Clinical Care of Patients with Neurocognitive Disorders: A Qualitative Study of the Psychiatric Residency Training Experience.

OBJECTIVE: Few data describe how general psychiatry residencies prepare trainees to care for individuals with neurocognitive disorders (NCDs), despite increasing recognition of the need for psychiatrists to provide care for the growing numbers of patients with NCD. This study aims to identify training needs and approaches, as the resident experience is one important perspective that can be added to others, such as milestones developed by expert educators. METHODS: The authors conducted three focus groups of third- and fourth-year general adult psychiatry residency trainees from three different training programs in May and June of 2021. Focus groups consisted of three to eight unique participants per group. Qualitative data analysis techniques derived in grounded theory were utilized to identify themes. RESULTS: Four main themes emerged from the focus groups: unique challenges of NCD care, intrinsic rewards of working with families, perceived gaps in educational experiences, and limited comfort in future practice. CONCLUSIONS: Participants expressed that aspects of NCD care were fundamentally different than care for other mental health conditions encountered in psychiatry residency. They found the progressive nature of the disease to be particularly challenging, and they also expressed challenges with clinical interviews and establishing rapport with individuals with NCDs. However, working with families was especially rewarding. Regardless of training program, participants expressed a need for additional longitudinal and diversified training opportunities to prepare them for future practice in this area.

Immunoaffinity extraction followed by enzymatic digestion for the isolation and identification of proteins employing automated µSPE reactors and mass spectrometry.

This work describes a novel automated and rapid method for bottom-up proteomics combining protein isolation with a micro-immobilised enzyme reactor (IMER). Crosslinking chemistry based on 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling was exploited to immobilise trypsin and antibodies onto customisable silica particles coated with carboxymethylated dextran (CMD). This novel silica-CMD solid-phase extraction material was characterised using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), conductometric titrations and enzymatic colorimetric assays. Micro-solid-phase extraction (µSPE) cartridges equipped with the modified CMD material were employed and integrated into an automated and repeatable workflow using a sample preparation workstation to achieve rapid and repeatable protein isolation and pre-concentration, followed by tryptic digestion producing peptide fragments that were identified by liquid chromatography mass spectrometry (LC-MS).

Psychiatry Resident Education in Neurocognitive Disorders: a National Survey of Program Directors in Psychiatry.

OBJECTIVE: As major neurocognitive disorders increase, little research has examined how psychiatry residents are prepared to provide neurocognitive care to patients. METHODS: A national survey was sent to program directors of general psychiatry in the USA and Canada, including questions about satisfaction, attitudes, and graduation expectations for training in major neurocognitive disorders. The authors examined descriptive statistics and a series of chi-squared analyses by training setting, residency type, and presence of subspecialty fellowships. The authors also collected free text responses about perceived needs for enhancing training. RESULTS: Program directors agreed that the scope of general psychiatry includes the evaluation of cognitive disorders (78.8%) and the treatment of cognitive symptoms (77.5%) and behavioral/psychological symptoms (78.8%). Required clinical rotations were the preferred method of teaching (63.7%), but didactics were most used (93.8%). The most frequently used clinical teaching setting was geriatric psychiatry (61.3%) and didactics were most frequently taught by geriatric psychiatrists (75.0%). Fifty-six percent were satisfied or very satisfied with their clinical training and 66.3% with their didactics. There were no significant differences in satisfaction or attitudes when compared by training setting, residency type, or presence of subspecialty fellowships. Additional trained faculty were most frequently listed as a need for improving clinical and didactic training. CONCLUSIONS: Psychiatry program directors view major neurocognitive disorders as part of the scope of psychiatric practice. The majority of training is provided within psychiatry rotations, especially geriatric psychiatry. Program directors reported several unmet needs for optimal training, particularly related to clinical training services.

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

Evaluation and Management of Alcohol use Disorder among Older Adults.

PURPOSE OF REVIEW: The prevalence of alcohol use disorder (AUD) among older adults in the United States is rising, but remains underdiagnosed, underreported, and inadequately managed. This review highlights the medical, social, and cultural factors of AUD in older adults and provides guidelines for its screening, evaluation, and management. RECENT FINDINGS: The COVID-19 pandemic has created additional challenges and barriers to care, as older adults may have disproportionate worsening of anxiety, depression, and substance use resulting from increased isolation related to physical distancing and shelter-in-place guidelines. SUMMARY: All older adults should be routinely screened for AUD with standardized screening tools. If a patient's screening results are positive, a clinician should conduct a brief assessment, which may be supplemented by laboratory tests. Most older adults at risk for alcohol misuse do not need specialized SUD treatment, but most can benefit from Screening, Brief Intervention, and Referral to Treatment (SBIRT) to prevent substance misuse before it occurs. Medications for the treatment of AUD in older adults include naltrexone, acamprosate, disulfiram, gabapentin and topiramate. Psychosocial treatments, including mutual help groups, are equally important.

Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features.

Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13 -/- ) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13 -/- neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13 -/- neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13 -/- neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.

Hydralazine modifies Aß fibril formation and prevents modification by lipids in vitro.

Lipid oxidative damage and amyloid ß (Aß) misfolding contribute to Alzheimer's disease (AD) pathology. Thus, the prevention of oxidative damage and Aß misfolding are attractive targets for drug discovery. At present, no AD drugs approved by the Food and Drug Administration (FDA) prevent or halt disease progression. Hydralazine, a smooth muscle relaxant, is a potential drug candidate for AD drug therapy as it reduces Aß production and prevents oxidative damage via its antioxidant hydrazide group. We evaluated the efficacy of hydralazine, and related hydrazides, in reducing (1) Aß misfolding and (2) Aß protein modification by the reactive lipid 4-hydroxy-2-nonenal (HNE) using transmission electron microscopy and Western blotting. While hydralazine did not prevent Aß aggregation as measured using the protease protection assay, there were more oligomeric species observed by electron microscopy. Hydralazine prevented lipid modification of Aß, and Aß was used as a proxy for classes of proteins which either misfold or are modified by HNE. All of the other hydrazides prevented lipid modification of Aß and also did not prevent Aß aggregation. Surprisingly, a few of the compounds, carbazochrome and niclosamide, appeared to augment Aß formation. Thus, hydrazides reduced lipid oxidative damage, and hydralazine additionally reduced Aß misfolding. While hydralazine would require specific chemical modifications for use as an AD therapeutic itself (to improve blood brain barrier permeability, reduce vasoactive side effects, and optimization for amyloid inhibition), this study suggests its potential merit for further AD drug development.

Satisfaction with justice and desire for revenge in survivors of the September 11, 2001, attacks on New York City's World Trade Center.

This study investigated gaps in existing knowledge on justice, desire for revenge, and associated factors in disaster research through data collected nearly three years post disaster on justice and revenge from survivors of the September 11, 2001 (9/11) attacks. A volunteer sample of 379 employees of eight affected businesses completed interviews and self-report questionnaires. Individual ratings on satisfaction with justice and desire for revenge were compared with demographic characteristics, disaster-related experience, posttraumatic stress disorder (PTSD), disaster-related distress, anger, and concerns about danger and safety. High levels of desire for revenge and relatively low levels of satisfaction with accountability for perpetrators of the 9/11 attacks were endorsed. Most of the associations between the justice scores and the revenge score with the disaster response variables were directionally consistent. Dissatisfaction with perpetrator accountability was associated with greater desire for revenge. Both of these variables were associated with greater concerns about danger and endorsement of security regulations at the expense of personal freedoms.

Perception of Exercise Lifestyle as a Valid Tool for Prevention and Treatment of Depression in Rural Communities.

BACKGROUND: This study examines perception of exercise lifestyle prescription as a valid treatment for depression among rural patients at a primary care clinic in Texas. METHODS: The researchers created a depression and exercise survey completed by 104 patients ages 18 and up living in central, economically disadvantaged rural Texas. Logistic regression was used to analyze data obtained. RESULTS: There was a significant difference (p = 0.01) in perception of exercise as a valid treatment for depression as a function of demographic variables, however not as a function of exercise duration (p = 0.12) in the rural primary care clinic's patients. Even though it was not a statistically significant finding, there was a positive correlation found between the amount of exercise engaged in per day and the likelihood to have a positive perception of exercise prescription as a tool in depression prevention and treatment. CONCLUSION: Participants between ages 40 to 59 years old, female, and of Hispanic ethnicity independently are most likely to perceive exercise lifestyle as a valid treatment for depression. This is the first study to look specifically at patient perception of exercise as a valid treatment tool for depression not only in rural areas, but also in the nation. Findings from this pilot study may help healthcare service providers learn how to best incorporate exercise prescription into depression prevention and treatment in rural areas, leading to reducing depression epidemics.

Small molecules and Alzheimer's disease: misfolding, metabolism and imaging.

Small molecule interactions with amyloid proteins have had a huge impact in Alzheimer's disease (AD), especially in three specific areas: amyloid folding, metabolism and brain imaging. Amyloid plaque amelioration or prevention have, until recently, driven drug development, and only a few drugs have been advanced for use in AD. Amyloid proteins undergo misfolding and oligomerization via intermediates, eventually forming protease resistant amyloid fibrils. These fibrils accumulate to form the hallmark amyloid plaques and tangles of AD. Amyloid binding compounds can be grouped into three categories, those that: i) prevent or reverse misfolding, ii) halt misfolding or trap intermediates, and iii) accelerate the formation of stable and inert amyloid fibrils. Such compounds include hydralazine, glycosaminoglycans, curcumin, beta sheet breakers, catecholamines, and ATP. The versatility of amyloid binding compounds suggests that the amyloid structure may serve as a scaffold for the future development of sensors to detect such compounds. Metabolic dysfunction is one of the earliest pathological features of AD. In fact, AD is often referred to as type 3 diabetes due to the presence of insulin resistance in the brain. A recent study indicates that altering metabolism improves cognitive function. While metabolic reprogramming is one therapeutic avenue for AD, it is more widely used in some cancer therapies. FDA approved drugs such as metformin, dichloroacetic acid (DCA), and methylene blue can alter metabolism. These drugs can therefore be potentially applied in alleviating metabolic dysfunction in AD. Brain imaging has made enormous strides over the past decade, offering a new window to the mind. Recently, there has been remarkable development of compounds that have the ability to image both types of pathological amyloids: tau and amyloid beta. We have focused on the low cost, simple to use, near infrared fluorescence (NIRF) imaging probes for amyloid beta (Aß), with specific attention on recent developments to further improve contrast, specificity, and sensitivity. With advances in imaging technologies, such fluorescent imaging probes will open new diagnostic avenues.

Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.

OBJECTIVE: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). METHODS: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. RESULTS: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up. CONCLUSIONS: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Probing and trapping a sensitive conformation: amyloid-ß fibrils, oligomers, and dimers.

Alzheimer's disease (AD) is a devastating neurodegenerative disease with pathological misfolding of amyloid-ß protein (Aß). The recent interest in Aß misfolding intermediates necessitates development of novel detection methods and ability to trap these intermediates. We speculated that two regions of Aß may allow for detection of specific Aß species: the N-terminal and 22-35, both likely important in oligomer interaction and formation. We determined via epitomics, proteomic assays, and electron microscopy that the Aß(42) species (wild type, ΔE22, and MetOx) predominantly formed fibrils, oligomers, or dimers, respectively. The 2H4 antibody to the N-terminal of Aß, in the presence of 2% SDS, primarily detected fibrils, and an antibody to the 22-35 region detected low molecular weight Aß species. Simulated molecular modeling provided insight into these SDS-induced structural changes. We next determined if these methods could be used to screen anti-Aß drugs as well as identify compounds that trap Aß in various conformations. Immunoblot assays determined that taurine, homotaurine (Tramiprosate), myoinositol, methylene blue, and curcumin did not prevent Aß aggregation. However, calmidazolium chloride trapped Aß at oligomers, and berberine reduced oligomer formation. Finally, pretreatment of AD brain tissues with SDS enhanced 2H4 antibody immunostaining of fibrillar Aß. Thus we identified and characterized Aßs that adopt specific predominant conformations (modified Aß or via interactions with compounds), developed a novel assay for aggregated Aß, and applied it to drug screening and immunohistochemistry. In summary, our novel approach facilitates drug screening, increases the probability of success of antibody therapeutics, and improves antibody-based detection and identification of different conformations of Aß.