The Parkinson's Disease Spectrum PDF

# The Parkinson's Disease Spectrum ## Sygrid van der Zee and Annelien Duits ## 21.1 Introduction Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. British physician James Parkinson was the first to describe the disease in 1817 in his *Essay on the...

# The Parkinson's Disease Spectrum ## Sygrid van der Zee and Annelien Duits ## 21.1 Introduction Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. British physician James Parkinson was the first to describe the disease in 1817 in his *Essay on the Shaking Palsy* (see Box 21.1). The clinical presentation of Parkinson's disease is complex and includes both motor and non-motor symptoms. The disease has a chronic progressive nature; symptoms increase in severity and new symptoms may appear as the disease progresses. In addition to Parkinson's disease, we distinguish the atypical parkinsonisms, which include multiple system atrophy (MSA), progressive supranuclear paralysis (PSP), corticobasal degeneration (CBD) and Lewy body dementia (DLB). Vascular parkinsonism is a secondary form of parkinsonism in which parkinsonian symptoms occur due to cerebrovascular damage or abnormalities. Atypical parkinsonism has some clinical similarities to Parkinson's disease, but also some important differences, including faster progression, limited response to medication and prominent cognitive decline at a relatively early stage of disease. To date, Parkinson's disease cannot be prevented, cured or its progression delayed, and only symptomatic treatment is available. ## Box 21.1 James Parkinson Parkinson's disease is a noticeable syndrome, often involving shaking of the head, trembling of the hands, a somewhat forward-bent posture, and small shuffling steps made by the patient to move forward. The physician James Parkinson (1755-1824) was the first to document this syndrome. In 1817, he described the clinical picture as follows: “Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace: the senses and intellects being uninjured." He proposed that the disease should be referred to as shaking palsy (the word palsy is derived from the Greek paralysis, meaning ‘detachment, weakening’). Another term used to refer to the disease was paralysis agitans. In his *Essay on the Shaking Palsy*, James Parkinson described six patients, three of whom he had examined meticulously; he had seen two of the remaining three patients in the street, and one from a distance. There are earlier descriptions of the clinical picture (for example, by William Shakespeare), but Parkinson was the first person to argue that this was a syndrome - an independent clinical picture. Parkinson had a physician's practice in London, but mainly made a name for himself as a palaeontologist and as an author of medical books for the general public, a chemical reference book, and more politically biased pamphlets under the pseudonym of Old Hubert. In 1877, the term Parkinson's disease was introduced by the French neurologist and psychiatrist Jean-Martin Charcot. Charcot considered that the description by Parkinson was fairly accurate, but noted that Parkinson had failed to note the rigidity in the joints even though this is an essential characteristic of the disease. ## 21.1.1 Epidemiology Currently, there are an estimated 58,000 people with parkinson(ism) in the Netherlands, two-thirds of whom have Parkinson's disease and one-third with atypical parkinsonism (Eimers et al., 2021). Men are more often affected than women: the prevalence is estimated at 3.7 per thousand men and 2.5 per thousand women. The onset of Parkinson's disease is commonly later in life, usually between the ages of 50 and 70. About 1% of people aged over 60 have Parkinson's disease (Tysnes & Storstein, 2017). The incidence increases significantly with age, but there are also younger people who develop Parkinson's disease. People diagnosed before age 50 are referred to as young-onset Parkinson's. The prevalence of Parkinson's disease is expected to increase sharply in the coming decades due to an ageing population, increased life expectancy and industrialisation. Industrialisation and the associated pollution of the environment with solvents, heavy metals and specific pesticides, among others, are associated with Parkinson's disease and therefore may contribute to the continued increase in the prevalence of the disease (Dorsey et al., 2018). ## 21.2 Clinical Presentation Parkinson's disease is characterised by both motor and non-motor symptoms. Broadly, three disease stages can be distinguished: preclinical, prodromal and clinical. In the preclinical stage, the neurodegenerative process has already begun, but does not yet manifest in symptoms. The prodromal stage is characterised by symptoms that may be related to the disease, but on the basis of which the disease cannot yet be determined with certainty. In the clinical phase, the (motor) symptoms are visible and the diagnosis of Parkinson's disease is made. ## 21.2.1 Motor Symptoms Parkinson's disease is characterised by four cardinal motor symptoms: 1. **Bradykinesia**, the slowing of movements, is the most common motor symptom of Parkinson's disease. In addition to bradykinesia, difficulty starting movements (akinesia), or lack of automatic movements (hypokinesia) can also occur. Hypokinesia is characterised by reduction of facial expression (facial masking), drooling due to less automatic swallowing, and loss of automatic movements, such as a decreased arm swing. In addition, sudden, short and temporary episodes of an inability to move the feet forward despite the intention to walk can be present. This is called freezing of gait and is more common as the disease progresses. 2. **Rigidity** is stiffness of the muscles. It is experienced as a tense feeling of the muscles and can occur in the arms or shoulders, but also in the trunk, hips or legs. Combined with slowness of movement, symptoms including micrographia (small writing), hypophonia (low voice volume) and shuffling, small steps when walking, can be present. 3. **Resting tremor** is the shaking or trembling of a limb at rest and can occur in various parts of the body, such as a hand, arm or leg, as well as the tongue or chin. The tremor begins on one side of the body and can get worse with stress or anxiety. It can significantly affect the patient's daily life as it is clearly visible for others and difficult or impossible to suppress. 4. **Postural instability** is the inability to balance due to loss of postural reflexes. This symptom usually appears in the later stages of the disease and may include a stooped posture, small shuffling steps and a tendency to lean forward when walking. Patients presenting with postural instability are more prone to falls if they cannot recover from changes in motion. The disease has many different manifestations and there is great heterogeneity in the severity and course of symptoms. Based on the motor symptoms, two subtypes can be distinguished, the tremor-dominant (TD) subtype and the subtype in which postural, balance and gait difficulties are prominent (postural instability and gait difficulty, PIGD type). The PIGD subtype is often associated with a more progressive course, faster cognitive decline and more frequent occurrence of depressive symptoms (Aleksovski et al., 2018). To determine the severity and course of symptoms, the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is used. This is a multidimensional scale consisting of four parts: 1) non-motor experiences of daily living; 2) motor experiences of daily living; 3) motor examination; and 4) motor complications. The MDS-UPDRS, and particularly Part III for the motor examination, is the most widely used scale for evaluating the clinical status of parkinsonian patients and the effects of therapeutic interventions. In addition to the MDS-UPDRS, the Hoehn & Yahr Scale is used for disease classification (see Box 21.2). ## Box 21.2 Modified Hoehn and Yahr scale (Goetz et al., 2004) 1. Unilateral involvement only 2. Bilateral involvement without impairment of balance 3. Mild to moderate bilateral disease; some postural instability; physically independent 4. Severe disability; still able to walk or stand unassisted 5. Wheelchair-bound or bedridden unless aided ## 21.2.2 Non-motor Symptoms Although Parkinson's disease is traditionally viewed as a movement disorder, non-motor symptoms are frequently observed and contribute strongly to patients' reduced quality of life (Lawson et al., 2014). Non-motor symptoms are present in the majority of patients and are already frequently present in the early stages of the disease or even before the onset of motor symptoms. Like the motor symptoms, there is a large variability in clinical characteristics and progression of non-motor symptoms. An overview of non-motor symptoms (Schapira et al., 2017): * **Sensory symptoms:** common sensory symptoms include pain, olfactory impairment, and visual impairment. Olfactory impairment (hyposmia) is present in more than 90% of patients with Parkinson's disease and often occurs early in the disease, or prior to diagnosis. * **Sleep disturbances:** a large proportion of patients with Parkinson's disease experience sleep disturbances to some extent, including difficulty falling asleep, insomnia or excessive daytime sleepiness. Furthermore, REM-sleep behavioural disorder (RBD) is frequently observed, which is characterised by dream-enactment behaviour, including thrashing, punching and kicking during dreaming. Often, the patient is little affected, but the bed partner is even more so. RBD can manifest several years before the motor symptoms, in the so-called premotor or prodromal phase. * **Autonomic symptoms:** these include constipation, sexual dysfunction, bladder problems, excessive sweating, weight loss and orthostatic hypotension (a drop in blood pressure when standing). * **Neuropsychiatric disorders:** neuropsychiatric symptoms, including depressive symptoms, anxiety, impulse control disorders, apathy, hallucinations and delusions, may manifest throughout the course of the disease. * **Cognitive impairment:** cognitive impairment can already be present in the early stages of the disease, and the majority of people with Parkinson's disease eventually develop dementia (parkinsonian dementia) over the span of the disease. In the earlier stages, when the cognitive impairment is present but does not interfere significantly with a patient's daily life, it is described as mild cognitive impairment (MCI). * **Fatigue:** fatigue is experienced by about half of the patient population and may be related to depression, sleep disorders or autonomic symptoms. ## 21.3 Aetiology and Neuropathology ### 21.3.1 Aetiology The cause of Parkinson's disease is largely unknown. Ageing is considered one of the major risk factors for developing Parkinson's disease. However, in addition to normal ageing, there are other factors that play a role in the development of Parkinson's disease. Over the past few years several risk factors, including environmental, lifestyle and genetic risk factors, have been identified. Important environmental factors that may play a role in the aetiology include exposure to pesticides, heavy metals and solvents. On the other hand, certain lifestyle factors, such as smoking, caffeine consumption and adequate exercise are thought to be protective factors. It is estimated that in 5 to 10% of patients with Parkinson's disease, a genetic mutation plays a role. The main genes known so far are *SNCA, PARKIN, LRRK2 and GBA*. A demonstrated mutation in one of these genes gives an increased risk of developing Parkinson's disease but does not mean that the disease will occur with certainty. The clinical presentation of Parkinson's disease with a genetic background may differ from idiopathic meaning (with unknown cause) Parkinson's disease. For example, the age at which the disease first appears is often lower in patients with a genetic mutation. Patients with a *GBA* mutation usually have a more progressive disease course and cognitive functioning is often affected earlier and more severely (Jankovic & Tan, 2020). ### 21.3.2 Neuropathology Parkinson's disease is characterised by the degeneration of dopamine-producing neurons in the pars compacta of the substantia nigra. The substantia nigra is located in the middle part of the brain and is part of the basal ganglia, which, as part of the cortico-basal ganglia-thalamo-cortical circuit, plays an important role in the regulation of motor, cognitive and behavioural processes. Neurodegeneration is not limited to the substantia nigra; many other areas of the brain are also affected in Parkinson's disease, even before the substantia nigra is affected. Characteristic pathological markers in Parkinson's disease are Lewy bodies. Lewy bodies are abnormal deposits of accumulated protein called alpha-synuclein. Alpha-synuclein also occurs normally, in healthy people, but the accumulation of misfolded alpha-synuclein is characteristic of Parkinson's disease. Neuropathologically, within the parkinsonian spectrum, a distinction can be made between parkinsonisms with alpha-synuclein pathology, including Parkinson's disease, DLB and MSA, and parkinsonisms without alpha-synuclein, including psp and CBD, which belong to the tauopathies. Lewy pathology in Parkinson's disease can also be found outside the brain, including in the peripheral nervous system, vagal nerve and spinal cord. The pathology gradually spreads during the disease (Jankovic & Tan, 2020; Kalia & Lang, 2015). It is believed that the spread of pathology follows a certain pattern of six stages, with cortical brain regions eventually affected (Braak et al., 2003). In addition to these processes, several other mechanisms contribute to the neurodegenerative process, including inflammation, oxidative stress and mitochondrial dysfunction (Kalia & Lang, 2015). This makes the underlying pathology of Parkinson's disease a complex process involving many factors that account for the heterogeneous clinical picture. ### Neuropathology of cognitive impairment Several studies show that typical Lewy body pathology is also associated with cognitive decline in Parkinson's disease, particularly in Parkinson's disease dementia. In addition to Lewy body pathology, Alzheimer pathology likely plays a role in Parkinson's disease dementia, and it is possibly the combination of both that underlies more rapid cognitive decline in Parkinson's disease (Tsamakis & Mueller, 2021). The degeneration of dopaminergic neurons also affects the non-motor symptoms of Parkinson's disease. For example, there is a link between dopaminergic degeneration and deficits in executive functioning. In addition to degeneration of the dopaminergic system, other neurotransmitter systems are also affected, including the serotonergic, noradrenergic and cholinergic systems. The latter has a strong association with cognitive functioning. For example, in patients with Parkinson's disease dementia, the cholinergic system is more strongly affected than in Parkinson's disease patients without dementia. Furthermore, also in the earlier stages with MCI, cholinergic degeneration plays a role and there is a relationship between cortical cholinergic innervation and cognitive functioning in the domains of memory, attention and executive functioning (Bailey & Goldman, 2017; Halliday et al., 2014). ## 21.4 Diagnostic Process Parkinson's disease is a clinical diagnosis. This means that the diagnosis is made by the neurologist based on the symptoms that occur. The initial symptoms of Parkinson's disease are usually non-specific. Before the onset of motor symptoms, patients often experience non-motor symptoms, including constipation, loss of sense of smell, RBD and depressive symptoms. This is called the prodromal phase. Parkinson's disease is diagnosed when the motor symptoms are also apparent, which requires at least the presence of bradykinesia in combination with at least one of the other cardinal motor symptoms, rigidity or resting tremor. Supporting factors are a strong improvement of motor symptoms after taking dopaminergic medication and the presence of olfactory impairment (Postuma et al., 2015). There is no test or neuroimaging assessment that can be used to make a definite Parkinson's disease diagnosis. However, multiple neuroimaging techniques can be used in case of atypical features or progression of the disease. An MRI scan can rule out other causes, such as vascular abnormalities or tumours. In addition, SPECT OF PET imaging can be used to investigate the presence of a dopaminergic deficiency (Richtlijn ziekte van Parkinson, 2020). ## 21.4.1 Parkinsonisms At disease onset, it can be difficult to distinguish Parkinson's disease from atypical parkinsonisms. However, distinguishing Parkinson's disease and atypical parkinsonisms as early as possible is of great importance because the course of the disease and treatment can be very different. The distinction between the different forms is done based on clinical symptomatology and the course of the disease. Imaging assessment can support the diagnosis but cannot differentiate conclusively. A definitive diagnosis can only be made post-mortem based on the neuropathology findings. A diagnosis of atypical parkinsonisms (MSA, PSP, CBD and DLB) will be considered if motor symptoms do not improve significantly after the use of Parkinson's medication. Other indications include a rapid progression, severe balance issues or eye movement disorders early in the disease or if there are severe autonomic disorders. The most prominent clinical features included in the diagnosis of the various atypical parkinsonisms are listed below. * **Characteristic for MsA** are early autonomic disorders, including incontinence, erectile dysfunction and orthostatic hypotension. In addition, MSA is characterised by severe speech and swallowing disorders, cold and blue discoloured hands and feet, impaired trunk balance and a severely stooped posture, making patients relatively quickly wheelchair-dependent. * **In patients with PSP, the posture** is more upright or even slightly stretched backwards. Typical symptoms in the early phase of PSP are disturbances in eye movements (vertical gaze paresis), disinhibition and emotional instability. * **CBD is the most heterogeneous** of the atypical parkinsonisms and therefore difficult to diagnose. There is generally a highly asymmetrical picture. In addition, there may be persistent muscle contraction (dystonia) and difficulty controlling a limb, where it appears as if the affected limb is moving on its own (alien limb phenomenon). * **DLB is an atypical parkinsonism** in which cognitive impairment and neuropsychiatric symptoms are particularly prominent. The clinical picture is characterised by early fluctuations in cognitive functioning and the presence of visual hallucinations. The motor symptoms of DLB are often symmetrical and characterised by the presence of rigidity and bradykinesia. There is extensive clinical and neuropathological overlap between DLB and parkinsonian dementia, and the distinction is based on the order in which symptoms develop. If visual hallucinations or severe cognitive impairment occur prior to, or within the first year of, the onset of motor symptoms, it is considered DLB. This arbitrary distinction is still a subject of debate in the literature (Jellinger et al., 2018). ## 21.5 Treatment Currently, there is no cure for Parkinson's disease or treatment to slow down the neurodegenerative process. Treatment therefore focuses on the relief of symptoms, and consists of medication, neurosurgery and supportive therapies, such as physical therapy. Medication can be used to improve the main symptoms of Parkinson's disease. Most prescribed medication targets the dopaminergic system in the brain. These include *levodopa*, dopamine agonists, monoamine oxidase type-B inhibitors and amantadine. However, side effects can occur. For example, levodopa and dopamine agonists can cause nausea, daytime sleepiness and hallucinations. In particular, dopamine agonists have been associated with impulse control disorders, including gambling and hypersexuality. In addition to drugs that act on the dopaminergic system, anticholinergic drugs are also used. These have a particular effect on tremor but have the significant side effects that they can lead to cognitive impairment, confusion and hallucinations (Kalia & Lang, 2015; Jankovic & Tan, 2020; Richtlijn ziekte van Parkinson, 2020). In addition, long-term use of dopaminergic drugs can cause motor complications. For example, a delayed response and/or wearing off of effects of medication can occur, in which it takes longer for the medication to become effective, and/or the effect lasts for a shorter period. In addition, involuntary, uncontrollable movements called dyskinesias may occur when the amount of levodopa in the blood is highest. Periods when the medication is not (yet) effective and the patient is highly affected by Parkinson's disease symptoms ('off') and periods when the medication is effective ('on'), but dyskinesias may occur, may fluctuate during the day, related to medication intake. These are called response fluctuations and are related to more advanced disease stages (see Figure 21.1). ## Figure 21.1 Response fluctuations related to levodopa therapy [Describe the Figure: It is a graph that shows blood levels of levodopa over time. The graph is divided into three sections: early, moderate, and advanced. The blood levels of levodopa are highest at the beginning of the early stage and gradually decline over time. However, the levels of levodopa fluctuate throughout the day, with peaks being on the 'on' state and lows being on the 'off' state.] When the effectiveness of the medication decreases and response fluctuations arise, advanced therapies may be considered. These include deep brain stimulation (DBS), levodopa-carbidopa intestinal gel (LCIG, brand name Duodopa) and subcutaneous administration of apomorphine, a dopamine agonist. LCIG is administered percutaneously as a gel directly into the first part of the small intestine to offer more continuous dopaminergic stimulation leading to more constant levodopa levels. DBS involves implanting a thin wire with electrodes into the brain. The electrodes are placed into brain regions with abnormal signals, with the subthalamic nucleus (STN) being the most common region for DBS. High-frequency stimulation of the electrodes will alter the abnormal signals, thereby leading to symptom improvement. The electrodes are connected to a (battery) stimulator, which is placed under the skin of the chest or abdomen (Figure 21.2). DBS often improves motor symptoms, but also affects non-motor symptoms. For example, there can be a decline in executive functions and impulse control, as well as an improvement in sleep and anxiety (Kurtis et al., 2017). ## Figure 21.2 Deep brain stimulation [Describe the Figure: It is a schematic representation of deep brain stimulation in which the electrode is placed in the brain and connected to a stimulator.] Furthermore, medication may also be prescribed to treat non-motor symptoms, such as antidepressants for mood-related problems, and antipsychotics for hallucinations and delusions. For cognitive impairment, rivastigmine may be prescribed. Rivastigmine is an acetylcholinesterase inhibitor that slows the breakdown of acetylcholine in the brain, allowing for a stronger cholinergic signal. This has been shown to be particularly effective in Parkinson's disease dementia (Emre et al., 2004). However, its effectiveness in MCI is still under debate (Richtlijn ziekte van Parkinson, 2020). In addition to pharmacological treatment, supportive care is considered of great additional value, specifically to compensate for impairments and helping patients to remain mobile and independent for a longer period. For example, in more advanced disease stages, a multidisciplinary treatment team can help, including physical and exercise therapy, occupational therapy, speech therapy and dietetics. Furthermore, cognitive behavioural therapy may be used for treatment of anxiety and depression, and compensatory strategies or cognitive function training may be used for cognitive impairment (Richtlijn ziekte van Parkinson, 2020). In people with atypical parkinsonism, dopaminergic medication is often less effective. In addition, the disease course is highly variable, making treatment difficult. Medication and supportive treatment are tailored for each patient based on the motor and non-motor symptoms present, the possible (temporary) response to levodopa, and the patient's physical and cognitive abilities (Kwaliteitsstandaard atypische parkinsonismen, 2020). ## 21.6 Cognitive Impairments ### 21.6.1 Clinical Presentation Cognitive changes occur in most patients with Parkinson's disease. Despite an estimated prevalence of 25 to 40%, cognitive impairments are often not adequately recognised in clinical practice. Cognitive impairment in Parkinson's disease is associated with decreased quality of life and more frequent apathy and depression. Mild cognitive impairment (referred to as Parkinson-MCI) can already be present at the onset of the disease. The clinical presentation of cognitive impairment in Parkinson's disease is heterogeneous, but due to the underlying degeneration of the fronto-striatal areas, impairments in executive functioning and attention are particularly common. One of the most fundamental problems in this is inadequate internal generation of behaviour for both automatic and more controlled actions. Previously automatic actions needed more active cognitive control (e.g. breaking the action down into small steps). In addition, there are often problems with cognitive flexibility, working memory, planning and keeping track, which make it extra difficult for patients to perform the controlled actions purposefully. The traditional idea that the cognitive profile of Parkinson's disease is strictly subcortical has been abandoned. As the disease progresses, a more posterior cortical profile may emerge in which memory, language and visuospatial functions are also affected in addition to impairments in executive functioning and attention (Baiano et al., 2020). The impairments in memory can be secondary to the impairments in executive functioning and attention, because selective and sustained attention as well as generating a strategy to remember certain information is needed. However, the memory impairments can also occur in isolation, with difficulties in learning new skills (implicit learning) and retrieving previous learned information (explicit learning) (Bailey & Goldman, 2017; Martinez-Horta & Kulisevsky, 2019). Language disorders in Parkinson's disease involve difficulties in understanding long and complex sentences as well as word-finding, word fluency and speech production (Auclair-Ouellet et al., 2017). Visuospatial disorders involve problems in perception and orientation in space, such as navigation and visuoconstruction. Although not common, spatial neglect on the left can be present in patients with Parkinson's disease predominantly affecting their left side, suggesting involvement of the right parietal cortex (Weil et al., 2016). Impairments in social cognition are often less prominent in the early phase but may occur. For example, patients may have difficulty recognising emotions in facial expressions and forming an image of another person's perspective (Theory of Mind, see Chapter 10). ### 21.6.2 Parkinson's Dementia and DLB In addition to a heterogeneous cognitive profile as described earlier, large variability in the progression of cognitive impairment over time is observed in Parkinson's disease. While some patients experience no cognitive problems for a long time, others develop dementia within a few years. Progressive cognitive impairment developing within the context of established Parkinson's disease that is severe enough to impair daily functioning, is considered as Parkinson's disease dementia. In addition to cognitive impairment, the presence of disorders in mood or behaviour is supportive in the diagnosis of Parkinson's disease dementia. Common neuropsychiatric symptoms in Parkinson's disease dementia include apathy, anxiety, depression and visual hallucinations. The cognitive profile of Parkinson's disease dementia is heterogeneous, but different from other clinical presentations of dementia. Patients with Parkinson's disease dementia show more severe visuospatial impairment than patients with Alzheimer's disease (Mosiman et al., 2004). Furthermore, memory impairment in Parkinson's disease dementia is characterised by an impairment in the active retrieval of information. In contrast with Alzheimer's disease, retention and (cued) recognition of information is preserved. Fluctuations in cognitive functioning, particularly in attention are characteristic of Parkinson's disease dementia. The cognitive profile and neuropsychiatric symptoms of DLB are almost similar to those of Parkinson's disease dementia, especially the fluctuations in cognitive functioning and the presence of visual hallucinations in the case of DLB. Consequently, both conditions are seen as two parts of the same spectrum. When the cognitive and/or neuropsychiatric impairments developed prior to, or within a year of, the onset of motor symptoms, the diagnosis of DLB is made. If the severe cognitive impairment starts later in the disease progression, it is considered Parkinson's disease dementia. However, as stated previously, this differentiation is still subject to debate (Jellinger & Korczyn, 2018). Risk factors for developing Parkinson's disease dementia include the presence of MCI, older age, longer disease duration, severe motor symptoms, the PIGD subtype, and the presence of mood-related problems. There is also evidence that early impairments in memory and visuospatial functions have a less favourable prognosis than when executive functions dominate the early phase of cognitive impairment (Kehagia et al., 2013; Bailey & Goldman, 2017). To what extent cognitive complaints are predictive of cognitive impairment is still debated. However, a relationship has been found between cognitive complaints and psychiatric symptoms such as anxiety and depression (Pan et al., 2021). ## Box 21.3 Case A 62-year-old man comes to the outpatient clinic together with his partner. He mentions he is depressed as he no longer gets things done. He relies on routine, and changes in this routine result in increased feelings of stress to which he can react irritably. He owned several clothing stores, of which one is still left. He has had a mild tremor for some time and had a neuropsychological assessment three years earlier after memory complaints, in which were memory disturbances were identified at the time. The tremor has increased slightly in recent years, as have his memory complaints. His partner has to accompany him to appointments to help him find his way around the hospital and remember the information provided at appointments. His partner reports that he has problems learning new procedures and sticking to the correct order when cooking. Finally, there are problems with spelling and word-finding. These cognitive problems have caused him to feel insecure such that he compulsively checks things. He prefers to stay at home on the couch. He has no problems falling and staying asleep, but often wakes up early. Shortly after his first visit to the outpatient clinic, levodopa was started with little effect on the tremor, even after increasing the dose, and in addition he complains about severe fatigue during the day. A few months later he came back to the neurologist and reported the presence of visual hallucinations (at stable low doses of levodopa) after which clozapine was started. Since then, there have been no more hallucinations. Daily functioning is characterised by fluctuations, in which he has good and lucid days, but also days with severe memory problems. However, there is increasing interference with work and daily life, and repetition of the neuropsychological assessment shows multiple cognitive impairments and a clear deterioration compared with the previous assessments. The question here is whether it is considered Parkinson's disease dementia or DLB. The cognitive profile is not helpful here, but because of the rapid cognitive decline, hallucinations, fluctuations and relatively mild motor symptoms, the working diagnosis of DLB was set. ### 21.6.3 Atypical Parkinsonism In atypical parkinsonism, cognitive impairment is common, primarily characterised by slowness in information processing and related impairment in complex attention, memory and word finding. There is an increased risk of developing dementia. Relatively little research has been conducted on differences in cognitive profiles within the parkinsonism spectrum. Moreover, in the few studies on the topic, patient groups are small and not all forms of parkinsonism are represented in all studies. In general, it can be said that cognitive impairment and psychiatric symptoms in Parkinson's disease are relatively mild compared with atypical parkinsonism. When comparing forms of parkinsonism with alpha-synuclein pathology, cognitive impairment and psychiatric symptoms in Parkinson's disease are relatively mild compared with DLB and MSA. DLB patients show the most severe cognitive impairment and frequent psychiatric symptoms, and in MSA patients severity is often worse than Parkinson's disease, but milder than DLB. When these groups are compared in the domains of memory, executive and visuospatial functions, DLB patients show the most severe memory impairments, and both DLB and MSA patients perform lower on executive and visuospatial functions than patients with Parkinson's disease (Kao et al., 2009). PSP and CBD belong to the tauopathies and are both associated with language disorders. Furthermore, the cognitive profile of PSP shows more subcortical symptoms, with disinhibition already present in the early stages of the disease. In addition to language disorders, CBD is associated with other cortical disorders such as visuospatial impairment and apraxia. CBD can also show similarities in cognitive profile with that of patients with frontotemporal dementia (FTD), also classifiable within the tauopathies (Kertesz & McMonagle, 2010). The language impairment of PSP and CBD have much in common with the non-fluent variant of primary progressive aphasia (nfVPPA), including agrammatism, difficulties in naming and impaired syntactic comprehension (Peterson et al., 2021). ### 21.6.4 Classification of Cognitive Impairment (MCI and Dementia) There are international criteria and guidelines to describe the cognitive impairments and the extent to which they affect daily functioning. The Movement Disorders Society (MDS) published criteria for MCI (Litvan et al., 2012) as well as for Parkinson's dementia (Emre et al., 2007). Following these criteria, the working group has made recommendations for two-level diagnostic procedures (Dubois et al., 2007). Level 1 procedures can be performed by the treating specialist and do not require expertise in neuropsychological diagnosis. Level 2 procedures, on the other hand, do require expertise from the (clinical) neuropsychologist, with the aim of establishing the severity and complexity of the disorders. Level 1 involves a global cognitive screening and in some cases can provide sufficient information to make the diagnosis of dementia. Level 2 assessment includes an extensive neuropsychological examination with a minimum of two tests per cognitive domain. This standard examination is generally preferred in diagnosing cognitive impairment and Parkinson's disease dementia. ### 21.6.5 Neuropsychiatric Disorders Psychiatric symptoms, including depressive symptoms, anxiety symptoms, psychotic experiences (such as hallucinations, delusions and illusions), apathy and disinhibition, are common in Parkinson's disease and can be present in both the early and later stages of the disease. Neuropsychiatric symptoms have a strong impact on the patient's quality of life and often contribute to the process towards nursing home admission. Depression is estimated to affect one in three patients with Parkinson's disease. Disruption of dopaminergic circuits, as well as a decrease in serotonin and norepinephrine, may play a role in the development of depression in Parkinson's disease. Depressive symptoms are particularly characterised by a depressed mood, fatigue and the inability to experience pleasure (anhedonia). Negative thoughts such as guilt or feelings of inferiority are less common. Suicide is relatively less common in Parkinson's disease, but suicidal thoughts are frequently reported. Depressive symptoms can sometimes be difficult to recognise because of overlap with other, non-motor symptoms. For example, disturbed sleep, change in appetite and weight, problems with sustained attention, fatigue and slowed mental and movement tempo may be related to depression, but are also common symptoms of Parkinson's disease. In addition, depressive symptoms may be related to 'off' periods or fluctuations in non-motor symptoms. Decreased mood, anxiety, apathy and fatigue may occur due to the wearing off effects of dopaminergic medications. These non-motor fluctuations do not always correlate with motor fluctuations and may therefore be difficult to recognise in clinical practice. Depressive symptoms related to non-motor fluctuations can be well treated by an adjustment in dopaminergic medication (Mueller et al., 2018). In addition to depressive symptoms, anxiety symptoms are also common in Parkinson's disease. Anxiety symptoms are characterised by physical symptoms of anxiety and tension, and a sense of internal tremor. Like depressive symptoms, anxiety symptoms may be related to non-motor fluctuations, and a change in dopaminergic medication may provide relief (Mueller et al., 2018). Although anxiety and depression symptoms occur primarily in more advanced stages of the disease, they may also be present in the prodromal or early phase of the disease. Early recognition of the symptoms as related to Parkinson's disease can contribute to early diagnosis, allowing patients to receive appropriate care (Wilbers & Duits, 2021). Apathy is defined as a lack of interest, motivation and emotion, reduced goal-directed behaviour and decreased cognitive activity (Robert et al., 2009). The reduced initiative is often reported by patients' caregivers and increases the perceived caregiver burden. Apathy can co-occur with other symptoms, including depression or dementia, but can also be present by itself (Mueller et al., 2018). In addition, apathy can occur during rapid tapering of dopaminergic medications, for example after treatment with deep brain stimulation. Psychotic experiences related to Parkinson's disease manifest in the form of delusions and (mostly visual) illusions and hallucinations. In the early stage of the disease, illusions (a false perception or distortion of an existing stimulus) and mild visual hallucinations, such as seeing a figure in the peripheral visual field, are most common. As the disease progresses, more complex hallucinations may occur, for example seeing people and animals. In the beginning stages, there is often still awareness and understanding of the hallucinations and the hallucinations are usually not threatening. In later stages of the disease, however, psychotic symptoms may lack insight and degenerate into frightening images. Psychotic experiences are relatively common in patients with depression, severe cognitive impairment and sleep disorders (Mueller et al., 2018). Finally, impulsive-compulsive behaviours may be present in Parkinson's disease. These include impulse control disorders (ICDS), stereotyped behaviour characterised by intense fascination with repetitive and excessive handling and examining of objects (punding), and dopamine dysregulation syndrome in which there is an increased need, or even addiction, to dopaminergic medication (Bhattacharjee, 2018). In impulsivity, there is impaired inhibitory control, inability to delay rewards, and an increased need to seek thrills without regard to consequences. Common ICDS in Parkinson's disease include hypersexuality, pathological gambling and compulsive eating and buying. Increased impulsivity in Parkinson's disease is often due to dopaminergic medication. The effect of DBS on symptoms is variable; although studies have found improvement in ICDS and reduced risk of developing dopamine dysregulation syndrome,