Publications by authors named "Scott A Sperling"

27 Publications

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Cholinergic nucleus 4 grey matter density is associated with apathy in Parkinson's disease.

Clin Neuropsychol 2022 Apr 21:1-19. Epub 2022 Apr 21.

Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.

The generation and maintenance of goal-directed behavior is subserved by multiple brain regions that receive cholinergic inputs from the cholinergic nucleus 4 (Ch4). It is unknown if Ch4 degeneration contributes to apathy in Parkinson's disease (PD). We analyzed data from 106 pre-surgical patients with PD who had brain MRIs and completed the Frontal Systems Behavior Scales (FrSBe). Eighty-eight patients also completed the Beck Depression Inventory-2nd Edition. Cholinergic basal forebrain grey matter densities (GMD) were measured by applying probabilistic maps to T1 MPRAGE sequences processed using voxel-based morphometry methods. We used linear and hierarchical regression modelling to examine the association between Ch4 GMD and the FrSBe Apathy subscale scores. We used similar methods to assess the specificity of this association and potential associations between Ch4 target regions and apathy. Ch4 GMD ( = .021) and Ch123 GMD ( = .032) were significantly associated with Apathy subscale scores on univariate analysis. Ch4 GMD, but not Ch123 GMD, remained significantly associated with apathy when adjusting for age, sex, levodopa equivalent doses, and disease duration. Centromedial amygdala GMD, which receives cholinergic inputs from Ch4, was also associated with apathy. Ch4 GMD was not associated with depression or disinhibition, nor was it associated with executive dysfunction when adjusting for clinical and demographic variables. Ch4 GMD is specifically associated with apathy in PD. Ch4 degeneration results in cholinergic denervation of multiple cortical and limbic regions, which may contribute to the cognitive and emotional-affective processing deficits that underlie the behavioral symptoms of apathy.
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http://dx.doi.org/10.1080/13854046.2022.2065362DOI Listing
April 2022

What makes for a competitive fellowship candidate? A survey of clinical neuropsychology postdoctoral training directors.

Clin Neuropsychol 2021 Aug 24:1-20. Epub 2021 Aug 24.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

To obtain objective data about the factors that clinical neuropsychology postdoctoral training directors (TDs) look for and prioritize in their review and selection of fellowship candidates.

We identified 167 TDs who were overseeing postdoctoral training programs that provided training consistent with the Houston Conference Guidelines. We invited all TDs to complete an anonymous online survey that assessed their expectations as they relate to the selection of fellowship candidates. Eighty-eight TDs completed the survey in full. We used descriptive statistics to analyze the data and investigate potential between-group differences in TDs' responses across patient populations, training settings, and APPCN member program status.

TDs ranked the intensity of candidates' neuropsychology education and training experiences, their fellowship interviews, and letters of recommendation as most important. Increasing the representation of under-represented minorities and other factors were ranked lower. Minimum benchmarks related to candidates' scholarly productivity, dissertation progress, and the time they spent engaged in clinical neuropsychology activities during internship were revealed. There were relatively few differences in TDs' responses when compared across patient populations, training settings, or APPCN member program status.

Students may increase their competitiveness for clinical neuropsychology fellowships by obtaining intensive education and training experiences in the specialty, which includes clinical training and coursework, and by producing scholarly work. Students may also benefit from improving their interviewing skills, completing an internship with at least 40% of time spent in neuropsychological activities, and at minimum by having their dissertation data collected before their fellowship interviews.
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http://dx.doi.org/10.1080/13854046.2021.1967451DOI Listing
August 2021

Olfaction, cholinergic basal forebrain degeneration, and cognition in early Parkinson disease.

Parkinsonism Relat Disord 2021 09 27;90:27-32. Epub 2021 Jul 27.

Department of Radiology and Medical Imaging, Division of Neuroradiology, University of Virginia Health System, Charlottesville, VA, USA.

Introduction: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD.

Methods: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions.

Results: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (βˆ= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (βˆ= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time.

Conclusion: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.024DOI Listing
September 2021

Evaluating the efficacy of TeleFAMILIES: a telehealth intervention for caregivers of community-dwelling people with dementia.

Aging Ment Health 2021 Jun 14:1-7. Epub 2021 Jun 14.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Examine the efficacy of a telehealth-administered intervention for caregivers of persons with dementia.

Two hundred sixteen caregivers engaged in the FAMILIES intervention over six months, either virtually ( = 59) or in-person ( = 157). The telehealth protocol (TeleFAMILIES) was conducted online. Caregivers engaged in six sessions, including individual and family/group counseling, ad hoc counseling, and had access to support groups. Sessions included person-centered assessments of caregivers' physical, emotional, social needs, and current support networks. Primary outcome variables were change in total score between baseline and completion on the Zarit Burden Interview (ZBI), Center for Epidemiologic Studies Depression Scale-Revised (CESD-R), and the Revised Memory and Behavior Problems Checklist (RMBPC).

TeleFAMILIES caregivers reported significant reductions in ZBI ( = .002) and CESD-R scores ( < .001). RMBPC reaction scores significantly improved ( = .02) and improved more than in-person caregivers' scores (F (3, 119) = 2.71, = .048, partial eta = .06). For those classified as having a higher risk of depression at baseline, a significantly larger portion TeleFAMILIES caregivers converted to a classification of lower depression risk at completion ( = .02).

Compared to the in-person group, TeleFAMILIES caregivers experienced the same, if not greater improvements in perceived burden, depressive symptomatology, and their ability to manage their reactions to behavioral symptoms of dementia. The strengths of TeleFAMILIES are the convenience of telehealth services and its mitigation of barriers to care.
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http://dx.doi.org/10.1080/13607863.2021.1935462DOI Listing
June 2021

Factor structure of the BDI-II in Parkinson's disease.

Neuropsychology 2021 Jul 29;35(5):540-546. Epub 2021 Apr 29.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic.

Objective: There is substantial heterogeneity in depressive symptomology for individuals with Parkinson's disease (PD). It is unknown whether the Beck Depression Inventory-Second Edition (BDI-II) is capable of identifying such phenotypic variations of depression.

Method: We investigated the factor structure of the BDI-II and its associations with demographic characteristics and other nonmotor symptoms in PD. We reviewed the cases of 236 patients with a confirmed PD diagnosis. Evaluations included the BDI-II, Montreal Cognitive Assessment (MoCA), Apathy Scale (AS), and Geriatric Anxiety Inventory (GAI). We used exploratory structural equation modeling (ESEM) with target rotations as this method integrates aspects of exploratory and confirmatory factor analysis. We conducted hierarchical regressions to assess for associations between the BDI-II factors and gender, age, education, disease duration, cognition, anxiety, and apathy.

Results: ESEM supported the retention of a Somatic factor and an Affective factor that accounted for 53% of the model variance. Model goodness-of-fit measures were within normal limits. Higher AS scores were positively associated with the Somatic and Affective factors. Higher GAI scores were positively associated only with the Affective factor. There were no other significant relationships with factor scores.

Conclusions: This study supports the retention of a two-factor model of the BDI-II in PD. These unique clusters of depressive symptoms in PD can be used to guide clinical decisions about the need for further psychiatric evaluation and the appropriateness of different therapeutic interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000739DOI Listing
July 2021

Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson's Disease.

N Engl J Med 2020 12;383(26):2501-2513

From HM Centro Integral en Neurociencias AC (CINAC), University Hospital HM Puerta del Sur, CEU San Pablo University, Mostoles (R.M.-F., J.U.M.-M., R.R.-R., M.A., F.H.-F., J.A.P.-P., M.H.G.M., B.F.-R., D.M.-M., P.G., F.A.-F., I.O., C.G.-S., L.V.-D., J.A.O.), and the Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid (R.M.-F., R.R.-R., M.A., F.H.-F., J.A.P.-P., D.M.-M., P.G., F.A.-F., I.O., C.G.-S., L.V.-D., J.A.O.) - both in Spain; and the University of Virginia Health Sciences Center, Charlottesville (B.B.S., S.A.S., W.J.E.).

Background: The subthalamic nucleus is the preferred neurosurgical target for deep-brain stimulation to treat cardinal motor features of Parkinson's disease. Focused ultrasound is an imaging-guided method for creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus.

Methods: We randomly assigned, in a 2:1 ratio, patients with markedly asymmetric Parkinson's disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure. The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (i.e., part III) for the more affected body side (range, 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state. The primary safety outcome (procedure-related complications) was assessed at 4 months.

Results: Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control). The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95% confidence interval [CI], 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95% CI, 0.0 to 3.5); the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001). Adverse events in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months.

Conclusions: Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia. (Funded by Insightec and others; ClinicalTrials.gov number, NCT03454425.).
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http://dx.doi.org/10.1056/NEJMoa2016311DOI Listing
December 2020

Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease.

J Neurol 2021 Jan 28;268(1):95-101. Epub 2020 Jul 28.

Department of Neurology, University of Virginia, 1221 Lee St 4th Floor, Charlottesville, VA, 22908, USA.

Background: There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson's Disease (PD), especially reduced gait speed.

Objectives: The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients.

Methods: We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex.

Results: Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the "on" medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the "on" medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021).

Conclusions: Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.
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http://dx.doi.org/10.1007/s00415-020-10111-2DOI Listing
January 2021

Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity.

Front Neurol 2019 18;10:1329. Epub 2019 Dec 18.

Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA, United States.

Models which assess the progression of Lewy pathology in Parkinson's disease have proposed ascending spread in a caudal-rostral pattern. human evidence for this theory is limited, in part because there are no biomarkers that allow for direct assessment of Lewy pathology. Here, we measured neurodegeneration via MRI, an outcome which may serve as a proxy for a more direct assessment of ascending models using a combination of (1) MRI-based measures of gray matter density and (2) regions of interest (ROIs) corresponding to cortical and subcortical loci implicated in past MRI and stereological studies of Parkinson's disease. Gray matter density was measured using brain MRI voxel-based morphometry from three cohorts: (1) early Parkinson's disease, (2) more advanced Parkinson's disease and (3) healthy controls. Early Parkinson's disease patients ( = 228, mean age = 61.9 years, mean disease duration = 0.6 years) were newly diagnosed by the Parkinson's Progression Markers Initiative (PPMI). Advanced Parkinson's disease patients ( = 136, mean age = 63.5 years, mean disease duration = 8.0 years) were collected retrospectively from a local cohort undergoing evaluation for functional neurosurgery. Control subjects ( = 103, mean age = 60.2 years) were from PPMI. Comparative analyses focused on gray matter regions ranging from deep gray subcortical structures to the neocortex. ROIs were defined with existing probabilistic cytoarchitectonic brain maps. For subcortical regions of the basal forebrain, amygdala, and entorhinal cortex, advanced Parkinson's disease patients had significantly lower gray matter density when compared to both early Parkinson's disease and healthy controls. No differences were seen in neocortical regions that are "higher" in any proposed ascending pattern. Across early and advanced Parkinson's disease, gray matter density from nearly all subcortical regions significantly decreased with disease duration; no neocortical regions showed this effect. These results demonstrate that atrophy in advanced Parkinson's patients compared to early patients and healthy controls is largely confined to subcortical gray matter structures. The degree of atrophy in subcortical brain regions was linked to overall disease duration, suggesting an organized pattern of atrophy across severity.
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http://dx.doi.org/10.3389/fneur.2019.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930693PMC
December 2019

Comparison of Parkinson's Disease Patients' Characteristics by Indication for Deep Brain Stimulation: Men Are More Likely to Have DBS for Tremor.

Tremor Other Hyperkinet Mov (N Y) 2019 17;9. Epub 2019 Sep 17.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Background: We investigated whether the characteristics of Parkinson's disease (PD) patients differ based on the primary indication for deep brain stimulation (DBS).

Methods: We reviewed data for 149 consecutive PD patients who underwent DBS at the University of Virginia. Patients were categorized based on primary surgical indication, and clinical characteristics were compared between groups.

Results: Twenty-nine (93.5%) of 31 PD patients who underwent DBS for medication refractory tremor were men, and 66 (62.3%) of 106 PD patients who underwent DBS for motor fluctuations were men (p = 0.001). Other primary indications for DBS were tremor and fluctuations ( = 5), medication intolerance ( = 5), and dystonia ( = 2).

Discussion: Patients who underwent DBS for medication refractory tremor were predominantly men, while patients who had DBS for motor fluctuations approximated the gender distribution of PD. Possible explanations are that men with PD are more likely to develop medication refractory tremor or undergo surgery for medication refractory tremor in PD compared to women.
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http://dx.doi.org/10.7916/tohm.v0.676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749750PMC
March 2020

FAMILIES: an effective healthcare intervention for caregivers of community dwelling people living with dementia.

Aging Ment Health 2020 10 31;24(10):1700-1708. Epub 2019 Jul 31.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Caregiving for a person with dementia (PWD) carries increased risk of poorer health and quality of life. Non-pharmacological interventions improve outcomes for caregivers of PWDs. We evaluated the efficacy of a modified New York University Caregiver Intervention (NYUCI), named FAMILIES, delivered to spousal and non-spousal caregivers of PWDs from diverse etiologies in a reduced number of sessions. Participants were 122 primary caregivers for community dwelling PWDs in Virginia. The intervention included two individual and four family/group counseling sessions that integrated dementia education, coping skills and behavioral management training, emotional support, and identification of family and community resources. Assessment of depression, caregiver well-being and burden, and caregiver reactions to the behavioral symptoms of dementia (BSD) were completed at baseline, the sixth session, and 6-month follow-up. Symptoms of depression ( < .001) and caregiver burden ( = .001) and caregivers' capacity to effectively manage their reactions to BSD ( = .003), significantly improved at the sixth session. Benefits were maintained at 6-month follow-up. Being married and female predicted improvement in caregiver burden; being male and living in a rural area predicted reduced risk of depression. Caregivers reported that the intervention was helpful and had a positive impact on the PWD. Modifications to the NYUCI did not diminish its efficacy. Caregivers in FAMILIES experienced improvements in depressive symptoms, caregiver burden, and their ability to effectively manage their reactions to BSD. Systemic support for implementing FAMILIES could have a broad impact on caregivers, PWDs, and the healthcare system.
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http://dx.doi.org/10.1080/13607863.2019.1647141DOI Listing
October 2020

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

J Neurol Neurosurg Psychiatry 2019 11 7;90(11):1251-1256. Epub 2019 Jun 7.

Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA.

Objective: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD.

Methods: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models.

Results: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (β=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (β=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (β=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (β=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (β=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (β=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (β=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls.

Conclusion: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.
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http://dx.doi.org/10.1136/jnnp-2019-320450DOI Listing
November 2019

Predictors of health-related quality of life in Parkinson's disease.

Parkinsonism Relat Disord 2019 08 7;65:86-90. Epub 2019 May 7.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Background: Health-related quality of life in Parkinson's disease may be affected by a wide range of motor and non-motor symptoms. Identifying which symptoms are significant predictors of health-related quality of life in Parkinson's disease prioritizes symptoms for treatment, therapeutic development, and clinical outcomes.

Objectives: To determine predictors of health-related quality of life in patients with Parkinson's disease.

Methods: We recruited 102 subjects into a prospective study to investigate neuropsychiatric symptoms in Parkinson's disease. Health-related quality of life was measured with the 39-item Parkinson's Disease Questionnaire. Subjects completed the Movement Disorder Society Unified Parkinson's Disease Rating Scale Parts I-IV as well as validated scales to assess anxiety, depression, apathy, cognition, psychosis, impulsive-compulsive disorder, autonomic dysfunction, sleep quality, excessive daytime sleepiness, and rapid eye movement sleep behavior disorder. We used univariate analyses to select clinical predictors to construct a multivariate regression model to determine which predictors were independently associated with worse health-related quality of life.

Results: In a multivariate linear regression model adjusted for age and gender, higher scores for the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale part II as well more severe symptoms of depression, anxiety, apathy, and excessive daytime sleepiness were associated with worse health-related quality of life. The model explained 78% of the variance of health-related quality of life, and the non-motor symptoms explained 49% of the variance.

Conclusions: Anxiety, depression, excessive daytime sleepiness, apathy, and impairment in activities of daily living related to motor symptoms were independently associated with worse health-related quality of life.
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.009DOI Listing
August 2019

Clinical and demographic correlates of apathy in Parkinson's disease.

J Neurol 2019 Feb 2;266(2):507-514. Epub 2019 Jan 2.

Department of Neurology, University of Virginia, PO Box 800394, 22908-0394, Charlottesville, VA, USA.

Objective: To better understand the demographic, neuropsychiatric, cognitive, and motor predictors of apathy in Parkinson's disease (PD).

Method: 112 participants (M = 68.53 years; M = 6.17 years) were administered the Apathy Scale (AS), Beck Depression Inventory-II (BDI-II), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Trail Making Test (TMT), Wechsler Adult Intelligence Scale-IV Matrix Reasoning subtest, letter (F-A-S) and category (Animals) fluency, and Hopkins Verbal Learning Test-Revised. Psychosis was assessed. A stepwise logistic regression analysis was performed to investigate the ability of demographic factors and clinical assessments to predict nonapathetic (AS ≤ 13) versus apathetic (AS > 13) group membership.

Results: The regression analysis yielded a robust model in which older age, less education, elevated BDI-II, current psychosis, higher MDS-UPDRS Part III (motor score), and slower TMT-B performance predicted membership in the apathetic group, with a correct classification rate of 77.5% (Nagelkerke R = 0.48, p < .001). Depression (OR = 9.20, p < .001) and education (OR = 0.66, p = 0.002) contributed significantly to the overall model. A linear regression with AS score as the outcome variable was similar, but TMT-B additionally contributed significantly (p = 0.02) to the overall model, F(6, 86) = 12.02, p < .001, adjusted R = 0.42.

Conclusions: Of the factors examined, depression, education, and executive functioning were the strongest correlates of apathy in PD. These results support the idea that common underlying frontosubcortical disruptions in this population contribute to apathy, depression, and executive dysfunction.
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http://dx.doi.org/10.1007/s00415-018-9166-3DOI Listing
February 2019

Focused ultrasound thalamotomy in Parkinson disease: Nonmotor outcomes and quality of life.

Neurology 2018 10 29;91(14):e1275-e1284. Epub 2018 Aug 29.

From the Departments of Neurology (S.A.S., B.B.S., M.J.B.), Neurosurgery (A.E.B., W.J.E.), and Physical Therapy (D.S.H.), University of Virginia Health Science Center, Charlottesville; and College of Arts and Sciences (J.A.G.M.), University of Virginia, Charlottesville.

Objective: To examine nonmotor outcomes and correlates of quality of life (QoL) 3 and 12 months after unilateral focused ultrasound thalamotomy in tremor-dominant Parkinson disease (TDPD).

Methods: Twenty-seven patients with TDPD in a double-blind, sham-controlled, randomized clinical trial underwent comprehensive neuropsychological evaluations. These included assessment of mood, behavior, and QoL at baseline, 3 months, 3 months post crossover in the sham group, and 12 months after active treatment. We used Mann-Whitney tests to assess differences between the active (n = 20) and sham (n = 7) groups at 3 months and Friedman tests to assess within-group changes after active treatment. We assessed correlations between disease variables and postoperative QoL using Kendall tau-b tests.

Results: There were no differences in cognition, mood, or behavior between the active and sham groups at 3-month blinded assessment. After active treatment, there were no differences in mood or behavior. Only declines in Stroop Color Naming and phonemic fluency were observed. Patients experienced postoperative improvements in QoL and activities of daily living (ADL). Mood and behavioral symptoms, aspects of cognitive functioning, ADL, and overall motor symptom severity, but not tremor severity specifically, were associated with QoL.

Conclusions: In TDPD, unilateral focused ultrasound thalamotomy appears safe from a cognitive, mood, and behavioral perspective. QoL and ADL significantly improved following surgery. Nonmotor symptoms and ADL were more closely associated with QoL than tremor severity.

Classification Of Evidence: This study provides Class II evidence that for patients with TDPD, unilateral focused ultrasound thalamotomy did not adversely change cognition, mood, or behavior at 3 months.
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http://dx.doi.org/10.1212/WNL.0000000000006279DOI Listing
October 2018

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

Neurology 2018 05 4;90(18):e1618-e1626. Epub 2018 Apr 4.

From the Departments of Neurology (M.J.B., S.A.S.) and Public Health Sciences (M.E.S.), University of Virginia; and Department of Radiology and Medical Imaging (J.C.B., T.J.D.), Division of Neuroradiology, University of Virginia Health System, Charlottesville.

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 Parkinson's 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 Parkinson's 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 ( = 0.002), RBD ( = 0.021), and excessive daytime sleepiness (EDS) ( = 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 ( = 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], = 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.
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http://dx.doi.org/10.1212/WNL.0000000000005421DOI Listing
May 2018

Selection of Normative Group Affects Rates of Mild Cognitive Impairment in Parkinson's Disease.

Mov Disord 2018 05 14;33(5):839-843. Epub 2018 Feb 14.

University of Virginia, Department of Neurology, Charlottesville, VA.

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

Methods: Cognitive data from 423 participants with Parkinson's disease were included (age = 61.7 [9.7], education = 15.6 [3.0]). Internal norms were calculated using the group mean and standard deviation of the healthy control group. Published norms were compared to the overall group mean of and to age-stratified norms from healthy controls for each neuropsychological test over 4 visits. Rates of mild cognitive impairment were calculated using established criteria.

Results: The use of internal norms resulted in lower standardized scores than published norms on all tests with the exception of memory and processing speed (P ≤ .001). Individuals were 1.5 to 2.1 times more likely to be diagnosed with mild cognitive impairment using internal norms than published norms.

Conclusions: Standardization approaches with cognitive data are not interchangeable. Selection of a normative comparison group impacts research and clinical interpretations of cognitive data. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992013PMC
May 2018

Capgras Syndrome in Advanced Parkinson's Disease.

J Neuropsychiatry Clin Neurosci 2018 14;30(2):160-163. Epub 2017 Nov 14.

From the Department of Neurology, University of Virginia, Charlottesville, Va. (CLG, SAS, GFW, MJB); the School of Medicine, University of Virginia, Charlottesville, Va. (AP); the Department of Physical Therapy, University of Virginia, Charlottesville, Va. (DSH); and the Department of Neurosurgery, University of Virginia, Charlottesville, Va. (WJE).

Psychosis is common in Parkinson's 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.
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http://dx.doi.org/10.1176/appi.neuropsych.17030052DOI Listing
September 2018

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

JAMA Neurol 2017 12;74(12):1412-1418

Department of Neurosurgery, University of Virginia Health Science Center, Charlottesville.

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.
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http://dx.doi.org/10.1001/jamaneurol.2017.3098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822192PMC
December 2017

Subjective Memory Change, Mood, and Cerebrovascular Risk Factors in Older African Americans.

J Geriatr Psychiatry Neurol 2017 Nov 27;30(6):324-330. Epub 2017 Sep 27.

1 Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Objective: Subjective memory change (SMC) in older individuals may represent a harbinger of cognitive decline. This study examined the factors associated with SMC in older African Americans (AA), who have greater risk of developing dementia. We predicted that symptoms of depression and anxiety, as well as the total number of cerebrovascular risk factors (tCVRFs), but not performances on objective memory measures, would be positively associated with SMC.

Methods: Ninety-six AA completed brief cognitive testing and answered questions about mood and memory at their primary care appointment. Vascular data were obtained from medical records.

Results: Symptoms of depression and anxiety, but not performances on objective memory measures, were positively associated with SMC, t(χ(1) = 16.55 and 12.94, respectively, both P < .001). In nondepressed participants, the tCVRF was important in distinguishing between those with and without SMC.

Conclusions: In older AA, symptoms of depression or anxiety were associated with SMC. In nondepressed AA, the tCVRFs were important in distinguishing between those with and without SMC.
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http://dx.doi.org/10.1177/0891988717732153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772652PMC
November 2017

Blood Pressure Variability and Cognitive Function Among Older African Americans: Introducing a New Blood Pressure Variability Measure.

Cogn Behav Neurol 2017 09;30(3):90-97

*Department of Epidemiology, Columbia University, New York, New York Departments of †Neurology and §Medicine, and ∥School of Nursing, University of Virginia, Charlottesville, Virginia ‡Department of Neurology, Korea University College of Medicine, Seoul, Republic of Korea.

Background: Although blood pressure (BP) variability has been reported to be associated with cognitive impairment, whether this relationship affects African Americans has been unclear. We sought correlations between systolic and diastolic BP variability and cognitive function in community-dwelling older African Americans, and introduced a new BP variability measure that can be applied to BP data collected in clinical practice.

Methods: We assessed cognitive function in 94 cognitively normal older African Americans using the Mini-Mental State Examination (MMSE) and the Computer Assessment of Mild Cognitive Impairment (CAMCI). We used BP measurements taken at the patients' three most recent primary care clinic visits to generate three traditional BP variability indices, range, standard deviation, and coefficient of variation, plus a new index, random slope, which accounts for unequal BP measurement intervals within and across patients.

Results: MMSE scores did not correlate with any of the BP variability indices. Patients with greater diastolic BP variability were less accurate on the CAMCI verbal memory and incidental memory tasks. Results were similar across the four BP variability indices.

Conclusions: In a sample of cognitively intact older African American adults, BP variability did not correlate with global cognitive function, as measured by the MMSE. However, higher diastolic BP variability correlated with poorer verbal and incidental memory. By accounting for differences in BP measurement intervals, our new BP variability index may help alert primary care physicians to patients at particular risk for cognitive decline.
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http://dx.doi.org/10.1097/WNN.0000000000000128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663453PMC
September 2017

Characteristics, correlates, and assessment of psychosis in Parkinson disease without dementia.

Parkinsonism Relat Disord 2017 Oct 15;43:56-60. Epub 2017 Jul 15.

Department of Neurology, University of Virginia, Charlottesville, VA, USA. Electronic address:

Introduction: Considering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia.

Methods: 101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied.

Results: Of the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis.

Conclusion: This study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.
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http://dx.doi.org/10.1016/j.parkreldis.2017.07.011DOI Listing
October 2017

Health Variables Are Informative in Screening for Mild Cognitive Impairment Among Elderly African Americans.

J Appl Gerontol 2019 10 29;38(10):1421-1444. Epub 2017 May 29.

2 University of Virginia, Charlottesville, USA.

To aid primary care providers in identifying people at increased risk for cognitive decline, we explored the relative importance of health and demographic variables in detecting potential cognitive impairment using the Mini-Mental State Examination (MMSE). Participants were 94 older African Americans coming to see their primary care physicians for reasons other than cognitive complaints. Education was strongly associated with cognitive functioning. Among those with at least 9 years of education, patients with more vascular risk factors were at greater risk for mild cognitive impairment. For patients with fewer than 9 years of education, those with fewer prescribed medications were at increased risk for dementia. These results suggest that in addition to the MMSE, primary care physicians can make use of patients' health information to improve identification of patients at increased risk for cognitive impairment. With improved identification, physicians can implement strategies to mitigate the progression and impact of cognitive difficulties.
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http://dx.doi.org/10.1177/0733464817711961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773399PMC
October 2019

Cognitive Function and Vascular Risk Factors Among Older African American Adults.

J Immigr Minor Health 2018 Jun;20(3):612-618

Department of Neurology, Memory Disorders Clinic, University of Virginia, Charlottesville, VA, USA.

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.
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http://dx.doi.org/10.1007/s10903-017-0583-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645214PMC
June 2018

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

Clin Neuropsychol 2017 Jul 10;31(5):817-828. Epub 2017 Apr 10.

g Department of Veterans Affairs Medical Center , Memphis , TN , USA.

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.
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http://dx.doi.org/10.1080/13854046.2017.1314017DOI Listing
July 2017

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

J Geriatr Psychiatry Neurol 2017 May 28;30(3):178-183. Epub 2017 Mar 28.

1 Department of Neurology, University of Virginia, Charlottesville, VA, USA.

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.
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http://dx.doi.org/10.1177/0891988717701001DOI Listing
May 2017

Assessment of the internal structure of Computer-based Assessment of Memory and Cognitive Impairment.

Psychogeriatrics 2017 May 30;17(3):204-205. Epub 2016 Jun 30.

Department of Neurology, School of Medicine, University of Virginia, Charlottesville, Virginia, USA.

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http://dx.doi.org/10.1111/psyg.12210DOI Listing
May 2017

A pilot study of focused ultrasound thalamotomy for essential tremor.

N Engl J Med 2013 Aug;369(7):640-8

Department of Neurosurgery, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.

Background: Recent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor.

Methods: From February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. We recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. We assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100%, with higher scores indicating greater perceived disability).

Results: Thermal ablation of the thalamic target occurred in all patients. Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesias in four patients. Scores for hand tremor improved from 20.4 at baseline to 5.2 at 12 months (P=0.001). Total tremor scores improved from 54.9 to 24.3 (P=0.001). Disability scores improved from 18.2 to 2.8 (P=0.001). Quality-of-life scores improved from 37% to 11% (P=0.001).

Conclusions: In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy. Large, randomized, controlled trials will be required to assess the procedure's efficacy and safety. (Funded by the Focused Ultrasound Surgery Foundation; ClinicalTrials.gov number, NCT01304758.).
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http://dx.doi.org/10.1056/NEJMoa1300962DOI Listing
August 2013
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