Neuropsychological profile of dementia with Lewy bodiespsy_283

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1 doi: /j x PSYCHOGERIATRICS 2009; 9: REVIEW ARTICLE Neuropsychological profile of dementia with Lewy bodiespsy_283 Haruhiko ODA, Yasuji YAMAMOTO and Kiyoshi MAEDA Division of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan Correspondence: Dr Haruhiko Oda, Division of Psychiatry, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuou-ku, Kobe, Hyogo , Japan. Received 1 September 2008; accepted 30 September This review article was presented by the author in Symposium of the 23rd annual meeting of Japanese Psychogeriatric Society in Kobe, June Key words: Alzheimer disease, attentional dysfunction, dementia with Lewy bodies, memory, visuospatial impairment. Abstract Dementia with Lewy bodies (DLB) accounts for 10 25% of all dementia cases in clinical populations and is considered to be the second most common degenerative dementia in elderly people after Alzheimer s disease (AD). Dementia with Lewy bodies is characterized by the presence of cognitive, psychiatric, and motor symptoms. Although the neuropsychological profiles of patients with DLB often differ from those of patients with AD, the diagnostic sensitivity, specificity, and predictive values of these profiles remain largely unknown. The present paper reviews the neuropsychological profiling of DLB and attempts the neuropsychological differentiation of DLB from AD. INTRODUCTION Dementia with Lewy bodies (DLB) is considered the second most common form of neurodegenerative dementia after Alzheimer s disease (AD). Considerable attention has focused on discrimination between DLB and AD. Originally, DLB was defined as a clinicopathologic entity with a specific constellation of clinical features, and a descriptive approach was proposed to assess its neuropathology. 1 From a pathological standpoint, DLB is a common disorder of a-synuclein metabolism and is characterized by the development of abnormal cytoplasmic inclusions, called Lewy bodies, throughout the brain. A Lewy body is composed of a-synuclein associated with other proteins, such as ubiquitin, neurofilament protein, and ab crystallin. Lewy bodies were first seen and linked to Parkinson s disease ( paralysis agitans ) in 1912 by the neurologist Frederic Lewy. 2 Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types of Lewy bodies, brain stem and cortical. A brain stem Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core surrounded by a halo, approximately 10 mm in diameter, of radiating fibrils, the primary structural component of which is a-synuclein. Hematoxylin and eosin staining is not sufficient for the detection of cortical Lewy bodies and is not capable of detecting Lewy neurites. Lewy did not ascribe neurobehavioral significance to Lewy bodies initially observed in postencephalitic parkisonian patients in Okazaki et al. described two patients with parkinsonism and dementia with cortical Lewy body like eosiophilic inclusions in Although these inclusion bodies lacked the distinctive halo of brain stem Lewy bodies, this group of investigators made an association between these cerebral inclusions and dementia. In 1976, Kosaka et al. reported an autopsied case with progressive dementia and parkinsonism, the neuropathologic features of which were the widespread presence of Lewy bodies thoroughout the central nervous system as well as Alzheimer s changes. 4 In 1978, Kosaka described three cases with distribution of cortical Lewy bodies. 5 In 1984, Kosaka et al. proposed the term diffuse Lewy body disease (DLBD). 6 Based on the concept of DLBD, the term DLB was proposed by the consortium on DLB international workshop. 1 Recently DLB, Parkinson disease (PD), and PD with dementia (PDD) have been identified as being part of the spectrum of Lewy body disease. 7 There are four subtypes of DLB: a neocortical type (nearly equal DLBD), a limbic type, a brain stem type and a cerebral type. Dementia with 2009 The Authors 85

2 H. Oda et al. Table 1 Revised clinical diagnostic criteria for DLB 11 Criteria Central feature Core features (any two = probable DLB; any one = possible DLB) Suggestive features (one or more + a core feature = probable DLB; any one alone = possible DLB) Supportive features (common but lacking diagnostic specificity) Details Dementia defined as progressive cognitive decline Fluctuating cognition Recurrent visual hallucinations Spontaneous features of parkinsonism REM sleep behavior disorder Severe neuroleptic sensitivity Low dopamine transporter uptake in basal ganglia Repeated falls and syncope Transient, unexplained loss of consciousness Systematized delusions Hallucinations in other modalities Relative preservation of medial temporal lobe on CT or MRI scans Decreased tracer uptake on SPECT or PET imaging in occipital regions Prominent slow waves on EEG with temporal lobe transient sharp waves CT, computed tomography; MRI, magnetic resonance imaging; SPECT, single photon emission computed tomography; PET, positron emission tomography; EEG, electroencephalography. Lewy bodies exhibits a clinical overlap between AD and PD. Pathologically, Lewy bodies are present in DLB as well as in PD. In addition, there is a loss of dopamine-producing neurons (in the substantia nigra) similar to that seen in PD and a loss of acetylcholine (ACh)-producing neurons (in the basal nucleus of Meynert and elsewhere) similar to that seen in AD. Cerebral atrophy (or shrinkage) also occurs as the cerebral cortex degenerates. Autopsy series have revealed that the pathology of DLB is often concomitant with the pathology of AD. That is, when Lewy body inclusions are found in the cortex, they often co-occur with AD pathology found primarily in the hippocampus, including neurofibrillary tangles (abnormally phosphorylated tau protein), senile plaques (a-amyloid protein deposits), and granulovacuolar degeneration. Kosaka proposed two distinct pathological subtypes of DLB: (i) the common form, found in approximately 75% of cases, with mixed Lewy body and amyloid pathology; and (ii) the pure form, with only Lewy body pathology. 8 Within DLB, the loss of cholinergic (ACh-producing) neurons is thought to account for the degradation of cognitive and emotional functioning, as in AD, whereas the loss of dopaminergic (dopamineproducing) neurons is thought to account for the degradation of motor control, as in PD. Thus, DLB is similar in to the dementia resulting from both AD and PD. In fact, DLB is often confused in its early stages with AD and/or vascular dementia (multi-infarct dementia). The overlap of neuropathologies and presenting symptoms (cognitive, emotional, and motor) may make an accurate differential diagnosis difficult to make. The need for an early and accurate diagnosis of DLB to enable the proper clinical treatment has been emphasized by reports of severe neuroleptic sensitivity 9 and preferential response to cholinesterase inhibitors in these patients. 10 Careful cognitive assessment may aid in the differential diagnosis between these different types of dementia and can provide theoretical insight into the nature of the underlying impairments. The clinical diagnosis of DLB is supported and facilitated by the recent revision of clinical diagnostic criteria for DLB (Table 1). 11 In most studies examining the clinical criteria for the operational diagnosis of DLB, the specificity of diagnosis has been high, but sensitivity poor. There has been a need for studies examining the neuropsychological profile of DLB and the contribution of neuropsychological evaluation to the diagnostic workup. In the present article, we review the cognitive profile of DLB for future research and clinical issues, such as the problem of differential diagnosis. ATTENTION There have been studies demonstrating a greater attentional impairment in DLB than in AD. Hansen et al. compared nine patients with DLB with nine patients with AD. More severe deficits of attentional function (digit span sub-test from the Wechsler Adult Intelligence Scale-Revised (WAIS-R)) were seen in DLB. 12 Sahgal et al. reported that DLB patients had significantly greater impairment on a computerized delayed matching-to-sample task. 13 Ayre et al. used The Authors

3 Neuropsychology of DLB the Cognitive Drug Research Computerized Assessment System for Dementia Patients (COGDRAS-D) computerized test battery to compare attention in 46 patients with AD and 24 patients with DLB. 14 The DLB group performed significantly worse on simple reaction time (SRT) and choice reaction time (CRT) tasks and digit vigilance (VIG) compared with the AD group. Ballard et al. compared 85 patients with DLB with 80 patients with AD using the COGDRAS-D. 15 They showed that slowed processing speed, attentional impairments, and fluctuations in attentional impairments are significantly more severe in DLB than AD patients. The DLB patients were significantly more impaired than the AD patients on all tests of attention and fluctuating attention. In both DLB and AD, most measures of attentional performance and most indices of fluctuating attention were significantly correlated with the Mini-Mental State Examination (MMSE) score. The severity and fluctuation of attentional impairments are particularly pronounced in DLB patients with MMSE scores of 10 or less. Ballard et al. 15 concluded that their results confirmed that the attentional deficits and fluctuations in attention are substantially more severe in DLB patients than in patients with AD. A number of other factors, such as parkinsonism with slowed motor speed, depression, or general slowing of cognitive processing speed, could theoretically have contributed to these findings. Ballard et al. 15 noticed that deficits of attention became more pronounced with increasing dementia severity and, hence, that these deficits need to be interpreted within the context of overall cognitive deficits. Oda et al. 16 compared 26 patients with DLB with 78 patients with AD and demonstrated that patients with AD had significantly greater scores on the weighted sum score of the Attention of Wechsler Memory Scale-Revised (WMS-R) than did patients with DLB (P = ). The overall pattern is consistent, with DLB patients showing significantly greater impairment on a range of attentional tasks. Both neuropsychological and clinical observations strongly suggest that DLB patients experience great difficulty in sustaining attention. The neural basis of the attentional impairment in DLB requires further investigation, but it is likely that a dysfunction of the basal forebrain cholinergic system is involved. Several lines of evidence support this proposal. Cholinergic neuronal loss and depletion of choline acetyltransferase are seen early in DLB. 17 Administration of anticholinergic drugs can disturb attention and cause hallucinations, whereas cholinesterase inhibitors can improve cognition in DLB. 11 VISUOPERCEPTUAL AND SPATIAL FUNCTIONS Numerous studies have observed greater impairments in DLB compared with AD on visuospatial and constructional tasks. Ala et al. compared 17 patients with autopsy confirmed DLB and 27 patients with autopsy confirmed AD by using copies of the double pentagon from the MMSE. 18 They showed that only two patients with DLB drew the pentagon acceptably, in contrast with 16 AD patients, and that an unacceptable copy of the pentagon was associated with DLB with a sensitivity of 88% and a specificity of 59%. They concluded that their results confirmed the greater visuospatial/constructional impairment of patients with DLB than patients with AD and suggested that the pentagon copying task of the MMSE may be useful in a diagnostic sense. 18 Cormack et al. reported that patients with DLB were found to draw significantly worse double pentagons than those with AD or PD. 19 In their report, a correlation between MMSE score and pentagon drawing score was observed in patients with AD; however, DLB patients did not show any significant correlation between MMSE scores and the pentagon drawing score. In order to investigate the hypothesis that DLB patients have a different neuropsychological basis to their drawing impairments to the other dementia groups, the global cognitive performance of subjects was measured using the cognitive section of the Cambridge Mental Disorders in the Elderly Examination (CAMCOG). Cormack et al. 19 found that pentagon copying scores were significantly correlated with all CAMCOG subscales except visual and recent memory in the AD group, whereas DLB patients scores were significantly correlated only with Praxis and Perception. This result suggested that constructional disability was proportionate to global cognitive impairment in the AD group, but there was a dissociation of constructional ability from global cognitive ability in the DLB group. Mori et al. addressed problems in visual perception in patients with DLB and compared them with patients with AD. 20 Mori et al. assessed the visual perception of 24 patients with DLB and 48 patients with DLB by using a subset of the object and spacial vision test battery. The dis The Authors 87

4 H. Oda et al. crimination of object size task was used to examine elementary visual perception, the form discrimination task was used to examine more complex visuoperceptual function that requires analysis of twodimensional visual stimuli, the overlapping figure identification task was used to examine the ability to actively extract concrete shapes and to recognize objects, and the visual counting task was used to examine the ability to explore and identify the spatial relationship of visual stimuli to count targets without duplication or omission. Mori et al. 20 found that DLB subjects performed more poorly than an AD group not only in discriminating size and form and visual counting, but also in identifying overlapping figures. Moreover, DLB subjects with visual hallucinations performed significantly worse on the overlapping figures task. Oda et al. reported that patients with DLB scored significantly worse on the Block Design, Object Assembly, and Digit Symbol subtests of the WAIS-R than did patients with AD. 16 Because the set of the Block Design, Object Assembly, and Digit Symbol is considered to be involved in visual perception/processing meaningful stimuli and visual organization, these results were considered to suggest that patients with DLB have a more severe impairment of both their visual perception of meaningful stimuli and visual organization than do AD patients. Oda et al. 16 also showed that except for Comprehension, Similarities, and Object Assembly, all subtests and IQ of the WAIS-R showed a significant correlation with the MMSE score in the AD group. This suggests that the fall in IQ is proportional to global cognitive impairment in the AD group. However, in the DLB group, there was no correlation between all subtests of the WAIS-R and MMSE score. There seemed to be a dissociation of the IQ from global cognitive abilities in the DLB group. Oda et al. 16 ascribed the lack of correlation between the global cognitive impairment and the fall in intellectual ability in the DLB group to selective impairment of visuoperceptual function in addition to global cognitive impairment. The fact that visual perceptual disturbances in patients with DLB predispose them to visual hallucinations has important clinical implications. First, because visual hallucinations are among the strongest diagnostic predictors of DLB, the neuropsychological assessment of visual perceptual and constructional functions is critical in suspected DLB and its differentiation from AD. Indeed, visuoconstructional tasks, in combination with other tests, can differentiate DLB from normal aging and from AD with high sensitivity and specificity. 21 Furthermore, poor performance on visuoperceptual and constructional tasks may indicate the need for more careful monitoring for the development of hallucinations. It is likely that occipital dysfunction is implicated in visuoperceptual abnormalities of DLB and both the ventral occipitotemporal and dorsal occipitoparietal streams have been implicated. The visuoperceptual dysfunction in DLB can be attributed to accentuated damage in the occipital lobes. Albin et al. demonstrated that regional glucose metabolism was decreased in the occipital association cortex and primary visual area in six patients with autopsy proved DLB. 22 In the study of Ishii et al., using fludeoxyglucose F18 and positron emission tomography (PET), the glucose metabolic rate in the occipital cortices was found to be significantly lower in patients with probable DLB than in controls with probable AD matched for age, sex, disease duration, and MMSE score, despite similar decreases in the parietotemporal lobe in patients with DLB and AD. 23 Similarly, a single photon emission computed tomography (SPECT) study demonstrated that occipital blood flow was significantly lower in patients with DLB than in patients with AD. 24 Therefore, in DLB, not only does the parietotemporal damage provoke visuocognitive dysfunctions, but occipital damage also causes disturbances of visual sensations and intensifies the higher-order visuocognitive dysfunctions. Defective visual perception, resulting in illusions including distortions of form, size, movement, or color, in combination with general defects such as confusion and mental deterioration may cause a sense of strangeness or inexplicable familiarity. The mechanism of occipital involvement and visuoperceptual deficits in DLB is highly speculative. Bashir et al. reported a unique patient with DLB who initially complained of heaviness in the right upper extremity and subsequently developed a dense left homonymous hemianopsia during the course of a rapidly progressing dementia. 25 Their patient fulfilled all the consensus criteria for the clinical diagnosis of probable DLB: their case exhibited progressive cognitive decline, parkinsonism, visual hallucinations, and fluctuating agitation, confusion, and depression. The neuropathologic findings in their patient fulfilled the diagnostic criteria for DLB, proposed by the Consortium on Dementia The Authors

5 Neuropsychology of DLB with Lewy Bodies. 1 In addition; their patient exhibited a striking predominance of neurofibrillary tangles in the right inferotemporal and occipital cortices. However, in general, the pathologic features of DLB (including Lewy bodies) hardly affect the occipital lobes. 8 In a PET study with (+)-[ 11 C]- dihydrotetrabenazine, a greater reduction of blood-tobrain ligand transport occurred in occipital cortex in DLB than in AD. 26 Bodis-Wollner speculated that in patients affected by PD, as well as in the monkey model of this disease, the visual defects may be caused by systemic dopaminergic deficiency. 27 Conversely, involvement of the occipital cholinergic system also has been assumed. The activity of a cholinergic enzyme, namely choline acetyltransferase, is reportedly lower in the temporoparietal and occipital neocortex in patients with DLB compared with those with AD. 28 MEMORY With regard to memory, in general DLB subjects perform better on tests of episodic (declarative) memory than do AD patients, and this appears particularly true on tests of verbal rather than visual memory. Shimomura et al. demonstrated that patients with DLB scored significantly better (P < 0.05 on the verbal memory subtest of the Alzheimer Disease Assessment Scale (ADAS) than did AD patients who were comparable in the global severity of dementia and the global assessment of cognitive impairment. 29 To determine what the degree to which elementary visual perceptual dysfunction may contribute to visual memory impairment in DLB, Oda et al. compared patients with DLB with AD patients using the WMS- R. 16 In that study, the DLB group showed significantly better scores than did the AD group on Verbal Memory (P < ) and Delayed Recall (P < ) of the WMS-R. However, the DLB and AD groups demonstrated comparable scores on Visual Memory ( vs , respectively; P = ). The authors speculated that the selective visuoperceptual impairment in DLB may explain this similarity: the relatively preserved short- and mediumterm recall would compensate for severe visuoperceptual impairment in the DLB group on the visual memory tasks. Lambon Ralph et al. reported that both DLB and AD groups exhibited impaired performance across a range of tasks designed to assess semantic memory. 30 Whereas patients with AD showed equivalent comprehension of written words and picture stimuli, patients with DLB demonstrated more severe semantic deficits for pictures than words. The major pathological substrate of more severe amnestic deficits in AD relative to DLB likely reflects the burden of neurofibrillary tangles in the entorhinal cortex and surrounding medial temporal lobe regions in AD. NEUROPSYCHOLOGICAL DIFFERENTIATION OF DLB FROM AD The third report of the DLB Consortium mentioned that a double discrimination can help differentiate DLB from AD, with relative preservation of confrontation naming and short- and medium-term recall as well as recognition, and greater impairment on verbal fluency, visual perception, and performance tasks. 1 Ala et al. reported a retrospective study in which pathologically confirmed cases of AD and DLB could be differentiated on the basis of a subscore derived from the MMSE. 31 Based on the greater impairment of attentional and visuospatial function, and the relative preservation of memory function in DLB compared with AD, Ala et al. 31 derived a weighted score, calculated as follows: Ala score = Attention 53Memory + Construction An Ala score <5 was associated with a pathological diagnosis of DLB with a sensitivity of 82% and a specificity of 81%. By using the Ala score and the z-score in the medial occipital lobe from a brain SPECT study, Hanyu et al. derived a combined index of SPECT/MMSE that achieved a high discrimination between DLB and AD with a sensitivity of 81% and a specificity of 85%. 32 Oda et al. derived a weighted score consisting of the Object Assembly subtest of the WAIS-R and the Logical Memory II subtest of the WMS-R to differentiate DLB from AD 16 that had a sensitivity of 81% and a specificity of 76%. SUMMARY AND CONCLUSIONS Given that DLB is a relatively new disease concept, most of the work so far has been concerned with the first step of characterization and description of DLB as a separate disease. Most of the studies suggest that in the early stages of the disease, DLB patients tend to exhibit pronounced visual perceptual, attentional, and frontal executive impairments, whereas 2009 The Authors 89

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