Reprint of: The impact of alpha-1-adrenergic receptor antagonists on the progression of Parkinson disease.

BACKGROUND: Alpha-1-adrenergic receptor antagonists (AARAs) are used in the treatment of benign prostatic hypertrophy. Some AARAs, such as terazosin, stimulate glycolysis and increase cellular adenosine triphosphate levels through activation of phosphoglycerate kinase 1 (PGK1), which has been suggested to be of therapeutic benefit in patients with Parkinson disease (PD). OBJECTIVE: This study aimed to determine whether exposure to PGK1-activating AARAs was associated with slower PD progression. METHODS: National Veterans Affairs administrative data were used to identify patients who initiated PD-related pharmacotherapy during 2000 to 2019 and were concurrently prescribed an AARA. Using a retrospective cohort design, the count of incident PD-related outcome events within 1 year of follow-up was contrasted between patients prescribed a PGK1-activating AARA versus tamsulosin (an AARA without PKG1 stimulation), using multivariable negative binomial regression. PD-related outcome events were identified using ICD codes indicating motor symptoms, nonmotor symptoms, and other potential complications as clinical markers for the progression of PD. RESULTS: A total of 127,142 patients initiated drug therapy for PD during the observation period, of whom 24,539 concurrently received an AARA. Incident PD-related events were observed significantly less often in patients receiving a PGK1 AARA (n = 14,571) than tamsulosin (n = 9968) (incidence rate ratio [IRR] 0.80 [95% CI 0.77-0.83]). These results remained significant after adjustment for confounding factors (IRR 0.85 [95% CI 0.81-0.88]) and in sensitivity analyses. CONCLUSION: Patients prescribed a PGK1-activating AARA experienced fewer PD-related outcome events than patients prescribed tamsulosin. These results may indicate a role for terazosin and other PGK1 activators in slowing disease progression of PD; however, randomized controlled trials are needed.

A pilot dose-finding study of Terazosin in humans.

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.

The human subthalamic nucleus transiently inhibits active attentional processes.

The subthalamic nucleus (STN) of the basal ganglia is key to the inhibitory control of movement. Consequently, it is a primary target for the neurosurgical treatment of movement disorders like Parkinson's Disease, where modulating the STN via deep-brain stimulation (DBS) can release excess inhibition of thalamo-cortical motor circuits. However, the STN is also anatomically connected to other thalamo-cortical circuits, including those underlying cognitive processes like attention. Notably, STN-DBS can also affect these processes. This suggests that the STN may also contribute to the inhibition of non-motor activity, and that STN-DBS may cause changes to this inhibition. We here tested this hypothesis in humans. We used a novel, wireless outpatient method to record intracranial local field potentials (LFP) from STN DBS implants during a visual attention task (Experiment 1, N=12). These outpatient measurements allowed the simultaneous recording of high-density EEG, which we used to derive the steady-state visual evoked potential (SSVEP), a well-established neural index of visual attentional engagement. By relating STN activity to this neural marker of attention (instead of overt behavior), we avoided possible confounds resulting from STN's motor role. We aimed to test whether the STN contributes to the momentary inhibition of the SSVEP caused by unexpected, distracting sounds. Furthermore, we causally tested this association in a second experiment, where we modulated STN via DBS across two sessions of the task, spaced at least one week apart (N=21, no sample overlap with Experiment 1). The LFP recordings in Experiment 1 showed that reductions of the SSVEP after distracting sounds were preceded by sound-related γ-frequency (>60Hz) activity in the STN. Trial-to-trial modeling further showed that this STN activity statistically mediated the sounds' suppressive effect on the SSVEP. In Experiment 2, modulating STN activity via DBS significantly reduced these sound-related SSVEP reductions. This provides causal evidence for the role of the STN in the surprise-related inhibition of attention. These findings suggest that the human STN contributes to the inhibition of attention, a non-motor process. This supports a domain-general view of the inhibitory role of the STN. Furthermore, these findings also suggest a potential mechanism underlying some of the known cognitive side-effects of STN-DBS treatment, especially on attentional processes. Finally, our newly-established outpatient LFP recording technique facilitates the testing of the role of subcortical nuclei in complex cognitive tasks, alongside recordings from the rest of the brain, and in much shorter time than perisurgical recordings.

Resting-state EEG measures cognitive impairment in Parkinson's disease.

Cognitive dysfunction is common in Parkinson's disease (PD). We developed and evaluated an EEG-based biomarker to index cognitive functions in PD from a few minutes of resting-state EEG. We hypothesized that synchronous changes in EEG across the power spectrum can measure cognition. We optimized a data-driven algorithm to efficiently capture these changes and index cognitive function in 100 PD and 49 control participants. We compared our EEG-based cognitive index with the Montreal cognitive assessment (MoCA) and cognitive tests across different domains from National Institutes of Health (NIH) Toolbox using cross-validations, regression models, and randomization tests. Finally, we externally validated our approach on 32 PD participants. We observed cognition-related changes in EEG over multiple spectral rhythms. Utilizing only 8 best-performing electrodes, our proposed index strongly correlated with cognition (MoCA: rho = 0.68, p value < 0.001; NIH-Toolbox cognitive tests: rho ≥ 0.56, p value < 0.001) outperforming traditional spectral markers (rho = -0.30-0.37). The index showed a strong fit in regression models (R2 = 0.46) with MoCA, yielded 80% accuracy in detecting cognitive impairment, and was effective in both PD and control participants. Notably, our approach was equally effective (rho = 0.68, p value < 0.001; MoCA) in out-of-sample testing. In summary, we introduced a computationally efficient data-driven approach for cross-domain cognition indexing using fewer than 10 EEG electrodes, potentially compatible with dynamic therapies like closed-loop neurostimulation. These results will inform next-generation neurophysiological biomarkers for monitoring cognition in PD and other neurological diseases.

Digital driving data can track driving exposure and quality of life in Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) impairs motor and non-motor functions. Driver strategies to compensate for impairments, like avoiding driving in risky environments, may reduce on-road risk at the cost of decreasing driver mobility, independence, and quality of life (QoL). It is unclear how PD symptoms link to driving risk exposure, strategies, and QoL. We assessed associations between PD symptoms and driving exposure (1) overall, (2) in risky driving environments, and (3) in relationship to QoL. METHODS: Twenty-eight drivers with idiopathic PD were assessed using the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and RAND 36-Item Short Form Health Survey (SF-36). Real-world driving was monitored for 1 month. Overall driving exposure (miles driven) and risky driving exposure (miles driven in higher risk driving environments) were assessed across PD symptom severity. High traffic, night, and interstate roads were considered risky environments. RESULTS: 18,642 miles (30,001 km) driven were collected. Drivers with PD with worse motor symptoms (MDS-UPDRS Part III) drove more overall (b = 0.17, P < .001) but less in risky environments (night: b = -0.35, P < .001; interstate roads: b = -0.23, P < .001; high traffic: b = -0.14, P < .001). Worse non-motor daily activities symptoms (MDS-UPDRS Part I) did not affect overall driving exposure (b = -0.05, P = .43) but did affect risky driving exposure. Worse non-motor daily activities increased risk exposure to interstate (b = 0.36, P < .001) and high traffic (b = 0.09, P = .03) roads while reducing nighttime risk exposure (b = -0.15, P = .01). Daily activity impacts from motor symptoms (MDS-UPDRS Part II) did not affect distance driven. Reduced driving exposure (number of drives per day) was associated with worse physical health-related QoL (b = 2.87, P = .04). CONCLUSIONS: Results provide pilot data revealing specific PD symptom impacts on driving risk exposure and QoL. Drivers with worse non-motor impairments may have greater risk exposure. In contrast, drivers with worse motor impairments may have reduced driver risk exposure. Reduced driving exposure may worsen physical health-related QoL. Results show promise for using driving to inform clinical care.

The impact of alpha-1-adrenergic receptor antagonists on the progression of Parkinson disease.

BACKGROUND: Alpha-1-adrenergic receptor antagonists (AARAs) are used in the treatment of benign prostatic hypertrophy. Some AARAs, such as terazosin, stimulate glycolysis and increase cellular adenosine triphosphate levels through activation of phosphoglycerate kinase 1 (PGK1), which has been suggested to be of therapeutic benefit in patients with Parkinson disease (PD). OBJECTIVE: This study aimed to determine whether exposure to PGK1-activating AARAs was associated with slower PD progression. METHODS: National Veterans Affairs administrative data were used to identify patients who initiated PD-related pharmacotherapy during 2000 to 2019 and were concurrently prescribed an AARA. Using a retrospective cohort design, the count of incident PD-related outcome events within 1 year of follow-up was contrasted between patients prescribed a PGK1-activating AARA versus tamsulosin (an AARA without PKG1 stimulation), using multivariable negative binomial regression. PD-related outcome events were identified using ICD codes indicating motor symptoms, nonmotor symptoms, and other potential complications as clinical markers for the progression of PD. RESULTS: A total of 127,142 patients initiated drug therapy for PD during the observation period, of whom 24,539 concurrently received an AARA. Incident PD-related events were observed significantly less often in patients receiving a PGK1 AARA (n = 14,571) than tamsulosin (n = 9968) (incidence rate ratio [IRR] 0.80 [95% CI 0.77-0.83]). These results remained significant after adjustment for confounding factors (IRR 0.85 [95% CI 0.81-0.88]) and in sensitivity analyses. CONCLUSION: Patients prescribed a PGK1-activating AARA experienced fewer PD-related outcome events than patients prescribed tamsulosin. These results may indicate a role for terazosin and other PGK1 activators in slowing disease progression of PD; however, randomized controlled trials are needed.