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1.  Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease 
OBJECTIVE—To test the hypotheses that visuoperceptual and attentional ability are disproportionately impaired in patients having dementia with Lewy Bodies (DLB) compared with Alzheimer's disease (AD).
METHODS—A comprehensive battery of neuropsychological tasks designed to assess working, episodic, and semantic memory, and visuoperceptual and attentional functions was given to groups of patients with DLB (n=10) and AD (n=9), matched for age, education, and mini mental state examination (MMSE), and to normal controls (n=17).
RESULTS—Both patient groups performed equally poorly on tests of episodic and semantic memory with the exception of immediate and delayed story recall, which was worse in the AD group. Digit span was by contrast spared in AD. The most striking differences were on tests of visuoperceptual/spatial ability and attention. Whereas patients with AD performed normally on several subtests of the visual object and space perception battery, the DLB group showed substantial impairments. In keeping with previous studies, the AD group showed deficits in selective attention and set shifting, but patients with DLB were more impaired on virtually every test of attention with deficits in sustained, selective, and divided attention.
CONCLUSIONS—Patients with DLB have substantially greater impairment of attention, working memory, and visuoperceptual ability than patients with AD matched for overall dementia severity. Semantic memory seems to be equally affected in DLB and AD, unlike episodic memory, which is worse in AD. These findings may have relevance for our understanding of the genesis of visual hallucinations, and the differential diagnosis of AD and DLB.


doi:10.1136/jnnp.70.2.157
PMCID: PMC1737215  PMID: 11160462
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.  Striatal and extrastriatal dopamine transporter levels relate to cognition in Lewy body diseases: an 11C altropane positron emission tomography study 
Introduction
The biological basis of cognitive impairment in parkinsonian diseases is believed to be multifactorial. We investigated the contribution of dopamine deficiency to cognition in Parkinson disease (PD) and dementia with Lewy bodies (DLB) with dopamine transporter (DAT) imaging.
Methods
We acquired 11C altropane PET, magnetic resonance imaging and cognitive testing in 19 nondemented subjects with PD, 10 DLB and 17 healthy control subjects (HCS). We analyzed DAT concentration in putamen, caudate, anterior cingulate (AC), orbitofrontal and prefrontal regions, using the Standardized Uptake Volume Ratio with partial volume correction, and we related DAT concentration and global cortical thickness to neuropsychological performance.
Results
DAT concentration in putamen and in caudate were similar in PD and DLB groups and significantly lower than in HCS. Reduced caudate DAT concentration was associated with worse Clinical Dementia Rating Scale–sum of boxes (CDR-SB) scores and visuospatial skills in DLB but not in PD or HCS groups. Adjusting for putamen DAT concentration, as a measure of severity of motor disease, caudate DAT concentration was lower in DLB than in PD. Higher AC DAT concentration was associated with lower putamen DAT concentration in DLB and with higher putamen DAT concentration in PD. Higher AC DAT concentration in DLB correlated with greater impairment in semantic memory and language.
Conclusions
Caudate and AC dopamine dysfunction contribute in opposing directions to cognitive impairment in DLB.
doi:10.1186/s13195-014-0052-7
PMCID: PMC4245149  PMID: 25429309
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.  PET radioligands reveal the basis of dementia in Parkinson disease and dementia with Lewy bodies 
Neuro-degenerative diseases  2015;16(1-2):118-124.
Background
Effective therapies for dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD.
Summary
We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition (PD-nl), PD with mild cognitive impairment (PD-MCI), and PD with dementia (PDD), contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurologic examination, detailed neuropsychological assessments, MRI, and PET scans with radioligands altropane (DAT: dopamine transporter) and PiB (Aβ amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies.
Key messages
Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathologic processes that contribute to their course. Multimodal PET imaging has potential to increase diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.
doi:10.1159/000441421
PMCID: PMC4838335  PMID: 26655867
6.  Utility of the combination of DAT SPECT and MIBG myocardial scintigraphy in differentiating dementia with Lewy bodies from Alzheimer’s disease 
Purpose
123I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy can be used to assist in the diagnosis of patients with dementia with Lewy bodies (DLB). We compared the diagnostic value of these two methods in differentiating DLB from Alzheimer’s disease (AD). Furthermore, we evaluated whether a combination of DAT SPECT and MIBG myocardial scintigraphy would provide a more useful means of differentiating between DLB and AD.
Methods
Patients with AD (n = 57) and patients with DLB (n = 76) who underwent both DAT SPECT and MIBG myocardial scintigraphy were enrolled. The sensitivity, specificity, and accuracy of both methods as well as their combination for differentiating DLB from AD were calculated. Moreover, we examined whether symptoms of the patients with DLB were associated with the patterns of the abnormalities displayed on DAT SPECT and MIBG myocardial scintigraphy.
Results
The sensitivity and specificity of differentiating DLB from AD were 72.4 and 94.4 % by the heart to mediastinum ratio of MIBG uptake, 88.2 and 88.9 % by the specific binding ratio on DAT SPECT, and 96.1 and 90.7 % by their combination, respectively. The combined use of DAT SPECT and MIBG myocardial scintigraphy enabled more accurate differentiation between DLB and AD compared with either DAT SPECT or MIBG myocardial scintigraphy alone. There was a significantly higher frequency of parkinsonism in the abnormal DAT SPECT group than the normal DAT SPECT group. On the other hand, there was a higher frequency of the appearance of rapid eye movement (REM) sleep behavior disorder in the abnormal MIBG uptake group than the normal MIBG uptake group.
Conclusion
These results suggested that using a combination of these scintigraphic methods is a useful and practical approach to differentiate DLB from AD.
doi:10.1007/s00259-015-3146-y
PMCID: PMC4679785  PMID: 26233438
123I-FP-CIT; DAT; SPECT; MIBG myocardial scintigraphy; Alzheimer’s disease; Dementia with Lewy bodies
7.  A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer's-type and dementia with Lewy bodies 
OBJECTIVE—Scintigraphy with [123I]metaiodobenzyl guanidine ([123I]MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Recently, myocardial [123I]MIBG scintigraphy has been found to be useful in distinguishing Parkinson's disease, a Lewy body disease, from other akinetic rigid syndromes. Some patients initially diagnosed with dementia of the Alzheimer's type (DAT) are discovered to have an alternative disease such as dementia with Lewy bodies (DLB), despite the application of stringent diagnostic criteria. In the present study, examinations were performed to clarify the usefulness of myocardial [123I]MIBG scintigraphy in improving the differential diagnosis between patients with DLB and DAT.
METHODS—Fourteen patients with DLB and 14 patients with DAT underwent scintigraphy with [123I]MIBG, combined with orthostatic tests and cardiac examinations.
RESULTS—In all patients with DLB, the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in both early and delayed images, independently of the duration of disease and autonomic failure. All patients with DAT had successful MIBG uptake in the heart regardless of duration of disease and autonomic failure. Orthostatic hypotension was seen in four patients with DAT and 13 patients with DLB.
CONCLUSIONS—[123I]MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in DLB and might provide useful diagnostic information to discriminate DLB from DAT. The distinction between DLB and DAT may be improved by greater emphasis on cardiac sympathetic disturbances.


doi:10.1136/jnnp.71.5.583
PMCID: PMC1737586  PMID: 11606666
8.  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
9.  Different Clinical and Neuroimaging Characteristics in Early Stage Parkinson’s Disease with Dementia and Dementia with Lewy Bodies 
Journal of Alzheimer's Disease  null;52(1):205-211.
Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p = 0.013 and 8.6±4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in “orientation to place” tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients’ lower average scores for “repetition” (MMSE), “recent memory” (HDS-R), and “lexical fluency” (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients’ poorer average subscale scores of “orientation to place” (MMSE) and “similarities”, “conflicting instructions”, and “go-no go” (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.
doi:10.3233/JAD-150952
PMCID: PMC4927815  PMID: 27060948
Affective function; cognitive function; dementia with Lewybodies; Parkinson’s disease with dementia; 99mTc-ECD images
10.  Dementia with Lewy Bodies versus Alzheimer's Disease and Parkinson's Disease Dementia: A Comparison of Cognitive Profiles 
Background and Purpose
It is particularly difficult to differentiate dementia with Lewy bodies (DLB) from the related dementias of Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Few studies have been designed to comparatively analyze detailed neuropsychological assessments of DLB patients and patients with AD and PDD.
Methods
Three groups of patients participated in this study: 10 with DLB, 76 with AD, and 17 with PDD, who had been diagnosed as probable DLB, AD, and PDD, respectively, according to the clinical criteria of the consortium on DLB, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorder Association, and the clinical diagnostic criteria for PDD. All patients were evaluated by careful neurological examination with detailed neuropsychological testing.
Results
Significant differences among the three groups were found for attention, memory, and executive function, which included tasks of backward digit span, three-word recall, verbal delayed recall, and the Stroop test. Post hoc analysis revealed that the deficiencies of attention on the digit span task were greater in the DLB group than in the AD and PDD groups. The scores for episodic verbal memory tasks were significantly lower in the DLB and AD groups than in the PDD group. The performance in frontal executive function, as indicated by the Stroop test, was significantly worse in the DLB and PDD groups than in the AD group.
Conclusions
The results of the present study show that the pattern of cognitive dysfunction, in terms of attention, episodic memory, and executive functions, differ between patients with DLB and patients with AD and PDD.
doi:10.3988/jcn.2011.7.1.19
PMCID: PMC3079155  PMID: 21519522
dementia with lewy bodies; Alzheimer's disease; Parkinson's disease dementia; cognition; neuropsychology
11.  Recognition Memory Span in Autopsy-Confirmed Dementia with Lewy Bodies and Alzheimer’s Disease 
Neuropsychologia  2015;75:548-555.
Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and normal control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from Long-Term Storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease.
doi:10.1016/j.neuropsychologia.2015.07.014
PMCID: PMC4752828  PMID: 26184443
Working Memory; Secondary Memory; Cognition; Dementia with Lewy Bodies; Alzheimer’s Disease
12.  [123]FP-CIT SPECT scans initially rated as normal became abnormal over time in patients with probable dementia with Lewy bodies 
Purpose
Decreased striatal dopamine transporter (DAT) binding on SPECT imaging is a strong biomarker for the diagnosis of dementia with Lewy bodies (DLB). There is still a lot of uncertainty about patients meeting the clinical criteria for probable DLB who have a normal DAT SPECT scan (DLB/S−). The aim of this study was to describe the clinical and imaging follow-up in these patients, and compare them to DLB patients with abnormal baseline scans (DLB/S+).
Methods
DLB patients who underwent DAT imaging ([123I]FP-CIT SPECT) were selected from the Amsterdam Dementia Cohort. All [123I]FP-CIT SPECT scans were evaluated independently by two nuclear medicine physicians and in patients with normal scans follow-up imaging was obtained. We matched DLB/S-− patients for age and disease duration to DLB/S+ patients and compared their clinical characteristics.
Results
Of 67 [123I]FP-CIT SPECT scans, 7 (10.4 %) were rated as normal. In five DLB/S− patients, a second [123I]FP-CIT SPECT was performed (after on average 1.5 years) and these scans were all abnormal. No significant differences in clinical characteristics were found at baseline. DLB/S− patients could be expected to have a better MMSE score after 1 year.
Conclusion
This study was the first to investigate DLB patients with the initial [123I]FP-CIT SPECT scan rated as normal and subsequent scans during disease progression rated as abnormal. We hypothesize that DLB/S− scans could represent a relatively rare DLB subtype with possibly a different severity or spread of alpha-synuclein pathology (“neocortical predominant subtype”). In clinical practice, if an alternative diagnosis is not imminent in a DLB/S− patient, repeating [123I]FP-CIT SPECT should be considered.
doi:10.1007/s00259-016-3312-x
PMCID: PMC4844648  PMID: 26830298
Dementia with Lewy bodies; Neuroimaging; Dopamine transporter; [123I]FP-CIT SPECT
13.  Clinical and multimodal biomarker correlates of ADNI neuropathological findings 
Background
Autopsy series commonly report a high percentage of coincident pathologies in demented patients, including patients with a clinical diagnosis of dementia of the Alzheimer type (DAT). However many clinical and biomarker studies report cases with a single neurodegenerative disease. We examined multimodal biomarker correlates of the consecutive series of the first 22 Alzheimer’s Disease Neuroimaging Initiative autopsies. Clinical data, neuropsychological measures, cerebrospinal fluid Aβ, total and phosphorylated tau and α-synuclein and MRI and FDG-PET scans.
Results
Clinical diagnosis was either probable DAT or Alzheimer’s disease (AD)-type mild cognitive impairment (MCI) at last evaluation prior to death. All patients had a pathological diagnosis of AD, but only four had pure AD. A coincident pathological diagnosis of dementia with Lewy bodies (DLB), medial temporal lobe pathology (TDP-43 proteinopathy, argyrophilic grain disease and hippocampal sclerosis), referred to collectively here as MTL, and vascular pathology were present in 45.5%, 40.0% and 22.7% of these patients, respectively. Hallucinations were a strong predictor of coincident DLB (100% specificity) and a more severe dysexecutive profile was also a useful predictor of coincident DLB (80.0% sensitivity and 83.3% specificity). Occipital FDG-PET hypometabolism accurately classified coincident DLB (80% sensitivity and 100% specificity). Subjects with coincident MTL showed lower hippocampal volume.
Conclusions
Biomarkers can be used to independently predict coincident AD and DLB pathology, a common finding in amnestic MCI and DAT patients. Cohorts with comprehensive neuropathological assessments and multimodal biomarkers are needed to characterize independent predictors for the different neuropathological substrates of cognitive impairment.
doi:10.1186/2051-5960-1-65
PMCID: PMC3893373  PMID: 24252435
Alzheimer’s disease; Mild cognitive impairment; CSF; MRI; Autopsy; Neuropathology; Dementia; Biomarkers; Amyloid; Tau
14.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
15.  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
16.  Visual association test to detect early dementia of the Alzheimer type 
Background: The visual association test (VAT) is a brief learning task based on imagery mnemonics. The test materials consist of six line drawings of pairs of interacting objects or animals—for example, an ape holding an umbrella. The person is asked to name each object and, later, is presented with one object from the pair and asked to name the other.
Objective: To verify that the task induces robust incidental or effortless learning (study 1), and to study the efficiency of the test as a discriminator between early dementia of the Alzheimer type (DAT) and non-demented people (study 2) and non-DAT types of dementia (study 3).
Methods: Study 1: two groups of elderly volunteers were administered the VAT. The stimuli were presented in the interactive fashion to group A—for example, a monkey carrying an umbrella (n=83)—and side by side to group B—for example, separate pictures of a monkey alone and an umbrella alone (n=79). Group B received learning instructions, but group A did not. Study 2: three groups of subjects were selected from a population based follow up study: incident DAT cases (n=24), cognitively declining subjects not diagnosed with dementia (n=21), and stable non-demented subjects (n=204). Test performance of the non-demented group at baseline was compared with that of patients with DAT at the time of their diagnosis, of patients with DAT a year before their diagnosis, and of non-demented declining subjects at baseline. Study 3: subjects were patients referred for neuropsychological assessment because of suspected dementia. They were diagnosed by consensus criteria of various dementia syndromes.
Results: Study 1: recall was more than twice as high in group A as in group B. Thus interactive presentation, even in the absence of learning instructions, enhances learning. Study 2: at a level of 97.5% specificity, the VAT had a sensitivity of 87.5% for DAT cases at the time of diagnosis and 66.7% one year before diagnosis. The cognitively declining group scored significantly lower on the VAT at baseline than the non-demented group. The VAT discriminated more effectively than both the MMSE and the six item picture learning task from the CAMCOG. Study 3: VAT scores were significantly lower in patients with DAT (n=48) than in patients with vascular dementia (n=37), frontotemporal dementia (n=9), or subcortical dementia (n=15), but not lower than in patients with Lewy body dementia (n=7). Mean mini mental state examination scores of these groups were not significantly different. The VAT discriminated patients with DAT from patients with other types of dementia more effectively than a prose recall test. Sensitivity was 79% and specificity 69%.
Conclusions: The VAT detects with high specificity a sizeable proportion of patients with DAT a year before the diagnosis, and a low VAT score is relatively uncommon in patients with non-DAT dementia.
doi:10.1136/jnnp.73.2.126
PMCID: PMC1737993  PMID: 12122168
17.  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
18.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
19.  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
20.  Brain perfusion in dementia with Lewy bodies and Alzheimer’s disease: an arterial spin labeling MRI study on prodromal and mild dementia stages 
Background
We aimed to describe specific changes in brain perfusion in patients with dementia with Lewy bodies (DLB) at both the prodromal (also called mild cognitive impairment) and mild dementia stages, relative to patients with Alzheimer’s disease (AD) and controls.
Methods
Altogether, 96 participants in five groups (prodromal DLB, prodromal AD, DLB with mild dementia, AD with mild dementia, and healthy elderly controls) took part in an arterial spin labeling MRI study. Three analyses were performed: a global perfusion value comparison, a voxel-wise analysis of both absolute and relative perfusion, and a linear discriminant analysis. These were used to assess the global decrease in perfusion, regional changes, and the sensitivity and specificity of these changes.
Results
Patterns of perfusion in DLB differed from AD and controls in both the prodromal stage and dementia, DLB having more deficits in frontal, insular, and temporal cortices whereas AD showed reduced perfusion in parietal and parietotemporal cortices. Decreases but also increases of perfusion in DLB relative to controls were observed in both absolute and relative measurements. All these regional changes of perfusion classified DLB patients with respect to either healthy controls or AD with sensitivity from 87 to 100 % and specificity from 90 to 96 % depending on the stage of the disease.
Conclusions
Our results are consistent with previous studies. We extend the scope of those studies by integrating prodromal DLB patients and by describing both hypo- and hyperperfusion in DLB. While decreases in perfusion may relate to functional impairments, increases might suggest a functional compensation of some brain areas.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-016-0196-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-016-0196-8
PMCID: PMC4940880  PMID: 27401267
Cerebral blood flow; Prodromal phase; MRI; Early diagnosis; Insula
21.  Regional functional synchronizations in dementia with Lewy bodies and Alzheimer's disease 
International Psychogeriatrics / Ipa  2016;28(7):1143-1151.
Background:
Dementia with Lewy bodies (DLB) is a common cause of dementia in the elderly population after Alzheimer's disease (AD), and at early stages differential diagnosis between DLB and AD might be difficult due to their symptomatic overlap, e.g. cognitive and memory impairments. We aimed to investigate functional brain differences between both diseases in patients recently diagnosed.
Methods:
We investigated regional functional synchronizations using regional homogeneity (ReHo) in patients clinically diagnosed with DLB (n = 19) and AD (n = 18), and for comparisons we also included healthy controls (HC, n = 16). Patient groups were matched by age, education, and by the level of cognitive impairment (MMSE p-value = 0.36). Additionally, correlations between ReHo values and clinical scores were investigated.
Results:
The DLB group showed lower ReHo in sensory-motor cortices and higher ReHo in left middle temporal gyrus when compared with HCs (p-value < 0.001 uncorrected). The AD group demonstrated lower ReHo in the cerebellum and higher ReHo in the left/right lingual gyri, precuneus cortex, and other occipital and parietal regions (p-value < 0.001 uncorrected).
Conclusions:
Our results agree with previous ReHo investigations in Parkinson's disease (PD), suggesting that functional alterations in motor-related regions might be a characteristic of the Lewy body disease spectrum. However, our results in AD contradict previously reported findings for this disease and ReHo, which we speculate are a reflection of compensatory brain responses at early disease stages. ReHo differences between patient groups were at regions related to the default mode and sensory-motor resting state networks which might reflect the aetiological divergences in the underlying disease processes between AD and DLB.
doi:10.1017/S1041610216000429
PMCID: PMC4894061  PMID: 26976496
Dementia with Lewy bodies (DLB); Alzheimer's disease (AD); magnetic resonance imaging (MRI); hallucinations; neuroimaging
22.  Structural Connectivity is Differently Altered in Dementia with Lewy Body and Alzheimer’s Disease 
The structural connectivity within cortical areas and between cortical and subcortical structures was investigated in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). We hypothesized that white matter (WM) tracts, which are linked to visual, attentional, and mnemonic functions, would be differentially and selectively affected in DLB as compared to AD and age-matched control subjects. Structural tensor imaging and diffusion tensor imaging (DTI) were performed on 14 DLB patients, 14 AD patients, and 15 controls. DTI metrics related to WM damage were assessed within tracts reconstructed by FreeSurfer’s TRActs Constrained by UnderLying Anatomy pipeline. Correlation analysis between WM and gray matter (GM) metrics was performed to assess whether the structural connectivity alteration in AD and DLB could be secondary to GM neuronal loss or a consequence of direct WM injury. Anterior thalamic radiation (ATR) and cingulum-cingulate gyrus were altered in DLB, whereas cingulum-angular bundle (CAB) was disrupted in AD. In DLB patients, secondary axonal degeneration within ATR was found in relation to microstructural damage within medio-dorsal thalamus, whereas axonal degeneration within CAB was related to precuneus thinning. WM alteration within the uncinate fasciculus was present in both groups of patients and was related to frontal and to temporal thinning in DLB and AD, respectively. We found structural connectivity alterations within fronto-thalamic and fronto-parietal (precuneus) network in DLB whereas, in contrast, disruption of structural connectivity of mnemonic pathways was present in AD. Furthermore, the high correlation between GM and WM metrics suggests that the structural connectivity alteration in DLB could be linked to GM neuronal loss rather than by direct WM injury. Thus, this finding supports the key role of cortical and subcortical atrophy in DLB.
doi:10.3389/fnagi.2015.00208
PMCID: PMC4629464  PMID: 26578952
Alzheimer’s disease; dementia with Lewy bodies; diffusion tensor imaging; magnetic resonance imaging; structural connectivity
23.  Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies 
Neurology  2009;73(14):1127-1133.
Background:
Recent studies raised questions about the severity of cognitive impairment associated with dementia with Lewy bodies (DLB). However, there have been few analyses of large, multicenter data registries for clinical–pathologic correlation.
Methods:
We evaluated data from the National Alzheimer's Coordinating Center registry (n = 5,813 cases meeting initial inclusion criteria) and the University of Kentucky Alzheimer's Disease Center autopsy series (n = 527) to compare quantitatively the severity of cognitive impairment associated with DLB pathology vs Alzheimer disease (AD) and AD+DLB pathologies.
Results:
Mini-Mental State Examination (MMSE) scores showed that persons with pure DLB had cognitive impairment of relatively moderate severity (final MMSE score 15.6 ± 8.7) compared to patients with pure AD and AD+DLB (final MMSE score 10.7 ± 8.6 and 10.6 ± 8.6). Persons with pure DLB pathology from both data sets had more years of formal education and were more likely to be male. Differences in final MMSE scores were significant (p < 0.01) between pure DLB and both AD+DLB and pure AD even after correction for education level, gender, and MMSE–death interval. Even in cases with extensive neocortical LBs, the degree of cognitive impairment was most strongly related to the amount of concomitant AD-type neurofibrillary pathology.
Conclusions:
Dementia with Lewy bodies can constitute a debilitating disease with associated psychiatric, motoric, and autonomic dysfunction. However, neocortical Lewy bodies are not a substrate for severe global cognitive impairment as assessed by the Mini-Mental State Examination. Instead, neocortical Lewy bodies appear to constitute or reflect an additive disease process, requiring Alzheimer disease or other concomitant brain diseases to induce severe global cognitive deterioration.
GLOSSARY
= Alzheimer disease;
= AD Center;
= Consortium to Establish a Registry for Alzheimer's Disease;
= dementia with Lewy bodies;
= Lewy bodies;
= Mini-Mental State Examination;
= National Alzheimer's Coordinating Center;
= neurofibrillary;
= National Institute of Aging-Reagan Institute;
= University of Kentucky Alzheimer's Disease Center.
doi:10.1212/WNL.0b013e3181bacf9e
PMCID: PMC2764396  PMID: 19805729
24.  The Underlying Mechanisms of Semantic Memory Loss in Alzheimer’s Disease and Semantic Dementia 
Neuropsychologia  2007;46(1):12-21.
Patients with Alzheimer’s Disease (AD) and patients with Semantic Dementia (SD) both exhibit deficits on explicit tasks of semantic memory such as picture naming and category fluency. These deficits have been attributed to a degradation of the stored semantic network. An alternative explanation attributes the semantic deficit in AD to an impaired ability to consciously retrieve items from the semantic network. The present study used an implicit lexical-decision priming task to examine the integrity of the underlying semantic network in AD and SD patients matched for degree of impairment on explicit semantic memory tasks. The AD (n=11) and SD (n=11) patient groups were matched for age, education, level of dementia and impairment on four explicit semantic memory tasks. Healthy elderly participants (n=22) were matched for age and education. Semantic priming effects were evaluated for three types of semantic relationships (attributes, category coordinates, and category superordinates) and compared to lexical associative priming. Healthy controls showed significant priming across all conditions. In contrast, AD patients showed normal superordinate priming, and significant (although somewhat reduced) coordinate priming, but no attribute priming. SD patients showed no priming effect for any semantic relationship. All groups showed significant associative priming. The results indicate that SD patients do indeed have substantial degradation of semantic memory, while AD patients have a partially intact network, accounting for priming in superordinate and coordinate conditions. These findings suggest that AD patients’ impairment on explicit semantic tasks is the product of deficient explicit retrieval in combination with a partially degraded semantic network.
doi:10.1016/j.neuropsychologia.2007.08.010
PMCID: PMC2255584  PMID: 17897685
25.  Verbal Learning and Memory in Patients with Dementia with Lewy Bodies or Parkinson's Disease with Dementia 
This study compared verbal learning and memory in patients with autopsy-confirmed dementia with Lewy Bodies (DLB) and patients with Parkinson's disease with dementia (PDD). Twenty-four DLB patients, 24 PDD patients, and 24 normal comparison participants were administered the California Verbal Learning Test. The three groups were matched on demographic variables and the two patient groups were matched on the Mattis Dementia Rating Scale. The results indicated that DLB patients recalled less information than PDD patients on all but one recall measure and displayed a more rapid rate of forgetting. In contrast, the PDD patients committed a greater percent of perseveration errors than the DLB patients. The two groups did not differ in the percentage of recall intrusion errors or any measures of recognition. A discriminant function analysis (DFA) using short delay cued recall, percent perseveration errors, and list b recall, differentiated the DLB and PDD groups with 81.3% accuracy. The application of the DFA algorithm to another sample of 42 PDD patients resulted in a 78.6% correct classification rate. The results suggest that, despite equivalent levels of general cognitive impairment, patients with DLB or PDD exhibit a different pattern of verbal learning and memory deficits.
doi:10.1080/13803390802572401
PMCID: PMC2935683  PMID: 19221922

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