority, working in independent practice as their primary work setting, and self-employed as compared to other respondents. In addition, frequent providers of services to older adults were more likely to be in practices colocated with medical professionals and to accept Medicare as payment. Low reimbursement rates were cited as a reason for not accepting Medicare by those who did not. There was strong interest in further education in aging from all psychologists in areas including adjustment to medical illness/disability, depression, bereavement, dementia, anxiety, psychotherapy, and caregiver stress. The results of this survey suggest a continued urgent need to train psychologists across subfields in foundational geropsychology competencies that all psychologists should possess to be prepared for the rapidly growing and increasingly diverse population of older adults.

A major risk factor for Gaucher's disease is loss of function mutations in theiGBA1/igene that encodes lysosomal β-glucocerebrosidase, resulting in accumulation of glucosylceramide (GlcCer), a key lysosomal sphingolipid.iGBA1/imutations also enhance the risk for Parkinson's disease, whose hallmark is the aggregation of α-synuclein (αSyn). However, the role of accumulated GlcCer in αSyn aggregation is not completely understood. Using various biophysical assays, we demonstrate that GlcCer self-assembles to form amyloid-like fibrillar aggregatesiin vitro/i. The GlcCer assemblies are stable in aqueous media of different pH and exhibit a twisted ribbon-like structure. Near lysosomal pH GlcCer aggregates induced αSyn aggregation and stabilized its nascent oligomers. We found that severalibona fide/iinhibitors of proteinaceous amyloids effectively inhibited aggregation of GlcCer. This study contributes to the growing evidence of cross-talk between proteinaceous amyloids and amyloid-like aggregates of metabolites accumulated in diseases and suggests these aggregates as therapeutic targets.

Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils. The best characterized among them is a 39 amino acid peptide PAP(248–286), which forms amyloid fibrils termed SEVI (semen-derived enhancer of viral infection) that increase the infectivity of HIV-1 by orders of magnitude. Inhibiting amyloid formation by PAP(248–286) may mitigate the sexual transmission of HIV-1. Several vitamins have been shown to reduce the aggregation of amyloids such as Aβ, α-Synuclein, and Tau, which are associated with neurodegenerative diseases. Since ascorbic acid (AA, vitamin C) is the most abundant vitamin in semen with average concentrations of 0.4 mM, we here examined how AA affects PAP(248–286) aggregation in vitro. Using ThT binding assays, transmission electron microscopy, and circular dichroism spectroscopy, a dual and concentration-dependent behavior of AA in modulating PAP(248–286) fibril formation was observed. We found that low molar ratios of AA:PAP(248–286) promoted whereas high molar ratios inhibited PAP(248–286) fibril formation. Accordingly, PAP(248–286) aggregated in the presence of low amounts of AA enhanced HIV-1 infection, whereas excess amounts of AA during aggregation reduced the infectivity enhancing effect in cell culture. Collectively, this work provides a biophysical insight into the effect of AA, an important seminal component, on SEVI fibrillation which might impact amyloid formation kinetics, thereby modulating the biological activity of semen amyloids., Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils.

The interpersonal circumplex is a model that places interpersonal problems along two axes (communion and agency), resulting in eight theoretically derived patterns. Application of the circumplex to older adults is poorly understood. Subsequently, this study examined relationships between the interpersonal circumplex and personality disorder (PD) features among older adults, since social impairments are core components of PDs. Two models of PDs were examined: the traditional model of 10 PDs and the Alternative Model of PDs (AMPD) with its personality functioning and pathological personality trait features. Older adults (N = 202) completed the Inventory of Interpersonal Problems-Short Circumplex, Coolidge Axis II Inventory, Levels of Personality Functioning Scale-Self-Report, and Personality Inventory for DSM-5. Overlap between the interpersonal circumplex and PD features were detected, but patterns were distinct from prior studies with younger samples. Cluster B and C PD features showed meaningful relationships, whereas Cluster A did not. The circumplex was limited in its relation to the AMPD's personality functioning. The communion component of the circumplex significantly related to the AMPD's pathological trait model, whereas the agency component was limited in its association with pathological traits. Overall, the circumplex meaningfully related to PD features across two different PD models, providing some evidence of validity.

γD-crystallin is among the most abundant γ-crystallins in the human eye lens which are essential for preserving its transparency. Aging, and environmental changes, cause crystallins to lose their native soluble structure and aggregate, resulting in the formation of cataract. Current treatment of cataract is surgical removal which is costly. Pharmaceutical therapeutics of cataract is an unmet need. We report a screen for small molecules capable of inhibiting aggregation of human γD-crystallin. Using a highly amyloidogenic hexapeptide model 41GCWMLY46 derived from the full-length protein, we screened a library of 68 anthraquinone molecules using ThT fluorescence assay. A leading hit, the cochineal Carmine, effectively reduced aggregation of the model GDC6 peptide in dose dependent manner. Similar effect was observed toward aggregation of the full-length γD-crystallin. Transmission electron microscopy, intrinsic Tryptophan fluorescence and ANS fluorescence assays corroborated these results. Insights obtained from molecular docking suggested that Carmine interaction with monomeric GDC6 involved hydrogen bonding with Ace group, Cys, Met residues and hydrophobic contact with Trp residue. Carmine was non-toxic toward retinal cells in culture. It also reduced ex vivo the turbidity of human extracted cataract material. Collectively, our results indicate that Carmine could be used for developing new therapeutics to treat cataract.

The experience of clinically significant anxiety and anxiety disorders represent significant and often debilitating problems for many residents in long-term care (LTC) settings. However, anxiety problems often go undetected and untreated in this growing population. The purposes of this paper are to examine the prevalence and impact of anxiety problems among residents in LTC facilities, describe the efficacy of the current instruments that are used to detect anxiety in these settings, and provide clinical guidance for the thorough assessment of anxiety. Regarding measurement tools, the GAI, GAI-SF, GAS-LTC, and the BADS are the only self-report measures designed for older adults that have been successfully validated for use with older adults living in LTC settings. Clinicians should focus on ways to educate LTC directors and staff to emphasize the importance of screening and assessing for anxiety, using validated measures, to improve the assessment and treatment of anxiety in their residents.

International audience; Accumulation and aggregation of the intrinsically disordered protein α‐synuclein (α‐Syn) into amyloid fibrils are hallmarks of a series of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of α‐Syn aggregation in PD makes it an attractive target for the development of disease‐modifying therapeutics that would inhibit α‐Syn aggregation or disrupt its preformed fibrillar assemblies. To this end, we have designed and synthesized two naphthoquinone–dopamine‐based hybrid small molecules, NQDA and Cl‐NQDA, and demonstrated their ability to inhibit in vitro amyloid formation by α‐Syn using ThT assay, CD, TEM, and Congo red birefringence. Moreover, these hybrid molecules efficiently disassembled preformed fibrils of α‐Syn into nontoxic species, as evident from LUV leakage assay. NQDA and Cl‐NQDA were found to have low cytotoxicity and they attenuated the toxicity induced by α‐Syn towards SH‐SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood–brain barrier model. These naphthoquinone–dopamine based derivatives can be an attractive scaffold for therapeutic design towards PD.

Glycosylation of amyloidogenic proteins enhances their solubility and reduces propensity for aggregation. We therefore, prepared tryptophan-glucosamine conjugates to modulate aggregation of tau-derived PHF6-peptide. Combined in vitro and in silico approaches indicated that these conjugates inhibited oligomerization and fibril formation of PHF6 and disrupted its preformed fibrils at very low concentration. These effects mainly arise from the glucopyranoside moiety.

At the end of life, hospice patients frequently rely on surrogate decision makers (SDMs) for healthcare decisions, which creates anxiety among SDMs. This project evaluated whether an educational intervention to create a plan of care for hospice patients would reduce anxiety among SDMs. Before the intervention, immediately after the intervention, and 2 weeks following the intervention SDM anxiety was measured with the Geriatric Anxiety Scale, State Trait Anxiety Inventory-State Anxiety Scale, and one question about decision-making anxiety. Twelve patients (80±14.7 years) and 18 SDMs (60±12.9 years) completed the intervention. Immediately after the intervention SDMs showed a significant decrease (P=0.003) in anxiety. When anxiety was measured 2 weeks post-intervention, anxiety had increased again, and was no longer significantly different from pre-intervention levels. This project demonstrated that an educational intervention in the hospice setting can be effective in creating a short-term decrease to SDM anxiety levels.

Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer’s disease (AD) and Type-2 diabetes Mellitus (T2DM). Aggregation of specific peptides, like Aβ42 in AD and hIAPP in T2DM, causes cellular dysfunction resulting in the respective pathology. While these amyloidogenic proteins lack sequence homology, they all contain aromatic amino acids in their hydrophobic core that play a major role in their self-assembly. Targeting these aromatic residues by small molecules may be an attractive approach for inhibiting amyloid aggregation. Here, various biochemical and biophysical techniques revealed that a panel of tryptophan-galactosylamine conjugates significantly inhibit fibril formation of Aβ42 and hIAPP, and disassemble their pre-formed fibrils in a dose-dependent manner. They are also not toxic to mammalian cells and can reduce the cytotoxicity induced by Aβ42 and hIAPP aggregates. These tryptophan-galactosylamine conjugates can therefore serve as a scaffold for the development of therapeutics towards AD and T2DM., Paul et al. provide a rational design strategy to develop dual inhibitors, in the form of tryptophan-galactosylamine conjugates, against amyloid formation and aggregation of Aβ42 and hIAPP peptides. These conjugates are not toxic to mammalian cells and reduce cytotoxicity of Aβ42 and hIAPP aggregates, hence potentially could serve as scaffolds for development of Alzheimer’s disease therapeutics.

Protein phosphorylation and O-GlcNAcylation are very common nucleoplasmic post-translational modifications. Mono-addition of either the phosphate or the O-GlcNAc group were shown to inhibit the self-aggregation of amyloidogenic proteins and peptides, which is the hallmark of various protein misfolding diseases. However, their comparable effect upon co-incubation with a native non-modified amyloid scaffold has not been reported. O-linked glycans and phosphate variants of the tau protein-derived VQIVYK hexapeptide motif were generated as a simplified amyloid scaffold model and demonstrate that, while self-aggregation can be attenuated by either a single glycan or a phosphate unit, only co-incubation with the O-GlcNAc variant inhibits aggregation of the native peptide. These results shed light on the role of post-translational modifications in protein aggregation and suggest a novel therapeutic approach to protein misfolding diseases.

The psychometric properties of a new measure, the 33-item Abrasive Personality Traits scale, were investigated. College students (N = 84) completed the scale about someone they perceived as abrasive and an additional 75 college students completed it about someone who they did not consider abrasive. The scale had good internal reliability and acceptable test-retest reliability. Abrasive people were rated significantly higher on the scale than non-abrasive people (large effect size). The scale was also strongly and significantly correlated with the Narcissistic, Paranoid, Sadistic, Antisocial, and Passive-Aggressive personality disorders on the Coolidge Axis II Inventory. The results preliminarily demonstrate that abrasiveness may constitute a psychometrically reliable personality cluster, warranting further investigation.

The pathological hallmarks of Alzheimer's disease (AD) are pathogenic oligomers and fibrils of misfolded amyloidogenic proteins (e.g., β-amyloid and hyper-phosphorylated tau in AD), which cause progressive loss of neurons in the brain and nervous system. Although deviations from normal protein glycosylation have been documented in AD, their role in disease pathology has been barely explored. Here our analysis of available expression data sets indicates that many glycosylation-related genes are differentially expressed in brains of AD patients compared with healthy controls. The robust differences found enabled us to predict the occurrence of AD with remarkable accuracy in a test cohort and identify a set of key genes whose expression determines this classification. We then studied in vivo the effect of reducing expression of homologs of 6 of these genes in transgenic Drosophila overexpressing human tau, a well-established invertebrate AD model. These experiments have led to the identification of glycosylation genes that may augment or ameliorate tauopathy phenotypes. Our results indicate that OstDelta, l(2)not and beta4GalT7 are tauopathy suppressors, whereas pgnat5 and CG33303 are enhancers, of tauopathy. These results suggest that specific alterations in protein glycosylation may play a causal role in AD etiology.

Inhibiting the toxic aggregation of amyloid-β and the tau protein, the key pathological agents involved in Alzheimer's, is a leading approach in modulating disease progression. Using an aggregative tau-derived model peptide, Ac-PHF6-NH2 , the substitution of its amino acids with proline, a known efficient β-breaker, is shown to reduce self-assembly. This effect is attributed to the steric hindrance created by the proline substitution, which results in disruption of the β-sheet formation process. Moreover, several of the proline-substituted peptides inhibit the aggregation of Ac-PHF6-NH2 amyloidogenic peptide. Two of these modified inhibitors also disassemble pre-formed Ac-PHF6-NH2 fibrils and one inhibits induced cytotoxicity of the fibrils. Taken together, these lead β-breaker peptides may be developed into novel Alzheimer's disease therapeutics.

Protein misfolding and aggregation have been associated with several human disorders, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as senile systemic amyloidosis and Type II diabetes. However, there is no current disease-modifying therapy available for the treatment of these disorders. In spite of extensive academic, pharmaceutical, medicinal and clinical research, a complete mechanistic model for this family of diseases is still lacking. In this review, we primarily discuss the different types of small molecular entities which have been used for the inhibition of the aggregation process of different amyloidogenic proteins under diseased conditions. These include small peptides, polyphenols, inositols, quinones and their derivatives, and metal chelator molecules. In recent years, these groups of molecules have been extensively studied using in vitro, in vivo and computational models to understand their mechanism of action and common structural features underlying the process of inhibition. A salient feature found to be instrumental in the process of inhibition is the balance between the aromatic unit that functions as the amyloid recognition unit and the hydrophilic amyloid breaker unit. The establishment of structure–function relationship for amyloid-modifying therapies by the various functional entities should serve as an important step toward the development of efficient therapeutics.

It has been reported that many molecules could inhibit the aggregation of Aβ (amyloid-β) through suppressing either primary nucleation, secondary nucleation, or elongation processes. In order to suppress multiple pathways of Aβ aggregation, we screened 23 small molecules and found two types of inhibitors with different inhibiting mechanisms based on chemical kinetics analysis. Trp-glucose conjugates (AS2) could bind with fibril ends while natural products (D3 and D4) could associate with monomers. A cocktail of these two kinds of molecules achieved co-inhibition of various fibrillar species and avoid unwanted interference.

Amyloid assemblies of Tau are associated with Alzheimer's disease (AD). In AD Tau undergoes several abnormal post-translational modifications, including hyperphosphorylation and glycosylation, which impact disease progression. N-glycosylated Tau was reported to be found in AD brain tissues but not in healthy counterparts. This is surprising since Tau is a cytosolic protein whereas N-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated that N-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specific Tau residue(s) that undergo N-glycosylation and their effect on Tau-engendered pathology are unknown. High-performance liquid chromatography and mass spectrometry (LC-MS) analysis indicated that both N359 and N410 were N-glycosylated in wild-type (WT) human Tau (hTau) expressed in human SH-SY5Y cells. Asparagine to glutamine mutants, which cannot undergo N-glycosylation, at each of three putative N-glycosylation sites in hTau (N167Q, N359Q, and N410Q) were generated and expressed in SH-SY5Y cells and in transgenic Drosophila. The mutants modulated the levels of hTau phosphorylation in a site-dependent manner in both cell and fly models. Additionally, N359Q ameliorated, whereas N410Q exacerbated various aspects of hTau-engendered neurodegeneration in transgenic flies.