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1.  Semantic memory is impaired in both dementia with Lewy bodies and dementia of Alzheimer's type: a comparative neuropsychological study and literature review 
OBJECTIVE—To test the hypothesis that semantic impairment is present in both patients with dementia with Lewy bodies (DLB) and those with dementia of Alzheimer's type (DAT).
METHODS—A comprehensive battery of neuropsychological tasks designed to assess semantic memory, visuoperceptual function, verbal fluency, and recognition memory was given to groups of patients with DLB (n=10), DAT (n=10) matched pairwise for age and mini mental state examination (MMSE), and age matched normal controls (n=15).
RESULTS—Both DLB and DAT groups exhibited impaired performance across the range of tasks designed to assess semantic memory. Whereas patients with DAT showed equivalent comprehension of written words and picture stimuli, patients with DLB demonstrated more severe semantic deficits for pictures than words. As in previous studies, patients with DLB but not those with DAT were found to have impaired visuoperceptual functioning. Letter and category fluency were equally reduced for the patients with DLB whereas performance on letter fluency was significantly better in the DAT group. Recognition memory for faces and words was impaired in both groups.
CONCLUSIONS—Semantic impairment is not limited to patients with DAT. Patients with DLB exhibit particular problems when required to access meaning from pictures that is most likely to arise from a combination of semantic and visuoperceptual impairments.


doi:10.1136/jnnp.70.2.149
PMCID: PMC1737202  PMID: 11160461
2.  Comparison of Clinical Manifestation in Familial Alzheimer's disease and Dementia with Lewy Bodies 
Archives of neurology  2008;65(12):1634-1639.
Background
The clinical delineation of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) remains unclear.
Objective
To compare the neuropsychological profiles of patients with clinically diagnosed Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
Methods
We first compared measures of memory, orientation, language, executive, visual perception and visual construction function between persons with DLB and AD in two Caribbean Hispanic cohorts, including a family dataset (DLB =89; AD: n=118) and an epidemiologic dataset (DLB: n=70; AD: n=157). DLB in the family sample was further divided into i) families with two or more affected family members (DLB), or ii) one affected family member (DLB). To determine whether observed differences in cognitive profiles were driven by heritable factors, we then repeated the analyses in the epidemiologic cohort excluding all familial cases. We applied general linear models adjusting for age, sex, education, disease duration, and APOE-ε4 genotype.
Results
Persons with DLB were in both cohorts more severely impaired in orientation, visual construction and non verbal reasoning after controlling for potential confounders. Persons with 2 or more DLB cases per family had the most severe impairment in episodic and semantic memory, followed by those with one DLB case per family, then by those with AD. When familial AD and DLB cases were excluded from the analysis in the epidemiologic cohort, the differences between the AD and DLB groups persisted but were attenuated.
Conclusions
Compared to persons with AD, persons with DLB are more severely impaired in various cognitive domains, particularly orientation, visual perception and visual construction. The difference appears strong in familial rather than sporadic DLB. Whether this divergence in cognitive functions is caused by gene-gene or gene-environmental interactions remains unclear.
doi:10.1001/archneur.65.12.1634
PMCID: PMC2633487  PMID: 19064751
3.  Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study 
BMJ Open  2012;2(1):e000380.
Objectives
Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer's disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future.
Design
In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures.
Setting
Patients were recruited from 40 European centres.
Participants
Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging.
Outcome measures
The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI).
Results
The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed.
Conclusions
DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.
Article summary
Article focus
Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features.
At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer's disease (AD).
Key messages
In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up.
Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline.
Strengths and limitations of this study
Inclusion of high number of subjects from 40 European clinical centres.
Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging.
No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB.
Only 1 year of follow-up.
There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.
doi:10.1136/bmjopen-2011-000380
PMCID: PMC3330257  PMID: 22318660
4.  Higher cortical deficits influence attentional processing in dementia with Lewy bodies, relative to patients with dementia of the Alzheimer's type and controls 
Background
Attentional dysfunction is believed to be a prominent and distinguishing neuropsychological feature of dementia with Lewy bodies (DLB); yet, the specific nature of the attentional deficit and factors that can potentially influence attentional processing in DLB have not been fully defined.
Aims
To clarify the nature of the attentional deficit in early‐stage DLB relative to patients with early‐stage dementia of the Alzheimer's type (DAT) and elderly controls, and examine the effect of task complexity and type of cognitive load on attentional processing in DLB.
Methods
Attentional impairment and fluctuating attention were investigated in three groups of subjects—patients with clinical features of early probable DLB (n = 20), a group with early probable DAT (n = 19) and healthy elderly controls (n = 20)—using an experimental computerised reaction time paradigm.
Results
Patients with DLB showed greater attentional impairment and fluctuations in attention relative to patients with DAT and elderly controls. The attentional deficit was generalised in nature but increased in magnitude as greater demands were placed on attentional selectivity. Attentional deficits in DLB were most pronounced under task conditions that required more active recruitment of executive control and visuospatial cognitive processes.
Conclusions
Attentional deficits in DLB are widespread and encompass all aspects of attentional function. Deficits in higher cortical function influence the degree of attentional impairment and fluctuating attention, suggesting that attentional processing in DLB is mediated by interacting cortical and subcortical mechanisms. These findings serve to clarify the nature of the attentional deficit in DLB and have potentially important ramifications for our understanding of the neurocognitive underpinnings of fluctuations.
doi:10.1136/jnnp.2006.090183
PMCID: PMC2077555  PMID: 16772356
5.  Early Visuospatial Deficits Predict the Occurrence of Visual Hallucinations in Autopsy-Confirmed Dementia with Lewy Bodies 
Objectives
The current study explored the value of visuospatial findings for predicting the occurrence of visual hallucinations (VH) in a sample of patients with Dementia with Lewy bodies (DLB) compared to patients with Alzheimer’s disease (AD).
Participants/Measurements
Retrospective analysis of 55 autopsy-confirmed DLB and 55 demographically-similar, autopsy-confirmed AD cases determined whether severe initial visuospatial deficits on the WISC-R Block Design subtest predicted the development of VH. Visuospatial deficits were considered severe if Block Design z-scores were 2.5 or more standard deviations below the mean of a well-characterized normal control group (Severe-VIS; DLB: n=35, AD: n=26) and otherwise were considered mild (Mild-VIS; DLB: n=20, AD: n=29).
Results
Forty percent of the Severe-VIS DLB group had baseline VH compared to 0% of Mild-VIS DLB patients. Only 8% of the Severe-VIS and 3% Mild-VIS AD patients had baseline VH. During the follow-up period (mean=5.0 years), an additional 61% of the Severe-VIS but only 11% of the Mild-VIS DLB patients developed VH. In that period, 38% of the Severe-VIS and 20% of the Mild-VIS AD patients developed VH. After considering initial MMSE score and rate of decline, logistic regression analyses found that performance on Block Design significantly predicted the presence of VH in the DLB group but not the AD group.
Conclusions
The presence of early, severe deficits on neuropsychological tests of visuospatial skill increases the likelihood that patients with suspected DLB will develop the prototypical DLB syndrome. The presence of such deficits may identify those DLB patients whose syndrome is driven by alpha-synuclein pathology rather than AD pathology and may inform treatment plans as well as future research.
doi:10.1097/JGP.0b013e31823033bc
PMCID: PMC3260388  PMID: 21997600
Lewy body disease; Hallucinations, visual; Alzheimer’s disease; Visuospatial cognition
6.  Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease 
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
doi:10.1136/jnnp.74.9.1215
PMCID: PMC1738667  PMID: 12933921
7.  Visuospatial Deficits Predict Rate of Cognitive Decline in Autopsy-Verified Dementia with Lewy Bodies 
Neuropsychology  2008;22(6):729-737.
Dementia with Lewy Bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer’s disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict two-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed “pure” AD patients. Generalized Estimating Equations (GEE) revealed a significant interaction such that poor baseline performances on tests of visuospatial skills were strongly associated with a rapid rate of cognitive decline in DLB but not AD (p < .001). No effect of confrontation naming was found. DLB patients with poor visuospatial skills had fewer neurofibrillary tangles and were more likely to experience visual hallucinations than those with better visuospatial skills. These results suggest that the severity of visuospatial deficits in DLB may identify those facing a particularly malignant disease course and may designate individuals whose clinical syndrome is impacted more by Lewy body formation than AD pathology.
doi:10.1037/a0012949
PMCID: PMC2587484  PMID: 18999346
Dementia with Lewy bodies; cognitive decline; visuospatial skills; Alzheimer’s disease
8.  Low sensitivity in clinical diagnoses of dementia with Lewy bodies 
Journal of neurology  2009;257(3):359-366.
The success of future neurodegenerative disease (ND) therapies depends partly on accurate antemortem diagnoses. Relatively few prior studies have been performed on large, multicenter-derived datasets to test the accuracy of final clinical ND diagnoses in relation to definitive neuropathological findings. Data were analyzed from the University of Kentucky Alzheimer's Disease Center autopsy series and from the National Alzheimer's Coordinating Center (NACC) registry. NACC data are derived from 31 different academic medical centers, each with strong clinical expertise and infrastructure pertaining to NDs. The final clinical diagnoses were compared systematically with subsequent neuropathology diagnoses. Among subjects meeting final inclusion criteria (N = 2,861 for NACC Registry data), the strength of the associations between clinical diagnoses and subsequent ND diagnoses was only moderate. This was particularly true in the case of dementia with Lewy bodies (DLB): the sensitivity of clinical diagnoses was quite low (32.1% for pure DLB and 12.1% for Alzheimer's disease (AD + DLB) although specificity was over 95%. AD clinical diagnoses were more accurate (85.0% sensitivity and 51.1% specificity). The accuracy of clinical DLB diagnoses became somewhat lower over the past decade, due apparently to increased “over-calling” the diagnosis in patients with severe cognitive impairment. Furthermore, using visual hallucinations, extrapyramidal signs, and/or fluctuating cognition as part of the clinical criteria for DLB diagnosis was of minimal utility in a group (N = 237) with high prevalence of severe dementia. Our data suggest that further work is needed to refine our ability to identify specific aging-related brain disease mechanisms, especially in DLB.
doi:10.1007/s00415-009-5324-y
PMCID: PMC2839040  PMID: 19795154
9.  Demography, diagnostics, and medication in dementia with Lewy bodies and Parkinson’s disease with dementia: data from the Swedish Dementia Quality Registry (SveDem) 
Introduction
Whether dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) should be considered as one entity or two distinct conditions is a matter of controversy. The aim of this study was to compare the characteristics of DLB and PDD patients using data from the Swedish Dementia Quality Registry (SveDem).
Methods
SveDem is a national Web-based quality registry initiated to improve the quality of diagnostic workup, treatment, and care of patients with dementia across Sweden. Patients with newly diagnosed dementia of various types were registered in SveDem during the years 2007–2011. The current cross-sectional report is based on DLB (n = 487) and PDD (n = 297) patients. Demographic characteristics, diagnostic workup, Mini-Mental State Examination (MMSE) score, and medications were compared between DLB and PDD groups.
Results
No gender differences were observed between the two study groups (P = 0.706). PDD patients were significantly younger than DLB patients at the time of diagnosis (74.8 versus 76.8 years, respectively; P < 0.001). A significantly higher prevalence of patients with MMSE score ≤24 were found in the PDD group (75.2% versus 67.6%; P = 0.030). The mean number of performed diagnostic modalities was significantly higher in the DLB group (4.9 ± 1.7) than in the PDD group (4.1 ± 1.6; P < 0.001). DLB patients were more likely than PDD patients to be treated with cholinesterase inhibitors (odds ratio = 2.5, 95% confidence interval = 1.8–3.5), whereas the use of memantine, antidepressants, and antipsychotics did not differ between the groups.
Conclusion
This study demonstrates several differences in the dementia work-up between DLB and PDD. The onset of dementia was significantly earlier in PDD, while treatment with cholinesterase inhibitors was more common in DLB patients. Severe cognitive impairment (MMSE score ≤24) was more frequent in the PDD group, whereas more diagnostic tests were used to confirm a DLB diagnosis. Some similarities also were found, such as gender distribution and use of memantine, antidepressants, and antipsychotics drugs. Further follow-up cost-effectiveness studies are needed to provide more evidence for workup and treatment guidelines of DLB and PDD.
doi:10.2147/NDT.S45840
PMCID: PMC3700781  PMID: 23847419
dementia with Lewy bodies; Parkinson’s disease with dementia; age; diagnostic approach; medication; Mini-Mental State Examination
10.  Focal atrophy in Dementia with Lewy Bodies on MRI: a distinct pattern from Alzheimer's disease 
Brain : a journal of neurology  2007;130(Pt 3):708-719.
SUMMARY
Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB.
doi:10.1093/brain/awl388
PMCID: PMC2730778  PMID: 17267521
Dementia with Lewy Bodies; Alzheimer's disease; voxel-based morphometry; magnetic resonance imaging; neurotransmitter systems
11.  fMRI resting state networks and their association with cognitive fluctuations in dementia with Lewy bodies 
NeuroImage : Clinical  2014;4:558-565.
Cognitive fluctuations are a core symptom in dementia with Lewy bodies (DLB) and may relate to pathological alterations in distributed brain networks. To test this we analysed resting state fMRI changes in a cohort of fluctuating DLB patients (n = 16) compared with age matched controls (n = 17) with the aim of finding functional connectivity (FC) differences between these two groups and whether these associate with cognitive fluctuations in DLB. Resting state networks (RSNs) were estimated using independent component analysis and FC between the RSN maps and the entirety of the brain was assessed using dual regression. The default mode network (DMN) appeared unaffected in DLB compared to controls but significant cluster differences between DLB and controls were found for the left fronto-parietal, temporal, and sensory–motor networks. Desynchronization of a number of cortical and subcortical areas related to the left fronto-parietal network was associated with the severity and frequency of cognitive fluctuations. Our findings provide empirical evidence for the potential role of attention–executive networks in the aetiology of this core symptom in DLB.
Highlights
•We report resting state network (RSN) alterations in dementia with Lewy bodies (DLB).•The default mode network was intact in DLB compared to healthy controls (HC).•Fronto-parietal, temporal, and sensory–motor RSNs showed differences (DLB < HC).•The left fronto-parietal network (FPN) correlated with cognitive fluctuations in DLB.•The FPN therefore may be a potential marker for cognitive fluctuations in DLB.
doi:10.1016/j.nicl.2014.03.013
PMCID: PMC3984441  PMID: 24818081
Cognitive fluctuations; Visual hallucinations; Resting state network; Lewy bodies; Dementia
12.  Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease 
Neurology  2011;76(21):1797-1803.
Objective:
Clinicopathologic phenotypes of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) often overlap, making discrimination difficult. We performed resting state blood oxygen level–dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB.
Methods:
Participants (n = 88) enrolled in a longitudinal study of memory and aging underwent 3-T fcMRI. Clinical diagnoses of probable DLB (n = 15) were made according to published criteria. Cognitively normal control participants (n = 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh compound B (PiB). Probable AD cases (n = 35) met published criteria and had appreciable amyloid deposits with PiB imaging. Functional images were collected using a gradient spin-echo sequence sensitive to BOLD contrast (T2* weighting). Correlation maps selected a seed region in the combined bilateral precuneus.
Results:
Participants with DLB had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. In the DLB group, we found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task-negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus.
Conclusions:
Changes in functional connectivity in DLB indicate patterns of activation that are distinct from those seen in AD and may improve discrimination of DLB from AD and cognitively normal individuals. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity can shed further light on neuroanatomic connections that distinguish DLB from AD.
doi:10.1212/WNL.0b013e31821ccc83
PMCID: PMC3100121  PMID: 21525427
13.  Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer's disease 
Objectives: To determine whether dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) can be differentiated on the basis of qualitative performance characteristics during neuropsychological evaluation.
Methods: Forty one patients with clinically defined DLB were matched with 26 patients with AD for age, illness duration, nature and severity of cognitive deficits, and regional blood flow distribution on SPECT. The presence or absence of a set of qualitative performance characteristics, observed and recorded during the patients' initial cognitive evaluation, was identified by retrospective analysis of patients' records and the groups compared.
Results: Inattention, visual distractibility, impairments in establishing and shifting mental set, incoherence, confabulatory responses, perseveration, and intrusions were significantly more common in DLB than AD. Intrusions were particularly common in DLB, occurring in 78% of the group. They included externally cued intrusions arising from the visual environment, a feature never seen in AD. In a stepwise logistic regression analysis impaired mental set shifting, perseveration, and the presence of intrusions correctly classified 79% of patients.
Conclusion: It is possible to differentiate DLB and AD on the basis of qualitative features of performance. As many features are amenable to detection at clinical interview, they ought to contribute to clinicians' diagnostic armoury, leading to improved clinical recognition of DLB.
doi:10.1136/jnnp.72.5.602
PMCID: PMC1737879  PMID: 11971046
14.  Covariant perfusion patterns provide clues to the origin of cognitive fluctuations and attentional dysfunction in Dementia with Lewy bodies 
International Psychogeriatrics / Ipa  2013;25(12):1917-1928.
Background:
Fluctuating cognition (FC), particularly in attention, is a core and defining symptom in dementia with Lewy bodies (DLB) but is seen much less frequently in Alzheimer's dementia (AD). However, its neurobiological origin is poorly understood. The aim of our study was therefore to characterize perfusion patterns in DLB patients that are associated with the severity and frequency of FC as measured both clinically and using objective neuropsychological assessments.
Methods:
Spatial covariance analyses were applied to data derived from single photon emission computed tomography (SPECT) HMPAO brain imaging in 19 DLB and 23 AD patients. Patients underwent clinical assessment of their FC and cognitive function as well as objective testing of their attention.
Results:
Covariant perfusion principal components (PCs) were not associated with either FC or cognitive or attentional measures in AD. However, in DLB patients, the second PC (defined as DLB-cognitive motor pattern, DLB-PCI2) which was characterized by bilateral relative increases in cerebellum, basal ganglia, and supplementary motor areas and widespread bilateral decreases in parietal regions, positively correlated with poorer cognitive function, increased FC and worse attentional function measured both clinically and neurophysiologically (p < 0.05) as well as with the severity of bradykinesia (p = 0.04).
Conclusions:
FC in DLB appears distinct from those seen in AD, and likely to be driven by internal neurobiological perturbations in brain circuitry as evidenced using spatial covariance analyses of cerebral perfusion. FC and certain aspects of attentional dysfunction in DLB may, in part, depend upon both distributed motor and non-motor networks.
doi:10.1017/S1041610213001488
PMCID: PMC3819183  PMID: 24148774
attention; Alzheimer’s disease; single photon emission computed tomography; SPECT; imaging
15.  Characterizing dementia with Lewy bodies by means of diffusion tensor imaging 
Neurology  2012;79(9):906-914.
Objective:
To investigate patterns of in vivo white matter tract change using diffusion tensor imaging (DTI), we conducted a cross-sectional study of dementia with Lewy bodies (DLB) in comparison with Alzheimer disease (AD) and normal aging.
Methods:
The study included 106 subjects (35 with DLB, 36 with AD, and 35 elderly controls) who underwent clinical and neuropsychological assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate patterns of reduced fractional anisotropy (FA) and increased mean diffusivity (MD) across the entire white matter tract skeleton and also investigated correlations with clinical features.
Results:
Areas of reduced FA in subjects with DLB vs controls were found primarily in parieto-occipital white matter tracts; in AD, the changes were much more diffuse. DLB was also associated with reduced FA in the pons and left thalamus, in comparison with AD. The pattern of MD increase was diffuse in AD and DLB. We found an association between DTI parameters and impaired episodic memory, letter fluency, and severity of motor parkinsonism in DLB.
Conclusions:
Despite a similar level of dementia severity, patterns of DTI changes in AD and DLB differed significantly. The selective involvement of the visual association areas and subcortical structures and the significant clinical correlations highlight the potential importance of white matter tract change in the pathogenesis of DLB. DTI may be a useful technique to investigate early and possible preclinical changes in DLB and warrants further investigation.
doi:10.1212/WNL.0b013e318266fc51
PMCID: PMC3425843  PMID: 22895591
16.  Fluctuating cognition in dementia with Lewy bodies and Alzheimer's disease is qualitatively distinct 
Objectives: To document and illustrate qualitative features of fluctuating cognition as described by care givers of patients with probable dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). To determine whether the quality of the fluctuations differs between DLB and AD. To examine the clinical utility of two recently developed rating scales.
Methods: Care givers of 13 patients with early probable DLB and 12 patients with early probable AD were interviewed using the Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale, both developed recently. Descriptions of fluctuating cognition were recorded verbatim, analysed, and rated.
Results: Descriptions of fluctuating cognition in DLB had a spontaneous, periodic, transient quality, which appeared to reflect an interruption in the ongoing flow of awareness or attention that impacted on functional abilities. Descriptions of fluctuations in AD frequently highlighted episodes of memory failure, or a more enduring state shift in the form of "good" and "bad" days, typically occurring in response to the cognitive demands of the immediate environment. These qualitative differences could be detected reliably by independent raters, but were not always captured in standard severity scores.
Conclusion: Fluctuations occuring in DLB have particular characteristics that are distinguishable from fluctuations occurring in AD. Interpretation and application of the fluctuation criterion continues to limit the diagnostic sensitivity of the consensus criteria for DLB. Findings suggest that explicit documentation and a wider appreciation of these distinctions could improve the reliability with which less experienced clinicians identify this core diagnostic feature in the clinical setting.
doi:10.1136/jnnp.2002.002576
PMCID: PMC1738966  PMID: 14966152
17.  Visuo-cognitive skill deficits in Alzheimer's disease and Lewy body disease: A comparative analysis 
Dementia is a chronic neurodegenerative disorder characterized by progressive cognitive loss. Alzheimer's disease (AD) and the Lewy body disease are the two most common causes of age-related degenerative dementia. Visuo-cognitive skills are a combination of very different cognitive functions being performed by the visual system. These skills are impaired in both AD and dementia with Lewy bodies (DLB). The aim of this review is to evaluate various studies for these visuo-cognitive skills. An exhaustive internet search of all relevant medical databases was carried out using a series of key-word applications, including The Cochrane Library, MEDLINE, PSYCHINFO, EMBASE, CINAHL, AMED, SportDiscus, Science Citation Index, Index to Theses, ZETOC, PEDro and occupational therapy (OT) seeker and OT search. We reviewed all the articles until March 2013 with key words of: Visual skills visual cognition dementia AD, but the direct neurobiological etiology is difficult to establish., Dementia of Lewy body disease. Although most studies have used different tests for studying these abilities, in general, these tests evaluated the individual's ability of (1) visual recognition, (2) visual discrimination, (3) visual attention and (4) visuo-perceptive integration. Performance on various tests has been evaluated for assessing these skills. Most studies assessing such skills show that these skills are impaired in DLB as compared with AD. Visuo-cognitive skills are impaired more in DLB as compared with AD. These impairments have evident neuropathological correlations, but the direct neurobiological etiology is difficult to establish.
doi:10.4103/0972-2327.128530
PMCID: PMC3992750  PMID: 24753653
Alzheimer's disease; Lewy body disease; visuo-cognitive skills
18.  Familial Aggregation of Dementia With Lewy Bodies 
Archives of Neurology  2011;68(1):90-93.
Background
Familial aggregation of dementia with Lewy bodies (DLB) remains unclear.
Objectives
To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB.
Design
Familial cohort study.
Setting
Academic research.
Patients
We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n=344) and siblings of probands with clinically diagnosed Alzheimer disease (n=280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment.
Main Outcome Measures
We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable.
Results
Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04–5.04) and visual hallucinations (2.32; 1.16–4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97–2.34) and cognitive fluctuations (1.55; 0.95–2.53).
Conclusions
Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.
doi:10.1001/archneurol.2010.319
PMCID: PMC3268781  PMID: 21220678
19.  Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia 
Background: There are inconsistencies in published reports regarding the profile of cognitive impairments in vascular dementia, and its differentiation from Alzheimer's disease.
Objectives: To identify the overall profile of cognitive impairment in subcortical vascular dementia as compared with Alzheimer's disease; and the tests which best discriminate between these groups.
Methods: 57 subjects participated: 19 with subcortical vascular dementia, 19 with Alzheimer's disease, and 19 controls. The dementia groups were matched for age, education, and general levels of cognitive and everyday functioning. Subcortical vascular dementia was defined by clinical features (prominent vascular risk factors plus a previous history of transient ischaemic events or focal neurological signs) and substantial white matter pathology on magnetic resonance imaging. All subjects were given a battery of 33 tests assessing episodic and semantic memory, executive/attentional functioning, and visuospatial and perceptual skills.
Results: Despite a minimal degree of overall dementia, both patient groups had impairments in all cognitive domains. The Alzheimer patients were more impaired than those with vascular dementia on episodic memory, while the patients with vascular dementia were more impaired on semantic memory, executive/attentional functioning, and visuospatial and perceptual skills. Logistic regression analyses showed that the two groups could be discriminated with 89% accuracy on the basis of two tests, the WAIS logical memory – delayed recall test and a silhouette naming test.
Conclusions: Subcortical vascular dementia and Alzheimer's disease produce distinctive profiles of cognitive impairment which can act as an adjunct to diagnosis. Many of the neuropsychological deficits thought to characterise Alzheimer's disease are also found in subcortical vascular dementia.
PMCID: PMC1757469  PMID: 14707310
20.  Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies 
Behavioural Neurology  2014;2014:694296.
Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.
doi:10.1155/2014/694296
PMCID: PMC4020531  PMID: 24868122
21.  Visual cortex in dementia with Lewy bodies: magnetic resonance imaging study 
The British Journal of Psychiatry  2012;200(6):491-498.
Background
Visual hallucinations and visuoperceptual deficits are common in dementia with Lewy bodies, suggesting that cortical visual function may be abnormal.
Aims
To investigate: (1) cortical visual function using functional magnetic resonance imaging (fMRI); and (2) the nature and severity of perfusion deficits in visual areas using arterial spin labelling (ASL)-MRI.
Method
In total, 17 participants with dementia with Lewy bodies (DLB group) and 19 similarly aged controls were presented with simple visual stimuli (checkerboard, moving dots, and objects) during fMRI and subsequently underwent ASL-MRI (DLB group n = 15, control group n = 19).
Results
Functional activations were evident in visual areas in both the DLB and control groups in response to checkerboard and objects stimuli but reduced visual area V5/MT (middle temporal) activation occurred in the DLB group in response to motion stimuli. Posterior cortical perfusion deficits occurred in the DLB group, particularly in higher visual areas.
Conclusions
Higher visual areas, particularly occipito-parietal, appear abnormal in dementia with Lewy bodies, while there is a preservation of function in lower visual areas (V1 and V2/3).
doi:10.1192/bjp.bp.111.099432
PMCID: PMC3365275  PMID: 22500014
22.  SENTENCE PROCESSING IN LEWY BODY SPECTRUM DISORDER: THE ROLE OF WORKING MEMORY 
Brain and Cognition  2012;78(2):85-93.
Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson’s disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferiorprefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease.
doi:10.1016/j.bandc.2011.12.004
PMCID: PMC3265703  PMID: 22218297
Lewy body; Parkinson’s; sentence processing; working memory; MRI; prefrontal
23.  Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies 
Neurology  2012;79(6):553-560.
Objective:
To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.
Methods:
We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.
Results:
Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).
Conclusion:
Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.
doi:10.1212/WNL.0b013e31826357a5
PMCID: PMC3413765  PMID: 22843258
24.  Discrimination of dementia with Lewy bodies from Alzheimer’s disease using voxel-based morphometry of white matter by statistical parametric mapping 8 plus diffeomorphic anatomic registration through exponentiated Lie algebra 
Neuroradiology  2013;55(5):559-566.
Introduction
The purpose of this study was to identify brain atrophy specific for dementia with Lewy bodies (DLB) and to evaluate the discriminatory performance of this specific atrophy between DLB and Alzheimer’s disease (AD).
Methods
We retrospectively reviewed 60 DLB and 30 AD patients who had undergone 3D T1-weighted MRI. We randomly divided the DLB patients into two equal groups (A and B). First, we obtained a target volume of interest (VOI) for DLB-specific atrophy using correlation analysis of the percentage rate of significant whole white matter (WM) atrophy calculated using the Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) based on statistical parametric mapping 8 (SPM8) plus diffeomorphic anatomic registration through exponentiated Lie algebra, with segmented WM images in group A. We then evaluated the usefulness of this target VOI for discriminating the remaining 30 DLB patients in group B from the 30 AD patients. Z score values in this target VOI obtained from VSRAD were used as the determinant in receiver operating characteristic (ROC) analysis.
Results
Specific target VOIs for DLB were determined in the right-side dominant dorsal midbrain, right-side dominant dorsal pons, and bilateral cerebellum. ROC analysis revealed that the target VOI limited to the midbrain exhibited the highest area under the ROC curves of 0.75.
Conclusions
DLB patients showed specific atrophy in the midbrain, pons, and cerebellum. Midbrain atrophy demonstrated the highest power for discriminating DLB and AD. This approach may be useful for determining the contributions of DLB and AD pathologies to the dementia syndrome.
doi:10.1007/s00234-013-1138-9
PMCID: PMC3659278  PMID: 23322456
Dementia with Lewy bodies (DLB); Alzheimer’s disease (AD); Statistical parametric mapping (SPM); Voxel-based morphometry (VBM); Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD)
25.  PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and Lewy body disorders 
BMC Neurology  2014;14:79.
Background
Biomarkers based on the underlying pathology of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson’s disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2).
Methods
Patients with DLB and AD, Parkinson’s disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism.
Results
11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011).
Conclusions
The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients (ClinicalTrials.gov identifier: NCT00857506, registered March 5, 2009).
doi:10.1186/1471-2377-14-79
PMCID: PMC4027995  PMID: 24716655
PET imaging; Alzheimer’s disease; Parkinson’s disease; Biomarkers

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