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.

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.

Sex-Specific Neurocognitive Impairment.

This article explores sex-specific neurocognitive impairment. It first defines relevant terms such as gender and sex. Next, it describes the nature of the problem including under-representation of women and other gender and sexual minorities in neuroscience research, including cognitive studies. A biopsychosocial framework is employed to account for structural and social determinants of health in sex/gender-specific neurocognitive impairment. Issues in assessment including the use of gender/sex-specific normative data are also discussed. Lastly, the article covers the current state of research as it relates to sex/gender-specific neurocognitive impairment across a range of medical conditions including neurodegenerative diseases and coronavirus disease-2019.

Huntington Study Group's Neuropsychology Working Group: Implementing Non-Motor Diagnostic Criteria.

Background: The clinical diagnosis of manifest Huntington's disease (HD) relies on a high level of clinical confidence (99% confidence) of HD-consistent motor signs. Longitudinal data have reliably identified cognitive and behavioral dysfunction predating clinical motor diagnosis by up to 15 years. Reliance on motor signs to establish a diagnosis of HD increases risk of early misdiagnosis or delayed diagnosis. Clinical neuropsychologists are uniquely positioned to advise on the clinical application of the Movement Disorder Society Task Force's recently proposed non-motor diagnostic criteria for HD. Objectives: To provide (1) a recommended clinical approach toward non-motor diagnostic criteria in persons with HD and facilitation of accurate diagnosis; (2) recommended practices for medical treatment providers to screen and longitudinally monitor non-motor signs of HD. Methods: The Huntington Study Group re-established the Neuropsychology Working Group, then recruited a multi-disciplinary group of neuropsychologists, neurologists, and psychiatrists to conduct an unstructured literature review and discuss expert opinions on practice, to facilitate an informal consensus opinion to accomplish the objectives. Results: The opinion and an example protocol for medical treatment providers to screen, monitor, and triage non-motor signs and symptoms of Huntington's disease is provided. Conclusions: Clinical diagnosis of non-motor HD is empirically justified and clinically important. Screening and triage by non-neuropsychologist clinicians can aid in detecting and monitoring non-motor Huntington's disease manifestation. The Neuropsychology Working Group consensus advances good clinical practice, clinical research, and quality of life. A companion position paper presenting the details of our consensus opinion regarding evidence-based guidelines for neuropsychological practice is forthcoming.

Huntington study group's neuropsychology working group position on best practice recommendations for the clinical neuropsychological evaluation of patients with Huntington disease.

Objective: Neuropsychological evaluation is critical to detection and management of cognitive and neuropsychiatric changes associated with Huntington disease (HD). Accurate assessment of non-motor complications of HD is critical given the prominent impact on functional disability, frequently commensurate with or exceeding that of motor symptoms. The increasing emphasis on developing disease-modifying therapies targeting cognitive decline in HD requires consensus on clinical neuropsychological assessment methods. The Neuropsychology Working Group (NPWG) of the Huntington Study Group (HSG) sought to provide evidence and consensus-based, practical guidelines for the evaluation of cognitive and neuropsychiatric symptoms associated with HD. Method: The NPWG recruited a multi-disciplinary group of neuropsychologists, neurologists, and psychiatrists to inform best practices in assessing, diagnosing, and treating the non-motor symptoms in HD. A review was circulated among the NPWG, and in an iterative process informed by reviewed literature, best practices in neuropsychological evaluation of patients with HD were identified. Results: A brief review of the available literature and rational for a clinical consensus battery is offered. Conclusion: Clinical neuropsychologists are uniquely positioned to both detect and characterize the non-motor symptoms in HD, and further, provide neurologists and allied health professions with clinically meaningful information that impacts functional outcomes and quality of life. The NPWG provides guidance on best practices to clinical neuropsychologists in this statement. A companion paper operationalizing clinical application of previous research-based non-motor diagnostic criteria for HD is forthcoming, which also advises on non-motor symptom screening methods for the non-neuropsychologist working with HD.

Comparison of motor, non-motor, and quality of life phenotype in Black and White patients with Parkinson's disease.

OBJECTIVE: To determine phenotypic differences between Black and White patients with Parkinson's disease (PD). DESIGN/METHODS: Patients with PD in a movement disorders clinic were approached to participate. After consent, a battery of tests was completed, including MDS-UPDRS Part III and the motor domains of the NIH Toolbox, Montreal Cognitive Assessment, Single Digit Modality Test, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, Parkinson's Disease Questionnaire (PDQ39), Schwab and England, Epworth Sleepiness Scale, UPSIT smell test, and others. RESULTS: Twenty-four Black PD and 25 White PD patients participated. There were no differences in demographics and MDS-UPDRS Part III scores. White PD participants performed better on the 4-m walk gait speed test (p < 0.0005), standing balance test (p < 0.001), Montreal Cognitive Assessment (p < 0.0005), and Single Digit Modality Test (p < 0.005). Black PD participants had lower scores on PROMIS Satisfaction with Participation (p = 0.023), PROMIS Physical Function Mobility (p = 0.007), total PDQ39 (p = 0.008), PDQ39 mobility (p = 0.012), PDQ39 ADL (p = 0.014), PDQ39 cognition (p = 0.023), and PDQ39 body discomfort (p = 0.041) scales. CONCLUSIONS: Significant differences were found in motor, non-motor and quality of life scales in Black and White PD participants with similar demographics. Further work will need to be done to identify the underlying reasons and ways to mitigate these disparities.

Sex differences in the relationship of regional dopamine release to affect and cognitive function in striatal and extrastriatal regions using positron emission tomography and [¹8F]fallypride.

The purpose of this study was to examine sex differences in the correlations of d-amphetamine (d-AMPH) induced displacements of [¹8F]fallypride in striatal and extrastriatal regions in relation to affect and cognition. Seven male and six female healthy subjects, whose mean age was 25.9 years, underwent positron emission tomography (PET) with [¹8F]fallypride at baseline and 3 h after a 0.43 mg/kg oral dose of d-AMPH. Percent displacements in striatal and extrastriatal regions were calculated using regions of interest (ROI) analysis and on a pixel-by-pixel basis. Subjects underwent neuropsychological testing prior to the baseline PET study and one hour after d-AMPH administration for the second PET. In order to examine the subjective effect of d-AMPH, subjects rated PANAS at baseline and after administration of amphetamine. Correlations of changes in cognition and affect with regional dopamine (DA) release revealed several significant sex related differences. The results of this study demonstrate in vivo sex related differences in the relationship of regional DA release to affect and cognitive function.

Determinants of placebo effects.

Determinants of placebo effects and placebo response can be considered from multiple intrinsic and extrinsic perspectives. Intrinsic factors may influence the patient and the clinician/researcher. Patient expectations and previous experiences are considered two of the major intrinsic determinants of placebo response. Other patient determinants include the neural systems under treatment/study, situational factors and reactions to the environment, and personality traits. Clinician/researcher determinants of placebo response include personality factors such as empathy, perceived expertise, the clinical relationship with the patient, and the clinician's belief in the efficacy of the treatment. Extrinsic determinants include the type of study design, influence of advertising or branding, and forces expressed by the cultural milieu. These determinants do not act in isolation, but rather form a complex interaction that ultimately impacts the promotion or deterrence of the placebo effect in clinical and research settings.

Parkinson's Disease in African Americans: A Review of the Current Literature.

Parkinson's disease (PD) is the second most common neurodegenerative disease, though evidence suggests that this disorder does not affect all racial groups similarly. Research in African Americans, in particular, has been conflicting. Some studies have found similar prevalence rates in African Americans and whites whereas other studies have found much lower prevalence and incidence rates in African Americans. A few studies identify potential factors underlying these discrepancies, including biologic differences as well as disparities in healthcare access. However, African Americans remain underrepresented in research studies, which make understanding the underlying reasons for these differences difficult. The purpose of this paper is to summarize existing research in African Americans with PD, highlight some of the reasons why differences exist in diagnostic rates of PD in this population, and briefly discuss interventions that may need to be made in order to ensure adequate care is provided to these patients.

Novel Outreach Program and Practical Strategies for Patients with Parkinsonism in the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has upended daily life and neurologic care for most patients, including those with Parkinson's disease and parkinsonism. Disruptions to routine care, high volumes of patient and caregiver calls, and our patients' risk of infection and complications inspired a proactive COVID-19 outreach program. This program targets patients with advanced Parkinson's disease and related disorders, specifically those who are homebound, receiving or eligible for palliative care, and/or lacking support networks. We describe the program and practical strategies providers can implement to support wellbeing and successful telehealth uptake during this time of social isolation and gradual reopening.

Sex differences in amphetamine-induced displacement of [(18)F]fallypride in striatal and extrastriatal regions: a PET study.

OBJECTIVE: The authors examined gender differences in d-amphetamine-induced displacements of [(18)F]fallypride in the striatal and extrastriatal brain regions and the correlations of these displacements with cognition and sensation seeking. METHOD: Six women and seven men underwent positron emission tomography (PET) with [(18)F]fallypride before and after an oral dose of d-amphetamine. Percent displacements were calculated using regions of interest and parametric images of dopamine 2 (D(2)) receptor binding potential. RESULTS: Parametric images of dopamine release suggest that the female subjects had greater dopamine release than the male subjects in the right globus pallidus and right inferior frontal gyrus. Gender differences were observed in correlations of changes in cognition and sensation seeking with regional dopamine release. CONCLUSION: Findings revealed a greater dopamine release in women as well as gender differences in the relationship between regional dopamine release and sensation seeking and cognition.

Amphetamine-induced displacement of [18F] fallypride in striatum and extrastriatal regions in humans.

This study examined D-amphetamine (D-AMPH)-induced displacements of [18F] fallypride in striatal and extrastriatal regions and the correlations of these displacements with cognition, affect, and sensation-seeking behavior. In all, 14 normal subjects, six females and eight males (ages 21-32, mean age 25.9 years), underwent positron emission tomography (PET) with [18F]fallypride before and 3 h after a 0.43 mg/kg oral dose of D-AMPH. Levels of dopamine (DA) D2 receptor density were calculated with the reference region method of Lammerstma. Percent displacements in striatal and extrastriatal regions were calculated for the caudate, putamen, ventral striatum, medial thalamus, amygdala, substantia nigra, and temporal cortex. Correlations of changes in cognition, affect, and sensation seeking with parametric images of D-AMPH-induced DA release were computed. Significant displacements were seen in the caudate, putamen, ventral striatum substantia nigra, and temporal cortex with a trend level change in the amygdala. Greatest displacements were seen in striatal subdivisions-5.6% in caudate, 11.2% in putamen, 7.2% in ventral striatum, and 6.6% in substantia nigra. Lesser decrements were seen in amygdala-4.4%, temporal cortex-3.7%, and thalamus-2.8%. Significant clusters of correlations of regional DA release with cognition and sensation-seeking behavior were observed. The current study demonstrates that [18F]fallypride PET studies using oral D-AMPH (0.43 mg/kg) can be used to study D-AMPH-induced DA release in the striatal and extrastriatal regions in humans, and their relationship with cognition and sensation-seeking behavior.

Estimation of baseline dopamine D2 receptor occupancy in striatum and extrastriatal regions in humans with positron emission tomography with [18F] fallypride.

BACKGROUND: This study examined whether positron emission tomography (PET) studies with [18F] fallypride performed before and after alpha-methyl-para-tyrosine (AMPT) administration can be used to estimate baseline dopamine (DA) D2 receptor occupancy in striatal and extrastriatal regions. METHODS: Six normal subjects underwent PET with [18 F] fallypride before and after administration of AMPT. The DA D2 receptor binding potentials (bp) were calculated with the reference region method. Percent changes in bp in striatal and extrastriatal regions were calculated with both region-of-interest analysis and on a voxel by voxel basis with parametric images of DA D2 receptor levels. RESULTS: The results of the current study indicate that AMPT treatment significantly increased the bp in the caudate, putamen, ventral striatum, and substantia nigra. A trend level increase was seen in the medial thalamus. CONCLUSIONS: This study demonstrates that PET with [18F] fallypride can be used to estimate baseline DA D2 receptor occupancy in striatal and extrastriatal regions.