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.

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis).

BACKGROUND: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Management of impulse control disorders in Parkinson's disease: Controversies and future approaches.

Impulse control disorders in Parkinson's disease are a group of impulsive behaviors most often associated with dopaminergic treatment. Presently, there is a lack of high quality evidence available to guide their management. This manuscript reviews current management strategies, before concentrating on the concept of dopamine agonist withdrawal syndrome and its implications for the management of impulse control disorders. Further, we focus on controversies, including the role of more recently available anti-parkinsonian drugs, and potential future approaches involving routes of drug delivery, nonpharmacological treatments (such as cognitive behavioral therapy and deep brain stimulation), and other as yet experimental strategies.

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.

Prospective cohort study of impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs) are potentially serious side effects of dopamine agonist therapy in Parkinson's disease (PD), but prospective data are lacking about their incidence, time course, and risk factors. This work was a 4-year, prospective cohort study of outpatients with PD and no previous ICDs (N = 164). All subjects treated with a dopamine agonist during the study were followed longitudinally for new-onset ICDs. Baseline characteristics were compared in groups with (ICD+) and without (ICD-) subsequent ICDs. Forty-six subjects were treated with a dopamine agonist, including 25 who were newly treated and 21 who received ongoing dopamine agonist therapy. Of these 46 subjects, 18 (39.1%) developed new-onset ICDs. The timing of ICD onset varied from 3.0 to 114.0 months (median, 23.0) after initiation of dopamine agonist therapy. Baseline demographic characteristics were similar in ICD+ and ICD- groups. At baseline, ICD+ subjects had a greater prevalence of motor complications (61.1% versus 25.0%; P = 0.01) than ICD- subjects, despite comparable total dopaminergic medication usage in both groups (median, 150.0 versus 150.0 levodopa equivalents; P = 0.61). Compared with ICD- subjects, ICD+ subjects had a greater baseline prevalence of caffeine use (100% versus 66.7%; P = 0.007) and higher lifetime prevalence of cigarette smoking (44.4% versus 14.3%; P = 0.04). Peak dopamine agonist doses were higher in ICD+ than ICD- subjects (median 300.0 versus 165.0 L-dopa equivalents; P = 0.03), but cumulative dopamine agonist exposure was similar in both groups. In summary, the timing of new-onset ICDs in PD is highly variable. Risk factors include cigarette smoking, caffeine use, motor complications, and higher peak dopamine agonist dosage.

Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study.

AIM: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD. METHODS: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [(18)F]fluorodeoxyglucose positron emission computed tomography (FDG-PET) and magnetic resonance imaging, and a complete neuropsychological battery. RESULTS: FDG-PET of subjects with PD revealed significant metabolic elevations in the bilateral posterior lentiform nucleus, posterior cingulate, and parahippocampus, and metabolic reductions in the bilateral temporoparietal association cortex and occipital lobe versus controls. PD subjects had significant reductions in executive/attention function, memory/verbal learning, and speed of thinking, and significantly increased depression, anxiety and apathy scores compared with controls. Motor dysfunction correlated with increased metabolism in the posterior lentiform nucleus, pons, and cerebellum, and decreased metabolism in the temporoparietal lobe. Cognitive dysfunction correlated with increased posterior cingulate metabolism and decreased temporoparietal lobe metabolism. Depressive symptoms correlated with increased amygdala metabolism; anxiety scores correlated with decreased caudate metabolism, and apathy scores correlated with increased metabolism in the anterior cingulate and orbitofrontal lobe and decreased metabolism in the temporoparietal association cortex. CONCLUSIONS: Our findings showed that motor, cognitive, and emotional dysfunction in PD are associated with distinct patterns of cerebral metabolic changes.

Impulse control and related disorders in Parkinson's disease.

Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized complication of dopamine replacement therapy in Parkinson's disease (PD). Other impulsive-compulsive behaviors have been linked to dopaminergic medications; these include punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), particularly at higher dosages; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Risk factors for ICDs may include male sex; younger age; younger age at PD onset; a pre-PD history of ICD(s); personal or family history of substance abuse; bipolar disorder; gambling problems; and impulsive personality traits. The primary treatment of ICDs in PD is discontinuation of DA therapy. Not all patients can tolerate this, however, due to worsening motor symptoms and/or DA withdrawal syndrome (a severe, stereotyped drug withdrawal syndrome similar to that of other psychostimulants). While psychiatric medications are frequently used to treat ICDs in the general population, there is no empirical evidence to suggest that they are effective in PD. Given the paucity of treatment options and potentially serious consequences of ICDs in PD, it is critical for patients to be monitored closely for their development. As empirically validated treatments for ICDs emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD.

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing and analyzed 45,559 high quality nuclei targeting the subthalamic nucleus and adjacent structures from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was the top activated pathway in vulnerable cell types. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.

New-Onset Movement Disorders in COVID-19: Much Ado about Nothing?

This is an editorial commenting on the paper by Brandão and colleagues [Brandão PRP, Grippe TC, Pereira DA, Munhoz RP, Cardoso F. New-Onset Movement Disorders Associated with COVID-19. Tremor and Other Hyperkinetic Movements. 2021; 11(1): 26. DOI: http://doi.org/10.5334/tohm.595].

Carbidopa/levodopa pharmacy errors in Parkinson's disease.

Outpatient pharmacy errors are common, but little is known about their occurrence in Parkinson's disease (PD). We prospectively studied carbidopa/levodopa pharmacy errors in a cohort of PD outpatients. Over 1 year, pharmacy errors occurred in 8/73 (11%) subjects treated with this medication, producing adverse drug events (ADEs) in 7/8 (87.5%) and increased healthcare utilization in 6/8 (75%) cases. The most common errors were substitution of controlled-release for immediate-release carbidopa/levodopa 25/100 mg (5/8; 62.5%) or dispensation of the wrong carbidopa/levodopa dosage (2/8; 25%). All errors involved ongoing prescriptions, including three interpharmacy transfers. Three subjects (37.5%) questioned pharmacy staff about the change in appearance of the tablets, but the error was corrected in only 1/3 of these cases. Carbidopa/levodopa outpatient pharmacy errors are a common, preventable cause of morbidity and excessive healthcare utilization in PD. Education of healthcare providers, patients, and pharmacy staff is warranted to reduce these errors and associated ADEs.

Comprehensive identification of delusions and olfactory, tactile, gustatory, and minor hallucinations in Parkinson's disease psychosis.

INTRODUCTION: Psychotic symptoms are underdiagnosed in Parkinson's disease (PD), and there is a need for a comprehensive PD psychosis rating scale. METHODS: Cross-sectional analysis of 199 consecutive PD outpatients. After a routine clinical visit that included the Unified Parkinson's Disease Rating Scale (UPDRS) and Non-Motor Symptoms Questionnaire (NMS-Quest), subjects completed the enhanced Scale for the Assessment of Positive Symptoms in PD (eSAPS-PD), a structured clinical interview that included the standard SAPS-PD with additional prompts for delusions and olfactory, gustatory, and minor hallucinations. Based on the combined results of these assessments, subjects were categorized as having major psychotic symptoms (hallucinations or delusions; PDP-major), isolated minor psychotic symptoms (passage hallucinations, presence hallucinations, or illusions; PDP-minor), or no psychotic symptoms (PD-controls). RESULTS: We identified 58 subjects (29%) with psychotic symptoms, including 28 (14%) with major psychotic symptoms and 30 (15%) with isolated minor psychotic symptoms. Hallucinations were present in 56 subjects (28%); most commonly visual (24%, of which 21% were minor only), followed by olfactory (6%), tactile (4%), auditory (2%), and gustatory (1%). The eSAPS-PD detected psychotic symptoms in more subjects (n = 55, 28%) than all other assessments combined (clinical visit, UPDRS part 1, and NMS-Quest) (n = 22, 11%). Compared with PD-controls, PDP-minor subjects had a higher burden of other non-motor symptoms on the Non-Motor Symptoms Scale (37 [27-51] vs. 18 [9-36], p < 0.001) and lower quality of life scores on the PD Quality of Life Questionnaire (138 [125-151] vs. 149 [137-165], p = 0.01). CONCLUSION: The eSAPS-PD can markedly improve detection of psychotic symptoms in PD.

Usefulness of proton and phosphorus MR spectroscopic imaging for early diagnosis of Parkinson's disease.

BACKGROUND AND PURPOSE: Cerebral mitochondrial dysfunction has been observed in Parkinson's disease (PD). If mitochondrial dysfunction is an early event contributing to PD development, then noninvasive techniques that detect disturbed energy metabolism in vivo might be useful tools for early diagnosis and treatment monitoring. In the present study, we tested the hypothesis that proton ((1) H) and phosphorus ((31) P) magnetic resonance spectroscopy (MRS) measures of brain metabolites are able to differentiate between individuals with early PD and healthy volunteers (HVs). METHODS: During this cross-sectional study including 20 subjects with early PD and 15 age-matched HV, ventricular lactate (anaerobic glycolysis); and regional levels of N-acetylaspartate (neuronal integrity); choline (membrane turnover); creatine (energy metabolism); ATP and other phosphate-containing compounds (oxidative phosphorylation) were determined using brain (1) H and (31) P MRS. RESULTS: No metabolic abnormalities were detectable in early-stage PD patients. Metabolite concentrations were not related to age, disease duration, or Unified Parkinson's Disease Rating Scale motor scores. DISCUSSION: In early PD, neither (1) H nor (31) P MRS were able to detect metabolic abnormalities, a finding that is in contrast to published data in more advanced PD cohorts. MRS under dynamic conditions might uncover latent energy deficits in early PD, thus warranting future study.

A Pilot Prospective, Multicenter Observational Study of Dopamine Agonist Withdrawal Syndrome in Parkinson's Disease.

Dopamine agonist withdrawal syndrome (DAWS) has been reported in patients with Parkinson's disease (PD) who rapidly decrease or stop their dopamine agonist (DA) treatment. Retrospective studies suggest a high prevalence of DAWS (14%-18%) in PD, but there are no prospective studies. We report data from the first pilot European multicenter prospective study addressing the frequency of probable DAWS (Rabinak-Nirenberg criteria) in PD patients. The self-completed Nonmotor Symptoms Questionnaire (which addresses the core features of DAWS) was administered at clinical follow-up at 1 month in 51 patients (33 male; mean age: 73.0 ± 9.9 years; PD duration: 12.2 ± 6.3 years) who had discontinued dopamine agonists. Twelve out of fifty-one patients (24%) met clinical criteria for DAWS, the most common symptoms of which were anxiety (91.7%), pain (50%), sweating (41.7%), and anhedonia (16.7%), after the withdrawal of a DA (ropinirole, pramipexole, or cabergoline). In this first prospective evaluation of DAWS in the clinic, preliminary data indicate a high rate after discontinuation of a range of DAs, particularly in the context of impulse control disorders. Larger, controlled studies are required to establish a definitive management pathway.

Sex differences in cerebral energy metabolism in Parkinson's disease: a phosphorus magnetic resonance spectroscopic imaging study.

OBJECTIVE: To test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson's disease (PD). METHODS: Phosphorus magnetic resonance spectroscopy ((31)P MRS) was used to determine high-energy phosphate (phosphocreatine and ATP) and low-energy phosphate (free phosphate) levels in the striatum and temporoparietal cortical gray matter (GM) in 10 men and 10 women with PD, matched for age at onset, disease duration, and UPDRS scores. RESULTS: In the hemisphere more affected by PD, both ATP and high energy phosphate (HEP: phosphocreatine + ATP) content in striatum was 15% lower in men versus women with PD (p = .050 and p = .048, respectively). Similar decreases by 16% in ATP (p = .023) and 12% in HEP (p = .046) were observed in GM in men versus women with PD. In contrast, there were no detectable sex differences in ATP or HEP in healthy age-matched controls. CONCLUSIONS: Men with PD have lower levels of ATP and high energy phosphate than women in brain regions affected by PD. These findings suggest that there may be a greater burden of mitochondrial dysfunction in PD in men versus women with PD.

iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease.

Parkinson's disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation (GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins' fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of "footprint-free" iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ∼50% GBA enzymatic activity, ∼3-fold elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin's neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized α-synuclein and dopamine levels, suggesting a combination therapy for the affected twin.