ABSTRACT
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.
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.
•Little is known about the significance of extrastriatal SPECT-DAT alterations in PD.•Cortical reductions in SPECT-DAT uptake in de novo PD patients are described.•These alterations correlated with the patient's motor and cognitive status.•Extrastriatal DAT uptake was also associated with CSF α-syn levels and COMT genotype.•These findings motivate the study of extrastriatal SPECT-DAT in PD.
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.
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.
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-β and tau pathology.
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.
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.
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.
BackgroundPrimary orthostatic tremor (POT) is a rare disorder for which current treatments are largely ineffective. Following up on our recent report of complete resolution of POT symptoms in a ...patient using low doses of perampanel, we describe our experience of perampanel in 20 patients. MethodsTwenty patients whose neurologists prescribed perampanel were recruited. Initial dose was 2 mg/day, which was increased to 4 mg/day after the first month. Treatment efficacy was self-scored from +3 to -3 at 1 and 3 months. ResultsEight patients withdrew due to adverse effects. Of the 12 patients who completed the study, 92% indicated that their POT symptoms had improved after 1 month, with 75% indicating moderate to marked improvement (mean score 1.9 ± 0.9). This improvement was not sustained by follow-up at 3 months (mean score 0.9 ± 1.3). A rebound of POT symptoms that lasted 2-6 weeks was observed in most patients who withdrew. DiscussionOur experience with this series of cases points to the potential of low-dose perampanel as a treatment for POT, although poor tolerance and the possibility of a non-persistent therapeutic benefit need to be considered. Controlled studies are needed to confirm these findings.
Background. The current classification of tremor types in Parkinson disease (PD) is potentially confusing, particularly for mixed tremor, and there is no label for pure resting tremor. With a view to ...better defining the clinical phenomenological classification of these tremors, our group relabeled the different types as follows: pure resting tremor (type I); mixed resting and action tremor with similar frequencies (type II) divided, according to action tremor presentation, into II-R when there is a time lag and II-C otherwise; pure action tremor (type III); and mixed resting and action tremor with differing frequencies (type IV). We performed a descriptive study to determine prevalence and clinical correlates for this new tremor classification. Patient/Methods. A total of 315 consecutively recruited patients with PD and tremor were clinically evaluated. X2 tests were used to assess tremor type associations with categorical variables, namely, sex, family history of PD, motor fluctuations, and anticholinergic and beta-blocker use. With tremor type as the independent variable, ANOVA was performed to study the relationship between dependent quantitative variables, namely, age, age at PD diagnosis, disease duration, and UPDRS scores for rigidity. Results. The studied patients had tremor types as follows: type I, 30%; type II, 50% (II-R, 25% and II-C, 25%); type III, 19%; and type IV, 1%. No significant association was found between the studied clinical variables and tremor types. Conclusions. Mixed tremor was the most common tremor type in our series of patients with PD according to our proposed classification, which we hope will enhance understanding of the broad clinical phenomenology of PD.
The MAPT H1 haplotype has been identified as a predictor of cognitive decline in Parkinson's disease (PD). However, its underlying pathological mechanisms have not been fully established. In this ...work, using a cohort of 120
PD patients with preserved cognition from the Parkinson's Progression Markers Initiative (PPMI) database, we found that patients who were homozygous for MAPT H1 had less gray matter volume (GMV) and greater 1-year GMV loss than patients without this genetic profile. Importantly, these changes were associated with a longitudinal worsening of cognitive indicators. Our findings suggest that early GMV loss in MAPT H1H1 PD patients increases their risk to develop cognitive decline.
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