CRISPR-Cas9 treatment partially restores amyloid-ß 42/40 in human fibroblasts with the Alzheimer's disease PSEN 1 M146L mutation.

Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-ß (Aß) peptide that deposits as plaques in the Alzheimer's disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone Aß42. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1 M146L allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular Aß42/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the PSEN1 M146L allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.

Patient Characteristics and Emergency Treatment Orders in Three Florida Inpatient Psychiatric Units.

Background: Florida law defines emergency treatment orders (ETOs) as an immediate administration of psychotropic medications to a person to expeditiously treat symptoms that may present an immediate danger to the safety of the person or others.1 There is currently little information on who receives ETOs. In this study, we aim to explore correlations between patients' demographics and administering ETOs in order to understand this cohort, which could allow for improved services and alternative interventions. Methods: This retrospective study examined data from 1,460 adult patients who were admitted to an acute inpatient psychiatric unit from January 2015 to December 2017 and who received at least one ETO during their hospital admission. Results: Results revealed that younger patients (18-25 years) were at increased risk of receiving more than one ETO (p=0.039) than patients who were 26 and older. Patients with an elevated body mass index (BMI) (25 kg/m2 or more) also had a significantly increased likelihood of being administered more ETOs (≥4 ETOs) than patients with a lower BMI (defined as less than 25 kg/m2 [p=0.037]). Moreover, patients with a length of stay (LOS) of more than 14 days were more likely to receive more ETOs compared to patients with LOS less than or equal to 14 days (p<0.001). Lastly, patients with a neurocognitive disorder and/or within the schizophrenia spectrum or other psychotic disorders were more likely to receive ETOs (p<0.001) than patients with other diagnoses. Conclusion: There are some correlations in administering ETOs in that younger patients with an elevated BMI, longer LOS and certain diagnoses receive more ETOs. The reason for these findings is not clear. Therefore, prospective studies should be conducted in order to analyze these correlations.

Six-Nine Year Follow-Up of Deep Brain Stimulation for Obsessive-Compulsive Disorder.

OBJECTIVE: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) region has shown promise as a neurosurgical intervention for adults with severe treatment-refractory obsessive-compulsive disorder (OCD). Pilot studies have revealed improvement in obsessive-compulsive symptoms and secondary outcomes following DBS. We sought to establish the long-term safety and effectiveness of DBS of the VC/VS for adults with OCD. MATERIALS AND METHODS: A long term follow-up study (73-112 months) was conducted on the six patients who were enrolled in the original National Institute of Mental Health pilot study of DBS for OCD. Qualitative and quantitative data were collected. RESULTS: Reduction in OCD symptoms mirrored the one-year follow-up data. The same four participants who were treatment responders after one year of treatment showed a consistent OCD response (greater than 35% reduction in Yale Brown Obsessive Compulsive Scale (YBOCS)). Another subject, classified as a non-responder, achieved a 26% reduction in YBOCS score at long term follow-up. The only patient who did not achieve a 25% or greater reduction in YBOCS was no longer receiving active DBS treatment. Secondary outcomes generally matched the one-year follow-up with the exception of depressive symptoms, which significantly increased over the follow-up period. Qualitative feedback indicated that DBS was well tolerated by the subjects. DISCUSSION: These data indicate that DBS was safe and conferred a long-term benefit in reduction of obsessive-compulsive symptoms. DBS of the VC/VS region did not reveal a sustained response for comorbid depressive symptoms in patients with a primary diagnosis of OCD.

Acute and Chronic Mood and Apathy Outcomes from a randomized study of unilateral STN and GPi DBS.

OBJECTIVE: To study mood and behavioral effects of unilateral and staged bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) for Parkinson's disease (PD). BACKGROUND: There are numerous reports of mood changes following DBS, however, most have focused on bilateral simultaneous STN implants with rapid and aggressive post-operative medication reduction. METHODS: A standardized evaluation was applied to a subset of patients undergoing STN and GPi DBS and who were also enrolled in the NIH COMPARE study. The Unified Parkinson Disease Rating Scale (UPDRS III), the Hamilton depression (HAM-D) and anxiety rating scales (HAM-A), the Yale-Brown obsessive-compulsive rating scale (YBOCS), the Apathy Scale (AS), and the Young mania rating scale (YMRS) were used. The scales were repeated at acute and chronic intervals. A post-operative strategy of non-aggressive medication reduction was employed. RESULTS: Thirty patients were randomized and underwent unilateral DBS (16 STN, 14 GPi). There were no baseline differences. The GPi group had a higher mean dopaminergic dosage at 1-year, however the between group difference in changes from baseline to 1-year was not significant. There were no differences between groups in mood and motor outcomes. When combining STN and GPi groups, the HAM-A scores worsened at 2-months, 4-months, 6-months and 1-year when compared with baseline; the HAM-D and YMRS scores worsened at 4-months, 6-months and 1-year; and the UPDRS Motor scores improved at 4-months and 1-year. Psychiatric diagnoses (DSM-IV) did not change. No between group differences were observed in the cohort of bilateral cases. CONCLUSIONS: There were few changes in mood and behavior with STN or GPi DBS. The approach of staging STN or GPi DBS without aggressive medication reduction could be a viable option for managing PD surgical candidates. A study of bilateral DBS and of medication reduction will be required to better understand risks and benefits of a bilateral approach.

Impulsive and compulsive behaviors in Parkinson Study Group (PSG) centers performing deep brain stimulation surgery.

BACKGROUND: Impulse control disorders (ICDs), dopamine dysregulation syndrome (DDS), and dopamine agonist withdrawal syndrome (DAWS) have been reported commonly in Parkinson's disease (PD) populations. The treatment approaches may be widely variable and there is not much information on these syndromes in the setting of deep brain stimulation (DBS). OBJECTIVE: To evaluate (1) ICDs, DAWS and DDS pre- and post DBS in PD and (2) to investigate pre-DBS treatment strategies regarding these behaviors among Parkinson Study Group (PSG) centers. METHODS: Forty-eight PSG centers were surveyed on ICDs, DAWS and DDS, as well as on potential relationships to DBS and treatment approaches. RESULTS: Sixty-seven percent of PSG centers reported that they served a population of over 500 PD patients per year, and 94% of centers performed DBS surgery. Most centers (92%) reported screening for ICDs, DAWS and DDS. Of the centers screening for these symptoms, 13% reported always employing a formal battery of pre-operative tests, 46% of sites inconsistently used a formal battery, while 23% of sites reported never using a formal battery to screen for these symptoms. The estimated numbers of centers observing ICDs, DAWS and DDS pre-operatively in individuals with PD were 71%, 69%, and 69%, respectively. PSG DBS centers observing at least one case of a new de novo occurrence of an ICD, DAWS or DDS after DBS surgery were 67%, 65% and 65%, respectively. CONCLUSIONS: The results suggest that addiction-like syndromes and withdrawal syndromes are prevalent in expert PSG centers performing DBS. Most centers reported screening for these issues without the use of a formal battery, and there were a large number of centers reporting ICDs, DAWS and DDS post-DBS. A single treatment strategy did not emerge.

Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes.

Major depressive disorder (MDD) is a widespread, severe, debilitating disorder that markedly diminishes quality of life. Medication is commonly effective, but 20-30 % of patients are refractory to medical therapy. The surgical treatment of psychiatric disorders has a negative stigma associated with it owing to historical abuses. Various ablative surgeries for MDD have been attempted with marginal success, but these studies lacked standardized outcome measures. The recent development of neuromodulation therapy, especially deep brain stimulation (DBS), has enabled controlled studies with sham stimulation and presents a potential therapeutic option that is both reversible and adjustable. We performed a systematic review of the literature pertaining to DBS for treatment-resistant depression to evaluate the safety and efficacy of this procedure. We included only studies using validated outcome measures. Our review identified 22 clinical research papers with 5 unique DBS approaches using different targets, including nucleus accumbens, ventral striatum/ventral capsule, subgenual cingulate cortex, lateral habenula, inferior thalamic nucleus, and medial forebrain bundle. Among the 22 published studies, only 3 were controlled trials, and 2, as yet unpublished, multicenter, randomized, controlled trials evaluating the efficacy of subgenual cingulate cortex and ventral striatum/ventral capsule DBS were recently discontinued owing to inefficacy based on futility analyses. Overall, the published response rate to DBS therapy, defined as the percentage of patients with > 50 % improvement on the Hamilton Depression Rating Scale, is reported to be 40-70 %, and outcomes were comparable across studies. We conclude that DBS for MDD shows promise, but remains experimental and further accumulation of data is warranted.

An eight-year clinic experience with clozapine use in a Parkinson's disease clinic setting.

BACKGROUND: To examine our eight year clinic-based experience in a Parkinson's disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinson's disease (PD). METHODS: The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy. RESULTS: There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45-87 years (mean 68.3±10.15), disease duration of 17-240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = -0.36, p<0.01) and H&Y score (r = -0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05). CONCLUSIONS: This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.

Surgical neuroanatomy and programming in deep brain stimulation for obsessive compulsive disorder.

OBJECTIVES: Deep brain stimulation (DBS) has been established as a safe, effective therapy for movement disorders (Parkinson's disease, essential tremor, etc.), and its application is expanding to the treatment of other intractable neuropsychiatric disorders including depression and obsessive-compulsive disorder (OCD). Several published studies have supported the efficacy of DBS for severely debilitating OCD. However, questions remain regarding the optimal anatomic target and the lack of a bedside programming paradigm for OCD DBS. Management of OCD DBS can be highly variable and is typically guided by each center's individual expertise. In this paper, we review the various approaches to targeting and programming for OCD DBS. We also review the clinical experience for each proposed target and discuss the relevant neuroanatomy. MATERIALS AND METHODS: A PubMed review was performed searching for literature on OCD DBS and included all articles published before March 2012. We included all available studies with a clear description of the anatomic targets, programming details, and the outcomes. RESULTS: Six different DBS approaches were identified. High-frequency stimulation with high voltage was applied in most cases, and predictive factors for favorable outcomes were discussed in the literature. CONCLUSION: DBS remains an experimental treatment for medication refractory OCD. Target selection and programming paradigms are not yet standardized, though an improved understanding of the relationship between the DBS lead and the surrounding neuroanatomic structures will aid in the selection of targets and the approach to programming. We propose to form a registry to track OCD DBS cases for future clinical study design.