Objective: To explore the feasibility of repurposing candesartan for the treatment of cognitive impairment and neuropsychiatric symptoms in PD.

Background: There is an urgent need to explore novel compounds targeting biological mechanisms implicated in the pathophysiology of PD with potential to improve or halt the progression of cognitive impairment (CI). A neuroinflammatory response induced by microglia activation accompanies widespread cortical α-synuclein deposition, a major driver of progressive CI in PD. These changes can be inhibited by AT1-Bs like candesartan.

Method: 28-week, single-site, double-blind, placebo-controlled trial (Eudra 2016-000679-25). 36 participants with different degrees of PD-CI [PD-subjective cognitive complaints (PD-SCC); mild cognitive impairment (PD-MCI); and mild dementia (PDD)] were randomized (1:1) to candesartan (4mg for 4 weeks; 8mg for 20 weeks; 4mg for other 4 weeks) or placebo. Safety and tolerability measures were obtained at weeks 4, 12, 16, 24 and after treatment withdrawn at week 28. Efficacy outcome was mean change in global cognitive status as measured with the Parkinson’s Disease Cognitive Rating Scale (PD-CRS) from baseline to week 24. Secondary outcomes included specific cognitive tests, mood and apathy measures.

Results: Thirty subjects (PD-SCC=11; PD-MCI=13; PDD=6; candesartan=14; placebo=16) completed the study. Adverse events were mild with no serious events related to candesartan and with no worsening of motor or behavioral status. No significant interaction was found for global cognitive status. Treatment with candesartan was associated with significant improvement on apathy scores as measured with the Apathy Scale (AS) [p=0.045].
Post-hoc t-test analysis showed a significant difference between groups in the measure of change between 28-week and baseline [p=0.037] mediated by a significant decrease of -2.46±5.7 in apathy severity in the candesartan group and a significant increase of 4.1±10.3 in the placebo group.

Conclusion: Candesartan is safe and well tolerated but produced no objective differences in global cognitive status of patients with different degrees of CI. Attending to the candesartan mechanism of action this failure may be both due to the relatively short period of study or to the advanced stages of cognitive impairment in many patients. Improvement on apathy scores deserves further studies.

References: Rodriguez-Perez AI et al. Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death. Neurotherapeutics 2018.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-double-blind-randomized-clinical-trial-to-evaluate-the-effects-of-candesartan-for-cognitive-and-neuropsychiatric-impairment-in-parkinsons-disease/