Structural MRI Correlates of Anosognosia in Huntington's Disease.

Background: Anosognosia, or unawareness of symptoms, is common in Huntington's disease (HD), but the neuroanatomical basis of this is unknown. Objective: To identify neuroanatomical correlates of HD anosognosia using structural MRI data. Methods: We leveraged a pre-processed dataset of 570 HD participants across the well-characterized PREDICT-HD and TRACK-HD cohort studies. Anosognosia index was operationalized as the score discrepancies between HD participants and their caregivers on the Frontal Systems Behavior Scale (FrSBe). Results: Univariate correlation analyses identified volumes of globus pallidus, putamen, caudate, basal forebrain, substantia nigra, angular gyrus, and cingulate cortex as significant correlates of anosognosia after correction for multiple comparisons. A multivariable model constructed with stepwise regression that included volumetric data showed globus pallidus volume alone explained more variance in anosognosia severity than motor impairment or CAP score alone. Conclusions: Anosognosia appears to be related to degeneration affecting both cortical and subcortical areas. Globus pallidus neurodegeneration in particular appears to be a key process of importance.

Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis.

Importance: A clear and comprehensive understanding of risks associated with psychedelic-assisted therapy is necessary as investigators extend its application to new populations and indications. Objective: To assess adverse events (AEs) associated with classic psychedelics, particularly serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric evaluation. Data Sources: The search for potentially eligible studies was conducted in the Scopus, MEDLINE, PsycINFO, and Web of Science databases from inception through February 8, 2024. Study Selection: Two independent reviewers screened articles of classic psychedelics (lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], and 5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) involving administration in clinical or research contexts. Data Extraction and Synthesis: AE data were extracted and synthesized by 2 reviewers and were used for random-effects meta-analysis of AE frequency and heterogeneity. Risk of bias assessment focused on AE ascertainment (eg, systematic assessment and quality of follow-up). Main Outcomes and Measures: A hybrid approach was used for capture of all reported AEs following high-dose classic psychedelic exposure and confirmatory capture of AEs of special interest, including suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder. AEs were stratified by timescale and study population type. Forest plots of common AEs were generated, and the proportions of participants affected by SAEs or NSAEs requiring medical intervention were summarized descriptively. Results: A total of 214 unique studies were included, of which 114 (53.3%) reported analyzable AE data for 3504 total participants. SAEs were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders; among these SAEs were worsening depression, suicidal behavior, psychosis, and convulsive episodes. NSAEs requiring medical intervention (eg, paranoia, headache) were similarly rare. In contemporary research settings, there were no reports of deaths by suicide, persistent psychotic disorders, or hallucinogen persisting perception disorders following administration of high-dose classic psychedelics. However, there was significant heterogeneity in the quality of AE monitoring and reporting. Of 68 analyzed studies published since 2005, only 16 (23.5%) described systematic approaches to AE assessment, and 20 studies (29.4%) reported all AEs, as opposed to only adverse drug reactions. Meta-analyses of prevalence for common AEs (eg, headache, anxiety, nausea, fatigue, and dizziness) yielded comparable results for psilocybin and LSD. Conclusions and Relevance: In this systematic review and meta-analysis, classic psychedelics were generally well tolerated in clinical or research settings according to the existing literature, although SAEs did occur. These results provide estimates of common AE frequencies and indicate that certain catastrophic events reported in recreational or nonclinical contexts have yet to be reported in contemporary trial participants. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit profiles of these substances and to communicate such risks to prospective study participants and the public.

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.

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.

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.

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.

Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease.

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus.

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.

Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

Parkinson's disease (PD) is mediated, in part, by intraneuronal accumulation of α-synuclein aggregates andsubsequent death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). Microglial hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been well-documented in various neurodegenerative diseases, including PD. We show here that loss of parkin activity in mouse and human DA neurons results in spontaneous neuronal NLRP3 inflammasome assembly, leading to DA neuron death. Parkin normally inhibits inflammasome priming by ubiquitinating and targeting NLRP3 for proteasomal degradation. Loss of parkin activity also contributes to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS. Inhibition of neuronal NLRP3 inflammasome assembly prevents degeneration of DA neurons in familial and sporadic PD models. Strategies aimed at limiting neuronal NLRP3 inflammasome activation hold promise as a disease-modifying therapy for PD.

STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy.

In idiopathic Parkinson's disease (PD), pathologic αSyn aggregates drive oxidative and nitrative stress that may cause genomic and mitochondrial DNA damage. These events are associated with activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) immune pathway, but it is not known whether STING is activated in or contributes to α-synucleinopathies. Herein, we used primary cell cultures and the intrastriatal αSyn preformed fibril (αSyn-PFF) mouse model of PD to demonstrate that αSyn pathology causes STING-dependent neuroinflammation and dopaminergic neurodegeneration. In microglia-astrocyte cultures, αSyn-PFFs induced DNA double-strand break (DSB) damage response signaling (γH2A.X), as well as TBK1 activation that was blocked by STING inhibition. In the αSyn-PFF mouse model, we similarly observed TBK1 activation and increased γH2A.X within striatal microglia prior to the onset of dopaminergic neurodegeneration. Using STING-deficient (Stinggt) mice, we demonstrated that striatal interferon activation in the α-Syn PFF model is STING-dependent. Furthermore, Stinggt mice were protected from α-Syn PFF-induced motor deficits, pathologic αSyn accumulation, and dopaminergic neuron loss. We also observed upregulation of STING protein in the substantia nigra pars compacta (SNpc) of human PD patients that correlated significantly with pathologic αSyn accumulation. STING was similarly upregulated in microglia cultures treated with αSyn-PFFs, which primed the pathway to mount stronger interferon responses when exposed to a STING agonist. Our results suggest that microglial STING activation contributes to both the neuroinflammation and neurodegeneration arising from α-synucleinopathies, including PD.

Bidirectional Correlations Between Dopaminergic Function and Motivation in Parkinson's Disease.

OBJECTIVE: To test the hypothesis that striatal dopamine function influences motivational alterations in Parkinson disease (PD), we compared vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DaT) imaging data in PD patients with impulse control disorders (ICDs), apathy, or neither. METHODS: We extracted striatal binding ratios (SBR) from VMAT2 PET imaging (18F-AV133) and DaTscans from the Parkinson's Progression Markers Initiative (PPMI) multicenter observational study. Apathy and ICDs were assessed using the Movement Disorders Society-revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP), respectively. We used analysis of variance (ANOVA) and log-linear mixed-effects (LME) regression to model SBRs with neurobehavioral metrics. RESULTS: Among 23 participants (mean age 62.7 years, mean disease duration 1.8 years) with VMAT2 imaging data, 5 had apathy, 5 had an ICD, and 13 had neither. ANOVA indicated strong groupwise differences in VMAT2 binding in right anterior putamen [F(2,20) = 16.2, p < 0.0001), right posterior putamen [F(2,20) = 16.9, p < 0.0001), and right caudate [F(2,20) = 6.8, p = 0.006)]. Post-hoc tests and repeated-measures analysis with LME regression also supported right striatal VMAT2 elevation in the ICD group and reduction in the apathy group relative to the group with neither ICD nor apathy. DaT did not exhibit similar correlations, but normalizing VMAT2 with DaT SBR strengthened bidirectional correlations with ICD (high VMAT2/DaT) and apathy (low VMAT2/DaT) in all striatal regions bilaterally. CONCLUSIONS: Our findings constitute preliminary evidence that striatal presynaptic dopaminergic function helps describe the neurobiological basis of motivational dysregulation in PD, from high in ICDs to low in apathy.

Mind the gap: Inequalities in mental health care and lack of social support in Parkinson disease.

Inequalities in mental healthcare and lack of social support during the COVID-19 pandemic have lowered quality of life and increased overall burden of disease in people with Parkinson's (PWP). Although the pandemic has brought attention to these inequalities, they are long standing and will persist unless addressed. Lack of awareness of mental health issues is a major barrier and even when recognized disparities based on race, gender, and socioeconomic factors limit access to already scarce resources. Stigma regarding mental illness is highly prevalent and is a major barrier even when adequate care exists. Limited access to mental healthcare during the pandemic and in general increases the burden on caregivers and families. Historically, initiatives to improve mental healthcare for PWP focused on interventions designed for specialty and academic centers generally located in large metropolitan areas, which has created unintended geographic disparities in access. In order to address these issues this point of view suggests a community-based wellness model to extend the reach of mental healthcare resources for PWP.

Attentional dysfunction and the punding spectrum in Parkinson's disease.

BACKGROUND: Punding is a complication of Parkinson's disease (PD) treatment and stimulant abuse that features excessive preoccupation with repetitive and/or aimless behaviors. We hypothesized that cognitive impairment and functional limitations influence how punding behaviors manifest in PD. METHODS: We extracted data on punding, hobbyism, and cognition from the Parkinson's Progression Marker Initiative (PPMI). Punding and hobbyism were measured with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) scale. We determined how cognition predicted punding and hobbyism behaviors-adjusting for levodopa dose, Hoehn & Yahr stage, disease duration, and age-using generalized estimating equation (GEE) logistic regression. Activities of daily living (ADL) and motor impairment were measured with the MDS-UPDRS scale. RESULTS: In GEE logistic regression models, punding was selectively associated with lower scores on the Letter Number Sequencing test (LNS), the primary attention test in PPMI (Odds ratio: 0.87 (95% CI: 0.79-0.96); p = 0.022). This was corroborated by a subscale-analysis of Montreal Cognitive Assessment (MoCA) scores, as only the attention subscale was significantly associated with punding (OR: 0.59 (0.45-0.77); p < 0.001). Baseline impairment in LNS (Hazard ratio: 2.52 (1.22-5.20); p = 0.012) and MoCA attention (HR: 2.68 (1.32-5.42); p = 0.006) predicted earlier punding in Cox regression. In turn, ADL dysfunction predicted punding (OR: 1.55 (1.20-2.00); p < 0.001), but not hobbyism. CONCLUSION: Attentional dysfunction is a domain-specific cognitive biomarker of punding risk in PD. Further, attentional capacity and functional impairment may determine the complexity of perseverative behaviors on the continuum from rudimentary punding to semi-purposeful hobbyism.