Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Relationship of Movement Disorders Society-Unified Parkinson's Disease Rating Scale Nonmotor Symptoms to Cognitive Functioning in Patients with Parkinson's Disease.

BACKGROUND: Few studies assess the relationships between nonmotor aspects of experiences of daily living and cognitive functioning in Parkinson's disease (PD). OBJECTIVE: To evaluate the relationships among the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I items and neuropsychological tests in PD.Methods: We assessed 151 PD patients with the MDS-UPDRS part I and a battery of cognitive tests focused on the following 5 cognitive domains: attention/working memory, executive functioning, recent memory, language, visuoperception. Raw scores for individual cognitive tests were transformed to z scores, and cognitive domain scores were calculated by averaging z scores within each domain. Individual items from the MDS-UPDRS part I were entered in a stepwise linear regression analysis assessing item contribution to cognitive domain scores. RESULTS: The MDS-UPDRS part I item scores for hallucinations and psychosis and light headedness on standing predicted attention/working memory domain scores (P = 0.004). These same item scores, along with apathy, depressed mood, and dopamine dysregulation syndrome, predicted executive functioning (P = 0.044). The apathy and dopamine dysregulation syndrome items predicted language (P = 0.006). In addition, the cognitive impairment and sleep items were predictors of recent memory (P = 0.031). None of the items were predictors of visuoperception (P = 0.006). Other part I items were not significantly related to cognitive domain scores. CONCLUSIONS: Specific nonmotor MDS-UPDRS part I items, particularly mood, behavior, and autonomic-related items, exhibited significant relationships with cognitive domains. The highest number of items were predictive of the executive functioning domain, which is the hallmark cognitive dysfunction in PD.

The effects of dual-task cognitive interference on gait and turning in Huntington's disease.

Huntington's disease (HD) is characterized by motor, cognitive, and psychiatric dysfunction. HD progression causes loss of automaticity, such that previously automatic tasks require greater attentional resources. Dual-task (DT) paradigms and fast-paced gait may stress the locomotor system, revealing deficits not seen under single-task (ST). However, the impact of gait "stress tests" on HD individuals needs further investigation. Therefore, the aims of this study were to investigate whether: 1) fast-paced and dual-task walking uncover deficits in gait and turning not seen under single-task, 2) cognitive and gait outcomes relate to fall incidence, and 3) gait deficits measured with wearable inertial sensors correlate with motor symptom severity in HD as measured by the Unified Huntington's disease Rating Scale-total motor score (UHDRS-TMS). Seventeen HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative gait testing via a 25m, two-minute walk test with APDMTM inertial sensors. Gait was assessed under a 1) ST, self-selected pace, 2) fast-as-possible (FAP) pace, and 3) verbal fluency DT. The UHDRS-TMS and a cognitive test battery were administered, and a retrospective fall history was obtained. During ST, DT, and FAP conditions, HD participants demonstrated slower gait, shorter stride length, and greater lateral step and stride length variability compared to controls (p<0.00001 to 0.034). Significant dual-task costs (DTC) were observed for turns; HD participants took more time (p = 0.013) and steps (p = 0.028) to complete a turn under DT compared to controls. Higher UHDRS-TMS correlated with greater stride length variability, less double-support, and more swing-phase time under all conditions. Decreased processing speed was associated with increased gait variability under ST and FAP conditions. Unexpectedly, participant's self-reported falls did not correlate with any gait or turn parameters. HD participants demonstrated significantly greater DTC for turning, which is less automatic than straight walking, requiring coordination of body segments, anticipatory control, and cortical regulation. Turn complexity likely makes it more susceptible to cognitive interference in HD.

The Effects of Dual-Task Cognitive Interference and Environmental Challenges on Balance in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is characterized by chorea, balance and gait impairments, and cognitive deficits, which increase fall risk. Dual task (DT) and environmentally challenging paradigms reflect balance related to everyday life. Furthermore, the impact of cognitive deficits on balance dysfunction and falls in HD is unknown. OBJECTIVE: To determine the impact of DT interference, sensory feedback, and cognitive performance on balance and falls in HD. METHODS: Seventeen participants with HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative balance testing with APDM inertial sensors. Postural sway was assessed during conditions of manipulated stance, vision, proprioception, and cognitive demand. The DT was a concurrent verbal fluency task. Neuropsychological assessments testing multiple cognitive domains were also administered. RESULTS: HD participants exhibited significantly greater total sway area, jerk, and variability under single-task (ST) and DT conditions compared to controls (P = 0.0002 - < 0.0001). They also demonstrated greater DT interference with vision removed for total sway area (P = 0.01) and variability (P = 0.02). Significantly worse postural control was observed in HD with vision removed and reduced proprioception (P = 0.001 - 0.01). Decreased visuospatial performance correlated with greater total sway and jerk (P = 0.01; 0.009). No balance parameters correlated with retrospective falls in HD. CONCLUSIONS: HD participants have worse postural control under DT, limited proprioception/vision, and greater DT interference with a narrowed base and no visual input. These findings may have implications for designing motor and cognitive strategies to improve balance in HD.

Cognitive function impacts gait, functional mobility and falls in fragile X-associated tremor/ataxia syndrome.

BACKGROUND: Executive function and information processing speed deficits occur in fragile X premutation carriers (PMC) with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Gait is negatively impacted by cognitive deficits in many patient populations resulting in increased morbidity and falls but these relationships have not been studied in FXTAS. RESEARCH QUESTION: We sought to investigate the associations between executive function and information processing speed and gait, turning and falls in PMC with and without FXTAS compared to healthy controls. METHODS: Global cognition and the cognitive domains of information processing speed, attention, response inhibition, working memory and verbal fluency were tested with a neuropsychological test battery in 18 PMC with FXTAS, 15 PMC without FXTAS, and 27 controls. An inertial sensor based instrumented Timed Up and Go was employed to test gait, turns and functional mobility. RESULTS: Lower information processing speed was significantly associated with shorter stride length, reflecting slower gait speed, in PMC with FXTAS (p = 0.0006) but not PMC without FXTAS or controls. Lower response inhibition was also significantly associated with slower turn-to-sit times in PMC with FXTAS (p = 0.034) but not in those without FXTAS or controls. Lower information processing speed (p = 0.012) and working memory (p = 0.004), were significantly correlated with a greater number of self-reported falls in the past year in FXTAS participants. SIGNIFICANCE: This is the first study demonstrating that worse executive function and slower information processing speed is associated with reduced gait speed and functional mobility, as well as with a higher retrospective fall history in participants with FXTAS. This information may be important in the design of cognitive and motor interventions for this neurodegenerative disorder.

Corpus callosal atrophy and associations with cognitive impairment in Parkinson disease.

OBJECTIVE: To investigate atrophy of the corpus callosum on MRI in Parkinson disease (PD) and its relationship to cognitive impairment. METHODS: One hundred patients with PD and 24 healthy control participants underwent clinical and neuropsychological evaluations and structural MRI brain scans. Participants with PD were classified as cognitively normal (PD-NC; n = 28), having mild cognitive impairment (PD-MCI; n = 47), or having dementia (PDD; n = 25) by Movement Disorder Society criteria. Cognitive domain (attention/working memory, executive function, memory, language, visuospatial function) z scores were calculated. With the use of FreeSurfer image processing, volumes for total corpus callosum and its subsections (anterior, midanterior, central, midposterior, posterior) were computed and normalized by total intracranial volume. Callosal volumes were compared between participants with PD and controls and among PD cognitive groups, covarying for age, sex, and PD duration and with multiple comparison corrections. Regression analyses were performed to evaluate relationships between callosal volumes and performance in cognitive domains. RESULTS: Participants with PD had reduced corpus callosum volumes in midanterior and central regions compared to healthy controls. Participants with PDD demonstrated decreased callosal volumes involving multiple subsections spanning anterior to posterior compared to participants with PD-MCI and PD-NC. Regional callosal atrophy predicted cognitive domain performance such that central volumes were associated with the attention/working memory domain; midposterior volumes with executive function, language, and memory domains; and posterior volumes with memory and visuospatial domains. CONCLUSIONS: Notable volume loss occurs in the corpus callosum in PD, with specific neuroanatomic distributions in PDD and relationships of regional atrophy to different cognitive domains. Callosal volume loss may contribute to clinical manifestations of PD cognitive impairment.

Sildenafil in the Treatment of Erectile Dysfunction in Parkinson's Disease.

BACKGROUND: Erectile dysfunction (ED) is a common nonmotor feature in patients with Parkinson's disease (PD). Data regarding the tolerability and efficacy of anti-ED medication in the PD population are limited. The aim of this work was to assess the safety and efficacy of sildenafil in treatment of ED in men with PD. METHODS: This was a double-blind, placebo-controlled, cross-over study consisting of two 4-week arms separated by a 2-week washout period. Treatment sequence (placebo-sildenafil vs. sildenafil-placebo) was randomized. Sildenafil was started at 50 mg and adjusted to 25, 50, or 100 mg after 2 weeks, depending upon side effects. The Erectile Function domain of the International Index of Erectile Function (IIEF-EF; primary outcome measure) and the Parkinson's Disease Quality of Life (secondary outcome measure) were obtained at baseline and end of each treatment period. The UPDRS was obtained at each study visit. The difference between group means was tested for statistical significance using t tests. RESULTS: Twenty men participated and completed both treatment arms of the study. There was one instance of headache as a side effect. There was a significant effect of sildenafil on sexual functioning as measured by the IIEF-EF domain (P < 0.0001; mean for sildenafil = 23.2 ± 7.0; mean for placebo = 12.3 ± 7.5). There were no treatment effects for quality of life (P = 0.3) or PD symptoms (P = 0.86). CONCLUSIONS: Sildenafil was safe and improved ED in this sample of men with PD. Overall, PD symptoms and quality of life were not impacted by use of sildenafil.

Global cognitive function and processing speed are associated with gait and balance dysfunction in Parkinson's disease.

BACKGROUND: Our primary objective was to determine the relationship between global cognitive function and specific domains of gait and balance in a cohort of Parkinson's disease (PD) subjects. In a secondary analysis, we determined whether specific cognitive domains correlated with gait and balance performance. METHODS: Fourteen PD subjects (mean age 61.1 ± 7.8 years) were recruited from the Rush University Medical Center Movement Disorders clinic. Subjects underwent clinical assessment using the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS) followed by quantitative gait and balance assessments using the APDM Mobility Lab™ system (Mobility Lab, APDM Inc., Portland, OR). Subjects completed global cognitive testing using the Mattis Dementia Rating Scale (MDRS) as well as domain specific cognitive measures. Spearman's rho was used to assess correlations between cognitive measures and gait and balance function, with False Discovery Rate (FDR) correction for multiple comparisons. RESULTS: Global cognitive function had the strongest correlation with stride velocity (r = 0.816, p = 0.001), turn duration (r = -0.806, p = 0.001), number of steps to turn (r = -0.830, p = 0.001), and mean velocity of postural sway in the medio-lateral direction (r = -0.726, p = 0.005). A significant correlation was found between processing speed and two turning measures (turn duration, r = -0.884, p = 0.001; number of steps to turn, r = -0.954, p < 0.001), but no other associations were found between specific cognitive domains and gait domains. CONCLUSIONS: This pilot study provides preliminary data regarding the association between global cognitive function and pace-related measures of gait, turning, and postural sway. Furthermore, reduced processing speed was found to be associated with difficulty in performing turns.

Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

IMPORTANCE: Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. OBJECTIVE: To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. DESIGN, SETTING, AND PARTICIPANTS: The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. MAIN OUTCOMES AND MEASURES: Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. RESULTS: Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (ß = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (ß = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (ß = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (ß = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (ß = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia. CONCLUSIONS AND RELEVANCE: GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease.

BACKGROUND: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. METHODS: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. RESULTS: Mutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10(-6) ; E326K, odds ratio = 6.4; P = 5.7 × 10(-7) ) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc ] = 9.0 × 10(-4) ; E326K, Pc = 0.036), Trail Making B-A (mutations, Pc = 0.018; E326K, Pc = 0.018), and Benton Judgment of Line Orientation (mutations, Pc = 0.0045; E326K, Pc = 0.0013). CONCLUSIONS: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

Cognitive profile of LRRK2-related Parkinson's disease.

BACKGROUND: Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized. METHODS: A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models. RESULTS: LRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter-Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03). CONCLUSIONS: Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society.

The Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease (CAPSIT-PD): Tolerability of Preoperative Neuropsychological Testing for Deep Brain Stimulation in Parkinson's Disease.

OBJECTIVE: We examined tolerability of preoperative neuropsychological testing (the Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease [CAPSIT-PD] protocol) for DBS. We also examined factors that may influence tolerability, including fatigue, global cognitive function, depression, and patient-based characteristics. METHODS: In this retrospective study, we reviewed preoperative neuropsychological testing results from 35 patients who were scheduled to undergo DBS. We examined the overall tolerability of the full battery and the tolerability of each test. We placed attention on a test's placement in the fixed order of the battery to measure whether there was a clustering of poorly tolerated tests toward the end of the battery as an indication of fatigue. Spearman's rank correlation was used to determine the relationship between tolerability and (1) global cognitive function, (2) depression, and (3) patient-based characteristics. RESULTS: Fourteen subjects (40%) were able to tolerate the full battery and completed all 10 tests. The domains that were least tolerated pertained to executive function and procedural memory. There was a consistent time-based tolerability pattern that was observed. There was a significant correlation between tolerability and global cognitive function (ρ = 0.344; P = 0.043), but not depression (P = 0.197). There was a significant correlation between tolerability and age (ρ = -0.491; P = 0.003) and disease duration (ρ = -0.442; P = 0.008), but not UPDRS-III scores (P = 0.284). CONCLUSION: Our results have shown limited tolerability of the full neuropsychological battery as outlined by the CAPSIT-PD protocol. We suggest the consideration of updating the neuropsychological assessment used in the CAPSIT-PD protocol.

Diagnosing PD-MCI by MDS Task Force criteria: how many and which neuropsychological tests?

BACKGROUND: The optimal properties of a comprehensive (level II) neuropsychological battery for determining Parkinson's disease mild cognitive impairment (PD-MCI) by Movement Disorder Society (MDS) Task Force criteria remain unresolved. METHODS: Seventy-six nondemented PD patients underwent PD-MCI classification using a consensus diagnosis and level II criteria. We examined the optimal number of tests in each of the five designated cognitive domains, identified the best tests within each domain, and determined the best overall battery for PD-MCI level II diagnosis. RESULTS: A battery with two tests per domain provided a highly practical, robust diagnostic assessment. Level II testing with the two best tests and impairment defined as 2 standard deviations below norms was highly sensitive and specific for PD-MCI diagnosis. CONCLUSIONS: Our findings strongly support the MDS Task Force Level II testing recommendations, provide a framework for creating an optimal, efficient neuropsychological test battery for PD-MCI diagnosis, and offer specific test recommendations.

New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype.

PURPOSE: Fragile X-associated tremor/ataxia syndrome (FXTAS) was originally defined as tremor, ataxia, cognitive decline, and parkinsonism in individuals who carry between 55 and 200 CGG repeats in the promoter region of the fragile X mental retardation 1 (FMR1) gene. This paper describes a series of patients who meet the definition of FXTAS who presented for care between 2009 and 2014. METHODS/RESULTS: Retrospective chart review of patients seen in the FXTAS clinic at Rush University in Chicago. CONCLUSIONS: Patients with FXTAS may present with a progressive supranuclear palsy-like phenotype and other eye movement abnormalities are common in these patients as well. Rapid worsening of gait abnormalities in FXTAS may be due to a secondary spinal issue and should be aggressively treated to regain function. Finally, the FXTAS Rating Scale score does not reliably inform the certainty of diagnosis or CGG repeat size in these patients.

Comparison of the Movement Disorder Society Parkinson's disease dementia criteria with neuropsychological testing.

The objective of our study was to compare Movement Disorder Society Task Force criteria for diagnosis of Parkinson's disease dementia (PDD) with the gold standard of traditional neuropsychological testing. A short checklist (Level I) and a protocol of neuropsychological tests (Level II) have been proposed by a Movement Disorder Society Task Force but not fully validated in clinical practice. Ninety-one Parkinson's disease (PD) subjects were categorized as having dementia or no dementia based on a battery of neuropsychological test results and clinical judgment. The isolated components needed for Level I and Level II diagnoses were then culled from the neuropsychological evaluations and independently used to designate PDD. Compared with traditional neuropsychological testing, the sensitivity and specificity of Level I criteria for PDD was 66.7% and 98.8%, and for Level II criteria 100% and 92.7%, respectively. Using Level II criteria, 6 additional subjects were diagnosed with PDD that were classified as having no dementia when full neuropsychological data were used for the diagnosis. These 6 subjects had more education years and were less impaired on cognitive tests. The Movement Disorder Society's Level II criteria more frequently classify subjects with PDD than does traditional neuropsychological testing. Whereas Level II criteria may overclassify subjects as having PDD, they are very accurate in ruling out dementia. Movement Disorder Society's criteria are practical and timesaving, although full neuropsychological testing may still be needed.

Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson's disease with hallucinations.

Visual hallucinations are frequent, disabling complications of advanced Parkinson's disease, but their neuroanatomical basis is incompletely understood. Previous structural brain magnetic resonance imaging studies suggest volume loss in the mesial temporal lobe and limbic regions in subjects with Parkinson's disease with visual hallucinations, relative to those without visual hallucinations. However, these studies have not always controlled for the presence of cognitive impairment or dementia, which are common co-morbidities of hallucinations in Parkinson's disease and whose neuroanatomical substrates may involve mesial temporal lobe and limbic regions. Therefore, we used structural magnetic resonance imaging to examine grey matter atrophy patterns associated with visual hallucinations, comparing Parkinson's disease hallucinators to Parkinson's disease non-hallucinators of comparable cognitive function. We studied 50 subjects with Parkinson's disease: 25 classified as current and chronic visual hallucinators and 25 as non-hallucinators, who were matched for cognitive status (demented or non-demented) and age (± 3 years). Subjects underwent (i) clinical evaluations; and (ii) brain MRI scans analysed using whole-brain voxel-based morphometry techniques. Clinically, the Parkinson's disease hallucinators did not differ in their cognitive classification or performance in any of the five assessed cognitive domains, compared with the non-hallucinators. The Parkinson's disease groups also did not differ significantly in age, motor severity, medication use or duration of disease. On imaging analyses, the hallucinators, all of whom experienced visual hallucinations, exhibited grey matter atrophy with significant voxel-wise differences in the cuneus, lingual and fusiform gyri, middle occipital lobe, inferior parietal lobule, and also cingulate, paracentral, and precentral gyri, compared with the non-hallucinators. Grey matter atrophy in the hallucinators occurred predominantly in brain regions responsible for processing visuoperceptual information including the ventral 'what' and dorsal 'where' pathways, which are important in object and facial recognition and identification of spatial locations of objects, respectively. Furthermore, the structural brain changes seen on magnetic resonance imaging occurred independently of cognitive function and age. Our findings suggest that when hallucinators and non-hallucinators are similar in their cognitive performance, the neural networks involving visuoperceptual pathways, rather than the mesial temporal lobe regions, distinctively contribute to the pathophysiology of visual hallucinations and may explain their predominantly visual nature in Parkinson's disease. Identification of distinct structural MRI differences associated with hallucinations in Parkinson's disease may permit earlier detection of at-risk patients and ultimately, development of therapies specifically targeting hallucinations and visuoperceptive functions.

Immediate vs. delayed treatment of psychogenic movement disorders with short term psychodynamic psychotherapy: randomized clinical trial.

OBJECTIVE: In subjects with psychogenic movement disorders (PMDs), we conducted a 6 month randomized, cross-over design study to assess the effect of 3 months of psychodynamic psychotherapy followed by observation by the neurologist vs. observation by the neurologist, then 3 months of psychiatric intervention. BACKGROUND: PMDs are often disabling but no uniformly successful treatment strategies have been identified. Short term, open label psychodynamic psychotherapy has been successful in improving PMDs but whether PMDs improve equally well with neurological observation and support has not been tested. DESIGN: Fifteen patients with PMDs were randomized to immediate vs. delayed (after 3 months) weekly psychodynamic psychotherapy for 12 weeks. During the phase without psychiatric intervention, they were monitored by the treating neurologist. Patients were assessed at baseline, 3 and 6 months. Change in their movement disorder was assessed using a clinical global impression scale change (CGI-c), depression and anxiety using the Hamilton Depression Scale (HAM-D) and Beck Anxiety Inventory (Beck-A). RESULTS: Fourteen women and one man, age 42.3 ± 11, disease duration 63.2 ± 73 months, were randomized to immediate (7 patients) or delayed (8 patients) treatment. Over the six month study, PMDs, depression and anxiety were significantly improved but time was the determinant factor without an independent effect of treatment assignment. CONCLUSION: In this group of PMD patients, where patients were kept within the medical system and involved in a research program, PMDs as well as depression and anxiety improved, but without specific benefit time-linked to psychotherapy as opposed to neurological observation and support.

Defining optimal cutoff scores for cognitive impairment using Movement Disorder Society Task Force criteria for mild cognitive impairment in Parkinson's disease.

The recently proposed Movement Disorder Society (MDS) Task Force diagnostic criteria for mild cognitive impairment in Parkinson's disease (PD-MCI) represent a first step toward a uniform definition of PD-MCI across multiple clinical and research settings. However, several questions regarding specific criteria remain unanswered, including optimal cutoff scores by which to define impairment on neuropsychological tests. Seventy-six non-demented PD patients underwent comprehensive neuropsychological assessment and were classified as PD-MCI or PD with normal cognition (PD-NC). The concordance of PD-MCI diagnosis by MDS Task Force Level II criteria (comprehensive assessment), using a range of standard deviation (SD) cutoff scores, was compared with our consensus diagnosis of PD-MCI or PD-NC. Sensitivity, specificity, and positive and negative predictive values were examined for each cutoff score. PD-MCI subtype classification and distribution of cognitive domains impaired were evaluated. Concordance for PD-MCI diagnosis was greatest for defining impairment on neuropsychological tests using a 2 SD cutoff score below appropriate norms. This cutoff also provided the best discriminatory properties for separating PD-MCI from PD-NC compared with other cutoff scores. With the MDS PD-MCI criteria, multiple domain impairment was more frequent than single domain impairment, with predominant executive function, memory, and visuospatial function deficits. Application of the MDS Task Force PD-MCI Level II diagnostic criteria demonstrates good sensitivity and specificity at a 2 SD cutoff score. The predominance of multiple domain impairment in PD-MCI with the Level II criteria suggests not only influences of testing abnormality requirements, but also the widespread nature of cognitive deficits within PD-MCI.