Onset and Time Course
Mild cognitive impairment was found already at the time of diagnosis in some patients in an incident cohort of PD.10 There is some evidence that dementia is merely a progression of this early cognitive impairment,24 while other evidence suggests a different profile in PD-D and non-demented PD patients.25 Epidemiological studies suggest that dementia usually develops years after the onset of motor symptoms. This could be a methodological bias however, since patients with early dementia may be excluded due to subjects not fulfilling PD criteria.
The onset is insidious. In one prospective study, the mean annual decline on the MMSE during 4 years was 1 point in non-demented and 2.3 points in the PD-D group, the latter figure being similar to the decline observed in patients with AD.26 A similar rate of decline was reported in another longitudinal study, mean decline in MMSE over 2 years was 4.5, and comparable to that seen in patients with DLB, with a mean decline of 3.9 points.27
The majority of studies on cognitive function in patients with PD have reported on non-demented patients or on non-selected groups including those with dementia. A wide variety of cognitive impairments have been reported, even early in the course of the disease, including memory, visuospatial function, and executive function.28–33 Although the latter deficits are often described as dominating the cognitive profile, there is some evidence of heterogeneity, with some patients expressing an amnestic profile, while others present with a predominantly dysexecutive or mixed profile.32 There is some indication from prospective studies that executive deficits may be the more important predictors of subsequent decline.34, 35 However, the relationship between initial deficits and subsequent profile of dementia has not been clearly established. Therefore, this review was restricted to studies that report explicitly on cognitive function in groups of PD patients with dementia. Most studies included patients with mild or moderate dementia, with little published evidence on the cognitive manifestations of more severe PD-D. Unless clearly stated, the evidence reviewed relates only to the profile of cognitive impairment in mild-moderate PD-D. Comparative studies considered in this review successfully matched dementia groups on the basis of an extended mental status examination (e.g. Dementia Rating Scale [DRS]), or clinical rating of dementia severity.
Most of this review focuses on cognition defined in terms of primary domains. However, some caution must be exercised, as terms such as “attention ” and “executive function ” has been used interchangeably in different studies. Many neuropsychological tests tap a number of different domains, and patients may perform poorly on a given test for different reasons. Unfortunately, most published studies have not employed tests that permit the underlying cognitive processes to be defined in detail.
Assessment of attention has typically employed composite tasks that confound attention and vigilance with motor speed and working memory, such as the DRS Attention subscale. Deficits on this scale are reliably shown in PD-D, although these tend not to be distinguishable in severity from those in patients with DLB or AD.36–39 Differential impairments have been found in some studies using other measures. In one, a test involving letter cancellation revealed that PD-D and DLB groups were not only slower than a group with AD, but also showed more errors.40 Another study employing a composite index of attention also showed a greater deficit in PD-D than AD.41 Finally, in one of the most detailed investigations, attention was measured in terms of variability in performance over time in a series of reaction time tasks.42 This showed increased variability in both PD-D and DLB groups relative to controls and patients with AD. Clinically, 29% of the PD-D patients showed evidence of attentional fluctuation compared to 42% of those with DLB. On the basis of these studies, it can be concluded that attention is impaired in PD-D and may fluctuate, more so than in AD.
Memory complaint was reported to be the presenting problem in 67% of patients with PD-D, compared to 94% with DLB and 100% with AD.40 On the Memory subscale of the DRS significant deficits in mild PD-D have been reported, equivalent to DLB, but less severe than matched groups of patients with AD.36–39 However, in more severe dementia the severity appears to match that seen in AD.36
Studies using more detailed and comprehensive assessments of memory function have produced variable results. Short-term memory has received little attention, although digit span performance, more an attentional test, does not appear to distinguish PD-D and AD.43 Verbal tests of list learning, paired-associate learning, and story recall all show deficits in PD-D on initial learning and immediate recall that do not differ from those seen in AD40, 43–46 except for selected measures in one study.38, 47 Although delayed free recall has been reported to be more impaired in AD than PD-D,40, 44 other similarly powered studies have failed to confirm this result.43, 45, 46
A common claim is that the memory deficit in PD is one of retrieval, rather than encoding and storage. Evidence for this comes primarily from studies in non-demented patients with PD who tend to show intact recognition memory and enhanced performance when given retrieval cues. However, patients with PD-D also appear to be impaired on cued recall.44, 48 There is also growing evidence for recognition memory deficits in PD-D for both verbal40, 46, 48 and non-verbal40 material (see49 for a review). In some studies the recognition deficit in PD-D is less severe than that in AD,40, 44, 46 although comparable deficits have been reported on tests of visual recognition memory.40 However, all of these studies involved patients with predominantly mild-moderate PD-D. Implicit memory has been studied in one study considered for this review, which found no deficit in either PD-D or AD.45 On the basis of these studies it can be concluded that both verbal and visual memory are impaired in PD-D, that the degree of this impairment is probably less than that seen in AD, and that recognition may be less affected than recall in mild to moderate PD-D.
Verbal fluency has been extensively studied in PD-D. It accounts for the major part of the Initiation and Perseveration Scale of the DRS, where impaired performance is typical in patients with PD-D.36–39 Relative to AD, patients with PD-D may be more impaired on this scale,36 although other studies have found no significant difference.37, 38, 44 In more severe dementia, patients with PD-D, AD, and DLB appear equally impaired.44 Several other studies have used specific tests of verbal fluency, both phonemic and semantic, with similar results. The severity of the fluency deficit does not appear to differ in AD and PD-D.37, 43, 44
Concept formation has been tested using the “Conceptualization subscale” of the DRS, “Similarities subtest” of the Wechsler Adult Intelligence Scale (WAIS), Raven's Progressive Matrices (RPM) and Wisconsin Card Sorting Test (WCST). Performance on such measures is impaired in PD-D relative to controls and/or non-demented patients with PD.36–40, 43, 50 Compared to patients with AD, similar performance is observed on the DRS subscale in most,36, 39, 40, 42 but not in all studies.38 On the WCST patients with PD-D were more impaired in terms of total errors, but not on any other index of performance including number of categories sorted,50 while greater impairment of PD-D patients on the RPM has been noted.43 There is no evidence that patients with PD-D are generally more perseverative than patients with AD, at least as measured by WCST.50 The results of these studies reveal that executive functions are impaired in patients with PD-D, probably more so than in patients with AD. There is also some suggestion that the memory deficits in PD-D may be more closely associated with executive dysfunction than those in AD.44
Construction and Praxis.
Typically, drawing tests are used to assess constructional ability and praxis, either copying designs or drawing common objects. The Clock-Drawing Test (CDT) is markedly impaired in PD-D as evidenced by the baseline data in the large cohort recruited for a clinical trial.51 A deficit on the same task was identified in a smaller study that failed to distinguish the performance of patients with PD-D, DLB, and AD,52 although there was evidence that the former two groups showed more “planning ” errors in their performance. Other studies using design copying tests all showed impairment in PD-D. These studies have shown either no difference in performance between groups with PD-D and AD,36–38, 40, 41, 43 or more severe deficits in PD-D,39, 53 particularly with more severe dementia.36 Comparisons of PD-D and DLB have revealed either no difference42 or greater deficit in DLB.40
Construction/drawing tasks involve significant motor control and a range of cognitive functions. The contribution of motor dysfunction to such deficits has rarely been examined in PD-D. This may account for at least part of the reported performance deficit. In terms of cognitive function, the tasks tap both visuo-perceptual and visuo-spatial processes, and executive processes in terms of planning or response alternation. Little is known about the primary source of the deficits in PD-D in performing such tasks, although one study employing a qualitative assessment of the CDT suggested that PD-D and DLB patients showed more evidence of a planning deficit than a group with AD.52 Based on these studies, it can be concluded that visuo-spatial construction is impaired in PD-D, probably to a greater extent than that seen in AD.
The assessment of visuo-spatial function without the demands of fine motor control has received little attention in PD-D. One study used the Raven's Progressive Matrices test, which involves complex visuo-perceptual/spatial function,43 and reported the PD-D group to be more impaired than a group with AD. However, the test also requires significant conceptual processing so that at least part of the deficit may have been due to executive problems. In another study, visual perception (as measured by tests of visual discrimination, space-motion, and object-form perception without needing manual responses) was globally more impaired in PD-D than in non-demented controls, but was not different from DLB. Compared to AD, PD-D patients tended to perform worse in all perceptual scores.54 It is concluded that PD-D is associated with substantial visuo-perceptual impairments similar to DLB, but different from AD.
Language function has received little attention in PD-D, perhaps because clinically evident aphasia is rare. In one study, performance on verbal comprehension, naming, and repetition did not show any significant difference between AD and PD-D patients,40 although a more severe picture naming deficit in AD has been reported.44 In another study, patients with AD were also found to have significantly more impoverished information content of spontaneous speech, more impaired word list generation, and more severe anomia as compared to those with PD-D, and a stepwise discriminant analysis revealed that 96% of patients were correctly classified on the basis of information content of spontaneous speech (worse in AD) and speech melody (worse in PD-D).55 Verbal fluency is sometimes included in the language domain, and in this review it is considered as a test of executive function. Based on the little available data, it is suggested that patients with PD-D have less impairment in core language functions as compared to AD.
The Pattern of Cognitive Impairment Across Domains.
Rather than considering individual domains, additional evidence can be obtained by considering relative performance across domains. In a study by Janvin et al.,56 the DRS was used to define a “cortical profile ” (performance on the Memory subscale relatively worse than that on the Initiation and Perseveration subscale) and a “subcortical profile ” with the opposite pattern of relative performance. Both profiles were present in patients with mild-moderate PD-D, as well as in DLB and AD. This may reflect the similar clinical heterogeneity reported in non-demented PD patients.57 The “cortical ” profile predominated in the AD group by a ratio of 2:1 while the opposite was seen in the groups with PD-D and DLB. Only PD-D and DLB patients showed a pattern of severe global impairment in memory and executive function. Another study used pairs of performance indices from a standardized neuropsychological battery.41 In this case, a “subcortical ” score was derived from tests of visuo-spatial function, construction, and attention, and a “cortical ” score from language and delayed memory. In the PD-D group, the mean subcortical score was greater than the cortical score, with the opposite pattern for the AD group. Although relatively accurate at distinguishing the groups, the indices also showed significant overlap between the groups and cannot be considered of primary diagnostic significance.
Conclusions on the Profile of Cognitive Impairment
Impaired cognitive domains in PD-D include attention, memory, visuo-spatial, constructional, and executive functions. There are some phenomenological differences between PD-D and AD, particularly in executive functions, so that a “subcortical” or “dysexecutive ”pattern predominates in PD-D, although there are overlaps. These differences are most apparent in the early and middle stages of dementia and difficult to identify in the later stages. Many studies involving a wide range of tests have failed to distinguish between patients with PD-D and AD with certainty. The differentiation between PD-D and DLB in terms of cognitive profile is even less evident. Many of the tests used may be insufficiently sensitive to disentangle alternative mechanisms underpinning impaired performance, such as role of impaired attention in poor memory function as opposed to primary deficits in memory.
Neuropsychological assessment serves an important role in providing objective evidence of cognitive impairment to support the clinical diagnosis of dementia in PD. However, its role in differential diagnosis is not conclusive, at least with the standard tests typically employed in published studies. While indicative profiles can be described on the basis of sets of tests, the evidence is not yet sufficiently robust to use these as the sole basis of diagnosis.
Behavioral and Neuropsychiatric Symptoms
While formal diagnostic criteria can be applied to elicit symptoms such as depression or anxiety, the majority of clinical features are identified by informant ratings, the most popular one in the assessment of PD-D being the Neuropsychiatric Inventory (NPI).58 While there is evidence that symptoms often occur in clusters,59 the organization of this review is based on individual symptoms. The review focused on those symptoms that occur in a significant proportion of PD-D patients, namely, hallucinations, delusions, mood disturbance, and apathy.
Hallucinations and Delusions.
Hallucinations have been reported as common in both population-based studies of PD (25%)60, 61 and in clinic samples (40%)62 assessed by NPI, with a substantially higher prevalence in PD-D (45–65%).62–65 When found in non-demented patients, hallucinations are a major predictor of subsequent dementia,18 and nursing home placement.66 In DLB, hallucinations are even more common than in PD-D, with figures in the range of 60 to 80%.63, 67, 68 The high prevalence of hallucinations in PD-D and DLB contrasts with relatively low rates reported in mild-moderate AD (4–8% on NPI).67, 69, 70 The significance of hallucinations as marker of Lewy-body pathology has been confirmed by both retrospective and prospective post-mortem studies.68, 71, 72
The phenomonology of hallucinations in PD-D and DLB is very similar. Visual hallucinations occur twice as frequently as auditory ones, the majority being complex, formed hallucinations.62, 63, 73 Most common are anonymous people, but they may also be family members, body parts, animals, or machines. They tend to be in color, static and centrally located, and occur with similar frequency and severity in PD-D and DLB.62, 73
Delusions are less common than hallucinations in PD-D, although the two symptoms often coexist. While occurring in ∼17% of patients with PD overall,60, 61 their prevalence in PD-D is 25 to 30%,63–65 somewhat lower than rates seen in AD,64, 67, 70, 74 and particularly in DLB where rates of 57 to 78% have been reported.63, 67, 74 Another study suggested that when delusions occur they do so with similar frequency over time and severity in DLB and PD-D,73 and with similar phenomenology. Paranoid delusions and “phantom boarder ” are among the most common content in both disorders.63 Mis-identification syndromes appear to be particularly prevalent in DLB occurring in up to 40% of patients, compared to 10% in AD.68 Whether mis-identification delusions are also characteristic of PD-D is currently unclear. The prevalence of Capgras delusions is reported to be 10% in DLB, when compared with no cases in patients with PD-D.63
In a community-based sample applying formal diagnostic criteria, the rate of major depression in PD-D has been reported as 13%, compared to 9% for non-demented patients, and 19% for patients with DLB.63 Both severity of depressed mood and prevalence of major depression may be higher in PD-D than in AD.43 However, dysphoric mood as assessed by the NPI occurs with the same frequency in PD-D and AD (40–58%),64 possibly higher than seen in patients with DLB.65, 74
Anxious mood occurs at a similar frequency (30–49%) to depressed mood; the two disturbances are frequently co-morbid,75 or occur in the same symptom cluster.59, 65 The prevalence of anxious mood in PD-D, DLB, and AD appears similar to that of depressed mood.64, 68, 70, 74, 76 Irritable mood and problems with anger and aggression, common in AD, are not prominent clinical features of PD-D, while the frequency in DLB is similar to that seen in AD.76 Irritability has a prevalence of less than 10% in non-demented patients with PD,61 with only a slightly higher rate in PD-D (14%).64 and tends to be infrequent even in patients who show significant problems in other domains.59
Elevated mood is rare in PD-D, being reported as either absent,43 or occurring in only 2% of the population.64 A similar picture is reported in DLB,74 with a somewhat higher rate in AD, although it remains relatively rare.70, 74
Apathy is often regarded as a hallmark feature of frontotemporal dementia67 and progressive supranuclear palsy,61 where frequencies of 80% or more have been reported. Similar rates are also reported in DLB,67 with increasing severity with worsening dementia.77 However, apathy is also a significant problem in AD, with frequencies of 50% or more,64, 70, 74 increasing with cognitive deterioration.70 In PD-D, lower figures had been reported with a frequency of 23 to 24%,64 although a recent study analyzing a large sample of mild-moderate PD-D patients reported a higher figure (54%),65 compared to 17% in non-demented patients.61
Conclusions on Behavioral and Neuropsychiatric Features
Neuropsychiatric symptoms are common in all types of dementia and are of little specific differential diagnostic value. Hallucinations stand out as one of the few features that usefully distinguish between DLB/PD-D and AD. In general, patients with PD-D appear to have less frequent or less severe psychiatric symptoms than patients with DLB. Such differences, however, may simply reflect disparity in the overall dementia severity. Similar issues apply when trying to distinguish demented and non-demented patients with PD, as all of the symptoms may occur in non-demented patients. Thus, although psychiatric symptoms may be risk factors for developing dementia, and may support the diagnosis of dementia, they do not appear to be useful in differentiating PD-D from DLB and AD in individual cases.