Scott A. Sperling

132 A Randomized, Sham-Controlled Trial of Transcranial Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Trial for the Treatment of Tremor-Dominant, Idiopathic Parkinson Disease.

INTRODUCTION Traditional stereotactic radiofrequency thalamotomy has been used with success in medication-refractory tremor-dominant Parkinson disease (PD). Recently, transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been used to successfully perform thalamotomy for essential tremor. We designed a double-blinded, randomized controlled trial to investigate the effectiveness of MRgFUS thalamotomy in tremor-dominant PD. METHODS Patients with medication-refractory, tremor-dominant PD were enrolled in the 2-center study and randomly assigned 1:2 to receive either a sham procedure or treatment. After the 3-month blinded phase, the sham group was offered treatment. Outcome was measured with blinded Clinical Rating Scale for Tremor (CRST) and Unified Parkinsons Disease Rating Scale (UPDRS) ratings. The primary outcome compared improvement in hand tremor between the treatment and sham procedure at 3 months. Secondary outcomes were measured with UPDRS and hand tremor at 12 months. Safety was assessed with MRI, adverse events, and comprehensive neurocognitive assessment. RESULTS Twenty-seven patients were enrolled and 6 were randomly assigned to a sham procedure. For the primary outcome assessment, there was a mean 50% improvement in hand tremor from MRgFUS thalamotomy at 3 months compared with a 22% improvement from the sham procedures (P = .088). The 1-year tremor scores for all 19 patients treated with 1-year follow-up data (blinded and unblinded) showed a reduction in tremor scores of 40.6% (P = .0154) and a mean reduction in medicated UPDRS motor scores of 3.7 (32%, P = .033). Sham patients had a notable placebo effect with a mean 21.5% improvement in tremor scores at 3 months. Twenty-seven patients completed the primary analysis, 19 patients completed the 12-month assessment, 3 patients opted for deep brain stimulation, 3 were lost to follow-up, 1 patient opted for no treatment, and 1 is pending a 12-month evaluation. CONCLUSION Transcranial MRgFUS demonstrates a trend toward improvement in hand tremor, and a clinically significant reduction in mean UPDRS. A significant placebo response was noted in the randomized trial.cause of intractable epilepsy in children. Seizure freedom following resection of FCD is determined by complete resection of the dysplastic cortical tissue.However, difficulty with intraoperative identification of the FCD lesion may limit the ability to achieve the surgical objective of complete extirpation of these lesions. The use of intraoperative magnetic resonance imaging (iMRI) may aid in real-time detection of these lesions and improve seizure control outcomes compared with traditional resective surgery.

Safety and Efficacy of Focused Ultrasound Thalamotomy for Patients With Medication-Refractory, Tremor-Dominant Parkinson Disease: A Randomized Clinical Trial

Importance Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown. Objective To assess safety and efficacy at 12-month follow-up, accounting for placebo response, of unilateral FUS thalamotomy for patients with TDPD. Design, Setting, and Participants Of the 326 patients identified from an in-house database, 53 patients consented to be screened. Twenty-six were ineligible, and 27 were randomized (2:1) to FUS thalamotomy or a sham procedure at 2 centers from October18, 2012, to January 8, 2015. The most common reasons for disqualification were withdrawal (8 persons [31%]), and not being medication refractory (8 persons [31%]). Data were analyzed using intention-to-treat analysis, and assessments were double-blinded through the primary outcome. Interventions Twenty patients were randomized to unilateral FUS thalamotomy, and 7 to sham procedure. The sham group was offered open-label treatment after unblinding. Main Outcomes and Measures The predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor (CRST). Secondary outcomes included descriptive results of Unified Parkinson’s Disease Rating Scale (UPDRS) scores and quality of life measures. Results Of the 27 patients, 26 (96%) were male and the median age was 67.8 years (interquartile range [IQR], 62.1-73.8 years). On-medication median tremor scores improved 62% (IQR, 22%-79%) from a baseline of 17 points (IQR, 10.5-27.5) following FUS thalamotomy and 22% (IQR, −11% to 29%) from a baseline of 23 points (IQR, 14.0-27.0) after sham procedures; the between-group difference was significant (Wilcoxon P = .04). On-medication median UPDRS motor scores improved 8 points (IQR, 0.5-11.0) from a baseline of 23 points (IQR, 15.5-34.0) following FUS thalamotomy and 1 point (IQR, −5.0 to 9.0) from a baseline of 25 points (IQR, 15.0-33.0) after sham procedures. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (4 events [20%]), finger paresthesia (1 event [5%]), and ataxia (1 event [5%]). Conclusions and Relevance Focused ultrasound thalamotomy for patients with TDPD demonstrated improvements in medication-refractory tremor by CRST assessments, even in the setting of a placebo response. Trial Registration ClinicalTrials.gov identifier NCT01772693

Diagnostic Accuracy and Confidence in the Clinical Detection of Cognitive Impairment in Early-Stage Parkinson Disease

Background/Aims: Mild cognitive impairment (MCI) is present in up to 34% of patients with early-stage Parkinson disease (PD); however, it is difficult to detect subtle impairment without objective cognitive testing. Methods: Data were obtained from the Parkinson Progression Marker Initiative. All 341 participants were administered the Montreal Cognitive Assessment (MoCA) and a brief neuropsychological battery. Participants were classified as PD-MCI if MoCA was <26 or if they scored ≥1 standard deviation below the normative mean in 2 or more domains, based upon established criteria. The sensitivity/specificity for the clinical detection of PD-MCI was determined. Results: Overall accuracy for clinical detection of PD-MCI was 67.4%. Although clinical determination was highly specific (96.3%; 95% confidence interval [CI]: 0.92-0.98), sensitivity was poor (32.0%; 95% CI: 0.25-0.40). Conclusion: Identifying MCI in early-stage PD based on clinical interview alone appears to be insufficient. The inclusion of objective cognitive tests allowing for normative sample comparisons is needed to increase the detection of cognitive impairment in this population.

Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease

Objective Determining baseline predictors of future psychosis in Parkinson disease (PD) may identify those at risk for more rapidly progressive disease, i.e., a more malignant PD subtype. Methods This cohort study evaluated 423 patients with newly diagnosed PD collected as part of the Parkinsons Progression Markers Initiative. Psychotic symptoms were assessed with the Movement Disorders Society–Unified Parkinson Disease Rating Scale item 1.2, which assesses hallucinations and psychosis over the past week. At baseline, participants completed the Scales for Outcomes in Parkinsons Disease–Autonomic, the REM Sleep Behavior Disorder (RBD) Screening Questionnaire, and the Epworth Sleepiness Scale. Cholinergic nucleus 4 (Ch4) density was calculated for 228 participants with PD and 101 healthy controls. Results Multivariate logistic regression adjusted for age and sex found that greater autonomic symptoms (p = 0.002), RBD (p = 0.021), and excessive daytime sleepiness (EDS) (p = 0.003) at baseline were associated with increased risk of reporting psychotic symptoms on ≥2 occasions. Having 2 or 3 of these baseline symptoms was associated with lower Ch4 density (p = 0.007). In a logistic regression model adjusted for age and sex, higher Ch4 gray matter density was associated with lower risk of reporting psychotic symptoms on ≥2 occasions (odds ratio 0.96 [for an increase in density of 1 unit], p = 0.03). Conclusions This study confirms that RBD, EDS, and greater autonomic symptom burden are associated with greater risk of future psychotic symptoms in PD. Reduced Ch4 density at baseline is associated with future psychotic symptoms and a greater burden of RBD, EDS, and autonomic symptoms.

Taxonomy for Education and Training in Clinical Neuropsychology: past, present, and future

Abstract Objective: Historically, the clinical neuropsychology training community has not clearly or consistently defined education or training opportunities. The lack of consistency has limited students’ and trainees’ ability to accurately assess and compare the intensity of neuropsychology-specific training provided by programs. To address these issues and produce greater ‘truth in advertising’ across programs, CNS, with SCN’s Education Advisory Committee (EAC), ADECN, AITCN, and APPCN constructed a specialty-specific taxonomy, namely, the Taxonomy for Education and Training in Clinical Neuropsychology. The taxonomy provides consensus in the description of training offered by doctoral, internship, and postdoctoral programs, as well as at the post-licensure stage. Although the CNS approved the taxonomy in February 2015, many programs have not adopted its language. Increased awareness of the taxonomy and the reasons behind its development and structure, as well as its potential benefits, are warranted. Methods: In 2016, a working group of clinical neuropsychologists from the EAC and APPCN, all authors of this manuscript, was created and tasked with disseminating information about the taxonomy. Group members held regular conference calls, leading to the generation of this manuscript. Results: This manuscript is the primary byproduct of the working group. Its purpose is to (1) outline the history behind the development of the taxonomy, (2) detail its structure and utility, (3) address the expected impact of its adoption, and (4) call for its adoption across training programs. Conclusions: This manuscript outlines the development and structure of the clinical neuropsychology taxonomy and addresses the need for its adoption across training programs.

The use of magnetic resonance-guided high intensity focused ultrasound to treat essential tremor

Advances in ultrasound transducer technology have enabled for transcranial sonication with energy levels adequate to achieve tissue ablation. With MR-guidance and monitoring, precise lesioning is now possible of deep brain targets such as the thalamus and basal ganglia so that stereotactic lesioning is being reconsidered for the treatment of movement disorders. In this phase 1 clinical trial, we investigate the feasibility and safety of MRgFUS for performing a unilateral thalamotomy for medication-refractory essential tremor (ET). According to an FDA-approved protocol, 15 patients with medication-resistant ET underwent unilateral MRgFUS lesioning of the thalamus for dominant limb tremor. Intraprocedural monitoring was conducted with each incremental sonication using MR thermometry and clinical examination. Neurological assessments, validated tremor ratings, MRI, and quality of life data were recorded preoperatively and during a year post treatment. Adverse events were recorded throughout the study duratio...

Selection of Normative Group Affects Rates of Mild Cognitive Impairment in Parkinson's Disease: Normative Data and Rates of MCI in PD

Objective: The objective of this study was to examine the impact of different methods of standardizing cognitive data in the Parkinsons Progression Marker Initiative.

Cognitive Function and Vascular Risk Factors Among Older African American Adults

To evaluate the association between vascular risk factors and cognitive impairment among older African American (AA) adults in a primary care clinic. Participants included 96 AA adults aged 60 years or older who were evaluated for global and domain-specific cognition. Participants were interviewed using the Computerized Assessment of Memory and Cognitive Impairment (CAMCI). The relationship between CAMCI cognitive domain scores and vascular risk factors were examined using hierarchical regression models. Patients who smoked, those with higher SBP/DBP values had lower accuracy rates on CAMCI cognitive domains (attention, executive, memory).Those with higher BMI had better attention scores. Patients with higher HbA1C values had worse verbal memory. Patients with higher blood pressure were significantly faster in responding to tasks in the executive domain. Primary care providers working with older AA adults with these VRFs could implement cognitive screening earlier into their practice to reduce barriers of seeking treatment.

Assessment of the internal structure of Computer‐based Assessment of Memory and Cognitive Impairment

The Computer-based Assessment of Mild Cognitive Impairment (CAMCI) is a relatively rapid and easy-toadminister computerized neuropsychological test that uses a tablet. The CAMCI purportedly assesses six neuropsychological domains including attention, executive function, verbal memory, nonverbal memory, functional memory, and incidental memory (Table 1). The CAMCI measures speed as well as accuracy on various tasks. However, these additional speed measurements have sometimes shown different scoring results than the original accuracy scores in the same neuropsychological domain. This study sought to investigate the structural relationship of various measurements from the CAMCI in a sample of older African Americans being treated by their primary care physicians. All participants (37 men, 59 women; age (mean SD): 73.2 7.7 years; educational level: 6.8 5.4 years; Mini-Mental Status Examination: 27.75 3.3) were recruited from the University Medical Associates Clinic at the University of Virginia. They completed the CAMCI and demographic questionnaires, and gave access to their health records. No participant had previously been diagnosed with dementia or mild cognitive impairment. The study was approved by the ethics committee of the University of Virginia. Using the CAMCI, we extracted and evaluated 21 data measurements (Table 1). The accuracy and speed data of the CAMCI were transformed into standardized z-scores. Exploratory factor analysis was performed using principal component analysis with a varimax rotation. The Kaiser–Meyer–Olkin test and Bartlett’s test of sphericity were calculated to check the sampling adequacy. The number of factors to be retained in the final solution was determined by examining the scree plot and then using those with eigenvalues >1. To be retained in the final solution, a factor needed to have at least three measurement loadings greater than 0.60 on that factor, with no loading of those measurements on other factors. The results are shown in Table 1. Our exploratory factor analysis suggested that the CAMCI has a twofactor structure. The Kaiser–Meyer–Olkin measure of sampling adequacy (0.691) and Bartlett’s test of sphericity (<0.001) indicated that the correlation matrix was factorable. The first factor, ‘verbal memory and choice points’, explained 26.9% of the total variance; it included all data from the verbal memory tasks (i.e. the number of correct answers and median reaction time (RT) on the verbal-recognition task and the number of correct answers on the word-recall task) and the number of choice points in the routefinding task. The second factor, ‘reaction time’, explained 9.9% of the total variance and included percentage of correct (target) responses on the simple RT task, RT (first trial) on the digit-span-reverse task, and the median RT (correct target) on the recurring pictures task. Although these two factors were extracted from more than one neuropsychological domain, the composition of these factors can be reasonably related. The first factor included all measurements of verbal memory, which assessed verbal recognition and word recall, and one measurement of executive function, which investigated the nature of the difficulties in route plotting by counting the number of shopping-trip choice points. Because the relationship between memory, executive function, and spatial abilities is known and because route-finding tasks require spatial abilities including memory, attention, and perception, the level of accuracy may reasonably express the higher-order functioning of these relationships. The second factor is composed of only RT measurements, although they come from differing neuropsychological domains (attention, executive function, and non-verbal memory). This factor is, therefore, thought to express the similar properties of RT measurements. This study had some limitations. It was performed on African Americans who had visited their physician for reasons other than cognitive impairment, and the

Capgras Syndrome in Advanced Parkinson’s Disease

Psychosis is common in Parkinsons disease (PD), especially in advanced disease, and can lead to a number of psychotic symptoms, including delusions. One uncommon delusion is Capgras syndrome (CS). The authors report on three PD patients with a history of deep brain stimulation (DBS) who developed this delusion. The anatomic targets in these three patients were the subthalamic nuclei in two patients and the globus pallidus interna in one patient. The length of time between surgery and development of CS varied but was greater than 6 months. Additionally, all three patients showed evidence of impaired cognition prior to development of CS. Therefore, due to the length of time between DBS and CS in all three cases and the fact that one patient developed CS months after DBS explanation, DBS does not appear to be associated with CS. Given the distressing nature of this condition, patients with advanced PD who undergo DBS should be regularly screened for symptoms of psychosis with awareness of CS as a potential form.