Jordan L. Schultz

Background: Parkinson's disease (PD) is a common neurodegenerative disease lacking treatments that modify progressive neuron loss. Terazosin (TZ) increases activity of the glycolytic enzyme phosphoglycerate kinase 1 and could potentially benefit impaired brain bioenergetics in PD. Preclinical data are encouraging, but we lack human data on relationships between TZ dose and measures of TZ target engagement in women and men. Objective: This study evaluated the dose-dependent effects of TZ on brain and systemic bioenergetics and safety and tolerability in neurologically healthy older adults. Methods: We administered TZ (1, 5, and 10 mg/day) to 18 neurologically healthy 60–85-year-old people. We measured plasma and cerebrospinal fluid TZ concentrations and changes in levels of whole blood ATP, brain ATP with ³¹ P magnetic resonance spectroscopy, cerebral metabolic activity with ¹⁸ F-FDG PET imaging, and plasma metabolomics. We also assayed tolerability and safety. Results: TZ crossed the blood-brain barrier, and 5 mg/day increased whole blood ATP and decreased brain ¹⁸ F-FDG uptake. TZ 1 mg/day lacked significant effects, and 10 mg/day did not produce additional metabolic benefit compared to 5 mg/day. These effects were similar for both sexes. Mild dizziness occurred in 3 females and 1 male. Conclusions: These findings in humans align with results from preclinical cell, animal, and epidemiological studies. Our data show that TZ increases markers of energy metabolism with a biphasic dose-response and suggest that 5 mg/day TZ may provide maximal benefit while minimizing adverse consequences of higher doses. These results lay groundwork for clinical trials in people with PD.

There is a need to understand how different factors influence health care utilization for patients with Huntington disease (HD) to maximize benefits of primary and specialty care while minimizing need for costly emergency visits or hospitalizations. The primary objective of this study was to characterize how settings where patients with HD in Northern America receive care change throughout the disease course and determine whether the likelihood of different types of service utilization is influenced by clinical, sociodemographic, and caregiver characteristics. Data from the Enroll-HD study and joinpoint regression were used to assess trends in neurology visits, general practitioner visits, emergency department visits, and inpatient stays over the disease course and as a function of total functional capacity. Generalized estimating equation models were then used to identify factors associated with use of these different services in the 6 months before their study visit. Visits from 1,631 participants in the Northern America region from the Enroll-HD study were included in this study. Trends in neurology, emergency, and inpatient visits remained constant over most of the disease duration. For the general practitioner visits, there was an increasing trend in use throughout the course of disease. Clinical factors, such as psychiatric symptoms, functional ability, and comorbidities, were associated with use of multiple types of health care services. Sociodemographic and caregiver factors, such as race or ethnicity, urban or rural residence, and caregiver employment status, were also associated with use of multiple health care services. Clinical, sociodemographic, and caregiver-related factors were all associated with outpatient, emergent, and inpatient care. This work identifies multiple avenues for future research on how to improve access to and quality of care for patients with HD, specifically relating to reducing the need for emergency visits and inpatient stays and promoting collaboration among primary and specialty clinicians.

Cognitive symptoms are common in Parkinson’s disease (PD), yet the underlying brain mechanisms remain poorly understood. To address this gap, we investigated the relationship between functional connectivity and cognition at multiple time points using longitudinal functional MRI (fMRI) and cognitive assessments from the Parkinson’s Progression Marker Initiative (PPMI). We calculated resting-state functional connectivity within and between three key cortical brain networks that have been linked with cognitive function in PD: the frontoparietal network (FPN); the salience network (SAL); and the default mode network (DMN). Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA). Linear mixed-effects modeling revealed that decreased FPN-DMN functional connectivity is associated with lower MoCA scores over time. This finding suggests that cortical connectivity is associated with and may contribute to the progression of cognitive symptoms in PD. Our findings advance knowledge about cognitive changes in PD and emphasize the importance of functional brain network architecture. Highlights We studied cortical functional connectivity and cognition in PD over time. FPN-DMN functional connectivity robustly predicted cognition at multiple time points. These data provide insight into brain networks underlying cognitive progression in PD.

Importance: Huntington disease (HD) is characterized by motor, cognitive, and psychiatric decline. β-Blockers may play a therapeutic role by decreasing enhanced sympathetic tone in HD.Objective: To evaluate the impact of β-blockers on the timing of motor diagnosis onset and progression of HD symptoms.Design, Setting, and Participants: This observational, longitudinal multicenter study used the Enroll-HD platform database (initiated September 2011 to present), including propensity score–matched cohorts of patients with premanifest HD (preHD) and early motor-manifest HD (mmHD) who were either users or nonusers of β-blockers. Participants included patients with genetically confirmed preHD (n = 4683 eligible participants) or mmHD (n = 3024 eligible participants) who were taking a β-blocker and were matched to similar non–β-blocker users.Exposure: Uninterrupted use of a β-blocker for more than 1 year.Main Outcomes and Measures: For PreHD: risk of receiving a motor diagnosis of HD over time. For mmHD: progression rate of total motor score, total functional capacity score, and the symbol digit modalities test. Post hoc analyses were performed to test additional clarifying hypotheses after the primary analyses were completed.Results: This study included 174 preHD β-blocker users (59 males; 115 females) with a mean age of 46.4 (SD, 13.1) years and a mean cytosine-adenine guanine repeat length of 41.1 (SD, 2.4) who were well matched to 174 preHD non–β-blocker users. The preHD β-blocker users showed a statistically significant reduction in the annualized hazard of receiving a motor diagnosis compared with nonusers (n = 174) (hazard ratio, 0.66; 95% CI, 0.46-0.94; P = .02). There were 149 mmHD β-blocker users (86 males; 60 females) with a mean age of 58.9 (SD, 11.3) years and a mean cytosine-adenine guanine repeat length of 42.0 (SD, 2.3) matched to 149 mmHD non–β-blocker users. The β-blocker users had a slower mean annualized worsening in total motor score (mean difference [MD], −0.45; 95% CI, −0.85 to −0.06; q = 0.025), total functional capacity score (MD, 0.10; 95% CI, 0.02-0.18; q = 0.025), and symbol digit modalities test (MD, 0.33; 95% CI, 0.10-0.56; q = 0.017) compared with matched nonusers.Conclusions and Relevance: In this study, β-blocker use was associated with delayed motor onset in preHD and reduced the rate of worsening of symptoms in mmHD. These findings demonstrated that β-blockers may have a therapeutic role in HD but further studies are required.

Background: Previous studies suggest that early developmental delay is a common feature of Juvenile‐Onset Huntington's disease (JOHD), with highest incidence in those with very high CAG repeats (> 80). However, all reports of developmental delay in JOHD are exclusively based on retrospective review of medical charts. Comprehensive assessment of birth history metrics may provide better insight into the question of early life development in JOHD.Objective: To explore the prevalence of prematurity, birth complications, low birth weight and developmental delay in patients with JOHD in comparison to control participants.Methods: Parents of patients with JOHD and gene‐non‐expanded (GNE) control participants from Kids‐HD (n = 104) and Kids‐JOHD (n = 34, 24% with CAG > 80) studies completed a comprehensive birth history questionnaire. Answers focused on prematurity, birth complications, and birth weight, and along with reports of early developmental milestones, were compared between groups.Results: There were no statistically significant differences in prematurity, birth weights, birth complications, or motor and verbal developmental milestones between JOHD patients and GNE controls (all P values > 0.1). Furthermore, stratifying JOHD patients by CAG expansion (low vs. high) also showed no significant differences (GNE vs. low or GNE vs. high).Conclusions: These findings support the notion that JOHD does not manifest as developmental delay before motor symptom onset and highlight a new framework to understand the course and nature of the disease.

Objective: Huntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging‐related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years‐to‐onset paradigm in a unique sample of children and young adults at risk for HD.Methods: Cognitive, behavioral, motor, and brain structural measures from premanifest gene‐expanded (n = 79) and gene nonexpanded (n = 112) participants (6–21 years) in the Kids‐HD study were examined. All measures in the gene‐expanded group were modeled using a mixed‐effects regression approach to assess years‐to‐onset‐based changes while controlling for normal growth. Simultaneously, structure–function associations were also examined.Results: Decades from motor onset, gene‐expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences.Interpretation: Mutant HTT may drive the development of a larger than normal brain that subserves superior early‐life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024;96:1006–1019

Background: Parkinson’s disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 – 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, ³¹ Phosphorous magnetic resonance spectroscopy for brain ATP levels, ¹⁸ F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral ¹⁸ F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ’s efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.