J Neuropsychiatry Clin Neurosci 12:425-450, November 2000
© 2000 American Psychiatric Press, Inc.
A Review of the Cognitive and Behavioral Symptoms in Dementia With Lewy Bodies
Martine Simard, Ph.D.,
Robert van Reekum, M.D., F.R.C.P.C. and
Tammy Cohen, B.A.(H)
Received November 4, 1999; revised March 1, 2000; accepted March 15, 2000. From the Department of Psychiatry and Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care and the Division of Geriatric Psychiatry, Department of Psychiatry, University of Toronto, Ontario, Canada. Address correspondence to Dr. Simard, Département de Psychologie, Université de Moncton, Moncton, Nouveau-Brunswick, E1A 3E9, Canada.
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ABSTRACT
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Dementia with Lewy bodies is a relatively common cause of dementia. Much has been learned about this disorder, yet much remains to be elucidated, especially in regard to early clinical diagnosis. To clarify the future research agenda in this area, the authors critically appraise the literature on cognitive and behavioral changes in DLB and provide a brief overview of the history of DLB, the main pathological changes, and the findings related to extrapyramidal symptoms and treatment issues. Twenty-one studies on cognition and 47 on behavioral changes in DLB are reviewed. Impairments of working memory and visuospatial functions, visual hallucinations, and depression (or symptoms of depression such as apathy and anxiety) have been identified as early indicators of DLB. However, longitudinal and cross-sectional data are lacking, particularly for different aspects of working memory, visual perception, and nonpsychotic behavioral symptoms.
Key Words: Dementia • Dementia With Lewy Bodies • Psychosis
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INTRODUCTION
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According to the neuropathological findings of McKeith et al.,1 gathered in a U.K. geriatric department between 1982 and 1987, dementia with Lewy bodies (DLB) is the second most common cause of dementia following Alzheimer's disease (AD), with a prevalence of 19% compared with 52% for AD. Other data gathered in 284 autopsied cases, in a Norwegian general hospital without a geriatric department, suggest that Lewy body pathology is the third most common cause of dementia (7.7%), after AD changes (71.4%) and cerebrovascular lesions (33.8%).2 Almost 96% of subjects with Lewy bodies also had AD changes. Clinically, the prevalence of dementia with Lewy bodies varies depending on the clinical criteria that are applied. Shergill et al.3 reported that the prevalence of DLB among 114 patients diagnosed with dementia (ICD-10) was 26.3% according to the McKeith et al.4 criteria for Senile Dementia of Lewy Body Type, 7% according to Byrne "probable" criteria, and 16.6% according to Byrne "possible" criteria.5
Although prevalence estimates clearly vary, it is also clear that DLB is relatively common. Much has been learned about this disorder, yet much remains to be elucidated, especially with regard to the cognitive and behavioral symptoms of this disease. A proper and early detection of the cognitive and behavioral symptoms is crucial for the differential diagnosis of dementia with Lewy bodies, because these symptoms frequently are the principal complaints at the initial consultation. Therefore, our goals in this review are 1) to provide a critically appraised synopsis of the literature with a focus on the cognitive and behavioral changes of DLB and 2) to target critical areas of needed research. To address these goals, we review the history of DLB, summarize the pathological changes, briefly review findings related to extrapyramidal symptoms and treatment issues regarding behavioral and cognitive symptoms in DLB, and then provide an extensive review of the literature relative to cognitive and behavioral changes in DLB.
Clinically, a better understanding of the cognitive and behavioral symptoms will help to generate an early diagnosis and hence the early planning of an appropriate treatment. In addition, a better understanding of the cognitive and behavioral symptoms of DLB will contribute to the development of a mechanistic model of the disease. Such a model is at this moment difficult to establish because a lot of neuropsychological and imaging data are still lacking.
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METHODS OF THE LITERATURE SEARCH
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MEDLINE and Psychological Abstracts were searched by using the following key words: 1) "Lewy bodies"; 2) "cognitive ability (explode)" AND "dementia (explode)," "cognitive ability (explode)" AND "Alzheimer's disease," "cognitive ability (explode)" AND "prediction of dementia"; 3) "dementia (explode)" AND "screening (explode)," 4) "Lewy bodies" AND "psychotic disorders (explode)" OR "delusions" OR "schizophrenia," and "dementia and psychosis"; and 5) "Lewy bodies" AND "depression (text words)," "Lewy bodies" AND "anxiety (text words)," "Lewy bodies" AND "apathy (text words)," and "Lewy bodies" AND "agitation (text words)." The search included literature that has been published within the past 5 to 8 years. A manual search was also conducted on English and French journal articles to obtain references to other publications. Case reports and retrospective studies that did not mention the presence of cortical Lewy bodies were excluded. For the review of cognitive impairments, only papers with quantified data were retained.
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HISTORICAL OVERVIEW
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Lewy bodies (LB) are intracytoplasmic, spherical, eosinophilic neuronal inclusions that were originally identified in subcortical nuclei as one of the cardinal characteristics of Parkinson's disease (PD).6–8 Following the publication of several case reports of Japanese and Austrian subjects with dementia presenting Lewy bodies in brainstem nuclei as well as in cortical areas (Table 1, section A),4,5,9 Kosaka10 described the appearance of cortical versus brainstem Lewy bodies. This detailed description had been aimed for researchers using various hematoxylin and eosin staining preparations in combination with other techniques such as Klüver-Barrera, Nissl, Mallory azan, PTAH, Bodian, pyridine silver, bromphenol blue, CTR, Millon, Sakaguchi, Sudan III, Sudan black B, periodic acid-Schiff, Best's carmine, Alcian blue, and Congo red. The development, by Kuzuhara et al.,11 of the monoclonal anti-ubiquitin immunostaining method, a more sensitive technique to detect cortical Lewy bodies than the conventional staining methods, has prompted studies in Europe and America in patients presenting an atypical dementia and cortical Lewy bodies at autopsy. In the 1980s, retrospective studies and case reports showed that some of the atypical patients initially diagnosed as suffering from Alzheimer's disease, Parkinson's disease, and/or multi-infarct dementia12,13 actually had cortical Lewy bodies.1,14–56
Kosaka and colleagues12,57 classified diseases in which Lewy bodies are found into three groups: 1) group A, diffuse type, also called Lewy Body Disease Variant or LBV; 2) group B, transitional type; and 3) group C, "brainstem" type, related to Parkinson's disease. The diffuse type was also classified into two subgroups: 1) the "common form" group in which senile plaques and neurofibrillary tangles as well as Lewy bodies are found in the cortex in sufficient number to meet the pathologic diagnostic criteria for Alzheimer's disease and 2) the "pure form" group in which cortical Lewy bodies are found in sufficient number but the number of senile plaques and neurofibrillary tangles in the cortex does not meet the criteria for Alzheimer's disease per Khatchaturian.58 Recently, the Consortium on Dementia with Lewy Bodies (CDLB) recommended Dementia With Lewy Bodies (DLB) as a generic term for all of these cases, acknowledging the presence of LB without specifying their relative importance in symptom formation with respect to other degenerative or vascular pathology that might be simultaneously present.9
The CDLB defined the pathological features associated with DLB as follows: 1) essential for the diagnosis of DLB: Lewy bodies; 2) associated but not essential: Lewy- related neurites; plaques (all morphologic types); neurofibrillary tangles; regional neuronal loss especially in brainstem (substantia nigra and locus ceruleus) and nucleus basalis of Meynert; microvacuolation (spongiform change) and synapse loss; neurochemical abnormalities and neurotransmitter deficits.9 The Consortium also recommended the examination of three neocortical regions (the frontal, temporal, and parietal cortices); two limbic cortical regions (the anterior cingulate and transentorhinal cortices); and brainstem regions (substantia nigra, locus ceruleus, and dorsal nucleus of vagus) to establish the definite neuropathological diagnosis.9 Following a study with 20 cases having a pathological diagnosis of Alzheimer's disease and/or Parkinson's disease and 8 control cases, Harding and Halliday59 have proposed the following changes to the CDLB neuropathologic diagnostic procedure: 1) elimination of the parietal and frontal association regions from the analysis, 2) elimination of cortical layers I and II from the sampling, and 3) exclusion of cases without brainstem Lewy bodies.
Clinical criteria were developed in the 1990s following the case reports and the first retrospective studies (see Table 1). 4,5,9 The first clinical criteria5 were inspired by the school of Kosaka et al.,12 where DLB is viewed as closely related to idiopathic Parkinson's disease. According to Byrne et al.,5 extrapyramidal symptoms (EPS), together with a dementia per DSM-III-R, are necessary for a diagnosis of dementia with Lewy bodies (see section C of Byrne's criteria, Table 1). To meet criteria for probable dementia, a subject must have dementia at onset or later in classical Parkinson's disease or have EPS at onset of dementia. To meet criteria for possible dementia, a subject must have EPS appearing later in the dementing process. The time of onset and the number of EPS make the difference between a diagnosis of possible and one of probable DLB, according to Byrne et al.5 The only indication regarding cognition refers to prominent attention deficits and acute confusional states. Byrne et al.5 did not mention any behavioral or psychotic symptoms.
A year later, criteria for Senile Dementia of Lewy Body Type (SDLT) were published.4 McKeith et al.4 based their clinical description of SDLT primarily on the retrospective data collected in their geriatric psychiatry unit in Newcastle.1,4 More of a focus on the cognitive changes of DLB was evident. The cognitive impairment, affecting memory and higher cognitive functions, was seen to fluctuate. These cognitive fluctuations were felt to be the hallmark of dementia with Lewy bodies. EPS were considered as a possible feature, but they were not felt to be requisite anymore. McKeith et al.4 have introduced to the diagnostic criteria psychiatric features such as hallucinations (auditory or visual) accompanied by paranoid delusions, neuroleptic sensitivity syndrome, repeated unexplained falls, and clouding or loss of consciousness.4 For a subject to meet criteria for SDLT, cognitive fluctuations, occurring with either hallucinations and paranoid delusions, mild EPS, neuroleptic sensitivity, repeated falls, or transient clouding of consciousness, are required. These criteria have been found to have a high diagnostic specificity of 90.0% to 97.0%, with a mean sensitivity of 74%. Sensitivity was greater in the more experienced clinicians (90%) than in the least experienced clinician (55%).48 Interrater reliability has varied between the most experienced raters (94%; kappa=0.87) and the least experienced rater (78%; kappa=0.50).48
In 1996, another set of criteria was proposed by the CDLB, being an update, an integration, and a refinement of the previous criteria.9 The notions of gradual impairment and of the "possible" and "probable" diagnoses were reintroduced, and a progressive cognitive decline became the central feature. Together with the cognitive decline, fluctuations in attention and alertness, recurrent visual hallucinations, and/or EPS (no more than 1 year before the onset of cognitive decline) should be present. The difference between a possible and a probable diagnosis lies in the number of core features exhibited (see Table 1). The CDLB criteria have also added supportive features to the diagnosis of DLB: repeated falls; syncope; transient loss of consciousness; neuroleptic sensitivity syndrome; systemized delusions (usually paranoid); and hallucinations in other modalities.
Using retrospective chart review, done by 5 neurologists, and a blinded pathologic evaluation, Mega et al.60 have studied reliability and validity of the clinical criteria of the CDLB. They found the sensitivity/specificity ratio of the CDLB's probable DLB clinical criteria was 75%/79%. Reformulated clinical criteria that required the presence of EPS significantly predicted those patients with many LBs versus those with few or no LBs and increased clinical specificity to 100%.60 Interrater reliability results for each of the CDLB possible features were used to extract the best-operationalized combination of symptoms. These include (from the most likely to the least likely): hallucinations, cogwheeling, rigidity, bradykinesia, neuroleptic sensitivity, and evidence of fluctuations in cognition. Fluctuation in cognition has been the most difficult feature to identify and agree on.60 Because the typical AD patient loses about 3 points per year61,62 on the Mini-Mental State Examination (MMSE) total score, Mega et al.60 recommended that fluctuations of 5 points or more on the MMSE total score over 3 administrations in a 6-month period be considered significant "fluctuations" for DLB.
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PATHOLOGICAL CHANGES IN DLB
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Cortical Lewy bodies are found in small and middle neurons, in deep cortical layers of every lobe, with a predilection for the anterior frontal and temporal areas,22,33 the cingulate area,12,33,63 and the insula.12,22,33 In the subcortical structures, Lewy bodies are numerous in the substantia nigra and can also be observed in the nucleus basalis of Meynert, in the locus ceruleus, in the nucleus raphe dorsalis, and in the amygdaloid complex.12,17,22,33,34 In the amygdala, Lewy bodies can be found in conjunction (in the same neuron) with neurofibrillary tangles (NFT) in both DLB and AD.64
Neuritic degeneration in the CA2/3 region of the hippocampus, not seen in AD or in normal aging, is correlated with the presence of cortical Lewy bodies.65 More significant neuronal losses than in AD are described in the substantia nigra, the nucleus basalis of Meynert,34,47,66 and the frontal lobe of subjects with LBV (i.e., DLB).34
Subjects with DLB also present neurochemical dysfunction. Perry et al.67–69 described reductions in the cortical cholinergic enzyme choline acetyltransferase (ChAT) that is more severe in individuals with hallucinations (80%–85%) than in those without (50%–55%).67–68 These ChAT reductions were more extensive in neocortical as opposed to archicortical regions66,69,70 and were more marked in the parietal and temporal cortex67 as well as in the hippocampus and entorhinal cortex in patients with DLB69,71 than in patients with AD.71 Frontal depletion of ChAT was also observed.69–71 As a consequence of these ChAT reductions, there is a lack of cortical acetylcholine in DLB brains. However, an ACh compensation mechanism seems to be present. Unlike the pathological process in AD, in DLB the number of cortical postsynaptic muscarinic receptors (particularly of the low-affinity subtype L) is significantly increased.68,69 Simultaneously to the depletion of cortical ACh, a reduction of dopamine (DA) levels, related to the substantia nigra neuronal loss, has been described in the basal ganglia of subjects with DLB. An approximate loss of 40% to 60% of dopamine in DLB brains, compared with an 80% loss in Parkinson's disease brains, was reported,68–72 as well as a decrement in the basal ganglia levels of homovanillic acid.70 Cell loss in the ventral tegmental area, observed in one case of dementia with cortical LB, suggests abnormalities in the DA mesocorticolimbic system.73
Some recent PET data collected in two groups of mildly to moderately demented subjects meeting criteria for probable DLB (CDLB criteria)9 and probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria)74 showed a more severe glucose hypometabolism in DLB compared with AD in the cerebellar hemispheres and the temporal-parietal-occipital association cortices,75 and especially in the medial and lateral occipital lobes.55 A more severe hypometabolism in the medial temporal and cingulate areas has otherwise been found in AD when compared with DLB.75
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RELATIONSHIP TO OTHER DEMENTIAS
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The nature of dementia with Lewy bodies is currently a controversial matter. Yoshimura22 and Kosaka et al.12 have suggested that diffuse Lewy body disease or dementia with Lewy bodies might be an extended form of idiopathic Parkinson's disease. Their description of the various forms of the disorder were based on the observation that their demented patients all had clinical signs of parkinsonism and pathological evidence of Lewy bodies in the brainstem. Some of these patients had cortical LB (cLB), and some were devoid of them.12,22 Although it is well recognized that all demented patients with cortical LB also present brainstem LB, cLB have however been reported in demented patients with no clinical signs of parkinsonism but presenting some pathological AD changes.9,16,24 Therefore, other authors hypothesize that DLB is the coexistence of AD and PD.76,77
Brown et al.76,77 argue that LB surimpose on gradually existing AD changes in the brain, starting in the brainstem and then invading the cortex. They demonstrated that cLB were more numerous in 22 AD subjects with concomitant substantia nigra (SN) LB than in 6 pure AD (without SN LB) and 8 pure PD subjects with SN LB.76 All patients with pure AD and AD/PD were clinically demented, whereas only 75% of patients with pure PD (with SN LB) were demented.76 Brown et al.77 also found that synaptophysin concentrations, related to synaptic density, were significantly lower in 14 DLB and 31 AD subjects when compared with 10 healthy control subjects. DLB and AD patients showed a comparable loss of synapses in the frontal, temporal, and parietal lobes.76
Neurofibrillary tangles are a fundamental neuropathological feature of Alzheimer's disease.58,74 However, Brown and co-workers76,77 showed a significant negative correlation between neocortical LB and NFT density in the brain of patients with AD/PD or LBV. The scarcity of NFT in DLB brains has been reported by other authors65,71,78 and was characterized, by Dickson et al.,65 as a hallmark of a disease distinct from Alzheimer's disease. According to Dickson et al.,65 this distinct disease, DLB, can occur independently or in coexistence with pathological aging or AD. In support of their argument, they mention other neuropathological changes that take place in DLB, such as the neuritic degeneration in the CA2/3 region of the hippocampus, which does not occur in AD.65 More recently, other authors have reported findings supportive of the hypothesis of Dickson et al.65 They found a positive correlation between cLB and cognitive impairment, whereas NFT and synapse density did not correlate with cognitive status71,78 and the number of senile plaques correlated less significantly than cLB with the MMSE score.71
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ANTEMORTEM PRESENTATION: EXTRAPYRAMIDAL SYMPTOMS
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Until recently, results regarding the relationship of EPS and hallucinations to severity of dementia and rate of cognitive decline, as measured with brief assessments in cross-sectional and longitudinal studies, have been controversial (see review by Ellis et al.79 on EPS in Alzheimer's disease). Methodological problems might explain this controversy. There has been confusion between neuroleptic-induced and noninduced EPS, a lack of consideration for concomitant behavioral disturbances and institutionalization, and an absence of matching of the groups with and without EPS on baseline dementia severity.79
One group of researchers80–82 has strictly and retrospectively studied the presentation of EPS in autopsied cases of demented (per DSM-III-R) subjects with DLB and PD. They have identified some EPS that may distinguish between idiopathic Parkinson's disease and dementia with Lewy bodies. They found, in 31 DLB and 34 PD subjects, that the occurrence of any one of four clinical features—myoclonus, absence of resting tremor, no response to levodopa, or no perceived need to treat with levodopa—was 10 times more likely in DLB than in PD (odds ratio=10.29, 95% confidence interval=2.58–41.11).82 The likelihood of having DLB, given any one of these four features, was 85.7% (positive predictive value). Most patients with DLB had either bradykinesia (89.5%) or rigidity (92.8%).82 Gnanalingham et al.83 compared 16 patients with DLB and 15 patients with PD. The mean duration of illness for the PD group was 9.2±2 years, whereas the mean duration of illness for the DLB group was 6.3±1.1 years. Using the Unified Parkinson's Disease Rating Scale, they have shown that patients with DLB presented more rigidity, but less left/ right asymmetry, than patients with PD.83 There was no significant difference between the two groups on the other measures of parkinsonism.
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DEMENTIA WITH LEWY BODIES AND TREATMENT ISSUES
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The early clinical diagnosis of DLB is crucial, given that 81% of patients with DLB treated with classical neuroleptics such as haloperidol experience a neuroleptic sensitivity syndrome, compared with 29% in AD.1 In order to avoid or lessen the risk of neuroleptic sensitivity syndrome in patients with DLB, treatment strategies have recently been focused on the use of atypical neuroleptics such as clozapine and risperidone. There are no randomized placebo-controlled trials of atypical neuroleptics for the treatment of behavioral disturbances in dementia, and the anecdotal results have been controversial. Some authors reported a favorable response in patients with DLB treated with clozapine84 and risperidone,35,85 while others86–88 described a neuroleptic sensitivity syndrome mainly characterized by the onset or exacerbation of EPS. However, a new atypical neuroleptic, olanzapine, which binds more on serotonergic receptors and less on dopaminomimetic receptors than the other atypical neuroleptics, could be a good treatment choice, given some promising preliminary data on 1 patient89 and on 5 of 8 patients90 with probable DLB per McKeith et al.9 criteria.
Regarding trials of cognition-enhancing drugs, some retrospective data suggest that patients with DLB respond better to treatment with the cholinesterase inhibitor tacrine than do patients with AD.91 A trial of another anti-acetylcholinesterase compound, donepezil, resulted in improvement in hallucinations, and sometimes in cognition and overall function, in 9 patients meeting CDLB clinical criteria for DLB.92
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COGNITIVE SYMPTOMS
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Retrospective Studies With Autopsy-Proven DLB
Six retrospective studies, with cross-sectional data, have compared small groups of subjects (mean number of DLB subjects per group=12.51, range 5–23; mean number of AD subjects per group=11.51, range 5–23) using different matching procedures: the Information-Memory-Concentration subtest score of the Blessed scale;93 the MMSE94 or Mattis Dementia Rating scale (MDRS)95 total score, alone or in combination with age, gender, and education; the duration of the disease; and the number of months between last testing and death (see Table 2). 34,47,51,52,71,96 These subjects were mildly51,96 to moderately47,52 demented. In two studies, the subjects with Lewy Body Variant (or DLB) and AD were severely demented,34,71 whereas the 5 subjects of Samuel et al.,71 with pure DLB, were moderately demented. Only one study included a healthy control group (of 5 subjects).71
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TABLE 2. Retrospective studies with autopsy-proven Lewy body disease: performance on tests of attention and executive function, language and verbal fluency, visuospatial functions, and memory
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Table 2 (tests described in Table 4) indicates that mildly and moderately demented patients with DLB perform more poorly than patients with AD on tests of visual tracking (Trail Making Test A) and visual attention shifting (Trail Making Test B)51,52 that rely on working memory (WM).97,98 Working memory is the system necessary for holding and manipulating information while performing various tasks including learning, reasoning, and comprehending. The central executive system (CES) is the supra component of this model. It is assumed to be an attention controller and to have, among other roles, that of coordinating and distributing attention resources between the two slave subsystems of WM. The visuospatial sketchpad is the slave subsystem that maintains information under a visuospatial code. The other slave subsystem, the articulatory loop, maintains phonologically encoded material in primary memory through short-term storage and translates, when applicable, visually presented material into verbal material.97,98 Regarding verbal attention (articulatory loop) capacities, two studies with mildly demented patients have reported that patients with DLB and AD were equally impaired in performance on the Digit Span subtest of the Wechsler Adult Intelligence Scale–revised (WAIS)51 and on the Attention subtest of the MDRS.96 Another study, with moderately demented subjects, described a poorer performance of patients with DLB when compared with AD subjects on the Digit Span task.47
In respect to verbal and motor initiation capacities (Table 2), mildly and moderately demented patients with DLB are more impaired than patients with AD.47,52,96 The most sensitive tests in this regard have been the lexical fluency tasks47,52 and the Initiation/Perseveration subtest of the MDRS.96 One study51 reported that subjects with DLB and AD perform equally poorly on the lexical fluency tasks. However, this study had a very small number of subjects per group, and they were matched on the MDRS scores.51 The MDRS includes tasks of verbal fluency and tests of other frontal functions as well, thus potentially masking differences that might otherwise have been found. Performance in tasks of semantic fluency and knowledge (naming) were equally impaired in mildly, moderately, and severely demented DLB and AD patients.34,47,51,52
Regarding executive functions such as abstraction capacity (Table 2), the performance of mildly demented subjects with DLB and AD is equally poor on the Conceptualization subtest of the MDRS and the Similarities subtest of the WAIS.51,96 The performance of moderately demented patients with DLB is more impaired than that of patients with AD on the Similarities subtest of the WAIS.47 The two studies assessing moderately demented subjects reported different results on the Arithmetic subtest of the WAIS. According to Galasko et al.,52 patients with DLB have a poorer performance than patients with AD on the Arithmetic subtest, whereas according to Hansen et al.,47 these two groups perform equally poorly on the Arithmetic subtest. The subjects did not differ enough between the two studies in regard to demographics (education, age) and EPS features to account for the different results. These two studies47,52 both included only a small number of subjects in each group (see Table 2). They both performed several analyses on several variables, sometimes with nonparametric statistics (Mann-Whitney U-test), but often with parametric statistics like analysis of variance and Student's t-test, without any correction for the number of analyzed variables. Thus, some results could have been inappropriately identified as significant, or significant results might have been missed, because of the lack of statistical power.
Regarding visuospatial functions, Table 2 shows that mildly and moderately demented patients with DLB perform more poorly than patients with AD on visuospatial praxis tests such as the Block Design subtest of the WAIS and drawing tasks such as the Clock.51,52 Mildly and moderately demented patients with DLB have been found to be more severely impaired on the copy part of drawing tasks (Clock-copy and the Construction subtest of the MDRS), as opposed to the free drawing part, when compared with AD subjects.51,52 However, some authors have described no difference between the two groups, in mildly and severely demented subjects, regarding visuospatial praxis capacities (drawing in two and three dimensions) and the copy part of these tasks (Cambridge Cognitive Examination [CAMCOG]-visuospatial praxis and the Construction subtest of the MDRS).34,96 Connor et al.96 and Salmon et al.51 obtained different results on the Construction subtest of the MDRS (copy of two-dimensional designs). Both studies assessed mildly demented subjects. The DLB subjects of Connor et al.96 had neuropathological changes associated with AD as well as cortical Lewy bodies, whereas the DLB subjects of Salmon et al. had only cortical Lewy bodies. Given also that subjects of Connor et al. had slightly inferior total scores on the MDRS to the subjects of Salmon et al., one would have expected to find more severe deficits in Connor and colleagues' DLB patients. However, it was not the case. The two patient groups of Connor et al. performed equally badly, whereas the DLB patients of Salmon et al. had a poorer performance than the AD patients. The samples of Connor et al.96 (where the two groups performed equally) were larger than the ones of Salmon et al.51 (where the DLB patients performed worse), and therefore the study of Connor et al.96 had better power than the one of Salmon et al.51
Table 2 (last section) shows that most of the studies found performance on episodic and semantic memory tests to be equally impaired in subjects with DLB and AD with mild,51,96 moderate,47,52 and severe dementia.34,71 The data have been collected with the Buschke Selective Reminding Test (SRT),47,52 the California Verbal Learning Test (CVLT; episodic memory tests with free and cued recall paradigms),51 the Visual Reproduction of the WMS (visual episodic memory test),47,52 the Vocabulary subtest of the WAIS,47 the Number Information Test (NIN; semantic memory tests),52 the CAMCOG Memory subtest,34 and the Information-Memory- Concentration subtest (IMC; attention, semantic and autobiographical memory) of the Blessed Scale.71 However, some caution is in order regarding these findings. The results of Hansen et al.47 might have been prone to masking effects, since the two groups of patients were matched for overall severity of dementia with a measure of memory (IMC of the Blessed Scale). Statistical analyses have not been applied to the data of Salmon et al.51 collected with the CVLT, because the studied groups were too small (n=5 subjects per group). Finally, in the study of Förstl et al.,34 dementia as measured with the MMSE, was more severe in patients with AD (MMSE score=7.5±6.1) than in patients with DLB (9.8±6.7). Only one study, with mildly demented patients, has described better performance in subjects with DLB than in subjects with AD on the memory subscale of the MDRS.96 Although this subscale gives some information on short-term free recall and forced-choice recognition capacities, it does not assess short- and long-term cued recall or long-term free recall and recognition capacities. These paradigms are crucial to differentiate between subcortical and cortical types of dementia, especially in the mild stage of dementia.99,100 Unfortunately, Connor et al.96 did not use other measures of memory.
Studies With Antemortem Clinical Criteria
Eight studies have compared relatively small groups of subjects (mean number of DLB subjects per group=12.6, range 7–26; mean number of AD subjects per group=18.5, range 10–52), using the following matching procedures: the MMSE total score, the Clinical Dementia Rating Scale (CDR),101 or the CAMCOG global score,102 in combination with age, gender, education, the duration of the disease, or the premorbid IQ.56,83,103–107 These subjects were mildly103–107 and moderately56,83,108,109 demented. No severely demented subjects have been assessed. Criteria for Senile Dementia of Lewy Body Type4 have been used to enroll patients with DLB in 7 of 8 studies83,103–108 (see Tables 1 and 3). Gnanalingham et al.83,108 also used the criteria of Byrne et al.5 (see Table 1)4,5,9 for Cortical Lewy Bodies. Only Shimomura et al.56 used the criteria for probable DLB per McKeith et al.9 The NINCDS-ADRDA criteria for probable Alzheimer's disease have been used in order to include patients with AD in 8 of 8 studies.56,83,103–108 Five studies also included a healthy control group, matched with the patients by age106 and premorbid IQ,103–105 and/or by education.83,108
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TABLE 3. Studies with clinical criteria for Lewy body disease: performance on tests of visual attention and memory; spatial working memory; verbal attention and memory, executive function; visual perception; and visuospatial praxis
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Table 3 (tests described in Table 4) shows that mildly103–106 and moderately56 demented patients with DLB are more impaired than patients with AD on some tests of visuospatial working memory56,103–106 and are impaired to the same extent as AD patients on other tests of visual memory and attention. Galloway et al.103 showed that mildly demented patients with DLB perform significantly worse than subjects with AD on the conditional pattern-location paired-associate learning task (spatial working memory). On a task with similar demands, the Digit Symbol subtest of the WAIS, moderately demented subjects with probable DLB performed more poorly than patients with AD.56 However, the impairments of DLB and AD subjects on a visual recognition memory test (abstract designs) did not differ.103 Sahgal et al.104,105 have assessed visual attention, learning, and memory capacities of DLB and AD patients. They have reported worse deficits for patients with DLB on a delayed-matching-to-sample task104 and on a visual search matching-to-sample task,105 both relying on spatial working memory. Patients with DLB and AD performed equally badly on a semantic learning task, the Kendrick Object Learning Task (KOLT).105 Sahgal et al.106 have reported worse deficits in mildly demented DLB subjects compared with AD subjects on the spatial working memory task testing visuospatial planning abilities, one of the attributes of the central executive system in the working memory model.97,98,110 This spatial working memory task has been previously described as very sensitive to frontal lobe impairment111,112 as well as Parkinson's disease,113–115 even in mild stages of PD,114,115 and to frontal lobe impairment in patients with amygdalo-hippocampectomy.112 However, the two patient groups of Sahgal et al.106 performed equally poorly on the Corsi's block test, a visuospatial span task assessing the visuospatial sketchpad of working memory.106
Regarding verbal attention and memory capacities (Table 3, section 2), the results of three studies suggest that mildly and moderately demented patients with DLB are as impaired as patients with AD on some verbal attention and memory tests, but less impaired than AD subjects on some tasks of episodic memory. Mildly and moderately demented subjects with DLB and AD have been equally impaired on the Attention/Calculation subtest (counting backwards and serial subtractions) of the CAMCOG107 and the Digit Span subtest of the WAIS.83 Mildly demented subjects with DLB have been as impaired as AD subjects on tests of semantic and autobiographical memory such as the Vocabulary subtest of the WAIS105 and the Orientation, Remote Memory (semantic memory), and Current Information (public episodic memory) subtests of the CAMCOG.107 Mildly and moderately demented patients with AD have been more impaired than DLB patients on tests of verbal long-term free recall such as the CAMCOG delayed recall107 and the word recall of the ADAS-COG.56
Regarding visuospatial praxis (Table 3, last section), four studies have reported that patients with DLB are more impaired than patients with AD on various visuospatial tasks. Mildly demented patients with DLB have demonstrated poorer performance than patients with AD on the visuospatial praxis subtest (two- and three- dimensional drawing) of the CAMCOG.107 Moderately demented patients with DLB have performed more poorly than both AD and PD patients on the Copy part of the Clock Test.83,108 The two studies of Gnanalingham et al.83,108 and a third study109 (not included in Table 3 because it involved only one subject with DLB, compared to 64 subjects with AD) investigated the differential performance between the Copy (C) and Free Drawing (D) parts of the Clock Test. They found that patients with DLB also performed equally poorly on the Copy (C) and the Free Drawing (D) parts of the Clock Test, whereas patients with AD and PD performed more poorly on the D part than on the C part of the test.83,108,109 However, the three patient groups in the study of Gnanalingham et al.83 were not matched for severity of dementia. Patients with DLB and AD were moderately demented, whereas patients with PD, in the mild stage of dementia, were significantly less cognitively impaired, as measured with the MMSE. Gnanalingham et al.108 have found a low sensitivity but a high predictive value for DLB with individuals presenting higher scores on the D part than on the C part. This finding has, however, been based on only 3 cases with DLB.108,109 Moderately demented patients with DLB have also performed more poorly than patients with AD on the Object Assembly and Block Design subtests of the WAIS.56 Regarding visual perception, two studies have shown no difference between mildly demented subjects with DLB and AD104,107 on tasks depending on the functioning of the occipital and parietal lobes (object, design, and face recognition tasks).
Regarding executive functions (Table 3, section 2), the only difference between patients with DLB and AD has been found in moderately demented patients, on tasks of visuospatial conceptualization and visuospatial judgment. The capacities of visuospatial conceptualization and judgment, as measured by the Raven Progressive Matrices and the Picture Arrangement subtest of the WAIS, have been more disrupted in moderately demented patients with DLB compared to patients with AD.56 However, mildly and moderately demented patients with DLB and AD performed equally badly on two tasks of mental flexibility, a test of visual set-shifting,105 and the Nelson Card Sorting Task.83 Nevertheless, subjects with DLB and AD were more impaired than PD and control subjects on the Nelson test.83
The capacities of verbal conceptualization and judgment, as measured by the Abstract Reasoning subtest of the CAMCOG107 and the Comprehension subtest of the WAIS-R,105 have not differed between mildly demented subjects with DLB and AD.105,107 Other executive functions, such as the motor (motor sequencing task) and verbal (lexical and semantic fluency tasks) initiation capacities, have been equally impaired in mildly107 and moderately83 demented patients with DLB and AD.
Longitudinal Studies
Four of the six longitudinal studies assessed demented patients at the baseline evaluation by using a short cognitive test, the MMSE.94 Another study used the short assessment CAMCOG, from the CAMDEX,102 which is an elaborated version of the MMSE. Only one longitudinal study followed patients with an end diagnosis of DLB confirmed at autopsy.116 Of the remaining five studies, only one117 recruited patients with DLB by using criteria for DLB or SDLT.4 Four studies enrolled patients with the diagnosis of AD with EPS and/or hallucinations.118–121
Twenty-four of the 81 AD patients followed by Miller et al.118 had non–neuroleptic-induced extrapyramidal symptoms. Patients with EPS deteriorated 67% faster on the MMSE (4.5 points per year) than patients without EPS (2.7 points per year). All of the subjects were matched at baseline for age and MMSE total score (mean scores of 18 and 20).118 Chui et al.120 reported that 85 of 135 patients reached the individual end point of a 6- point decline on the MMSE. Among these 85 patients, 46 were mildly demented and 39 were moderately demented at baseline. Significant predictors of cognitive decline were hallucinations and agitation in the mild dementia group, and the presence of non–neuroleptic- induced EPS at baseline in the moderate group.120 In another study, the EEG at baseline, but not the presence of hallucinations, was the best predictor of more rapid cognitive decline in moderately demented patients, as measured by the MMSE.121 Nevertheless, hallucinations predicted a more rapid functional decline.121
Only one longitudinal study has given more information about the cognitive deterioration of subjects with AD and EPS compared with 1) subjects with AD lacking EPS and 2) subjects with PD and dementia.119 At baseline, no significant difference on the formal neuropsychological testing was found between the three groups, with the exception that patients with AD (with and without EPS) had more false positive targets on the recognition paradigm of the word learning task compared with PD patients. After a year of follow-up, the difference between the AD and PD patients regarding the false positive targets remained the only significant distinction between AD (with and without EPS) and PD. Nevertheless, 14 subjects with AD+EPS had greater deficits on tests of verbal comprehension, automatic speech, semantic fluency, and praxis than 16 AD subjects without EPS.119 This study presents a methodological problem of importance. The two groups of patients with AD were not properly matched at baseline, the subjects with AD+EPS being significantly more impaired at baseline than the group without EPS as measured on the Brief Cognitive Rating Scale of Reisberg et al.122 The AD+EPS patients also tended to be more impaired at baseline than the group without EPS as measured on the Clinical Dementia Rating Scale (which showed that 57.14% of subjects with AD+EPS, versus 31.25% of AD subjects without EPS, were moderately demented).
Ballard et al.117 followed, for one year, subjects with Alzheimer's disease, vascular dementia (VaD), and dementia with Lewy bodies, using, respectively, the NINCDS-ADRDA criteria for probable and possible AD,74 the Hachinski scale for vascular dementia,123 and the criteria for SDLT.4 The total CAMCOG scores of the 116 moderately demented subjects with AD, VaD, and SDLT did not differ significantly at baseline, having respective means of 42.68, 44.50, and 47.67 (total possible score on the CAMCOG=106). Nevertheless, patients with DLB had a better performance than patients with AD on the recent memory subtest and a better performance than patients with VaD on the visual memory subtest. After one year, approximately 70% of the patients were reassessed. The 7 patients with DLB tended to deteriorate more rapidly on only the CAMCOG total score versus the 53 AD subjects and the 14 VaD subjects (mean deterioration=27±19.77, 13.21±12.61, and 13.29±13.48 points, respectively). However, a logistic regression analysis showed that patients with DLB deteriorated significantly more than patients with AD and VaD on the verbal (semantic) fluency subtest, and also more than patients with VaD on the Remote Memory subtest of the CAMCOG.117 There was no significant difference among the three groups of patients on the other subtests of the CAMCOG: Orientation, Comprehension, Expression, Praxis, Recent Memory, Visual Memory, Attention and Calculation, Perception (Agnosia), and Abstract Thinking.117
More recently, Olichney et al.116 reviewed the autopsied cases of 40 patients with Lewy body variant and 148 patients with Alzheimer's disease. The two groups of moderately demented patients were matched according to their age, education, and MMSE scores (mean MMSE scores: LBV, 18.2; AD, 17.8) at baseline. They found that LBV subjects had a rate of cognitive decline significantly more rapid and severe than the rate for AD subjects as measured by MMSE scores. The average rate of decline was –5.8±4.5 points per year in LBV compared with –4.1±3.0 points per year in AD (t-test, P<0.01). The LBV group declined a similar amount on the MMSE over a significantly shorter time interval than did the AD group (1.9 vs. 2.7 years; P<0.005). The LBV patients presented significantly more parkinsonian signs at entry compared with AD patients (30% vs. 14%; P=0.02). The patients with LBV had a shorter survival time from the onset of cognitive symptoms and a shorter mean survival after baseline.116
Summary and Discussion Related to the Cognitive Changes of DLB
In this review, 9 studies have assessed mildly demented patients,51,96,103–107,118,120 11 studies have assessed moderately demented patients,47,52,56,83,108,109,116,117,119–121 and 2 studies have assessed severely demented patients.34,71 More than one-third (36.36%) of studies with moderately demented patients used comprehensive neuropsychological batteries, compared with 11.11% of the studies with mildly demented patients. The other studies used short assessments such as the MMSE,34 the CAMCOG,102 or the MDRS.95 Nearly one-half of the studies (44.44%) with mildly demented patients specifically focused their cognitive assessment on tasks of spatial working memory. The 2 studies with severely demented patients used only short assessments. As a result, more cross-sectional and longitudinal information, regarding different aspects of cognition, is available in moderately demented subjects with DLB and AD than in mildly and severely demented subjects.
All of the longitudinal studies demonstrated a significantly faster cognitive or functional decline in patients with DLB |
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ABSTRACT
INTRODUCTION