Influence of anosognosia on patient-reported outcomes for psychiatric symptoms and quality of life in Huntington's disease.

INTRODUCTION: Anosognosia, defined as reduced awareness of one's deficit or symptom, is common in Huntington's disease (HD) and detectable at each disease stage. The impact of anosognosia on self-reporting in HD populations is critical to understand given growing use of patient-reported outcomes in HD clinical care and research. We aimed to determine the influence of anosognosia on patient-reported outcome measures assessing psychiatric symptoms and quality of life in HD. METHODS: We enrolled HD patients to complete a battery of patient-reported and rater-administered measures, including the Anosognosia Scale, at baseline and 6 months later. Patient-reported outcome measures included NeuroQoL short forms for depression, anxiety, satisfaction with social roles and activities, and positive affect and well-being and Patient-Reported Outcomes Measurement Information System short forms for emotional distress-anger and sleep-related impairment. Anosognosia Scale-Difference Score indexed patient-clinician agreement on patient motor, cognitive, and behavioral abilities. We conducted multivariable linear regression analyses to quantify the association of baseline anosognosia with 6-month patient-reported outcomes. RESULTS: Of 79 patients with complete Anosognosia Scale data at baseline, 25 (31.6 %) met the scale's criterion for anosognosia. In the regression analyses, baseline Difference Score improved prediction of 6-month patient-reported outcomes for depression, anxiety, anger, and positive affect and well-being (χ2(1) value range for likelihood ratio tests contrasting models with and without Difference Score: 13.1-20.9, p-values <0.001). Patients with more anosognosia self-reported less severe psychiatric symptoms and more positive affect and well-being. CONCLUSION: Study results suggest that anosognosia influences patient-reported outcomes for psychiatric symptoms and quality of life in HD populations.

An Exploratory Pilot Study of Neuropsychological Performance in Two Huntington Disease Centers of Excellence Clinics.

OBJECTIVES: To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations). METHOD: Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables. RESULTS: Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency. CONCLUSIONS: This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted.

Accentuated Paralimbic and Reduced Mesolimbic D2/3-Impulsivity Associations in Parkinson's Disease.

Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson's disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is regulated by D2/3 autoreceptors in mesocorticolimbic circuits. While altered D2/3 binding is noted in ICB+ PD patients, there is limited prior assessment of the trait impulsivity-D2/3 relationship in PD, and no prior direct comparison with patterns in HCs. We examined 54 PD (36 M; 18 F) and 31 sex- and age-matched HC (21 M; 10 F) subjects using [18F]fallypride, a high-affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Subcortical and cortical assessment exclusively used ROI or exploratory-voxelwise methods, respectively. All completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. Subcortical ROI analyses indicated a negative relationship between trait impulsivity and D2/3 BPND in the ventral striatum and amygdala of HCs but not in PD. By contrast, voxelwise methods demonstrated a positive trait impulsivity-D2/3 BPND correlation in ventral frontal olfactocentric-paralimbic cortex of subjects with PD but not HCs. Subscale analysis also highlighted different aspects of impulsivity, with significant interactions between group and motor impulsivity in the ventral striatum, and attentional impulsivity in the amygdala and frontal paralimbic cortex. These results suggest that dopamine functioning in distinct regions of the mesocorticolimbic circuit influence aspects of impulsivity, with the relative importance of regional dopamine functions shifting in the neuropharmacological context of PD.SIGNIFICANCE STATEMENT The biological determinants of impulsivity have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease. This is the first study to evaluate a large cohort of Parkinson's disease patients and age-matched healthy controls with a measure of trait impulsivity and concurrent [18F]fallypride PET, a method that allows quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in the trait impulsivity-dopamine relationship, including (1) loss of subcortical relationships present in the healthy brain and (2) emergence of a new relationship in a limbic cortical area. This illustrates the loss of mechanisms of behavioral regulation present in the healthy brain while suggesting a potential compensatory response and target for future investigation.

The Role of a Dopamine-Dependent Limbic-Motor Network in Sensory Motor Processing in Parkinson Disease.

Limbic and motor integration is enabled by a mesial temporal to motor cortex network. Parkinson disease (PD) is characterized by a loss of dorsal striatal dopamine but relative preservation of mesolimbic dopamine early in disease, along with changes to motor action control. Here, we studied 47 patients with PD using the Simon conflict task and [18F]fallypride PET imaging. Additionally, a cohort of 16 patients participated in a single-blinded dextroamphetamine (dAMPH) study. Task performance was evaluated using the diffusion model for conflict tasks, which allows for an assessment of interpretable action control processes. First, a voxel-wise examination disclosed a negative relationship, such that longer non-decision time is associated with reduced D2-like binding potential (BPND) in the bilateral putamen, left globus pallidus, and right insula. Second, an ROI analysis revealed a positive relationship, such that shorter non-decision time is associated with reduced D2-like BPND in the amygdala and ventromedial OFC. The difference in non-decision time between off-dAMPH and on-dAMPH trials was positively associated with D2-like BPND in the globus pallidus. These findings support the idea that dysfunction of the traditional striatal-motor loop underlies action control deficits but also suggest that a compensatory parallel limbic-motor loop regulates motor output.

Dopamine-induced changes to thalamic GABA concentration in impulsive Parkinson disease patients.

Impulsivity is inherent to behavioral disorders such as substance abuse and binge eating. While the role of dopamine in impulse behavior is well established, γ-aminobutyric acid (GABA) therapies have promise for the treatment of maladaptive behaviors. In Parkinson disease (PD), dopaminergic therapies can result in the development of impulsive and compulsive behaviors, and this clinical syndrome shares similar pathophysiology to that seen in addiction, substance abuse, and binge-eating disorders. We hypothesized that impulsive PD patients have a reduced thalamic GABAergic response to dopamine therapy. To test this hypothesis, we employed GABA magnetic resonance spectroscopy, D2-like receptor PET imaging, and clinical and quantitative measures of impulsivity in PD patients (n = 33), before and after dopamine agonist administration. We find a blunted thalamic GABA response to dopamine agonists in patients with elevated impulsivity (p = 0.027). These results emphasize how dopamine treatment differentially augments thalamic GABA concentrations, which may modify behavioral impulsivity.

Substance Use in the Performing Artist with Chronic Pain.

OBJECTIVES: To evaluate how performing artists (PAs) with chronic pain may differ on measures of substance use compared to non-PA controls. METHODS: 157 participants reporting chronic pain (89 PAs, 68 non-PA controls) completed an online cross-sectional survey. Participants were assessed for self-reported current pain severity using the Brief Pain Inventory Short-Form, opioid misuse risk using the Screener and Opioid Assessment for Patients with Pain-Revised, opioid withdrawal using the Subjective Opiate Withdrawal Scale, and symptoms of opioid use disorder (OUD) using a modified version of the DSM-V checklist. RESULTS: PAs had lower pain severity (p <0.05, t=2.196, df=155) and lower pain interference (p <0.05, t=2.194) than non-PA controls. 24% of PAs and 13% of controls reported using opioids within the past month. Among PAs, the number of days using opioids in the past month was positively associated with hours spent practicing per week (r=0.508, p <0.05). PAs (66%) were more likely to endorse current alcohol use than controls (44.1%, t= -2.136, X2=7.72, p <0.01). Importantly, PAs (19%) were more likely than controls (3%) to endorse symptoms of at least mild OUD (X2(3)=11.3, p <0.01) and higher ratings of opioid misuse risk (t=-2.166, p <0.05). Past month opioid withdrawal was also greater in PAs than controls (t=-2.136, p <0.05), and 5.6% of PAs and 1.5% of controls reported at least one prior incidence incident of opioid overdose in their lifetime (X2 =1.80, NS). CONCLUSIONS: Among persons with chronic pain, PAs may have higher risk for opioid-related consequences, including OUD, and should be screened during health care encounters.

Amphetamine-induced dopamine release and impulsivity in Parkinson's disease.

Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson's disease population. Here, we applied 18F-fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson's disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty patients with Parkinson's disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with 18F-fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson's disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson's disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours.

D2-Like Receptor Expression in the Hippocampus and Amygdala Informs Performance on the Stop-Signal Task in Parkinson's Disease.

The stop-signal task is a well-established assessment of response inhibition, and in humans, proficiency is linked to dorsal striatum D2 receptor availability. Parkinson's disease (PD) is characterized by changes to efficiency of response inhibition. Here, we studied 17 PD patients (6 female and 11 male) using the stop-signal paradigm in a single-blinded d-amphetamine (dAMPH) study. Participants completed [18F]fallypride positron emission topography (PET) imaging in both placebo and dAMPH conditions. A voxel-wise analysis of the relationship between binding potential (BPND) and stop-signal reaction time (SSRT) revealed that faster SSRT is associated with greater D2-like BPND in the amygdala and hippocampus (right cluster qFDR-corr = 0.026, left cluster qFDR-corr = 0.002). A region of interest (ROI) examination confirmed this association in both the amygdala (coefficient = -48.26, p = 0.005) and hippocampus (coefficient = -104.94, p = 0.007). As healthy dopaminergic systems in the dorsal striatum appear to regulate response inhibition, we interpret our findings in PD to indicate either nigrostriatal damage unmasking a mesolimbic contribution to response inhibition, or a compensatory adaptation from the limbic and mesial temporal dopamine systems. These novel results expand the conceptualization of action-control networks, whereby limbic and motor loops may be functionally connected.SIGNIFICANCE STATEMENT While Parkinson's disease (PD) is characteristically recognized for its motor symptoms, some patients develop impulsive and compulsive behaviors (ICBs), manifested as repetitive and excessive participation in reward-driven activities, including sex, gambling, shopping, eating, and hobbyism. Such cognitive alterations compel a consideration of response inhibition in PD. To investigate inhibitory control and assess the brain regions that may participate, we assessed PD patients using a single-blinded d-amphetamine (dAMPH) study, with [18F]fallypride positron emission topography (PET) imaging, and stop-signal task performance. We find a negative relationship between D2-like binding in the mesial temporal region and top-signal reaction time (SSRT), with greater BPND associated with a faster SSRT. These discoveries indicate a novel role for mesolimbic dopamine in response inhibition, and advocate for limbic regulation of action control in this clinical population.

Clinical implications of photophobia in progressive supranuclear palsy.

OBJECTIVE: To determine the impact of photophobia on persons with Progressive Supranuclear Palsy (pwPSP) by determining the functional impact of light sensitivity using methods established in migraine research. METHODS: All 60 participants (pwPSP = 15, persons with Parkinson Disease (pwPD) = 15, Older adults = 30) completed a series of questionnaires designed to assess the impact of photophobia on activities of daily living. Group comparisons were controlled for multiple comparisons using a false discovery rate of 0.05. RESULTS: Most (14/15) pwPSP participants noted that bright light hurt their eyes, and this proportion was significantly greater than pwPD (6/15; p = 0.03, corrected). PSP participants reported statistically significantly more severe light sensitivity on a subjective 0-100 scale (p = 0.003, corrected), and noted reduced time spent in both indoor and outdoor activities. Some PSP participants (n = 3) noted that they needed to wear sunglasses indoors, but most noted a reluctance to leave their house during the day due to photophobia. PwPSP indicated that they require more help from others to complete daily tasks that require them to be outside during daylight hours. CONCLUSIONS: Overall, we note a significant debility due to photophobia in PSP, and this impacts outdoor more than indoor activities. The functional disability in PSP caused by photophobia appears to cause a substantive reduction in quality of life. Future studies could consider incorporating specific metrics to evaluate measurable differences with photophobia onset and worsening severity.

Healthcare Delivery and Huntington's Disease During the Time of COVID-19.

BACKGROUND: Safer-at-home orders during the COVID-19 pandemic altered the structure of clinical care for Huntington's disease (HD) patients. This shift provided an opportunity to identify limitations in the current healthcare infrastructure and how these may impact the health and well-being of persons with HD. OBJECTIVE: The study objectives were to assess the feasibility of remote healthcare delivery in HD patients, to identify socioeconomic factors which may explain differences in feasibility and to evaluate the impact of safer-at-home orders on HD patient stress levels. METHODS: This observational study of a clinical HD population during the 'safer-at-home' orders asked patients or caregivers about their current access to healthcare resources and patient stress levels. A chart review allowed for an assessment of socioeconomic status and characterization of HD severity. RESULTS: Two-hundred and twelve HD patients were contacted with 156 completing the survey. During safer-at-home orders, the majority of HD patients were able to obtain medications and see a physician; however, 25% of patients would not commit to regular telehealth visits, and less than 50% utilized an online healthcare platform. We found that 37% of participants were divorced/single, 39% had less than a high school diploma, and nearly 20% were uninsured or on low-income health insurance. Patient stress levels correlated with disease burden. CONCLUSION: A significant portion of HD participants were not willing to participate in telehealth services. Potential explanations for these limitations may include socioeconomic barriers and caregiving structure. These observations illustrate areas for clinical care improvement to address healthcare disparities in the HD community.

Symptoms of Medication Withdrawal in Parkinson's Disease: Considerations for Informed Consent in Patient-Oriented Research.

INTRODUCTION: Dopamine medication withdrawal in Parkinson's disease (PD) is commonly employed in clinical practice and can be required for participation in research studies. When asked to withdraw from medications, participants often enquire as to what symptoms they should expect. OBJECTIVES: This study sought to improve the informed consent process by identifying patient-reported symptoms when dopamine treatment is withheld. We also sought to provide clinical guidance regarding the extent of these symptoms and consider participant willingness to undergo these assessments. METHODS: Participants were recruited from community-based PD programs and support groups in Nashville, Tennessee, USA. A patient-based questionnaire determined the frequency and severity of motor and nonmotor symptoms. The questionnaire also assessed whether patients would be willing to abstain from medication at a future date and under what circumstances. RESULTS: A total of 31/90 participants reported willingness to withdraw from dopaminergic medications for clinical or research purposes. Tremor, walking, and balance were the most common motor symptoms that worsened during this time. Sleep dysfunction, constipation, and tremor were noted as the most severe symptoms. Of note, 10% of participants indicated that they would not be willing to go off medications again, suggesting that a minority of patients find this to be most discomforting. When prompted for a reason why participants would be willing to come off of their medications again, "for clinical purposes" was selected the most. CONCLUSIONS: Study teams should list these symptoms in the applications to their institutional review board and in the informed consent to provide guidance for participants.

Elevated cerebral blood flow in patients with pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) results from an impaired peripheral autonomic nervous system, and clinical symptoms present with orthostatic hypotension. While the impact on cardiovascular indices of orthostatic intolerance are well-characterized, more limited information is available regarding cerebral hemodynamic dysfunction in PAF. The objective of this study was to test the hypothesis that cerebral blood flow (CBF) is reduced in PAF, and to quantify the relationship between CBF and clinical indicators of disease severity, including peripheral supine arterial blood pressure. METHODS: Participants with PAF (n = 17) and age- and sex-matched normotensive healthy controls (n = 17) were examined using established clinical rating scales, cardiovascular autonomic function tests, and 3T MRI measurements of CBF. CBF-weighted images were also used to determine the prevalence of venous hyperintensities from the major dural sinuses as evidence of abnormal capillary flow. Nonparametric tests and general linear models were used to evaluate differences and correlations between study variables. RESULTS: Gray matter CBF was higher in PAF (51.1 ± 13.4 mL/100 g/min) compared to controls (42.9 ± 6.5 mL/100 g/min, p = 0.007). Venous hyperintensities were more prevalent in PAF relative to controls, and the presence and degree of venous hyperintensities was associated with higher mean CBF (p = 0.027). In PAF participants, CBF and supine systolic blood pressure were inversely related (Spearman's rho = -0.545, p = 0.024). CONCLUSIONS: Findings suggest that PAF patients may exhibit elevated CBF and provide evidence that this condition exerts a hemodynamic impact in the central nervous system.

Recovery Goals and Long-term Treatment Preference in Persons Who Engage in Nonmedical Opioid Use.

BACKGROUND: While most opioid use disorder (OUD) treatment providers consider opioid abstinence to be the preferred outcome, little is known about the treatment preferences of the larger population of individuals who engage in nonmedical opioid use and have not yet sought treatment. This study sought to descriptively quantify the proportion of out-of-treatment individuals with nonmedical opioid use that have abstinent and nonabstinent recovery goals. METHODS: Participants (N = 235) who engage in nonmedical opioid use and met self-reported criteria for OUD were recruited online and participated in a cross-sectional survey on recovery goals and treatment perceptions. Participants were dichotomized as having either abstinent (70.6%) or nonabstinent (29.4%) recovery goals. Participants were presented with 13 treatment options and asked which treatment they would "try first" and which treatment they thought would be the best option for long-term recovery. RESULTS: Persons in the nonabstinent group were more likely to want to continue use of prescription opioids as prescribed by a physician compared with the abstinent group (χ[1] = 9.71, P = 0.002). There were no group differences regarding preference for individual OUD treatments. The most frequently endorsed treatments that participants would "try first" were physician visits (23.4%), one-on-one counseling (18.7%), and 12-step groups (13.2%), whereas the most frequently endorsed treatments for long-term recovery were one-on-one counseling (17.4%), residential treatment (16.7%), and buprenorphine (15.3%). CONCLUSION: Public health initiatives to engage out-of-treatment individuals should take into account recovery goals and treatment preferences to maximize treatment initiation and retention.