Facilitating Smoking Cessation in Primary Care Settings.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

Increasing COVID-19 Vaccination Rates Among Patients With Serious Mental Illness: A Pilot Intervention Study.

OBJECTIVE: This pilot project aimed to maximize COVID-19 vaccine uptake among patients with serious mental illness. Psychiatric providers were engaged to directly address COVID-19 vaccine-related concerns with patients during outpatient visits. METHODS: A quality improvement project encouraged COVID-19 vaccinations in a cohort of outpatients treated with clozapine (N=193, ages 19-81 years, mean age=46.4 years) at a community mental health center. In-service education was provided to clinicians to identify vaccine-hesitant patients and build vaccine confidence. A vaccination-monitoring tool was created and embedded in patients' electronic medical records. Starting in February 2021, the tool guided semistructured interviews at each visit and supported population-based management. RESULTS: The full COVID-19 vaccination rate by June 30, 2021, was 84% among the outpatients, compared with the estimated state rate on the same date of between 62.1% and 77.3%. CONCLUSIONS: The active involvement of psychiatric providers in preventive health care can help increase vaccination rates among patients with serious mental illness.

Feasibility and Acceptability of a Collaborative Lung Cancer Screening Educational Intervention Tailored for Individuals With Serious Mental Illness.

PURPOSE: Individuals with serious mental illness (SMI) experience disparities in lung cancer mortality. Using a two-phase, mixed-methods approach, we developed a person-centered lung cancer screening (LCS) educational intervention (phase 1) for individuals with SMI (schizophrenia and bipolar disorder) and evaluated acceptability, feasibility, and changes in attitudes toward LCS (phase 2). METHODS: Phase 1: We conducted three focus groups with mental health, primary care, and radiology clinicians and utilized rapid qualitative analysis to adapt the LCS intervention (LCS walk-through video and smoking cessation handouts) tailored for individuals with SMI. Phase 2: We enrolled LCS-eligible patients with SMI (n = 15) and assessed the feasibility (>50% enrollment; >75% completion) and acceptability (>75% overall satisfaction) of an LCS educational intervention delivered by a radiologist and a mental health clinician at a community mental health clinic. We explored changes in participant attitudes about lung cancer, LCS, and smoking before and after the intervention. RESULTS: Phase 1: Focus groups with primary care (n = 5), radiologists (n = 9), and mental health clinicians (n = 6) recommended person-centered language and adapting a video demonstrating the process of LCS to address concerns specific to SMI, including paranoia and concrete thinking. Phase 2: Fifty percent (15 of 30) of eligible patients enrolled in the LCS intervention, 100% (15 of 15) completed the intervention, and 93% (14 of 15) were satisfied with the intervention. Participants reported a significantly greater worry about developing lung cancer postintervention, but there were no other significant differences. CONCLUSIONS: Radiologists can partner with primary care and community mental health clinics to lead equity efforts in LCS among individuals with SMI.

Alpha-synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease.

In Parkinson's disease (PD), the second most common neurodegenerative disorder, non-motor symptoms often precede the development of debilitating motor symptoms and present a severe impact on the quality of life. Lewy bodies containing misfolded α-synuclein progressively develop in neurons throughout the peripheral and central nervous system, which may be correlated with the early development of non-motor symptoms. Among those, increased fear and anxiety is frequent in PD and thought to result from pathology outside the dopaminergic system, which has been the focus of symptomatic treatment to alleviate motor symptoms. Alpha-synuclein accumulation has been reported in the amygdala of PD patients, a brain region critically involved in fear and anxiety. Here we asked whether α-synuclein overexpression alone is sufficient to induce an enhanced fear phenotype in vivo and which pathological mechanisms are involved. Transgenic mice expressing human wild-type α-synuclein (Thy1-aSyn), a well-established model of PD, were subjected to fear conditioning followed by extinction and then tested for extinction memory retention followed by histopathological analysis. Thy1-aSyn mice showed enhanced tone fear across acquisition and extinction compared to wild-type littermates, as well as a trend to less retention of fear extinction. Immunohistochemical analysis of the basolateral nucleus of the amygdala, a nucleus critically involved in tone fear learning, revealed extensive α-synuclein pathology, with accumulation, phosphorylation, and aggregation of α-synuclein in transgenic mice. This pathology was accompanied by microgliosis and parvalbumin neuron loss in this nucleus, which could explain the enhanced fear phenotype. Importantly, this non-motor phenotype was detected in the pre-clinical phase, prior to dopamine loss in Thy1-aSyn mice, thus replicating observations in patients. Results obtained in this study suggest a possible mechanism by which increased anxiety and maladaptive fear processing may occur in PD, opening a door for therapeutic options and further early biomarker research.

Wilson Disease: An Overview and Approach to Management.

Wilson's disease is one of the few preventable movement disorders in which there are therapies that modify disease progression. This disease is caused by copper overload caused by reduced copper excretion secondary to genetic mutations in the ATP7B gene. Copper overload can lead to a variety of clinical presentations, including neurologic symptoms, liver failure, and/or psychiatric manifestations. There is often a delay in diagnosis of Wilson disease, and awareness of the diagnosis and management is important because of the treatable nature of this condition. This article reviews the clinical presentation, epidemiology, genetics, pathophysiology, diagnosis, and management of Wilson disease.

Education Research: Evaluation of curriculum to teach resilience skills to neurology residents.

OBJECTIVE: To evaluate feasibility and acceptability of a health professional resilience skills training program with neurology residents. METHODS: The curriculum consists of five 1-hour-long modules that included the following skills: reflective narrative practices, emotion regulation, communication with highly distressed individuals, boundary management, and the identification of depression and trauma. Using a web-based survey tool, we administered the Brief Resilience Scale (BRS) and Abbreviated Maslach Burnout Inventory (aMBI) at baseline, in addition to a pre- and post-survey assessing change in beliefs and self-efficacy, as well as satisfaction with the intervention. Means were compared using the Wilcoxon rank-sum and signed rank tests. RESULTS: Twenty-two residents representing each year of training completed the pre-survey; 41% were women. Subscale scores on the aMBI revealed that 50% had moderate or high emotional exhaustion, 41% had moderate depersonalization, and 37% had moderate or low personal accomplishment, though 77.3% reported high career satisfaction. Female residents had lower scores on the BRS (mean 3.26 vs 3.88, p < 0.05), though scores on aMBI subscales did not differ by sex. Scores did not differ by year of training. Sixteen residents completed both the pre- and post-survey. Significant increases were detected in 4 of 9 self-efficacy statements. Seventy-one percent of residents were satisfied or extremely satisfied with the training. CONCLUSIONS: Residents were satisfied with the curriculum and reported improved ability to identify and cope with work-related stress. Further study is needed to evaluate the influence of skills adoption and practice on resilience and burnout.

A GCase chaperone improves motor function in a mouse model of synucleinopathy.

Mutation of the lysosomal hydrolase acid-ß-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons.

Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson's disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

Incidence and behavioral correlates of epileptiform abnormalities in autism spectrum disorders.

Autism spectrum disorders (ASD) are associated with an increased incidence of epilepsy and of epileptiform discharges on electroencephalograms. It is unknown whether epileptiform discharges correlate with symptoms of ASD. We completed a retrospective chart review of 101 patients with ASD who had overnight electroencephalograms. We looked for a relationship between epileptiform abnormalities and diagnosis, history of regression, communication skills, and other features associated with ASD. There was a higher incidence of epileptiform activity in children with stereotypies and aggressive behavior. The incidence of epileptiform abnormalities was significantly lower in Asperger's compared with more severe forms of autism. Results suggest that increasing severity of autistic symptoms may be associated with higher likelihood of epileptiform abnormalities. Whether treatment alters outcome is unknown.

Impaired baroreflex function in mice overexpressing alpha-synuclein.

Cardiovascular autonomic dysfunction, such as orthostatic hypotension consequent to baroreflex failure and cardiac sympathetic denervation, is frequently observed in the synucleinopathy Parkinson's disease (PD). In the present study, the baroreceptor reflex was assessed in mice overexpressing human wildtype alpha-synuclein (Thy1-aSyn), a genetic mouse model of synucleinopathy. The beat-to-beat change in heart rate (HR), computed from R-R interval, in relation to blood pressure was measured in anesthetized and conscious mice equipped with arterial blood pressure telemetry transducers during transient bouts of hypertension and hypotension. Compared to wildtype, tachycardia following nitroprusside-induced hypotension was significantly reduced in Thy1-aSyn mice. Thy1-aSyn mice also showed an abnormal cardiovascular response (i.e., diminished tachycardia) to muscarinic blockade with atropine. We conclude that Thy1-aSyn mice have impaired basal and dynamic range of sympathetic and parasympathetic-mediated changes in HR and will be a useful model for long-term study of cardiovascular autonomic dysfunction associated with PD.

A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions.

Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson's disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for 2 months starting at 1 month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured 1 month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 months) NAP administration in a mouse model of synucleinopathy.

Olfactory deficits in mice overexpressing human wildtype alpha-synuclein.

Accumulation of alpha-synuclein in neurons of the central and peripheral nervous system is a hallmark of sporadic Parkinson's disease (PD) and mutations that increase alpha-synuclein levels cause familial PD. Transgenic mice overexpressing alpha-synuclein under the Thy1 promoter (Thy1-aSyn) have high levels of alpha-synuclein expression throughout the brain but no loss of nigrostriatal dopamine neurons up to 8 months, suggesting that they may be useful to model pre-clinical stages of PD. Olfactory dysfunction often precedes the onset of the cardinal motor symptoms of PD by several years and includes deficits in odor detection, discrimination and identification. In the present study, we measured olfactory function in 3- and 9-month-old male Thy1-aSyn mice with a buried pellet test based on latency to find an exposed or hidden odorant, a block test based on exposure to self and non-self odors, and a habituation/dishabituation test based on exposure to non-social odors. In a separate group of mice, alpha-synuclein immunoreactivity was assessed in the olfactory bulb. Compared with wildtype littermates, Thy1-aSyn mice could still detect and habituate to odors but showed olfactory impairments in aspects of all three testing paradigms. Thy1-aSyn mice also displayed proteinase K-resistant alpha-synuclein inclusions throughout the olfactory bulb. These data indicate that overexpression of alpha-synuclein is sufficient to cause olfactory deficits in mice similar to that observed in patients with PD. Furthermore, the buried pellet and block tests provided sufficient power for the detection of a 50% drug effect, indicating their usefulness for testing novel neuroprotective therapies.