Cognitive Aspects of Parkinson’s Disease and Other Neurodegenerative Movement Disorders

Joshua R. Steinerman

Enrique Noé Sebastián

Yaakov Stern

Although Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration (CBGD), multiple system atrophy (MSA), and Huntington’s disease (HD) have traditionally been described as neurodegenerative processes preserving mental functions, cognitive impairment is now fully accepted as part of the clinical presentation of these diseases (Table 23-1). Furthermore, cognitive dysfunction is a common source of disability for patients with degenerative movement disorders. Together with neurobehavioral disturbance, impaired cognition results in significant caregiver burden and is a powerful predictor of institutionalization. Because of their prevalence and impact, such nonmotor disease manifestations should be recognized and treated in conjunction with motor symptoms.

PARKINSON’S DISEASE

PD represents between 70% and 75% of all the parkinsonisms. It is the most common movement disorder in the elderly and one of the most common causes of disability in this population. The prevalence of PD is up to 1% of the population over 65 years of age, and this percentage increases with age. In fact, aging is the most consistent recognized risk factor for the disease. The age of onset varies between 40 and 70 years, with an incidence peak above 60 years of age. Less than 20% of cases have onset before 50 years of age. The progression and evolution of PD vary from patient to patient, with a mean survival time of approximately 10 to 15 years. The impact of the disease is clear if we consider that the risk for death or developing dementia in this disease is
more than twofold greater than in an age-adjusted population (75).

Table 23-1. Neuropsychological Pattern in Patients with Movement Disorders

		PD	PD-D	CBGD	PSP	MSA	HD	AD
Orientation		–	++	–	–	–	−/+	+++
Language
	Naming	−/+	+	−/+	−/+	−/+	−/+	++
	Fluency	++	+++	++	++	++	+++	+
	Aphasia/paraphasia	–	−/+	++	–	–	−/+	+
Visuospatial function
	Visual memory	−/+	++	−/+	−/+	−/+	+	+++
	Spatial reasoning	+	+++	+	++	+	++	++
	Visuoconstructive	+	++	++	+	+	++	++
Memory
	Immediate recall	+	++	−/+	−/+	+	+	++
	Delayed recall	−/+	++	−/+	−/+	−/+	+	+++
	Recognition	–	+	–	–	–	−/+	+++
Praxis		–	++	+++	−/+	–	−/+	++
Executive function		++	+++	++	+++	++	++	+
Attention		+	+++	+	++	+++	++	++
(-) Normal function; (+) mild impairment; (++) moderate impairment; (+++) severe impairment. AD, Alzheimer’s disease; CBGD, corticobasal ganglionic degeneration; HD, Huntington’s disease; MSA, multiple system atrophy; PD, Parkinson’s disease; PD-D, Parkinson’s disease with dementia; PSP, progressive supranuclear palsy. Shading underlines the principal symptoms of each disease.

PSYCHOSOCIAL ASPECTS AND HEALTH CARE

Since the advent of levodopa therapy, the mortality rate for patients with PD is not different compared with ageand sex-matched controls. Today, approximately 60% of patients are over 75 years at death, and the prevalence of the disease is as high as 3% among individuals older than 85 years of age. The decrease in elderly mortality and the improvement in treatment for early PD are generating an increasing number of families living with affected relatives and a greater percentage of patients living to experience the advanced stages of this disease.

The combination of the progressive course of the disease, the prolonged survival, and the broad range of impairment suggests that a high proportion of patients with PD may eventually need long-term care. European and American studies have estimated that the prevalence of patients with PD in nursing homes is about 5% to 10% and that up to 20% of older patients with the disease will eventually be institutionalized. Risk factors for nursing home placement are old age, living alone, motor disability, impairment of activities of daily living, dementia, and psychosis (3,85). A proactive treatment approach, focusing on optimization of general health, stress education, and disease education, is advisable from the time of diagnosis and may mitigate the need for auxiliary care.

PD markedly reduces patients’ health-related quality of life, generates an important dysfunction on family roles and activities, and places a major socioeconomic impact on society. The economic costs of PD, including both direct health care costs (for drugs, physician services, and hospitalization) and indirect costs (for lost worker productivity), have been estimated to be around $25 billion per year (108). The total mean societal burden per individual with PD in the United States is more than $6,000/year ($4,000 for drugs, physician services, and hospitalization, and $2,000 for earnings loss) (123). The largest components of family burden are not direct health care costs, but providing informal care giving and earnings loss. The caregiver, usually the spouse, provides an average of 22 hours of care per week. After income loss ($12,000/patient/year), informal care giving is the single most expensive element of burden attributable to PD ($5,000/patient/year) (123).

CIRCUMSCRIBED COGNITIVE DEFICITS

Typical cognitive alterations present in PD include circumscribed deficits in memory, visuospatial, attention, and executive functions. Although mild cognitive deficits can be present in nearly all patients with the disease, they do not invariably progress to dementia. However, a clear progression was shown in approximately 20% of community-based PD patients over 2 years, with a relative risk of 1.7 compared to control subjects (77).

Executive Function

The broad set of abilities that comprise executive function include initiating and planning activities, attentional shifts, concept formation, problem solving, implementing behavior, self-control, and maintenance of socially appropriate behavior. Impairment in these processes has been associated with damage to the frontal lobes or frontal-subcortical circuitry. Numerous authors have reported executive deficits in patients with PD assessed with different tests. Set-shifting deficits have been reported in PD patients who have been tested using the Wisconsin Card Sorting Test (WCST), a conditional associative learning task based on three categorical sorting rules (number-colorshape). Patients with PD show a diminished number of categories and an increased number of perseverative errors. These deficits are present even in de novo patients, regardless of the age of onset, and especially if they are depressed (62,67,118). Similarly, set-shifting and set-maintenance difficulties (Odd-Man-Out Test, Stroop Test) have been reported, even at the beginning of the disease (48,103). Many other attentional and executive tasks are also altered in patients with PD (27,118), including:

Working memory [Digit Span and Arithmetic subtests of the Wechsler Adult Intelligence Scale (WAIS)]
Problem solving (Tower of London/Hanoi)
Verbal or visuospatial abstract reasoning (Raven Progressive Matrices, Similarities and Comprehension subtests of the WAIS)
Switching or planning (Trail Making Test, WCST)

Results of these tests taken by patients with PD suggest that these patients initially have difficulties in focusing attention and mental flexibility, which are necessary to shift and maintain mental sets. Deficits in initiation and in planning strategies needed to solve problems can occur later in the evolution of the disease.

Visuospatial Function

Visuospatial impairments are among the most common deficits described in PD for tasks including visual recognition, visual analysis and synthesis, spatial planning and attention, visual orientation, and visuoconstructive praxis. Deficits in facial recognition, which can appear 2 to 3 years after the diagnosis of the disease, may be the earliest affected visuospatial function in patients with PD (66). This impairment might not be noted in juvenile forms, suggesting that age might
influence performance on this test (118). Deficits in perception, construction, and mental management of objects and figures and alterations in judgment of direction, orientation, and distance can appear later in the evolution of the disease, whatever the age of onset (94,118). Patients show deficits in almost all the performance subtests of the WAIS, including Picture Completion, Block Design, and Object Assembly. These deficits usually appear some years after the diagnosis of the disease, even in the juvenile onset, and are not related to motor dysfunction (66). Other studies have reported deficits in visuoconstructive graphomotor tasks, including difficulties copying complex figures (Rey-Osterrieth Figure) and impairments in copying simple designs (e.g., a house or a clock) with the evolution of the disease (28,56).

Most of the visuospatial tests studied in patients with PD demand manual dexterity or require active planning and strategy formation. However, visuoperceptual impairments have been reported even when motoric task demands are minimized. These impairments were not correlated with the duration of the disease or the severity of motor dysfunction (12,50). A significant correlation between executive and visuospatial tasks has been described, as have beneficial effects of problem-solving clues in visuospatial tasks in patients with PD (14). Qualitative analysis of visuoconstructive test performance shows figures reduced in size, distortions, poor organization, and significant omissions. These data suggest that impoverished performance on visuospatial function in patients with this disease is more related to difficulties in executive tasks and shifting attention than to pure visuospatial difficulties (18).

Memory and Learning

Explicit (declarative) memory deficits and implicit (procedural) memory impairments have consistently been reported in nondemented patients with PD. Explicit memory refers to the conscious recollection (free recall and cued recall) or recognition of a previous event or experience, whereas implicit memory includes perceptual or motor skills learned during life and not readily accessible to conscious recollection. Semantic explicit material (memory for conceptual knowledge and relations that are context free) is usually preserved compared with episodic explicit memory (memory for personally experienced events or episodes). However, some aspects of episodic memory, especially immediate memory, are more affected than long-term memory, cued retrieval, and recognition tasks. Verbal learning and working memory are also commonly affected.

Verbal memory is usually affected later than visuospatial memory because visuospatial material is not semantically related and the recall process requires a greater cognitive effort. As less external supports (fewer cues) are offered and more cognitive demand or self-initiated activities are required, more difficulties appear. For example, conditional associative learning would be more impaired than cuedependent, paired associative learning because the former requires learning by trial and error. Also, recall of a text or a paragraph that has a semantic structure sufficient to guide memory is less affected than word list learning tasks in which organization must be selfelaborated (27,95). This factor could also explain the superior performance of patients with PD on recognition (which relies on external cues) as opposed to free recall tasks (relying on internal cues) and their ability to benefit from cueing (5). Long-term memory is generally less (and later) impaired than immediate memory, reflecting a problem in acquisition of information (immediate organization) more than a genuine storage, retention, and retrieval deficit (long-term recall) (19). Remote memory is generally preserved.

Although some controversial results have been seen, performance on implicit memory tasks can be affected in patients with PD (13). Because implicit memory refers to a form of remembering that can be expressed only through the performance of task operations, these deficits represent a slowness in the acquisition of new motor, perceptual, and cognitive skills. Some authors have also reported patients having difficulty maintaining these skills against a competing stimulus, suggesting, again, an attentional deficit (35).

Language and Communication

Typically, PD affects mechanical aspects of speech, especially articulatory components (e.g., speed, tone, and volume). These alterations generate monotonous, hypophonic, and dysarthric speech that can compromise communication with these patients. Repetitive speech disorders such as stuttering and palilalia are observed, especially in long-standing PD (8). Handwriting is commonly limited by motor impairments, typically manifest as small, cramped script (micrographia).

Patients with PD without dementia have been shown to be only slightly impaired in syntax and grammar tests and in lexical and semantic tasks. Lack of spontaneous speech, delayed responses, single-word answers, and reduction in the length of the phrases can reflect difficulty planning linguistic sentences and an effort to generate as much information as possible in single sentences (32,53). Vocabulary and naming tasks are usually preserved in nondemented patients with PD at the beginning of the disease, and they become affected with the evolution of the disease (45). Verbal fluency can be affected, even at early stages of the disease, especially if loosely defined categories (e.g., objects) or alternating categories (e.g., birds/colors)
are included. Letter verbal fluency tasks are usually affected later than category tasks, suggesting that a “letter” rather than a “category” might act as a cueing device to facilitate semantic retrieval (26,28). Perseverative intrusions in fluency tasks suggest a difficulty shifting between letter categories under a time constraint. Similar to visuospatial and memory dysfunction, it is not clear whether verbal fluency deficits represent a specific language dysfunction or are the expression of an impairment in planning and initiating a systematic search in semantic memory (executive dysfunction).

DEMENTIA IN PARKINSON’S DISEASE

Cross-sectional studies of prevalence of dementia in PD have yielded varied results. Incidence is a better estimate than prevalence of the frequency of dementia in PD because dementia significantly reduces survival in this disease (75). There is an estimated dementia incidence of 3% new cases per year in patients under 60 years of age and up to 14% new cases per year in patients older than 80 years of age (77,80). A longitudinal study of 224 subjects with mean illness duration of 9 years revealed a baseline prevalence of 26% and a cumulative dementia prevalence of 78% after an 8-year follow-up period (1).

Risk factors for PD with dementia (PDD) include increased age, a lower educational background, older age at onset, depression, and longer duration or more severe disease (Table 23-2). Additionally, individuals presenting with PD motor subtypes such as akinetic-dominant (1) and postural instability gait disorder (PIGD) (20) have been shown to be at significantly increased risk for cognitive decline and dementia. Thus, their parkinsonism is more likely to consist of rigidity, bradykinesia, and postural instability instead of tremor (77,115). Demented patients respond poorly to levodopa and are more likely to have adverse psychiatric effects (depression and psychosis) related to dopaminergic therapy.

Neuropsychological studies in nondemented PD subjects have generally associated impairment in executive functions with increased risk for dementia; some have found memory or visuospatial impairment to be predictive as well. One study found that impairment in letter and category fluency tests increased the likelihood of later incident dementia (55). A follow-up study from the same group using an expanded cohort and longer follow-up demonstrated that, in addition to tests of executive function, impaired verbal memory was a significant predictor of incident dementia (68). A separate report related increased dementia risk to impairments in a visuospatial task and the Stroop interference task, in addition to verbal fluency (76). A recent study found that performance on the Stroop interference task was the only significant neuropsychological predictor of dementia in their sample (57).

As in nondemented patients, almost all patients with PDD show prominent executive dysfunction that includes difficulties with planning, problem solving, concept formation, and abstract reasoning when evaluated with frontal-executive tests previously
described (73). Visuospatial, visuoperceptual, and visuoconstructive problems are common, even when patients are evaluated with tasks requiring minimal motor demands. Demented patients with PD demonstrate difficulties recognizing faces, assembling objects, drawing figures, mentally assembling puzzles, formulating line and angular judgments, and identifying embedded figures. Most of these deficits are similar to those found in Alzheimer’s disease (AD); however, patients with PD performed significantly better on visuospatial memory tasks and had worse visual abstract reasoning when compared with patients with AD. Both declarative and procedural memory may be affected in a similar pattern described previously in nondemented patients with PD.

Table 23-2. Risk Factors for Dementia in Parkinson’s Disease

Risk Factors		Risk Ratio
Demographic factors
	Age	1.06
	Education	1.01
	Gender (female)	0.73
Clinical factors
	Age of onset of Parkinson’s disease (>60 years)	4.1
	Duration of Parkinson’s disease (years)	1.01
	Unified Parkinson’s Disease Rating Scale-Motor Scale (>25)	1.04-3.56
	Hamilton Depression Scale (>10)	1.11-3.55
Neuropsychological factors
	Picture Completion of the Wechsler Adult Intelligent Scale (<10)	4.9
	Stroop Test (interference <21)	3.8
	Letter fluency (CFL <27, M <9)	3.3-2.7
	Category fluency (animal, food, clothing <42)	6.01
Data from Jacobs DM, Marder K, Cote LJ, et al. Neuropsychological characteristics of preclinical dementia in Parkinson’s disease. Neurology. 1995;45:1691-1696; Marder K, Tang MX, Cote L, et al. The frequency and associated risk factors for dementia in patients with Parkinson’s disease. Arch Neurol. 1995;52:695-701; and Mahieux F, Fenelon G, Flahault A, et al. Neuropsychological prediction of dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1998;64:178-183, with permission.

Cross-sectional studies comparing demented patients with PD with AD patients have shown that the former perform worse on verbal fluency tasks and show better recognition memory (despite equally impaired recall) and a slower rate of forgetting from immediate to delayed recall. Longitudinal studies have confirmed these results and have reported a more rapid decline in naming, delayed recall, and category verbal fluency in PDD. They also described how patients with AD had a poorer performance on delayed recognition memory (47,52,116,117).

Although aphasia is rare, language deficits are present in PDD and include naming and word-finding difficulties, perseverations, decreased phrase length, diminished verbal fluency, and impaired strategies in sentence comprehension (32,52). Compared with AD patients, patients with PD are less likely to have poorer semantic than phonemic fluency.

There remain outstanding questions regarding the overlap and boundary issues between PDD and dementia with Lewy bodies (DLB), although a consensus statement and research agenda have recently been put forth (69). The traditional clinical distinction between the two syndromes reflects the timing of the cognitive decline relative to the motor symptoms (≤1 year in DLB vs. >1 year in PDD). The clinical and cognitive profiles of the two disorders are much the same, and no single feature distinguishes between them. Where there are differences, they are subtle and not qualitatively distinct: DLB patients may make more conceptual and attentional errors, have more pronounced hallucinations and psychosis, and display more frequent adverse reactions to antipsychotic medications; PDD patients tend to have more cardinal signs of parkinsonism and motor asymmetry.

PSYCHIATRIC FEATURES

Up to 60% of patients with PD experience psychiatric complications. The most frequent are mood disorders, anxiety syndromes, and drug-induced psychosis (Table 23-3) (3).

Depression

The prevalence rate of depression in PD is unclear, ranging from 5% to 90%, a percentage significantly higher than in age-matched control groups. Depression in PD may be difficult to recognize because many of the traditional symptoms associated with the diagnosis of depression may be present because of motor disability. Major depression is present in 20% of the cases, whereas others experience adjustment disorders, dysthymia, or bipolar disorders (30). Depression in PD shares symptoms of primary affective depressive disorders, including feelings of poor self-esteem and loss of social, family, and interpersonal relationships. Other atypical features include comorbid anxiety and panic attacks (40% of the cases), irritability and disinhibition (30%), and psychosis (10%) (109).

Depressive symptoms in PD are a combination of endogenous and exogenous factors. Depression can antedate any recognizable motor symptoms and occur independently of disease duration and motor impairment. These data suggest that the depressive syndrome may be caused by endogenous deficiency in monoamines, especially serotonin, more than a reaction to physical impairment. On the other hand, some studies have shown that successful treatment of depression can be associated with better motor function, and motor improvement may be associated with improved mood. So, reactive depression in response to having an inexorably progressive and debilitating disease can predominate at some point in the evolution of the disease (112).

Apathy can be present in PD as a symptom of major depression, delirium, or dementia or as an independent syndrome. Emotional lability is present in 40% of patients from the onset of the disease.

Anxiety

Generalized anxiety disorders occur in 20% to 40% of patients with PD; social phobia or panic disorder is seen in up to 25% of the patients; and mania or euphoria can appear in 10% of the patients. These symptoms may precede the onset of motor features, accompany a major depressive syndrome, and persist after the depressive illness is treated (23,114). Commonly, anxiety appears in fluctuating patients (“on-off” motor fluctuations) during “off” periods, when the patient experiences worsening of parkinsonian symptoms. Anxiety syndromes have to be differentiated from the understandable psychological response to motor impairment, the somatic complaints related to autonomic symptoms, and akathisia (the necessity to be in constant motion), which is a frequent feature of PD.

Table 23-3. Neuropsychiatric Disturbances in Movement Disorders

	PD %	CBGD %	PSP %	MSA %	HD %	AD %
Depression	5-90	38-75	18	30-50	9-44	20-50
Apathy	41	40	91	90	34-50	70-90
Anxiety	20-66	13	18	8	34	40-60
Delusions	10-20	7	0	15	6-25	20-50
Hallucinations	4-40	0	0	15	10	5-40
Irritability	30	20	9	?	38-50	42
Euphoria	2-33	0	0	?	10-17	3-17
Disinhibition	12-30	20	36	?	24	36
Agitation	30	20	5	?	50	48-70
Sleep disorders	67-88	?	?(Most)	?(Most)	20	45
AD, Alzheimer’s disease; CBGD, corticobasal ganglionic degeneration; HD, Huntington’s disease; MSA, multiple system atrophy; PD, Parkinson’s disease; PSP, progressive supranuclear palsy.
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