Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Essential Tremor: Update of Therapeutic Strategies. / Temblor esencial: actualización de las estrategias terapéuticas.

In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques.

Facial emotion recognition deficits are associated with hypomimia and related brain correlates in Parkinson's disease.

Hypomimia is a frequent manifestation in Parkinson's disease (PD) that can affect interpersonal relationships and quality of life. Recent studies have suggested that hypomimia is not only related to motor dysfunction but also to impairment in emotional processing networks. Therefore, we hypothesized that the severity of hypomimia could be associated with performance on a task aimed at assessing facial emotion recognition. In this study, we explored the association between hypomimia, recognition of facial expressions of basic emotions using the Ekman 60 Faces Test (EF), and brain correlates of both hypomimia and performance on the EF. A total of 94 subjects underwent clinical assessments (neurological and neuropsychological examinations), and 56 of them participated in the neuroimaging study. We found significant correlation between hypomimia, EF Disgust (r = -0.242, p = 0.022) and EF Happiness (r = -0.264, p = 0.012); an independent reduction in Cortical Thickness (Cth) in the postcentral gyrus, insula, middle and superior temporal gyri, supramarginal gyrus, banks of the superior temporal sulcus, bilateral fusiform gyri, entorhinal cortex, parahippocampal gyrus, inferior and superior parietal cortex, and right cuneus and precuneus; and multiple correlations between negative emotions such as EF Disgust or EF Anger and a reduced Cth in fronto-temporo-parietal regions. In conclusion, these results suggest that the association between hypomimia and emotion recognition deficits in individuals with PD might be mediated by shared circuits, supporting the concept that hypomimia is not only the result of the dysfunction of motor circuits, but also of higher cognitive functions.

Non-Persistence of Tremorolytic Effect of Perampanel in Essential Tremor: Real-World Experience with 50 Patients.

Background: We describe our experience of using perampanel to treat essential tremor (ET) over 12 months. Methods: We enrolled 50 ET patients in an open-label trial. Perampanel was titrated to 4 mg/day as adjuvant therapy. The main outcome measures were baseline, +1, +3, +6, and + 12 month scores of the Tremor Clinical Rating Scale (TCRS) and the Glass scale (GS). Results: Twenty patients withdrew because of adverse effects. At +1 month, 27 of 30 patients improved: 68% reduction in both TCRS 1 + 2 (P < 0.001) and TCRS 3 (P < 0.001); TCRS 4 + 1.8 and GS 1.1 point reduction. By +12 months non-persistence of therapeutic effect occurred in 70% of patients: the mean reduction in TCRS 1 + 2 was 33% (P = 0.03), TCRS 3 (0.04), TCRS 4 + 0.8, GS 0.2 points reduction. Conclusions: We report important peramapanel acute tremorolytic effects, but poor tolerance to adverse effects and a non-sustained therapeutic effect in most patients.

Predicting Impulse Control Disorders in Parkinson Disease through Incentive Biomarkers.

OBJECTIVE: This study was undertaken to evaluate whether the feedback-related negativity (FRN)-a neurophysiological marker of incentive processing-can be used to predict the development of impulse control disorders (ICDs) in Parkinson disease (PD). METHODS: The longitudinal cohort consisted of consecutive nondemented PD patients with no ICD history. We recorded FRN signals while they performed a gambling task. We calculated the mean amplitude difference between losses and gains (FRNdiff) to be used as a predictor of future ICD development. We performed prospective biannual follow-up assessments for 30 months to detect incident ICDs. Finally, we evaluated how basal FRNdiff was associated with posterior development of ICDs using survival models. RESULTS: Between October 7, 2015 and December 16, 2016, we screened 120 patients. Among them, 94 patients performed the gambling and 92 completed the follow-up. Eighteen patients developed ICDs during follow-up, whereas 74 remained free of ICDs. Baseline FRNdiff was greater in patients who developed ICDs than in those who did not (-2.33µV vs -0.84µV, p = 0.001). No other significant baseline differences were found. The FRNdiff was significantly associated with ICD development in the survival models both when not adjusted (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.58-0.91, p = 0.006) and when controlling for dopamine replacement therapy, sex, and age (HR = 0.74, 95% CI = 0.55-0.97, p = 0.035). None of the impulsivity measures evaluated was related to ICD development. INTERPRETATION: Reward-processing differences measured by FRN signals precede ICD development in PD. This neurophysiological marker permits identification of patients with high risk of ICD development. ANN NEUROL 2022;92:974-984.

The role of attentional control over interference in minor hallucinations in Parkinson's disease.

BACKGROUND: Minor hallucinations in Parkinson's disease are associated with connectivity changes in attentional networks and increased risk of structured hallucinations. However, the clinical translation of these abnormalities in attention processes is not well-defined, and commonly used neuropsychological tests are not able to detect significant deficits in Parkinson's disease patients with isolated minor hallucinations. OBJECTIVES: To analyze the behavioral and electrophysiological correlates of minor hallucinations in Parkinson's disease during an attentional task assessing response inhibition and interference control. METHODS: Fifty-five non-demented Parkinson's disease patients with (PD-mH; n = 27) and without minor hallucinations (PD-NH; n = 28) were included in the analysis. An Ericksen flanker task was performed to compare the effect of presenting congruent and incongruent stimuli on accuracy, reaction times and stimulus-locked event-related potentials morphology. RESULTS: Although both groups showed equivalent performance in a standard neuropsychological assessment, in the flanker task accuracy rates were lower in the PD-mH group in incongruent trials (p = 0.005). In the event-related potentials, PD-mH patients showed increased amplitude of the N2 at Fz [t(53); p < 0.05] and decreased amplitude of the P300 at Pz [t(53); p < 0.05] for the incongruent trials. CONCLUSIONS: Parkinson's disease patients with isolated minor hallucinations were more susceptible to interference mediated by irrelevant stimuli and had less cognitive control for suppressing these interferences. The failure of these systems could precipitate the intrusion and overrepresentation of peripheral irrelevant stimuli perceived as minor hallucinations. The Ericksen flanker task could be used as a sensitive clinical marker of the attentional defects leading to hallucinations in Parkinson's disease.

A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease.

Background: Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective: We studied the effects of safinamide on apathy in PD. Methods: Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures. Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (-7.5 ± 6.9) than with placebo (-2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups. Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies. Trial Registration: EudraCT 2017-003254-17.

Dissociable contribution of plasma NfL and p-tau181 to cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive dysfunction is a disabling complication in Parkinson's disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI) depends on the tests performed, which limits results generalization. Blood-based biomarkers could provide additional objective information for PD-MCI diagnosis and progression. Blood neurofilament light chain (NfL), a marker of neuronal injury, has shown good performance for PD disease stratification and progression. While NfL is not disease-specific, phosphorylated-tau at threonine-181 (p-tau181) in blood is a highly specific marker of concomitant brain amyloid-ß and tau pathology. METHODS: We investigated the potential of plasma NfL and p-tau181 levels as markers of cognitive impairment in a prospective cohort of 109 PD patients with and without PD-MCI (age 68.1 ± 7 years, education 12.2± 5 years), and 40 comparable healthy controls. After a follow-up of 4 years, we evaluated their predictive value for progression to dementia. RESULTS: Although NfL and p-tau181 levels were significantly increased in PD compared with healthy controls, only NfL levels were significantly higher in PD-MCI compared with PD with normal cognition (PD-NC) at baseline. After a follow-up of 4 years, only NfL predicted progression to dementia (HR 1.23, 95% CI 1.02-1.53; p = 0.038). Significant correlations between fluid biomarkers and neuropsychological examination were only found with NfL levels. CONCLUSIONS: Plasma NfL levels objectively differentiates PD-MCI from PD-NC patients, and may serve as a plasma biomarker for predicting progression to dementia in PD. Plasma levels of p-tau181 does not seem to help in differentiating PD-MCI or to predict future cognitive deterioration.

Apathy Reflects Extra-Striatal Dopaminergic Degeneration in de novo Parkinson's Disease.

BACKGROUND: Apathy represents a core neuropsychiatric symptom in Parkinson's disease (PD). As there is currently no established effective treatment for apathy in PD, further investigating the biological origin of this symptom is needed to design novel therapeutic strategies. Among the multiple neurotransmitter alterations that have been associated with apathy, the involvement of extra-striatal dopaminergic degeneration remains to be fully explored. OBJECTIVE: To investigate whether apathy in PD reflects increased dopaminergic degeneration extending beyond striatal regions. METHODS: In the de novo PD cohort of the Parkinson's Progression Markers Initiative (PPMI), we performed whole-brain I123-Ioflupane Single Photon Emission Computed Tomography (DAT-SPECT) analyses to characterize cross-sectional and longitudinal differences in DAT uptake associated with the presence of apathy. We also assessed the relationship between apathy and cognition in this sample, as apathy has been suggested to herald cognitive decline. RESULTS: Apathetic PD patients (N = 70) had similar sociodemographic, clinical, and biomarker profiles compared to the non-apathetic group (N = 333) at baseline. However, apathy was associated with an increased risk of developing cognitive impairment after a four-year follow-up period (p = 0.006). Compared to non-apathetic patients, apathetic patients showed a widespread reduction of extra-striatal DAT uptake at baseline as well as an increased longitudinal loss of DAT uptake (corrected p < 0.05). CONCLUSIONS: Isolated apathy in PD is associated with extra-striatal dopaminergic degeneration. As this abnormal dopamine depletion was in turn related to cognitive performance, this might explain, at least partially, the increased risk of apathetic PD patients to develop cognitive impairment or dementia.

Tipping the scales: how clinical assessment shapes the neural correlates of Parkinson's disease mild cognitive impairment.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with consistent structural and functional brain changes. Whether different approaches for diagnosing PD-MCI are equivalent in their neural correlates is presently unknown. We aimed to profile the neuroimaging changes associated with the two endorsed methods of diagnosing PD-MCI. We recruited 53 consecutive non-demented PD patients and classified them as PD-MCI according to comprehensive neuropsychological examination as operationalized by the Movement Disorders Task Force. Voxel-based morphometry, cortical thickness, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. 18 patients (32%) were classified as PD-MCI with Level-II criteria, 19 (33%) with the Parkinson's disease Cognitive Rating Scale (PD-CRS) and 32 (60%) with the Montreal Cognitive Assessment (MoCA) scale. Though regions of atrophy differed across classifications, reduced gray matter in the precuneus was found using both Level-II and PD-CRS classifications in PD-MCI patients. Patients diagnosed with the PD-CRS also showed extensive changes in cortical thickness, concurring with the MoCA in regions of the cingulate cortex, and again with Level-II regarding cortical thinning in the precuneus. Functional connectivity analysis found higher coherence within salience network regions of interest, and decreased anticorrelations between salience/central executive and default-mode networks in the PD-CRS classification for PD-MCI patients. Graph theoretical metrics showed a widespread decrease in node degree for the three classifications in PD-MCI, whereas betweenness centrality was increased in select nodes of the default mode network (DMN). Clinical and neuroimaging commonalities between the endorsed methods of cognitive assessment suggest a corresponding set of neural correlates in PD-MCI: loss of structural integrity in DMN structures, mainly the precuneus, and a loss of weighted connections in the salience network that might be counterbalanced by increased centrality in the DMN. Furthermore, the similarity of the results between exhaustive Level-II and screening Level-I tools might have practical implications in the search for neuroimaging biomarkers of cognitive impairment in Parkinson's disease.

Neural signatures of predictive language processing in Parkinson's disease with and without mild cognitive impairment.

Cognitive deficits are common in Parkinson's disease (PD), with some PD patients meeting criteria for mild cognitive impairment (MCI). An unaddressed question is whether linguistic prediction is preserved in PD. This ability is nowadays deemed crucial for achieving fast and efficient comprehension, and it may be negatively impacted by cognitive deterioration in PD. To fill this gap of knowledge, we used event-related potentials (ERPs) to evaluate mechanisms of linguistic prediction in a sample of PD patients (on dopamine compensation) with and without MCI. To this end, participants read sentence contexts that were predictive or not about a sentence-final word. The final word appeared after one sec, matching or mismatching the prediction. The introduction of the interval allowed to capture neural responses both before and after sentence-final words, reflecting semantic anticipation and semantic processing. PD patients with normal cognition (N = 58) showed ERP responses comparable to those of matched controls. Specifically, in predictive contexts, a slow negative potential developed prior to sentence-final words, reflecting semantic anticipation. Later, expected words elicited reduced N400 responses (compared to unexpected words), indicating facilitated semantic processing. PD patients with MCI (N = 20) showed, in addition, a prolongation of the N400 congruency effect (compared to matched PD patients without MCI), indicating that further cognitive decline impacts semantic processing. Finally, lower verbal fluency scores correlated with prolonged N400 congruency effects and with reduced pre-word differences in all PD patients (N = 78). This relevantly points to a role of deficits in temporal-dependent mechanisms in PD, besides prototypical frontal dysfunction, in altered semantic anticipation and semantic processing during sentence comprehension.

Quantitative evaluation of oculomotor disturbances in progressive supranuclear palsy.

OBJECTIVES: To explore and quantify systematically the ocular abnormal movements present in progressive supranuclear palsy (PSP) from the early stages, to assess the ability of this standardized examination in the differential diagnosis of PSP from Parkinson's disease (PD), and to compare in more detail oculomotor disturbances between PSP variants. METHODS: Sixty-five consecutive PSP patients with <5 years of disease duration diagnosed according to MDS-PSP criteria, 25 PD patients and 25 controls comparable in age, education and disease duration were explored using a bedside battery of tests for the quantitative evaluation of oculomotor dysfunction in clinical practice. Other accepted scales were used for measurement of motor (PSPRS), cognitive (FAB) and behavioral (FBI) impairment. RESULTS: Measurement of oculomotor dysfunction significantly differentiated PSP from PD and controls (p < 0.001) and showed high accuracy in the differential diagnosis of early-to-mid stage PSP from PD. PSP-Parkinsonism and PSP-Progressive Gait Freezing phenotypes showed more preserved ocular motor function compared to PSP-Richardson Syndrome, although no differences were found between PSP subtypes in the number of square wave jerks, optokinetic nystagmus defects, degree of apraxia of eyelid opening, or presence of the "Round the Houses" sign. CONCLUSIONS: Using a bedside clinical instrument for quantifying oculomotor disturbances in PSP shows promising potential at differentiating PSP from PD, and it seems able to provide a qualitative and quantitative description of ocular motor function in parkinsonian disorders.

Cognitive and behavioral profile of progressive supranuclear palsy and its phenotypes.

BACKGROUND: Although several progressive supranuclear palsy (PSP) phenotypes have recently been described, studies identifying cognitive and neuropsychiatric differences between them are lacking. METHODS: An extensive battery of cognitive and behavioural assessments was administered to 63 PSP patients, 25 PD patients with similar sociodemographic characteristics, and 25 healthy controls. We analysed differences in phenomenology, frequency and severity of cognitive and neuropsychiatric symptoms between PSP, PD and HC, and between PSP subtypes. RESULTS: Regarding phenotypes, 64.6% met criteria for Richardson's syndrome (PSP-RS), 10.7% PSP with predominant Parkinsonism (PSP-P), 10.7% with PSP progressive gait freezing (PSP-PGF), and 10.7% PSP with predominant speech/language disorder (PSP-SL). Impairment was more severe in the PSP group than in the PD and HC groups regarding motor scores, cognitive testing and neuropsychiatric scales. Cognitive testing did not clearly differentiate between PSP phenotypes, but PSP-RS and PSP-SL appeared to have more cognitive impairment than PSP-PGF and PSP-P, mainly due to an increased impairment in frontal executive domains. Regarding neuropsychiatric disturbances, no specific behavior was more common in any of the PSP subtypes. CONCLUSION: Motor deficits delineate the phenotypes included in currently accepted MDS-PSP criteria. Cognition and behavioural disturbances are common in PSP and allow us to distinguish this disorder from other neurological diseases, but they do not differentiate between PSP phenotypes.

Extrastriatal SPECT-DAT uptake correlates with clinical and biological features of de novo Parkinson's disease.

Striatal dopamine transporter (DAT) uptake assessment through I123-Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid α-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val158met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD.

Subclinical affective and cognitive fluctuations in Parkinson's disease: a randomized double-blind double-dummy study of Oral vs. Intrajejunal Levodopa.

BACKGROUND: Chronic levodopa treatment in Parkinson's disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous infusion of levodopa/carbidopa intestinal gel (LCIG) in advanced PD reduces motor fluctuations. However, differences in their effect on acute non-motor changes were not formally demonstrated. OBJECTIVE: We performed a randomized, double-blind, double-dummy, crossover study to compare acute non-motor changes between intermittent oral immediate-release carbidopa/levodopa (LC-IR) and LCIG. METHODS: After > 12-h OFF, thirteen PD patients chronically treated with LCIG and without history of non-motor swings, were allocated to receive first, LCIG infusion plus three oral doses of placebo, or placebo infusion plus three oral doses of LC-IR. Over-encapsulated oral medication (LC-IR or placebo) was administered every 2 h. We monitored plasmatic levels of levodopa, motor status (UPDRS-III), mood, anxiety, and frontal functions at baseline (0-h) and hourly after each oral challenge. RESULTS: Repeated-measures ANOVAs showed significant group by treatment interaction indicating more fluctuations of levodopa plasma levels with LC-IR. No significant interactions were seen in the temporal profile of motor status, anxiety, mood and cognition. However, point-to-point parametric and nonparametric tests showed a significant more marked and more sustained improvement in anxiety scores under LCIG. A significant improvement of mood and verbal fluency was seen a + 3-h only under LCIG. DISCUSSION: Our sample of advanced PD patients exhibited moderate but significant non-motor fluctuations. LCIG was associated with a more favorable profile of acute affective and cognitive fluctuations that was particularly expressed at the first part of the infusion curve.

Increased plasma neurofilament light chain levels in patients with type-1 diabetes with impaired awareness of hypoglycemia.

INTRODUCTION: Impaired awareness of hypoglycemia (IAH) is a common complication in patients with type-1 diabetes (T1D). IAH is a major risk factor for severe hypoglycemic events, leading to adverse clinical consequences and cerebral damage. Non-invasive, cost-effective, and logistically efficient biomarkers for this condition have not been validated. Here, we propose plasma neurofilament light chain (NfL) levels as a biomarker of neuroaxonal damage in patients with T1D-IAH. RESEARCH DESIGN AND METHODS: 54 patients were included into the study (18 T1D-IAH, 18 T1D with normal awareness of hypoglycemia (NAH) and 18 healthy controls). We measured plasma NfL levels and studied cerebral gray matter alterations on MRI. RESULTS: We found that NfL levels were increased in patients with T1D-IAH compared with patients with T1D-NAH and healthy controls. Importantly, increased NfL levels correlated with reduced cerebral gray matter volume and increased IAH severity in patients with T1D-IAH. CONCLUSION: Overall, our findings identify plasma NfL levels as a potential biomarker of cerebral damage in this population, motivating further confirmatory studies with potential implications in clinical trials.