Differential Cognitive Effects of Unilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: The aim of this study was to investigate the cognitive effects of unilateral directional versus ring subthalamic nucleus deep brain stimulation (STN DBS) in patients with advanced Parkinson's disease. METHODS: We examined 31 participants who underwent unilateral STN DBS (left n = 17; right n = 14) as part of an National Institutes of Health (NIH)-sponsored randomized, double-blind, crossover study contrasting directional versus ring stimulation. All participants received unilateral DBS implants in the hemisphere more severely affected by motor parkinsonism. Measures of cognition included verbal fluency, auditory-verbal memory, and response inhibition. We used mixed linear models to contrast the effects of directional versus ring stimulation and implant hemisphere on longitudinal cognitive function. RESULTS: Crossover analyses showed no evidence for group-level changes in cognitive performance related to directional versus ring stimulation. Implant hemisphere, however, impacted cognition in several ways. Left STN participants had lower baseline verbal fluency than patients with right implants (t [20.66 = -2.50, p = 0.02]). Verbal fluency declined after left (p = 0.013) but increased after right STN DBS (p < 0.001), and response inhibition was faster following right STN DBS (p = 0.031). Regardless of hemisphere, delayed recall declined modestly over time versus baseline (p = 0.001), and immediate recall was unchanged. INTERPRETATION: Directional versus ring STN DBS did not differentially affect cognition. Similar to prior bilateral DBS studies, unilateral left stimulation worsened verbal fluency performance. In contrast, unilateral right STN surgery increased performance on verbal fluency and response inhibition tasks. Our findings raise the hypothesis that unilateral right STN DBS in selected patients with predominant right brain motor parkinsonism could mitigate declines in verbal fluency associated with the bilateral intervention. ANN NEUROL 2024;95:1205-1219.

Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease.

BACKGROUND: PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico-striato-pallido-thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications. OBJECTIVE: To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD). METHODS: Participants with idiopathic PD were administered the oral Symbol Digit Modalities Test (SDMT; n = 181) and the Stroop test (n = 172) in the off-medication and "best on" medication states. ANCOVA was used to test for differences between off-medication and on-medication scores corrected for age and years of education. RESULTS: After administration of symptomatic medications, scores worsened on the SDMT (F = 11.70, P < 0.001, d = -0.13), improved on the Stroop color (F = 26.89, P < 0.001, d = 0.184), word (F = 6.25, P = 0.013, d = 0.09), and color-word (F = 13.22, P < 0.001, d = 0.16) test components, and the Stroop difference and ratio-based interference scores did not significantly change. Longer disease duration correlated with lower scores on the SDMT, Stroop color, word, and color-word scores; however, longer disease duration and higher levodopa-equivalents correlated with higher Stroop difference-based interference scores. CONCLUSIONS: Symptomatic medication differentially affects performance on two cognitive tests in PD. After acute treatment, core Stroop measures improved, Stroop interference was unchanged, and SDMT performance worsened, likely reflecting complex changes in processing speed and executive function related to acute treatment. When considering motor symptom therapies in PD, an individual's cognitive demands and expectations, especially regarding executive function, should be considered.

Hope vs. Hype I: Spreading alpha-synuclein explains cognitive deficits in Parkinson disease.

The Parkinson Study Group (PSG) gathered North American experts in Parkinson disease during the 9th Annual Symposium on "Shaping the Management of Parkinson Disease: Debating Current Controversies". Debaters were tasked with agree or disagree positions to a particular prompt. This is the first in three-part series of "Hype vs. Hope" debates involving current trends and advances in Parkinson disease. With the prompt of "Spreading alpha-synuclein explains cognitive deficits in Parkinson disease," Dr. Kelly Mills, MD, MHS was tasked with the "agree" stance and Dr. Abhimanyu Mahajan, MD, MHS was tasked with the "disagree" stance. The following point-of-view article is an adaptation of this debate.

The Association of Antidepressant Use and Impulse Control Disorder in Parkinson's Disease.

OBJECTIVES: To examine whether initiation of an antidepressant is associated with the development of impulse control disorder (ICD) in patients with Parkinson's disease (PD). DESIGN: We performed a retrospective analysis utilizing data from the Parkinson's Progression Markers Initiative (PPMI). Two-sample Mann-Whitney tests were used for comparison of continuous variables and Pearson χ2 tests were used for categorical variables. Kaplan-Meier survival analysis and cox proportional hazards regression analysis was used to assess the hazard of ICD with antidepressant exposure. SETTING: The PPMI is a multicenter observational study of early PD with 52 sites throughout North America, Europe, and Africa. PARTICIPANTS: Participants in the current study were those in the PPMI PD cohort with a primary diagnosis of idiopathic PD. MEASUREMENTS: The presence of ICD was captured using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Antidepressant use was defined based on medication logs for each participant. Depressive symptoms were captured using the Geriatric Depression Scale (GDS). RESULTS: A total of 1,045 individuals were included in the final analysis. There was a significant increase in the probability of ICD in those exposed to serotonergic antidepressants compared to those not exposed (Log-rank p <0.001). Serotonergic antidepressant use was associated with a hazard ratio for ICD of 1.4 (95% CI 1.0-1.8, z-value 2.1, p = 0.04) after adjusting for dopamine agonist use, depression, bupropion use, MAOI-B use, amantadine use, LEDD, disease duration, sex, and age. CONCLUSIONS: Serotonergic antidepressant use appears to be temporally associated with ICD in patients with PD.

Exploring [11C]CPPC as a CSF1R-targeted PET Imaging Marker for Early Parkinson's Disease Severity.

Neuroinflammation through enhanced innate immunity is thought play a role in the pathogenesis of Parkinson's disease (PD). Methods for monitoring neuroinflammation in living patients with PD are currently limited to positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. The colony stimulating factor 1 receptor (CSF1R) plays a crucial role in microglial function, an important cellular contributor to the nervous system's innate immune response. Using immunologic methods, we show that CSF1R in human brain is colocalized with the microglial marker, ionized calcium binding adaptor molecule 1 (Iba1). In PD, CSF1R immunoreactivity is significantly increased in PD across multiple brain regions, with the largest differences in the midbrain versus controls. Autoradiography revealed significantly increased [3H]JHU11761 binding in the inferior parietal cortex of PD patients. PET imaging demonstrated that higher [11C]CPPC binding in the striatum was associated with greater motor disability in PD. Furthermore, increased [11C]CPPC binding in various regions correlated with more severe motor disability and poorer verbal fluency. This study finds that CSF1R expression is elevated in PD and that [11C]CPPC-PET imaging of CSF1R is indicative of motor and cognitive impairments in the early stages of the disease. Moreover, the study underscores the significance of CSF1R as a promising biomarker for neuroinflammation in Parkinson's disease, suggesting its potential use for non-invasive assessment of disease progression and severity, leading to earlier diagnosis and targeted interventions.

Minor Phenomena in Parkinson's Disease-Prevalence, Associations, and Risk of Developing Psychosis.

BACKGROUND: Minor phenomena, including passage phenomena, feeling of presence, and illusions, are common and may represent a prodromal form of psychosis in Parkinson's disease (PD). We examined the prevalence and clinical correlates of minor phenomena, and their potential role as a risk factor for PD psychosis. METHODS: A novel questionnaire, the Psychosis and Mild Perceptual Disturbances Questionnaire for PD (PMPDQ), was completed by Fox Insight cohort participants with and without PD. Additional assessments included the Non-Motor Symptoms Questionnaire (NMSQuest), REM Sleep Behavior Disorder Single Question Screen (RBD1Q), Movement Disorder Society-Unified Parkinson Disease Rating Scale Part II, demographic features, and medication usage. For participants with PD, we used regression models to identify clinical associations and predictors of incident psychosis over one year of follow-up. RESULTS: Among participants with PD (n = 5950) and without PD (n = 1879), the prevalence of minor phenomena was 43.1% and 31.7% (P < .001). Of the 3760 participants with PD and no baseline psychosis, independent correlates of minor phenomena included positive responses on the NMSQuest apathy/attention/memory (OR 1.7, 95% CI 1.3-2.1, P < .001) or sexual function domain (OR 1.3, 95% CI 1.1-1.6, P = .01) and positive RBD1Q (OR 1.3, 95% CI 1.05-1.5, P = .01). Independent risk factors for incident PD psychosis included the presence of minor phenomena (HR 3.0, 95% CI 2.4-3.9, P < .001), positive response on the NMSQuest apathy/attention/memory domain (HR 1.8, 95% CI 1.3-2.6, P < .001), and positive RBD1Q (HR 1.5, 95% CI 1.1-1.9, P = .004). CONCLUSIONS: Minor phenomena are common, associated with specific non-motor symptoms, and an independent predictor of incident psychosis in PD.

Anxiety Change After Dopamine Therapy in Parkinson Disease is Independent of Motor Improvement.

BACKGROUND: Several anxiety syndromes have been associated with Parkinson disease (PD), but their interactions with dopamine replacement therapy (DRT) and motor function dynamics are not completely understood. We sought to delineate how DRT impacts anxiety phenomenology in PD and whether these changes are dissociable from improved motoric function. METHODS: We compared anxiety responses to DRT in two cohorts: 1) a study of 200 PD participants who completed neuropsychiatric assessments before and after taking their dopaminergic medications ("On-Off"); 2) participants in the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort who completed the State-Trait Anxiety Inventory (STAI) at the time of DRT initiation and a subsequent study visit (n = 113, mean 8-month interval). RESULTS: Among On-Off participants transitioning acutely to the On-state, scores on the Hamilton anxiety rating scale decreased by 37% (t = 14.8, df = 199, p <0.0001). Among PPMI participants, STAI-state scores decreased by 10.4% following DRT initiation (t = 4.5, df = 112, p <0.0001). Item-level anxiety changes exhibited weak and nonsignificant correlations (Spearman ρ: -0.24 to 0.33) with objective MDS-UPDRS motor improvements in both immediate and sustained dopamine replacement contexts. CONCLUSION: Dopamine repletion effected immediate relief of anxiety in an On-Off state comparison. A similar benefit was observed in the longitudinal PPMI cohort by comparing anxiety before and after DRT initiation, suggesting DRT confers sustained anxiolytic effects in early PD. The weak correlations between improvements to anxiety and motor function on both timescales support the view that these changes are not mediated by improved motor function.

Anatomical substrates and connectivity for bradykinesia motor features in Parkinson's disease after subthalamic nucleus deep brain stimulation.

Parkinsonian bradykinesia is rated using a composite scale incorporating the slowed frequency of repetitive movements, decrement amplitude and arrhythmicity. Differential localization of these movement components within the basal ganglia will drive the development of more personalized network-targeted symptomatic therapies. In this study, using an optical motion sensor, we evaluated the amplitude and frequency of hand movements during a grasping task with subthalamic nucleus deep brain stimulation 'on' or 'off' in 15 patients with Parkinson's disease. The severity of bradykinesia was assessed blindly using the Unified Parkinson's Disease Rating Part III scale. The volumes of activated tissue of each subject were estimated where changes in amplitude and frequency were mapped to identify distinct anatomical substrates of each component in the subthalamic nucleus. The volumes of activated tissue were used to seed a normative functional connectome to generate connectivity maps associated with amplitude and frequency changes. Deep brain stimulation-induced change in amplitude was negatively correlated with a change in Unified Parkinson's Disease Rating Part III scale for right (r = -0.65, P < 0.05) and left hand grasping scores (r = -0.63, P < 0.05). The change in frequency was negatively correlated with amplitude for both right (r = -0.63, P < 0.05) and left hands (r = -0.57, P < 0.05). The amplitude and frequency changes were represented as a spatial gradient with overlapping and non-overlapping regions spanning the anteromedial-posterolateral axis of the subthalamic nucleus. Whole-brain correlation maps between functional connectivity and motor changes were also inverted between amplitude and frequency changes. Deep brain stimulation-associated changes in frequency and amplitude were topographically and distinctly represented both locally in the subthalamic nucleus and in whole-brain functional connectivity.

Examining the link between impulse control disorder and antidepressant use in Parkinson's disease.

INTRODUCTION: Impulse control disorders (ICD) in Parkinson's disease (PD) and hypomanic episodes of bipolar disorder show overlapping symptoms, suggesting a shared neurobiology. To explore this, the following hypotheses are tested: (1) larger changes in affective symptoms from OFF to ON medication states will be associated with ICD, (2) antidepressant exposure will be associated with larger OFF to ON affective symptom changes, and (3) antidepressant exposure will be associated with ICD. METHODS: 200 participants (mean age 65, 61 % male) were evaluated in "off" and "on" dopamine states. Affective symptoms were captured using the Hamilton Anxiety and Depression Rating Scales. Differences in clinical outcomes were compared using two-sample Wilcoxon rank-sum tests and Pearson χ2 tests. We performed multivariable logistic regression to assess the association of antidepressant exposure on ICD. RESULTS: Participants with an ICD had higher anxiety and depressive scores in "on" and "off" states and larger changes in depressive symptoms from OFF to ON states compared to those without an ICD. Participants on antidepressants had higher anxiety scores in "on" and "off" states, higher depressive scores in the "off" state, and larger changes in anxiety symptoms from OFF to ON states than those not on an antidepressant. Antidepressant use was associated with a higher odds of an ICD (OR 2.3, CI [1.0-4.5], p-value 0.04). CONCLUSIONS: Affective symptom severity in "on" and "off" dopamine states is associated with ICD. Antidepressant therapy may be associated with ICD. Future prospective studies clarifying temporal associations between antidepressant initiation and ICD emergence are needed.

Differential cognitive effects of unilateral left and right subthalamic nucleus deep brain stimulation for Parkinson disease.

Objective: To investigate hemispheric effects of directional versus ring subthalamic nucleus (STN) deep brain stimulation (DBS) surgery on cognitive function in patients with advanced Parkinson's disease (PD). Methods: We examined 31 PD patients (Left STN n = 17; Right STN n = 14) who underwent unilateral subthalamic nucleus (STN) DBS as part of a NIH-sponsored randomized, cross-over, double-blind (ring vs directional) clinical trial. Outcome measures were tests of verbal fluency, auditory-verbal memory, and response inhibition. First, all participants were pooled together to study the effects of directional versus ring stimulation. Then, we stratified the groups by surgery hemisphere and studied the longitudinal changes in cognition post-unilateral STN DBS. Results: Relative to pre-DBS cognitive baseline performances, there were no group changes in cognition following unilateral DBS for either directional or ring stimulation. However, assessment of unilateral DBS by hemisphere revealed a different pattern. The left STN DBS group had lower verbal fluency than the right STN group (t(20.66 = -2.50, p = 0.02). Over a period of eight months post-DBS, verbal fluency declined in the left STN DBS group (p = 0.013) and improved in the right STN DBS group over time (p < .001). Similarly, response inhibition improved following right STN DBS (p = 0.031). Immediate recall did not significantly differ over time, nor was it affected by implant hemisphere, but delayed recall equivalently declined over time for both left and right STN DBS groups (left STN DBS p = 0.001, right STN DBS differ from left STN DBS p = 0.794). Conclusions: Directional and ring DBS did not differentially or adversely affect cognition over time. Regarding hemisphere effects, verbal fluency decline was observed in those who received left STN DBS, along with the left and right STN DBS declines in delayed memory. The left STN DBS verbal fluency decrement is consistent with prior bilateral DBS research, likely reflecting disruption of the basal-ganglia-thalamocortical network connecting STN and inferior frontal gyrus. Interestingly, we found an improvement in verbal fluency and response inhibition following right STN DBS. It is possible that unilateral STN DBS, particularly in the right hemisphere, may mitigate cognitive decline.

Anatomical Substrates and Connectivity for Parkinson's Disease Bradykinesia Components after STN-DBS.

Background: Parkinsonian bradykinesia is rated using a composite scale incorporating slowed frequency of repetitive movements, decrement amplitude, and arrhythmicity. Differential localization of these movement components within basal ganglia would drive the development of more personalized network-targeted symptomatic therapies. Methods: Using an optical motion sensor, amplitude and frequency of hand movements during grasping task were evaluated with subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) "on" or "off" in 15 patients with Parkinson's disease (PD). The severity of bradykinesia was assessed blindly using the MDS-UPDRS Part-III scale. Volumes of activated tissue (VAT) of each subject were estimated where changes in amplitude and frequency were mapped to identify distinct anatomical substrates of each component in the STN. VATs were used to seed a normative functional connectome to generate connectivity maps associated with amplitude and frequency changes. Results: STN-DBS-induced change in amplitude was negatively correlated with change in MDS-UPDRS-III right (r = -0.65, p < 0.05) and left hand grasping scores (r = -0.63, p < 0.05). The change in frequency was negatively correlated with amplitude for both right (r = -0.63, p < 0.05) and left hand (r = -0.57, p < 0.05). The amplitude and frequency changes were represented as a spatial gradient with overlapping and non-overlapping regions spanning the dorsolateral-ventromedial axis of the STN. Whole-brain correlation maps between functional connectivity and motor changes were also inverted between amplitude and frequency changes. Conclusion: DBS-associated changes in frequency and amplitude were topographically and distinctly represented both locally in STN and in whole-brain functional connectivity.

Association of caregiver strain with the trajectory of quality of life in Parkinson's disease.

We aimed to identify caregiver characteristics associated with the trajectory of quality of life (QoL) in Parkinson's disease (PD). We fit a growth mixture model to longitudinal data from the Parkinson Foundation Parkinson's Outcomes Project (POP) to identify the heterogeneity of QOL trajectories in PD. We then used multinomial logistic regression to model baseline factors that predicted class membership. Baseline growth models were fit to QOL scores measured over 4 disease duration time points. A random intercept and slope model was determined to best fit the data. Next, growth mixture models (1, 2, 3, 4, and 5-class) were fit with covariates (Hoehn & Yahr, sex, and depression) and a three-class model was found to provide the best fit. Class 1 (problematic class (10.0%)) represented individuals with poor QOL at baseline and minor improvement over time. Class 2 (moderate class (32.6%)) represented individuals with moderate QOL at baseline with slight worsening over time. Class 3 (favorable class (56.9%)) represented individuals with good QOL at baseline and slight worsening over time. Multinomial regression revealed that lower caregiver strain, better mobility, and better verbal fluency at baseline predicted membership in the favorable compared to the moderate class. Worse mobility and younger age predicted membership in the problematic compared to the moderate class. While previous studies have reported on the association between mobility and cognition, the novel finding of an association between caregiver strain and PD QOL trajectory suggests caregiver strain is important to measure and address in future research and practice.

The impact of caregiving on quality of life in Parkinson's disease: A systematic review.

OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disease that can reduce quality of life (QOL). Previous research has explored patient specific factors that influence QOL; but understanding external factors that may also affect patient QOL, such as caregiver characteristics, can provide additional intervention targets that may improve QOL for both the person with PD and their caregiver. METHODS: We conducted a systematic review of existing literature on caregiver factors that are related to QOL for the person with PD. We developed a tailored search strategy in six databases and performed a screening procedure according to PRISMA guidelines. We synthesized findings from articles that met inclusion criteria using a narrative approach and identified themes categorizing caregiver factors associated with PD QOL. RESULTS: We found 32 full-text articles that fulfilled the inclusion criteria and passed the quality appraisal. Seven themes were identified, including: (1) burden, (2) strain, (3) QOL and satisfaction, (4) demographic factors, (5) psychological factors, (6) relationship factors, and (7) caregiver input. CONCLUSIONS: Our review presents critical insights into the role of the caregiver in the QOL of a person with PD. Findings reveal several targets for intervention to improve QOL in this population.

'Anxious fluctuators' a subgroup of Parkinson's disease with high anxiety and problematic on-off fluctuations.

Anxiety that occurs in association with on-off dopamine medication fluctuations is a major cause of distress, dysfunction, and lower quality of life in people with Parkinson's disease (PD). However, the association between anxiety and on-off fluctuations is poorly understood and it is difficult to predict which patients will suffer from this atypical form of anxiety. To understand whether fluctuating anxiety in PD exists as part of an endophenotype that is associated with other signs or symptoms, we prospectively assessed the change in anxiety and a battery of clinical variables when transitioning from the off-dopamine medication state to the on state in 200 people with PD. We performed latent profile analysis with observed variables as latent profile indicators measuring the on-off-state difference in anxiety, depression, motor function, daily functioning, and the wearing off questionnaire 19 item scale (WOQ-19) in order to model unobserved (i.e., latent) profiles. A two-class model produced the best fit. The majority of participants, 69%, were categorized as having a 'typical on-off response' compared to a second profile constituting 31% of the sample who experienced a worsening in anxiety in the off state that was three times that of other participants. This profile referred to as "anxious fluctuators" had a Hamilton Anxiety Rating Scale change between the off and on medication state of 10.22(32.85) compared to 3.27 (7.62), higher depression scores, greater disability and was less likely to improve on select WOQ-19 items when in the on-state. Anxious fluctuators were more likely to be male and have a family history of anxiety disorder. Given the adverse impact of this profile we believe it may be important to distinguish patients with a typical on-off response from those with this more problematic course of fluctuations.

Brain MRI and clinical exam findings in women with multiple gadolinium-based contrast agent (GBCA) exposures due to screening breast MRIs.

OBJECTIVES: Multiple exposures to gadolinium-based contrast agents (GBCAs) is known to be associated with gadolinium deposition in the brain in certain patients. Such deposition has been correlated with specific brain MRI findings, although most available data is in patients with underlying neurologic disorders. We aim to prospectively evaluate brain MRI signal changes as well as neurologic and neuropsychologic testing results in women undergoing screening breast MRI. METHODS: In this IRB-approved, HIPAA-compliant prospective study, 9 women with 5 or more exposures to linear and/or macrocyclic GBCA due to screening breast MRI underwent noncontrast brain MRI, neurologic exam and neuropsychologic testing. Women with underlying neurologic, psychologic, hepatic or renal disorders were excluded. RESULTS: The mean total number of GBCA exposures was 8 (standard deviation 2.7), with 63/72 (87%) of the exposures being linear agents. There was no association between brain MRI signal changes and abnormalities on neurologic or neuropsychologic examination. There was no association between total number of GBCA exposures and abnormalities on neurologic or neuropsychologic examination. CONCLUSION: In this prospective exploratory study of 9 women with 5 or more GBCA exposures due to screening breast MRI, there was no association between brain MRI signal changes and clinical abnormalities on neurologic or neuropsychologic examination. While larger studies are needed in this patient population, the lack of clinical impact of multiple GBCA exposures in this study is reassuring.

The association between educational attainment and SCA 3 age of onset and disease course.

BACKGROUND: The number of trinucleotide CAG repeats is inversely correlated with the age at onset (AAO) of motor symptoms in individuals with Spinocerebellar Ataxia type 3 (SCA 3) and may be responsible for 50%-60% of the variability in AAO. Drawing from a social determinants of health model, we sought to determine if educational attainment further contributes to the AAO and motor symptom progression of SCA 3. METHODS: We performed a retrospective chart review in which twenty individuals met criteria for inclusion and had been seen by an ataxia specialist at our hospital between January 2005 and July 2019. AAO of motor symptoms and Scale for Assessment and Rating of Ataxia (SARA) scores were used as primary outcome measures. RESULTS: Using a linear regression, we found that having greater CAG repeat length and greater than 16 years of education results in an earlier AAO. The importance of the CAG repeat length on AAO, however, is greater amongst individuals with lower education. Using a linear mixed model evaluating SARA score over time with AAO, we found that less than 16 years of education is associated with faster progression of the disease. CONCLUSION: In our group of SCA 3 patients, level of education correlated with both the AAO and SARA scores. Though our findings need to be confirmed with a larger cohort, our study suggests that level of education can have a strong influence on health outcomes in SCA 3 and possibly other groups of patients with ataxia.