Diagnosis and Management of Dementia and Psychosis in Individuals With Parkinson Disease

Parkinson disease (PD) is a neurodegenerative syndrome characterized by bradykinesia along with muscular rigidity, rest tremor, gait instability, or a combination of these symptoms. PD is identified and diagnosed on the basis of its motor features, but impairment of cognition and behavior is a common cause of disability and caregiver burden later in the disease course. A PD pandemic has been predicted to occur in the next few decades, with an estimated global prevalence of 12 million cases over the next 15 years.¹

With an aging population and because >75% of people with PD eventually develop cognitive impairment, a corresponding increase in dementia associated with PD is expected.^2,3 Psychosis is present in 15% to 38.4% of people with PD^4,5 and can range from minor phenomena that evolve from passage hallucinations, illusions, and presence hallucinations to delusions and auditory, tactile, and olfactory hallucinations.⁶ Recognizing these nonmotor symptoms of PD and their potential treatments is essential to improve individuals’ and caregivers’ quality of life. In this review, we discuss clinical approaches to dementia and psychosis in people with PD. 

Dementia in PD
Dementia is defined as “cognitive decline that is substantial enough to interfere with daily functioning.”⁷ The 20% to 40% prevalence of dementia among people with PD increases over time and affects >75% of people with PD at 10 years from disease onset.^3,8 Dementia in PD is thought to be secondary to the involvement of limbic and neocortical brain regions, with postulated deficits in acetylcholine and dopamine transmission.⁹ Factors such as older age, male sex, rapid eye movement (REM) sleep behavior disorder (RBD), and vascular risk factors represent clinical predictors of dementia in PD.¹⁰

A thorough interview and physical examination are needed to distinguish functional impairment due to motor deficits vs cognitive changes to avoid motor confounds (ie, unintended influences from movement-related processes that interfere with the interpretation of experimental results). Scales used should be sensitive enough to differentiate effects of physiologic aging from neurodegenerative disease and to avoid a learning effect. The understanding of affected domains is not drawn from large epidemiologic studies that use a single screening test of global cognitive function, such as the Montreal Cognitive Assessment or Mini-Mental State Examination, so any conclusions derived from results of a single test should be made with caution.¹¹

A specific profile of cognitive impairment has been reported in individuals with PD with proposed fronto-striatal network dysfunction that is modulated by dopamine.¹² In people with PD, attention, working memory, and executive functions are predominantly affected. The involvement of memory, language, and visuospatial functioning is postulated to be related to greater cholinergic loss in people with PD with more posterior cortical degeneration.¹² Language abnormalities are less frequent, but verbal fluency and sentence comprehension can be impaired.^13,14 Such patterns are important when differentiating PD dementia from other prevalent forms of dementia, such as Alzheimer disease, in which language and memory involvement are more prominent.¹⁵ A single, specific pathology has traditionally been thought to accompany these cognitive phenotypes, but mixed pathology with both α-synuclein and β-amyloid may not be uncommon in individuals presenting to the clinic with dementia and parkinsonism^9,14 (Table 1). 

Evaluation of Cognitive Impairment in PD
Cognitive impairment in PD ranges from subjective cognitive decline to mild cognitive impairment (MCI) to dementia.¹⁶ In subjective cognitive decline, the individual or a family member reports changes in cognition, although the results of standardized testing do not show significant abnormalities. Cognitive deficits on bedside scales or formal neuropsychologic testing become evident in MCI, although with preserved functionality and ability to perform activities of daily living. The Movement Disorders Society criteria define dementia as a decline in >1 cognitive domain that impairs daily functionality and lasts for at least 6 months.¹⁷ The Movement Disorders Society has recommended scales for evaluating cognitive impairment in PD based on their clinometric properties (Table 2).¹⁵

A thorough medical history is essential to identify conditions (ie, hypothyroidism, vitamin deficiencies) and medications (ie, anticholinergic drugs) that can affect memory and other cognitive skills. Underlying comorbidities (eg, anxiety, depression), which are prevalent nonmotor symptoms of PD and can contribute to cognitive impairment, must be ruled out. Orthostatic hypotension (OH), a manifestation of underlying dysautonomia, has been associated with cognitive function. OH can be the result of dysautonomia, but is also a recognized side effect of dopaminergic therapies. OH can cause transient deficits in executive function, memory, and visuospatial function and contribute to chronic or fluctuating cognitive changes in people with PD, even in early disease stages without cognitive impairment.^18-20 A frequently overlooked effect of OH is on the neuropsychologic assessment of people with PD.²¹ Asking individuals and family members about this symptom and checking orthostatic vital signs during the clinic visit could help identify OH and treat it accordingly to optimize cognitive ability. The effect of OH on clinical outcomes is noted even in people without obvious symptoms.²²

Neuropsychologic evaluation can further characterize cognitive deficits in people with PD with detailed testing based on individual presentation. Biomarkers, including imaging and laboratory studies, have also been proposed for assessing cognitive disturbances in PD and differentiating it from other dementia syndromes. Basal forebrain atrophy on brain MRI has been reported in PD with MCI.¹⁶ Evidence suggests the utility of assessment using β-amyloid and tau cerebrospinal fluid biomarkers. In the right clinical context, amyloid PET may be used to investigate cognitive decline. Evidence suggests that resting-state EEG can be used to differentiate PD and dementia with Lewy bodies, even early in the disease.¹⁶ Ongoing research aims to study the use of α-synuclein seed amplification assays in cerebrospinal fluid with the goal of appropriate adoption in clinical practice. 

Important Considerations About Treatment and Medication Side Effects
Medications with different mechanisms of action may be used for the management of PD-related dementia^23,24 (Table 3). Rivastigmine, an acetylcholinesterase inhibitor, is the only Food and Drug Administration–approved medication for mild to moderate dementia in PD.²⁵ The oral and patch formulations provide flexibility to administer it to individuals with comorbid dysphagia or side effects from the oral formulation. Individuals receiving rivastigmine treatment should be counseled on gastrointestinal side effects, such as nausea and weight loss, and should be monitored for potential signs of presyncope. In addition to the cholinergic system, an antihypotensive effect has been noted as a potential mechanism of benefit.²⁶

Suggested nonpharmacologic interventions for cognitive impairment include cognitive training, exercise, and occupational therapy (eg, music therapy).²⁷ Exercise, known to improve motor disability and quality of life in people with PD, positively affects processing speed in a dose-dependent manner.²⁸ Activities such as stretching, breathing and balance exercises, and strength training can improve attention and working memory in people with PD without dementia.²⁹ Screening individuals for sleep disorders is also recommended; RBD, restless legs syndrome, and obstructive sleep apnea are associated with an increased risk of cognitive dysfunction.³⁰

A thorough medication reconciliation and interaction check is encouraged to prevent iatrogenic cognitive dysfunction in people with PD. Anticholinergic medications are associated with an increased risk of dementia, falls, death, and frailty.³¹ Given the heightened vulnerability of people with PD caused by degeneration of cholinergic basal forebrain neurons, it is important to regularly assess and minimize the anticholinergic burden in this population.³¹ Drugs with anticholinergic properties are often prescribed for the treatment of tremor (ie, trihexyphenidyl), or to manage nonmotor symptoms, such as bladder incontinence (ie, oxybutynin), depression (ie, paroxetine, amitriptyline), and psychosis (ie, quetiapine). These medications can also worsen OH and quality of life in people with PD.³² Other drugs that can cause sedation and possible cognitive impairment (eg, gabapentinoids, benzodiazepines, opiates) should be used with caution in people with PD.

Psychosis in PD
Psychosis has a prevalence of 15% to 38.4% in people with PD.^4,5 Its pathophysiology is not fully elucidated, but data show an increased risk of PD psychosis (PDP) is associated with dopaminergic replacement therapy, cognitive impairment, greater disease severity, longer disease duration, depression, and RBD,³⁸ indicative of a more malignant phenotype.³⁹ Hallucinations are defined as either abnormal perceptions in the absence of an external stimulus or delusions (ie, fixed false beliefs).³⁹ Visual hallucinations are considered one of the most characteristic features of PDP and differ in their severity.⁶ Individuals may report presence hallucinations (feelings of another person or animal being present) or passage hallucinations (images in peripheral vision).³⁹ Other less common types of hallucinations include auditory or tactile (ie, a feeling of insects crawling on the skin) phenomena. Delusions, with a prevalence ranging from 3% to 14% in people with PD, are commonly paranoid, and include Othello syndrome (delusion of infidelity), Capgras syndrome (the belief that someone has been replaced by an imposter), Fregoli syndrome (the belief that a known person is disguised as a stranger), and reduplicative amnesia (the belief that a person or object has been duplicated).³⁹ The degree of impact of psychosis on quality of life may vary.^40-42 PDP is associated with increased caregiver burden.^43,44

Figure 1. Representation of common forms of hallucination and psychosis in people with Parkinson disease.
Created in BioRender (https://BioRender.com/nbdl4yd).
Abbreviation: PD, Parkinson disease

Diagnosis of PDP
The National Institute of Neurological Disorders and Stroke and National Institute of Mental Health proposed a set of diagnostic criteria for PDP encompassing symptoms that are recurrent or persistent for ≥1 month in an individual with PD, after excluding other conditions, such as dementia with Lewy bodies, a primary psychiatric disorder, or delirium.⁴⁵ Different scales to evaluate PDP have been validated, including the Parkinson Psychosis Rating Scale and the Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis.⁴⁶ More recently, the Self-Administered Screening Questionnaire for Parkinson’s Disease-Associated Psychosis was developed, and has demonstrated high accuracy in diagnosing PDP.⁴⁷

Treatment Considerations in PDP
The first step in managing an individual with PD and psychotic symptoms is identifying possible exacerbating medical conditions, such as infections or metabolic abnormalities, or medications that could promote these symptoms, such as anticholinergic agents or sedatives (Figure 2). Dopaminergic replacement can increase PDP, and clinicians should carefully consider the risks and therapeutic benefit associated with this treatment. In case of a need for downtitration, the following treatment order may be considered: anticholinergics, amantadine, dopamine agonists, monoamine oxidase B inhibitors, catechol-O-methyltransferase inhibitors, and levodopa.⁴⁸ Individuals and family members should be advised about avoiding environmental situations that can trigger some of the symptoms (ie, low-light settings, overstimulation, visual refractory problems, loneliness). Safety measures regarding driving and access to weapons also should be discussed.³⁹

Figure 2. Suggested approach for the treatment of Parkinson disease psychosis. Recently, the requirement of frequent blood draws through the Risk Evaluation Mitigation Strategy (REMS) program was lifted for clozapine.
Created in BioRender (https://BioRender.com/rrmjd89).
Abbreviation: FDA, Food and Drug Administration

Antipsychotic medications, such as clozapine and quetiapine, have been used for treatment of PD psychosis, with different levels of evidence regarding their efficacy.⁴⁹ Clozapine has been underutilized due to the FDA requirement of regular blood draws to monitor potential neutropenia, which was part of the Risk Evaluation and Mitigation Strategy (REMS) program.^49a Recently, this requirement was lifted. Acetylcholinesterase inhibitors, such as rivastigmine, have also been used.⁵⁰ Dopamine-blocking agents may worsen parkinsonism. However, their use might be considered for the acute management of psychotic symptoms, or in individuals who have comorbid dementia.⁴⁸ Nuplazid (pimavanserin; Acadia Pharmaceuticals Inc., San Diego, CA), a 5-HT2A receptor inverse agonist, is the only Food and Drug Administration–approved medication for the management of PDP. This medication does not worsen parkinsonism or cognition,⁵¹ but the onset of efficacy may be delayed for 4 to 8 weeks after treatment, requiring combination therapy.^52,53

Conclusion
Early identification of cognitive and behavioral manifestations is essential to provide appropriate care to people with PD and their caregivers. Initial management of dementia and psychosis should prioritize nonpharmacologic strategies and environmental modifications. When medications are necessary, they should be used at the lowest effective dose and with caution, with attention to drug interactions and side effects. A multidisciplinary approach with input from palliative care, psychiatry, and rehabilitation medicine provides the greatest benefits.