A Randomized Phase 2 KINETIC Trial Evaluating SAGE-324/BIIB124 in Individuals with Essential Tremor.

BACKGROUND: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABAA receptors. OBJECTIVE: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET). METHODS: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo. RESULTS: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder. CONCLUSION: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS: We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS: Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS: MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

Parallel PARKing: Parkinson's genes function in common pathway.

Parkinson's disease (PD) is associated with diverse genetic and environmental susceptibilities. Functional connections between PD genes have remained elusive. In this issue of Neuron, MacLeod et al. (2013) link three PD susceptibility genes, LRRK2, PARK16, and VSP35, to a common cellular pathway and show how these deficits contribute to dysfunction.

The curious case of phenocopies in families with genetic Parkinson's disease.

Monogenic forms of Parkinson's disease account for ∼3% of all "idiopathic" Parkinson's disease. With reduced penetrance in dominant forms and manifesting heterozygotes in recessive forms of Parkinson's disease, it has been well recognized that inheritance patterns do not always follow classic Mendelian genetics. A novel twist to the puzzle is the presence of phenocopies (i.e., family members with the same clinical syndrome as the mutation carriers, but lacking the familial mutation). We reviewed all pedigrees published between 1997 and 2009 with α-synuclein, leucine-rich repeat kinase 2, Parkin, or PTEN-induced kinase 1 mutations with at least 2 affected individuals and known genetic status for the possible presence of phenocopies. Of 537 patients with clinical Parkinson's disease in 160 families meeting our inclusion criteria, 27 patients (5.0%) from 23 families (14.4%) were phenocopies. Phenocopies represented 3.8% of all blood relatives reported in the pedigrees containing phenocopies and an estimated 1.3% of all blood relatives in all pedigrees included. Both of these rates exceeded age-specific prevalences of Parkinson's disease. In 4 families, the phenocopy was explained by another known mutation: In 2 pedigrees, a monogenic cause was likely; in another 2, secondary parkinsonism was suspected; and in the remaining 15 families, "sporadic Parkinson's disease" was suggested as the cause of disease in the phenocopy. The unexpectedly high number of phenocopies of mostly unknown origin within families with a seemingly known etiology of Parkinson's disease adds another level of complexity to genetic research of Parkinson's disease, as well as to the interpretation of genetic testing results in the clinical diagnostic setting.

Serotonin and Parkinson's disease: On movement, mood, and madness.

An appreciation of the multiple roles that serotonin (5-HT) may play in Parkinson's disease (PD) has increased in recent years. Early pathological studies in PD demonstrated nonselective reductions of 5-HT in brain tissue but little correlation to comorbidities such as dyskinesia and mood disturbance. This, combined with treatment failures using serotonergic drugs in comparison to levodopa, meant the field was largely neglected until recently. The multitude of subtypes of 5-HT receptors in the brain and an increased understanding of the potential function 5-HT may play in modulating other neurotransmitter systems, including dopamine, GABA, and glutamate, have meant an expansion in efforts to develop potential serotonergic drugs for both motor and nonmotor symptoms in PD. However, several unanswered questions remain, and future studies need to focus on correlating changes in 5-HT neurotransmission in both pathological and in vivo imaging studies with a full clinical phenotype.

Parkinson's disease--opportunities for novel therapeutics to reduce the problems of levodopa therapy.

Long-term treatment for Parkinson's disease (PD) with the dopamine-precursor levodopa (l-DOPA) results in the development of motor fluctuations, including involuntary movements, termed l-DOPA-induced dyskinesia (LID). Currently, effective treatments for LID are limited. The neurodegenerative processes underlying PD result in loss of serotonin (5-HT) input from the dorsal raphe nucleus (DRN) to the striatum, but to a lesser extent than loss of dopamine input. l-DOPA may be converted to dopamine in remaining serotonergic neurons and the non-physiological release of dopamine may lead to abnormal dopamine receptor stimulation in the striatopallidal pathways and result in the generation of LID. Suppressing the activity of these 5-HT inputs to the striatum via presynaptic 5-HT(1A) agonists may reduce LID. However, to date, studies with 5-HT(1A) agonists have suggested a reduction in LID, but with worsening PD disability. Postsynaptic 5-HT(2A) and 5-HT(2C) receptors in the striatum may modulate dopamine to reduce LID and the atypical antipsychotic, clozapine is effective at reducing LID without worsening PD. Alternatively, postsynaptic 5-HT(1A), presynaptic 5-HT(1B/1D) receptors and 5-HT(2C) receptors may modulate GABA and glutamate release within other basal ganglia nuclei to reduce LID. Thus, 5-HT ligands can modulate basal ganglia function and hence motor function through several receptor subtypes and locations, with potential therapeutic benefit to the motor complications induced by long-term l-DOPA therapy in PD. Future studies are needed to develop 5-HT selective drugs that can reduce LID without affecting the anti-parkinsonian action of l-DOPA.