How to advance the pharmacological management of cognitive impairment in Parkinson's disease

Abstract

Cognitive impairment is a common non-motor symptom in people with Parkinson's disease (PD) and is associated to poor clinical outcomes. Currently, rivastigmine is the only approved medication for PD dementia, and there are no treatments available for people with PD and mild cognitive impairment. To advance the pharmacological management of cognitive impairment in PD, it is essential to optimize clinical trial design. This includes refining cognitive outcome measures, ensuring longer study durations, and incorporating PD-specific cognitive assessments. Biomarkers offer valuable opportunities for screening, stratification, enrichment, and monitoring in trials, increasing the likelihood of detecting treatment effects. Additionally, adopting patient-centered approaches that prioritize inclusivity can enhance trial validity and address the current lack of diversity in PD studies. Digital cognitive assessments offer a promising tool for improving participation and enabling longitudinal monitoring, especially in underrepresented and mobility-challenged populations. By tackling these challenges, this review outlines strategies for advancing the pharmacological management of cognitive impairment in PD. It emphasizes the need for precise, inclusive, and biomarker-driven trials to accelerate drug development.

Plain summary

There is an urgent need to develop treatments for cognitive impairment in Parkinson's disease, as it is a common symptom associated with poor health outcomes, with only one approved medication for patients in the dementia stage. This review outlines strategies for advancing pharmacological management of cognitive impairment in Parkinson's disease. These strategies include implementing systematic diagnosis of cognition, improving clinical trial design by using biomarkers, refining cognitive assessments, and extending study duration; increasing diversity and inclusivity through a patient-centered approach, and adopting digital cognitive assessments to enhance participation and enable more effective tracking.

Background: The importance of cognitive impairment in Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disorder mainly characterized and defined by its cardinal motor features and a heterogeneous burden of non-motor symptoms. Among these, cognitive impairment is common and of particular significance for patients and their care partners with implications for quality of life, morbidity and mortality.^1,2 In this review, we will focus on the status of therapies targeting cognition in people with PD, describe how to diagnose and manage cognitive impairment in clinical practice, identifying key gaps and suggesting strategies for how to advance the field.

The risk of developing dementia is at least 3 times greater in people with PD relative to age-matched people without PD, with an annual risk of developing dementia of almost 5%. ³ Although cognition can be impaired early, even at time of diagnosis,^4,5 it usually occurs later in the disease course, and ten years after diagnosis up to 50% of patients with PD are diagnosed with dementia.^6,7 However, the trajectory of cognitive decline, both in speed of progression and time to onset, is highly variable and is influenced by various factors including age, disease severity, concomitant neuropsychiatric symptoms, ³ as well as the type and degree of neuropathological changes. Importantly, cognitive impairment and dementia are among the most feared consequences of PD and invariably associated with reduced functioning, higher dependency, reduced quality of life, increased risk of psychosis, and higher caregiver burden.^8–13

Establishing a diagnosis of dementia in PD (PDD) is important to optimize the management of patients and support for caregivers. PDD is most commonly defined by the Movement Disorders Society-endorsed PDD criteria which requires cognitive decline in at least two of four cognitive domains (executive function, attention, visuospatial function and memory) that is severe enough to impact daily activities. ¹⁴ Mild cognitive impairment (MCI) is identified when gradual cognitive decline is accompanied by impairment in two cognitive tests but without impairing functional independence. ¹⁵ While PD-MCI is usually a precursor to the development of dementia, reversals to normal cognition can also infrequently occur. ¹⁶

The main pathological substrate underlying cognitive impairment in PD is the rostral spread of alpha-synuclein (aSyn) accumulation, with accompanying synaptic pathology and neuronal loss, from the brain stem, to involve the forebrain, limbic structure, and neocortex.^17,18 However, co-pathologies are common (see below). The pathology invariably involves neurotransmitter systems beyond dopamine, including serotonergic, noradrenergic and cholinergic nuclei. Both clinically and pathologically PD is closely related to dementia with Lewy bodies (DLB). The current arbitrary distinction between the two syndromes is based on the relative timing of cognitive and motor symptoms. For example, if cognitive impairment occurs more than one year after onset of parkinsonism the diagnosis is PD. In contrast, significant cognitive impairment occurring before or simultaneously with the motor symptoms is labelled as DLB (the “one-year rule”). However, the recent advances in biomarker assessment of aSyn pathology using seeding amplification assays have led to a new classification proposal, that categorizes both DLB and PD as sub-types of neuronal synuclein disorders. ¹⁹ In this narrative review, we describe the current treatment landscape of cognitive impairment in PD, assessment and diagnostic procedures, and review the PD drug pipeline with a particular focus on cognition. We searched literature databases, clinical trial databases, and the reference lists of recent reviews and original scientific papers.

Current treatment landscape

Despite the increasing recognition of the importance of cognition for PD patients and their families, few treatment options exist. Current therapies for PD, such as levodopa, dopamine agonists or monoamine oxidase inhibitors, focus on dopamine replacement and do not reduce the risk of dementia. Moreover, drugs with anticholinergic properties are associated with worse long-term cognition ² and increased risk of dementia in older adults. ²⁰

Although the use of anticholinergic medications for PD motor symptoms has declined over time, ²¹ these drugs are still prescribed for non-motor symptoms and comorbid conditions, including depression, psychosis, allergies, urological incontinence, among others. ²² The mechanism by which anticholinergic drugs contribute to cognitive impairment remains unclear. However, a retrospective pathological study in PD patients found significantly higher levels of senile plaques and neurofibrillary tangles in those treated with anticholinergic drugs long-term, compared to those with short-term or no use. ²³ This finding suggests that anticholinergics may accelerate AD pathology in PD, thereby facilitating neurotoxicity. ²¹ Additionally, PD patients have 40% lower levels of CYP2D6, an enzyme critical for metabolizing anticholinergic drugs, compared to controls. ²⁴ Reduced CYP2D6 activity may alter anticholinergic metabolism in the brain, potentially increasing adverse events and long-term neurotoxicity. ²¹ As a result, the 2018 International Parkinson and Movement Disorder Society review recommends restricting the use of anticholinergics to young, cognitively intact PD patients, due to their unfavorable neuropsychiatric profile and the long-term risk of memory impairment. ²⁵

Cholinesterase inhibitors, particularly rivastigmine, remain the only approved treatment for cognitive impairment in PDD, showing significant benefits in cognitive and functional measures in a randomized controlled trial published 20 years ago^26,27 along with potential reductions in visual hallucinations. ²⁸ Even if there is no symptomatic improvement, there is robust evidence that this will have a positive cognitive effect over time. ²⁹ Memantine, a NMDA receptor antagonist, has also been investigated, but results have been inconsistent, with possible greater efficacy in DLB than in PD.^27,30,31 Currently, no disease modifying treatments are available to prevent or delay cognitive decline in PD, although this is an active area of clinical trial research. ³²

Additionally, no treatments have been approved for use in PD-MCI to date, and the few published trials, most of them with less than 100 participants and short duration, have shown limited or no clear benefit, ² including studies on rasagiline and rivastigmine.^33,34 Until recently PD-MCI was often overlooked as a clinical entity, and very few clinical trials have focused on it. However, there has been a recent shift in recognizing PD-MCI as an early, transitional stage toward PDD, where the pathological and symptomatic burden is circumscribed. Enrolling patients at this stage offers greater opportunity for intervention with potential to halt the progression of cognitive decline. Addressing this stage remains a major gap and an important need for future trials.

Diagnosis and management of cognitive impairment in clinical practice

A detailed history outlining the onset and development of cognitive decline is important, as well as identification of precipitating and maintaining factors. Interviewing an informant is usually helpful, in particular if cognition is markedly impaired. It is important to ascertain the degree of functional impairment due to cognitive decline, since this is essential for a dementia diagnosis. However, this can be difficult given the motor impairment and other symptoms affecting functioning. A detailed mental status examination, covering mood, anxiety, and perception is important, including standardized cognitive testing (see below). Routine laboratory analyses and a structural brain imaging are important to identify possible causes of cognitive impairment other than PD. Increased mental and physical activities can improve or at least reduce cognitive decline (see below). If dementia is diagnosed, a cholinesterase inhibitor, usually donepezil or rivastigmine, should be prescribed. If cholinesterase inhibitors are not well tolerated or contraindicated, memantine can be prescribed, although the evidence is less clear. ²⁷ Similarly, anticholinergics should be reserved for young, cognitively intact PD patients, and deprescribing should be considered for those with cognitive impairment.

Strategies for advancing pharmacological management of cognitive impairment in PD

Optimizing PD trials for cognitive impairment

Future clinical trials for symptomatic and disease-modifying treatments (DMTs) in PD should prioritize cognitive outcomes, since reducing the progression of pathology is likely to benefit cognition as well as motor function. A recent review commissioned by the International Parkinson and Movement Disorder Society Non-Motor Parkinson's Disease Study Group, covering 2016 to 2021, identified 178 clinical trials evaluating cognitive outcomes in PD. These interventions included pharmacological agents, cognitive training, physical training and devices, ³² with most trials involving cognitively normal people with PD. At the time of the review, most of the trials were in the recruitment phase (48%, n = 85), while approximately a quarter had been completed (26%, n = 46). The remaining trials were active (13%, n = 23), registered but not recruiting (9%, n = 16) or terminated/withdrawn (4%, n = 8). Of the 64 reported drug trials, only eight had published results, with few showing significant improvement, and no proven long-lasting effects. ³²

Notably, two phase 2 placebo-controlled randomized trials reported statistically significant cognitive benefits. A small trial (34 participants) of varenicline, a nicotinic agonist, found improvement in one attentional test out of 14 cognitive assessments after 3 weeks. ³⁵ Similarly, another phase 1 trial investigating plasma infusions in 15 PD patients showed improvement in phonemic fluency. ³⁶ However, other trials with 6 drugs focusing on cognition did not find improvements.

One of the larger studies, with 344 participants, investigated mevidalen, a dopamine agonist, reported positive effects on global efficacy but not in cognitive outcomes. ³⁷ Likewise, a phase 2 trial investigating nabilone, a synthetic tetrahydrocannabinol analogue, showed no improvement in Montreal Cognitive Assessments (MoCA) scores after 4 weeks despite other significant non-cognitive effects. ³⁸ Another phase 2 trial of prasinezumab, a monoclonal antibody targeting aSyn, found no difference in MoCA scores between treatment and placebo groups after 52 weeks. ³⁹ A phase 1 trial investigating allogenic bone marrow-derived mesenchymal stem cells in 20 PD patients found no cognitive improvement after 12 months. ⁴⁰ A trial of low-dose of niacin in 47 PD patients found no significant differences in cognitive flexibility and cognitive ability after 6 months. ⁴¹ Finally, a phase 3 trial investigating inosine, aimed at increasing urate levels over 2 years in 297 PD patients, found no significant changes in MoCA scores between placebo and treatment groups (NCT02642393; ClinicalTrials.gov).

In 2024, another systematic review of the PD drug pipeline reported 60 clinical trials investigating DMTs in PD. ⁴² These trials investigate the following therapeutic categories: anti-inflammatory therapies, targeting aSyn, antioxidants, cell therapy, energy and mitochondria, glucocerebrosidase (GBA), glucagon-like peptide-1 (GLP-1) receptor agonists, kinase inhibitors, leucine-rich repeat kinase 2 (LRRK2), microbiome/gastrointestinal tract, neurotrophic factors, among others. However, whether these clinical trials investigated cognitive outcome measures was not reported. Understanding how cognition is being assessed in clinical trials investigating DMTs is essential for advancing PD drug development.

Targeting alpha-synuclein and co-pathologies: Amyloid-β and tau

Targeting aSyn is one therapeutic approach for DMT in PD. Cognitive benefits of aSyn-targeting have been investigated in only two drugs: prasinezumab and minzasolmin. As noted, prasinezumab has not shown improvement in global cognition. Minzasolmin (UCB0599), a small molecule that inhibits aSyn aggregation, was evaluated in a phase 2, placebo-controlled study involving 496 participants over 18 months (NCT04658186; ClinicalTrials.gov), with results pending from the recently completed trial.

As research progresses, interest in understanding the pathologies underlying cognitive decline in PD is increasing. While limbic and cortical aSyn pathology is the main substrate, emerging evidence highlights the role of mixed pathologies that may influence treatment response. Postmortem studies show that 10–40% PD patients have concomitant amyloid-β plaques in the cortex, and about two-thirds of these patients also have phosphorylated tau deposits in cortical neurofibrillary tangles.^43,44 Moreover, these pathologies are often accompanied by amyloid angiopathy and neuroinflammation. ⁴⁵

Amyloid-β deposition, is not only common in PD, but is also associated with worse cognition.^45,46 This association has two key implications for clinical trials: (1) PD patients with concomitant amyloid-β deposition (or amyloidosis) might benefit from anti-amyloid therapies approved for Alzheimer's disease (AD), and (2) trials focused on cognition in PD should determine the presence of amyloidosis for stratification.

For PD patients with cognitive impairment, anti-amyloid treatments could be viable options, but rigorous clinical trials are needed to evaluate their efficacy and safety. Evidence suggests that PD patients with cognitive impairment and concomitant amyloidosis, measured by cerebrospinal fluid amyloid-β42 and plasma phosphorylated tau 181 (pTau181), have worse baseline global cognition and functional impairment, and experience more rapid functional and cognitive decline.^46–48 Furthermore, rapid increases in plasma pTau181 have been associated with accelerated decline in functional impairment and memory. ⁴⁸ Since more than a quarter of AD patients also have concomitant aSyn pathology,^49,50 which is associated with greater cognitive decline, ⁵¹ the reverse may hold true as well: aSyn-targeting treatments could be viable options for AD patients with co-existing aSyn pathology. The role of tau pathology for cognitive decline in PD is less studied but there is evidence of a relationship. Thus, recent developments in trials of tau-targeting drugs may also be relevant for PD. ⁵²

However, multiple pathologies may complicate treatment response. Although AD patients with concomitant Lewy bodies also show worse cognitive decline, ⁵¹ a recent case study reported by VandeVrede et al. highlights the challenges of treatment in patients with mixed pathologies. ⁵³ More studies are needed to better understand how mixed pathologies might influence treatment response.

Regarding clinical trials for symptomatic therapy, there are currently nine active trials in PD. Among these, six agents target neurotransmitters, specifically glutamatergic, adrenergic and cholinergic pathways. ⁴² The other 3 agents under investigation are doxycycline, levetiracetam, and intranasal insulin (Novolin). More than half of these agents are novel (55.6%, n = 5), followed by repurposed agents (33.3%, n = 3) and one agent with a new claim (11.1%, n = 1). ⁴²

Drug repurposing refers to applying established compounds to new therapeutic uses, and offers a faster, more cost-effective alternative to developing new treatments for cognitive impairment in PD. ⁵⁴ A 2022 review identified 70 potential repurposed drugs for PDD and DLB through a Delphi consensus. Of these, nine agents or drug classes were prioritized by at least two panel members: ambroxol, a drug that increases GBA enzymatic activity; the tyrosine kinase inhibitors nilotinib and bosutinib, the GLP-1 receptor agonists liraglutide and exenatide, metformin, the angiotensin receptor blockers candesartan and telmisartan, fasudil, etanercept, rasagiline, and salbutamol. ⁵⁴

Other approaches used to identify repurposed agents in PD include isolated clinical observations, observational studies, and target-driven strategies based on genetic susceptibility loci linked to genes with functional significance in PD. Methods such as gene expression profiling, transcriptional analysis, genome-wide association studies, and network-based analyses have also been employed.^55,56 Future studies exploring repurposed drugs for cognitive impairment in PD can leverage novel method such as artificial intelligence combined with open data science. These tools can help in molecular design, drug selection, predicting adverse events and drug interactions, calculating trial sample sizes based on clinical and biological variability, and analyzing clinical trial data to tailor outcomes to patients most likely to benefit most from the treatment. ⁵⁷

Using biomarkers in PD patients in cognitive trials

Biomarkers identify underlying neuropathological changes in vivo enabling earlier and more precise diagnosis.^19,58 For instance, new seeding amplification assays for aSyn can detect Lewy body disease from prodromal stages, ⁵⁹ offering the potential to identify patients for inclusion in clinical trials at the pre-clinical or MCI stages of PDD. This approach, already used in AD, ensures that trial participants have the underlying pathology, leading to a more homogeneous population and potentially accelerating drug development. The rapid development of biomarkers, including biofluids, molecular PET and EEG, offer great opportunities for targeted clinical trials in PD and other neurodegenerative diseases facilitating precision medicine approaches.

Identifying co-pathologies in PD patients can help with screening, enrichment, stratification, and monitoring in clinical trials for DMT or symptomatic treatments. Screening for AD co-pathology can serve as an inclusion or exclusion criterion, again helping to create a more homogeneous study population. Biomarkers also enrich trials by selecting patients at higher risk of progression. For example, trials may target participants with abnormal plasma pTau181 or neurofilament light levels, as studies indicated that these PD patients have increased risk of cognitive impairment.^48,60 Enriching trials with these participants can improve the chances of detecting a treatment effect, potentially shortening trial duration and requiring fewer participants. For example, in a trial investigating neflamapimod in DLB, patients with amyloidosis as measured with plasma pTau181, did not respond to treatment. ⁶¹ This led to the following trial including only patients without AD pathology based on plasma biomarker assessment. Finally, since changes in amyloidosis, as indicated by plasma pTau181, correlate with accelerated declines in functional impairment and memory, amyloidosis could serve as a biomarker for monitoring treatment response in PD patients with cognitive impairment. ⁴⁸

Enhancing validity through inclusive, patient-centered care

Clinical trials investigating cognition in PD lack geographical diversity, with most trials conducted in North America and Europe. ³² A study by Lau et al. found that only 21.6% of PD clinical trials registered in ClinicalTrials.gov from 2017–2021 included underrepresented black and minority ethnic communities, and less than half reported racial distribution. ⁶² Similarly, only 33% of trial participants were female. ³² Ensuring balanced representation of sex, gender, race and ethnicity (and analyzing across these groups) will improve the validity and generalizability of trial results for all people with PD. While including participants from diverse geographic regions and stratifying by multiple subgroups may slow recruitment and increase heterogeneity, it is essential to study the efficacy and safety of treatments in all populations that will ultimately use them. ⁶³

Including diverse populations also ensures that cognitive interventions are culturally sensitive, respecting social, linguistic and cultural differences. This inclusivity makes treatments more accessible and acceptable across different communities.

A key strategy to achieving inclusivity is a patient-centered approach, which involves patients and caregivers in both the design of research and their own care. Patient-centered cares is defined as providing “care that is respectful of and responsive to patient's preferences, needs and values”. ⁶⁴ Cognitive decline is a concern for PD patients and their caregivers, ⁶⁵ and clinicians have highlighted the importance of considering future cognitive risks in treatment decisions in PD. ⁶⁶ A patient-centered approach can help to advance management of cognitive impairment of PD by empowering patients and caregivers through education about the disease. ⁶⁷ Informed patients and caregivers are better equipped to identify early cognitive changes through personalized assessment. This approach also fosters collaboration between patients and clinicians, leading to better adherence to treatment and interventions tailored to the patient's cognitive profile. Moreover, a patient-centered approach also ensures that meaningful outcomes are prioritized. ⁶⁸ Patient-reported outcomes help identify the symptoms that matter most to patients, which can help in the development of novel cognitive assessment that better reflect the patient experience. ⁶⁹ These new assessments may also be more sensitive in detecting treatment effects in clinical trials.

Strategies for detecting a treatment effect

Most clinical trials investigating cognition in PD include individuals without cognitive impairment, with only three trials including PD-MCI and one trial including PDD patients. ³² To improve trial efficacy, more studies should target PD-MCI patients and prioritize those at higher risk of cognitive decline. Key predictors of PD dementia include older age at onset, male sex, rapid eye movement sleep behavior disorder, higher baseline blood pressure, orthostatic hypotension, abnormal color vision, gait impairment, and falls.^70,71

Similarly, clinical trials investigating cognition in PD often have relatively short durations, with a mean duration of 16.9 weeks, and most reported outcomes within one month. ³² Ideally, a follow-up of at least 18 months is needed to detect long-term cognitive effects.^72,73 Bayram et al. recommend a minimum follow-up duration of one year to provide adequate statistical power for detecting meaningful changes. ³²

Regarding outcome measures, while PD-specific cognitive screening scales have been validated in observational studies, ⁷⁴ the MoCA and Mini-Mental State Examination (MMSE) (both originally developed for AD) are still the most commonly used cognitive outcome measures in trials. ³² While these global cognitive measures are useful for screening, they may be less sensitive in detecting subtle changes over time and do not include validated assessments of specific cognitive domains. This limitation is especially true for the MMSE, which does not evaluate executive function: the cognitive domain most frequently affected in PD. Earlier trials for cognition in PD also used scales designed for AD, such as the Alzheimer's Disease Assessment Scale–Cognitive Subscale, which may have hindered the detection of treatment effects. Therefore, more comprehensive cognitive assessments that include domain-specific measures are crucial for detecting potential treatment effects in PD.

Several neuropsychological tests are available to assess cognition in PD.^75,76 Composite scores, which combine data from multiple cognitive tests, offer another useful approach for screening. Examples include the PD-Cognitive Rating Scale, ⁷⁷ the Scale for Outcomes in Parkinson's Disease-Cognition,^78,79 and the Parkinson's Disease Composite of Executive Functioning, ⁸⁰ among others. Longitudinal data of cognitive change are rare however, and there is no information yet regarding what is considered a clinically meaningful cognitive decline and relevant difference for clinical trials.

Advancing management through digital assessments

Digital cognitive assessments are now well validated and correlate closely with traditional in-person neuropsychological assessments.^81–83 Accessibility issues and difficulties traveling to clinics often create challenges recruiting patients for clinical trials, particularly in the context of PD where mobility issues are common. Consequently, studies have historically included patients recruited from movement disorder centers, leading to an overrepresentation of white men of higher socioeconomic status. ⁸⁴ Online cognitive testing, which is “culturally unbiased”, reduces the need for in-person visits, helping to remove barriers for participation and increasing the representation of patients from rural communities and underrepresented ethnic minorities.^85–87

Furthermore, the use of smart-phone based apps allows longitudinal tracking of cognition with reliable and consistent monitoring which shows good concordance with in-clinic measures of cognition and avoids issues with day-to-day variation in cognitive performance.^88,89 This has also been established in PD and, as a highly time-efficient and cost-effective means of assessment, these smart phone-based methods have significant potential to improve access and longitudinal monitoring of cognition in clinical trials.^90–92

However, while the feasibility of remote, unsupervised assessments in older populations has been demonstrated with generally high adherence and uptake,^93–95 in a minority the use of an app may be a barrier to participation. ⁸¹ This may be a particular issue in PD where motor impairments such as tremor may affect performance and willingness to undertake smart phone-based assessments. Cognitive assessments in PD do require adjustments to accommodate motor impairments and other non-motor symptoms such as fatigue which can reduce motivation and engagement. ⁸⁷ Additionally, differences in access to and familiarity with technology may contribute to differences in performance between patients.^96,97 Data privacy concerns around the storage and sharing of data also remain, particularly when identifiable personal data is collected and rigorous guidelines are required. ⁸¹

Non-pharmacological interventions

While outside the scope of this review, various non-pharmacological approaches have shown cognitive benefits in people with PD. These non-pharmacological approaches include physical exercise, cognitive training, or various brain stimulation techniques. Two recent systematic reviews and meta-analyses on the effects of physical exercise suggest that this intervention can lead to improvements in global cognition and, to a lesser extent, executive function in people with PD, though the interventions varied significantly among studies and the evidence remains uncertain.^98,99

Cognitive training is a non-invasive, safe and low-cost intervention, but its potential benefits in PD have not been established. A 2020 meta-analysis reviewed seven studies on cognitive training in PD, finding no evidence that PD-MCI or PDD patients benefited from it. ¹⁰⁰ However, a more recent meta-analysis in 2022 found that cognitive training improved global cognition, executive function and both short and long-term memory, but had no effect on attention, language, or visuospatial function. ¹⁰¹ This analysis was limited by the small number of studies (14), small sample sizes, and high heterogeneity, reducing its power.

Combination strategies have also been studied. A 2024 systematic review examined 21 studies on combined physical and cognitive training, with ten investigating cognitive outcomes. ¹⁰² The results were inconsistent, suggesting that more research is needed to determine whether combining physical and cognitive training is more effective than using either approach alone. Future clinical trials on physical exercise and cognitive training, whether separately or in combination, should clearly define the target population (cognitive status, disease severity, PD subtype, and presence or absence of comorbid psychiatric conditions), have adequately powered sample sizes, use clinically relevant outcome measures, and explore mechanisms of efficacy (e.g., dosage, program design, timing of boosters), over longer durations. ¹⁰³

Future perspectives

Cognitive impairment is a common non-motor symptom in PD, significantly impacting patient's and caregiver's quality of life, and increasing morbidity and functional decline. There is an urgent need to develop pharmacological treatments for cognitive impairment, as only one treatment is currently approved for people with PD in the dementia stage. Systematic cognitive evaluation across multiple cognitive domains is essential, along with assessing functional impairment for accurate diagnosis.

Developing new pharmacological treatments that improve cognition requires several considerations for clinical trial design and clinical trials of PD should include cognition as a key outcome. Future trials should prioritize patients with cognitive impairment who are at higher risk for decline, and incorporate biomarkers for screening, stratification, enrichment, and monitoring of treatment effects. Ensuring adequate representation of sex, gender, race and ethnicity could be achieved by leveraging global research efforts,^104–106 and promoting education in underrepresented communities to promote their engagement. Adopting a patient-centered approach further supports inclusivity, enhances trial design by focusing on outcomes that matter most to patients, and improves treatment adherence. Additionally, digital assessments offer a practical alternative for remote recruitment and cognitive evaluation, broadening participation in cognitive trials and ensuring diverse representation (Table 1).

Table 1.

Strategies for advancing pharmacological management of cognitive impairment in PD.

Strategies for advancing pharmacological management of cognitive impairment in PD
Accurate diagnosis	Systematic assessment of cognition and its influence in daily functioning
Prioritize cognitive outcomes	Focus on cognitive outcomes in clinical trials for both disease-modifying and symptomatic treatments in Parkinson's disease
Target co-pathologies	Address amyloid and tau co-pathologies in treatment strategies
Use biomarkers	Leverage biomarkers for screening, enrichment, stratification, and monitoring of treatment effects in clinical trials
Ensure diversity	Include diverse populations regarding sex, gender, race, and ethnicity
Adopt a patient-centered approach	Empowering patients through education improves adherence to treatment and allows patients to identify early symptoms. Additionally, this approach helps to identify meaningful outcomes
Focus on high-risk participants	Enroll participants in clinical trials who are more likely to progress to dementia
Lengthen trial duration	Design clinical trials with longer duration to better assess treatment effects
Enhance symptomatic clinical trials	Increase the number of clinical trials that prioritize cognition as the primary outcome for symptomatic therapies in PD
Use disease-specific measures	Use disease-specific outcome measures to effectively detect treatment effects
Leverage digital assessments	Use digital cognitive assessments to improve recruitment and evaluation processes

Conclusion

In summary, advancing pharmacological management of cognitive impairment in PD is crucial and requires a comprehensive approach. This includes accurate diagnosis, better trial designs that include biomarker assessments and diverse populations, a focus on patient-centered care, and innovative digital assessments.