Parkinson’s disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

Objective To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study. Methods We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36–59) and GNE (CAG <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups. Results Four of the six striatal–cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6–12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range. Conclusion These results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.

Objective To determine whether tetrabenazine (TBZ) use is associated with an increased incidence of depression and/or suicidal ideation. Methods In this retrospective cross-sectional study of the Enroll-HD database, we used multiple logistic regression analyses to determine whether TBZ use is associated with an increased incidence of depression and/or suicidal ideation. For both dependent variables (depression and suicidality), separate analyses were conducted on (1) all participants, (2) only participants with a history of depression, and (3) only participants with no history of depression. Adjustments were made for CAG repeat length, total motor score, total functional capacity, Symbol Digit Modalities Test score, sex, disease duration, history of depression (when applicable), antipsychotic use, and antidepressant use. Results Compared to participants who were not using TBZ (n = 3,548), TBZ users (n = 543) did not have an increased risk of depression (odds ratio [OR] = 0.78, p = 0.064). Participants taking TBZ actually had a relatively lower risk of suicidality (OR = 0.61, p = 0.043). Among only participants with a history of depression, those using TBZ had a lower incidence of depression (OR = 0.71, p = 0.016) and suicidal ideation (OR = 0.57, p = 0.028) compared to those not using TBZ. Finally, among only participants with no history of depression, TBZ use was not associated with a higher incidence of depression (OR = 1.59, p = 0.18) or suicidality (OR = 1.43, p = 0.66) compared to those who were not using TBZ. Conclusions TBZ use was not associated with an increased incidence of depression or suicidality. These findings suggest that TBZ may be safe to use in patients with Huntington disease who have a history of depression.

Objective: To investigate the relationship between substances of abuse and age at motor onset (AMO) in patients with Huntington disease (HD) in a large and diverse patient population. Methods: This was a retrospective, observational study of the Enroll-HD database. Participants were determined to belong to 1 of 3 substance abuse groups: (1) tobacco abusers, (2) alcohol abusers, and (3) drug abusers. A group of participants who had never abused substances served as a control group. The average AMO of patients in the substance abuse groups was compared to the control group. The number of CAG repeats was used as a covariate in all analyses. Results: The average difference in AMOs of participants in the tobacco (n = 566), alcohol (n = 374), and drug abuse groups (n = 217) compared to the control group (n = 692) were 2.3 (F_{1, 1,258} = 33.8, p < 0.0001), 1.0 (F_{1, 1,066} = 4.2, p = 0.04), and 3.3 (F_{1, 909} = 29.7, p < 0.0001) years earlier, respectively. In all substance abuse groups, the AMO was lowered to a greater degree in female participants than it was in male participants. Conclusions: Substances of abuse have a strong effect on the AMO in patients with HD. These effects seem to be amplified in women with HD compared to men. These results may provide a safe intervention capable of adding disease-free years to patients with HD.

Objective To investigate the relationships between CAG repeat length in the huntingtin gene and cognitive performance in participants above and below the disease threshold for Huntington disease (HD), we performed a cross-sectional analysis of the Enroll-HD database. Methods We analyzed data from young, developing adults (≤30 years of age) without a history of depression, apathy, or cognitive deficits. We included participants with and without the gene expansion (CAG ≥36) for HD. All participants had to have a Total Functional Capacity Score of 13, a diagnostic confidence level of zero, and a total motor score of 28.6 years from their predicted motor onset. We performed regression analyses to investigate the nonlinear relationship between CAG repeat length and various cognitive measures controlling for age, sex, and education level. Results There were significant positive relationships between CAG repeat length and the Symbol Digit Modalities, Stroop Color Naming, and Stroop Interference test scores. There were significant negative relationships between CAG repeat length and scores on Parts A and B of the Trails Making Test (p < 0.05), indicating that longer CAG repeat lengths were associated with better performance. Discussion An increasing number of CAG repeats in the huntingtin gene below disease threshold and low pathologic CAG ranges were associated with some improvements in cognitive performance. These findings outline the relationship between CAG repeats within the huntingtin gene and cognitive development. Classification of Evidence This study provides Class IV evidence that CAG repeat length is positively associated with cognitive function across a spectrum of CAG repeat lengths.